tbuckley/cabot-search huggingface dataset:
A phase 2 study of trastuzumab in combination with S-1 and cisplatin in first-line human epidermal growth factor receptor (HER)-2-positive advanced gastric cancer.
Authors: Su Pin Choo, Clarinda Wei Ling Chua, Yasuhide Yamada, Sun Young Rha, Wei Peng Yong, Chee Kian Tham, Matthew Ng, Wai Meng David Tai, Hwee Yong Lim, Iain B. Tan
Journal: Journal of Clinical Oncology (2014)

127 Background: The addition of trastuzumab to cisplatin and 5-fluorouracil or capecitabine has been shown to have superior survival benefit. In this study, the addition of trastuzumab to chemotherapy combination, S-1 (tegafur, gimeracil, oteracil potassium; TS-ONE R ) and cisplatin, a standard first line therapy for advanced gastric cancer in Japan, was evaluated for efficacy and safety. Methods: This was a single-arm, phase II trial recruiting patients with advanced HER-2 positive (IHC 3+ or FISH +) gastric adenocarcinoma who had not had prior systemic therapy. Patients included had measurable disease, ECOG 0-2, creatinine clearance &gt;60ml/min, LVEF at least 50%. Patients accrued received cisplatin at 60mg/m2 on day 1 of each cycle, trastuzumab at 8mg/kg as loading dose followed by 6mg/kg on day 1 of each cycle and oral S-1 for 14 days ( dosing based on BSA), every 3 weeks. Treatment continued till progressive disease or unbearable toxicity. Primary endpoint was response rate (ORR) and secondary endpoints were PFS, OS, CBR and safety. The study was designed to distinguish a favorable ORR of 55% from a null rate of 30% at 5% significance level and 80% power. Results: A total of 30 patients were recruited. Median age was 61.9 years, 73% were males and 90% had no prior resection of primary tumor. 56.7% were Chinese, 23.3% Japanese and 20% Korean. One patient achieved complete response, 16 had partial response and 2 had stable disease &gt;24 weeks (ORR 63%; CBR 70.4%). Three patients did not have evaluable disease. With a median follow-up of 7.2 months, the median PFS was 7.4 months with 67.7% free of disease progression at the 6-month mark. Median OS was 14.6 months. The most common AEs were anorexia (50%), fatigue (47%), diarrhea ( 47%), nausea (37%), neutropenia (33%), anemia (27%) and mucositis ( 27%). LVEF decreased &lt;50% in 14 patients and none led to treatment discontinuation nor death. Two patients had fatal SAEs that were deemed related to study drug ( neutropenic sepsis and hypotensive shock). Correlative studies will be reported later. Conclusions: The combination of trastuzumab with S-1 and cisplatin in advanced gastric cancer is active and tolerable. Clinical trial information: NCT01736410.
Treatment of nonresectable and metastatic gastrointestinal stromal tumors: Experience with the use of tyrosine kinase inhibitors in a third-level hospital in Mexico city.
Authors: Abdel Karim Dip Borunda, Alejandro J. Silva
Journal: Journal of Clinical Oncology (2015)

224 Background: Stromal tumors of the digestive tract are uncommon malignant diseases, and are subclassified as leiomyosarcomas and gastrointestinal stromal tumors (GIST) depending on the molecular expression of CD117 (KIT). GISTs represent 1% of malignant tumors affecting this anatomical site. Located diseases are reasonably well controlled by surgical resection and several criteria define the need for adjuvant therapy. In the case of metastatic disease a poor prognosis has been reported with systemic treatment based on chemotherapy. Recently, significant advances have been shown since Tyrosine – kinase inhibitors were introduced, with median overall survival close to 5 years. Unfortunately in Mexico, even though the therapy has been long used there are no published data of the experience in the treatment of these tumors. Methods: We used an electronic data base to obtain clinical, radiological and histological data of patients diagnosed with GIST and treated in the oncological center of the Mexican Institute of Social Security, patients were subclassified by stage, symptoms at diagnosis as well as the initial and subsequent systemic treatment. Finally we made an analysis for progression free survival and overall survival identifying prognostic factors. Results: We obtained information of 71 patients with metastatic, nonresectable or recurrent GIST, treated with a TKI, we observed a predominant relation for women (60.4%), with median age of 58 years. Stage at diagnosis was predominantly metastatic (46.5%) most frequently affected sites were lung, liver and retroperitoneum. Median progression free survival was 23.6m and overall survival was 81.3 months. All patients were initially treated with imatinib at a dose of 400mg per day. Treatment was well tolerated in most cases. Conclusions: Metastatic GIST evaluated in our center shows a different affection in gender and age, our population shows a different response to TKI’s, than reported in other series with superior overall survival, Poor prognosis is associated with lung affection. Biological studies will be started for the molecular evaluation of these tumors.
Mucinous and nonmucinous pneumonic-type adenocarcinoma: CT classification and clinical outcome.
Authors: S. Nakamura, K. Ashizawa, M. Fukuda, M. Uetani
Journal: Journal of Clinical Oncology (2011)

e18073 Background: Pneumonic-type adenocarcinoma (P-ADC) is defined radiologically as primary lung ADC, which presents consolidative opacity mimicking pneumonia. Histologically, these lesions are mixed-invasive and bronchioloalveolar carcinoma (BAC) predominant subtype in 2004 WHO classification. The purpose of this study is to classify P-ADC into mucinous (M) and non-mucinous (NM) type on CT, and reveal the clinical outcome in each type. Methods: We retrospectively studied 13 patients of P-ADC at 3 institutions from 1999 to 2011. The patients consisted of 7 females and 6 males with ages ranging from 55 to 87 years old (mean 75).All the patients underwent CT including 9 patients with contrast enhancement and the initial CT findings were analyzed based on the distribution (multifocal distribution and lower lung predominance) and internal characteristics (air bronchogram, cavitation, heterogeneity and CT angiogram sign) of consolidation, and associate findings (bulging fissure, surrounding grand- glass opacity (GGO), and centrilobular small nodules). Pathological findings were classified into M type (n=7) and NM type (n=6) and CT findings were compared between these two subtypes. Therapeutic strategies of these patients such as operation, chemotherapy, or best supportive care (BSC) and their outcomes were analyzed based on the overall survival rates. Results: M type P-ADC showed lower lung predominance (3/7), cavitation (6/7), CT angiogram sign (4/5), and bulging fissure (3/7). In contrast, those findings were not seen in NM type. Multifocal distribution (M:4/7,NM:5/6), air bronchogram (M:7/7,NM:5/6), heterogeneity (M: 5/7,NM: 2/6), surrounding GGO (M: 4/7,NM: 1/6), and centrilobular small nodules (M: 4/7,NM: 5/6) were seen in both types. Seven patients (M: 3, NM: 4) were treated with EGFR-TKI and effective in 5 patients; all patients with NM type and one in M type. Median survival time of M type and NM type were 52.6M and 66.9M, respectively, without statistical difference. Conclusions: The CT findings of cavitation and CT angiogram sign were seen in only M type, and were most usefull in differentiating M type from NM type P-ADC. EGFR-TKI were more effective in NM type, but no difference in survival.
Pharmacokinetics of melphalan and genotypes of glutathione S-transferases GSTM1 and GSTT1 and correlation to adverse effects
Authors: A. Kühne, S. Muhlke, U. Heider, T. Overbeck, K. Hohloch, I. Meineke, L. Trümper, O. Sezer, J. Brockmöller, R. Kaiser
Journal: Journal of Clinical Oncology (2005)

6614 Background: Melphalan is associated with side effects such as mucositis, diarrhea and myelosuppression. We investigated, whether the known interindividual differences in severity of these side effects might be explained by individual pharmacokinetics or by individual genotypes of glutathione S-tranferases GSTM1 and GSTT1, enzymes that might be involved in the detoxification of Melphalan. Methods: An eight point pharmacokinetic sampling was performed in 84 patients after first administration of intravenous melphalan. From these 61 suffered from multiple myeloma, 15 from non-Hodgkin lymphoma and 8 from various other malignancies. Forty-one patients were treated with 10–20 mg/m2, 12 patients with 50–70 mg/m2, 18 patients with 100 mg/m2 and 13 patients with 140 mg/m2. Occurrence and intensity of non-hematological and hematological toxicities were documented. Melphalan was measured with a newly developed sensitive HPLC method (limit of quantification 0.01 μg/ml). The entire gene deletion polymorphisms of GSTM1 and GSTT1 were analyzed by TaqMan real-time PCR assays. Results: A high interindividual pharmacokinetic variability was observed in each dose group with total clearances ranging between 115–715 ml/min/m2. There was a significant linear correlation to creatinine clearance and total melphalan clearance (p=0.0004). According to the r2 value of 0.14 only a small fraction of melphalan total clearance variability was explained by renal function. Multivariate analysis showed significant relationship between side effects and dose (p<0.001). A detailed analysis of the concentration to adverse-event relationship showed that incidence of mucositis was 5%, 35% and 71% with an AUC below 100, between 100 and 350 and above 350 mg/l*min. Patients treated with a dose above 50 mg/m2 had a 23-fold increased risk to develop mucositis (p<0.001, two sided-chi-square test) and a 12-fold increased risk to develop diarrhea (p<0.001, two sided-chi-square test). Genotypes of GSTM1 and GSTT1 showed no association with adverse effects. Conclusions: The occurrence of melphalan induced side effects is dose dependent. GTM1 and GSTT1 deficiencies showed no correlation with side effects. No significant financial relationships to disclose.
Development and validation of a bioanalytical assay on LC/MS/MS to quantify enzalutamide and N-desmethylenzalutamide in human plasma.
Authors: Mette Benoist, Eric van der Meulen, Inge Van Oort, Jack Schalken, Winald Gerritsen, David Burger, Nielka P van Erp
Journal: Journal of Clinical Oncology (2016)

330 Background: To study the relation between drug exposure and therapeutic effect of enzalutamide and its equipotent metabolite N-desmethylenzalutamide, a bioanalytical assay on liquid chromatography tandem mass spectrometry (LC-MS/MS) was developed and validated to determine plasma concentrations in vivo. Methods: Plasma samples were diluted 10-fold with 20% albumin solution. Protein precipitation with acetonitrile was used to pretreat the diluted plasma. A stable isotope (D6-enzalutamide) was used as the internal standard. During validation five quality controls were used (LLOQ, LQ, MQ, HQ, ULOQ). The method was validated according to EMA guidelines. Results: The LC-MS/MS method was validated over a concentration range from 500-50,000 ng/mL. Within – and between day precisions and accuracies were &lt; 5.1%. The LLOQ of the method was set at 500 ng/ml and the ULOQ was 50,000 ng/mL. Enzalutamide and N-desmethylenzalutamide are stable in plasma for at least 19 days at ambient temperature and at 2-8°C. Stability at -40°C was demonstrated for at least 3 months. Enzalutamide and N-desmethylenzalutamide are stable for at least for 24 hours in whole blood at ambient temperature. Stock solution stability was demonstrated for at least 5 months. Concentration levels of the LQ, MQ and HQ were 1000, 15,015 and 40,040 ng/mL. Conclusions: The bioanalytical method to quantify enzalutamide and N-desmethylenzalutamide is successfully developed and validated. The bioanalytical method is used to support pharmacokinetic study questions and for regular patient care in patients with prostate cancer.
Phase II study of nivolumab (ONO-4538/BMS-936558) in patients with esophageal cancer: Preliminary report of overall survival.
Authors: Takashi Kojima, Hiroki Hara, Kensei Yamaguchi, Shuichi Hironaka, Satoru Iwasa, Ken Kato, Takahiro Tsushima, Hirofumi Yasui, Takashi Ura, Kei Muro, Taroh Satoh, Yuichiro Doki, Atsushi Ohtsu, Yasuo Hamamoto, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2016)

TPS175 Background: Patients with esophageal cancer refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a human monoclonal IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced esophageal cancer. We conducted phase II, single-arm, multi-center trial in JAPAN (JapicCTI-No.142422).Methods: The target population was esophageal cancer patients aged ≥ 20 years with ECOG performance status of 0 or 1, who had received one or more previous treatments and not pre-selected by PD-L1 status. Nivolumab (3 mg/kg IV Q2W) was administered to patients until observing unacceptable toxicity or disease progression assessed at 6 week intervals. The primary endpoint was the proportion of patients with a confirmed objective response assessed by independent review committee according to RECIST 1.1. Planned sample size was 60 patients (P0 = 5, P1 = 15, α = 0.025 (one-side), 1-β = 0.8). Data cutoff, 17 May 2015.Results:We enrolled 65 patients with esophageal carcinoma: median age 62.0 years (range, 49-80 years); male/female, 54/11; ECOG PS 0/1, 29/36, Histological type was squamous in all pts. The median prior regimens was 3.0 (range, 1-8); 44 patients (67.7%) were treated with prior esophagectomy and 44 patients (67.7%) with prior radiation therapy. There were 64 evaluable patients for efficacy, and 11(17.2%) of 64 patients had objective response (CR/PR, 1/10). 16 (25.0%) of 64 patients had stable disease. The median overall survival was 12.1 months in 64 evaluable patients. The incidence of drug-related Serious AEs was 11 events (9/65 patients): Lung infection(2[3.1%]), Dehydration(2[3.1%]), Interstitial lung disease (2[3.1%]), etc. The patients with grade 3 pneumonitis improved with supportive care. There was no treatment-related death. We will introduce the updated efficacy and safety data of this trial. Conclusions: Nivolumab has meaningful activity and a manageable safety profile in pretreated esophageal cancer. These data support the assessment of nivolumab in randomized, controlled, phase III studies of second-line treatment. Funding: ONO Pharmaceutical CO.,LTD. Bristol-Myers Squibb Clinical trial information: 142422.
Arachidonic acid drives amoeboid transendothelial invasion through ligand independent activation of EphA2.
Authors: Mick D. Brown, Thomas Tawadros, Claire Hart, Noel W. Clarke
Journal: Journal of Clinical Oncology (2013)

221 Background: We have previously shown that the omega-6 poly unsaturated fatty acid arachidonic acid is a potent stimulator of prostate epithelial transendothelial migration across the bone marrow endothelium and can completely restore the invasive stimulatory capacity of adipocyte depleted human bone marrow stroma. Arachidonic acid induces of EphA2 ligand independent signaling via pAkt with subsequent downstream activation of FAK and Src. Here we present further characterization of the arachidonic acid induced EphA2 pathway. Methods: Transendothelial migration of PC-3 cells across the bone marrow endothelial cell line BMEC was followed by time lapse microscopy and by SEM with or without amoeboid or mesenchymal inhibitors. Western blot analysis of the PC-3 cells or their lipid raft (LR) components post AA stimulation was conducted and signaling pathways validated by siRNA knockdown. Results: Initial studies demonstrated a requirement of PC-3 cells to undergo a mesenchymal to amoeboid switch for transendothelial migration towards bone marrow stroma. The mesenchymal to amoeboid switch was also induced by direct treatment with arachidonic acid as characterized by induction of the Rho/Rock pathway and phosphorylation of myosin light chain. Knockdown of EphA2 by siRNA blocked the induction of the mesenchymal to amoeboid switch and prevented transendothelial invasion. Conclusions: Malignant prostate epithelial cells undergo a switch from mesenchymal to amoeboid movement in response to arachidonic acid in order to cross the bone marrow endothelial barrier.
A phase I and pharmacodynamic (PD) study of the histone deacetylase (HDAC) inhibitor belinostat (BEL) plus azacitidine (AZC) in advanced myeloid malignancies.
Authors: O. Odenike, L. A. Godley, J. Madzo, T. Karrison, M. Green, A. S. Artz, R. J. Mattison, K. W. L. Yee, M. Bennett, N. Fulton, G. Koval, G. Malnassy, R. A. Larson, M. J. Ratain, W. Stock
Journal: Journal of Clinical Oncology (2011)

6521 Background: We hypothesized that targeting two mechanisms of epigenetic silencing with a potent HDAC inhibitor BEL plus the DNA methyltransferase inhibitor AZC would be additive or synergistic with regard to transcriptional de-repression and up-regulation of specific target genes Methods: Part 1 of the study was a dose escalation phase to establish the MTD of BEL in combination with a fixed dose of AZC. 3 to 6 pts were enrolled per dose level in the absence of a DLT or until the 1000mg/m2 dose level of BEL was attained. AZC was given at a dose of 75mg/m2/d SC on days 1-5, with escalating doses of BEL given IV over 30 minutes on the same days in a 28 day cycle. In part 2, pts were randomized during cycle 1 to AZC alone, or BEL/AZC at the established MTD of BEL. Part 2 was designed to evaluate the relative contribution of BEL to the combination, based on change in PD variables analyzed at day 5 of therapy in comparison to baseline, in cycle 1. In subsequent cycles all pts could receive BEL/AZC. Results: 56 pts were enrolled, part 1 (n=24), part 2 (n=32). Median age 68, range (42-83). AML de novo=53% t-AML/MDS=18%, MDS/CMML=27%, PMF=2%; 68% had primary refractory or relapsed disease, 43% had poor risk cytogenetics. In part 1, dose escalation was feasible up to the 1000mg/m2 dose level of BEL, without first course DLT. In part 2, 18 pts (9 in each arm) had marrow samples at baseline and at day 5 for q-RT-PCR analysis for p21, MDR1 and HIST1H3H transcript levels. At day 5, MDR1 was significantly upregulated in the BEL/AZC arm when compared with AZC alone arm (p=0.0089), in contrast to p21 and HIST1H3H which were not significantly different between the 2 arms. There were18 responses (CR=6, marrow CR =2, PR= 1, HI-P=7, HI-N=2); 13 of these occurred at the 1000mg/m2 dose level of BEL. Conclusions: The combination of BEL and AZC is feasible, responses have been observed in several pts at the RP2D of 1000mg/m2 of BEL plus 75mg/m2 AZC. A significant upregulation in MDR1 was observed in the BEL/AZC arm at day 5 compared with the AZC alone arm, suggesting a relative biologic contribution of BEL to the combination. The clinical correlates of these observations require evaluation in the context of a larger trial.
LeukemiaNet: A transnational model for cooperative leukemia research.
Authors: R. Hehlmann, B. Simonsson, M. Baccarani, D. Grimwade, J. Apperley, T. Barbui, M. C. Bene, T. Buchner, T. J. de Witte, R. Foà, C. Haferlach, M. Hallek, J. Hasford, A. Hochhaus, D. Hoelzer, P. Ljungman, D. Niederwieser, M. A. Sanz, S. Saussele
Journal: Journal of Clinical Oncology (2011)

6556 Background: Leukemia research may be jeopardized by lack of communication structures or fragmentation of study activities, insufficient interaction and underestimation of the problem. Methods: Recognizing that the only way to cure leukemia is by cooperative research, scientists in Europe in 2002, set out to establish an exemplary cooperative network for research in leukemia, the European LeukemiaNet (ELN). At present, ELN integrates 105 national leukemia trial groups and networks, 105 interdisciplinary specialty groups and about 1000 leukemia specialists from 175 institutions. They care for ten thousands of leukemia patients in 33 countries. Results: The most visible results are 1.) those due to the cooperative research projects and trials as reflected by a large number of high impact publications; and 2.) the guidelines and management recommendations for virtually every type of leukemia and interdisciplinary specialty which have lain the groundwork for uniform definitions and standards required for common clinical trials and projects. Conclusions: ELN is a model of transnational cooperation. Working together successfully has created a spirit of cooperation and mutual trust. Due to its structured and long-term cooperation, ELN is likely to have a durable impact on leukemia research in Europe. By promoting cooperation over competition that is necessary for good research, ELN provides a competitive advantage for all participants to the benefit of every patient with leukemia worldwide.
Active surveillance for early stage prostate cancer: What do men and their partners think?
Authors: Jinping Xu, Arun Mallapareddi, Julie Ruterbusch, Elyse Reamer, Susan Eggly
Journal: Journal of Clinical Oncology (2016)

95 Background: Despite growing recognition over the last decade that active surveillance (AS) is a reasonable management option for men diagnosed with localized prostate cancer (LPC), only a minority of men choose AS. This study examines the conceptualizations, experiences, and reasons for choosing AS among men with LPC and their partners. Methods: We conducted three focus groups with men with LPC who had chosen AS (7 black, 5 white) and two focus groups with their partners (all women, 2 black, 4 white). Men were identified from a cancer registry or from an academic urologists’ practice. Focus groups were video/audio recorded, transcribed and analyzed using qualitative thematic analysis. Results: Men’s median time on AS was 18 months (range 6-72) and median age was 61 years (range 47-71). Men used many different terms (mostly “wait and see”) to describe similar AS protocols. AS was seen as delaying unnecessary treatment and keeping current function with curable treatment available later if needed. Black men mentioned concerns that some physicians profit by providing unnecessary treatments. Reasons for choosing AS included seeing their cancer as “small” or “low-risk” and trusting their physician’s advice/monitoring, despite reported concerns about PSA being an unreliable test and painful biopsies. Men recognized, but were comfortable with, the small but real threat their cancer could grow. Men found they had to justify their choice to other family members, even when their partners were supportive. Partners saw themselves as very involved and influential in the treatment decision. They were comfortable with AS because of their trust in physicians. Partners believed they know their husband’s physical and mental health better than the men themselves. Conclusions: Physician trust and description of the cancer as low-risk were the most cited reasons for adopting AS. Emphasizing the low-risk nature of the cancer and enhancing physician trust may increase the acceptability of AS.