Single nucleotide polypmorphisms in ERCC1 are associated with disease progression, and survival in patients with advanced stage ovarian and primary peritoneal carcinoma; A Gynecologic Oncology Group Study
Krivak T.C.,University of Pittsburgh |
Darcy K.M.,Roswell Park Cancer Institute |
Tian C.,Roswell Park Cancer Institute |
Tian C.,Precision Therapeutics Inc |
And 4 more authors.
Gynecologic Oncology | Year: 2011
Objective: This study evaluated common polymorphisms in excision repair cross-complementation group 1 (ERCC1) involved in repair of platinum-induced DNA damage in advanced-stage, epithelial ovarian/peritoneal/tubal cancer (EOC/PPC/FTC) patients treated with intravenous carboplatin- and paclitaxel-based chemotherapy. Methods: Pyrosequencing was performed to examine single nucleotide polymorphisms (SNPs) in codon 118 and C8092A in ERCC1 in leukocyte DNA from the Gynecologic Oncology Group phase III protocol, GOG-182. Kaplan-Meier method and adjusted Cox regression modeling were used to examine associations between ERCC1 polymorphisms and progression-free survival (PFS) and overall survival (OS). Results: The genotype distribution at codon 118 (n = 278) in ERCC1 for CC, CT, and TT was 23%, 45% and 32%, and the median OS was 32, 47 and 43 months, respectively. Patients with the CT + TT versus CC genotype in codon 118 in ERCC1 were at a reduced risk of death (hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.49-0.95, p = 0.025). The genotype distribution for C8092A in ERCC1 (N = 280) was 50%, 42% and 8%, and the median OS was 45, 40 or 30 months for CC, CA and AA, respectively. Women with the CA + AA versus CC genotype in C8092A in ERCC1 had a trend suggesting an increased risk of death (HR = 1.29, 95% CI = 0.97-1.72, p = 0.077). Conclusions: The polymorphism in codon 118 in the DNA repair gene ERCC1 was an independent predictor for better survival in EOC/PPC/FTC patients treated with intravenous carboplatin- and paclitaxel-based chemotherapy. The relationship between the C8092A polymorphisms in ERCC1 and survival was modest with an effect size that was not always statistically significant. © 2011 Elsevier Inc. All rights reserved.
Ortega P.,Medical College of Wisconsin |
Suster D.,Medical College of Wisconsin |
Falconieri G.,Policlinica di Cattinara |
Zambrano E.,Medical College of Wisconsin |
And 3 more authors.
Modern Pathology | Year: 2015
Sarcomas of the posterior mediastinum are rare and correspond mostly to neurogenic tumors. We studied 18 cases of liposarcoma presenting in the posterior mediastinum; because of their unusual location, some of these tumors posed difficulties for diagnosis. There were 11 men and 7 women aged 29-87 years (mean: 57). The tumors were large lobulated masses ranging from 6 to 30 cm in greatest diameter (median: 15 cm). Symptoms included cough, dysphagia, and chest pain. Four patients were asymptomatic and the tumors were discovered incidentally on chest X-rays. Histologically, 10/18 (55%) cases were atypical lipomatous tumor/well-differentiated liposarcoma, one of which harbored a smooth muscle component (lipoleiomyosarcoma); 3/18 (16%) were de-differentiated liposarcoma, one of which also harbored a smooth muscle component; 3/18 (16%) were myxoid/round cell liposarcoma; and 2/18 (11%) were pleomorphic liposarcoma. The cases of well-differentiated liposarcoma were mostly of the sclerosing type; however, five of them also showed prominent myxoid stroma closely resembling myxoid liposarcoma. Immunohistochemistry was performed in selected cases; 4/8 cases tested showed focal positivity for S-100 protein and 5/8 cases showed nuclear positivity for MDM-2. The three cases of myxoid liposarcoma were all negative for MDM2. Both cases of lipoleiomyosarcoma showed positivity for SMA and desmin in the smooth muscle component. FISH was performed in two cases of well-differentiated liposarcoma and high levels of amplification of MDM2 at 12q13-15 were observed; the CHOP translocation at 12q13.1-q13.2 was absent in both cases. Complete surgical excision was performed in 11 cases; however, negative surgical margins were achieved only in four. Clinical follow-up ranging from 1 to 192 months (median 28 months) was available for 13 patients. Two patients with myxoid/round cell liposarcoma died of tumor after 4 months and 3 years, respectively. Both had widely disseminated metastatic disease at the time of death. Six patients (6/10) with well-differentiated liposarcoma were alive and well with no evidence of disease (at 4, 7, 12, 15, and 25 months) and three (3/10) were alive with disease (at 3, 4, and 6 months). One patient with well-differentiated liposarcoma had multiple recurrences and a liver metastasis after 14 years; however, the patient was alive and well at 16 years. Five patients were lost to follow-up. In general, the biologic behavior of liposarcomas in the posterior mediastinum seems to correlate well with the histologic subtype and mirrors that of their counterpart in the retroperitoneum. © 2015 USCAP, Inc.
Kato Y.,Tokyo Medical University |
Kato Y.,Tokyo Metropolitan Tama Medical Center |
Yoshino I.,Tokyo Medical University |
Egusa C.,Tokyo Medical University |
And 3 more authors.
Journal of Dermatological Science | Year: 2014
Background: Histone deacetylase (HDAC) inhibitors are immunomodulatory, and demonstrate antitumor activity in various tumor models including malignant melanoma. Objective: The present study examines the effectiveness of IL-2 and HDAC inhibitor MS-275-combination therapy in a murine melanoma model. Methods: B16F10 cells were implanted subcutaneously in C57BL/6 mice which were randomly divided into four groups and treated with either IL-2 by subcutaneous injection, MS-275 by oral gavage (5 days/week, daily for 2 weeks), or a combination of the two agents. Results: MS-275 treatment showed a dose-dependent inhibitory effect on B16 cells in a colonogenic assay. Flow cytometry analysis indicated that MS-275 induced G1 arrest but not apoptosis in vitro, but IL-2 failed to inhibit cell proliferation. The combination of MS-275 and IL-2 had a statistically significant additive inhibitory effect on melanoma tumor weight and volume in vivo. Significantly higher survival was evident in the combination group compared with the control or single-agent groups. The combination therapy produced a greater ratio of CD8+ CD69+ T cells in lymph nodes than was seen in the MS-275-treatment and no-treatment groups among tumoriferous mice. Splenocytes from mice treated with MS-275 and the combination therapy demonstrated greater lysis of melanoma cells in vitro than splenocytes from mice treated with IL-2 or those without treatment. A significant antitumor effect from IL-2 and MS-275-combination therapy in vivo was seen in the increased number of activated CD8+ T cells. Conclusions: These data provide a convincing rationale for considering the role of epigenetics in future treatments for malignant melanoma. © 2014.
Alexiev B.A.,University of Maryland, Baltimore |
Levea C.M.,Roswell Park Cancer Center
International Journal of Surgical Pathology | Year: 2012
Nephrogenic adenoma (NA) is an uncommon and intriguing lesion in the urinary tract. The pathogenesis of NA is not entirely clear. NA was considered to be a metaplastic process of the urothelium in response to chronic irritation of the urinary tract. However, recent evidence has shown that NA is not a metaplastic lesion but rather a proliferation of exfoliated and implanted renal epithelial cells in the urinary tract. Histologically, NAs exhibit, singly or in combination, tubules, small papillae, and microcystic structures lined by cells with little cytological atypia and focal hobnail changes. Solid formations and compressed spindled cells within a fibromyxoid background are rarely observed. Differential diagnosis includes, but is not limited to, malignant neoplasms occurring at the same sites, in particular urothelial carcinoma with deceptively bland morphology (with small tubules, microcystic and nested variants), prostatic adenocarcinoma, and clear cell adenocarcinoma. Immunohistochemical studies with antibodies targeting members of the paired box gene family (PAX2 and/or PAX8) in NAs may be helpful in the differential diagnosis of urothelial lesions and prostatic adenocarcinoma. NAs are most likely to be confused with clear cell adenocarcinoma, especially in small biopsy specimens. This is confounded by both lesions being frequently positive for PAX2, PAX8, and CK7 and not infrequently positive for p504S (α-methylacyl-CoA-racemase, AMACR) by immunohistochemistry. Recognition of its characteristic morphological patterns and awareness of its unusual architectural and cytological features are important in making the diagnosis of NA and distinguishing this lesion from its mimickers. © 2012 The Author(s).
Greenberg C.C.,Dana-Farber Cancer Institute |
Greenberg C.C.,Brigham and Women's Hospital |
Lipsitz S.R.,Brigham and Women's Hospital |
Hughes M.E.,Dana-Farber Cancer Institute |
And 7 more authors.
Annals of Surgery | Year: 2011
Objective: To investigate the relationship between supply of subspecialty care and type of procedure preferentially performed for early stage breast cancer. Background: Three surgical options exist for early stage breast cancer: (1) breast conserving surgery (BCS), (2) mastectomy with reconstruction (RECON), and (3) mastectomy alone. Current guidelines recommend that surgical treatment decisions should be based on patient preference if a patient is eligible for all 3. However, studies demonstrate persistent variation in the use of BCS and RECON. Methods: Patients undergoing an operation for DCIS or stage I or II breast cancer at NCCN institutions between 2000 and 2006 were identified. Institutional procedure rates were determined. Spearman correlations measured the association between procedure types. Patient-level logistic regression models investigated predictors of procedure type and association with institutional supply of subspecialty care. Results: Among 10,607 patients, 19% had mastectomy alone, 60% BCS, and 21% RECON. The institutional rate of BCS and RECON were strongly correlated (r = -0.80, P = 0.02). Institution was more important than all patient factors except age in predicting receipt of RECON or BCS. RECON was more likely for patients treated at an institution with a greater supply of reconstructive surgeons or where patients live further from radiation facilities. RECON was less likely at institutions with longer waiting times for surgery with reconstruction. Conclusions: Even within the NCCN, a consortium of multidisciplinary cancer centers, the use of BCS and mastectomy with reconstruction substantially varies by institution and correlates with the supply of subspecialty care. Copyright © 2011 by Lippincott Williams & Wilkins.
Chanan-Khan A.,Roswell Park Cancer Center
Clinical advances in hematology & oncology : H&O | Year: 2010
Chronic lymphocytic leukemia (CLL) is a B-cell leukemia mainly affecting older adults. Historically, CLL has been regarded as an incurable disease, and treatment has been confined to cytotoxic chemotherapy regimens. However, prognosis for patients treated with these agents remained poor, prompting the development of new, targeted agents. The introduction of rituximab, a CD20-targeted monoclonal antibody, revolutionized the treatment for this disease. Rituximab in combination with fludarabine improved response rates and length of progression-free survival. The success of rituximab in this setting has prompted the development of many more investigational agents for CLL, including other antibody agents. However, as with any medication, the potential benefit achieved with CLL therapies is mitigated by the safety risk for the patient. These agents have been associated with adverse events such as immunosuppression, reactivation of cytomegalovirus, and infusion-related reactions that can occur with antibody administration. Adverse events can greatly affect the patient's quality of life and ability to tolerate therapy. Management of adverse events is a critical component of the overall treatment strategy for CLL, particularly in elderly patients. In this clinical roundtable monograph, 3 expert physicians discuss the latest clinical studies evaluating the treatment of CLL, focusing on the adverse events associated with each agent and the potential interventions that can be used to manage their occurrence.
Batty N.,Roswell Park Cancer Center |
Yarlagadda N.,Roswell Park Cancer Center |
Pili R.,Roswell Park Cancer Center
JNCCN Journal of the National Comprehensive Cancer Network | Year: 2013
Prostate cancer is the most common noncutaneous cancer among men. This case report describes a 43-year-old man with rapidly progressing castration-resistant prostate cancer (CRPC) that responded initially to docetaxel and did not tolerate cabazitaxel. He subsequently received a third line of chemotherapy with cyclo-phosphamide and prednisone, and experienced a dramatic clinical and radiographic response in his liver metastases. This therapeutic intervention led to a significant clinical benefit and confirms the potential use of cyclophosphamide in patients with CRPC, particularly those with liver metastases. Copyright © 2013 by the National Comprehensive Cancer Network. All rights reserved.
Parameswaran A.,State University of New York at Buffalo |
Attwood K.,Roswell Park Cancer Center |
Sato R.,State University of New York at Buffalo |
Seiffert-Sinha K.,State University of New York at Buffalo |
Sinha A.A.,State University of New York at Buffalo
British Journal of Dermatology | Year: 2015
Background Pemphigus vulgaris (PV) is a potentially fatal autoimmune blistering skin disease. It is known that individuals with autoimmune diseases such as PV, as well as their family members, are at increased risk of developing other autoimmune diseases. However, it is unknown whether there are specific autoimmune diseases that cluster with PV. Objectives To investigate the frequency of coexisting autoimmune diseases in patients with PV and their relatives, to determine the prevalence of specific autoimmune diseases in patients with PV vs. the general population and to identify statistically significant clinical clusters linking PV with other autoimmune disorders. Methods We performed a cross-sectional study and meta-analysis of patient data from our own patient database (n = 230), an anonymous online survey conducted by our laboratory (n = 171) and the International Pemphigus & Pemphigoid Foundation registry (n = 393). Results We found that the prevalences of autoimmune thyroid disease (AITD), rheumatoid arthritis and type 1 diabetes were significantly increased in patients with PV compared with the general population. These diseases were also among the most frequent in family members of patients with PV, in addition to systemic lupus erythematosus (SLE). Descriptive cluster analysis using basic principle components methods revealed that PV forms a distinct cluster with AITD, rheumatoid arthritis and type 1 diabetes, and another cluster with SLE, AITD and rheumatoid arthritis. Conclusions PV belongs to an established autoimmune disease cluster that includes AITD, rheumatoid arthritis and type 1 diabetes. Our data suggest the possibility of common genetic elements across clinically distinct diseases that might underlie autoimmune susceptibility. © 2014 British Association of Dermatologists.
Ouchi M.,Roswell Park Cancer Center |
Ouchi T.,Roswell Park Cancer Center
Cancer Biology and Therapy | Year: 2014
Checkpoint kinase 2 (Chk2) has been implicated in DNA damage signaling. By using BJ human fibroblasts, HCT116 colorectal cancer cells and HeLa cervical cancer cells, we further detailed phosphorylation kinetics of Chk2 under treatment with neocarcinostatin (NCS) or doxorubicin (Dox). After NCS treatment, phosphorylation of Chk2 Thr68 occurs in 3 min, followed by phosphorylation of Ser19 and Ser33/35. In ATM deficient fibroblasts, NCS does not induce phosphorylation of NBS1 Ser343 and Chk2 Ser19 and Ser33/35, however Chk2 Thr68 is still phosphorylated, indicating that ATM is essential for phosphorylation of these residues when treated with NCS. By using Chk2-de ficient HCT116 cells re-expressing phospho-mutant Chk2 (T68A), we found that inhibition of Thr68 phosphorylation enhances Ser19 phosphorylation in NCS treated cells. Interestingly, in contrast to NCS, Dox does not induce Ser33/35 phosphorylation in HeLa and HCT116 cells. Phosphorylation of Thr68 is sustained until 3 to 4 hours, and phosphorylation of Ser19 occurs 70 to 80 min after Dox treatment. These results demonstrate that Chk2 s involved in the early stages of DNA damage response. Differential phosphorylation kinetics of these residues suggests that DNA damage determines intermolecular and intramolecular interaction of Chk2, which may regulate phosphorylation. © Roswell Park Cancer Institute.
Shan W.,Baylor College of Medicine |
Akinfenwa P.Y.,Baylor College of Medicine |
Savannah K.B.,University of Texas M. D. Anderson Cancer Center |
Kolomeyevskaya N.,Baylor College of Medicine |
And 7 more authors.
Clinical Cancer Research | Year: 2012
Purpose: Uterine leiomyosarcoma (ULMS) is a poorly understood cancer with few effective treatments. This study explores the molecular events involved in ULMS with the goal of developing novel therapeutic strategies. Experimental Design: Genome-wide transcriptional profiling, Western blotting, and real-time PCR were used to compare specimens of myometrium, leiomyoma, and leiomyosarcoma. Aurora A kinase was targeted in cell lines derived from metastatic ULMS using siRNA or MK-5108, a highly specific small-molecule inhibitor. An orthotopic model was used to evaluate the ability of MK-5108 to inhibit ULMS growth in vivo. Results: We found that 26 of 50 gene products most overexpressed in ULMS regulate mitotic centrosome and spindle functions. These include UBE2C, Aurora A and B kinase, TPX2, and Polo-like kinase 1 (PLK1). Targeting Aurora A inhibited proliferation and induced apoptosis in LEIO285, LEIO505, and SK-LMS1, regardless of whether siRNA or MK-5108 was used. In vitro, MK-5108 did not consistently synergize with gemcitabine or docetaxel. Gavage of an orthotopic ULMS model with MK-5108 at 30 or 60 mg/kg decreased the number and size of tumor implants compared with sham-fed controls. Oral MK-5108 also decreased the rate of proliferation, increased intratumoral apoptosis, and increased expression of phospho-histone H3 in ULMS xenografts. Conclusions: Our results show that dysregulated centrosome function and spindle assembly are a robust feature of ULMS that can be targeted to slow its growth both in vitro and in vivo. These observations identify novel directions that can be potentially used to improve clinical outcomes for this disease. ©2012 AACR.