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Andrade, Paulina, Parnal Narvekar, Magelda Montoya, Daniela Michlmayr, Angel Balmaseda, Josefina Coloma, and Eva Harris. "Primary and Secondary Dengue Virus Infections Elicit Similar Memory B-Cell Responses, but Breadth to Other Serotypes and Cross-Reactivity to Zika Virus Is Higher in Secondary Dengue." Journal of Infectious Diseases 222, no. 4 (March 20, 2020): 590–600. http://dx.doi.org/10.1093/infdis/jiaa120.
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Abstract Background The 4 antigenically distinct serotypes of dengue virus (DENV) share extensive homology with each other and with the closely related Zika flavivirus (ZIKV). The development of polyclonal memory B cells (MBCs) to the 4 DENV serotypes and ZIKV during DENV infection is not fully understood. Methods In this study, we analyzed polyclonal MBCs at the single-cell level from peripheral blood mononuclear cells collected ~2 weeks or 6–7 months postprimary or postsecondary DENV infection from a pediatric hospital-based study in Nicaragua using a Multi-Color FluoroSpot assay. Results Dengue virus elicits robust type-specific and cross-reactive MBC responses after primary and secondary DENV infection, with a significantly higher cross-reactive response in both. Reactivity to the infecting serotype dominated the total MBC response. Although the frequency and proportion of type-specific and cross-reactive MBCs were comparable between primary and secondary DENV infections, within the cross-reactive response, the breadth of MBC responses against different serotypes was greater after secondary DENV infection. Dengue virus infection also induced cross-reactive MBC responses recognizing ZIKV, particularly after secondary DENV infection. Conclusions Overall, our study sheds light on the polyclonal MBC response to DENV and ZIKV in naive and DENV-preimmune subjects, with important implications for natural infections and vaccine development.
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Moelans, Cathy B., Joep de Ligt, Petra van der Groep, Pjotr Prins, Nicolle J. M. Besselink, Marlous Hoogstraat, Natalie D. ter Hoeve, et al. "The molecular genetic make-up of male breast cancer." Endocrine-Related Cancer 26, no. 10 (October 2019): 779–94. http://dx.doi.org/10.1530/erc-19-0278.
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Male breast cancer (MBC) is extremely rare and accounts for less than 1% of all breast malignancies. Therefore, clinical management of MBC is currently guided by research on the disease in females. In this study, DNA obtained from 45 formalin-fixed paraffin-embedded (FFPE) MBCs with and 90 MBCs (52 FFPE and 38 fresh-frozen) without matched normal tissues was subjected to massively parallel sequencing targeting all exons of 1943 cancer-related genes. The landscape of mutations and copy number alterations was compared to that of publicly available estrogen receptor (ER)-positive female breast cancers (smFBCs) and correlated to prognosis. From the 135 MBCs, 90% showed ductal histology, 96% were ER-positive, 66% were progesterone receptor (PR)-positive, and 2% HER2-positive, resulting in 50, 46 and 4% luminal A-like, luminal B-like and basal-like cases, respectively. Five patients had Klinefelter syndrome (4%) and 11% of patients harbored pathogenic BRCA2 germline mutations. The genomic landscape of MBC to some extent recapitulated that of smFBC, with recurrent PIK3CA (36%) and GATA3 (15%) somatic mutations, and with 40% of the most frequently amplified genes overlapping between both sexes. TP53 (3%) somatic mutations were significantly less frequent in MBC compared to smFBC, whereas somatic mutations in genes regulating chromatin function and homologous recombination deficiency-related signatures were more prevalent. MDM2 amplifications were frequent (13%), correlated with protein overexpression (P = 0.001) and predicted poor outcome (P = 0.007). In conclusion, despite similarities in the genomic landscape between MBC and smFBC, MBC is a molecularly unique and heterogeneous disease requiring its own clinical trials and treatment guidelines.
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Han, Jing, Ze-Tian Qin, Jing Zhang, Wen-Qiang Wang, Jing-Ya Wu, Yong-Ze Lu, and Li-Wei Sun. "Acute toxicity and ecological risk assessment of 4,4’-dihydroxybenzophenone, 2,4,4’-trihydroxybenzophenone and 4-MBC in ultraviolet (UV)-filters." PLOS ONE 16, no. 4 (April 8, 2021): e0249915. http://dx.doi.org/10.1371/journal.pone.0249915.
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Ultraviolet (UV) filters are used in cosmetics, personal care products and packaging materials to provide sun protection for human skin and other substances. Little is known about these substances, but they continue to be released into the environment. The acute toxicity of 4,4’-dihydroxybenzophenone, 2,4,4’-trihydroxybenzophenone and 4-MBC to Chlorella vulgaris and Daphnia magna were analyzed in this study. The 96 h-EC50 values of 4,4’-dihydroxybenzophenone, 2,4,4’-trihydroxybenzophenone and 4-MBC on C. vulgaris were 183.60, 3.50 and 0.16874 mg/L, respectively. The 48 h-LC50 of 4,4’-dihydroxybenzophenone, 2,4,4’-trihydroxybenzophenone and 4-MBC on D. magna were 12.50, 3.74 and 0.54445 mg/L, respectively. The toxicity of a mixture of 4,4’-dihydroxybenzophenone and 4-MBC showed addictive effect on C. vulgaris, while the toxicity of mixtures of 4,4’-dihydroxybenzophenone and 2,4,4’-trihydroxybenzophenone, 2,4,4’-trihydroxybenzophenone and 4-MBC as well as 4,4’-dihydroxybenzophenone, 2,4,4’-trihydroxybenzophenone and 4-MBC all showed antagonistic effect on C. vulgaris. The induced no-effect concentrations of 4,4’-dihydroxybenzophenone, 2,4,4’-trihydroxybenzophenone and 4-MBC by the assessment factor (AF) method were 0.0125, 0.00350 and 0.000169 mg/L, respectively.
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Komrakova, Marina, Stephan Sehmisch, Mohammad Tezval, Ulrich Schmelz, Holm Frauendorf, Thomas Grueger, Thomas Wessling, et al. "Impact of 4-methylbenzylidene camphor, daidzein, and estrogen on intact and osteotomized bone in osteopenic rats." Journal of Endocrinology 211, no. 2 (July 29, 2011): 157–68. http://dx.doi.org/10.1530/joe-11-0096.
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The study investigated the influence of 4-methylbenzylidene camphor (4-MBC), daidzein, and estradiol-17β-benzoate (E2) on either intact or osteotomized cancellous bone in ovariectomized (Ovx) rats. Three-month old Ovx rats were fed with soy-free (SF) diet over 8 weeks; thereafter, bilateral transverse metaphyseal osteotomy of tibia was performed and rats were divided into groups: rats fed with SF diet and SF diet supplemented with 4-MBC (200 mg), daidzein (50 mg), or E2(0.4 mg) per kilogram body weight. After 5 or 10 weeks, computed tomographical, biomechanical, histological, and ashing analyses were performed in lumbar spine and tibia of 12 rats from each group. 4-MBC and E2improved bone parameters in lumbar spine and tibia, were not favorable for osteotomy healing, and decreased serum osteocalcin level. However, daidzein improved bone parameters to a lesser extent and facilitated osteotomy healing. For lumbar spine, the bone mineral density was 338±9, 346±5, 361±6, and 360±5 mg/cm3in SF, daidzein, 4-MBC, and E2, respectively, after 10 weeks. For tibia, the yield load was 98±5, 114±3, 90±2, and 52±4 N in SF, daidzein, 4-MBC, and E2, respectively, after 10 weeks. Serum daidzein was 54±6 ng/ml in daidzein group and equol was not detected.AlpandIgf1genes were down-regulated in callus after daidzein and E2compared with 4-MBC (week 5). The response of bone tissue and serum markers of bone metabolism could be ordered: daidzein<4-MBC<E2. Treatments were more effective after 5 vs 10 weeks. In SF group, bone structure was impaired after 5 weeks and improved after 10 weeks probably due to adaptation mechanisms to osteoporosis. In conclusion, it is conceivable that 4-MBC may improve bone tissue in osteoporotic organisms; osteoporotic patients with fractures could benefit from daidzein treatment.
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Sasson, Clarice Scliar, Mayumi Eliza Sato, Klézia da Silva Beletti, Fabrício Cunha Mota, and Angela Dakiw Piaceski. "Influence of cosmetics vehicles on 4-methylbenzylidene-camphor's skin penetration, in vitro." Brazilian Archives of Biology and Technology 52, no. 2 (April 2009): 299–303. http://dx.doi.org/10.1590/s1516-89132009000200006.
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The aim of this work was to compare the skin penetration of 4-methylbenzylidene-camphor (4-MBC) in two vehicles, an oil-in-water (O/W) emulsion and an alcoholic gel. The penetration of this UVB filter through these vehicles was determined in vitro (Franz cells) using pig ear skin. The 4-MBC permeated through the skin both with the emulsion o/w as the alcoholic gel. However, with the alcoholic gel, 5 h after application of the product, the 4-MBC was found in the receptor fluid, while with the emulsion o/w, 24 h after it was detected. In both vehicles, the 4-MBC was present in the viable epidermis, dermis but most part of it, was found in the stratum corneum, being more remarkable for alcoholic gel. The right choice of the vehicle could decrease the potential toxicological risk and increase the efficacy of sunscreens products.
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Iskandar, Burhanuddin, Bambang Madiyono, Sudigdo Sastroasmoro, Sukman T. Putra, Mulyadi M. Djer, and Anis Karuniawati. "Comparison of minimal inhibitory and bactericidal capacity of oral penicillin V with benzathine penicillin G to Streptococcus beta--hemolyticus group A in children with rheumatic heart disease." Paediatrica Indonesiana 48, no. 3 (September 26, 2016): 152. http://dx.doi.org/10.14238/pi48.3.2008.152-5.
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Background Injection ofbenzatine penicillin G (BPG) every 28days is still the drug of choice for secondary prevention of rheu-matic heart disease (RHD). BPG sometimes poses problems dueto pain at the injection site, possible anaphylaxis, and is not alwaysavailable. Some centers choose oral penicillin over BPG.Objectives To compare minimal inhibitory capacity (MIC) andminimal bactericidal capacity (MBC) of oral penicillin V serumwith those of BPG among SGA infected RHD.Methods This was a clinical trial with crossover design study tocompare MIC of penicillin V and BPG. Outcome measures wereMIC and MBC. Statistical analysis was performed using pairedt-test and wilcoxon test.Result There were 32 subjects consisted of 17 males and 15females. The mean value of MIC and MBC serum of penicillinV were 0.031 and 0.125. The mean value of MIC and MBCserum of BPG3 were 0.094 and 0.031. Respectively the MICof penicillin V was similar to that of BPGy The mean value ofMIC and MBC of BPG4 were 0.125 and 0.250. Respectively theMIC of penicillin V was significantly higher than that of BPG 4.The MBC of penicillin V was significantly higher than that ofBPG 4. The MIC ofBPG 3 was similar to that ofBPG 4• The MBCof BPG 3 was similar to that of BPG 4.Conclusions The MIC of penicillin V was similar to that ofBPG 3,the MBC of oral penicillin V was higher than that ofBPG 3• TheMIC and MBC of penicillin V was higher than those of BPG 4.
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Komrakova, Marina, Carsten Werner, Michael Wicke, Ba Tiep Nguyen, Stephan Sehmisch, Mohammad Tezval, Klaus Michael Stuermer, and Ewa Klara Stuermer. "Effect of daidzein, 4-methylbenzylidene camphor or estrogen on gastrocnemius muscle of osteoporotic rats undergoing tibia healing period." Journal of Endocrinology 201, no. 2 (March 2, 2009): 253–62. http://dx.doi.org/10.1677/joe-08-0521.
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The effect of daidzein (D), 4-methylbenzylidene camphor (4-MBC) or estradiol-17β-benzoate (E2) on muscle of osteoporotic rats during fracture healing was studied. After performing a metaphyseal tibia osteotomy in 96 osteoporotic 5-month-old female Sprague–Dawley rats, they received daily 50 mg D, 200 mg 4-MBC or 0.4 mg E2 per kg body weight, or soy free (SF) diet up to 36 and 72 days. Mitochondrial activity, fiber area, and capillary density were analyzed in M. gastrocnemius. Osseous callus bridging of fracture was observed in half of the rats after 36 days. By day 72, fracture was healed in most of the animals. State 3 mitochondrial respiration significantly enhanced in E2, 4-MBC and D groups versus SF after 36 days (30, 32 and 32 vs 23 pmol O2/s per mg). It declined after 72 days, however, in E2 group it was still at a higher level versus SF (25, 23 and 21 vs 20 pmol O2/s per mg). Size of fast oxidative glycolytic (FOG) and fast glycolytic (FG) fibers, capillary density did not differ significantly between the groups, however, at day 36 an increase in D and 4-MBC groups was detectable. FOG diameter was 64, 66, 68, and 58 μm and FG diameter was 88, 98, 95, and 89 μm in SF, D, 4-MBC, and E2 groups. The ratio of capillaries to muscle fiber was 1.1, 1.4, 1.3, and 1.1 in SF, D, 4-MBC and E2 groups by day 36. D and 4-MBC react similar to estrogen thereby improving oxidative cell metabolism in severe osteoporotic rats. The level of mitochondrial activity was higher, though no significant morphological differences could be shown.
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Nelson, Ariel Ann, Shivaprasad Manjappa, Yuvraj Choudhary, Cheryl L. Thompson, Jeanine Agler, Bethany Lawrence, Manmeet Singh Ahluwalia, and Paula Silverman. "Phase II study of eribulin mesylate for treatment of CNS metastases (mets) in metastatic breast cancer (mBC)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e12571-e12571. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e12571.
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e12571 Background: There is no approved drug therapy for CNS mets from mBC. Eribulin mesylate (eribulin) is a microtubule inhibitor approved for treatment of mBC patients (pts) who have received at least 2 prior chemotherapy regimens. Previously reported cases have demonstrated significant CNS responses in mBC pts treated with eribulin. This study evaluates the CNS response in pts with mBC treated with eribulin. Methods: CASE7113 was a prospective phase II single-arm study to evaluate the 12-week CNS progression free survival (12-wk CNS-PFS) of pts with mBC and CNS mets treated with eribulin. 20 pts were to be enrolled to demonstrate a 40% 12-wk CNS-PFS (95% CI, 8.5% - 61.5%). All pts had radiologically confirmed mBC CNS lesions with at least one lesion that did not receive prior radiation or surgical resection. Eribulin was administered at standard dose of 1.4mg/m2 IV on days 1 and 8 of a 21 day-cycle. Pts underwent baseline and 12-week brain MRI. The study was closed due to slow accrual; an analysis of enrolled pts was performed. Results: 9 female pts were enrolled; median age was 56 (32-82) years. 55% and 67% had ER+ and/or PR+ and Her2+ mBC respectfully. 1 pt had triple negative breast cancer (TNBC). Median number of prior therapies was 3 (0-12). The 12-wk CNS-PFS (95% CI) was 88.9% (51.8% - 99.7%), the median PFS (95% CI) was 22.6 (4.3 - 31.9) weeks, the median OS (95% CI) was 15.7 (4.0 - 27.3) months. 4 pts achieved stable disease and 1 pt had a partial response. There were no unexpected toxicities. Conclusions: For mBCa pts with CNS mets, this estimate of 12-wk CNS-PFS suggests activity of eribulin and merits further investigation in this population in the context of clinical trials. Clinical trial information: NCT02581839.
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Zhang, Jing, Zhou-Tao Pei, Ya-Ni Zhao, Meng Zhang, Li-Ling Zhang, Wen-Qiang Wang, Jing-Ya Wu, Ran Yu, and Li-Wei Sun. "Mutagenicity evaluation to UV filters of benzophenone-6, benzophenone-8, and 4-methylbenzylidene camphor by Ames test." PLOS ONE 16, no. 9 (September 2, 2021): e0255504. http://dx.doi.org/10.1371/journal.pone.0255504.
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Benzophenone (BPs) and 4-Methylbenzylidene Camphor are used as ultraviolet (UV) filters to protect the skin and hair in personal care products. The discharging of the three chemicals may endanger the receiving water ecosystem. In the present study, the mutagenicity of BP-6, BP-8, and 4-Methylbenzylidene Camphor was tested using the Salmonella typhimurium reverse mutation test (Ames test) in the system with and without rat liver microsomal preparations (S9). Four S.typhimurium strains, TA97, TA98, TA100, and TA102 were employed in the Ames tests. The mutagenicity was detected from all three chemicals. The addition of S9 increased the mutation ratios of three chemicals to four strains, except BP-6 to TA100 strain and 4-MBC to TA97 and TA98 strain. In the mixed experiment, all positive effects were detected in the absence of S9. However, the results all became negative in the presence of S9. For the mixture of BP-6 and 4-MBC, positive results were detected on four tester strains except for the TA100 strain. For the mixture of BP-6, BP-8, and 4-MBC, positive results were detected on four strains. The mixture test results showed antagonism in mutagenicity for the mixture of BP-6 and 4-MBC to TA98 and TA100 strains and the mixture of BP-6, BP-8, and 4-MBC to TA100 and TA102 strains.
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Tökés, Anna-Mária, A. Marcell Szász, Franciska Geszti, Lilla V. Lukács, István Kenessey, Eszter Turányi, Nóra Meggyesházi, et al. "Expression of proliferation markers Ki67, cyclin A, geminin and aurora-kinase A in primary breast carcinomas and corresponding distant metastases." Journal of Clinical Pathology 68, no. 4 (January 16, 2015): 274–82. http://dx.doi.org/10.1136/jclinpath-2014-202607.
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AimsTo assess the expression of the following cell cycle regulatory proteins in primary metastatic breast carcinomas (MBCs) and on availability in matched distant metastases (DMs): Ki67, cyclin A, geminin and aurora-kinase A (aurkA); and to compare the expression of these markers in early MBC (EMBC) and late MBC separated into groups according to median time point on metastatic event occurred (28 months).MethodsThe expression of the above mentioned markers was analysed in a total of 47 primary MBCs and 59 DMs (out of which 37 were pairs) by immunohistochemistry. Fourteen breast carcinomas with no relapse over a 10-year follow-up period were utilised as control cases (CBC).ResultsAmong the MBCs, 22 metastasised to the bone, 4 to the lung and 21 to the central nervous system (CNS). Geminin (p<0.001) and Ki67 (p=0.001) were increased in the MBCs while aurkA and cyclin A showed no difference when compared with CBCs. There were no differences between aurkA, cyclin A and geminin expression in MBCs and DMs in general. Expression of Ki67 was, however, elevated (p=0.027) in DMs. In CNS metastases all markers showed elevated expression as compared to MBCs. In bone metastases, geminin was lower (p<0.001) compared with primary MBCs. In the metastases of the lung, the evaluated markers did not show different expression. According to the median follow-up until the metastatic event, Ki67 was found to be significantly elevated in EMBC (p=0.018).ConclusionsKi67 index and geminin distinguish a fraction of MBC with worse prognosis, showing increased levels in the latter in comparison to CBC being tumour-free over a 10-year follow-up period. Ki67 could possibly identify a group of MBCs that develop early DMs.
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Arends, E. J., M. Zlei, C. M. Tipton, Z. Osmani, S. Kamerling, T. Rabelink, I. Sanz, J. J. M. Van Dongen, C. Van Kooten, and Y. K. O. Teng. "POS0680 BELIMUMAB ADD-ON THERAPY MOBILISES MEMORY B CELLS INTO THE CIRCULATION OF PATIENTS WITH SLE." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 585.1–585. http://dx.doi.org/10.1136/annrheumdis-2021-eular.248.
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Background:Belimumab (BLM), a recombinant human monoclonal antibody directed against B-cell activating factor (BAFF), is the first approved biological agent for patients with active severe systemic lupus erythematosus (SLE) and lupus nephritis (LN). There is clinical evidence that combining BLM with B cell depleting therapy can ameliorate disease activity in severe, refractory SLE patients1. Although BLM is a B cell directed therapy and has been shown to significantly decrease total B cells, flow cytometry observations suggest a rapid increase of circulating memory B cells (MBC)2.Objectives:To investigate dynamics of B-cell subsets in SLE patients treated with or without BLM, with a focus on assessing MBC characteristics.Methods:Extensive B cell subset phenotyping was performed by high-sensitivity (HS) flow cytometry (acquisition of 107 leukocytes; per EuroFlow protocols3) on samples from active LN or SLE patients with major organ involvement treated with standard of care (SOC) consisting of high dose steroids and mycophenolate mofetil combined with or without the addition of BLM. MBC gene expression profiles were characterized with single-cell RNA and V(D)J sequencing (ScRNA-SEQ).Results:By employing HS flowcytometry, we established that the absolute increase in circulating MBC in SLE and LN patients was significant for patients who initiated BLM (Figure 1). The increase was observed in a broad range of MBC subsets (Unswitched, IgG1+, IgG2+, IgA1+, IgA2+) at 2 and 4 weeks following initiation of BLM treatment. This rise in MBC could hypothetically be attributed to either proliferation of blood MBC, BLM induced migration of tissue-resident MBCs or BLM related retention of tissue-destined MBC in the blood. ScRNA-SEQ analysis of cell cycle gene-expression was performed and established in both groups a non-proliferating phenotype [in approximately ~94%] of MBC post-treatment, including absence of MKI67 as active proliferation marker. Clonal diversity analysis comparing week 2 with baseline revealed an unexpected decrease of the largest MBC clones in BLM, whereas no change in clonality was observed with SOC alone. Together these data indicate that proliferation is unlikely to be responsible for the observed increase in MBC by BLM. Furthermore, a clear difference was found in gene-expression levels between both treatment groups: BLM was responsible for the upregulation of 72 vs 10 genes in SOC, likewise 162 vs 32 genes were downregulated. Most importantly, a significant downregulation of the migration genes SELL (CD62L), CCR7, ITGB1, RAC2 and ICAM2, were specifically seen in BLM treated patients. This may reflect disrupted lymphocyte trafficking, preventing MBCs from transmigrating from the blood into tissue owing to reduced migration molecules, or preventing MBCs from being retained at the tissue level owing to reduction in tissue adhesion proteins.Conclusion:The addition of BLM to SOC significantly increases MBCs in patients with SLE independently of proliferation, accompanied by a strong modulation of gene expression, including reduced expression of migration markers pointing towards disrupted lymphocyte trafficking. These data may have important implications for improving treatment strategies in patients with LN or severe SLE, as a deeper depletion of autoreactive MBCs could be established by adding B-cell-depleting therapy after the initiation of BLM.Figure 1.Change in pre-germinal center and memory B cell counts from baseline to week 4 of patients with SLE or LN treated with SOC (n=8) or SOC+BLM (n=11).References:[1]Arends EJ et al. Long-term effects of combined B cell immunomodulation with rituximab and belimumab in severe, refractory systemic lupus erythematosus: 2-year results. Nephrol Dial Transplant. 2020 Jun 27 gfaa117.[2]Stohl W et al. Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with SLE. Arthritis Rheum. 2012;64(7):2328-2337.[3]Blanco et al, Age-associated distribution of B and plasma cell subsets in peripheral blood - J Allergy Clin Immunol 2018 141 2208-2219.Disclosure of Interests:Eline J. Arends: None declared, Mihaela Zlei: None declared, Christopher M. Tipton: None declared, Zgjim Osmani: None declared, Sylvia Kamerling: None declared, Ton Rabelink: None declared, Ignacio Sanz: None declared, Jacques J.M. van Dongen Paid instructor for: BD Biosciences: Educational Services (fees for LUMC), Consultant of: BD Biosciences and Cytognos (fees for LUMC), Grant/research support from: GSK (flow cytometry studies for GSK BLISS-BELIEVE study NCT03312907), Cees van Kooten: None declared, Y.K. Onno Teng Consultant of: Aurinia provided financial compensation for consultancy, Grant/research support from: GSK provided belimumab for free for the Synbiose-2 clinical trial and provided an unrestricted grant to conduct the study.
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Egamberdieva, Dilfuza, Zohreh Zoghi, Khudayberdi Nazarov, Stephan Wirth, and Sonoko Dorothea Bellingrath-Kimura. "Plant growth response of broad bean (Vicia faba L.) to biochar amendment of loamy sand soil under irrigated and drought conditions." Environmental Sustainability 3, no. 3 (August 4, 2020): 319–24. http://dx.doi.org/10.1007/s42398-020-00116-y.
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Abstract The broad bean (Vicia faba L.) originated in the Near East, and is cultivated around the world, however, its cultivation is affected by drought stress in several central growing regions of the globe. The present study was designed to determine the effect of biochar on bean plant growth, acquisition of nitrogen (N), phosphorus (P), and potassium (K) and on soil nutrient contents under drought and irrigated conditions. Pyrolysis char from maize (MBC) at 2 and 4% concentrations was used for pot experiments. The shoot and/or root biomass of bean grown in soil amended with 2 and 4% MBC under irrigated condition was increased. Furthermore, increased nodule numbers of bean grown at 4% MBC amendment was observed under both irrigated and drought conditions. P and K uptake of plants under drought conditions increased by 14% and 23% under 2% MBC amendment, and by 23% and 34% under 4% MBC amendment as compared to plants grown without biochar application, respectively. This study demonstrated beneficial effects of biochar produced from maize on growth and nutrient uptake of broad bean, by improving the nodule formation and soil nutritional contents in a sandy loam soil.
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Agboke, A. A., C. N. Nwosu, D. O. Obindo, M. H. Ekanem, E. V. Edet, and I. F. Ubak. "Comparative Antimicrobial Activities of Alchornea cordifolia Leaf Crude Extracts and Cephalosporin Antibiotics on Some Pathogenic Clinical Isolates." Journal of Drug Delivery and Therapeutics 10, no. 5-s (October 17, 2020): 170–76. http://dx.doi.org/10.22270/jddt.v10i5-s.4363.
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Comparative antimicrobial activities of the aqueous and ethanol leaf extracts of Alchornea cordifolia and some Cephalosporin antibiotics of different generations available in Uy, LGA of Akwa Ibom state of Nigeria were evaluated using macro dilution assay to determine the Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) of the plant aqueouse and ethanol leaf extracts and of the Cephalosporin antibiotics against some pathogenic Gram positive and Gram negative organisms. Results: The extraction yielded 59.9g for aqueouse leaf extract (ALE) and 74.10 g of the ethanol leaf extract. The MIC of the leaf extracts ranging from (1.953 mg/mL - 15.625 mg/ mL) and MBC ranging from (3.906 mg/mL – 62.50 mg/mL). The cephalosporin antibiotics; Ceftriaxone (Chupet®) MIC ranging from (0.0078-0.25 mg/mL), MBC (0.0312 mg/mL – 0.25 mg/mL), Cephalexin (Sporidex®) MIC ranging from (0.009766 mg/ mL - 0.625 mg/ mL), MBC (0.01953 mg/ mL -2.50 mg/ mL) and Cefuroxime with MIC ranging from (0.0078 mg/mL-0.25 mg/mL) and MBC (1.25 mg/mL - 2.5 mg/mL). Antimicrobial substances are considered as bactericidal agent when the ratio MBC/MIC ≤ 4 and bacteriostatic when the ratio MBC/MIC is > 4. The antimicrobial activities evaluated increased in the following order of potency; A. cordifolia leaf extracts > Ceftriaxone > Cefalexin > Cefuroxime considering the values of MBC/MIC.
Keywords: Antimicrobial activities, bacteriostatic, bactericidal, cephalosporin, comparative.
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Haq, R., and P. Gulasingam. "Duration of trastuzumab in patients with HER2-positive metastatic breast cancer in prolonged remission." Current Oncology 23, no. 2 (April 18, 2016): 91. http://dx.doi.org/10.3747/co.23.2743.
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Background Outcomes in metastatic breast cancer (mbc) positive for her2 (human epidermal growth factor receptor 2) are generally unfavourable. Trastuzumab has revolutionized the prognosis of her2-positive mbc. Some her2-positive mbc patients go into prolonged remission, and a few patients remain in remission even after discontinuation of trastuzumab, suggesting the possibility of a cure. In our practice, 4 her2-positive mbc patients treated with chemotherapy and trastuzumab have remained in remission on maintenance therapy for 5 years or more. Of those 4 patients, 2 have continued in remission after discontinuation of trastuzumab for more than 1 year. The objective of the present paper was therefore to address the duration of trastuzumab therapy in her2-positive mbc patients in prolonged remission.Methods We conducted a literature review of the duration of trastuzumab in her2-positive mbc patients in remission. We also conducted an online survey of oncologists in Ontario to determine their treatment practices in her2-positive mbc patients.Results The literature search found no specific evidence about the optimal duration of trastuzumab maintenance therapy in her2-positive mbc in prolonged remission. However, retrospective studies suggest predictive markers of good prognosis in patients in complete remission taking maintenance trastuzumab. Identifying those markers could lead to more personalized treatment. Our survey of oncologists about their treatment practices in her2-positive mbc patients revealed that 82.93% of respondents (n = 34) follow the currently available guidelines.Conclusions With the emergence of patients in prolonged remission, duration of trastuzumab in her2-positive mbc has become an important and relevant clinical question worldwide. Collaborative efforts are needed for the further study of this topic.
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Caleffi, Maira, Norah Ana Burchardt, Helio Pasqualotto Scapin, Isabel Crivelatti, Carlos Spode Gomes, Ana Lucia Gomes, and Paula Raffin Pohlmann. "Patient-reported outcomes in metastatic breast cancer: QoL, needs, and expectations of survivors." Journal of Clinical Oncology 35, no. 5_suppl (February 10, 2017): 228. http://dx.doi.org/10.1200/jco.2017.35.5_suppl.228.
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228 Background: Breast cancer is still a leading cause of death and suffering worldwide. To date, metastatic breast cancer (MBC) is a treatable but incurable disease. Molecular subtypes influence outcomes, with recent increase in median overall survival to 56 months in HER2+ disease (Swain et al NEJM 2015). The success of MBC treatment underscores the increasing importance of discussing quality of life (QoL) and patients’ needs. A survey evaluating patient-reported outcomes was carried out in a Brazilian center with the aim of evaluating patient’s QoL, needs and expectations. Methods: In this IRB approved study, MBC patients were selected from clinical database for phone interviews. During the call, verbal consent was obtained and recorded. Patients answered a standardized questionnaire containing 28 questions about their experience with MBC. RedCap database was created with data from interviews for further analysis. Results: A total of 94 patients with MBC were initially screened. From these, 50 were interviewed (24 deceased, 6 declined and 14 had technical problems). Patient’s age ranged from 31-87y. In 44% family income decreased after MBC diagnosis. Median time from diagnosis of MBC to interview was 62 months (range 1-274 months). Most patients (86%) kept themselves informed about MBC; main sources being doctors (100%), internet (76%), media (71%), other patients (54%), and family (48%). Only 6% didn’t know what MBC meant. Majority were on therapy: chemotherapy/injectables (54%), oral medication (36%), and radiation (2%). Most (86%) preferred follow up by a multidisciplinary team, and 18% would prefer exclusive MBC clinics. Only 6% accepted the label “metastatic”. Less popular labels were “advanced disease” (6%), “recurred” (4%), “palliative” (4%), or “disseminated” (0%). They preferred this disease phase be called “controlled disease” (50%) or “chronic disease” (28%). Conclusions: The main sources of information about MBC for patients are the internet and their providers. In this center, communication between providers, policy makers and MBC patients could potentially be improved with terminology changes, since patients would prefer the metastatic phase of their disease be called “Controlled Disease”.
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Navarro, Alejandro, Mafalda Oliveira, Leticia De Mattos-Arruda, Gessamí Sánchez-Ollé, Meritxell Bellet, Judith Balmaña, Patricia Gómez-Pardo, et al. "Prognostic significance of PI3K pathway (PI3Kp) dysregulation in metastatic breast cancer (MBC) patients (pts)." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 566. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.566.
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566 Background: PI3Kp dysregulation represents a potential target for therapies that are currently being tested in clinical trials. This observational retrospective study aims to evaluate the prognostic implications of PI3Kp dysregulation in MBC. Methods: MBC pts with PI3Kp status assessment from Sep09 to Sep11 were reviewed. PIK3CA mutation status analyzed in paraffin-embedded tissue by DxS PI3K Mutation Test Kit or Sequenom MassARRAY. PTEN status determined by IHC. PI3Kp status: (a) No dysregulation: PIK3CA wt and PTEN normal; (b) PI3Kp dysregulation: PIK3CA mutation (PIK3CAmut) or PTEN low (HScore≤50). Results: 232 MBC pts screened, median age 49.8 (22.9-83.1) and median MBC lines 4 (1-15). Distribution: HR+/HER2- 99 (43%), HER2+ 52 (22%), triple negative 35 (15%), unclassified 46 (20%). Sites of metastasis: visceral 173 (75%), only skin 10 (4%), only bone 49 (21%). PIK3CA status assessed in 174 pts, 53 (22.8%) bearing a mutation (21 exon9, 32 exon20). PTEN status assessed in 229 pts, PTEN low 61 (26.6%). PI3Kp dysregulation in 103/185 pts (55.6%). Time to progression to first line MBC treatment (TTP) and overall survival after MBC diagnosis (OS) are shown. Disease free survival (DFS) and distant-disease free survival (DDFS) in pts initially diagnosed with early breast cancer (n=193) has also been calculated. Conclusions: These results suggest that PI3Kp dysregulation, either by PIK3CA mutation or PTEN low, does not seem to have impact on disease recurrence, response to first line MBC treatment or overall MBC survival.[Table: see text]
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Page, David B., Isaac K. Kim, Brie Chun, William L. Redmond, Maritza Martel, Motomi Mori, Dottie Wadell, et al. "A phase II study of dual immune checkpoint blockade (ICB) plus androgen receptor (AR) blockade to enhance thymic T-cell production and immunotherapy response in metastatic breast cancer (MBC)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): TPS1106. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.tps1106.
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TPS1106 Background: ICB (atezolizumab, anti-PD-L1) is known to improve survival when added to chemo, however only in PD-L1-positive, triple-negative MBC. ICB is less effective in hormone receptor positive (HR+) MBC, or when administered following palliative chemo. Novel approaches are required to broaden clinical benefit of ICB, particularly in PD-L1-negative, HR+, or chemo-experienced MBC. Dual ICB with anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab) is associated with enhanced activity in melanoma other malignancies, but has not been explored extensively in MBC. Androgen receptor (AR) blockade, in addition to known direct cytostatic effects in AR-expressing MBCs (50% of TNBC, > 75% of HR+ MBC), may also modulate immune response. AR blockade has been shown experimentally to stimulate thymic production of naïve T-cell clones, which in turn can facilitate de novo anti-tumor immune responses. Concurrent ICB can enhance the activity of these T-cell clones by interfering with PD-1-mediated peripheral tolerance. This combination approach is promising in MBC in light of known AR positivity, and the routine use of lymphodepleting chemo regimens in the curative-intent setting. Methods: This is a phase II trial of dual immune checkpoint blockade (nivolumab 240mg IV q2w; ipilimumab 1mg/kg IV q6w) plus AR blockade (bicalutamide, 150mg PO daily, dose reduction allowed) in triple-negative MBC (cohort A: AR-positive [ > 1% by IHC]; cohort B: AR-negative) or HR+ MBC (cohort C) in subjects who received 0/1 prior chemotherapies in the non-curative setting. Objectives include 24-week clinical benefit rate by iRECIST (primary), safety (CTCAE v4.0), and other response measures (RECIST1.1, PFS, OS). Efficacy for each cohort is defined as > 20% improvement in response over historical control (30% per EMBRACE clinical trial) employing a Simon 2-stage design to minimize futility (n = 46/cohort, stage I n = 15). Thymic generation of T-cells will be measured via quantitative deep sequencing of T-cell receptors (TcR, ImmunoSEQ assay) and TcR excision circles (TRECs), as well as real-time flow cytometry using surrogate cell surface markers of recent thymic emigration. Enrollment has commenced, sites: Earle A. Chiles Research Institute (Portland, OR), Memorial Sloan Kettering Cancer Center (New York, NY). Clinical trial information: NCT03650894.
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Durrer, Stefan, Kirsten Maerkel, Margret Schlumpf, and Walter Lichtensteiger. "Estrogen Target Gene Regulation and Coactivator Expression in Rat Uterus after Developmental Exposure to the Ultraviolet Filter 4-Methylbenzylidene Camphor." Endocrinology 146, no. 5 (May 1, 2005): 2130–39. http://dx.doi.org/10.1210/en.2004-1272.
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Abstract Because the estrogen receptor (ER) ligand type influences transactivation, it is important to obtain information on molecular actions of nonclassical ER agonists. UV filters from cosmetics represent new classes of endocrine active chemicals, including the preferential ERβ ligands 4-methylbenzylidene camphor (4-MBC) and 3-benzylidene camphor. We studied estrogen target gene expression in uterus of Long Evans rats after developmental exposure to 4-MBC (0.7, 7, 24, and 47 mg/kg·d) administered in feed to the parent generation before mating, during pregnancy and lactation, and to the offspring until adulthood. 4-MBC altered steady-state levels of mRNAs encoding for ERα, ERβ, progesterone receptor (PR), IGF-I, androgen receptor, determined by real-time RT-PCR in uterus of 12-wk-old offspring. Western-blot analyses of the same tissue homogenates indicated changes in ERα and PR but not ERβ proteins. To assess sensitivity to estradiol (E2), offspring were ovariectomized on d 70, injected with E2 (10 or 50 μg/kg sc) on d 84, and killed 6 h later. Acute up-regulation of PR and IGF-I and down-regulation of ERα and androgen receptor by E2 were dose-dependently reduced in 4-MBC-exposed rats. The reduced response to E2 was accompanied by reduced coactivator SRC-1 mRNA and protein levels. Our data indicate that developmental exposure to 4-MBC affects the regulation of estrogen target genes and the expression of nuclear receptor coregulators in uterus at mRNA and protein levels.
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Gøtzsche, Liv Bjørn-Hansen, Ninna Rosenqvist, Henning Grønbæk, Allan Flyvbjerg, and Ole Gøtzsche. "Increased number of myocardial voltage-gated Ca2+ channels and unchanged total β-receptor number in long-term streptozotocin-diabetic rats." European Journal of Endocrinology 134, no. 1 (January 1996): 107–13. http://dx.doi.org/10.1530/eje.0.1340107.
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Gøtzsche LB-H, Rosenqvist N. Grønbœk H, Flyvbjerg A, Gøtzsche O. Increased number of myocardial voltage-gated Ca2+ channels and unchanged total β-receptor number in long-term streptozotocin-diabetic rats. Eur J Endocrinol 1996;134:107–13. ISSN 0804–4643. In order to elucidate further the abnormal myocardial Ca+ metabolism in diabetes mellitus, voltage-gated Ca2+ channels and β-receptors were quantified in myocardial membranes of short- and long-term diabetic rats. Diabetes was induced by an injection of streptozotocin (STZ). Animals were killed 2, 4, 7, 90 and 200 days after STZ. A group of diabetic animals were treated with insulin for 20 days following 180 days of untreated diabetes. Diabetic animals developed low triiodothyronine syndrome. During short-term diabetes, the maximum binding capacity (MBC) for Ca+ channels was reduced by 25% at day 4 p<0.05) and the β-receptor MBC was reduced by 48% p<0.05). A normalizing tendency was observed at day 7 for both receptor types; insulin-treated rats did not differ from controls at that time. After 90 and 200 days of untreated diabetes the Ca+ channel MBC had increased by 36% and 27%, respectively (p < 0.05). Twenty days of strictly regulated blood glucose following 180 days of untreated diabetes totally normalized the Ca+ channel MBC. This is in contrast to a previous report where insulin treatment did not normalize the Ca+ channel MBC. Total β-receptor MBCs did not differ from control values 90 and 200 days after STZ. In conclusion, an increase in rat myocardial Ca2+ channel MBC during long-term diabetes was fully normalized by short-term insulin treatment. The increase in sarcolemmal Ca2+ channels could serve to compensate for a defect coupling of the β-receptor to adenylate cyclase. An elevated Ca+ channel number may, at least theoretically, lead to increased Ca2+ flow across the cardiac sarcolemma and in this way contribute to the diabetic cardiomyopathy by increasing the intracellular Ca2+ concentration. Liv Bjørn-Hansen Gøtzsche, Dept. of Internal Medicine M, (Diabetes and Endocrinology), Aarhus Kommunehospital, University Hospital of Aarhus, DK-8000 Aarhus C, Denmark.
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Bertelloni, Fabrizio, Giovanni Cilia, and Filippo Fratini. "Bacteriostatic and Bactericidal Effect of Tigecycline on Leptospira spp." Antibiotics 9, no. 8 (July 30, 2020): 467. http://dx.doi.org/10.3390/antibiotics9080467.
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Tigecycline is a relatively new antimicrobial, belonging to glycylcyclines with antimicrobial activity against a large spectrum of bacteria. Very few data are available on its effect on Leptospira spp., which consist in a bacteriostatic mechanism. The aim of this investigation was to evaluate the bacteriostatic and bactericidal effect of tigecycline on reference Leptospira strains belonging to 16 serovars. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined through the microdilutions method, and tetracycline was used as the control. Results showed that tigecycline had higher MIC and MBC values than tetracycline. Obtained MIC values were between 4 and 32 µg/mL, while MBC values between 16 and >128 µg/mL. Patoc (MIC: 4 µg/mL; MBC: 16 µg/mL) resulted in the most susceptible serovar, while the most resistant were Bataviae (MIC: 32 µg/mL; MBC: 64 µg/mL), Bratislava (MIC: 8 µg/mL; MBC 128 µg/mL), and Tarassovi (MIC: 8 µg/mL; MBC: >128 µg/mL). This is the first investigation focused on the effect of tigecycline against Leptospira spp. reference strains. Since tigecycline is used as a treatment for bacteremia and urinary tract disease, and these symptoms could be linked to Leptospira infection, the possibility of using this antibiotic as a treatment for leptospirosis should be evaluated. Further studies are needed to explore the possibility to use tigecycline for in vivo application against Leptospira.
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Cowley, Nicola L., Sarah Forbes, Alejandro Amézquita, Peter McClure, Gavin J. Humphreys, and Andrew J. McBain. "Effects of Formulation on Microbicide Potency and Mitigation of the Development of Bacterial Insusceptibility." Applied and Environmental Microbiology 81, no. 20 (August 7, 2015): 7330–38. http://dx.doi.org/10.1128/aem.01985-15.
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ABSTRACTRisk assessments of the potential for microbicides to select for reduced bacterial susceptibility have been based largely on data generated through the exposure of bacteria to microbicides in aqueous solution. Since microbicides are normally formulated with multiple excipients, we have investigated the effect of formulation on antimicrobial activity and the induction of bacterial insusceptibility. We tested 8 species of bacteria (7 genera) before and after repeated exposure (14 passages), using a previously validated gradient plating system, for their susceptibilities to the microbicides benzalkonium chloride, benzisothiozolinone, chlorhexidine, didecyldimethyl ammonium chloride, DMDM-hydantoin, polyhexamethylene biguanide, thymol, and triclosan in aqueous solution (nonformulated) and in formulation with excipients often deployed in consumer products. Susceptibilities were also assessed following an additional 14 passages without microbicide to determine the stability of any susceptibility changes. MICs and minimum bactericidal concentrations (MBC) were on average 11-fold lower for formulated microbicides than for nonformulated microbicides. After exposure to the antimicrobial compounds, of 72 combinations of microbicide and bacterium there were 19 ≥4-fold (mean, 8-fold) increases in MIC for nonformulated and 8 ≥4-fold (mean, 2-fold) increases in MIC for formulated microbicides. Furthermore, there were 20 ≥4-fold increases in MBC (mean, 8-fold) for nonformulated and 10 ≥4-fold (mean, 2-fold) increases in MBC for formulated microbicides. Susceptibility decreases fully or partially reverted back to preexposure values for 49% of MICs and 72% of MBCs after further passage. In summary, formulated microbicides exhibited greater antibacterial potency than unformulated actives and susceptibility decreases after repeated exposure were lower in frequency and extent.
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Huang, Weidong, Jonathan F. Lara, Richard Michaelson, Xiu Sun, Pierfranco Conte, Valentina Guarneri, Elena Barbieri, et al. "Quantitative HER2 measurement and PI3K mutation profile in matched primary and metastatic breast cancer tissues." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 614. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.614.
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614 Background: HER2 status of primary breast cancer (PBC) is routinely used to determine systemic treatment for metastatic breast cancer (MBC) patients. Discordance rates of HER2 status between PBC and MBC range from 5.5% to 29% based on published meta-analyses. The clinical benefit of re-assessing HER2 in MBC tissues remains controversial. In this study, we measured quantitative HER2 expression in matched PBC and MBC tissues and correlated changes of HER2 with mutations in the catalytic domain of PI3 kinase(PIK3CA). Methods: Total HER2 protein expression (H2T) was quantified by the HERmark assay in 41 matched PBC and MBC formalin-fixed, paraffin-embedded specimens. PIK3CA mutation status in exons 9 (E545K and E542K) and 20 (H1047R) was determined using a validated pyrosequencing assay. Results: MBC samples included 5 lymph node, 13 viscera, 6 brain, and 17 soft tissue lesions (N=41). 27 (66%) cases showed higher H2T in MBC than in matched PBC; and 14 (34%) cases had higher H2T in PBC than in matched MBC, indicating an overall increase of H2T in matched MBC lesions (fold change 0.25-17.57; p=0.005, paired Wilcoxon rank sum test). HER2 positive conversion (HERmark negative/equivocal in PBC, but positive in matched MBC) was found in 6 (15%) cases, while HER2 negative conversion (HERmark positive in PBC, but negative/equivocal in matched MBC) was seen in 2 (5%) cases. HER2 status was unchanged in 33 (80%) cases. PIK3CA mutations were detected in 13 (32%) of PBC and 19 (46%) of MBC samples. Among the HER2 positive conversion cases, PIK3CA mutation was identified in 50% (3/6) PBC and 67% (4/6) MBC, compared to 0% (0/2, PBC or MBC) in the HER2 negative conversion cases. Among cases with unchanged HER2 status, PIK3CA mutation was observed in 30% (10/33) PBC and 42% (14/33) MBC. Conclusions: Quantitative HER2 assessment revealed a 20% discordance in HER2 status between matched PBC and MBC tissues, with more frequent conversion from low HER2 in PBC to high HER2 in MBC. PIK3CA mutation was observed more frequently in patients who converted from HER2 negative PBC to HER2 positive MBC. These results suggest that re-assessment of biomarkers in MBC tissues may better inform the selection of therapeutic options for patients with MBC.
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Bruce, R. H., H. B. Hseih, D. N. Curry, R. T. Krivacic, N. Lazarus, P. Frankel, S. Lau, and G. Somlo. "Multiple biomarker expression in circulating tumor cells (CTCs) from locally advanced/inflammatory (LA/IBC) and metastatic breast cancer (MBC) patients (pts)." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 1092. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.1092.
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1092 Background: Numeration of CTCs from MBC pts is predictive of outcome. Quantitative changes in CTC-s are currently tested for their potential to monitor therapy (Rx). Biomarker characterization of CTCs may be a useful adjunctive guide for Rx selection. Methods: At the COHCC between May 1, 2008 and December 31, 2008, consecutively treated pts with LABC/IBC, or with newly diagnosed/progressing MBC were accrued. Blood samples (20–30 mL) were procured prior to initiating neoadjuvant (neo)Rx (LABC and IBC patients) or systemic Rx (MBC), and were sent to PARC for analysis. A novel high-speed scanning instrument located CTCs from cytokeratin (CK) labeling enabling high resolution images to be selectively acquired using digital microscopy. From these images, CTCs were identified by CK, DAPI (nuclear marker) and CD45, and protein expression levels were determined for HER-2, estrogen receptor (ER), Excision repair cross-complementation group 1 (ERCC1), and EGFR. Cell lines with expression of each marker were used for normalization of the cell intensities, and a scoring system was used to account for relative number and expression levels of markers on the CTCs. Results: Twenty-seven pts with LABC, 4 pts with IBC, and 11 pts with MBC were enrolled. We have observed CTCs prior to initiating neoRx in all pts with IBC relative to 39% of all LABC/IBC cases, and in 57% of pts (n:14) with HER-2+ primary BC versus 24% (n = 17) with HER-2- BC . ER status, size, or grade did not predict for CTC detection. Numeration of CTCs was seen in 45% of pts with MBC. Expression of EGFR and ERCC1 was detected in 3 of 4, and 2 of 4 tested CTC samples from MBC cases. Expression of HER-2 and ER was observed on 1 of 3 and 3 of 4 CTC samples; there was discrepancy between the CTC expression profile and HER-2 and ER status of the primary BC in one case each. Conclusions: Detecting multiple markers in CTCs from pts with MBC is feasible, and similar testing in LABC/IBC patients is needed. Such multiplex testing may allow for more personalized Rx for pts with LABC/IBC and MBC. No significant financial relationships to disclose.
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Nikolic, N. M., Z. Tomasevic, and S. Jelic. "Secondary malignancies developing during metastatic breast cancer treatment." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e12020-e12020. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e12020.
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e12020 Background: Secondary malignancies (SM) developing during metastatic breast cancer (MBC) are obviously more complicated for diagnosis, potential surgery and for further MBC treatment. However, the frequency of SM during MBC is not well explored, in contrast to SM after nonmetastatic BC. The aim of this paper is to determine frequency of SM in MBC patients and to determine the percentage of surgically treated SM. Methods: Hospital charts of BC patients were retrospectively analyzed at the Institute for Oncology and Radiology of Serbia. Patients who developed SM at any time point after BC were included in this analysis. Patients with contra-lateral BC and acute leukemia were excluded. Patients with SM during MBC were separately analyzed. Results: A cohort of 50 BC patients with SM was identified. Median age was 50 (range 32–78 years) median time to SM was 65.3 months (range 1–276). Forty-six patients had histological confirmation of SM. In 30 patients SM developed during treatment for MBC. Four SM were not confirmed by biopsy due to SM site or high burden of MBC. Median age was 53.4 years (range 34–74), median time to SM development was 78.9 months, and median time to BC metastases was 60.1 months. The most frequent SM in MBC patient were lung (5), endometrial (4, all treated with tamoxifen), ovarian (3), thyroid (3), cervical (3), and colon carcinoma (2). Only 14 patients with SM (14/30: 46%) could be treated with radical surgery and SM did not influenced further MBC treatment. Conclusions: According to our experience, SM develops more frequently in MBC than in non MBC patients, representing 60% (30/50 patients) of all SM in BC patients; 46.6% (14/30) of SM diagnosed during MBC could be surgically resected, and does not influence further MBC treatment. No significant financial relationships to disclose.
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Oliveira, Mafalda, Alejandro Navarro, Leticia De Mattos-Arruda, Gessamí Sánchez-Ollé, Meritxell Bellet, Judith Balmaña, Patricia Gómez-Pardo, et al. "PI3K pathway (PI3Kp) dysregulation and response to pan-PI3K/AKT/mTOR/dual PI3K-mTOR inhibitors (PI3Kpi) in metastatic breast cancer (MBC) patients (pts)." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 509. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.509.
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509 Background: The role of PI3Kp dysregulation as a predictor of sensitivity to PI3Kpi is unclear. We aimed to evaluate the efficacy of PI3Kpi in two cohorts of MBC pts with assessable PI3Kp status. Methods: MBC pts treated in ≥3rd line with PI3Kpi were reviewed. PI3Kp status: (a) No dysregulation: PIK3CA wt and PTEN normal; (b) PI3Kp dysregulation: PIK3CA mutation (PIK3CAmut) or PTEN low (HScore≤50). Cohort A: pts treated with single agent PI3Kpi. Cohort B: pts treated with PI3Kpi in combination with hormonal therapy (HT), chemotherapy (CT) and/or trastuzumab (T). Results: Out of 232 MBC pts screened for PI3Kp alterations from Sep09 to Sep11, 32 were treated with PI3Kpi. Cohort A (n=17): HR+/HER2- 88%, HER2+ 6%, triple negative 6%; median age 43, median MBC lines 4 (2-9); PIK3CAmut in 10/17 (58.8%; 6 exon9, 4 exon20), PTEN low 3/17 (17.6%), 1 pt both; PI3Kp dysregulation 12/17 pts. Cohort B (n=15): HR+/HER2- 40%, HER2+ 60%; median age 49, median MBC lines 4 (2-13); PIK3CAmut 3/13 assessable (23.1%; all exon20), PTEN low 6/15 (40%), 1 pt both; PI3Kp dysregulation 8/15 pts. Time to progression to PI3Kpi (TTP), overall survival from MBC diagnosis (OSMBC) and OS from PI3Kpi beginning (OSPI3Kpi), according to PIK3CA status and PI3Kp dysregulation, are shown. No differences were found according to PTEN status. Conclusions: These results suggest that the best outcomes with PI3Kpi in PIK3CAmut MBC pts occur when they are used in combination with HT/CT/T. Activity of non selective PI3Kpi used as single agents seems to be limited, making results from prospective trials with selective PI3Kα inhibitors and PI3Kpi in combinations eagerly awaited. [Table: see text]
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Chen, Yu, and Ming-Guo Zhou. "Characterization of Fusarium graminearum Isolates Resistant to Both Carbendazim and a New Fungicide JS399-19." Phytopathology® 99, no. 4 (April 2009): 441–46. http://dx.doi.org/10.1094/phyto-99-4-0441.
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Fusarium head blight (FHB) of wheat and other cereals, caused mainly by Fusarium graminearum, is one of the most economically important diseases worldwide, especially in the United States and China. The benzimidazole fungicides, particularly carbendazim (MBC), have been consistently used during the period of wheat heading and flowering in areas with warm and moist weather to control FHB in China for over 30 years. The effectiveness of MBC, however, has been threatened by the emergence of resistant pathogen populations in the field. JS399-19 (experimental number; a.i. 2-cyano-3-amino-3-phenylancryic acetate) is a novel cyanoacrylate fungicide discovered and patented by the Jiangsu Branch of National Pesticide Research & Development South Center of China. To evaluate the potential risk of resistance development in MBC-resistant F. graminearum isolates to this new fungicide JS399-19, five isolates each of MBC-resistant or -sensitive, which were classified into three different sensitivity phenotypes, such as sensitive (S), moderately resistant (MR), and highly resistant (HR) to MBC, were selected to induce JS399-19-resistant mutants by selecting resistance on potato sucrose agar (PSA) plates amended with JS399-19 at 10 μg/ml. In this way, a total of 24 JS399-19-resistant mutants were obtained from all tested MBC-resistant or -sensitive isolates. All 50 single-spore progenies of each of the resistant mutants could grow normally on PSA plates amended with JS399-19 at 10 μg/ml, indicating stability of resistance to this fungicide. Also, all of the resistant mutants maintained their resistance to JS399-19 and/or MBC through eight transfers on PSA plates for 40 days and when stored on PSA slants at 4°C for 60 days. The mycelial growth and conidial production capacity were decreased in 52.4% of the resistant mutants, indicating that a fitness cost was associated with JS399-19-resistant phenotypes of F. graminearum isolates. However, most of the mutants resistant to both MBC and JS399-19 exhibited high sexual reproduction capacity and pathogenicity as their parental isolates. Nevertheless, the majority of these mutants possessed fitness levels comparable to their parents. The results on the efficacy of the two fungicides for controlling FHB incited by the fungicide-resistant mutants were generally consistent with those of the in vitro sensitivity tests. JS399-19 was effective in controlling FHB caused by MBC-resistant isolates under field conditions, while it was not effective in controlling FHB caused by isolates resistant to JS399-19 or those that were resistant to both MBC and JS399-19. Moreover, the efficacy of the mixture of MBC and JS399-19 was also significantly lower in controlling FHB caused by the isolates resistant to both MBC and JS399-19 than the efficacy against the disease caused by the sensitive isolates, the MBC-resistant isolates, or the JS399-19-resistant isolates. The results suggest that JS399-19 possessed a high risk in development of resistance in MBC-resistant and -sensitive F. graminearum isolates, and this double resistance to both of these fungicides could presumable emerge and create a major problem since both these fungicides are extensively used in China. Therefore, careful use of JS399-19 should be followed to delay resistance development in natural populations of F. graminearum, avoid unexpected control failures, and sustain the usefulness of MBC and the new product JS399-19.
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Alexander, Melissa, Gabriel Acosta Gonzalez, Stefano Malerba, Tsivia Hochman, Judith D. Goldberg, and Farbod Darvishian. "Multifocal Invasive Ductal Cancer: Distinguishing Independent Tumor Foci From Multiple Satellites." International Journal of Surgical Pathology 25, no. 4 (November 10, 2016): 298–303. http://dx.doi.org/10.1177/1066896916676586.
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Patients with multifocal breast cancers (MBCs) have a poorer prognosis than patients with unifocal breast cancers. Studies have attributed this to tumor size underestimation in MBC. An alternative hypothesis is that some MBCs behave in a fashion analogous to the “satellite” and “in-transit metastasis” observed in melanoma and, thereby, are more clinically aggressive. We identified 79 cases of MBC, which we classified into 2 groups: study cases defined as ≥2 morphologically similar tumor foci with ≥1 focus without in situ carcinoma (n = 21); and a control group defined as ≥2 morphologically similar or dissimilar foci with associated in situ carcinoma in all foci (n = 58). The odds of being a study case is 1.86 (95% confidence interval [CI] 1.26-2.74) times greater per unit increase in number of tumor foci (median of 4 tumor foci; P = .002). Study cases were 73.33 (95% CI = 8.91-603.16) times more likely to have lymphovascular invasion (LVI) and 14.72 (95% CI = 4.37-49.61) times more likely to have nodal metastases. Grade I/II tumors were 0.20 (95% CI = 0.07-0.59) times less likely to be study cases. There was a significant positive interaction ( P < 0.001) indicated by the relationship of LVI status and nodal status with the study case and control group. We conclude that there is a subset of MBC that presents with more numerous tumor foci and a higher rate of nodal metastasis. The aggressive behavior of these cases may be attributed to their proclivity for LVI.
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Feinberg, Bruce A., Jeffrey Wojtynek, Igoni Dokubo, Yolaine Jeune-Smith, Jonathan Kish, and Ajeet Gajra. "Prescribing preferences for hormone sensitive (HR+) metastatic breast cancer (mBC) in the CDK 4/6 inhibitor (CDK 4/6i) era." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e13058-e13058. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e13058.
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e13058 Background: CDK 4/6i is a category 1 guideline-recommended therapy for HR+/HER2- mBC in both first-line (1L) with an aromatase inhibitor and second-line (2L) with fulvestrant and without prior CDK 4/6i. We sought to understand community oncologists’ (c-oncs) prescribing preferences and sequencing for 1L, 2L, and third-line (3L) HR+/HER2- mBC patients across several common clinical scenarios (CS). Methods: C-oncs were presented 4 hypothetical HR+/HER2- mBC clinical scenarios (CS 1-4) via web-based survey. CS differed by menopausal status, prior adjuvant therapy and nature of metastases (mets) (i.e., bulky liver, lung, bone), but otherwise uniform: asymptomatic presentation, PI3K negative, identical response extent and duration in 1L, 2L, and 3L. Treatment preferences: hormonal (H), single agent (SA) or combination chemotherapy (CC) for 1L, 2L, and 3L in each CS were queried. We describe these preference patterns. Results: 47 U.S. c-oncs participated: mean years in practice was 22.7 and mean mBC patients under active treatment was 23.3. Preference for treatment and sequence, regardless of CS, per LOT were: 1L = 71% H, 14% SA, 16% CC; 2L = 51% H, 31% SA, 16% CC; and 3L = 35% H, 59% SA, 6% CC (Table). Of the 71% who preferred 1L H, the CDK4/6i % were: 73% overall, 58% when mets described as bulky liver, 94% when described as bone and or lung. The preference for pre-planned sequential chemo-hormonal therapy in 1L resulted in 63% of initial chemotherapy followed immediately by H; of which CDK 4/6i was preferred in 47%. In total, the initial and post-chemo CDK4/6i 1L preference was 80%. 2L hormonal preferences by frequency were: everolimus + exemestane = 38%, CDK 4/6i + fulvestrant = 20%, fulvestrant = 19%. SA preferences: 2L = capecitabine 46%, taxane 25%; 3L = capecitabine 40%, eribulin 32%. CC preferences included atezolizumab + nab-paclitaxel 24% in 1L and 16% in 2L. Conclusions: 1L HR+/HER2- mBC treatment is highly variable and preferences that warrant further research include: the role of CC, specifically atezolizumab + nab-paclitaxel; repeated CDK4/6i line of therapy; H therapy post CDK4/6i progression; and optimal SA sequencing. [Table: see text]
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Gradishar, W. J., D. Krasnojon, S. V. Cheporov, A. Makhson, G. M. Manikhas, A. Clawson, and P. Bhar. "Albumin-bound paclitaxel (ab-pac) versus docetaxel for first-line treatment of metastatic breast cancer (MBC): Final overall survival (OS) analysis of a randomized phase II trial." Journal of Clinical Oncology 29, no. 27_suppl (September 20, 2011): 275. http://dx.doi.org/10.1200/jco.2011.29.27_suppl.275.
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275 Background: We previously reported the results of a phase II study evaluating the efficacy and safety of three different dosing regimens of ab-pac and docetaxel for the first-line treatment of MBC (Gradishar et al. J Clin Oncol. 2009;27:3611-3619). Here we report final OS outcomes. Methods: Patients (N = 300) with previously untreated MBC were randomized to 1 of 4 treatment arms (arms A–D listed in table). A step-down statistical approach was used for pairwise comparisons of treatment groups. Results: Patients (N = 300) with previously untreated MBC were randomized to 1 of 4 treatment arms (arms A–D listed in table). A step-down statistical approach was used for pairwise comparisons of treatment groups. These OS data were consistent with the investigator assessment of overall response rates (ORR) and progression-free survival (PFS) that were previously published. Rates of grade (gr) 3 sensory neuropathy (SN) were 21%, 9%, 22% and 12%, respectively in arms A, B,C, and D (p= 0.082). There were no cases of gr 4 SN. The median times to improvement to ≤ gr 2 SN were 22, 22, and 20 days for arms A, B, and C and 37 days for arm D. Gr 3/4 neutropenia occurred less frequently with ab-pac vs docetaxel (gr 3: 39, 20, 35, and 19% in arms A,B,C, and D, respectively; gr 4: 5, 5, 9, and 75%, p < .001 for gr 4). Conclusions: Ab-pac qw 3/4 at 150 mg/m2 resulted in a 33.8 mo OS, a longer OS than historically achieved with taxane monotherapy in MBC. The 150 mg/m2 qw 3/4 dosing regimen provided the best clinical outcome in this phase II trial in patients with MBC. [Table: see text]
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Masci, Giovanna, Michele Caruso, Agnese Losurdo, Piermario Salvini, Carlo Carnaghi, Luca Di Tommaso, Monica Zuradelli, et al. "HER2 assessment and Ki-67 labeling index in a cohort of male breast cases: The Ich Network on Cancer Research (INCaRe) experience." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 623. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.623.
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623 Background: The overall incidence of male breast cancers (MBC) is around 1% of all breast cancers and is on the rise.Most of our current knowledge regarding its biology and treatment strategies has been extrapolated from its female counterpart. However, from literature data, it is more and more evident that MBC has biological differences compared with female breast cancer (FBC). While hormone receptors are more frequently positive in MBC than in FBC, HER-2 seems to be less expressed in MBC than in FBC, with data ranging from 0 to 18%; no data on Ki-67 have been so far reported. Methods: We retrospectively analyzed the immunohistochemical expression of hormone receptors status, HER-2 protein expression, and Ki-67 in 76 consecutive MBCs, treated within the Humanitas Institutes Network on Cancer Research (INCaRe). HER-2 determinations were carried out according to ASCO/ACP and NEQAS guidelines: cases with score 2+ at IHC were further examined by fluorescent in situ hybridation (FISH). Results: From 2000 to 2011, we treated 76 male breast cases (age 25-87, median 64): 72 patients (94%) had ductal carcinoma and 4 had rare histotypes (2 papillary, 1 mucinous and 1 cribryform). Thirthy-two of 76 patients (42%) had positive axillary lymph-nodes, while 6 (8%) were metastatic at diagnosis. Of these, estrogen receptor and progesterone receptor were positive in 96% and 93% patients respectively; HER-2, evaluable in 67 patients, was positive in 11 (16%). Ki-67 was evaluable in 75 patients and was > 20% in 24 cases (32%), with 20/24 (26%) with Ki-67 > 30%. Grading was evaluable in 65 patients: G1 in 2 (3%), G2 in 41(63%) and G3 in 22 (34%), respectively. Conclusions: In these series, MBC show different patterns from FBC, with some favorable aspects such as higher hormone receptor status and much lower HER-2 expression and some unfavorable features, such as higher Ki-67 values. Although further studies are needed to confirm these data, different treatment strategies would be suggested in MBC than its female counterpart.
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Fernández-Ortuño, D., and G. Schnabel. "First Report of Thiophanate-Methyl Resistance in Botrytis cinerea on Strawberry from South Carolina." Plant Disease 96, no. 11 (November 2012): 1700. http://dx.doi.org/10.1094/pdis-06-12-0557-pdn.
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Botrytis cinerea Pers.:Fr. is the causal agent of gray mold disease and one of the most important plant-pathogenic fungi affecting strawberry (Fragaria× ananassa). Control of gray mold mainly depends on fungicides, including the methyl benzimidazole carbamate (MBC) thiophanate-methyl. In 2011, strawberries with gray mold symptoms were collected from commercial fields near Chesnee, Florence, Lexington, McBee, Monetta, and North Augusta, all in South Carolina. MBC fungicides were used in most of these fields for gray mold control during the last 3 years. A total of 124 single spore B. cinerea isolates were obtained, each from a different fruit. Resistance to thiophanate-methyl (Topsin M 70WP, Cerexagri-Nisso LLC, King of Prussia, PA) was determined using a conidial germination assay as described previously (1). The majority of isolates (81.4%) were resistant; the rest were sensitive. Resistant isolates were found in all locations with some populations (Chesnee, McBee, and Lexington) revealing no sensitive isolates. Genomic DNA from 35 resistant isolates (representing all locations) and 10 sensitive isolates (from Chesnee, Monetta, and North Augusta, SC) was extracted, and the molecular basis of MBC fungicide resistance was determined as described previously (2). All MBC-resistant isolates possessed the E198A mutation known to confer high levels of MBC fungicide resistance in many fungi, including B. cinerea (2,3). Disease was assessed using a detached strawberry fruit assay. Commercially grown strawberry fruit (24 in total for each isolate and fungicide treatment) were rinsed with water, dried, and sprayed 4 h prior to inoculation with either water or 2.4 g/liter of Topsin M to runoff using a hand mister. Fruit was stab-wounded with a sterile syringe and inoculated with a 30-μl droplet of a conidial suspension (106 spores/ml) of either a sensitive or resistant isolate. After inoculation, the fruit were kept at 22°C for 4 days. The sensitive isolate developed gray mold disease in untreated but not Topsin M-treated fruit. The resistant isolate developed gray mold disease of equal severity in both, the control and fungicide-treated fruit. This experiment was repeated once. The results of the study show that resistance to MBC fungicides is common and widespread in B. cinerea from strawberry in South Carolina. Prior to this study, resistance to MBCs has only been reported in B. cinerea from ornamental crops grown in greenhouses in South Carolina (4). References: (1) J. E. Luck and M. R. Gillings. Mycol. Res. 99:1483, 1995. (2) R. W. S. Weber and M. Hahn. J. Plant Dis. Prot. 118:17, 2011. (3) O. Yarden and T. Katan. Phytopathology 83:1478, 1993. (4) L. F. Yourman and S. Jeffers. Plant Dis. 83:569, 1999.
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Lutsar, I., A. Ahmed, I. R. Friedland, M. Trujillo, L. Wubbel, K. Olsen, and G. H. McCracken. "Pharmacodynamics and bactericidal activity of ceftriaxone therapy in experimental cephalosporin-resistant pneumococcal meningitis." Antimicrobial Agents and Chemotherapy 41, no. 11 (November 1997): 2414–17. http://dx.doi.org/10.1128/aac.41.11.2414.
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Adequate concentrations of beta-lactam antibiotics in cerebrospinal fluid (CSF) are difficult to achieve for meningitis caused by drug-resistant Streptococcus pneumoniae. Ceftriaxone in dosages of 150 or 400 mg/kg of body weight per day, given in one or two doses, was used for the treatment of experimental highly cephalosporin-resistant (MIC and MBC, 4 microg/ml) pneumococcal meningitis. The bacterial killing rate (delta log10 CFU per milliliter per hour) and pharmacokinetic indices, including percentage of time the antibiotic concentration exceeded the MBC during a 24-h period (T>MBC), CSF peak concentration above the MBC, and area under the concentration-time curve from 0 to 24 h above MBC, were measured and correlated. By multiple stepwise regression, only T>MBC independently predicted the bacterial killing rate. There was a direct linear correlation between T>MBC in CSF and the bacterial killing rate during the first 24 h of therapy (r = 0.87; P = 0.004). Sterilization of CSF was achieved only when the T>MBC was 95 to 100%. In the first 24 h, the 200-mg/kg/12-h regimen, compared with the 400-mg/kg/24-h regimen, was associated with a greater T>MBC (87% +/- 10% versus 60% +/- 22%; P = 0.03) and greater bacterial killing rate (0.2 +/- 0.04 versus 0.13 +/- 0.07; P = 0.003), confirming that ceftriaxone exhibits time-dependent bactericidal activity. After 24 h, the T>MBC and the CSF sterilization rates were similar whether ceftriaxone was given once or twice daily.
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Weger, J., M. Schanze, M. Hilber-Bodmer, T. H. M. Smits, and A. Patocchi. "First Report of the β-Tubulin E198A Mutation Conferring Resistance to Methyl Benzimidazole Carbamates in European Isolates of Monilinia fructicola." Plant Disease 95, no. 4 (April 2011): 497. http://dx.doi.org/10.1094/pdis-12-10-0922.
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The causal agent of brown rot on stone and pome fruits, Monilinia fructicola (G. Wint.), is a quarantine pathogen in Europe. It has been detected in Austria (later eradicated), Spain, the Czech Republic, Italy, Germany, and Switzerland (1). In the United States and other countries, M. fructicola isolates were reported to show resistance to different classes of fungicides, including methyl benzimidazole carbamates (MBC) (2). Lichou et al. (2) reported the presence of isolates resistant to the MBC carbendazim in France, but the mechanisms inducing MBC resistance in these isolates were not studied. Ma et al. (3) in California, and more recently, Zhu et al. (4) in South Carolina, demonstrated that the molecular mechanisms accounting for low and high levels of resistance to MBC fungicides in M. fructicola isolates were the mutations H6Y and E198A, respectively, in the β-tubulin gene. Four M. fructicola isolates each from Italy, France, Spain, and Switzerland (16 isolates total), all having an unknown level of MBC resistance, were selected. In each isolate, the section of the β-tubulin gene containing the two potentially mutant codons was PCR-amplified with the primers TubA and TubR1 (3) and the amplicons were sequenced directly. Sequence analysis revealed the amino acid histidine (H) at codon 6 in all the isolates, which would not predict MBC resistance, while alanine (A) at codon 198 (the mutation predictive of a high level of MBC resistance) was found in all isolates from Spain and Switzerland and in three isolates each from France and Italy. A representative sequence of the four identical partial β-tubulin gene sequences from the Swiss isolates was submitted to GenBank under the Accession No. HQ709265. All isolates were tested in a potato dextrose agar (PDA) petri dish assay for resistance to the MBC fungicide thiophanate-methyl (Nippon Soda Co., Ltd., Tokyo, Japan) at the discriminatory dose of 50 μg/ml (4). All isolates with the E198A mutation were able to grow on the media, while the two isolates without the E198A mutation were not able to grow. The result indicated that most isolates had a high level of resistance to the MBC fungicide. To our knowledge, this is the first report of the presence of the E198A mutation conferring resistance to MBC fungicides in European isolates of M. fructicola. As the mutation appears to be widely distributed, we anticipate that MBC fungicides may be ineffective at controlling brown rot in countries with occurrence of M. fructicola. References: (1) M. Hilber-Bodmer et al. Plant Dis. 94:643, 2010. (2) J. Lichou et al. Phytoma 547:22, 2002. (3) Z. H. Ma et al. Appl. Environ. Microbiol. 69:7145, 2003. (4) F. X. Zhu et al. Plant Dis. 94:1511, 2010.
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Payandeh, Mehrdad, Edris Sadeghi, Mehrnoush Aeinfar, and Saba Yari. "Complete response of Palbociclib in metastatic breast cancer patient: A case report." Biomedical Research and Therapy 5, no. 6 (June 23, 2018): 2365–69. http://dx.doi.org/10.15419/bmrat.v5i6.448.
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Palbociclib, an oral inhibitor of cyclin-dependent kinases 4 and 6 (CDK 4/6), has been approved for metastatic breast cancer (mBC) treatment of hormone receptor (HR)-positive/ human epidermal growth factor receptor 2 (HER2)-negative. The study reported the efficacy of Palbociclib as a new oral drug in a patient with mBC. A 40-year-old female with stage 2 right BC change to stage 4 after about two years later referred to oncology clinic. Due to HR-positivity/HER2-negative, she has treated with Palbociclib 125 mg (per one day for twoweek and one-week intervals) with Letrozole. In new assessment and after 8 months of this oral combination therapy, the chest x-ray of lung showed the complete response. Treatment with Palbociclib plus Letrozole had a complete response in the mBC patient after the common chemotherapies and hormone monotherapy.
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Bertho, Marion, Julien Fraisse, Anne Patsouris, Paul Cottu, Monica Arnedos, David Pérol, Anne Jaffré, et al. "Real-life prognosis of 5041 bone-only metastatic breast cancer patients in the multicenter national observational ESME program." Therapeutic Advances in Medical Oncology 13 (January 2021): 175883592098765. http://dx.doi.org/10.1177/1758835920987657.
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Background: Bone-only (BO) metastatic breast cancer (MBC) is considered a more favorable entity than other MBC presentations. However, only few retrospective series and data from selected randomized controlled trials have been reported so far. Methods: Using the French national multicenter ESME (Epidemiological Strategy and Medico Economics) Data Platform, the primary objective of our study was to compare the overall survival (OS) of patients with BO versus non-BO MBC at diagnosis, with adjustment on main prognostic factors using a propensity score. Secondary objectives were to compare first-line progression-free survival (PFS1), describe treatment patterns, and estimate factors associated with OS. Results: Out of 20,095 eligible women, 5041 (22.4%) patients had BO disease [hormone-receptor positive (HR+)/human epidermal growth-factor-receptor-2 negative (HER2−), n = 4 102/13,229 (31%); HER2+, n = 644/3909 (16.5%); HR−/HER2−, n = 295/2 957 (10%)]. BO MBC patients had a better adjusted OS compared with non-BO MBC [52.1 months (95% confidence interval (CI) 50.3–54.1) versus 34.7 months (95% CI 34.0–35.6) respectively]. The 5-year OS rate of BO MBC patients was 43.4% (95% CI 41.7–45.2). They also had a better PFS1 [13.1 months (95% CI 12.6–13.8) versus 8.5 months (95% CI 8.3–8.7), respectively]. This observation could be repeated in all subtypes. BO disease was an independent prognostic factor of OS [hazard ratio 0.68 (95% CI 0.65–0.72), p < 0.0001]. Results were concordant in all analyses. Conclusion: BO MBC patients have better outcomes compared with non-BO MBC, consistently, through all MBC subtypes.
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Thapa, Bicky, Salome Arobelidze, Xuefei Jia, Hassan Awada, Tariq Zuheir Kewan, Fahrettin Covut, Mita Patel, Hamed Daw, Timothy Peter Spiro, and Abdo S. Haddad. "Clinical characteristics and outcome of metaplastic breast cancer: A retrospective tertiary care center experience." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 1095. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.1095.
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1095 Background: Metaplastic breast cancer (MBC) is a rare neoplasm which accounts for less than 1% of all breast cancers. MBC is associated with worse prognosis and there is a paucity of literature on management. We evaluated the clinical characteristic and outcomes of MBC patients at our institution. Methods: After IRB approval, 136 patients diagnosed with MBC were reviewed from the Cleveland Clinic tumor registry from 2000-2017. Patients were evaluated for overall survival (OS) and progression free survival (PFS) using univariable analysis. Time to event variables were estimated by Kaplan-Meier method. Results: A total of 136 pathologically proven MBC patients were included in the study. Median age at diagnosis was 60 years (27-92). Eighty two percent (n = 112) had nuclear grade III, 7% (n = 10) had high grade dysplasia, 2% (n = 3) had nuclear grade I, and 4% (n = 5) had nuclear grade II; 60% (n = 82) patients were diagnosed at stage II, 21% (n = 28) at stage I, 14% (n = 19) at stage III, and 5% (n = 7) at stage IV. Estrogen receptor, progesterone receptor and Her2 expression were positive in 16% (n = 22), 9% (n = 12), and 10% (n = 14) respectively. Only 37% (n = 50) patient had lumpectomy, 18% (n = 25) received hormonal therapy, 56% (n = 76) received radiation, 51% (n = 70) received anthracycline chemotherapy and 26% (n = 36) received non-anthracycline chemotherapy; 37% (n = 50) had chemotherapy after 4 weeks of surgery and 35% (n = 48) patients had chemotherapy within 4 weeks of surgery. On univariable analysis, the 5-year OS for stage III was 30% (14% - 64%), hazard ration (HR) of 4.53 (95% CI, 1.71 - 12.01) (p = 0.002), for stage IV HR of 43.26 (95% CI, 12.34 - 151.64) (p = 0.001); chemotherapy within 4 weeks of surgery was associated with a higher risk of death, HR of 0.30 (95% CI, 0.12 - 0.74) (p = 0.009). Hormonal therapy, radiation therapy, surgery and type of chemotherapy was not associated with significant change in OS and PFS. In our cohort, 2-year OS was 79 % (73 % - 87 %) and 5-year OS was 69 % (61 % - 77 %); 2-year PFS was 61 % (52 % - 70 %) and 5-year PFS was 72 % (65 % - 81 %). Conclusions: Stage of MBC and chemotherapy within 4 weeks of surgery was associated with statistically significant OS and PFS on univariable analysis. Randomized clinical trials are warranted to improve outcomes in MBC patients.
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Obayashi, Kotaro. "Incidence and pathological features of metachronous bladder cancer in prostate cancer patients treated with brachytherapy or radical prostatectomy in a single institution." Journal of Clinical Oncology 37, no. 7_suppl (March 1, 2019): 111. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.111.
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111 Background: Although previous studies have reported that the incidence of metachronous bladder cancer (MBC) is not significantly different after brachytherapy (BT) compared to radical prostatectomy (RP), few studies have reported differences in the pathological features (PF) of MBC between them. This study was conducted to clarify differences in the incidence and PF of MBC between BT and RP in our hospital. Methods: We reviewed 504 patients treated with BT and 471 referred patients treated with RP from 2006 to 2017 in our hospital. We checked the incidence of MBC in all patients and examined the PF including the tumor number, location within the bladder, histology, and time from BT or RP to the occurrence. The chi-square test and Mann-Whitney U test were performed to analyze the differences between the two groups. Results: After a median follow-up time of 66 months, a total of 8 cases of BC occurred in the BT group (1.6 %) and 5 in the RP group (1.1 %). The median time from initial treatment to the occurrence of MBC was 56 months (12-121) in BT and 71 months (4-126) in RP (p = 0.622). Average tumor number was not significantly different (BT:1.38, RP: 2.2, p = 0.265). The incidence of MBC in each location within the bladder for BT vs. RP was 4 vs 0 in the right wall, 3 vs 0 in the left wall, 0 vs 3 in the posterior wall, 0 vs 2 in the dome, and 1 vs 0 in the trigone. The incidence in the lateral wall was significantly higher in BT than in RP (p = 0.00466). There were 3 muscle-invasive cases in BT and 1 case in RP (p = 1.00). High-grade urothelial cancer occurred more in BT 8 than in RP 1 (p = 0.00699). Conclusions: The risk of MBC after BT appeared to be equivalent to patients after RP. MBC after BT occurred more in the lateral wall with worse PF compared to those after RP.
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Krook, James Edward, Akhil Kumar, Marc L. Fishman, William S. Shimp, Laura Rose Bobolts, Val Fishman, Sharon Davis, et al. "Community use of anthracyclines in metastatic breast cancer (MBC)." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 1080. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.1080.
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1080 Background: For decades, anthracyclines have been among the most useful treatments for women with MBC. Though recent publications have confirmed an overall decline in the use of anthracyclines in BC, most of that decline was felt to be due to its diminished utilization in the adjuvant management of BC. Current community anthracycline usage pattern in MBC is not known. We investigate and report, herein, how community oncologists in the southeast USA are currently utilizing anthracyclines for MBC. Methods: All chemotherapy treatment requests for HER2+ and HER2- Stage 4 BC were examined, from 2009 through 2012. Chi-Square test was performed for interaction between age and anthracycline utilization, with p-value less than 0.05 considered significant. The proportion of women who had been treated previously in the adjuvant setting with low cumulative doses of anthracyclines, which would have some effect upon subsequent use, was not retrievable. Results: During this span, 420 unique chemotherapy requests were initiated for 247 patients. These included 54 anthracycline requests for 50 MBC patients. The use of anthracyclines for metastatic HER2+ BC was virtually absent (one in 63 requests among 42 patients). The remaining 357 chemotherapy requests were for treatment of 205 HER2- MBC patients. Anthracyclines were employed in 22% of women under 65 years of age and in 25% of those older than 65 (p = 0.77). Approximately 83% (45/54) of anthracycline-requests were for conventional doxorubicin, either alone or in combination with other agents. The rest were for liposomal doxorubicin (6/54) or epirubicin (3/54). Conclusions: Data from the southeast USA identifies that anthracyclines are virtually never used in HER2+ MBC. Even in HER2- MBC, anthracyclines are used in only one out of 4 patients suffering from this disease. The effect of this unheralded alteration in oncology practice must be carefully considered when trends in metastatic breast cancer control are examined. [Table: see text]
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Trietsch, Dan. "From Management by Constraints (MBC) to Management By Criticalities (MBC II)." Human Systems Management 24, no. 1 (February 23, 2005): 105–15. http://dx.doi.org/10.3233/hsm-2005-24109.
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The five-step “Theory of Constraints” as articulated and explained in Goldratt's books, is touted as “not only beneficial but mandatory”. However, although it is indeed a useful focusing heuristic methodology with an impressive track record, it is not really a theory and it is certainly not mandatory. Furthermore, it involves a serious internal inconsistency that must be “faced courageously”: To make drum-buffer-rope (DBR) work, Goldratt forbids balance, and yet Step 4 involves steps that tend to balance the system. I restrict the term Management by Constraints (MBC) to the correct aspects of the methodology and argue that successful MBC applications never follow the “official version” with complete faithfulness. MBC implicitly rejects DBR and allows balance. We should go further and plan the capacity (criticalities) taking into consideration the variability and the economic costs of the resources. This entails balancing the criticalities of resources based on their economic value relative to the value of the throughput they serve.
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Trietsch, Dan. "System-wide Management by Criticalities: Hierarchical balancing of stochastic resources." Human Systems Management 26, no. 1 (March 20, 2007): 11–21. http://dx.doi.org/10.3233/hsm-2007-26102.
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In a companion paper I argued that Management by Constraints (MBC) should be improved by replacing Step 4 (elevate the constraint) by a revised version that seeks to match the criticality of each constraint (defined as the probability it will be the binding constraint in any period) with its economic value. The result is Management by Criticalities (MBC II). In this paper I show how the principles of MBC II can be pursued in hierarchical systems. Instead of asking subsystems to meet rigid objectives (as in Management by Objectives or Policy Deployment), we ask them to meet the demand placed on them with a specified service level, defined as the complement of the criticality. In effect, the result is a combination of MBC and of policy deployment aimed to improve both.
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Demirci, Umut, Suleyman Buyukberber, Tansel Cakir, Aylar Poyraz, Meltem Baykara, Esra Karakus, Gulnihal Tufan, Mustafa Benekli, and Ugur Coskun. "Isolated mucinous adrenal metastasis in a breast cancer patient." Journal of Oncology Pharmacy Practice 17, no. 4 (January 31, 2011): 444–47. http://dx.doi.org/10.1177/1078155210384893.
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Mucinous breast carcinoma (MBC) is a rare histological type of breast cancer and rarely associated with advanced disease. We report a case that had MBC with an isolated adrenal metastasis which was removed by laparoscopic adrenelectomy. This case is unique due to the unexpected metastasis of pure mucinous carcinoma developed after 4 years of hormone therapy.
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Traina, T. A., H. Rugo, J. Caravelli, B. Yeh, K. Panageas, J. Bruckner, L. Norton, J. Park, C. Hudis, and M. Dickler. "Letrozole (L) with bevacizumab (B) is feasible in patients (pts) with hormone receptor-positive metastatic breast cancer (MBC)." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 3050. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.3050.
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3050 Background: Bevacizumab added to chemotherapy (CRx) prolongs PFS in pts with MBC. Data suggest that estrogen (E2) modulates VEGF-induced angiogenesis in physiologic and pathologic conditions. E2-induced VEGF expression may promote breast cancer growth therefore combination therapy with an aromatase inhibitor (AI) and an antibody to VEGF may be more effective than either agent alone. We performed a feasibility study testing B with L for the treatment (tx) of hormone receptor-positive MBC. Methods: Eligible pts have MBC and are candidates for AI therapy. Prior non-steroidal AI (NSAI) use without progression is permitted. Premenopausal pts undergo ovarian suppression/oophorectomy prior to tx. Therapy consists of L (2.5 mg daily) and B (15 mg/kg IV q3 weeks). The primary endpoint is frequency of Grade (Gr) 4 toxicity. Secondary endpoints include response rate, stable disease (SD) ≥ 6 mo and time to tumor progression. Using a two-stage design, 19 pts were accrued. Because <3 pts had Gr 4 toxicity, the 2nd stage is now enrolling an additional 23 pts. If <5 of the 42 pts have Gr 4 toxicity, the regimen will be considered feasible. Results: Thirty two pts are currently accrued and 28 are now evaluable. Medians: Age 49.5 yrs (32–77) and ECOG PS 0 (0–1). Sites of MBC: bone only 11/28, visceral 16/28, chest wall/soft tissue/lymph nodes 11/28. All are ER and/or PR (+); none are HER2 (+). Prior therapy: adjuvant CRx 20; adjuvant tamoxifen 14. Twenty five pts received an NSAI as first-line tx of MBC, starting a median of 23 wks (1–213) before B. Three pts received first-line tamoxifen; one pt had prior CRx for MBC. After a median of 8 cycles (1–20), tx-related toxicities: Gr 2: hypertension (HTN) 4, headache (HA) 4, proteinuria 3, fatigue 6, joint pain 5, hot flashes 1, epistaxis 1; Gr 3: HTN 5, HA 1, proteinuria 1. There has been no tx-related Gr 4/5 toxicity. Tx-related withdrawals: HTN 1 and headache 1. Twenty five pts are evaluable for response: PR 2, SD ≥ 6 mo 13, SD 4, progression 6. Conclusions: Combination L and B is well tolerated and will be studied in a randomized CALGB trial. Circulating endothelial and tumor cell data is reported separately. Supported in part by Genentech and Novartis. [Table: see text]
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Rizzi, Anna, Francesca Aroldi, Paola Bertocchi, Tiziana Prochilo, Stefano Mutti, Giordano Savelli, Anna Paola Fraccon, and Alberto Zaniboni. "GEMOX: An Active Regimen for the Treatment of Luminal and Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer." Chemotherapy 62, no. 1 (June 10, 2016): 30–33. http://dx.doi.org/10.1159/000445936.
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Background: Pretreated metastatic breast cancer (MBC) remains a formidable challenge with unmet needs both in terms of prolonged survival and quality-of-life-related issues. Methods: We collected data from 27 MBC patients treated with gemcitabine and oxaliplatin (GEMOX) at our institution between June 2009 and April 2015. The patients were heavily pretreated, and all had previously been exposed to anthracyclines and taxanes. Results: We achieved a complete response in 1 patient (4%), a partial response in 7 patients (26%) and stable disease in 12 patients (44%), while 6 patients (22%) experienced progressive disease. The response of 1 patient (4%) could not be evaluated because she interrupted her treatment during the first cycle due to a major reaction to oxaliplatin. We observed grade 4 hypertransaminasaemia in only 1 patient (4%) and grade 2 neuropathy in 16 patients (59%). Grade 3 leuconeutropenia was observed in 5 patients (18%). The median progression-free survival was 5.9 months and the median overall survival was 9.6 months. Conclusions: GEMOX is an efficient and well-tolerated salvage regimen for MBC patients.
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Gomes, Jessica Ribeiro, Raphael Brandao Moreira, Matheus Bongers Alessandretti, and Marcelo Rocha De Sousa Cruz. "Next-generation sequencing (NGS) for personalized therapy in metastatic breast cancer: Selection of therapy and outcomes." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e23166-e23166. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e23166.
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e23166 Background: Treatment for metastatic breast cancer (MBC) has been driven by hormone receptors, HER2 expressions or their absence. Resistance to therapy and progressive disease will occur and empirical chemotherapy lines usually are the next steps. We aim to analyze the role of next-generation sequencing (NGS) for a personalized therapy in metastatic breast cancer and its potential clinical benefit. Methods: We included patients diagnosed with MBC treated at Centro Oncologico Antonio Ermirio de Moraes – Brazil from April 2013 to December 2016. All patients had metastasis accessible for biopsy. The tumor tissue was stored in paraffin and then analyzed by NGS-based assay that identifies genomic alterations within 236 genes. Results: 19 patients with MBC were evaluated (10 triple-negative; 4 HER2-positive; 5 hormonal receptor positive/HER2-negative). The most frequent and relevant genomic alterations identified by NGS assay were in the following genes: 13 TP53 (68.4%); 4 ERBB2 (21%); 4 PTEN (21%); 4 FGFR (21%); 3 PIK3CA (15.8%); 2 BRCA (10.5%); 2 ATM (10.5%); 2 AKT (10.5%); 2 MYC (10.5%); 1 CCND1 (5.3%); and 1 KRAS (5.3%). The NGS assay was able to suggest further therapy in 16/19 patients (84%). The suggested therapies would not be an empirical option according to the cancer’s subtype in 12/16 patients (75%). Therapy could be personalized in nine patients, across multiple lines of therapies (median of 5th line, with a range of 1-14). Median PFS was 6 months, and 8/9 patients (90%) achieved an objective response with the treatment indicated by NGS. Therefore, the assay provided clinical benefit in 42% of patients. Conclusions: NGS panel identified potentially actionable alterations in the majority of patients with MBC (84%). The overall clinical benefit with use of NGS-based assay was 42%. Further studies are necessary to better evaluate the role of NGS for a personalized therapy in MBC.
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Dufour, P. R., F. Rousseau, N. Meyer, T. Delozier, D. Serin, M. Nabet, L. Djafari, and J. Kurtz. "Phase II trial of pegylated liposomal doxorubicin-cyclophosphamide combination as first-line chemotherapy in elderly metastatic breast cancer patients." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 19565. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.19565.
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19565 Background: Although the majority of metastatic breast cancer (MBC) patients (pts) responds to endocrine therapy, treatment failure is a concern, as well as front-line therapy for pts with ER/PR negative disease.The combination of anthracyclines (A) and cyclophosphamide (C) is active in younger pts, but cardiac toxicity of A in elderly MBC pts has to be considered. Pegylated liposomal doxorubicin (PLD) (Caelyx®) is active in MBC and has much less cardiotoxicity than A, and we present the preliminary data of the PLD/C in elderly MBC pts. Methods: This was a multicentric phase II trial. Inclusion criteria included: pts aged between 65 and 75, histologically proven measurable MBC, ECOG PS 0–1, LVEF = 50%, first-line chemotherapy for MBC. Prior adjuvant chemotherapy was allowed if stopped for = 6 or 12 months without and with anthracyclines, respectively. Endocrine therapy either in the adjuvant or metastatic setting had to be stopped for = 1 month. All pts gave a written informed consent. The treatment schedule was : PLD 40mg/m2 and C 500mg/m2 d1 every 4 weeks. Efficacy as well as response duration and tolerance were the primary and secondary end-points, respectively. Results: 35 patients were enrolled (Median age 71.3, range 65.6–75.9). A total of 166 cycles have been administered. The median number of cycles was 6 (range 1–9). No toxic death was reported, one patient died of diabetes mellitus decompensation. No congestive heart failure or decrease in LVEF was reported, although 1 pt experience grade 3 dyspnea and stopped treatment. Other (gr3–4) NCI-CTC toxicity included: neutropenia in 7 (gr3) and 3 (gr4) pts; gr3 mucositis (4). No febrile neutropenia was reported. Grade 3 hand-foot syndrome occurred in 1 pt, whereas treatment was stopped due to a generalized rash in 1 pt. An objective response (CR + PR) was achieved in 10 (28,6%) pts (1 CR and 8 PR), and a disease control in 24 (68.6%) with a progression free survival of 8.8 months and a median survival of 20.4 months Conclusions: The LPD-C combination is active in elderly MBC pts, with an acceptable toxicity profile. No significant financial relationships to disclose.
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Zinnen, Shawn, Eric Keith Rowinsky, Alexander Alexandrov, Larisa Plekhova, Marina Roudas, and Alexander Karpeisky. "Phase 1 study of the bone-targeting cytotoxic conjugate, etidronate-cytosine arabinoside (MBC-11), in cancer patients with bone metastases." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 2589. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.2589.
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2589 Background: MBC-11 is a first-in-class therapeutic conjugate of the bone targeting bisphosphonate etidronate covalently linked to the antimetabolite cytosine arabinoside (Ara-C). In preclinical studies, MBC-11 localizes at the site of cancer-induced bone disease (CIBD) where it demonstrates both antiresorptive and antitumor activities following local release of Ara-C. Robust efficacy was observed in several rodent models of CIBD, as well as in spontaneous osteosarcoma in dogs. Herein, the results of the first-in-human study of MBC-11 are reported. Methods: Patients with advanced solid cancers and CIBD were treated with escalating doses (0.5-10 mg/kg/day) of MBC-11 administered as an intravenous infusion daily for 5 days every 4 weeks for up to 4 cycles. Fifteen patients (prostate cancer [PC; 7], breast cancer [BC; 7], cervical cancer [1]) received 38 total cycles. The study sought to characterize the safety, pharmacokinetics, and the effects of MBC-11 on bone turnover, and tumor response by 18F-FDG-PET/CT imaging and tumor biomarkers. Results: Myelosuppression was generally grade 1-2, involved all lineages, and was the principal toxicity of MBC-11. Two of three patients treated at the 10 mg/kg dose level had dose-limiting toxicity (DLT), each with both grade 4 neutropenia and thrombocytopenia, the maximum tolerated dose (MTD) was 5 mg/kg. Four of 5 patients with pretreatment elevations of the bone resorption marker Trap5b had persistent decrements. 18F-FDG-PET/CT imaging demonstrated partial metabolic responses in 3 patients; one BC patient treated at the 0.5 mg/kg and two CRPC patients treated at 1.0 mg/kg dose levels. An additional 3 patients had stable metabolic responses according to PERSIST. SUV values were reduced by at least 25% in 111 (53.8%) of 206 measurable bone lesions; significant activity was noted at all doses. Conclusions: At doses that were well tolerated and even much lower than the MTD, MBC-11 treatment resulted in substantial reductions in metabolic activity in CIBD patients, providing a foundation for further disease-directed studies to further assess efficacy. Clinical trial information: NCT02673060.
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Guo, Wei, Shujuan Wang, Yunkai Wang, Shaoyong Lu, and Yue Gao. "Sorptive removal of phenanthrene from aqueous solutions using magnetic and non-magnetic rice husk-derived biochars." Royal Society Open Science 5, no. 5 (May 2018): 172382. http://dx.doi.org/10.1098/rsos.172382.
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A magnetically modified rice husk biochar (MBC) was successfully prepared by a hydrothermal method from original biochar (BC) and subsequently used to remove phenanthrene (PHE) from aqueous solutions. The porosity, specific surface area and hydrophobicity of BC were significantly improved (approx. two times) after magnetic modification. The adsorption data fitted well to pseudo-second-order kinetic and Langmuir models. Compared with BC, MBC had a faster adsorption rate and higher adsorption capacity of PHE. The adsorption equilibrium for PHE on MBC was achieved within 1.0 h. The maximum adsorption capacity of PHE on MBC was 97.6 mg g −1 based on the analysis of the Sips model, which was significantly higher than that of other sources of BCs. The adsorption mechanism of the two BCs was mainly attributed to the action of surface functional groups and π–π-conjugated reactions. The adsorption of PHE on MBC mainly occurred in the functional groups of C–O and Fe 3 O 4 , but that on BC was mainly in the functional groups of –OH, N–H, C=C and C–O.
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Lama Tamang, Tsering G., Daniel Kyung, Lauren Eisenbud, Tianyi Tang, Ritesh Parajuli, and Rita S. Mehta. "Use of alpelisib in the treatment of hormone receptor positive metastatic breast cancer: An institutional experience." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15216-e15216. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15216.
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e15216 Background: Mutations in PI3K pathway is a known mechanism of resistance to endocrine therapy in breast cancer. Alpelisib is an alpha-specific PI3K inhibitor. Alpelisib with Fulvestrant is approved for treatment (Tx) of PIK3CA mutated HR+ metastatic breast cancer (MBC) that progress on hormonal therapy. Despite its approval by the FDA, real world data on the use of Alpelisib for the management of MBC is lacking. This abstract reviews the safety and efficacy of Alpelisib in the management of patients with MBC. Methods: A retrospective review of the tumor registry database at a single institution was conducted to identify patients with HR+ MBC. Detailed clinical and pathologic data of PIK3CA mutated patients treated with Alpelisib were obtained. Genomic profiling was done with Foundation One. Results: Table highlights the characteristics of the four patients. All were treated with Alpelisib and Fulvestrant after PIK3CA mutation was demonstrated. 3 patients were heavily pretreated with systemic Tx including CDK 4/6 inhibitors. All patients responded to Alpelisib and Fulvestrant despite treatment history. Mucositis, rash, hyperglycemia and pancytopenia were the observed adverse events (A/E). All A/E were adequately managed except in one patient that required discontinuation of Tx. None has clinically progressed. Conclusions: Our data suggests that Alpelisib and Fulvestrant is tolerated and improves outcomes in patients with HR+ MBC. Alpelisib and Fulvestrant could be an effective therapy in patients who have also progressed on systemic chemotherapy including CDK 4/6 inhibitors. Although our sample size is small, we hope that our experience could guide clinicians in the management of patients with HR+ MBC who harbor the PIK3CA mutation and are being treated with Alpelisib. [Table: see text]
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Lee, Kimberley T., Elaine Chiao, David Lim, Morgane Mouslim, Chenguang Wang, Neha Mangini, Vered Stearns, and Karen L. Smith. "Predictors of non-receipt of first-line CDK 4/6 inhibitors (CDK4/6i) among patients with metastatic breast cancer (MBC)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 1016. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.1016.
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1016 Background: CDK4/6i improve survival outcomes for first-line treatment of patients with hormone receptor positive (HR+), human epidermal growth factor-2 negative (HER2-) MBC. Yet, not all eligible patients (pts) receive a first-line CDK4/6i. We sought to describe factors associated with not receiving a first-line CDK 4/6i among MBC pts treated at our institution. Methods: Retrospective cohort of pts with HR+, HER2- MBC diagnosed between May 1, 2015 and June 30, 2019 treated at Johns Hopkins clinic sites in Baltimore City (BCi), Baltimore County (BCo), and Washington DC (DC). Primary outcome was receipt of a first-line CDK 4/6i. Clinical and demographic factors were abstracted from the electronic medical record. Patient zip-code was used to define a low-income neighborhood (LIN) as an area where >10% of households have median income below the federal poverty level. Univariate and multivariable logistic regression models (determined using a stepwise model selection approach) were performed to identify factors associated with not receiving a first-line CDK 4/6i. Results: Of the 211 pts in the cohort, 203 (96.2%) were female, 133 (63%) were White, and 53 (25%) were Black. Median age was 58 yrs (range 25-90 yrs). 26% of pts had de novo MBC and 44% had visceral disease at diagnosis. About half, 104 (49%), were privately insured, 83 (49%) had Medicare, and 15 (7.1%) had managed care plans including Medicaid. 118 (56%), 43 (20%), and 50 (24%) pts were treated in BCi, BCo, and DC respectively. 60% (n=126) of pts received a first-line CDK 4/6i and there was a trend of increased utilization over time with 39% of pts receiving first-line CDK4/6i in 2015 and 67% in 2019. On univariate analysis, LIN, clinic site, and year of MBC diagnosis (2015-2017 vs 2018-2019) were associated with first-line CDK4/6i use. The multivariable model included age, race, clinic site, LIN, and year of MBC diagnosis. In this model, pts treated in BCi were 58% less likely to receive first-line CDK 4/6i compared to those treated in BCo (OR 0.42, 95% CI 0.18-0.95). Those diagnosed with MBC in 2017 or later were 2.6 times more likely to receive first-line CDK4/6i than those diagnosed prior (OR 2.63, 95% CI 1.45-4.83). Those who lived in a LIN were 39% less likely to receive first-line CDK4/6i vs those in a non-LIN, though this was no longer statistically significant (OR 0.61, 95% CI 0.32-1.13). Conclusions: We identified disparities in the use of CDK4/6i for first-line treatment of MBC. Lower use was observed among pts who received care at our urban Baltimore city site with a trend towards lower use among pts from lower-income neighborhoods. These findings highlight potential barriers with accessing oral cancer therapies - cost, patient distrust, and/or systemic bias. Further work is needed to delineate the multi-level factors contributing to these disparities and to develop resources to overcome these barriers and achieve equitable utilization of these drugs.
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Růžek, L., M. Nováková, K. Voříšek, I. Skořepová, L. Vortelová, Z. Kalfařová, J. Černý, T. Částka, and W. Barabasz. "Microbial biomass-C determined using CaCl2 and K2SO4 as extraction reagents." Plant, Soil and Environment 51, No. 10 (November 19, 2011): 439–46. http://dx.doi.org/10.17221/3615-pse.
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Microbial biomass-C [MBC] was determined by re-hydration [RHD] technique using two very similar salt solutions in dissociation potency (0.5 mol/l K<sub>2</sub>SO<sub>4</sub> [MBC-K] and 0.01 mol/l CaCl<sub>2</sub> [MBC-Ca]) in forest, grassland, arable Cambisols [Inceptisols] and Podzols [Spodosols]. MBC-Ca ranged from 254 to 5076 mg/kg dry soil (1.2–4.0% of C<sub>org</sub>). 114 soil samples were examined in the years 2002 and 2003. Organic C compounds extracted by 0.5 mol/l K<sub>2</sub>SO<sub>4 </sub>[EC-K] and 0.01 mol/l CaCl<sub>2</sub> [EC-Ca] increased in sequence: (1) arable Cambisols (100%), (2) cut and grazed grasslands (547%), (3) forest mineral horizon A<sub>H</sub>: 0–50 mm (783%) and (4) Norway spruce forest floor (2421%). The ratio EC-Ca/EC-K reached on average 62% and ranged from 48% to 74%. Correlation between EC-K and EC-Ca values is connected with soil organic matter status; the correlation was very close for Cambisols (r<sup>2</sup> = 0.925), a medium correlation was found for forest floor (r<sup>2</sup> = 0.380) and a weak correlation was observed for Podzols (r<sup>2</sup> = 0.042). The correlation between MBC-K and MBC-Ca was very close in all cases: Cambisols (r<sup>2</sup> = 0.811), Podzols (r<sup>2</sup> = 0.904) and forest floor (r<sup>2</sup> = 0.496). The ratio between organic carbon and organic nitrogen in 0.01 mol/l CaCl<sub>2</sub> extracts [EC-Ca/N<sub>org</sub>] could be declared as a new indicator for soil microbial association status.