tbuckley/cabot-search huggingface dataset:
Paclitaxel/carboplatin with or without sorafenib in the first-line treatment of patients with stage III/IV epithelial ovarian cancer: A randomized phase II study of the Sarah Cannon Research Institute.
Authors: Dana Shelton Thompson, B. Stephens Dudley, John A. Bismayer, Victor G. Gian, William McIver Merritt, Robert C. Whorf, Howard A. Burris, John D. Hainsworth
Journal: Journal of Clinical Oncology (2013)

5513 Background: The combination of paclitaxel and carboplatin is the most widely used chemotherapy regimen for patients (pts) with advanced ovarian cancer, producing a median survival of approximately 36 months. Recently, the addition of bevacizumab, an angiogenesis inhibitor, has improved progression-free survival (PFS) when compared to paclitaxel/carboplatin alone. Sorafenib is an oral multi-kinase inhibitor with effects on tumor angiogenesis through inhibition of the VEGF receptor. The purpose of this randomized phase II study was to compare efficacy of paclitaxel/carboplatin with and without sorafenib. Methods: Women with histologically confirmed, maximally debulked, previously untreated stage III/IV epithelial ovarian carcinoma were randomized to receive paclitaxel 175 mg/m 2 and carboplatin AUC 6 (PC) or PC + sorafenib 400 mg PO BID (S). All patients received 6 cycles, given every 3 weeks; pts receiving PC+S continued single agent sorafenib for 52 weeks total. The primary endpoint was 2-year PFS rate. Results: 85 pts were randomized between 1/07 and 10/11 (PC+S 43; PC 42). Pt characteristics were similar between groups, except that more patients with only CA125 elevation received PC+S (65% vs 43%). Overall, 67 pts (79%) completed 6 cycles of chemotherapy (PC+S 74%; PC 83%). More patients stopped PC+S due to toxicity (14% vs 7%). 22 pts (51%) receiving PC+S began single agent S after 6 cycles PC, and 12 pts (28%) completed 52 weeks of S. There was no difference in the 2-year PFS rates: PC+S 40%, PC 39%. Overall survival comparisons were also similar (p = 0.36). Pts receiving PC+S had more grade 3 rash (33% vs 0%) and hand-foot syndrome (9% vs 0%). Conclusions: The addition of sorafenib did not improve the efficacy of standard first-line PC in pts with stage III/IV ovarian carcinoma, and resulted in additional toxicity. Clinical trial information: NCT00390611.
Identification of Lynch syndrome cohort in a hospital system.
Authors: Andrew L. Salner, Richard Sekerak, Peter Paul Yu
Journal: Journal of Clinical Oncology (2017)

91 Background: Lynch Syndrome (LS) is a genetically inherited autosomal dominant disease that is the result of germline mutations in mismatch repair (MMR) genes. LS is the most common cause of inherited colorectal cancer (CRC), causes cancer at a younger age, and increases other cancer risk (pancreas, endometrium). Thus, it is important to identify patients who have LS so that patients and affected family members can receive the proper surveillance and care. Hartford HealthCare Cancer Institute (HHCCI) has developed a standard of care to screen patients who may have LS by testing CRC specimens for loss of expression of MMR genes, as well as to refer all patients under 50 for counseling. The aim of this research project is to determine how well each of our healthcare system's five hospitals is meeting the standard. Methods: This retrospective study explored all cases of CRC at each of the five HHCCI hospitals from 2014-2015. Patients were identified from the Cancer Registry and data was extracted from patient charts, pathology and genetics reports. The study analyzed: age, gender, stage, presence of MMR testing, and genetics counseling and testing for MMR positive patients and patients under 50. Results: 423 CRC patients were diagnosed at HHC cancer centers, 45% male, 55% female, average age of 68.2. In total, HHCCI tested 81.3% of patients diagnosed with CRC in 2014-2015, ranging from 30.8 to 94.5% among the hospitals. 7.6% of patients had abnormal MMR results. Of patients with MMR+ results, 57.7% had genetic consult and 10 of the 15 consulted had a germline test. Seven patients (70%) tested positive for LS. Patients with LS were younger (average age 47.6), and the majority were male. Ten of 45 patients under 50 were referred for genetics consult (22%), with a range of 0-67% amongst the hospitals. Three were LS positive on testing. Conclusions: Clinicians on our GI cancer team assumed that the agreed upon standard of MMR testing in CRC and referral of younger patients for genetics counseling would result in 100% compliance. The study outcomes suggest a need for improved implementation strategies for CRC testing at HHCCI hospitals. Overall, the study demonstrates the importance and need of quality improvement measures to inform and improve patient care.
The role of apoptosis in colorectal carcinogenesis and its prognostic value.
Authors: Julia Alcaide, Rafael Funez, Antonio Rueda, Elisabeth Pérez-Ruiz, Teresa Pereda, Isabel Rodrigo, Diego Perez, Rosa Villatoro, Esteban Nogales, Maximino Redondo
Journal: Journal of Clinical Oncology (2013)

e22131 Background: Most colorectal cancers (CRCs) progress through a multistep process from normal tissue to adenoma to carcinoma. The role of apoptosis during this tumourigenesis sequence has not yet been completely clarified. The aim of our study was to determine the influence of apoptotic variations on the carcinogenesis and prognosis of CRC. Methods: A TUNEL assay was performed on the formalin-fixed, paraffin-embedded tissues from 103 CRCs resected at the Costa del Sol Hospital (after excluding patients previously treated with chemotherapy or radiation therapy), 26 adenomas and 20 samples of normal epithelia. Clinical data were obtained from the tumour registry and hospital charts. The study was approved by Research Ethics Committee. We used the median (m) of apoptotic percentage (1%, range: 0-6%) as a threshold value for survival (sv) studies. Analysis of association between apoptosis and prognostic factors used the X 2 test for categorical variables and the analysis of variance test for continuous variables (natural log transformed if necessary). We estimated sv using the Kaplan-Meier method, and sv curves were compared with the log rank test. Cox’s proportional hazards sv analysis was used to determine the relative risk (RR) through multivariate analyses. Results: Median follow-up was 50 months (mo). Apoptotic index (AI) was higher in CRCs (1.09 ± 0.13) than in adenomas (0.38 ± 0.23, p=0.059) and significantly greater than in normal epithelium (0.06 ± 0.04, p=0.001). AI was greater in stage IV than in other stages (p=0.017). Higher AI was associated with lower disease-free survival (DFS) and overall survival (OS) than lower AI (Table). In multivariate analysis, AI (RR=2.18, 95% CI 1.08-4.37) and TNM stage (RR=2.41, 95% CI 1.20-4.85) were independent prognostic factors for OS. Conclusions: Our study demonstrates an increase in apoptosis during colorectal carcinogenesis and a correlation between apoptotic rates and survival. Higher AIs are associated with more aggressive tumours and a poorer prognosis in CRC. [Table: see text]
Chromogen in situ hybridisation (CISH) for HER2 assessment is highly concordant with FISH in core cut biopsies of primary T2 breast cancers
Authors: G. H. Raab, B. Hoegel, J. Biebl, W. Eiermann
Journal: Journal of Clinical Oncology (2004)

569 Background: For proper decision making concerning HER2 status in breast cancer FISH is the most accurate method especially when immunohistochemistry (IHC) results in a score 2+. But FISH is expensive and can routinely be implemented only in experienced centers. In addition fluorescence is not permanent so that quality checks are impossible. There is already some evidence that CISH may be as accurate as FISH with lower costs and a permanent staining for quality control. In order to deliver a reproducible and cheap method for HER2 testing in early breast cancer, we tested the concordance of CISH and FISH and evaluated the CISH and FISH results of IHC 2+ scores. Methods: HER2 testing in tumor tissue from core cut biopsies of T2 primary breast cancers was prospectively performed in our center with immunohistochemistry (DAKO Herceptest™). CISH and FISH were additionally done in all 2+ cases. Results: The HER2 status of 103 tissue samples from core cut biopsies was prospectively examined. In 71 samples CISH, FISH and IHC was performed concurrently. 56 samples with IHC score 2+ (78.9%) were reanalyzed by FISH and CISH and showed FISH and CISH negativity in 64.3% (n = 36). FISH and CISH positivity was found in 33.9% (n = 19). In one case (1.8%) FISH was negative while CISH was positive. This translates into a 98.2% concordance for differentiation between HER2 positivity or negativity. All samples with IHC score 3+ (n = 6) were FISH and CISH positive. In the whole series with 12.6% (n = 9) score 0 / 1+, 78.9% (n = 56) score 2+ and 8.5% (n = 6) score 3+, HER2 positivity was found in 40,8% (n = 29) with CISH and 39.4% (n = 28) with FISH. CISH + FISH were positive in 39.4% (n = 28) revealing a concordance for HER2 positivity of 96.6%. HER2 status was negative in CISH + FISH in 59.2% with a concordance for HER2 negativity of 97.9%. In 1 case (1.4%) FISH was negative and CISH positive. Conclusions: In this selected series of T2 breast cancer core cut biopsies FISH and CISH revealed a very high concordance of HER2 positivity and negativity when IHC showed a score 2+. Therefore CISH should be used as a cheaper and permanent assessable alternative to FISH for HER2 testing. No significant financial relationships to disclose.
Phase I trial of sargramostim and thalidomide for treatment of hormone-refractory prostate cancer
Authors: M. Lilly, E. H. Rowsell, R. Gurrola, H. Ruckle
Journal: Journal of Clinical Oncology (2004)

4690 Background: Sargramostim (GM-CSF) has been given to hormone-refractory prostate cancer (HRPC) patients to activate immune/inflammatory responses in situ. PSA and clinical responses have been seen but the response rates have been variable. We have combined sargramostim (activates dendritic cells)with thalidomide (modulates T cell and NK function) in an attempt to increase anti-tumor activity in HRPC patients. Methods: Sargramostim was administered subQ daily x 14 days, then QOD x 3 months. Thalidomide was administered po daily, beginning on day 15 and continuing for 3 months. PSA, clinical, and radiographic responses were monitored during therapy. Lymphocyte and dendritic cell populations were also monitored during treatment. Results: Ten patients with HRPC were enrolled on the study. The initial cohort (3 patients) dose level was sargramostim 500mcg/dose and thalidomide 200mg/d. Because of substantial toxicity, subsequent cohorts were treated with reduced doses (cohort 2 = sargramostim 500mcg/dose and thalidomide 100mg/day, and cohort 3 = sargramostim 250mcg/dose and thalidomide 100mg/day). One patient received only one week of Rx and was not considered to be evaluable. 7/9 evaluable patients (78%)had rapid PSA responses. Average PSA decrease was 50.4%. One patient with a soft tissue mass also had a 60% decrease in measurable disease. Substantial toxicity was noted in the first two cohorts, with 7 grade III toxicities (fatigue 2, DVT (on ASA) 1, acute MI (on coumadin)1, pleural/pericardial effusions 1, peripheral neuropathy 1, neurogenic bladder 1). The MTD appeared to be sargramostim 250mcg/d plus thalidomide 100mg/d. Time for PSA level to return to the pretreatment value was inversely correlated with PSA magnitude (PSA under 50ng/mL = 26.4wks, PSA over 50ng/mL = 9.5wks). Conclusions: Treatment of HRPC with sargramostim and thalidomide produced a high level of PSA responses. In patients with modest pretreatment PSA levels, freedom from PSA progression was often prolonged. However substantial toxicity was noted, leading to moderate morbidity. Immunomodulation may be useful in delaying progression of minimal HRPC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celegene Corporation
Phase II study of bevacizumab, cisplatin, and pemetrexed as first-line chemotherapy for advanced nonsquamous non-small cell lung cancer (NS-NSCLC) with EGFR wild-type.
Authors: Shuji Murakami, Haruhiro Saito, Fumi Karino, Tetsuro Kondo, Fumihiro Oshita, Kouzo Yamada
Journal: Journal of Clinical Oncology (2014)

e19125 Background: AVAPER trial demonstrated that a bevacizumab, cisplatin and pemetrexed combination regimen (CDDP/PEM/BEV) is beneficial in advanced nonsquamous non-small-cell lung cancer (NS-NSCLC), but there are few reports of the regimen, which combined these agents. The aim of this phase II study was to evaluate the feasibility and safety of a CDDP/PEM/BEV regimen in the treatment of NS-NSCLC with EGFR wild type in Japanese patients. Methods: Patients with stage III and IV NS-NSCLC with EGFR wild type were treated with CDDP/PEM/BEV. Chemotherapy treatments consisted of 4-6 cycles of CDDP 75mg/m2, pemetrexed 500mg/m2 and bevacizumab 15mg/kg on day 1 every 3 - 4 weeks. The primary endpoint of this study was the response rate and the secondary endpoint was PFS, OS and rates of adverse events. Results: Twenty-five patients were enrolled between August 2010 and February 2013. The patient’s demographics were: median age 62 years (range 42-70), 19 males and 6 females. 4 cases were stage III and 21 cases were stage IV. 22 (88%) Included EGFR wild type and 3 were unknown. The median number of cycles was 4 (range 1-6). 64% patients went to maintenance. Response rate (RR) was 64% and disease control rate (DCR) was 100%. The median progression free survival time was 10.3 months. Hematological adverse events reaching grade 3 to 4 were neutropenia (8%) with no febrile neutropenia, thrombocytopenia (4%), and anemia (4%). Nonhematological toxicities of grade 3/4 were hypertension (16%), infection (8%), hyponatremia (8%), thrombosis (4%), urticaria (4%), anorexia (4%), and hyperbilirubin (4%). Each of the toxicities were controllable and there were no treatment-related deaths. Conclusions: CDDP/PEM/BEV regimen is an effective and a tolerable regimen in patients with advanced NS-NSCLC with EGFR wild or unknown types. Clinical trial information: Is this clinical trial registered?.
Abstract P302: CaMKII Is Not Critical for Ischemia/Reperfusion Injury
Authors: Martin Weinreuter, Lorenz H Lehmann, Michael Kreußer, Hermann-Josef Gröne, Oliver J Müller, Eric N Olson, Hugo A Katus, Johannes Backs
Journal: Circulation Research (2011)

Objectives: The role of the Calcium/calmodulin-dependent protein kinase II (CaMKII) in Ischemia/Reperfusion of the heart (I/R) has not completely been clarified yet - partly due to lacking evidence from animal studies with specific gene knockout (KO) strategies. Moreover, the contribution of the nuclear and cytosolic CaMKIIδ splice variants δB and δC to I/R-induced myocardial damage have been controversially discussed. To investigate the role of CaMKII in myocardial I/R we used several KO mice with genetic deletion of the two major isoforms expressed in the heart, CaMKIIδ and CaMKIIγ, respectively. Both single and double KO models were examined. In addition, we developed a reliable approach to express CaMKII δB and δC splice variants in CaMKIIδ-null mice using adeno-associated-virus serotype 9 (AAV9) to investigate their specific roles in I/R. Methods and Results: A surgical in vivo I/R model was used following two protocols: 30 minutes ischemia with 48 hours of subsequent reperfusion (30/48) and 60 minutes ischemia followed by a 24 hour reperfusion period (60/24). Planimetric measurements of infarct size after staining with Evans Blue and Triphenyl tetrazolium chloride showed no significant difference between CaMKII KO and control groups (infarct-zone/area-at-risk ratio for 30/48-protocol: CaMKIIγ −/− vs. C57/Bl6: 0.49 ± 0.04 vs. 0.43 ± 0.05, p=0.43, n≥6; CaMKIIδ −/− vs. C57/Bl6: 0.42 ± 0.04 vs. 0.44 ± 0.04, p=0.69, n≥19; infarct-zone/area-atrisk ratio for 60/24-protocol: CaMKIIδ −/− vs. C57/Bl6: 0.52 ± 0.02 vs. 0.56 ± 0.03, p=0.33, n≥8; CaMKIIγ loxP/loxP δ loxP/loxP ; alphaMHC-Cre vs. CaMKIIγ loxP/loxP δ loxP/loxP : 0.52 ± 0.03 vs. 0.52 ± 0.04, p=0.86, n≥9). Consistently, no differences in high-sensitive serum troponin T levels 24 hours after onset of ischemia could be detected. Neither histologic TUNEL-staining nor Caspase3/7-acivity assays revealed any significant differences in apoptotic cell death processes. Importantly, specific expression of CaMKII δB or δC splice variants via AAV9 gene transfer - at approximate endogenous protein levels - in CaMKIIδ −/− mice had no effect on infarct size and necrotic or apoptotic markers. Conclusion: Our findings indicate that CaMKII is not critical for myocardial infarct size and apoptosis in response to I/R.
Frequency and survival impact of osseous metastases in patients with untreated renal cell carcinoma
Authors: S. A. Misbah, E. Segota, T. Mekhail, R. Abou Jawde, T. Olencki, R. Dreicer, G. T. Budd, P. Elson, R. M. Bukowski
Journal: Journal of Clinical Oncology (2004)

4631 Background: The impact of OM on survival in patients with RCC is controversial. In several recent database studies OM have been reported to have a negative effect on survival (Negrier, Ann Oncol. 2002; 13:1460, Atzpoodien, B J Cancer. 2003; 88:348), while in others it has been reported to have no effect (Motzer, J Clin Oncol. 2002; 20:289). Methods: We evaluated a database comprised of 309 previously untreated metastatic RCC patients entered into IRB approved clinical trials at our institution between 1987 and 2002. Univariable and multivariable analyses were performed to evaluate the association between OM and survival. Results: 95 patients (31%) had OM at the time of entry on study. Univariate analysis suggested a negative impact of OM on survival; median survival was 12.2 versus 16.3 months with OM present and absent, respectively (p=0.09). A multivariable analysis was performed to analyze the impact of OM while considering other important prognostic factors. This analysis adjusted for the number of poor risk factors present (Motzer, J Clin Oncol. 2002; 20:289), the number of metastatic sites present (Abou Jawde, ASCO Proceedings. 2003; #1545), and histology (clear cell versus non-clear cell). Motzer's poor risk factors include Karnofsky performance status (< 80%), hemoglobin (< 13.5 g/dL for males and < 12.0 g/dL for females), LDH (> 220 U/L), corrected calcium (> 10 mg/dL), and time from tumor diagnosis to metastases (< 1 year). In this analysis the number of poor risk factors present, the number of metastatic sites present, and histology were found to be independent predictors of survival (p < 0.001, p=0.002, and p < 0.001, respectively). Correcting for these factors the impact of OM was not statistically significant (p=0.33). Conclusions: Adjusting for other important predictors, the presence of OM does not have an impact on survival in previously untreated RCC patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene; Chiron
Improving immune-related adverse event management in a thoracic clinic.
Authors: Meghan Shea, Deepa Rangachari, Daniel Botelho Costa, Aya Sato-DiLorenzo, Jessica A. Zerillo
Journal: Journal of Clinical Oncology (2017)

74 Background: Widespread use of immunotherapeutic agents has transformed the profile of adverse events associated with systemic cancer therapy. Management of immune-related adverse events (IRAEs) is contingent upon grading severity using the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE). Nivolumab and Pembrolizumab were recently approved for metastatic non-small cell lung cancer (NSCLC). United States Food and Drug Administration (US FDA)-approved package label inserts provide guidance on IRAE management and are predicated on CTCAE grade, including when to discontinue drug. Currently, clinicians in the thoracic oncology group are documenting CTCAE grade of IRAEs infrequently, and management is varied. Methods: A retrospective chart review of baseline data revealed 45 patients (8 on Pembrolizumab, 37 on Nivolumab) who initiated immunotherapy for metastatic NSCLC between March 2015 and August 2016. A team of clinicians developed a process map from diagnosis of IRAE to initiation of toxicity management. Physicians were surveyed. The team’s aim is by February 1, 2017, at least 50% of patients who develop an IRAE on immunotherapy for metastatic NSCLC have documentation of toxicity grade using the CTCAE criteria. Results: The physician survey response rate was 12 of 16 (75%). Physicians reported not using grade to guide management of IRAEs over two thirds (67%) of the time. Time to look up CTCAE criteria and knowing that grade is needed ranked as the top barriers. At baseline, 18 of 45 (40%) patients had 22 IRAEs, of which 6 IRAEs (27%) had grading documented; all graded IRAEs (100%) were managed according to guidelines in the drug-specific package insert. IRAEs included hypothyroidism, pneumonitis, hepatitis, dermatitis, adrenal insufficiency, colitis, and encephalitis. Conclusions: Education on toxicity grading and ease of accessibility to information regarding management of IRAEs are needed. Because clinicians were engaged, a survey to evaluate the current process succeeded with a high response rate. At baseline, there are significant gaps and variability in current practice. Interventions are underway to standardize documentation of grade and management of patients experiencing IRAEs.
Abstract 13083: Anatomy Characterization Informs Implant Procedure Design for a Novel Extravascular ICD System
Authors: Ryan Lahm, Varun Bhatia, Megan Harris
Journal: Circulation (2016)

Introduction: Extravascular approaches to ICD therapy in some clinical situations require unique implant methods. Current systems require high energy and don’t provide anti-tachycardia pacing. A new extravascular approach involves placement of a defibrillation lead between the heart and sternum. Due to the unfamiliarity most ICD implanters have with this space, quantification of the anatomy there is crucial for development of a safe and effective procedure. Methods: CT scans were segmented and analyzed to characterize relative locations of structures in or near the substernal space including heart, lungs, sternum, and mammary arteries. Segmentation resulted in faceted 3D surface models. A lead was virtually implanted behind the sternum in the intended location. Proximity distributions from the lead to various structures in the space were characterized at multiple levels of the sternum (up to the 3 rd intercostal space (ICS)). Additionally, the location along the right ventricular (RV) long axis where the lead was closest to the heart was measured. Results: Analysis was completed in 68 patients. The myocardium was closest on average to the virtual lead at the level of the xiphisternal junction (Fig. 1)(5 th - 95 th percentile: 1.0 - 9.9 mm) and furthest away at the 3 rd ICS (4.2 - 47.5 mm). It was closest to lung tissue at the 3 rd ICS (1.2 -14.7 mm) and furthest away at the tip of the xiphoid process (20.7 - 73.9 mm). The mammary arteries were found to be no closer than 11.5 mm to either margin of the sternum at any level. At the xiphisternal junction, the lead sat at ~60% along the RV long axis (0%=RV apex, 100%=tricuspid valve), suggesting close proximity to the central portion of the RV. Conclusions: Meaningful variation exists in the geometric relationships between many of the anatomical structures of the substernal space. Despite this variation, these results support that a lead can be placed in the substernal space close to myocardium while avoiding other organs.