Academic literature on the topic '29:1 1 st. 2 men. ABL'

Abstract Background: Expression of p190 BCR-ABL mRNA is generally considered to be confined to patients with acute lymphoid or more rarely myeloid leukemias, whereas p210 BCR-ABL mRNA is the hallmark of CML. In reality it is not uncommon the presence of p190 m-RNA in p210 CML in chronic phase, due to alternative or missplicing. Its presence seems to have no impact on prognosis in the pre-TKI era, although it may be expression of genomic instability. Aim: Primary object of this study was to investigate if the co-expression might influence the rate of early outcome surrogate endpoints such as such as optimal molecular response (EMR; BCR-ABL < 10% (IS) at 3 month and BCR-ABL < 1% or 6 month). in patients treated with TKI. Methods: Were evaluated patients with CML in chronic phase treated with TKI at our institution. We excluded cases with less than one year of treatment or treated with conventional chemotherapy. The fusion transcripts BCR-ABL were evaluated at diagnosis in peripheral blood by NESTED-PCR and the molecular response were evaluated in peripheral blood with Real-Time PCR. The patients were divided into two groups, "double transcripts" (DT) and "single transcript" (ST). Results: A total of 34 patients were analyzed. The median age was 61 years (range 22-80) and 26 (68%) were male. Ten patients (29%) were DT and twenty-fouru(71%) ST. The distribution according to Sokal score was: 2 (10%), 5 (50%) 3(30%) patients for low, intermediate and high risk in the DT, whereas 13 (54%), 10 (41%) 1 (5%) low, intermediate and high risk in ST, respectively. The optimal response at 3 month was achieved in 3 patients with DT and 20 patients with ST ( 10% vs 83), at 6-month optimal response was achieved in 3 patients with DT and 20 patients with ST (10% vs 83). No patients with BCR-ABL > 10 % at 3 months, achieved molecular response at 6 months. Summary/Conclusion: In our study the co-expression of p190 and p210 BCR-ABL transcripts influences the early molecular response to TKI and suggesting the need for a larger validation study Disclosures No relevant conflicts of interest to declare.

The relationship between bone mineral density and tooth loss in men is unclear. The aim of this retrospective cohort study was to determine if relative metacarpal bone area (MCA) predicts tooth loss in a cohort of 273 male participants in the Dental Longitudinal Study and Normative Aging Study of the Department of Veterans Affairs. Outer and inner cortical bone widths of the middle metacarpal of the nondominant hand were measured on anteroposterior hand radiographs approximately 11 y apart. Baseline MCA was computed and categorized into quartiles. The men were followed from 1971 to 2015. Incident tooth loss during 2 intervals was examined: concurrent with the MCA measurements and long term over the total follow-up (17 ± 7 y). Radiographic alveolar bone loss (ABL) was measured on periapical radiographs as a percentage of the distance from the cementoenamel junction to root apex, and the number of teeth with ABL >40% was computed. Negative binomial generalized linear regression models estimated the mean number of teeth with ABL >40% and the number lost (concurrent and total), controlling for age, smoking, number of teeth at baseline, percentage teeth with ≥1 decayed/filled surface, and years of follow-up. At baseline, MCA was inversely related to number of teeth with >40% ABL. Men in the lowest MCA quartile (Q1) lost the most teeth, both concurrent with MCA measurements and long term, but the association differed by caries level (≤55% or >55% decayed/filled teeth). At the low caries level, the numbers lost in Q1 were 29% greater than in the highest MCA quartile (Q4). At the high caries level, the numbers lost in Q1 were more than twice those in Q4. Associations were attenuated when further controlled for number of teeth with ABL>40%. These findings suggest that systemic bone status plays a role in tooth loss and that the association may be mediated by alveolar bone loss. Knowledge Transfer Statement: Low relative metacarpal bone area was related to loss of alveolar bone and incident tooth loss in men. This information extends previous research, primarily studies of women, showing that osteoporosis adversely affects oral health. Knowledge of a patient’s systemic bone status may be important for managing his or her periodontal disease. Tooth loss in the absence of periodontal inflammation may signify systemic bone loss. Interprofessional communication is central to maintaining optimal oral and bone health.

To determine the effects of strength training (ST) on muscle quality (MQ, strength/muscle volume of the trained muscle group), 12 healthy older men (69 ± 3 yr, range 65–75 yr) and 11 healthy older women (68 ± 3 yr, range 65–73 yr) were studied before and after a unilateral leg ST program. After a warm-up set, four sets of heavy-resistance knee extensor ST exercise were performed 3 days/wk for 9 wk on the Keiser K-300 leg extension machine. The men exhibited greater absolute increases in the knee extension one-repetition maximum (1-RM) strength test (75 ± 2 and 94 ± 3 kg before and after training, respectively) and in quadriceps muscle volume measured by magnetic resonance imaging (1,753 ± 44 and 1,955 ± 43 cm3) than the women (42 ± 2 and 55 ± 3 kg for the 1-RM test and 1,125 ± 53 vs. 1,261 ± 65 cm3 for quadriceps muscle volume before and after training, respectively, in women; both P < 0.05). However, percent increases were similar for men and women in the 1-RM test (27 and 29% for men and women, respectively), muscle volume (12% for both), and MQ (14 and 16% for men and women, respectively). Significant increases in MQ were observed in both groups in the trained leg (both P < 0.05) and in the 1-RM test for the untrained leg (both P < 0.05), but no significant differences were observed between groups, suggesting neuromuscular adaptations in both gender groups. Thus, although older men appear to have a greater capacity for absolute strength and muscle mass gains than older women in response to ST, the relative contribution of neuromuscular and hypertrophic factors to the increase in strength appears to be similar between genders.

Abstract Abstract 4432 Background: The incidence of chronic myeloid leukemia (CML), reported from some population based registries, varies significantly. CML is known as age-dependent disease, so population age structure may strongly influent on the data. For international comparisons several systems for age-standardization are using in epidemiological studies. We conducted our retrospective study to reveal differences in CML incidence rates on the basis of calculation – crude or age-adjusted according to different population standards in St. Petersburg and Leningrad region. Methods: In 2005 the database of Ph- and/or bcr-abl- positive CML patients (pts) was conducted in St. Petersburg and Leningrad region. Since then the data from all newly diagnosed CML patients were included prospectively on population basis. The database was updated at least bi-annually. The data were obtained from hematologists, as general practitioners and private physicians are not licensed to treat oncohematological disorders. The data were double checked from the list of Imatinib distribution (the only drug reimbursed for first line treatment). To calculate crude CML incidence rate we use the data of the general census of the population in Russia in 2010 (the whole population of our region is 6596434 with population in age 15 and above 5821133). For age-adjusted CML incidence rate we use three of currently existing standards: The Segi (“World”), The Scandinavian (“European”) and the WHO standard (based on world average population between 2000–2025). Results: There are 258 (242 in chronic, 9 in accelerated and 7 in blastic phases) CML adult (15 years and above) pts, registered during 2006–2011. The median age is 53 years (48,5 and 55,5 years for men and women respectively). Sokal score was evaluable in 209 pts. It is low in 37%, intermediate in 35% and high in 28% pts. The crude CML incidence rate is slightly higher in men than in women with ratio 1,2:1. Mean annual crude CML incidence rate was 0,65 per 100 000 whole population of Saint Petersburg and Leningrad region, but it was 0,74 in adult population (15 years old and above). Mean annual CML incidence rates in the same age groups were slightly higher in all three standardized systems: 0,94 in Segi, 0,84 in Scandinavian and 0,88 in WHO standard populations. CML incidence rates in all age groups are presented in the table 1. CML incidence rate was lowest in young pts. It was unexpectedly very low in senior pts. CML incidence rates nearly for all age groups were slightly higher in St. Petersburg than in the Leningrad region. The majority of pts (98%) were treated with Imatinib (93% first or second line) or other tyrosine kinase inhibitors (5% first line-in international clinical trials, 18% after Imatinib failure or intolerance). Stem cell transplantation was performed only in 8/258 (3%) pts. Only 25235 (7,5%) evaluable pts progressed from chronic to advanced phases. Only 29/258 (11%) pts dead mostly due to CML (21 CML related deaths were reported). Estimated 5 years overall survival is 91,5%. Mean annual overall CML pts death rate was 1,9% (mean annual death rate between 2006–2010 in whole population of our region was 1,6%). Mean pts accumulated very fast - annual CML prevalence increasing rate between 2005–2011 was more than 14% (Picture 1). Conclusions: CML incidence both crude and age-adjusted in our population based registry is nearly the same in young and middle age, but much lower in senior (65 years and above) pts groups in comparison with published data from other registries which probably represents peculiarities of health system rather than real incidence. In the tyrosine kinase inhibitors era CML patients death rate is very low (nearly the same as in whole population) and CML pts is accumulated very fast in our region. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 4431 The European Treatment Outcome Study (EUTOS) is register based international investigation started in June 2007. [1] The aim is to study the epidemiology of CML and to gain insight into the ‘real world’ treatment of patients with CML. Population base section (EUTOS-PBS) is the prospective study directed mostly to epidemiology aims. Russian part of the EUTOS-PBS registry collect data of newly diagnosed patients lived in 7 large regions of about 10 millions of population totally. EUTOS-PBS inclusion criteria are following: newly diagnosed CML (Ph +/BCR-ABL) started form 1st October 2009, age: older than 18. Russian CML group includes additional protocol for collection data for patients with clinical symptoms of CML. These patients are included into the roster table and after laboratory confirmation are enrolled into the main phase of the study. Thus, 174 patients were included in pre-phase, 142 (82%) had the diagnosis of CML which was confirmed by cytogenetic/molecular-genetic tests (Ph +/BCR-ABL +), 32 (18%) was not confirmed as CML. Among them 87% (n = 20) - have other Ph–negative chronic myeloproliferative diseases, and also acute leukemia (n = 1), cancer (n = 1), chronic inflammatory processes (n = 1). 142 patients with CML are 73 men, 69 women have the age from 18 to 82 (Me 49) years. 136 (96%) of patients are in the chronic phase, 6 (4%) -in the phase of acceleration, nobody in a blast ñrisis. The standard frequency analysis with adjustment to the standard population of WHO was carried out to estimate distribution. The results was presented in the table 1. As shown registered morbidity in 6 regions is not varied so much: source incidence is 0,58 (0,44–0,69); standardized on WHO incidence is: 0,7 (0,57 – 0,85); per 100 thousands per year. Estimated registered morbidity of CML in Russian regions are in 1.5–2 times less, than published morbidity in western countries. The analysis of the incidence in age stratums (table 2) shows that there is no much growth of age morbidity as expected. It obviously points to low detectability of new CML incidents in senior age categories (are more senior 60 years). This fact is probably the main reason of low total registered morbidity. Tabl.1. Incidence rate of new CML cases in 6 regions of Russia Region population (mln.) N CML for 100000. in year Standard of WHO Mordovia Republic 0.87 14 0.69 0.85 Kirov region 1.46 18 0.53 0.6 Perm territory 2.77 45 0.68 0.8 Bryansk region 1.35 17 0.53 0.65 Irkutsk region 2.55 36 0.56 0.68 Zabaikal's territory 1.36 12 0.44 0.57 Total 10.13 142 0.58 0.7 Table 2.CML incidence in age groups Age groups Male Female Maleandfemale 18–29 0.65 0.57 0.61 30–39 0.86 0.39 0.62 40–49 0.50 0.57 0.54 Conclusion: The CML incidence in Russia regions is underestimated. The main reason is an insufficient CML diagnostic screening in the senior age groups of population. References. 1. http://www.eutos.org/content/registry/documents/documents/e940/infoboxContent941/CML-Registry_February09.pdf Disclosures: Vinogradova: BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Chelysheva:Novartis Pharma: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; MSD: Speakers Bureau. Senderova:Novartis: Consultancy. Turkina:Novartis Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Abstract The protein-tyrosine-phosphatase (PTPase) SHP-1 is expressed almost exclusively in hematopoetic cells. Most growth factor receptors rely on the Jak/Stat pathway for intracellular transduction, to drive specific gene expression which are involved in cell proliferation and differentiation. Abnormal signaling in some of these pathways has been linked to hematopoietic malignancies, like the ALL tel-Jak2 gene fusion. In some other cases activation is mediated by kinases not normally associated with Stats, like abl. Recently several authors have linked dysregulation of PTPases, especially SHP-1, to non-Hodgkin lymphoma, familial polycythemia, chronic neutropenia and AML. There are no reports on expression of SHP-1 in myelodysplastic syndromes. Here we hypothesize that SHP-1 downregulation may play a role in the leukemic transformation of myelodysplastic syndromes and may impact survival. Retrospectively, from January 1990 to January 2004, we studied 45 patients (29 men, 16 women; median age 70 yrs) with myelodysplastic syndromes (5 RA, 3 RAS, 3 RCMD, 9 RAEB-I, 11 RAEB-II, 2 5q-, 2 Unclass, 3 AML, 6 SMDS). Bone marrow biopsies were examined from each patient. 5 μm sections were dewaxed, heated for antigen retrieval in sodium citrate buffer, and immunostained by routine methods. Antibodies against SHP-1 and Jak-2p were purchased from Santa Cruz Biotechnology (Santa Cruz, CA) and Cell Signaling (Beverly, MA) respectively. SHP-1 and Jak-2p expression were evaluated on bone marrow samples as a percentage of positive cells. A percentage between 33 and 66 was considered normal for SHP-1 expression. Jak-2p positivity was defined as normal, if less or equal to 50 % of cells stained positively. Ranges of normal values were derived from healthy controls. With a median follow-up of 65 months, 13 (28%) showed disease progression, 9 of them towards AML. Median OS and EFS were 15 and 12 months respectively. 25 patients have died, mostly of disease related complications. The U-Mann-Whitney test comparing means between patients that progressed and those that did not was only significant (p<0.05) for hemoglobin and erythropoietin levels at diagnosis. A χ2 test failed to detect any qualitative variable at diagnosis associated with progression: only number of platelets and erythroid dysplasia approached statistical significance. Kaplan-Meier analysis showed that TTP was significantly shorter among those with less cytopenias (p=0.023) and previous history of radiation and/or chemotherapy (p=0.034). Overall survival was also worse among those with previous history of radiation and/or chemotherapy (p=0.009), high risk cytogenetics according to IPSS (p<0.001), lower expression of SHP-1 (p=0.03) or a combination of higher expression of Jak-2p plus lower expression of SHP-1 (p=0.0517). Interestingly none of the commonly accepted prognostic methods for MDS (IPSS, FAB or WHO) showed statistical significance in OS in this analysis. In conclusion, immunostaining of SHP-1 of bone marrow biopsies at diagnosis may be a new prognostic marker for MDS patients.

Background: Out of the total number of patients admitted in coronary care unit (CCU) with acute coronary syndrome (ACS), 75 - 85% presented with conventional risk factors. On the other hand, lipid profile modification after a cardiovascular event related to acute coronary syndrome has also been recognized. But there are controversies regarding the temporary changes in lipid profile after ACS. In our country, there are limited studies about the basal characteristics of lipid profile and the variability of its components after an ACS.Objectives: 1) To analyze the changes in lipoprotein levels in a group of patients hospitalized with ACS. 2) To describe the basal lipid profile. 3) To find out the prevalence of conventional risk factors of ACS patients.Methods: A total of 300 patients with the diagnosis of ACS were studied and the presence of conventional risk factors including smoking, hypertension, dyslipidemia and diabetes were recorded. In addition, we also analyzed the lipid profile within the first 24 hours of admission and body mass index (BMI) of all the patients included in the study.Results: Among a total of 300 patients, the mean age of men was 45 – 75 years and women 50 – 65 years. There were 47.5% patients with non-STEMI and 52.5% with ST-elevated myocardial infaraction (STEMI). In patients with BMI <24, 23.9% were males and 32.2% females; in patients with BMI 25 - 29, 55.4% were males and 48.7% females and in patients with BMI >30, 20.7% were males and 19.1% females. Among the study population, prior myocardial infaraction (MI) was seen in 29%, prior CABG in 4.2% and 10.5% had family history of CAD. In this study, diabetes and dyslipidemia were more in STEMI whereas dyslipidemia was common in non-STEMI. Among the conventional risk factors, smoking and hypertension were more common in STEMI in both men and women.Conclusions: In all patients admitted in CCU, basal lipid profile should be evaluated at the time of admission for choosing the most adequate treatment.Journal of Gandaki Medical College Volume, 09, Number 2, July December 2016, page: 13-16

Objective: to characterize the clinical and laboratory parameters of patients with HIV infection with newly diagnosed Kaposi’s sarcoma.Materials and methods. The analysis of clinical and laboratory data of 25 HIV-infected patients with newly diagnosed Kaposi’s sarcoma who were treated in the in-patient department of St. Petersburg Center for the Prevention and Control of AIDS and Infectious Diseases in 2009-2017Results. Ninety-two (n=23) patients were men. The median age at detecting HIV infection is 36 years. The manifestation age of Kaposi’s sarcoma is a median of 37 years. Elements of Kaposi’s sarcoma were located mainly on the skin of the lower and upper extremities, trunk, face and oral mucosa. Manifest CMV infection was registered in one patient, candidiasis of various localizations was found in 19 patients (76%), 2 of them also had one case of tuberculosis and toxoplasmosis. The viral load of HIV in the serum of patients upon admission to the hospital ranged from 26 159 to 2 755,549 copies/ml. The number of CD4 lymphocytes in the serum of patients is from 4 to 674 cells/μl. First-line antiretroviral drugs were prescribed to 20 (80%) patients, while the positive dynamics of sarcoma was observed in 8 patients. Four (16%) patients received antitumor treatment. The duration of hospitalization of patients ranged from 8 to 85 days (median 29). Twenty-one patients were discharged from the hospital, death was registered in 4 patients (16%).Conclusion. Characteristics of patients with HIV infection with newly diagnosed Kaposi’s sarcoma are: the predominance of males aged 30-39 years; skin lesions of the limbs and trunk in the debut of the clinical picture of sarcoma; laboratory signs of pronounced immunodeficiency (in 75% of patients, CD4 lymphocytes in the serum are less than 200 cells/μl); high viral load of HIV in serum (in 88% of patients more than 100 000 copies/ml); frequent combination with other opportunistic diseases.

Abstract Abstract 2295 Background: During first-line BCR-ABL inhibitor therapy for CML-CP, concomitant medication use is associated with worse adherence to CML therapy, which may detrimentally affect efficacy (St Charles, ASH 2009; Marin, J Clin Oncol 2010). Medications may include adjuvants to anti-CML therapy or treatments for comorbid conditions. Depending on posology, the number of medications may affect BCR-ABL inhibitor efficacy and safety. Dasatinib is a BCR-ABL inhibitor 325-fold more potent than imatinib at inhibiting BCR-ABL in vitro and is taken once daily (QD) at any time of day with or without food. Medications that prolong QTc, or increase or decrease dasatinib levels (CYP3A4 substrates/inhibitors/inducers, PPIs and H2 antagonists) should be avoided. In the phase 3 DASISION trial, first-line dasatinib 100 mg QD had superior efficacy vs imatinib 400 mg QD in pts with newly diagnosed CML-CP, including significantly higher complete cytogenetic response (CCyR) and major molecular response (MMR) rates. Here, efficacy and safety of dasatinib (and imatinib) by number and type of baseline medications were analyzed. Methods: 519 pts with newly diagnosed CML-CP were randomized to dasatinib 100 mg QD (n=259) or imatinib 400 mg QD (n=260) arms. Exclusion criteria included prior interferon or systemic anti-CML therapy (except anagrelide, hydroxyurea, or ≤28 days of imatinib), and baseline pleural effusion, cardiovascular disease, or bleeding disorder unrelated to CML. Efficacy and safety were assessed using rates of CCyR/MMR or drug-related adverse events (AE), respectively. Baseline medications were defined as any additional medication taken prior to initiating study therapy, as reported by individual investigators. Results: 189/259 pts (73%) in the dasatinib arm and 194/260 pts (75%) in the imatinib arm were receiving ≥1 baseline medication (median 2, range 1–7). Medications taken by ≥5% of pts were prophylactic allopurinol therapy for tumor lysis syndrome (51%); alimentary tract or metabolism therapies, eg, antacids or PPIs (33%: omeprazole 6%, famotidine <1%); nervous system therapies, eg, NSAIDs or other analgesics (22%); cardiovascular therapies, eg, calcium channel blockers, loop diuretics, β blockers, and ACE inhibitors (21%); agents for blood or blood-forming organs, eg, folic acid or statins (15%); systemic antibiotics/antifungals/vaccines (7%); and respiratory system therapies, eg, antihistamines or inhaled steroids (7%). 12-month CCyR and MMR rates were unaffected by the number of baseline medications. Pts in the dasatinib arm receiving 0, 1–3, or ≥4 medications (27%, 56%, and 17%, respectively) had CCyR rates of 79%, 85%, and 87% and MMR rates of 43%, 49%, and 42%, respectively. Pts in the imatinib arm receiving 0, 1–3, or ≥4 medications had CCyR rates of 76%, 70%, and 71% and MMR rates of 35%, 26%, and 23%, respectively. In pts receiving baseline medications, safety was similar irrespective of the number received. Respective grade 3/4 thrombocytopenia rates for pts receiving 0, 1–3, or ≥4 medications were 28%, 17%, and 13% in the dasatinib arm and 9%, 9%, and 17% in the imatinib arm; grade 3/4 neutropenia rates were 29%, 13%, and 31% in the dasatinib arm and 31%, 18%, and 11% in the imatinib arm. Nonhematologic AEs of any grade occurring in ≥10% of pts receiving dasatinib and 0, 1–3, or ≥4 medications, respectively, were diarrhea in 17% vs 19% vs 13% (13% vs 19% vs 17% with imatinib), nausea/vomiting in 12% vs 9% vs 18% (25% vs 23% vs 23% with imatinib), arthralgia/myalgia in 12% vs 10% vs 11% (28% vs 13% vs 14% with imatinib), rash in 6% vs 12% vs 18% (19% vs 16% vs 20% with imatinib), fluid retention in 9% vs 23% vs 24% (41% vs 44% vs 37% with imatinib), pleural effusion in 1% vs 13% vs 13% (0% with imatinib) and superficial edema in 7% vs 8% vs 16% (25% vs 41% vs 31% with imatinib). Efficacy and safety patterns were generally comparable in pts receiving various baseline medication categories. Additional analyses of on-study medication characteristics and effects on efficacy or safety will be presented. Conclusions: Although occurrence of pleural effusion and fluid retention appeared higher in patients receiving ≥1 medication with dasatinib, overall, the number of medications administered at baseline in the DASISION trial did not appear to affect efficacy or safety of dasatinib (or imatinib) in pts with newly diagnosed CML-CP. Disclosures: Guilhot: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Off Label Use: This abstract discusses the use of first-line dasatininb in CML-CP. Kantarjian: Bristol-Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding; Wyeth: Research Funding. Shah: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Ariad: Consultancy. Hochhaus: Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Bradley-Garelik: Bristol-Myers Squibb: Employment. Dejardin: Bristol-Myers Squibb: Employment, Equity Ownership. Cortes: Bristol-Myers Squibb: Research Funding.

Abstract Background: Nilotinib is a novel orally active aminopyrimidine. It is a highly specific Bcr-Abl tyrosine kinase inhibitor (TKI) 30-fold more potent than imatinib. Based on the efficacy and favorable tolerability demonstrated by nilotinib in the phase I study, this phase II open-label study was designed to evaluate the safety and efficacy of nilotinib in adult pts with Ph+ chronic myeloid leukemia in blast crisis (CML-BC) resistant to or intolerant of imatinib. The prognosis for these pts remains poor. Methods: The primary endpoint was confirmed hematologic response (HR). Imatinib resistance was defined as either treatment with imatinib >600 mg/day with disease progression, no HR in bone marrow after 4 weeks, or pts receiving <600 mg/day with mutations in any of the following amino acids: L248, G250, Q252, Y253, E255, T315, F317, or H396. Imatinib intolerance was defined as grade 3/4 adverse events, or grade 2 events persisting for >1 month while on imatinib. Nilotinib therapy was commenced at 400 mg twice daily (BID) with escalation to 600 mg BID for pts who had inadequate responses and no safety concerns. Results: Safety and efficacy data are reported for 135 BC (myeloid, n=103; lymphoid, n=29; unknown, n=3). The median age was 55 (18–79) years, the median time since CML diagnosis was 1.6 (<1–73) months, and 61.5% were men. 82% of the patients were imatinib-resistant and 18% were intolerant. Treatment with nilotinib is ongoing for 16 (12%) pts. The median treatment duration was 84 (3–485) days and the median average dose intensity was 800 mg/day. 119 (88%) pts discontinued treatment, of which 71 (53%) discontinued due to disease progression; 13 (10%) discontinued due to AEs. 38% of pts had >/=95% Ph+ metaphases at study entry. Chromosomal abnormalities other than Ph+ were also noted in 54% of pts at study entry. Extramedullary involvement was present in 39% of the pts. The most common Grade 3/4 hematologic laboratory abnormalities were neutropenia (67%), thrombocytopenia (62%), anemia (42%). The most common Grade 3/4 non- hematologic AEs were as follows: pneumonia (11%), pyrexia (7%), nausea (4%), diarrhea (4%), and asthenia (4%). Conclusions: Based on the CHR rates achieved in this very advanced patient population, nilotinib monotherapy appears to have clinical activity in pts with imatinib-resistant CML BC. Overall nilotinib is well tolerated in this patient population with advanced disease and with non-heme toxicity comparable to that observed for pts with CML-CP. The hematological responses were similar between myeloid and lymphoid Ph+ CML blast crises. Response for Patients With CML-BC With at Least 6 Months of Follow-up Myeloid (N = 103) n (%) Lymphoid (N = 29) n (%) Hematologic response 40 (39) 11 (38) CHR 25 (24) 8 (28) Marrow response 5 (5) 1 (3) Return to chronic phase 10 (10) 2 (7) SD 31 (30) 7 (24) PD 18 (17) 6 (21) Not evaluable 5 (5) 1 (3) Missing 9 (9) 4 (14)

I de fall enskilda aktieägare tillfogas skada, genom organledamots handlande, innehar dessa rättigheten att påkalla skadeståndsansvar enligt 29:1 1 st. 2 men. ABL. I den svenska rättstillämpningen ter sig dock tillämpningen av paragrafen, i samband med indirekta skador, problematisk. Problematiken hänför sig till vilka regler, vars åsidosättande, aktualiserar tillämpningen av paragrafen tillsammans med aktieägares talerätt. Två tolkningar kan i fallet identifieras, vilka framförts inom doktrinen, varvid en begränsad och en mer liberal. Även om den liberala tolkningen är förenad med viss problematik, är denna enligt mitt förmenande den vilken bör tillämpas. En sådan tillämpning skulle således innebära att enskilda aktieägare tillerkänns talerätt vid indirekt skada, då regler vilka ger uttryck för normskyddsläran och bolagsledningens lojalitetsplikt åsidosatts. Rättsutvecklingen har vidare givet upphov till frågan, huruvida en ”indirekt” indirekt skada kan omfattas av paragrafens tillämpningsområde. En sådan skada uppstår särskilt i koncernförhållanden då dotterbolaget tillfogas en direkt skada, vilken därigenom åsamkar aktieägarna i dess moderbolag en ”indirekt” indirekt skada. Skadan faller utanför paragrafens tillämpningsområde, då de skadedrabbade inte utgör aktieägare i dotterbolaget. En lösning enligt mitt förmenande, varigenom paragrafens tillämpning koncernanpassas, är att principen om ansvarsgenombrott i betydelsen genomsyn nyttjas. Principens aktualisering medför att ett moder- och dotterbolag betraktas som en juridisk enhet, om erforderliga rekvisit uppfylls, varigenom de skadedrabbade aktieägarna från ett teoretiskt perspektiv även ses som aktieägare i dotterbolaget. Effekten av principens tillämpning är sålunda att en ”indirekt” indirekt skada faller inom paragrafens tillämpningsområde.
Whenever individual shareholders inflict an injury, due to action taken by a corporate member, they possess the right to impose liability in accordance with 29:1 1 st. 2 men. ABL. The paragraph is though associated with some difficulties when it comes to an indirect injury. The difficulties regard which rules that have to be infringed, in order for the paragraph to be applicable and thereby providing shareholders with the right to sue. Two different interpretations can hereby be identified, whereby one limited and the other one more liberal. Even if the liberal interpretation is associated with some difficulties, I find that this one should be applied. Such an application would mean that an individual shareholder acquire the right to sue, for an indirect injury, when rules protecting a third person and the corporate member’s duty of loyalty have been infringed. Legal progress has also given rise to another question, whether an “indirect” indirect injury falls within the paragraphs application. Such an injury is mostly affiliated with corporate groups where the daughter company causes a direct injury, whereby the shareholders in the mother company causes an “indirect” indirect injury. Since the shareholder here is not an owner of the daughter company, the paragraph could not be applied. A solution to this problem is, according to me, an application of the principle piercing the corporate veil, whereby the paragraphs application extends to corporate groups. The effect of the principles application is that a mother- and daughter company becomes one legal entity, if the prerequisites are fulfilled. The outcome is hereby that a shareholder in the mother company, from a theoretical perspective, also is regarded to be an owner of the daughter company. Wherefore an “indirect” indirect injury hereby falls within the scope of the paragraphs application.

Defibrotide was able to prevent the hemodynamic and biochemical alterations caused by acute myocardial ischemia (AMI) induced by coronary occlusion in the cat when infused 3.5 h before and 5 h after left anterior descending coronary artery (LAD) occlusion. In the platelet perfused heart, Defibrotide was a selective stimulator of coronary vascular PGI^ but not of platelet thromboxane formation. The present study was designed both to investigate the effects of Defibrotide injected 30 min after the induction of acute myocardial ischemia (AMI) in the cat and to evaluate the ability of this drug to reduce infarct size. In the first set of experiments a permanent ligature (5 hours) was placed around LAD. ST segment from ECG, mean aortic pressure (MAP), heart rate (HR) and the pressure-heart rate index (PRI) were considered. Plasma and tissue creatine phosphckinase activity (CFK), tissue lactate and ATP were measured by enzymatic kits from Boehringer Biochemia. 30 min after coronary occlusion a loading dose of Defibrotide (32 ng Kg-1 ) was administered i.v. immediately followed by an infusion (32 ng Kg-1 h 4.5 h-1) MAP, HR and PRI were not modified either by AMI or by the infusion of Defibrotide. AMI-ST segment increases were reduced by Defibrotide from 0.5 h after the beginning of the treatment (—49% vs. AMI control) to the and of experiments (-83% vs. AMI control after 5 h occlusion period). Plasma CFK was reduced from 2.5 h after the beginning of the treatment (-29%) till the end of experiments (-52%). Ischemic tissue CFK, lactate and ATP were normalized by Defibrotide. In the second set of experiments the animals were infused with Defibrotide (50 or 200 mg Kg-1 h-1 , i.v.) starting 2 hours before coronary ligature. The infusion was maintained throughout the 5 h occlusion period. The risk and infarct areas were measured by Evans blu and nitroblue tetrazoliun staining. The 51 ± 3% of risk area was infarcted in AMI control cats. Defibrotide at the two tested doses significantly reduced these infarct areas to 42 ± 4% and 34 ± 2% of risk areas respectively. The beneficial effects of Defibrotide observed in AMI could be attributed both to its ability to enhance PGI2 release from vascular walls and to improved local tissue oxygenation and energy supplies. However it could be taken into account a direct cytoprotective action.