tbuckley/cabot-search huggingface dataset:
Differential effects of galeterone, abiraterone, orteronel, and ketoconazole on CYP17 and steroidogenesis.
Authors: Douglas Burtner Jacoby, Martin Williams
Journal: Journal of Clinical Oncology (2013)

184 Background: Because CYP17 has a central role in converting progestogens to androgens, inhibitors have been developed to treat CRPC. CYP17 has both hydroxylase and lyase catalytic functions. However, selective hydroxylase inhibition causes build-up of progestogens and mineralocorticoids, resulting in secondary mineralocorticoid excess (ME), edema, hypokalemia and hypertension (treated clinically with prednisone). We analyzed four inhibitors for their effects on CYP17 hydroxylase and lyase activities, and more globally on the steroidogenic pathway. Methods: Human CYP17 expressed in yeast microsomes was incubated with pregnenolone or 17α-hydroxypregnenolone and products quantitated using LC/MS/MS. Galeterone, abiraterone, orteronel or ketoconazole were added, and hydroxylase or lyase IC 50 values calculated. In a separate experiment, H295R adenocarcinoma cells were incubated with a range of drug concentrations between 0.316 nM and 10 μM for 24 hours and media was analyzed for steroid production by LC/MS/MS. Results: All drugs inhibited CYP17. However, potency and selectivity for hydroxylase and lyase varied significantly. Galeterone was the most potent and selective CYP17 lyase inhibitor. Abiraterone most selectively inhibited hydroxylase, while orteronel and ketoconazole were less potent lyase inhibitors than galeterone. In the cell-based assay, all drugs inhibited testosterone synthesis ≥94% at 1 μM. However, at this concentration, evidence of hydroxylase inhibition was supported by significant elevation of progesterone (abiraterone increased 293-fold), mineralocorticoids (orteronel increased DOC 74-fold), or reductions in cortisol (abiraterone, orteronel, ketoconazole reduced by 91%, 70% and 94%, respectively). In contrast, galeterone produced minimal changes in cortisol (decreased 14%) and other intermediate precursors. Conclusions: Galeterone is a selective and potent CYP17 lyase inhibitor that also antagonizes and degrades the AR, and exhibits minimal evidence of deleterious steroid changes associated with ME. These experimental data recapitulate phase I clinical experience where no ME was observed or prednisone required in CRPC patients.
Decision support needs-assessment in newly diagnosed malignant glioma.
Authors: Lara Kunschner Ronan, Camilo E. Fadul, Heather Wishart
Journal: Journal of Clinical Oncology (2016)

33 Background: Diagnosis of malignant glioma is catastrophic and standard treatment options remain non-curative. Patients are not guaranteed a good outcome, have significantly decreased QOL and exposure to risk. Shared decision making, is believed to diffuse decisional distress accompanying complex situations. Methods: Semi-structured interviews explored patient, caregiver and physician perceptions of standard of care treatment recommendations following diagnosis. Cognitive, neurological and functional ability was evaluated with neurological examination, Karnofsky Performance Scale (KPS), Trail-Making Test and The Hopkins Verbal Learning Test (HVLT). Physical and emotional distress was scored with the FACT-BR and the MD Anderson Symptom Inventory (MDASI). Results: Common themes emerging from patients’ interviews were identified, characterized and evaluated in comparison to those of treating physicians and caregivers. Several themes pertained to existential concerns, all of which were underappreciated by the physicians and to a lesser extent caregivers. Physicians emphasized the potential advantages of improved survival within a limited lifespan, but this advantage was perceived by patients as a binary life or death construct without differentiation of prognostic subtleties. Physicians and caregivers perceived shared decision making to be occurring to a greater degree than did patients. Cognitive and language dysfunction were not significant barriers to communication in this group of patients. Conclusions: Although physicians believed that shared decision making was occurring, there was poor patient comprehension of the complex situation and patients did not feel empowered or capable to make independent decisions. Patients endorsed moderate to severe distress in the setting of these treatment decisions. Improved physician-patient communication and patient education is needed to support engagement of patients and caregivers in therapy, to address the overwhelming existential crisis that patients face, and to avoid shepherding patients into treatments that are poorly understood, insufficiently explained for informed consent purposes, or accompanied by unrealistic expectations.
Sarcomatoid renal cell carcinoma (SRCC): University of Nebraska Medical Center experience.
Authors: Pavankumar Tandra, Jue Wang, Fausto R. Loberiza, George P. Hemstreet, Jairam Krishnamurthy, Vijaya Raj Bhatt
Journal: Journal of Clinical Oncology (2013)

472 Background: Sarcomatoid differentiation is not a distinct histological entity and it can present in any of the subtypes of renal cell carcinoma (RCC). Although many studies were published in the literature about its aggressive clinical course, limited clinical data was available about its management and especially about the role of newer targeted therapies. At our institution, we looked at the prognostic factors in SRCC and the role of systemic therapy in its management. Methods: During the years of 1997 to 2012, we studied the records of over 400 patients diagnosed with RCC. Out of them, 43 were identified as having SRCC. Cox proportional hazards risk analysis was used to analyze the factors associated with the risk of mortality. Survival probability was estimated using Kaplan Meier method. Results: Median age at diagnosis was 58. Median tumor size was 9.75 cm. High Furhmans grades (III &amp; IV) were seen in 67.44%. 68.29% patients presented with stage IV disease. 74.42 % patients had upfront nephrectomy. Of the systemic therapies given, 20.9% received cytokines, 16.2% received chemotherapy and 34.8% received target therapy. Probability of survival at 1 year was 50% (95% CI 33-65) and at 5 years was 24% (95% CI 10-41). Median time to progression was 13 months (95% CI 7 -23). Factors associated with risk of mortality were mainly the stage at diagnosis [HR 2.174, p = 0.0123, CI (1.184-3.992)], Nephrectomy [HR0.243, p = 0.0012, CI (0.104- 0.571)] and the use of target therapy [HR 0.313, p = 0.0070, CI (0.134-0.728)]. Conclusions: Our study confirmed that the SRCC is more aggressive than conventional RCC in its presentation and in its median time to progression. It responds poorly and unpredictably to systemic therapies. In our study, upfront nephrectomy and target therapy appeared to be independent predictors of survival. SRCC needs to be considered as a different disease entity and new treatment options need to be explored for this unfortunate subset of patients with kidney cancer.
Whole-exome sequencing (WES) of penile squamous cell carcinoma (PSCC) to identify multiple recurrent mutations.
Authors: Gurudatta Naik, Dongquan Chen, Michael Crowley, David Crossman, Katherine C. Sexton, William E. Grizzle, Amitkumar N. Mehta, Guru Sonpavde
Journal: Journal of Clinical Oncology (2016)

484 Background: Molecular alterations and drivers of PSCC, an orphan malignancy, remain unclear. The Cancer Genome Atlas is not studying PSCC and the Catalogue of Somatic Mutations in Cancer has performed targeted analyses only. We report WES of PSCC tumors from a group of patients (pts). Methods: Freshfrozen macrodissected PSCC tumor tissue and adjacent normal tissue samples were procured from the Cooperative Human Tissue Network. DNA was isolated from tissue sections by phenol chloroform extraction. Exome capture was performed with the Agilent SureSelect clinical research exome kit and whole exome-seq was done on the Illumina HiSeq2500 with paired end 100bp chemistry. Raw sequence data in Fastq format were aligned to human reference genome and quantified, and compared by using a local instance of Galaxy (galaxy.uabgrid.uab.edu). These data were analyzed for mutations (SNPs) analysis, by Partek Genomic Suite/Flow(PGS, Partek, St. Louis, MO) for variance calling against human reference genome (hg19) as referenced to dbSNP; and copy number variants (cnv) by FishingCNV tool together with picard tools/samtools/GATK). We focused on missense mutations and amplifications among ≥ 2 tumor samples but not in normal samples as they may cause upregulation of gene/protein function, which may be therapeutically actionable. Results: PSCC tumors were available from 11 patients and adjacent normal tissue from 3 patients. The 10 most common genes with &gt; 4 missense mutations among ≥ 2 tumor samples overall were the following in decreasing order of frequency: MUC4, HLA-DPA1, MUC16, XIRP2, SSPO, TTN, FCGBP, PABPC3, ALPK2 and MKI67. The top upstream transcriptional regulators were PIH1D3, PRDM5, PTK2, Coup-Tf and NBEAL2. When examining candidate actionable genes, recurrent missense alterations were seen in PIK3C2A and PIK3C2G. Additional analysis will study alterations in functional domains and cnv. Conclusions: WES identified a relatively high mutation burden in PSCC withrecurrent missense mutations in multiple genes, notably including the PI3K gene among potentially actionable genes. Validation of these findings and further study of downstream effects is required.
Defining clinical and statistical improvement in consolidation single-arm trials in ovarian cancer.
Authors: D. R. Spriggs, A. Iasonos, P. Sabbatini, R. E. O'Cearbhaill, H. T. Thaler
Journal: Journal of Clinical Oncology (2010)

5032 Background: The design of single-arm consolidation or maintenance trials is challenging from an endpoint perspective. Studies are currently designed to show an improvement in PFS when considered against historical controls. PFS includes duration of second- line therapy (SLT), treatment-free interval (TFI), and time on protocol therapy (TPT). We illustrate how statistical power is affected by the duration of SLT. Methods: Efficacy data from four published single-arm consolidation therapies in second remission in ovarian cancer (Sabbatini et al, Gyn Onc 2010, 116[1]:66-71) are used for illustration. The studies were designed to show increase in median PFS from 9 to 13.5 months (mos). Three intervals: duration of SLT, TFI, and TPT were calculated. We assumed that PFS follows exponential distribution from start of SLT with a drop in hazard at start of protocol therapy. We calculated the sample sizes required to have 80% power, 33% or 40% hazard reduction, for a 1-sided comparison versus historical PFS of 9 mos using intent to treat paradigm. Results: Median duration of SLT was 4.5 mos (IQR 3.6-5.9), median TFI: 2.5 mos, TPT varied from 4 mos to 7.5 mos. Required sample sizes varied with duration of SLT (Table). Alternatively, if one accrues 35 patients with planned 33% hazard reduction and the duration of SLT delays the start of protocol consolidation therapy to 7.5 months, the power drops to less than 40%. To maintain 80% power in this scenario, either the protocol therapy would have to reduce the hazard by 57%, or sample size would have to increase to approximately 170 events. Conclusions: A longer duration of SLT is associated with lower statistical power unless the magnitude of benefit with the new investigational treatment is greater than expected, or the sample size is increased. Designs of consolidation trials should take into account the duration of SLT, by either excluding it from the definition of PFS or restricting it per protocol. Time of initiating consolidation 33% hazard reduction sample size 40% hazard reduction sample size 0 mos (at start SLT) 35 22 4.5 mos 90 55 6 mos 124 75 7.5 mos 170 103 No significant financial relationships to disclose.
Soluble mesothelin, megakaryocyte potentiating factor, and osteopontin as markers of patient response and outcome in malignant pleural mesothelioma.
Authors: K. Hollevoet, K. Nackaerts, R. Gosselin, W. De Wever, L. Bosquée, P. De Vuyst, P. R. Germonpre, E. Kellen, C. Legrand, Y. Kishi, J. R. Delanghe, J. P. Van Meerbeeck
Journal: Journal of Clinical Oncology (2011)

7086 Background: Radiological response evaluation is notoriously difficult in patients with malignant pleural mesothelioma, an asbestos-related malignancy. Soluble mesothelin (SM), megakaryocyte potentiating factor (MPF), and osteopontin (OPN) are blood biomarkers of mesothelioma. This study evaluates their use as markers of response to therapy and outcome. Methods: 62 patients with malignant pleural mesothelioma were surveilled in a Belgian observational multicenter study. Blood samples and CTs were collected at diagnosis and, when possible, during and after therapy, until disease progression or death. SM and MPF levels were measured in serum with the Mesomark ELISA and the non-commercial Human MPF ELISA, respectively. OPN levels were measured in plasma with the Human Osteopontin ELISA. For each patient, the best overall radiological response was compared with the change in serum SM, MPF and plasma OPN levels across the corresponding time points. Survival analysis was performed with Cox proportional hazard regression and log-rank statistics. Results: In five patients who underwent extrapleural pneumonectomy, SM and MPF markedly decreased after surgery, whereas OPN showed a median increase. Of the 57 patients who received chemotherapy, 27 (47%) had radiological stable disease (SD), 14 (25%) partial response (PR), and 16 (28%) progressive disease (PD). In patients with SD, biomarker levels did not change significantly (SM and MPF), or decreased (OPN). For PR and PD, biomarker levels typically decreased and increased, respectively. A change ≥15% in all three biomarkers significantly correlated with patient response, whereas SM and MPF appeared more accurate than OPN. Low baseline OPN levels were independently associated with favorable overall and progression free survival. Neither SM nor MPF were informative for patient outcome. Conclusions: Relative changes in SM, MPF and OPN all three correlated with disease course, whereas SM and MPF appeared most suitable for monitoring of patients with mesothelioma. Baseline OPN levels were an independent negative predictor of survival. Further validation of these promising results remains mandatory.
Relation of methylation profiling between DNA repair gene MGMT and estrogen receptor alpha (ERα) gene in breast cancer (BC).
Authors: P. Stravoravdi, S. Voyatzi, K. Desiris, M. Markopoulos, D. A. Paikos, G. Zafiriou, A. Kiziridou, G. Simbilidis
Journal: Journal of Clinical Oncology (2011)

e13579 Background: The silencing of key cancer genes, via promoter methylation, affects molecular pathways involved in DNA repair and cell signaling. This epigenetic event is currently being investigated as a possible strategy for improving cancer therapy in BC. We studied the promoter methylation of DNA repair gene MGMT (O6-methylguanine-DNA methyltransferase) in relation with the ERα methylation status in ERα- negative BC patients (pts). Methods: A panel of 50 pts with primary BC of known ERα status (40/50 ERα-negative; 10/50 ERα-positive) was studied. Genomic DNA was extracted from archive formalin-fixed paraffin-embedded tumor tissues. DNA methylation of MGMT and ERα genes was determined by chemical modification of DNA and subsequent double “hot start” methylation-specific polymerase chain reaction (MSP) followed by detection on agarose gel. Results: Methylation of MGMT gene was observed in 24/40 (62.5%) and in 10/10 (100%) pts. Methylation of ERα gene was observed in 13/40 (32.2%) and in 0/10 (0%) pts. Methylation of MGMT gene alone was presented in 15/40 and of ERa gene in 4/40 pts. No methylation was observed in 11/40 pts. Both genes were methylated in 9/40 pts. The tumors of these pts did not express either progesterone receptors or HER2 protein (triple negative tumors). Conclusions: The frequency and the importance of methylation of MGMT gene is not well documented in BC. Our findings suggest that the methylation of MGMT gene is a common epigenetic event in BC and is higher in ERα (+) vs. ERα (-) tumors. Methylation of ERα gene is also a frequent event in ERα (-) tumors. Both epigenetic alterations may be potential targets for therapeutic strategies. The DNA repair protein MGMT confers resistance to alkylating agents, thus the silencing of MGMT gene leads to increased sensitivity for treatment. On the other hand, the silencing of ERα gene can be reversed, partially or completely, thus restoring the ERα (-) tumor sensitivity to endocrine therapies.
Integration of palliative care services into standard oncology practice at diagnosis of metastatic lung cancer at VA New York Harbor Healthcare System.
Authors: Felix Manuel Rivera Mercado, Carol Luhrs, Alice Beal, Maura Langdon, Joan Secrest, Susan M. Talbot
Journal: Journal of Clinical Oncology (2015)

165 Background: The 2012 ASCO provisional clinical opinion addressed the integration of palliative care into standard oncology practice at the time a person is diagnosed with metastatic or advanced cancer. The inclusion of Palliative Care among the National Quality Forum (NQF) framework represented a major advance in palliative care. NQF metrics include chemotherapy administered in the last 14 days of life, hospice less than 3 days before death, ICU or hospital admission, more than one Emergency Room visit in the last 30 days, and death in hospital. Although the use of hospice and other palliative care services has increased, many are enrolled in hospice less than 3 weeks before death. By improving quality of life, cost, and survival in patients with metastatic cancer, palliative care has increasing relevance for the care of patients with cancer. Methods: Retrospective chart review study of lung cancer patients diagnosed at VA from 2010-2013. Inclusion criteria: &gt; 18 years of age with new diagnosis of metastatic lung cancer. Exclusion criteria: &lt; 18 years of age, Stage I-III lung cancer. Results: Total of 125 patients were diagnosed with Stage IV lung cancer. The mean time from diagnosis to death was only 185 days (6.1 months). The VA NYHHS patients were more likely to visit the ED, be admitted to the hospital and ICU in the last 30 days of life, and subsequently die in the hospital. Conclusions: Several confounders were identified, including climate related closure of facilities (2012 Sandy storm), lack of social support, low ICU admission criteria, burial benefits for patients dying in a VA, and delay in transition to Hospice. Currently 392 patients with stage IV solid tumors diagnosed 2010-2014 are being studied. [Table: see text]
Impact of Total Body Irradiation on Successful Neutrophil Engraftment in Unrelated Bone Marrow or Cord Blood Transplantation
Authors: Hideki Nakasone, Kimikazu Yakushijin, Shigeo Fuji, Makoto Onizuka, Akihito Shinohara, Kazuteru Ohashi, Koichi Miyamura, Naoyuki Uchida, Minoko Takanashi, Tatsuo Ichinohe, Yoshiko Atsuta, Takahiro Fukuda, Masao Ogata
Journal: Blood (2016)
Frequency of unplanned surgical intervention in patients with stage IV colorectal cancer receiving palliative chemotherapy: An analysis of SEER-Medicare.
Authors: Patrick D. Lorimer, Kendall K Walsh, Russell C. Kirks, Yimei Han, Jimmy J. Hwang, Jonathan C. Salo, Joshua S. Hill
Journal: Journal of Clinical Oncology (2016)

640 Background: Patients (pts) with synchronous stage IV colorectal cancer commonly begin palliative chemotherapy while the primary tumor remains. Single institution series report low rates of surgical intervention, but this has not been examined nationally. The present study utilizes a large national dataset to examine the natural history of unplanned surgical intervention in stage IV colorectal cancer pts on palliative chemotherapy. Methods: SEER-Medicare was queried for pts with metastatic colorectal cancer (1998-2009) who underwent resection or diversion (ICD9 procedure/CPT). The cohort was separated into 3 groups: elective (surgery on admission without urgent/emergent flag), urgent (surgery not on day of admission but within hospitalization or with urgent flag) and emergent (emergent flag). Pts who underwent any procedure for curative intent (elective colorectal surgery, liver directed therapy or surgery for pulmonary metastases) at any time were excluded. Demographics, tumor grade and comorbidities were analyzed for effect on intervention rate. Time to event for either urgent or emergent surgical intervention or censorship by death, were measured. Conditional analyses were performed to determine the risk of surgical intervention at 6 months, 1 and 2 years post diagnosis. Results: 3,992 pts met inclusion criteria. Median age=73; 53% male. White 79%, black 11% and other 10%. The overall intervention rate was 6%; 35% emergent, 65% urgent. At 42 months, 90% of the pts had died. The probability of requiring unplanned surgery between 6-12 months was 2.5%; 12-24 months=1.9%, and &gt;24 months=0.8%. Charlson comorbidity score of 1 was a significant predictor of surgical intervention (HR 1.64 [1.24, 2.19]). Sex, age and race had no influence on the likelihood of surgical intervention. Conclusions: This study represents a large series of stage IV colorectal cancer pts and the frequency of unplanned surgery in pts receiving palliative chemotherapy. Pts treated with palliative chemotherapy are unlikely to require urgent or emergent surgery, and therefore prophylactic surgery to reduce the risk of perforation or obstruction should not be routinely performed.
Heparanase expression in melanoma
Authors: A. Kuten, R. Abdah-Bortnyak, N. Ilan, V. Kaplan, I. Vlodavsky
Journal: Journal of Clinical Oncology (2005)

7534 Background: No effective systemic treatment exists for advanced stage of melanoma. Identification of new markers involved in the initiation and progression of melanocytic tumorigenesis, that will be the basis for developing new therapeutic tools are still needed. The expression of the heparanase gene and its protein has been associated with metastatic potential of several human tumors. The purpose of the study is to determinate the expression of heparanase in nevus and melanoma in different stages of tumor progression and to evaluate the clinico-pathologic significance these findings. Methods: 60 formalin-fixed and paraffin-embedded specimens of nevus (15) and melanoma (45) were examined by immunohistochemical staining for heparanase expression. Results: No (in 7 specimens) or weak (+1 in 8) heparanase expression was detected in nevus. Heparanase was detected in both the cytoplasm and the nucleus of heparanase positive cells. Heparanase expression +1 was confirmed in 11 specimens, +1–2 in 2 and +2 in 2 specimens of superficial spreading melanoma (Breslow <4 mm). Intermediate intensity staining (+2) was detected in 14 cases of thick melanoma (Breslow >4 mm) and only one case showed weak staining. Strong heparanase expression (+3) predominated in 10 cases from different metastatic sites and intermediate to strong staining in 5 specimens (3 from lymph nodes and 2 from lung metastases). Conclusions: Heparanase expression in melanoma is significantly correlated with tumor stage and metastatic potential. No significant financial relationships to disclose.