tbuckley/cabot-search huggingface dataset:
Evaluation of CYP24A1 mRNA expression as a prognostic marker and predictor of calcitriol activity in lung adenocarcinoma.
Authors: N. Ramnath, A. N. King, G. Chen, L. Zhao, R. U. Simpson, D. E. Brenner, P. J. Christensen, D. G. Beer
Journal: Journal of Clinical Oncology (2010)

10631 Background: 1α25,dihydroxycholecalciferol (calcitriol) is antiproliferative in cancers, including lung adenocarcinoma (AC). Calcitriol, however, rapidly induces expression of cytochrome P450 24R-hydroxylase (CYP24A1). CYP24A1 inactivates calcitriol. We examined the prognostic and predictive (of calcitriol efficacy) significance of CYP24A1 in lung AC. Methods: Tumors and corresponding normal lung from patients with resected lung AC (stages I-III) were used to examine CYP24A1 mRNA expression with Affymetrix arrays. Affymetrix SNP arrays were used to assess copy number changes. A subsequent set of 101 lung AC were used to confirm high/low CYP24A1 mRNA expression by qRT-PCR. We examined antiproliferative activity of calcitriol (using WST-1 colorimetric assay) on two lung cancer cell lines, A549 and SKLU1 (high and low CYP24A1 mRNA). siRNA against CYP24A1 was used to demonstrate effects of blocking CYP24A1 in the same cell lines. Results: CYP24A1 mRNA was elevated 8-15 fold compared to normal lung in 30% of 86 lung AC patients and higher in poorly differentiated tumors, but not associated with histology, pathological stage or gender. At 5 years the probability of survival in the high CYP24A1 group was 42% versus 87% in the low CYP24A1 group (p = 0.0008). In tumors with elevated CYP24A1, 30% showed a gain in the region of 20q (location for CYP24A1 gene). A second set of 101 tumors confirmed that higher CYP24A1 expression was independently prognostic of survival (p = 0.008) using a multivariate Cox proportional model. In vitro studies demonstrated a 30% reduction in cell growth in SKLU-1, but little effect in A549 with 100nM calcitriol. Blocking CYP24A1 expression with CYP24A1 siRNA partially restored sensitivity to calcitriol in A549 cells and to a greater extent in SKLU-1 cells. Conclusions: CYP24A1 over expression is associated with poorer survival in lung AC. Growth inhibitory action of calcitriol was observed in the low CYP24A1 but not in the high CYP24A1 cell line. The translational relevance of these findings relate to a potential role for calcitriol as adjuvant therapy in resected lung cancer, based on CYP24A1 expression in the tumor. No significant financial relationships to disclose.
Combination therapy with docetaxel and S-1 as a first-line treatment in patients with advanced or recurrent gastric cancer: A retrospective analysis.
Authors: K. Tanabe, T. Suzuki, N. Tokumoto, H. Yamamoto, K. Yoshida, H. Ohdan
Journal: Journal of Clinical Oncology (2010)

e14563 Background: We performed a single-institution retrospective study to evaluate the efficacy and toxicities of combination therapy with docetaxel and S-1 in patients with advanced or recurrent gastric cancer. We previously demonstrated the mechanisms underlying the synergistic effects of docetaxel with S-1 and performed phase I/II study, which showed promising data as a first-line therapy for advanced gastric cancer. Methods: Eighty-six patients with advanced or recurrent gastric cancer were enrolled. Patients received docetaxel, 40 mg/m2, on day 1 and oral S-1, 80 mg/m2/day, on days 1 to 14 every 3 weeks. Results: All 84 patients were assessable for response. The overall response rate was 52.4% (44/84) and the disease control rate was 96.4% (81/84). Median time to progression (TTP) and overall survival (OS) were 6.5 (95% CI, 4.8-8.1 months) and 15.1 months (95% CI, 11.7-18.5 months), respectively. The major toxicities were neutropenia, leukopenia, alopecia and anorexia. Grade 3 or 4 hematologic toxicities included neutropenia in 31 patients (36.0%), leukopenia in 27 (31.7%), febrile neutropenia in four (4.7%), and anemia in one (1.2%). Other grade 3 toxicities included anorexia in five patients (5.8%), and stomatitis, diarrhea and nausea in one each (1.2%). There was on treatment-related death (1.2%). Conclusions: The combination of docetaxel and S-1 had good clinical activity with acceptable toxicity in patients with advanced or recurrent gastric cancer. No significant financial relationships to disclose.
Pegylated liposomal doxorubicin and carboplatin plus bevacizumab in patients with platinum sensitive recurrent ovarian, fallopian tube, or primary peritoneal cancers: Results of a phase II study.
Authors: M. G. del Carmen, J. P. Micha, L. A. Small, D. G. Street, A. Londhe, T. McGowan
Journal: Journal of Clinical Oncology (2011)

5061 Background: Due to reported activity of bevacizumab (B) in ovarian cancer treatment, we evaluated the safety and efficacy of adding B to pegylated liposomal doxorubicin (PLD, Doxil) and carboplatin (C) in patients (pts) with ovarian, fallopian tube, or primary peritoneal cancers. Methods: This single arm, open-label study enrolled women (≥ 18 yrs) with a relapse-free interval of > 6 months (m) after first-line platinum-based chemotherapy and measurable disease. Inclusion criteria: ECOG PS of 0 or 1; adequate renal, bone marrow, and cardiac function. Pts received PLD 30 mg/m2 and C (AUC 5) on Day 1 + B 10 mg/kg on Days 1 and 15 of each 28-day cycle, maximum 10 cycles. Primary endpoint was objective response rate (ORR, complete + partial response) using RECIST criteria. Duration of response (DR), progression-free survival (PFS), and time to progression (TTP) were also evaluated. Results: Fifty-four pts were enrolled. Mean age was 62.1 yrs; > 90% were white. Median cycles administered were 6. Intent-to-treat (n = 54 [all enrolled pts]) ORR was 72.2% (95% CI 58.4 - 83.5%). DR was 12.1 m (95% CI 9.4 m, NA), median TTP 14.1 m (95% CI 11.6-16.2 m), and PFS 14.1 m (95% CI 11.4-16.2 m). Per protocol cohort (n = 46 [received study agent with > 1 post-baseline tumor evaluation]) ORR was 78.3% (95% CI 63.6-89.1%). Serious adverse events (SAEs) occurred in 15 pts (13 drug-related), which consisted of gastrointestinal (GI), infectious, injury/procedural, respiratory, or vascular complications (5.6% across each category). One pt died of a pulmonary embolism, deemed unrelated to study drug. Thirty-nine (72.2%) pts stopped therapy due to an AE [22 (40.7%)], choice/violation [14 (25.9%)], and disease progression [3 (5.6%)]. Grade 3/4 AEs included blood/lymphatic system (29.6%), GI (18.5%), and vascular (14.8%) disorders. Four (7.4%), 2 (3.7%), and 1 (1.9%) pts had Grade 3 hand-foot syndrome, DVT, and small intestinal perforation, respectively. Conclusions: This combination demonstrated a high response rate with a manageable AE profile, and presents a potential treatment option for women with ovarian, fallopian tube, or primary peritoneal cancers.
An exploratory analysis of gemcitabine/vinorelbine/cisplatin in 83 patients with advanced NSCLC in a single brazilian institution
Authors: N. H. Yamaguchi, M. T. Arruda, S. M. Nikaedo, F. K. Ikan, T. Takagaki, J. R. Pereira
Journal: Journal of Clinical Oncology (2008)

13552 Background: Non Small Cell Lung Cancer is a very aggressive disease, and is still the number one cause of cancer deaths. The Lung Division of the Instituto do Cancer Dr. Arnaldo Vieira de Carvalho(ICAVC), headed by Dr. Jose Rodrigues has been very active in the lung cancer research and has collaborations with the University of Sao Paulo Lung Division for the academic development and publications of the results. It has been proven that Gemcitabine, Vinorelbine and Cisplatin are quite active agents but the survival is still poor with the doublets combination and until now, there are mixed results with the use of different triplets, specially due to additional toxicities without clear advantages. The ICAVC Lung Division has accumulated experience in the management of NSCLC with the triplet that will be described. Methods: 83 patients with stage IIIB (57 patients-68,7%) and IV(39 patients-31,3%) of NSCLC were treated in a single institution between 2000 and 2007. Males were 68,7%(57) and females were 31,3%(26). Age was 37–49 years old 14,4%(12), 50–59 y/o 38,5% (32), 60–69 y/o 31,3% (26) and more than 70 y/o was 14,4%(21). Performance KPS was 60 to 70% - 13,2% (11) and 80–100 % - 86,6% (71). Chemotherapy with 60 mg sqm of Cisplatin, 1500 mg sqm of Gemcitabine and Vinorelbine 30 mg sqm every 21 days were delivered for 4 cycles until analysis of response. Results: After 4 cycles the Response Rate was: Stable Disease 25,3%(21); Partial Response 54,2% (45); Minimal Response 1,2%(1); Complete Response 1,2%(1); Progressive Disease 3,6% (3); Not evaluable 14,4%(12). Toxicity was tolerable, mostly hematologic that was fully recoverable. 45,8%(38) were treated just with chemotherapy, 16,9% (14) with chotherapy followed by Surgery and 45,8% (38) with chemotherapy alone. Median Survival was 312 days (44,6 weeks), media was 17,3 months (520 days) Conclusions: Chemotherapy for stage IIIB and IV with Gemcitabine, Vinorelbine and Cisplatin was given to 83 patients, the toxicity was tolerable and survival was better than historical controls. Local controls for locally advanced diseases was possible, either by chemoradiation or by tumor resection after primary chemotherapy. Combination therapy with molecular agents can improve the response rate. No significant financial relationships to disclose.
The acute effect of palonosetron on ECG parameters in patients with cancer.
Authors: C. Yavas, U. Dogan, G. Yavas, O. Ata
Journal: Journal of Clinical Oncology (2011)

e19686 Background: The 5-hydroxytryptamine 3 receptor antagonists are used for the prevention and treatment of chemotherpy and radiotherapy-induced emesis. Despite their effectiveness and safety profile, it was reported in many studies that they may cause electrocardiographic changes related to heart rate and repolarization. The purpose of this study is to determine acute influence of paronosetron on ECG parameters in cancer patients. Methods: Forty-seven cancer patients with normal cardiac function who received paronosetron for the prevention of chemotherapy/radiotherapy induced emesis were enrolled into this prospective study. Standard 12-lead ECG recordings were performed at baseline and 30 min after palonosetron administration. P wave durations and corrected QT intervals were measured; P wave dispersion (Pd) and QTc dispersion were calculated. Statistical comparison of quantitative data was performed by paired sample t test. A P value of <0.05 was considered to be statistically significant. Results: In comparison with baseline, no statistically significant change in any ECG parameters, including QT and RR intervals, P wave durations, Pd and QTd, was observed after infusion of Palonosetron. Conclusions: In this study palonosetron did not show any ventricular and atrial arrhythmogenic effect because of repolarization abnormalities.
Outcome analysis of breast cancer patients treated with cardiotoxic agents in the community setting: A single-institution experience.
Authors: Yousef Khelfa, Munthir Mansour, Todd W. Gress, Maria R. B. Tria Tirona
Journal: Journal of Clinical Oncology (2016)

213 Background: Anthracyclines and anti-Her-2 targeted therapy are commonly used effective breast cancer treatments. They are known to decrease Left Ventricular Ejection Fraction (LVEF), which may increase patients’ morbidity and mortality. There is currently no consensus on post treatment cardiac follow-up. Recent observations suggested that ACEI and B blocker drugs could have cardioprotective effects. We conducted a retrospective study to assess patients’ cardiac outcome using post-treatment LVEF follow-up and effect of ACEI and B blocker on cardiac outcome for breast cancer patients who received cardiotoxic agents in our institution. Methods: We reviewed 155 charts of non-metastatic breast cancer patients between 2000-2008, who received anthracyclines and/or anti-Her-2 targeted therapy. Patients were stratified into groups A (anthracycline), B (trastuzumab) and C (anthracycline+trastuzumab). Results: Patients’ median age was 52.5 years. Six patients had coronary artery disease and 45 received radiation to the left breast. After a median follow-up of 93 months, only 3 of 155 (2%) patients developed symptoms of congestive heart failure. One hundred twenty patients had pre-treatment LVEF evaluation, while only 31 patients had pre and post LVEF evaluation. Mean LVEF difference was -7.89, - 9.01, -9 and -6.08 for all patients, group A, group B and group C, respectively. Thirty patients were on ACEI, 7 of them had LVEF follow-up with mean difference of -6.86. Thirty patients were on B blocker, 7 of them had LVEF follow-up with mean difference of -15. Because of the small size of the groups who had LVEF follow-up, no statistical difference can be detected. Conclusions: Our patient population showed very low incidence of clinically significant cardiac events in relation to anthracycline and anti-her-2 directed therapy after a median follow-up of 93 months. However, further follow is required to assess cardiac outcome that may affect quality of life and survival later in life. In this regard, our institution is establishing a dedicated cardio-oncology service to closely monitor patients who have been treated with cardiotoxic agents and provide early cardiac management if needed.
A phase I study of GC33 in Japanese patients with advanced hepatocellular carcinoma (HCC).
Authors: Takuji Okusaka, Masafumi Ikeda, Shinichi Ohkawa, Shunsuke Yamamoto, Ikue Suzuki, Junji Furuse
Journal: Journal of Clinical Oncology (2013)

235 Background: Glypican-3 (GPC3) belongs to a family of cell-surface heparan sulfate proteoglycans and is specifically expressed in HCC. In this phase I study, we examined the safety, tolerability, and pharmacokinetics of GC33, a recombinant, humanized monoclonal antibody against GPC3, in Japanese patients (pts) with advanced HCC. Methods: This study was a 3+3 design for dose escalation to determine the maximum tolerated dose (MTD) of GC33 given intravenously at 5, 10, and 20 mg/kg weekly. Key eligibility criteria included histological or cytological confirmation of HCC, ECOG PS ≤ 1, Child-Pugh A or B, adequate organ function, and tumor tissues available for GPC3 immunohistochemistry. Results: Thirteen pts were enrolled at 3 dose levels: median age=65 years (range 48-78), M/F=12/1, ECOG PS 0/1=9/4, HBV/HCV=4/8, liver cirrhosis +/-=8/5, Child-Pugh A (5-6)/B (7) =10/3. All pts received prior systemic therapy including sorafenib. Treatment was well tolerated at all dose levels without DLT, and MTD was not reached. The most common AEs were lymphocyte count decrease (77%), Natural Killer cell count decrease (77%), C-reactive protein increase (69%) and pyrexia (62%). Grade 3 AEs (≥ 2 pts) were lymphocyte count decrease (23%), blood pressure increase (23%) and platelet count decrease (15%). Infusion reactions were seen in 62% of pts and medically manageable. Anti-GC33 antibody was not detected in any of the patients. PK analysis of GC33 showed a half-life of 4 to 7 days and dose proportional for AUC after the first dose. Trough concentrations reached a steady state after 4 to 6 doses. Twelve out of 13 biopsied tumor specimens showed immunoreactivity with mouse GC33 antibody. There was no CR or PR, but 7 SD and 3 of them had SD for more than 5 months before progression (all with GPC3 expression). Conclusions: GC33 was well-tolerated up to 20 mg/kg weekly in Japanese HCC pts with Child-Pugh A or B liver cirrhosis and potentially beneficial to GPC3+ HCC. A randomized phase II study of GC33 monotherapy as 2nd line therapy in advanced HCC pts is currently ongoing. Clinical trial information: JapicCTI-101255.
Prognostic factors in gastroenteropancreatic neuroendocrine tumors - A retrospective multivariate analysis
Authors: M. Böhmig, U. F. Pape, N. Tiling, U. Berndt, J. Müller-Nordhorn, S. N. Willich, B. Wiedenmann
Journal: Journal of Clinical Oncology (2005)

4086 Background Only few data exist on long-term outcome and independent prognostic factors of neuroendocrine tumors (NET) of the gastroenteropancreatic (GEP) system. Low incidence, heterogeneous classifications and various treatment modalities influence the sparsity of epidemiologic data. Here we present long-term outcome data from a large cohort of a referral center. Methods Descriptive statistical analysis of retrospective data from 392 patient records of histologically proven GEP-NET treated at our institution from 1980–2003 was followed by a multivariate analysis after adjustment for gender and age using a Cox-regression-model. Among the studied parameters were localization and size of the primary tumor, presence of a hypersecretion syndrome, clinical symptoms and metastasis at initial diagnosis, and surgical therapy. We analyzed the whole study cohort and the subgroup for which histopathological information about the proliferation fraction (ki67-index) was known. Results Localization of the primary tumor was foregut in 47% (pancreas 25%), midgut in 38% (jejunoileum 29%), hindgut in 4%, and unknown in 10%. In 73% the NET had already metastasized at initial diagnosis and 23% of the patients had symptoms of hormone hypersecretion. The ki67-index was distributed as follows (n=255): <5%: 52%, 5–10%: 25%, >10%: 23%. Mean follow-up was 25.6 months. 96 patients died during the observation period, 85% of NET-associated causes. The results of the multivariate analysis are displayed in the table. Conclusion While unknown size of the primary, a primary tumor larger than 2.5 cm, and a ki67-index >5% (with even higher significance for GEP-NET with a ki67-index >10%) were independent prognostic factors of an unfavourable outcome, a surgical intervention with curative intent proved to indicate a favourable prognosis. Thus, these informations are of crucial importance for the management of patients with GEP-NET. No significant financial relationships to disclose.
Phase I/II trial of autophagy inhibition in combination with neoadjuvant gemcitabine in patients with high-risk pancreatic adenocarcinoma: Safety, clinical response, and correlative studies.
Authors: Michael T. Lotze, Brian A. Boone, Amer H. Zureikat, Nathan Bahary, David Lehman, Lance A. Liotta, Herbert J. Zeh
Journal: Journal of Clinical Oncology (2014)

218 Background: Autophagy is a cell survival mechanism, upregulated in pancreatic ductal adenocarcinoma, correlating adversely with response to therapy and prognosis. The autophagy inhibitor hydroxychloroquine (HCQ) is a novel treatment. Methods: A Phase I/II trial examined pre-operative gemcitabine with HCQ in the treatment of pancreatic cancer patients. Eligibility was restricted to those predicted to have limited survival following surgical resection. Two doses of gemcitabine (1500mg/m 2 ) were administered with oral HCQ (200-1200mg/day) for 31 days until operation in a Storer phase 1 design. Primary endpoint was the safety and tolerability of HCQ. Secondary endpoints were clinical response as assessed by CA 19-9 and R0 resection rates. LC3 and cleaved caspase 3 staining were assessed as biologic correlates to clinical response. Additional exploratory endpoints included serum levels of HMGB1, IL-6, and DNA DAMPs. Results: Thirty-five patients were enrolled in the safety phase of the trial. Two patients withdrew consent prior to treatment and two others were removed due to a stroke and allergic rash, resulting in 31 patients completing treatment. There were no dose limiting toxicities and no treatment delays. 14 patients (45%) had a decrease in CA19-9 of &gt;50% following treatment. 29 patients (94%) underwent surgical resection with an R0 resection rate of 81%. There was one peri-operative mortality (3.2%) with significant morbidity (Grade 3/4) affecting 29% of patients. Increases in pancreatic LC3 staining were consistent with autophagy inhibition. There was a statistically non significant trend towards increased apoptosis with increasing doses of HCQ. Both mitochondrial and nuclear DNA (p = .09) decreased. During treatment, HMGB1 and IL-6 levels rose and then returned to normal levels. Conclusions: Pre-operative autophagy inhibition with HCQ in combination with gemcitabine is safe and tolerable and associated with biomarkers of response. This regimen has promise as a biologically active strategy and future trials will examine HCQ in combination with Nab-paclitaxol/Gemcitabine combinations. Clinical trial information: NCT01128296.
Prevalence of <i>DPYD</i> gene mutations among patients receiving 5-FU therapy.
Authors: Jennifer Saam, Karla Bowles, Laurie Korst, Kendel Kline, Benjamin Roa, Susanne Wagner, Glenn Eldredge, Brian L. Abbott, Rajesh R. Kaldate
Journal: Journal of Clinical Oncology (2013)

447 Background: Dihydropyrimidine dehydrogenase (DPYD) is the major enzyme that metabolizes 5-Fluoruracil (5-FU), a component of many chemotherapy regimens. Patients with a DPYD gene mutation have higher 5-FU plasma levels, leading to a 50-60% risk of a grade 3-4 toxicity. DPYD mutations have an estimated prevalence of 3-5% in the general population, but full sequencing is rarely performed in published studies. Analyses of the largest set of full DPYD gene sequencing test results from a commercial laboratory database are presented. Methods: A set of 3,083 patients was analyzed. Patient demographics (age, gender, ethnicity) and pre-test grade 3-4 toxicity status (none, 5-FU related, other) were obtained from the test request form. Descriptive analyses were performed to estimate mutation prevalence overall, and by toxicity and ancestry classifications, as well as to characterize mutations of interest. A subset of 24 patients tested for DPYD mutations in response to high 5-FU exposure levels was also analyzed. Results: The overall DPYD mutation prevalence was 7.3%. Mutations were present in 4.7% and 10.3% of patients experiencing none and at least one 5-FU related toxicity pre-test, respectively. Among patients with toxicities pre-test, the prevalence increased from 7.8% to 31.6% for those experiencing a single to all four toxicity types. Among 5-FU related toxicities, mutation prevalence was highest (18.5%) for hematopoietic events. The previously reported founder mutation IVS14+1G&gt;A had a relative prevalence 42.7%, but 30.9% of these mutations were seen in patients not reporting a Western/Northern European ancestry. Among the subset of patients with high 5-FU exposure levels, 29% had a DPYD mutation showing a genetic causality. Conclusions: 5-FU in chemotherapy regimens remains widespread, yet DPYD gene testing utilization remains minimal. Most testing occurs post-treatment in response to a severe toxicity rather than pre-treatment, which would permit physicians to adapt treatment and reduce toxicity risk. Compared to previous studies, this study using full sequencing data from 3083 patients provides robust estimates of DPYD mutation prevalence and helps characterize DPYD mutations of particular interest.