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1
Mafficini, Andrea, Rita T. Lawlor, Claudio Ghimenton, Davide Antonello, Cinzia Cantù, Gaetano Paolino, Alessia Nottegar, et al. "Solid Pseudopapillary Neoplasm of the Pancreas and Abdominal Desmoid Tumor in a Patient Carrying Two Different BRCA2 Germline Mutations: New Horizons from Tumor Molecular Profiling." Genes 12, no. 4 (March 26, 2021): 481. http://dx.doi.org/10.3390/genes12040481.
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This case report describes the history of a 41 year-old woman with a solid pseudopapillary neoplasm (SPN) of the pancreas and a metachronous abdominal desmoid tumor (DT) that occurred two years after the SPN surgical resection. At next-generation sequencing of 174 cancer-related genes, both neoplasms harbored a CTNNB1 somatic mutation which was different in each tumor. Moreover, two BRCA2 pathogenic mutations were found in both tumors, confirmed as germline by the sequencing of normal tissue. The BRCA2 mutations were c.631G>A, resulting in the amino-acid change p.V211I, and c.7008-2A>T, causing a splice acceptor site loss. However, as the two neoplasms showed neither loss of heterozygosity nor somatic mutation in the second BRCA2 allele, they cannot be considered as BRCA-dependent tumors. Nevertheless, this study highlights the important opportunities opened by extensive tumor molecular profiling. In this particular case, it permitted the detection of BRCA2-germline mutations, essential for addressing the necessary BRCA-related genetic counseling, surveillance, and screening for the patient and her family.
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Jadhav, N. C., and D. L. Gang. "Multifocal Pancreatic Neuroendocrine Neoplasms In Tuberous Sclerosis: A Rare Case." American Journal of Clinical Pathology 154, Supplement_1 (October 2020): S77. http://dx.doi.org/10.1093/ajcp/aqaa161.168.
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Abstract Casestudy: Pancreatic neuroendocrine neoplasms (PanNEN) are rare accounting for 2-5% of pancreatic tumors. Although mostly sporadic, 10-20% are associated with inherited syndromes, notably MEN-1, Von Hippel- Lindau disease, neurofibromatosis type 1, and tuberous sclerosis (TS). When compared to sporadic cases, PanNEN in hereditary syndromes occur at a younger age, are often multifocal, cystic, and may show characteristic microscopic patterns. TS is an autosomal dominant multi-system disorder with mutations involving TSC1 or TSC2 genes which function as tumor suppressors by inhibiting mTORC1 kinase. PanNEN is observed in 1.5-1.8% of patients with TS and no surveillance guidelines for the assessment of pancreatic lesions are established. Compared to other syndromes, PanNEN associated with TS are solitary. To our knowledge, only two cases of multifocal PanNEN in TS patients have been reported. We present a case of a 67-year-old gentleman with a history of TS also affecting two daughters. He presented to the emergency department with severe abdominal pain. Abdominal ultrasound suggested acute appendicitis and an incidental 2.0 cm solid lesion was noted in the head of the pancreas. Follow-up MRI revealed two additional non-cystic masses in the pancreatic tail. Endoscopic ultrasound-guided biopsy of a tail lesion revealed monomorphic tumor cells with stippled chromatin without cytologic atypia. Immunohistochemical staining was positive for synaptophysin and chromogranin. Ki-67 labelling index was under 1%. Diagnosis of a well-differentiated neuroendocrine tumor (G1) was made. The patient denied symptoms of the carcinoid syndrome and no biologically active hormones were detected. Gallium PET scan revealed multiple foci of radiotracer uptake throughout the pancreas in addition to those described on MRI. Although PanNEN are rare in TS, malignant behavior has been reported. This case reinforces the importance of early detection through active surveillance, especially as surgical options may be limited in multifocal disease.
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Tulpule, Sunil, Hiyam Ibrahim, Mohamed Osman, Shoaib Zafar, Romana Kanta, Gregory Shypula, Mohammed A. Islam, Shuvendu Sen, and Abdalla Yousif. "Muir-Torre Syndrome Presenting as Sebaceous Adenocarcinoma and Invasive MSH6-Positive Colorectal Adenocarcinoma." Case Reports in Oncology 9, no. 1 (February 4, 2016): 95–99. http://dx.doi.org/10.1159/000443788.
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Muir-Torre syndrome (MTS) is a rare genodermatosis, diagnosed by the presence of sebaceous neoplasms along with an internal malignancy, most commonly colorectal carcinomas. MTS is most commonly caused by microsatellite instabilities of the hMLH1 and hMSH2 mismatch repair genes, and is rarely caused by mutations of the hMSH6 gene. We describe the case of a 56-year-old male who presented with an enlarging mass on his back as well as hematochezia. The back mass was excised, and pathology confirmed microsatellite instability in MSH2 and MSH6. Abdominal CT and colonoscopy confirmed the presence of synchronous masses in the cecum, ascending colon, and the transverse colon. He refused any further workup or treatment, only to return 8 months later complaining of hematochezia and discomfort due to an enlarging mass protruding from the rectum. After consenting to surgical intervention, he agreed to outpatient chemotherapy treatment. The presence of sebaceous neoplasms should raise suspicion for the possibility of an associated internal malignancy.
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Al-Saleem, Tahseen, and Hamid Al-Mondhiry. "Immunoproliferative small intestinal disease (IPSID): a model for mature B-cell neoplasms." Blood 105, no. 6 (March 15, 2005): 2274–80. http://dx.doi.org/10.1182/blood-2004-07-2755.
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AbstractImmunoproliferative small intestinal disease (IPSID) was recently added to the growing list of infectious pathogen-associated human lymphomas. Molecular and immunohistochemical studies demonstrated an association with Campylobacter jejuni. IPSID is a variant of the B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), which involves mainly the proximal small intestine resulting in malabsorption, diarrhea, and abdominal pain. Geographically, IPSID is most prevalent in the Middle East and Africa. IPSID lymphomas reveal excessive plasma cell differentiation and produce truncated α heavy chain proteins lacking the light chains as well as the first constant domain. The corresponding mRNA lacks the variable heavy chain (VH) and the constant heavy chain 1 (CH1) sequences and contains deletions as well as insertions of unknown origin. The encoding gene sequence reveals a deletion of V region and parts of CH1 domain. Cytogenetic studies demonstrated clonal rearrangements involving predominantly the heavy and light chain genes, including t(9;14) translocation involving the PAX5 gene. Early-stage IPSID responds to antibiotics (30%-70% complete remission). Most untreated IPSID patients progress to lymphoplasmacytic and immunoblastic lymphoma invading the intestinal wall and mesenteric lymph nodes, and may metastasize to a distant organ. IPSID lymphoma shares clinical, morphologic, and molecular features with MALT lymphoma, lymphoplasmacytic lymphoma, and plasma cell neoplasms.
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Thao Hoang, Phuong, Tsay Eric, John Mace, and Eba Hathout. "Congenital Adrenocortical Tumor in an Asymptomatic Neonate with Positive Newborn Screen for Congenital Adrenal Hyperplasia: A Case Report." International Journal of Integrative Pediatrics and Environmental Medicine 3 (February 14, 2017): 1–4. http://dx.doi.org/10.36013/ijipem.v3i0.30.
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Adrenocortical tumors (ACTs) are rare in childhood, particularly in the neonatal period. ACTs in children usually secrete hormones that can cause virilization, precocious puberty, or Cushing syndrome. However, in many cases the diagnosis is delayed because of the generally healthy appearance of the child and the lack of a palpable abdominal mass. ACTs can also be misdiagnosed as congenital adrenal hyperplasia (CAH) especially if 17-hydroxyprogesterone (17-OHP) is elevated. We describe a case of neonatal ACT diagnosed in an asymptomatic newborn with positive/elevated 17-OHP on newborn screening. On examination there were no signs of virilization, Cushing syndrome, hemihypertrophy, or hypertension, and there was no palpable abdominal mass. While awaiting confirmatory results of an elevated 17-OHP level, an abnormally low adrenocorticotropic hormone level was noted. Abdominal ultrasound, obtained to evaluate the adrenal glands, showed a right adrenal mass with peripheral calcification. MRI revealed a 3.6 x 3.5 x 3.4 cm heterogeneously enhancing ovoid mass in the right adrenal gland. Diagnosis of an ACT was also confirmed by laboratory data, and histopathology of the tumor. Surgical resection was safely performed with perioperative steroid replacement. Genetic analysis of CYP21A2 and CYP11B1 genes was negative. A germ-line point mutation in the TP53 region was discovered, suggesting Li-Fraumeni syndrome. ACTs should be considered in the differential diagnosis of neonates with elevated 17-OHP detected by newborn screening for CAH. Adrenal ultrasound is recommended in cases of significantly abnormal CAH screen results to rule out or treat adrenal neoplasms.
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Gao, Limin, Weiping Liu, Wenyan Zhang, Sha Zhao, Yueqiang Song, Jinwei Hu, Kai Wang, and Haiyan Wu. "Clinicopathology, Disease Progression/Transformation and Genomic Alterations of Indolent T-Cell Lymphoproliferative Disorder of the Gastrointestinal Tract." Blood 136, Supplement 1 (November 5, 2020): 36. http://dx.doi.org/10.1182/blood-2020-139080.
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Introduction: Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract (ITCLD-GT) is a newly recognized entity in the 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms. ITCLD-GT is defined as a clonal T-cell proliferation occurring in the GT, mostly in colon and small bowel. So far only 52 ITCLD-GT cases have been reported. It has a pathologically nondestructive expansionary growth pattern, a less than 10% Ki67 proliferative index and an indolent clinical course. However, the pathological characteristics of ITCLD-GT in lesions except the small and large intestines, its clinical progress/transformation and pathogenetic mechanisms and molecular alterations remain unknown. Methods: Nine ITCLD-GT cases were collected from one center in southwest China, and their clinicopathological were analyzed. Of these patients, 7 had indolent clinical courses; one had lymph node metastasis in the late stage; and another one transformed into diffuse large B-cell lymphoma (DLBCL) after 16 months (Figure A). In one patient, neoplastic cells involved most of the digestive tract from esophagus to rectum. Whole-exome sequencing was performed in 9 samples from 7 cases. Genome-wide mutation landscape was analysed on these ITCLD-GT samples and pairwise comparison was made between stomach and colon lesions as well as between ITCLD-GT and transformed DLBCL samples. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed. Results: The median age of the patients was 47 years, and the male/female ratio was 7:2. Clinically, these patients presented with diarrhea with or without abdominal pain, abdominal distension, fatigue or hematochezia. Colonoscopy showed thickened intestinal mucosa in 8 cases, with small nodularity and folds in 7 cases and polyps resembling in 1 case. Intestinal mucosa surfaces showed patchy erythema, erosion or superficial ulcer with diameter ≥ 2.5cm. Endoscopy showed thickened gastric mucosa, nodular protrusion or multiple wide pedicle polyps. Microscopically, the lamina propria was displaced by the infiltrate of dense, monotonous and small lymphocytes, but the mucosal glands were not destroyed. All the infiltrated lymphocytes were positive for CD3p and TIA-1, mostly positive for CD2, CD5 and CD7 and negative for CD20 and Granzyme B. 8 cases were positive for CD8 and 1 case expressed CD4. In the case with esophagus and GT involvement, CD56 was positive in gastric and intestinal lesions, but negative in esophageal and colon. The proliferative index of Ki67 was less than 10% in all cases at diagnosis, but in one case it increased to 20% after 4 years (Figure B). In all cases, monoclonal TCR gene rearrangement was positive and EBER1/2 was negative. The landscape of gene alterations using WES in these patients were analysed (Figure C). The recurrent mutated genes included cancer-related gene PDE4DIP, transcription regulatory genes BAZ2B and CNOT6L, signaling transduction-related genes MUC17 and PIEZO2, metabolism regulatory genes PLA2G4D and FRG2C, cytoskeleton and cell adhesion-associated genes COL14A1, DNAH5 and many other genes were shown in Figure C. GO analysis showed that mutated genes were significantly enriched in microtubule cytoskeleton organization. KEGG pathway analysis indicated that the mutated genes were mostly enriched in focal adhesion and ECM-receptor interaction, both associated with cancer development. Pairwise comparison analysis of lesions from the stomach and colon showed that there was almost no genetic difference between the two lesions. JAK3, NRAS and SETD2 mutations and BCOR deletion may contribute to the entire digestive tract distribution of ITCLD-GT. The transformed aggressive DLBCL sample carried 253 more mutated genes than the indolent ITCLD-GT sample. Mutations of TP53, ARID1A, KMT2D and M2P2K1 only in the DLBCL sample may contribute to the transformation of ITCLD-GT to DLBCL. Conclusion: Our study summarized the clinicopathological characterization of 9 cases of ITCLD-GT. ITCLD-GT is generally inert, but it may develop with an increased Ki67 proliferation index in the late stage or even turn into aggressive DLBCL. We characterized the genomic alterations in ITCLD-GT and revealed its molecular pathogenesis and progression, which might be helpful for diagnosis, prognosis and treatment of this rare lymphoid neoplasm. Figure 1 Disclosures No relevant conflicts of interest to declare.
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Zapater, Andrea, Fernando Santamaria-Martos, Adriano Targa, Lucía Pinilla, Alicia Sánchez-de-la-Torre, Iván David Benítez, Miguel Ángel Martínez-García, Ferran Barbé, and Manuel Sánchez-de-la-Torre. "Canonical Pathways Associated with Blood Pressure Response to Sleep Apnea Treatment: A Post Hoc Analysis." Respiration 100, no. 4 (2021): 298–307. http://dx.doi.org/10.1159/000511963.
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<b><i>Background:</i></b> Several studies have reported an association between microRNAs (miRNAs) and hypertension or cardiovascular disease (CVD). In a previous study performed on a group of 38 patients, we observed a cluster of 3 miRNAs (miR-378a-3p, miR-100-5p, and miR-486-5p) that were functionally associated with the cardiovascular system that predicted a favorable blood pressure (BP) response to continuous positive airway pressure (CPAP) treatment in patients with resistant hypertension (RH) and obstructive sleep apnea (OSA) (HIPARCO score). However, little is known regarding the molecular mechanisms underlying this phenomenon. <b><i>Objectives:</i></b> The aim of the study was to perform a post hoc analysis to investigate the genes, functions, and pathways related to the previously found HIPARCO score miRNAs. <b><i>Methods:</i></b> We performed an enrichment analysis using Ingenuity pathway analysis. The genes potentially associated with the miRNAs were filtered based on their confidence level. Particularly for CVD, only the genes regulated by at least 2 of the miRNAs were studied. <b><i>Results:</i></b> We observed that the miRNAs studied regulate 200–249 molecules associated with several functions and diseases, including extracranial solid tumors and abdominal neoplasms, among others. The cardiac hypertrophy and NF-kB signaling pathways were identified as the cardiovascular pathways most influenced by these 3 miRNAs. <b><i>Conclusions:</i></b> The mechanisms by which CPAP treatment decreases the BP in OSA patients with RH could be related to the cardiac hypertrophy and NF-kB signaling pathways. Further investigations will be necessary to confirm these findings, contributing to the elucidation of new therapeutic targets in patients who do not respond to CPAP treatment.
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Baughn, Linda B., Scott Gilles, Elizabeth L. Courville, Andrew C. Nelson, and Zohar Sachs. "Germline Calr Mutation and Thrombocytosis Presenting with Concomitant BCR-ABL1+ CML." Blood 128, no. 22 (December 2, 2016): 5494. http://dx.doi.org/10.1182/blood.v128.22.5494.5494.
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Abstract CALR mutations are present in 70-84% of JAK2 wild-type myeloproliferative neoplasms (MPN) and 67% and 88% of essential thrombocytopenia (ET) and primary myelofibrosis (PMF) respectively. Most cases of MPN are apparently sporadic, but 7-11% have evidence of familial predisposition. While germline mutations in ET-associated genes, MPL and JAK2, have been described in hereditary thrombocytosis, germline mutations in CALR have not been described in any setting. Two types of CALR mutations are common in MPN: a 52-base pair deletion (bp) and a 5 bp insertion, both in exon 9. With rare exceptions, CALR mutations are generally mutually exclusive with JAK2 or MPL mutations and have very rarely been reported in conjunction with the BCR-ABL1translocation. Here, we report a patient with a germline CALR mutation, thrombocytosis, and subsequent development of BCR-ABL+ CML. A 67-year-old female with no significant medical history presented with severe abdominal pain and nausea. Peripheral blood analysis revealed a marked leukocytosis composed of 66% neutrophils, 16% myelocytes, 6.5% monocytes, 3.5% basophils, 2.5% promyelocytes, 2.5% metamyelocytes, 1.5% lymphocytes, 1.5% blasts, and no eosinophils. The patient was non-anemic and had a normal platelet count (340,000/mm3). Bone marrow biopsy revealed a hypercellular marrow with myeloid predominant trilineage hematopoiesis and 1-2% blasts with morphology consistent with chronic myelogenous leukemia (CML). Fluorescence in-situ hybridization analysis of peripheral blood identified a BCR-ABL1fusion in 98.5% of interphase cells. After 3 months of standard imatinib therapy, quantitative RT-PCR showed a reduction of BCR-ABL1/ABL1 in the peripheral blood, however platelet count was elevated at 539,000/mm3. Thrombocytosis persisted over 2 years with a maximal platelet count of 584,000/mm3. Given the patient's thrombocytosis, her peripheral blood was subjected to a next generation sequencing of JAK2, MPL, and CALR genes. A 52-bp out-of-frame deletion in exon 9 of the CALR gene was detected (52% allele frequency) in peripheral blood. In addition, the same 52-bp CALR deletion (63% allele frequency) was present at the time of diagnosis and within a buccal specimen (47% allele frequency) when the BCR-ABL1 transcript was 1% in the peripheral blood. Immunostain of the buccal sample was strongly positive for cytokeratin (CK) AE1/AE3 but CD45 was not detected indicating no leukocyte contamination. This case reports the first instance of a germline CALR mutation associated with thrombocytosis and is the fourth report of the co-occurrence of BCR-ABL1 and CALR mutation in a single patient. Evolution to BCR-ABL1+ CML suppressed the CALR-mutant thrombocytosis phenotype, emphasizing the effect of these genes on lineage determination in abnormal myeloid proliferation. Disclosures No relevant conflicts of interest to declare.
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Herrera-Goepfert, Roberto. "Postradiation Synovial Sarcoma of the Common Bile Duct: A Previously Unreported Anatomic Site." International Journal of Surgical Pathology 26, no. 5 (January 16, 2018): 469–74. http://dx.doi.org/10.1177/1066896917752863.
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Synovial sarcoma is a ubiquitous neoplasm predominantly affecting soft tissues of young adults of any gender; few cases have been described in the digestive system, mostly in the stomach. The (X;18)(p11.2; q11.2) translocation yields unique SS18-SSX fusion genes. Synovial sarcoma has been related to radiotherapy, but no synovial sarcoma has been associated with the digestive system. This article describes the case of a synovial sarcoma arising along the extrahepatic biliary tree, 10 years after the application of an abdominal radiotherapy schedule due to a retroperitoneal metastatic seminoma in a male who developed progressive obstructive jaundice. Ninety percent of the analyzed cells carried the SS18 gene with separation of sequences, thus denoting a translocation. There are only 8 post-radiotherapy synovial sarcomas that have been reported previously, and this is the first report of a radiotherapy-related synovial sarcoma arising from the extrahepatic biliary tree, and the second case described in this anatomic region.
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Martins, Rute, and Maria João Bugalho. "Paragangliomas/Pheochromocytomas: Clinically Oriented Genetic Testing." International Journal of Endocrinology 2014 (2014): 1–14. http://dx.doi.org/10.1155/2014/794187.
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Paragangliomas are rare neuroendocrine tumors that arise in the sympathetic or parasympathetic nervous system. Sympathetic paragangliomas are mainly found in the adrenal medulla (designated pheochromocytomas) but may also have a thoracic, abdominal, or pelvic localization. Parasympathetic paragangliomas are generally located at the head or neck. Knowledge concerning the familial forms of paragangliomas has greatly improved in recent years. Additionally to the genes involved in the classical syndromic forms:VHLgene (von Hippel-Lindau),RETgene (Multiple Endocrine Neoplasia type 2), andNF1gene (Neurofibromatosis type 1), 10 novel genes have so far been implicated in the occurrence of paragangliomas/pheochromocytomas:SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, EGLN1, HIF2A,andKIF1B. It is currently accepted that about 35% of the paragangliomas cases are due to germline mutations in one of these genes. Furthermore, somatic mutations ofRET, VHL, NF1, MAX, HIF2A,andH-RAScan also be detected. The identification of the mutation responsible for the paraganglioma/pheochromocytoma phenotype in a patient may be crucial in determining the treatment and allowing specific follow-up guidelines, ultimately leading to a better prognosis. Herein, we summarize the most relevant aspects regarding the genetics and clinical aspects of the syndromic and nonsyndromic forms of pheochromocytoma/paraganglioma aiming to provide an algorithm for genetic testing.
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Visconte, Valeria, Vera Adema, Anand D. Tiwari, Cassandra M. Kerr, Hassan Awada, Bartlomiej Przychodzen, Allison Noe, et al. "Pharmacologic Normalization of Altered Transcriptome of SF3B1 Mutant Myeloid Neoplasia." Blood 134, Supplement_1 (November 13, 2019): 564. http://dx.doi.org/10.1182/blood-2019-129189.
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SF3B1 mutations disrupt normal pre-mRNA splicing to cause disease. Drugs inhibiting the interaction between the SF3b complex and RNA or agents degrading auxiliary splicing factors are being tested as new avenues for targeted therapy in myeloid neoplasia (MN) with SF3B1 mutations. Here we describe the ability of small molecules to restore altered RNA processes in SF3B1MT MN. We previously reported (Visconte, ASH 2018) the identification of the small molecule 4-pyridyl-2-anilinothiazole (PAT) which showed growth inhibition of CRISPR/Cas9 SF3B1+/K700E cells and primary SF3B1MT cells. PAT did not influence the growth of other cell models without (THP1, MOLM13FLT3, OCIAML3DNMT3A, SIGM5TET2/DNMT3A, K562PHF6) and with other splicing factor mutations (K562U2AF1, K562LUC7L2). We now describe data from medicinal chemistry, transcriptome, and in vivo studies to advance drug development for SF3B1MT MN. SAR studies focused on logical and systematic modifications of PAT, e.g., i) replacement of the 2,4-disubstituted thiazole spacer ring with other heteroatom containing rings (5,6,7 membered aromatic or aliphatic ring structures); ii) alternative linking groups for the NH linker of the aniline of the tail region (sulfonamide, amide, substituted amine linkers); iii) alternative substituted aromatic and aliphatic ring structures for the phenyl head region substituent, led us to identify permissive sites for further chemical optimization. For example, a 4-chlorophenyl analog demonstrated activity [IC50, 3μM] similar to PAT. Competitive repopulation assays of bone marrow (BM) cells from dual reporters (ACTBtdTomato; EGFP) B6.GtROSA26 mixed with BM cells from conditional knock-in Sf3b1+/K700E mice injected in pre-lethally irradiated B6.SJL-PtprcaPepcb/BoyJ (CD45.1) recipients (n=18) were used as a preclinical murine model. This model then allowed i) demonstration of drug efficacy in reducing the competitiveness of SF3B1MT cells and ii) evaluation of therapeutic index in normal hematopoiesis. Post-transplant recovery, recipients of B6.GtROSA26 cells underwent PAT treatment (10 mg/Kg/IP/5 days weekly) for a period of 6 weeks without showing any signs of distress or drug intolerance (drop in blood count, weight loss, abdominal swelling, liver or kidney toxicity). Two weeks after transplantation, donor Sf3b1+/K700E cells had an engraftment capability similar to that of donor B6.GtROSA26 cells (83.6 ± 4 vs. 86.4 ± 2.4) when transplanted as a sole graft in CD45.1 recipients. PAT reduced almost half the percentage of Sf3b1+/K700E donor cells at 6 weeks of treatment (47.4%) vs. pre-treatment (83.6%). In mixed (1:1) BM transplants, Sf3b1+/K700E cellshad a repopulative disadvantage against competitors B6.GtROSA26 contributing for 16% of the marrow reconstitution. Similar to single graft transplants, PAT decreased the percentage of Sf3b1+/K700E cells at 6 weeks vs. pre-treatment (average, 6% vs. 16%) in chimeras. Consistent with the lack of toxicity of PAT treatment B6.GtROSA26 cells in chimeras were not affected by PAT and gradually repopulated the host (post-treatment, 80% vs. pre-treatment, 64%). Subsequently, we focused our efforts identifying important genes known to be dysregulated in MDS that were mostly influenced by drug treatment and minimally affected in normal cells. Our approach was based on the analyses of genes linked to erythropoiesis (a key hallmark of low-risk MDS). In normal hematopoiesis TGF-β signaling inhibits terminal erythroid maturation. Out of 13,775 genes, 5% (664/13,775) were found differentially expressed between CRISPR/Cas9 SF3B1+/K700E and parental cells of which 60% of these genes were significantly up-regulated and 40% down-regulated. Pathway analysis showed that the expression levels of SMAD family of genes and GDF factors changed significantly upon drug treatment. SMAD7 mRNA levels are 3-fold lower in MDS CD34+ cells (n=159) compared to the ones of healthy subjects (n=17) (GEO accession GSE58831) leading to TGF-β over activation. PAT treatment normalized SMAD7 expression levels in CRISPR/Cas9 SF3B1+/K700E cells by 3-fold while reducing the levels of GDF11. In summary, we have identified new drug entities that are modulators of transcriptomic changes which decrease the competitiveness of SF3B1MT cells. These results suggest combination therapies with current TGF-β pathway inhibitors. Disclosures Advani: Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding. Kelly:Novartis, Bayer, Janssen, Pharmacyclics, Celgene, Astrazeneca, Seattle Genetics: Honoraria, Speakers Bureau; Takeda: Research Funding; Genentech, Verastem: Consultancy. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Novartis: Consultancy; Alexion: Consultancy.
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Dias, Daniela Ferreira, Marcelo Bellesso, Rodrigo Santucci, Renata Campos Elias, Veronica Ramos Oliveira, Renato Centrone, and Adelson Alves. "Myeloproliferative Neoplasm with BCR-JAK2 Fusion Gene As the Result of t(9;22)(p24,11.2) in a Brazilian Patient." Blood 120, no. 21 (November 16, 2012): 4808. http://dx.doi.org/10.1182/blood.v120.21.4808.4808.
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Abstract Abstract 4808 Introduction Chronic Myeloid Leukemia (CML) is the most well described disease result of t(9;22)(q34,q11.2). This chromosomal rearrangement leads to well-know BCR-ABL fusion that promotes tyrosine kinase activity. There are others oncogenic BCR fusion found such as PDGFRA (4q12), FGFR1(8p12) that causes myeloproliferative disorders (MD). JAK2 gene is one of the 4 genes members of JAK family. The JAK2 V617F mutation which results from a G –>T transversion at nucleotide 1849 in exon 14 of the JAK2 gene, the consequence of which is substitution of valine by phenylalanine at codon 617 is associated with MD and it is a major diagnosis criterion for Primary Myeloficrosis, Polycythaemia vera and Essential thrombocytemia. There are described a lot chromosomal translocations involving the JAK2 locus. We report an extremely rare case with BCR-JAK2 fusion gene as the result of t(9;22)(p24,q11.2) for the first time in Brazilian people, and it is the 6thcase all of the world. Case Report In April 2010, a 54 years old male patient presented fatigue, abdominal pain and splenomegaly. A blood count revealed leukocytosis 93.380/mm3 with a predominance of neutrophils and left shift. Conventional cytogenetic analysis was performed and it was evidenced 46,XY, t(9;22)(p24;q11.2) in 90% metaphases examined, due to expected association it was promoted BCR-ABL1 fusion gene and it was not detected by using RT-PCR. He was treated with imatinib 400mg/day because the involvement of BCR gene. After three months he presented weight loss, progressive splenomegaly without hematologic response and it was modified to Dasatinib 150mg/day plus hydroxyureia 3g/day. In August 2011, due to not hematologic response, it was stopped Dasatinib treatment and nowadays patient has been treating with hydroxyureia 1.5g/day. His last follow up in May 2012, blood count was abnormal Hb 16.8g/dl leukocytes 7730/mm3 and low platelets count 32.000/mm3. The differential count showed 65.3% segmented granulocytes, 13.6% eosinophlis, 1.6% basophil, 2.6% monocytes, 16.9% lymphocytes. It was repeated conventional Karyotyping and it was evidenced 46,XY, t(9;22)(p24;q11.2) in all of metaphases examined. The presence of BCR-ABL rearrangement was excluded by using the fluorescence in situ hybridization (FISH) using a BCR-ABL probe. In addition, it was not evidenced FIP1L1-PDGFRa fusion gene and JAK2 V617F mutation by using RT-PCR. Discussion We have described a male patient with MD with t(9;22)(p24;q11.2) wich leads to the BCR-JAK2 fusion and it was not evidenced BCR-ABL1, FIP1L1-PDGFRa fusion genes and JAK2 V617F mutation by using RT-PCR. Moreover, patient has not been achieved hematologic response with tyrosine kinase inhibitors: imatinib and dasatinib. In the five cases reported three presented MD, one Acute Myeloid Leukemia and one Acute Lymphoblastic Leukemia. Only in one case report it was prescribed imatinib and the patient lost the follow up (Table1). The BCR-JAK2 fusion protein contain the coiled-coil dimerization domain of BCR and the protein tyrosine Kinase domain (JH1) of JAK2. It was not possible to define what would be the best therapy, because tyrosine kinase inhibitors may not be effective to the BCR-JAK2 fusion. Maybe in MD presentation, we could return to pre- tyrosine kinase inhibitors era based on treatments with hydroxyureia, subcutaneous cytarabine and interferon for patients that were not potential candidates for allogeneic transplant. Disclosures: No relevant conflicts of interest to declare.
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Stein, Brady, Jerry L. Spivak, and Alison R. Moliterno. "Gender Is a Core Modifier of Disease Outcomes and Survival in the MPN." Blood 126, no. 23 (December 3, 2015): 2106. http://dx.doi.org/10.1182/blood.v126.23.2106.2106.
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Introduction: Host modifiers contribute to variation in disease pathogenesis and clinical features in the myeloproliferative neoplasms (MPN), essentialthrombocytosis (ET), polycythemia vera (PV), and myelofibrosis (MF).Gender modifies the JAK2 V617F allele burden (women had lower levels and lower annual increases), influences PV gene expression (men had twice as many differentially-regulated genes as women) and influences thrombotic events (a predominance of abdominal vein thrombosis in women). The MPN symptom burden also appears to differ by gender. In this analysis, we describe gender differences in disease presentation and outcome in relation tomutational status. Methods: We analyzed a prospective cohort of 612 PV, ET and MF patients enrolled between 2005 and 2013 to study genomic modifiers of the MPN and disease outcomes. We stratified disease evolution and survival by both gender and mutational status. Results: In this cohort, 26% were newly diagnosed, and 61% were female. The current median follow-up is 8 years (> 4800 patient-years) and 110 have died. Prevalence of Molecular lesions JAK2 V617F was identified in 468/612 MPN patients (76%; 61% female), and comprised the majority of ET (62%; 70% female), PV (99.5%; 59% female), MF (62%; 39% female) and post MPN AML (80.7%; 38% female) patients. CALR mutations were identified in 81/612 MPN patients (13%; 58% female), representing 23% of all ET (59% female), and 21 % of all MF (52% female) and 3.8% of post MPN AML. MPL mutations were identified in 9 MPN patients (1.5%): 7 females with ET, and 2 males with MF. Disease presentation Among JAK2 V617F positive patients, more females presented with ET compared to males (43% vs 29%; p=0.002) and more males presented with MF (21% vs 9%; p=0.001). Gender differences in presentation were less apparent in those with CALR -mutated ET (59% women) and MF (53% women). Disease transformation By gender, among 197 women with an original diagnosis of ET, 62% retained their phenotype, whereas 20%, 17%, and 1.5% evolved to PV, MF, and AML, respectively. Among men with ET, 63% retained their phenotype, while 16%, 20%, and 1.1% evolved to PV, MF, and AML. Among MF patients, regardless of mutational status, 1 (3%) women and 5 (10%) men evolved to AML (p=0.39). With regard to transformations by gender, rates of MF (16% in both) and AML (2.6% and 5.5%p=0.083) were similar between women and men. Among 123 JAK2V617F- positive ET women, during the follow-up period, 66 (54%) retained an ET phenotype, while 32%, 14%, and 0.8% evolved to PV, MF, and AML, respectively. Among 53 JAK2V617F-positive ET men, 54% retained an ET phenotype; 25%, 17%, and 4% evolved to PV, MF, and AML, respectively. Among 141 JAK2V617F-positive PV females, 109 (77%) retained PV, 26 (18%) evolved to MF, and 6 (4%) evolved to AML (1 via MF, 5 PV to AML); among 100 JAK2V617F-positive males, 73% retained a PV phenotype, 20% evolved to MF, and 7% to AML (3 PV to AML, 4 via MF phase). Among JAK2V617F -positive patients with an original MF diagnosis, 1/20 (5%) and 3/31 (10%) women and men evolved to AML (p=NS); 22% vs. 18% of JAK2V617F -positive men versus women evolved to MF or AML (p=0.28). No CALR -mutated ET patient evolved to PV. Of 38 CALR- ET women, 27 (71%) retained their phenotype, 10 evolved to MF (26%), and 1 to AML (3%). Among the 26 CALR -mutated ET men, 81% retained their phenotype, while 19% evolved to MF (no AML transformations). Survival The proportion of deaths differed by gender; of the 612 patients, despite the predominance of females in the cohort, at the time of last follow-up, there were 110 deaths (18%): 50/375 women died, compared to 60/237 men (13% vs. 25%; p value=0.0002). A larger proportion of male deaths were due to MF and MF to AML, but this was not statistically different (male deaths in MF/AML phase: 54/60; (90%); women 38/50 (75%); p=0.0692)). Conclusion: We identified a gender influence on disease distribution at presentation, particularly in the JAK2V617F-positive subset with females presenting more commonly with ET and males more commonly with MF. Despite the predominance of females in this MPN cohort, the distribution of females at presentation and evolution into more indolent phenotypes compared to males and a trend toward lower rates of AML evolution may have accounted for longer disease duration and fewer deaths in females compared to males. This trend in MPN evolution complements a theme of gender differences in symptom burden, clinical consequences, and genomic changes. Disclosures Stein: Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees. Spivak:Incyte: Membership on an entity's Board of Directors or advisory committees. Moliterno:Incyte: Membership on an entity's Board of Directors or advisory committees.
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Carvalho, Ana Clara Lacerda Cervantes de, Waldeir De Souza Ferreira Júnior, Suanam Altair Tavares de Menezes, and Mariana Machado Bueno. "DIETOTERAPIA NA EQUIPE INTERDISCIPLINAR PARA O TRATAMENTO DE CÂNCER DO OVÁRIO." ID on line REVISTA DE PSICOLOGIA 13, no. 46 (September 8, 2019): 5–6. http://dx.doi.org/10.14295/idonline.v13i46.1991.
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Introdução: o câncer do ovário é um dos mais incidentes e a segunda neoplasia ginecológica mais comum nas regiões do Brasil, estimando 6.150 novos casos entre os anos de 2018 e 2019, refere-se a alterações na expressão do padrão de genes, que na maioria dos casos, agridem as células epiteliais e germinativas, ocasionando vários déficits nutricionais, principalmente, o energético-protéico. Objetivo: o objetivo do estudo foi analisar o protocolo nutricional, pela equipe multidisciplinar, no tratamento para o câncer do ovário. Método: trata-se de uma revisão sistemática sem metanálise da literatura nas bases de dados LILACS e SCIELO, com buscas realizadas em julho de 2019, utilizando os descritores associados ao operador booleano (AND): Dietoterapia. Multidisciplinar. Câncer do ovário. Os critérios de inclusão foram estudos disponíveis em português e inglês, publicados entre os anos de 2011 a 2018, excluindo os que não abordassem a temática. Resultados: Foram selecionados 9 artigos, após a aplicação dos critérios, restaram 5 artigos. Apesar do difícil diagnóstico e de não apresentar sintomatologia específica, muitas vezes confundindo-se com outras patologias, e além de não haver um método de diagnóstico de fácil execução e aplicável nas mulheres, dificultando assim o tratamento e a expectativa de sobrevida da paciente, prevalecendo a taxa de mortalidade elevada. Diante disso, o tratamento ofertado pela equipe de saúde garante a assistência integral para a compressão da neoplasia. No contexto nutricional, o nutricionista auxilia na manutenção e evolução dietoterápica do paciente para o melhor desempenho das demais terapêuticas, como cirurgia e quimioterapia, dependendo do estadiamento da doença e da condição clínica; na redução da sintomatologia, como dores, distensão abdominal, redução do apetite e sensação de saciedade precoce, isto posto, influencia na recuperação e na estabilização do caso, fracionando a dieta diária, de acordo com a aceitação alimentar, estimulando a ingestão hídrica, provendo o consumo de alimentos como frutas e hortaliças que contenham antioxidantes. Conclusão: a dietoterapia é fundamental para o tratamento do câncer do ovário, ofertando as recomendações nutricionais ideias conforme os dados da avalição nutricional e o grau de manifestação clínica, apresentando-se imprescindível na equipe multiprofissional durante a terapêutica, abrangendo a individualidade de cada paciente.
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Divoka, Martina, Tomas Pika, Lenka Krupkova, Monika Orviska, Romana Janska, Jiri Minarik, and Tomas Papajik. "Clinical Implications of MYD88 and CXCR4 in Patients with Waldenström's Macroglobulinemia." Blood 132, Supplement 1 (November 29, 2018): 5314. http://dx.doi.org/10.1182/blood-2018-99-112855.
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Abstract Background Waldenström's macroglobulinemia (WM) is a rare B-cell neoplasm defined as lymphoplasmacytic lymphoma with bone marrow infiltration and monoclonal IgM in the serum. More than 90% of WM patients carry a point mutation L265P in the MYD88 gene and concurrently, almost one third of MYD88L265P-positive patients harbor frameshift (WHIM-FS) or non-sense (WHIM-NS) mutation in gene CXCR4. The mutations in CXCR4 result in premature stop codons and in shortening of CXCR4 protein product. Incomplete C-terminal domain of CXCR4 chemokine receptor is known to hyperactivate CXCR4-mediated signalization. The presence and type of mutation in genes MYD88 and CXCR4 appears to be significant in diagnostics and prognostic stratification of WM patients and it also influences the clinical manifestation of the disease. Aims To analyze mutational status of MYD88 and CXCR4 genes in patients with WM, to compare our results with laboratory parameters and to evaluate the prognostic stratification of the patients according to MYD88 and CXCR4 mutational status. Methods Analyzed DNA was isolated from mononuclear fraction of bone marrow or peripheral blood cells at the time of diagnosis. Mutational status of analyzed genes was determined using allele-specific PCR (in the case of MYD88) and using direct Sanger sequencing (in the case of CXCR4). All found mutations were confirmed by specific cleavage with restriction endonucleases at defined conditions. Results We analyzed 23 patients with WM. All patients were MYD88L265P-positive (100 %), and 7 of them (30,4%) were also CXCR4 mutants (1 patient harbored WHIM-FS mutation and 6 harbored WHIM-NS mutation). CXCR4 mutations were associated with more aggressive disease: higher ISSWM score (low 0/intermediate 1/ high 6 risk), anemia (7/7), hyperviscosity syndrome (2/7) at time of diagnosis. CXCR4WHIM-WT patients were often asymptomatic (5/16) with lower ISSWM score (low 5/intermediate 5/ high 6 risk) but with common adenopathy (11/16). CXCR4 mutations were also associated with worse treatment response (2 CXCR4WHIM-MUT patients were refractory to initial therapy and needed 2nd line treatment, 3 patients had only partial response to first-line therapy, one patient died after 2nd cycle due to abdominal septic complication and only one patient reached VGPR). Progression-free survival in treated patients was 32 vs. 8 months in CXCR4 mutants. Conclusion/summary The mutational analysis of MYD88 and CXCR4 genes is essential for the diagnostics and prognostic stratification of patients with WM and it allows a deeper understanding of the molecular pathogenesis of the diseases. CXCR4 mutations were found in nearly one third of WM patients. In accordance with published data, we confirmed that CXCR4 mutations are associated with more aggressive disease presentation and thus affect treatment outcome. On the contrary CXCR4WHIM-WT patients have more indolent course of the disease. This work was supported by grant IGA-LF-2018-004 and MH CR - RVO (FNOL, 00098892). Disclosures No relevant conflicts of interest to declare.
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Egorov, I. V. "Difficult patient: overlap-syndrome, paraneoplastic syndrome or random polymorbidity?" Doctor.Ru 19, no. 11 (2020): 46–51. http://dx.doi.org/10.31550/1727-2378-2020-19-11-46-51.
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Objective: to describe a clinical case of CRST syndrome in combination with an oncological disease. Materials and methods. Patient S., 64 years old, complained of dizziness, stiffness in the hands, numbness of fingers, loss of appetite. After a thorough questioning and examination, systemic scleroderma was suspected and an additional examination was prescribed, which included routine clinical and biochemical tests, a "thyroid panel", rheumatological parameters, tumor markers, chest x-ray, ultrasound of the abdominal cavity, thyroid ultrasound, electrocardiography, echo gastroscopy. Results: Based on the examination data, the diagnosis was made of adenocarcinoma of the antrum of the stomach, as well as limited scleroderma (CREST syndrome) in combination with chronic autoimmune thyroiditis (СAIT). The course of the disease almost completely fits into the CREST syndrome, but there was no confirmation of esophageal dysfunction or esophagitis (in this case, the term CRST syndrome is sometimes used). The rest of the limited version of scleroderma was beyond doubt. Cases when CAIT accompanied systemic lupus erythematosus, systemic scleroderma, Sjogren's syndrome, mixed connective tissue diseases, etc., have not only been described, but also studied for overlap conditions - overlap syndromes. Conclusion. The pathogenetic mechanisms of the association of various autoimmune diseases are not completely clear; it is assumed that the key role in the formation of polyautoimmunity is played by defects of the immune system associated with polymorphism of various genes, in combination with environmental factors and hormonal disorders. And the detection of an oncological process does not look random: because of autoimmunity, an aberrant immune response, or the use of immunomodulatory drugs, many of the rheumatic diseases seem to increase the risk of neoplasia Key words: gastric adenocarcinoma, CREST-syndrome, limited scleroderma, chronic autoimmune thyroiditis, overlap-syndrome, rare disease, etiology, diagnostic research, paraneoplastic syndrome, methodology of diagnosis.
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Reda, Sarah Alicia, Emily A. Japp, Qiusheng Si, Ketan Badani, and Alice C. Levine. "A Case of Renal Cell Carcinoma and Pheochromocytoma Due to Germline Inactivating Mutation in Fumarate Hydratase (FH)." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A986. http://dx.doi.org/10.1210/jendso/bvab048.2017.
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Abstract A 60-year-old female with a history of well-controlled hypertension, prediabetes, status post hysterectomy for fibroids, presented for evaluation of hematuria and unintentional weight loss. She denied palpitations, headaches, tremors, and diaphoresis. Initial CT demonstrated a right renal mass suspicious for renal cell carcinoma and an adrenal mass. Magnetic resonance imaging (MRI) confirmed a hypervascular, right adrenal mass (6.7 x 6 x 5 cm) without loss of signal. Laboratory Testing: elevated 24-hour urine vanillylmandelic acid (VMA) 17.5 mg/24 h (<6), and urine normetanephrines 2276 ug/24 h (122-676) with normal urine metanephrines 158 ug/24 h (90-315). 24-hour urine free cortisol was normal. The patient underwent a right adrenalectomy and partial nephrectomy. Pathology confirmed a low-grade renal cell carcinoma (RCC) and a 6.8 cm pheochromocytoma (PCC). Genetic analysis revealed an inherited mutation in the fumarate hydratase (FH) gene, which is diagnostic of hereditary leiomyomatosis and renal cell cancer (HLRCC). Wildtype FH codes for an enzyme that converts fumarate to malate in the mitochondrial Krebs cycle. Inactivating mutations in FH trigger the hypoxia pathway by activating hypoxia-inducible factor (HIF) thereby promoting tumor growth and angiogenesis. In PCC, 30-40% are hereditary and another 40-50% are found to have somatic mutations in 1 of 20 PCC susceptibility genes. Several autosomal dominant heritable syndromes, including Neurofibromatosis type 1 (NF-1), von Hippel-Lindau (VHL), Multiple Endocrine Neoplasia Type 2 (MEN 2), and Paraganglioma Syndromes Types 1–5, have an increased incidence of PCC, most of which modulate hypoxia pathways. FH mutations are similarly inherited in an autosomal dominant fashion and cause HLRCC. HLRCC is associated with 75-80% risk for cutaneous and uterine leiomyomas, and a 10-16% risk for type II papillary renal cell carcinoma. The risk of RCC in patients with FH mutations is much greater than in the general population, where the prevalence is ~2% in those who lack the mutation. In one study, FH deficiencies attribute between 19-41% of all RCC cases. Rare families with PGL/PCC have also been found to carry this germline FH mutation. This FH mutation is associated with increased risk of metastasis in patients with PGL/PCC by a similar mechanism of carcinogenesis via the hypoxia pathway. Currently, there are no strict guidelines for surveillance in individuals with HLRCC, however, patients should have a yearly abdominal MRI, skin examination every 2 years, and an annual gynecological evaluation for leiomyosarcoma. Each first-degree relative should be offered genetic testing of the FH mutation, as 50% of relatives may carry the gene. This case underscores the importance of genetic workups in patients with PCC, especially if associated with other tumors.
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Stein, Eytan M., Guillermo Garcia-Manero, David A. Rizzieri, Raoul Tibes, Jesus G. Berdeja, Mojca Jongen-Lavrencic, Jessica K. Altman, et al. "A Phase 1 Study of the DOT1L Inhibitor, Pinometostat (EPZ-5676), in Adults with Relapsed or Refractory Leukemia: Safety, Clinical Activity, Exposure and Target Inhibition." Blood 126, no. 23 (December 3, 2015): 2547. http://dx.doi.org/10.1182/blood.v126.23.2547.2547.
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Abstract Introduction: Aberrant fusion proteins involving the MLL histone methyltransferase (HMT) result in recruitment of another HMT, DOT1L, to a multi-protein complex. This leads to abnormal methylation of Histone H3 lysine 79 (H3K79) at MLL target genes and enhanced expression of leukemogenic genes such as HOXA9 and MEIS1 ( Krivstov, 2007). Pinometostat is a small molecule inhibitor of DOT1L with sub-nanomolar affinity and >37,000 fold selectivity against non-MLL HMTs. Pinometostat treatment of MLL-rearranged cells and xenografts reduced histone H3K79 methylation, decreased MLL target gene expression, and induced selective leukemia cell kill (Daigle, 2013). We report the safety, activity, pharmacokinetics (PK) and pharmacodynamics (PD) in the phase 1 trial of pinometostat in adult patients (pts) with relapsed/refractory (R/R) leukemia. Methods: This open label dose escalation/expansion study of pinometostat enrolled pts >18 years (yrs) with R/R leukemia (NCT01684150). In the dose-escalation phase, pts with AML, ALL, mixed lineage leukemia (MLL), myelodysplastic syndrome, myeloproliferative neoplasm or chronic myeloid leukemia were eligible. Eligibility in the two expansion cohorts: 90 mg/m2 (n = 17) and 54 mg/m2 (n = 6), was restricted to pts with MLL-r or MLL-partial tandem duplication (MLL-PTD). Pinometostat was given via continuous intravenous infusion (CIV) for 21 of 28 day cycles in the dose escalation phase and CIV for 28 of 28 day cycles in the expansion phases, until disease progression or unacceptable toxicity. All pts underwent serial collection of PK and peripheral blood mononuclear cells (PBMC) for PD. Leukemic blasts were isolated from PBMCs using flow cytometry and quantified for dimethylation of H3K79 (H3K79-me2) by ChIP-Seq. Results: As of 28-June-2015, 49 pts have enrolled in the dose escalation and expansion phases. Pts receiving 21/28 day infusions: 12 (n=1), 24 (n=5), 36 (n=4), 54 (n=6) and 80 mg/m2/day (n=3). Pts receiving 28/28 day infusions: 54 (n=6) and 90 mg/m2/day (n=24). Table 1. Patient Characteristics n (%) Median age, yrs (range) 51 (19 - 81) Sex (M / F) 27/22 Diagnosis MLL-r* 29 (59) AML MLL-PTD** 5 (9) MLL-wt 7 (14) ALL MLL-r* 5 (10) MLL-wt 1 (2) MLL MLL-r 1 (2) CMML MLL-r 1 (2) # of prior therapeutic regimens 1 - 2 29 (59) 3 - 4 18 (36) >4 2 (4) Prior allogeneic hematopoietic cell transplant 20 (41) * centrally confirmed by karyotype/FISH ** centrally confirmed by NGS (next generation sequencing) Adverse events (AEs) reported in >15% of pts regardless of attribution were: nausea, constipation, vomiting, abdominal pain, diarrhea, hypocalcemia, hypokalemia, hypomagnesemia, fatigue, fever, peripheral edema, mucositis, febrile neutropenia, leukocytosis, anemia, cough, dyspnea, and pneumonia. Grade ≥3 non-hematologic related toxicities include: hypophosphatemia (n=1), decreased ejection fraction (n=3), or elevated transaminases (n=1). Nine patients had leukocytosis (absolute monocyte and neutrophil 50% above baseline and above upper limit of normal) or differentiation. The median days of pinometostat treatment was 35 days (range 3-189 days). To date, objective responses observed are morphologic CR (1 pt), cytogenetic CR (MLL negative by FISH) (1 pt), PR (1 pt) and resolution of leukemia cutis (3 pts). Dose proportional PK was observed with rapid attainment of steady-state plasma concentrations (Css) on Day 1 of treatment. Plasma Css correlated with inhibition of global H3K79-me2 in PBMCs. H3K79-me2 ChIP-Seq demonstrated pinometostat induced reductions in methylation at MLL -r target genes HOXA9 and MEIS1 (median inhibition = 61%: range = 13-91%) in all 9 pts analyzed to date from the 90 mg/m2 expansion cohort. Inhibition of H3K79-me2 in leukemic blasts is consistent with DOT1L suppression. PK-PD relationships in both expansion cohorts using both free and total plasma Css are being explored. Conclusions: Pinometostat administered as a CIV to adults with R/R leukemia has an acceptable safety profile. Clinical activity as demonstrated by both marrow responses and resolution of leukemia cutis were observed. In addition, analysis of H3K79-me2 by ChIP-Seq demonstrated PD reductions in the methylation of MLL-r target genes following pinometostat exposure, as expected from DOT1L inhibition. Relationships between PK exposure, reductions in pinometostat induced H3K79-me2 levels and clinical response are being interrogated. Disclosures Stein: Seattle Genetics: Consultancy; Agios Pharmaceuticals: Consultancy. Rizzieri:Teva: Other: ad board, Speakers Bureau; Celgene: Other: ad board, Speakers Bureau. Berdeja:Novartis: Research Funding; Takeda: Research Funding; BMS: Research Funding; Curis: Research Funding; MEI: Research Funding; Abbvie: Research Funding; Onyx: Research Funding; Array: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Acetylon: Research Funding. Altman:Novartis: Other: Advisory board; Spectrum: Other: Advisory board; Ariad: Other: Advisory board; Seattle Genetics: Other: Advisory board; BMS: Other: Advisory board; Astellas: Other: Participation in an advisory board December 2013. Thomson:Epizyme, Inc: Employment. Blakemore:Epizyme: Employment. Daigle:Epizyme, Inc: Employment. Fine:Epizyme: Employment. Waters:Epizyme, Inc: Employment. Armstrong:Epizyme, Inc: Consultancy. Ho:Epizyme, Inc: Employment.
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Grunwald, Luise, Christina Grosse-Thie, Sina Sender, Gudrun Knuebel, Saskia Krohn, Catrin Roolf, Christian Junghanss, Larissa Henze, and Hugo Murua Escobar. "Ultradeep targeted sequencing reveals low allele frequencies of somatic JAK2 and MPL variants in patients with abdominal vein thromboses: results of an ongoing prospective prevalence study in Mecklenburg-West Pomerania." Biomarker Research 8, no. 1 (December 2020). http://dx.doi.org/10.1186/s40364-020-00254-9.
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AbstractMyeloproliferative neoplasms are characterized by mutations in JAK2, MPL and CALR genes. Commonly in diagnostics and previous studies mainly sequencing and common PCR techniques under conventional detection limits are used.Splanchnic vein thromboses are rare, but often appear associated with myeloproliferative neoplasms and represent serious complications.Herein, blood from patients with abdominal vein thromboses in Mecklenburg-West Pomerania (federal district of northern Germany), included in an ongoing prospective prevalence study, was analyzed by next generation sequencing representing the complete protein coding regions of JAK2, MPL and CALR genes with a coverage of > 2000 reads, therefore an ultradeep targeting approach.JAK2 V617F mutations were detected in 11/44 patients. In four of these cases allele frequencies ranged below the conventional cut off of 2%. MPL W515R was detected in 3/44 cases in low frequencies.Very low allele frequencies of JAK2 and MPL variants in patients with abdominal vein thromboses may indicate early manifestations of myeloproliferative neoplasms.
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Cruz, Ofelia, Victoria Caloretti, Hector Salvador, Veronica Celis, Vicente Santa-Maria, Andrés Morales La Madrid, Mariona Suñol, et al. "Synchronous choroid plexus papilloma and Wilms tumor in a girl, disclosing a Li-Fraumeni syndrome." Hereditary Cancer in Clinical Practice 19, no. 1 (January 6, 2021). http://dx.doi.org/10.1186/s13053-020-00158-7.
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Abstract Background Li-Fraumeni Syndrome (LFS) is a cancer predisposition syndrome characterized by the early-onset of multiple primary cancers which can occur at different moments (metachronous onset) or, more rarely, coincidentally (synchronous onset). Here we describe a previously unreported patient with presentation of synchronous Wilms tumor and Choroid plexus papilloma, leading to the diagnosis of a Li-Fraumeni Syndrome (LFS). Case presentation A 6-year-old girl without previous complains presented with abdominal pain. Abdominal US and MRI showed a left renal tumor with subcapsular hematoma. Due to mild headaches, the diagnostic workup included a brain MRI that unexpectedly identified a large left parietal lobe tumor. Histopathological analysis determined the diagnosis of classic Wilms tumor and choroid-plexus papilloma (CPP), respectively. Both neoplasms showed intense nuclear p53 immunostaining associated with the pathogenic TP53 mutation c.844C > T (p.Arg282Trp). Our patient and her father shared the same heterozygous germline TP53 mutation, confirming the diagnosis of familiar Li-Fraumeni syndrome in the girl. The treatment was tailored to simultaneous tumor presentations. Conclusions LFS has been associated with Choroid plexus carcinoma (CPC), but rarely with CPP as in our patient. That suggests that it may be advisable to consider the possibility of analyzing TP53 mutation, not only in all patients with CPC, but also in some patients with CPP, especially when histological or clinical evidences point out to perform this study. The dissimilar presentation of LFS among our patient’s father, not having so far any neoplasia diagnosed, while her daughter presented precociously with two simultaneous different tumors, could be related to possible effects of modifier genes on the underlying mutant p53 genotype.
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Lin, Kuan-yu, Shyang-Rong Shih, and Jih-Hsiang Lee. "SUN-480 An Unusual Clear Cell Carcinoma in the Thyroid. Where Is the Primary?" Journal of the Endocrine Society 4, Supplement_1 (April 2020). http://dx.doi.org/10.1210/jendso/bvaa046.584.
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Abstract Background: Clear cell carcinoma in the thyroid gland is rare. It is important to distinguish primary thyroid clear cell carcinoma from metastases, since its clinical behaviors and treatment options were different. Clinical Case: A 47-year-old woman without past medical history presented to our outpatient surgery department with right neck mass for 8 months. Thyroid ultrasonography revealed a 3.9 cm nodule in the right thyroid. Thyroid function test was within the normal range. Fine needle aspiration cytology of the nodule showed suspicious for neoplasm. She underwent radical total thyroidectomy and lymph node dissection. Pathology revealed an unusual carcinoma comprising cuboidal cells with irregular nuclear contours, some eosinophilic or clear cytoplasm, arranged in infiltrating nests or cords with marked stromal hyalinization, highly suggestive of a clear cell carcinoma. Ectopic thymic tissue was present adjacent to the tumor. By immunohistochemical (IHC) staining, tumor cells were p63 (+), TTF-1 (-), thyroglobulin (-), PAX8 (-), synaptophysin (-), CD5 (-), and CD117 (-). Tumor genetic sequencing detected EWSR1-CREM fusion genes. For disease extent evaluation, two out of seven lymph nodes obtained during operation were positive of tumor metastases. Whole body computed tomography (CT) 3 months after operation revealed no residual thyroid tissue, neck lymphadenopathies or intra-abdominal metastases. A pulmonary ground-glass opacities of 7mm in diameter was found, which was stationary at a repeated CT scan 6 months later. Clinical Lesson: Clear cell carcinoma in the thyroid gland could be primary, arising from clear cell change of follicular or papillary thyroid carcinoma. The negative IHC stain of thyroglobulin, TTF, PAX8, as well as lack of papillary or follicular architecture made primary thyroid clear cell carcinoma unlikely. Most of the metastatic clear cell carcinoma to the thyroid gland arose from renal primary. However, there was no clinical or radiographic evidence of renal tumor in our case. Although ectopic thymic tissue was identified on pathology, negative IHC staining of PAX8, CD5 and CD117 made thymic origin less likely. Positive IHC staining of p63 and a novel EWSR1-CREM fusion gene confirmed the diagnosis of salivary clear cell carcinoma. According to our literature review, there were only 3 cases of clear-cell carcinoma with EWSR1-CREM fusion gene (1), and our case is the first case who presented with clear cell carcinoma in the thyroid. In conclusion, the importance of IHC stain and molecular testing in determining the primary origin of clear cell carcinoma were addressed in our case. Reference: (1) Chapman E, et al. Am J Surg Pathol. 2018;42(9):1182-1189
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Rondón-Ayala, José A. "Cáncer hereditario de colon no polipósico asociado a adenocarcinoma de endometrio, piel actínica y consanguinidad. A propósito de un caso." Bionatura 3, no. 4 (November 15, 2018). http://dx.doi.org/10.21931/rb/2018.03.04.10.
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