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Wilop S.,RWTH Aachen | van Gemmeren T.B.,RWTH Aachen | Lentjes M.H.F.M.,Maastricht University | van Engeland M.,Maastricht University | And 4 more authors.
Epigenetics | Year: 2011

The family of suppressor of cytokine signaling (SOCS) proteins negatively regulates cytokine signaling in different cellular pathways including interleukin-6 (IL-6). Since IL-6 plays an essential role in regulating growth and survival of multiple myeloma (MM) cells, methylation-associated dysregulation of SOCS3 may contribute to the malignant phenotype of MM cells. We used methylation-specific PCR (MSP) to assess the methylation status of the SOCS3 CpG island in 5 MM cell lines and 70 patient samples. Additional bisulfite sequencing and RNA expression analysis using reverse transcriptase polymerase chain reaction was performed in two cell lines. We identified aberrant SOCS3 methylation in 3/5 MM cell lines. Methylation of SOCS3 in cell lines was associated with transcriptional downregulation. Treatment of OPM-2 cells, which carry a methylated SOCS3 gene, with the demethylating agent 5-aza-2'-deoxycytidine restored SOCS3 expression in association with partial demethylation. In patient samples with malignant plasma cell disorders, SOCS3 was methylated in 5/70 (7.1%) cases, while there was no aberrant SOCS3 methylation in normal peripheral blood and non-malignant bone marrow cells. We found an association of SOCS3 methylation with extramedullary manifestations (p=0.03), plasma cell leukemia (P=0.003), elevated LDH (p=0.001), increased creatinine (p=0.01) and remarkably shortened survival (6.9 vs. 56.1 months, HR 5.9, p=0.0007). Our findings reveal a novel epigenetic event possibly implicated in the pathogenesis of MM and representing a potential prognostic biomarker. Epigenetic dysregulation of the SOCS3 gene may interfere with the cellular response to the complex cytokine network thus supporting survival and expansion of MM cells. © 2011 Landes Bioscience.

Kelly R.J.,The Sidney Kimmel Comprehensive Cancer Center | Thomas A.,U.S. National Cancer Institute | Rajan A.,U.S. National Cancer Institute | Chun G.,U.S. National Cancer Institute | And 12 more authors.
Annals of Oncology | Year: 2013

Background: This phase I/II study examined the safety and efficacy of Sepantronium Bromide (S), a small-molecule selective survivin suppressant, administered in combination with carboplatin (C) andpaclitaxel (P). Patients and methods: Forty-one patients were treated on study. Twenty-two patients received escalating doses of S (3.6-12 mg/m2) and 19 with untreated stage IV non-small-cell lung cancer (NSCLC) were treated with the maximum tolerated dose of 10 mg/m2 in combination with standard dosesof C (AUC6) and P (200 mg/m2) for six cycles. S was administered as a continuous intravenous infusion(CIVI) over 72 h in 21-day treatment cycles. Study end points included safety and toxic effect, response rate, progression-free and overall survival (PFS and OS), as well as exploratory pharmacodynamic correlates. Results: Treatment with S was well tolerated, and toxic effects were mostly hematologicalin the phase II study. Two (11%) partial responses were observed with a median PFS of 5.7 months and median OS 16.1 months. Pharmacodynamic analysis did not demonstrate an association with response. Conclusion: The combination of S (10 mg/m2/day 72-h CIVI) administered with C and P every 3 weeks exhibited a favorable safety profile but failed to demonstrate an improvement in response rate in advanced NSCLC. Clinical trial number: NCT01100931. © The Author 2013.

Pu J.J.,The Sidney Kimmel Comprehensive Cancer Center
BMJ case reports | Year: 2011

Gallbladder carcinosarcoma is a rare gastrointestinal tract malignant tumour, which contains both epithelial cancer component and mesenchymal sarcoma component. Because of its unique anatomic location and unspecific medical presentation, preoperative diagnosis is difficult. The prognosis of gallbladder carcinoma is poor with median survival time of 5.5 months. T- and N-staging system has no role in cancer prognostic stratification. Currently, we still have limited experience in managing this form of notorious cancer. Surgical resection is the common practice in treating gallbladder carcinoma though recurrence rate is high (80%). Here, we report a 59-year-old female with new diagnosed gallbladder carcinosarcoma. She was found to have a carcinosarcoma masse at gallbladder extending into proximal bile ducts with no metastatic lesion. She underwent a radical cholangiocholecystocholedochectomy and Roux-en-Y hepatocholangioduodenostomy. Postsurgery, she received six cycles of adjuvant chemotherapy consisting of oxaliplatin and 5-fluorouracil. She maintains in complete remission 6 months after adjuvant chemotherapy.

Franco-Paredes C.,Phoebe Putney Memorial Hospital | Womack T.,Phoebe Putney Memorial Hospital | Bohlmeyer T.,Phoebe Putney Memorial Hospital | Sellers B.,Phoebe Putney Memorial Hospital | And 7 more authors.
The Lancet Infectious Diseases | Year: 2015

Cryptococcosis is a fungal disease caused by Cryptococcus neoformans and Cryptococcus gattii. By inhalation and subsequent pulmonary infection, it may disseminate to the CNS and cause meningitis or meningoencephalitis. Most cases occur in immunosuppressed hosts, including patients with HIV/AIDS, patients receiving immunosuppressing drugs, and solid organ transplant recipients. However, cryptococcosis also occurs in individuals with apparently healthy immune systems. A growing number of cases are caused by C gattii, with infections occurring in both immunosuppressed and immunocompetent individuals. In the majority of documented cases, treatment of C gattii infection of the CNS requires aggressive management of raised intracranial pressure along with standard antifungal therapy. Early cerebrospinal fluid evacuation is often needed through placement of a percutaneous lumbar drain or ventriculostomy. Furthermore, pharmacological immunosuppression with a high dose of dexamethasone is sometimes needed to ameliorate a persistently increased inflammatory response and to reduce intracranial pressure. In this Grand Round, we present the case of an otherwise healthy adolescent female patient, who, despite aggressive management, succumbed to C gattii meningoencephalitis. We also present a review of the existing literature and discuss optimum clinical management of meningoencephalitis caused by C gattii. © 2015 Elsevier Ltd.

Wu D.,University of Louisville | Erwin D.,Management Information Services Inc. | Rosner G.L.,The Sidney Kimmel Comprehensive Cancer Center
Lung Cancer | Year: 2011

We investigate screening sensitivity, transition probability and sojourn time in lung cancer screening for male heavy smokers using the Mayo Lung Project data. We also estimate the lead time distribution, its property, and the projected effect of taking regular chest X-rays for lung cancer detection. Methods: We apply the statistical method developed by Wu et al. [1] using the Mayo Lung Project (MLP) data, to make Bayesian inference for the screening test sensitivity, the age-dependent transition probability from disease-free to preclinical state, and the sojourn time distribution, for male heavy smokers in a periodic screening program. We then apply the statistical method developed by Wu et al. [2] using the Bayesian posterior samples from the MLP data to make inference for the lead time, the time of diagnosis advanced by screening for male heavy smokers. The lead time is distributed as a mixture of a point mass at zero and a piecewise continuous distribution, which corresponds to the probability of no-early-detection, and the probability distribution of the early diagnosis time. We present estimates of these two measures for male heavy smokers by simulations. Results: The posterior sensitivity is almost symmetric, with posterior mean 0.89, and posterior median 0.91; the 95% highest posterior density (HPD) interval is (0.72, 0.98). The posterior mean sojourn time is 2.24 years, with a posterior median of 2.20 years for male heavy smokers. The 95% HPD interval for the mean sojourn time is (1.57, 3.35) years. The age-dependent transition probability is not a monotone function of age; it has a single maximum at age 68. The mean lead time increases as the screening time interval decreases. The standard error of the lead time also increases as the screening time interval decreases. Conclusion: Although the mean sojourn time for male heavy smokers is longer than expected, the predictive estimation of the lead time is much shorter. This may provide policy makers important information on the effectiveness of the chest X-rays and sputum cytology in lung cancer early detection. © 2010.

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