Over-representation of the G12S polymorphism of the SDHD gene in patients with MEN2A syndrome

OBJECTIVE: To evaluate whether germline variants of the succinate dehydrogenase genes might be phenotypic modifiers in patients with multiple endocrine neoplasia type 2. Mutations of genes encoding subunits of the succinate dehydrogenase are associated with hereditary paraganglioma/pheochromocytoma syndrome. Pheochromocytoma is one of the main manifestations of multiple endocrine neoplasia type 2 caused by germline mutation of the rearranged during transfection proto-oncogene. METHODS: Polymorphisms of the succinate dehydrogenase genes were analyzed in 77 rearranged during transfection mutation carriers, 47 patients with sporadic medullary thyroid cancer, 48 patients with sporadic Pheo, and 100 healthy individuals. Exons 10-16 of the rearranged during transfection proto-oncogene were analyzed by direct DNA sequencing, and all exons of the von Hippel-Lindau, succinate dehydrogenase B, and succinate dehydrogenase subunit D genes were tested by direct DNA sequencing and multiple ligation probe analysis. The G12S polymorphism of the succinate dehydrogenase subunit D gene was determined by restriction fragment length polymorphism. RESULTS: Of the 77 rearranged during transfection mutation carriers, 55 from 16 families had multiple endocrine neoplasia type 2A, three from three families had multiple endocrine neoplasia type 2B, and 19 from two families had familial medullary thyroid carcinoma. Eight of 55 (14.5%) patients with multiple endocrine neoplasia type 2A had this variant whereas it was absent in multiple endocrine neoplasia type 2B, familial medullary thyroid carcinoma, sporadic medullary thyroid carcinoma, and sporadic pheochromocytoma groups, and its prevalence in controls was 1% (p<0.002 multiple endocrine neoplasia type 2A versus controls). No associations between G12S and age of manifestation, incidence of pheochromocytoma or hyperparathyroidism, or level of serum calcitonin were observed. CONCLUSION: The high prevalence of the G12S variant in patients with multiple endocrine neoplasia type 2A raises questions about its role as a genetic modifier, but this proposal remains to be established

Anti-cancer potential of MAPK pathway inhibition in paragangliomas-effect of different statins on mouse pheochromocytoma cells.

To date, malignant pheochromocytomas and paragangliomas (PHEOs/PGLs) cannot be effectively cured and thus novel treatment strategies are urgently needed. Lovastatin has been shown to effectively induce apoptosis in mouse PHEO cells (MPC) and the more aggressive mouse tumor tissue-derived cells (MTT), which was accompanied by decreased phosphorylation of mitogen-activated kinase (MAPK) pathway players. The MAPK pathway plays a role in numerous aggressive tumors and has been associated with a subgroup of PHEOs/PGLs, including K-RAS-, RET-, and NF1-mutated tumors. Our aim was to establish whether MAPK signaling may also play a role in aggressive, succinate dehydrogenase (SDH) B mutation-derived PHEOs/PGLs. Expression profiling and western blot analysis indicated that specific aspects of MAPK-signaling are active in SDHB PHEOs/PGLs, suggesting that inhibition by statin treatment could be beneficial. Moreover, we aimed to assess whether the anti-proliferative effect of lovastatin on MPC and MTT differed from that exerted by fluvastatin, simvastatin, atorvastatin, pravastatin, or rosuvastatin. Simvastatin and fluvastatin decreased cell proliferation most effectively and the more aggressive MTT cells appeared more sensitive in this respect. Inhibition of MAPK1 and 3 phosphorylation following treatment with fluvastatin, simvastatin, and lovastatin was confirmed by western blot. Increased levels of CASP-3 and PARP cleavage confirmed induction of apoptosis following the treatment. At a concentration low enough not to affect cell proliferation, spontaneous migration of MPC and MTT was significantly inhibited within 24 hours of treatment. In conclusion, lipophilic statins may present a promising therapeutic option for treatment of aggressive human paragangliomas by inducing apoptosis and inhibiting tumor spread

Biological Activity of a Mouse-Human Chimeric Immunoglobulin G2 Antibody to Cryptococcus neoformans Polysaccharide

The variable regions of the heavy and light chains of the protective murine monoclonal antibody (MAb) 2H1 (m2H1) were expressed with the human constant region genes for immunoglobulin G2 (IgG2) and kappa, respectively, to construct a chimeric antibody (ch2H1). ch2H1 retains the specificity of the parent MAb, exhibits biological activity, and lacks the toxicity of the parent murine IgG1 in chronically infected mice

Incidence and Management of Proteasome Inhibitor-Related Cardiotoxicity in Multiple Myeloma Patients at Memorial Sloan Kettering Cancer Center

Abstract Introduction: Given that the rate of cardiovascular (CV) morbidity increases with age and the median age of patients with multiple myeloma (MM) is 65, CV complications can occur during MM treatment. The proteasome inhibitors (PIs), bortezomib and carfilzomib, may play a role in the development of treatment-related cardiotoxicity as suggested by phase 2 clinical studies and a phase 3 trial (Stewart AK et al. N Engl J Med 2015;372:142-52). Reported treatment-related cardiotoxicity includes hypertension, congestive heart failure (CHF), myocardial infarction, and cardiac arrest. The objectives of this study are to define the incidence of cardiotoxicity in MM patients treated with bortezomib and carfilzomib and to evaluate whether the dose and pre-existing cardiac history affects that incidence. Study design and methods:Using the pharmacy database, we identified all MM patients treated at Memorial Sloan Kettering Cancer Center between 1/2010 to 10/2014 who were treated with bortezomib or carfilzomib in the second-line and relapsed refractory setting. Of note, all patients in the carfilzomib arm received prior bortezomib; thus, MM patients in the carfilzomib arm were more heavily pretreated and the two arms should be compared with caution. Data collected included: baseline demographics, baseline disease status, treatment given including dose and number of cycles, baseline cardiovascular comorbidities and medications, and pre- and post-treatment ejection fraction. Cardiotoxicity recorded was defined as grade 3 or more (requiring intervention) and included: hypertension, CHF, coronary artery disease, pulmonary hypertension, myocardial infarction, stroke, and/or arrhythmias. Descriptive statistics were used to analyze baseline demographics, including median and range for continuous variables and frequency and percentage for categorical variables. Fisher's exact test was used to assess the association between clinical and treatment characteristics and cardiotoxicity. Results: 157 patients were eligible for analysis with 47 in the bortezomib arm and 110 in the carfilzomib arm. The overall incidence of cardiotoxicity across both arms was 17% with an incidence of 9% (n = 4) and 20% (n = 22) in the bortezomib and carfilzomib arms, respectively. The most common events reported were arrhythmias (n = 3) with bortezomib and CHF (n = 12) with carfilzomib. The incidence of CHF and cardiomyopathy was 4% and 19% in the bortezomib and the more heavily pretreated carfilzomib arms, respectively. Baseline cardiac comorbidities were not found to increase the risk of cardiotoxicity while on treatment with carfilzomib (p = 0.815); due to small numbers, we were unable to assess this aspect in the bortezomib arm. Based on a categorization of carfilzomib dose (≤20 mg/m2, 27 mg/m2, or ≥36 mg/m2) starting on cycle 2, there was a significant association between the dose level received and cardiotoxicity (p=0.003); patients treated at dose level ≥36 mg/m2 were most likely to have a cardiac-related event while on therapy. Patients receiving the higher doses were treated on a clinical trial (Lendvai et al. Blood 2014;124:899-906), and they were among the most heavily pretreated. Management of cardiac events with carfilzomib was largely supportive with all patients requiring pharmacological intervention, 64% (n= 14) requiring hospital admission, and 73% (n = 16) requiring treatment delays. Conclusion: Grade 3 or more cardiotoxicity is a potential complication of treatment with PIs. However, there is no increased risk of CV deaths noted in our study. The results show a higher risk of cardiac toxicity in heavily pretreated MM patients receiving higher doses (≥36 mg/m2) of carfilzomib. The number of prior lines of therapy is a major factor when defining CV events in relation to a given therapy. Importantly, both carfilzomib and bortezomib are highly efficacious anti-myeloma drugs; CV risks should be assessed for individual patients and in relation to benefits. Disclosures Landgren: BMJ Publishing: Honoraria; Medscape: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Onyx: Honoraria; International Myeloma Foundation: Research Funding; Onyx: Research Funding; BMJ Publishing: Consultancy; Medscape: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Onyx: Consultancy

Pilot Study of Bortezomib and Dexamethasone Pre- and Post-Risk-Adapted Autologous Stem Cell Transplantation in AL Amyloidosis

Treatment for AL amyloidosis aims to eradicate clonal plasma cells, thereby disrupting the amyloid deposition causing organ damage. Risk-adapted high-dose melphalan plus autologous stem cell transplantation (RA-ASCT) is an effective therapy. We conducted a prospective pilot analysis of a comprehensive approach using bortezomib and dexamethasone (BD) before and after RA-ASCT in 19 patients. BD induction (up to 3 cycles of bortezomib 1.3 mg/m i.v. and dexamethasone 40 mg orally [p.o.] or i.v. on days 1, 4, 8, and 11) was followed by RA-ASCT and then BD consolidation (6 cycles of bortezomib 1.3 mg/m i.v. and dexamethasone 20 mg p.o. or i.v. weekly for 4 weeks, every 12 weeks). The overall hematologic response rate (partial response or better) was 95%, including 37% minimal residual disease negative [MRD(-)] complete response (CR) by flow cytometry (sensitivity up to 1/10 cells). At 2 years, progression-free survival (PFS) and overall survival were 68% (95% confidence interval [CI], 50% to 93%) and 84% (95% CI, 69% to 99%), respectively, with median duration of follow-up in survivors of 61 months (range, 42 to 84 months). In a landmark analysis, patients achieving MRD(-) CR had superior PFS (P= .008). This approach is safe and yields deep and durable remissions promoting organ recovery. Each treatment phase deepened the response. Future aims include improving the efficacy and toxicity of each phase