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Fogelman D.,University of Texas M. D. Anderson Cancer Center | Sugar E.A.,Johns Hopkins Medical Institutions | Sugar E.A.,Johns Hopkins University | Oliver G.,Johns Hopkins Medical Institutions | And 17 more authors.
Cancer Chemotherapy and Pharmacology

Purpose: Metastatic pancreatic adenocarcinoma is considered a uniformly fatal disease with a median survival of 1 year with modern chemotherapy. While a subset of patients achieve prolonged survival, few of the factors that define this group of patients are known. Methods: For the determination of overall survival (OS), 549 patients with histologically confirmed metastatic pancreatic adenocarcinoma were evaluated. Emphasis was placed on treatment history and family history of breast, ovarian, and pancreatic cancers. To ensure a uniform metastatic population, patients treated with prior locoregional therapies (i.e., surgery or radiotherapy) were excluded as were patients with a prior history of stage I-III disease. Results: Patients with family history or pedigree history of cancer had superior OS. This was especially true in patients with three or more relatives with either breast, ovarian, or pancreatic cancers [hazard ratio (HR) 0.49, 95 % confidence interval (CI) 0.30-0.80, p = 0.003]. First-line platinum chemotherapy was associated with a poor survival (hazard ratio for death 1.74, 95 % CI 1.12-2.71, p = 0.01) for patients without a family history of these cancers but not for those without such a history (p = 0.31). In fact, as the number of relatives with these cancers increased, the OS survival improved for individuals receiving first-line platinum therapy (HR 0.76, 95 % CI 0.65-0.89, p = 0.0004), which was not the case for those receiving other therapies (p = 0.98). Conclusions: Treatment with platinum chemotherapy in patients with a family history of breast, ovarian, or pancreatic cancers was associated with a longer survival, whereas platinum use in patients without such a family history of cancer was associated with poor survival. These findings suggest that family history may serve as a predictive marker for platinum use in patients with metastatic pancreatic adenocarcinoma. © 2015 Springer-Verlag Berlin Heidelberg. Source

Le D.T.,Sidney Kimmel Cancer Center | Le D.T.,Swim Across America Laboratory at Johns Hopkins | Lutz E.,Sidney Kimmel Cancer Center | Uram J.N.,Sidney Kimmel Cancer Center | And 9 more authors.
Journal of Immunotherapy

Preclinical reports support the concept of synergy between cancer vaccines and immune checkpoint blockade in nonimmunogenic tumors. In particular, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibodies have been successfully combined with GM-CSF cell-based vaccines (GVAX). Ipilimumab (anti-CTLA-4) has been tested as a single agent in patients with pancreatic ductal adenocarcinoma (PDA) resulting in a delayed response at a dose of 3 mg/kg. Our study evaluated ipilimumab 10 mg/kg (arm 1) and ipilimumab 10 mg/kg+GVAX (arm 2). A total of 30 patients with previously treated advanced PDA were randomized (1:1). Induction doses were administered every 3 weeks for a total of 4 doses followed by maintenance dosing every 12 weeks. Two patients in arm 1 showed evidence of stable disease (7 and 22 wk) but none demonstrated CA19-9 biochemical responses. In contrast, 3 patients in arm 2 had evidence of prolonged disease stabilization (31, 71, and 81 wk) and 7 patients experienced CA19-9 declines. In 2 of these patients, disease stabilization occurred after an initial period of progression. The median overall survival (OS) (3.6 vs. 5.7 mo, hazards ratio: 0.51, P=0.072) and 1 year OS (7 vs. 27%) favored arm 2. Similar to prior ipilimumab studies, 20% of patients in each arm had grade 3/4 immune-related adverse events. Among patients with OS>4.3 months, there was an increase in the peak mesothelin-specific T cells (P=0.014) and enhancement of the T-cell repertoire (P=0.031). In conclusion, checkpoint blockade in combination with GVAX has the potential for clinical benefit and should be evaluated in a larger study. Copyright © 2013 by Lippincott Williams & Wilkins. Source

Jones S.,Personal Genome Diagnostics (PGD) | Stransky N.,Blueprint Medicines | McCord C.L.,Personal Genome Diagnostics (PGD) | Cerami E.,Blueprint Medicines | And 12 more authors.
Nature Communications

Malignant mixed Müllerian tumours, also known as carcinosarcomas, are rare tumours of gynaecological origin. Here we perform whole-exome analyses of 22 tumours using massively parallel sequencing to determine the mutational landscape of this tumour type. On average, we identify 43 mutations per tumour, excluding four cases with a mutator phenotype that harboured inactivating mutations in mismatch repair genes. In addition to mutations in TP53 and KRAS, we identify genetic alterations in chromatin remodelling genes, ARID1A and ARID1B, in histone methyltransferase MLL3, in histone deacetylase modifier SPOP and in chromatin assembly factor BAZ1A, in nearly two thirds of cases. Alterations in genes with potential clinical utility are observed in more than three quarters of the cases and included members of the PI3-kinase and homologous DNA repair pathways. These findings highlight the importance of the dysregulation of chromatin remodelling in carcinosarcoma tumorigenesis and suggest new avenues for personalized therapy. © 2014 Macmillan Publishers Limited. All rights reserved. Source

Holdhoff M.,Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Holdhoff M.,Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins | Holdhoff M.,Swim Across America Laboratory at Johns Hopkins | Ye X.,Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | And 6 more authors.
Journal of Neuro-Oncology

This study was conducted to assess the current pattern of use and the impact of available molecular predictive and prognostic biomarkers on clinical care in patients with glioblastoma (GBM). An online questionnaire consisting of 15 questions about the frequency of use and clinical utility of tissue-based molecular tests was distributed to 1,053 members of the Neuro-Oncology Community in the United States. A total of 320 responses (30.4 %) were collected. 73 respondents who did not see GBM patients were excluded from analysis. MGMT promoter methylation testing (MGMT-meth) was the most commonly requested (37.2; 95 % CI, 31-44), followed by EGFR amplification (22.7; 95 % CI, 18-28), co-deletion of 1p/19q (22.3 %), EGFR expression (21.5 %), P53 mutation (19.8 %), PTEN mutation or deletion (17.4 %), EGFRvIII mutation (12.1 %), IDH1/2 mutation (12.1 %), PDGFR (4.5 %), and PIK3CA (0.8 %). The perceived utility of these studies was variable between participants. A small percentage of respondents felt that any of the studies were always or almost always helpful in clinical decision making (MGMT-meth 10.9 %; range, 0-13.8 %), but more frequently never or almost never helpful (MGMT-meth 25.9 %; range, 25-54.7 %). 26.7 % reported not to routinely order any of these studies. Although molecular markers are frequently ordered for patients with GBM, only a minority of clinicians ordering these tests report that the results influence clinical decision-making. Molecular markers that are likely to affect patient care should be ordered with the goal to maximize benefit for patients and to avoid non-actionable results and additional costs. © 2012 Springer Science+Business Media, LLC. Source

Reese J.B.,Johns Hopkins University | Finan P.H.,Johns Hopkins University | Haythornthwaite J.A.,Johns Hopkins University | Kadan M.,Johns Hopkins Sidney Kimmel Comprehensive Cancer Center | And 7 more authors.
Supportive Care in Cancer

Purpose: Research examining effects of ostomy use on sexual outcomes is limited. Patients with colorectal cancer were compared on sexual outcomes and body image based on ostomy status (never, past, and current ostomy). Differences in depression were also examined. Methods: Patients were prospectively recruited during clinic visits and by tumor registry mailings. Patients with colorectal cancer (N =141; 18 past ostomy; 25 current ostomy; and 98 no ostomy history) completed surveys assessing sexual outcomes (medical impact on sexual function, Female Sexual Function Index, International Index of Erectile Function), body image distress (Body Image Scale), and depressive symptoms (Center for Epidemiologic Studies Depression Scale - Short Form). Clinical information was obtained through patient validated self-report measures and medical records. Results: Most participants reported sexual function in the dysfunctional range using established cut-off scores. In analyses adjusting for demographic and medical covariates and depression, significant group differences were found for ostomy status on impact on sexual function (p <.001), female sexual function (p =.01), and body image (p <.001). The current and past ostomy groups reported worse impact on sexual function than those who never had an ostomy (p <.001); similar differences were found for female sexual function. The current ostomy group reported worse body image distress than those who never had an ostomy (p <.001). No differences were found across the groups for depressive symptoms (p =.33) or male sexual or erectile function (p values≥.59). Conclusions Colorectal cancer treatment puts patients at risk for sexual difficulties and some difficulties may be more pronounced for patients with ostomies as part of their treatment. Clinical information and support should be offered. © Springer-Verlag 2013. Source

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