tbuckley/cabot-search huggingface dataset:
Pemetrexed: Target gene expression in human solid tumors correlates with chemosensitivity patterns
Authors: O. Oberschmidt, U. H. Eismann, K. Platzek, M. Ehnert, J. Blatter, M. M. Lahn, D. Ma, N. Clet, P. Paoletti, A.-R. Hanauske
Journal: Journal of Clinical Oncology (2004)

3128 Background: The novel antifolate ALIMTA (pemetrexed) exhibits clinical activity in a variety of solid tumors. Primary targets comprise thymidilate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). In the present study, target gene expressions were correlated with in vitro chemosensitivity of freshly explanted human tumor specimens. Such correlations in tumors taken directly from patients may help to rationally design subsequent clinical trials. Methods: Freshly biopsied tumor cells (solid tumors, pleural effusions, or ascites) were used for soft-agar cell cloning experiments. Cells were exposed to various concentrations of ALIMTA and clonogenic tumor growth was evaluated. Another part of the tumor specimens was shock frozen immediately after removal. Messenger RNA was isolated and reversely transcribed to cDNA followed by real-time multiplex PCR experiments. Results from these gene expression experiments were normalized against β-actin transcripts. Results: At present, 15 tumor samples from a variety of solid tumors are available for analysis of TS and DHFR and 14 samples for GARFT. No clear difference in TS or DHFR gene expression was observed between ALIMTA-sensitive and resistant specimens (mean ±SD: TS: 57 ±33 versus 76 ±89; DHFR 54 ±22 versus 61 ±21). GARFT expression was associated with sensitive specimens showing lower expression levels compared to resistant specimens (mean ±SD: 100 ±38 versus 331 ±212). GARFT expression levels and clonogenic survival after ALIMTA exposure were correlated (R=0,7810). Conclusions: These results indicate that low expression of GARFT might herald sensitivity to ALIMTA and that GARFT inhibition may be a clinically relevant mechanism of action. Supported in part by Eli Lilly & Company. No significant financial relationships to disclose.
Phase I/II Study of Escalating Doses of Vinorelbine in Combination With Oxaliplatin in Patients With Advanced Non–Small-Cell Lung Cancer
Authors: Isabelle Monnet, Patrick Soulié, Hubert de Cremoux, Sabine Saltiel-Voisin, Mohammed Bekradda, Jean-Claude Saltiel, Etienne Brain, Ghislaine Dupont-André, Esteban Cvitkovic
Journal: Journal of Clinical Oncology (2001)

Oxaliplatin is a platinum compound active in non-small-cell lung cancer (NSCLC) patients, and vinorelbine (VNB) is an active reference agent. This phase I/II study was performed to determine the dose-limiting toxicity (DLT), the maximum-tolerated dose (MTD), and the recommended dose (RD) of a VNB/oxaliplatin combination given to previously untreated patients with advanced NSCLC.Oxaliplatin was given at the fixed dose of 130 mg/m2 (2-hour intravenous [IV] infusion) on day 1. VNB was administered on days 1 and 8 (10-minute IV infusion), with doses starting at 22 mg/m2/d and escalated by 2 mg/m2 increments until MTD. Treatment was repeated every 3 weeks. No special hydration measures or prophylactic granulocyte colony-stimulating factors were used.Twenty-seven patients (20 men, 7 women) received 110 cycles total at six different VNB dose levels. Neutropenia was the DLT. Although no patient experienced DLT at the highest dose level (32 mg/m2/d), multiple treatment delays (54% of cycles) and dose reductions (34% of cycles) were required at this dose level. Others toxicities were mainly limited to grade 1 peripheral neuropathy and grade 1/2 nausea/vomiting. The relative dose-intensity of administered VNB from dose levels 3 to 6 (26 to 32 mg/m2) remained stable, whereas grade 3/4 neutropenia increased. All patients were assessable for activity; there were 10 objective responses, including one complete response (37% response rate).The present combination can be safely administered in an outpatient setting. The RD is VNB 26 mg/m2 days 1 and 8 with oxaliplatin 130 mg/m2 day 1 every 3 weeks.
Technical Description and Results of Endoscopic Treatment of Various Solitary Rectal Ulcer Syndrome Pictures
Authors: A. Ederle, G. Bulighin, S. Pilati, S. Desideri
Journal: Endoscopy (1995)

Solitary rectal ulcer syndrome is a rare disease producing different pictures, such as superficial ulcers, deep and large ulcers with elevated margins, and polypoid formations modifying the architecture of the rectum. The medical and surgical treatment usually suggested reduces symptoms but gives only partial results on the lesions. We have tried to treat this syndrome ulcers with Tissucol using the colonscope. We applied the product on small ulcers and both injected and applied it on large and elevated ulcers. Four-lumen catheter or sclerotherapy needles were used. Rapidly solidifying Tissucol was used for application and slowly solidifying Tissucol for injection. Two groups (1 and 2) of six patients each were treated both with dietetic and hygienic measures; group 1 was also treated with an application of Tissucol. After 15 days all six ulcers were healed in group 1 and none in group 2. After 1 year no ulcer was present in group 1 and 3/6 in group 2. Five patients with large elevated ulcers sometimes with multiple polypoid formations and with partial stenosis were treated as described above. Good results on symptoms were obtained in all patients. Complete healing was obtained in 3/5 patients and partial healing in 2/5 patients. However, the rectal lesions of these two patients were probably due to tuberculosis and endometriosis, rather than to solitary rectal ulcer syndrome.
Oncocontraception in breast cancer care.
Authors: A. Patel, A. Uy, E. K. Radeke, V. Barrera, H. A. Zaren
Journal: Journal of Clinical Oncology (2010)

e19679 Background: Based on a case series of patients, the need for providers to address pregnancy as it relates to the diagnosis of breast cancer was realized. Equally as important as the emphasis on intended pregnancy is the prevention of unintended pregnancy during cancer treatment. Thus, the growing interest in oncofertility calls for a developed algorithm for reproductive health management. The objective was to incorporate and investigate the implementation of a reproductive health assessment tool in breast cancer care for women of childbearing age (18-55) and to study outcome measures to determine the tool effectiveness. Methods: This prospective observational study was executed by providing training on reproductive health in the context of cancer care for oncology staff in the breast cancer clinic. Referral lines for various components of reproductive health care were developed. The reproductive health algorithm was developed for each patient according to their reproductive goals. Women with newly diagnosed with breast cancer were eligible for this study. Eleven patients were enrolled and will continue to be followed through the end of the study. We are in the second of a three year study. Baseline surveys, lab data and subsequent treatment plans were recorded and implemented. Results: All participants received contraception/family planning counseling. Before study entry, only 4 out of 11 (36%) women presented with long-term contraception (LTC). Of the 7 others, 2 had become pregnant post-diagnosis, 1 had a miscarriage days prior to diagnosis, 2 were abstinent, and 2 used condoms. Eight of 11 (73%) had completed childbearing at study entry. After algorithm implementation, LTC use increased to 64% (n = 7). Four (36%) used Paraguard IUD and 3 (27%) had permanent sterilizations. The others used abstinence (n = 3, 27%) and one used condoms (9%). Women who completed childbearing increased to ten (91%). Fertility preservation counseling referral was made for the woman interested in future childbearing. Conclusions: The reproductive health algorithm allows patients to gain perspective of their reproductive goals in light of their diagnosis, enhancing options for management of those goals, minimizing unintended pregnancies, and increasing efficiency of cancer treatment. No significant financial relationships to disclose.
Prevalence of hereditary GIST susceptibility in adults with GIST.
Authors: I. R. Rainville, E. J. Root, M. Salerno, L. DiGianni, D. A. Nelson, C. L. Corless, M. C. Heinrich, M. E. Robson, J. E. Garber
Journal: Journal of Clinical Oncology (2011)

10043 Background: GIST is the most common mesenchymal tumor of the GI tract, associated with somatic gain-of-function mutations in KIT and less often, PDGFRA. Families with inherited mutations in KIT/PDGFRA have autosomal dominant transmission of GIST predisposition. Germline mutations of the succinate dehydrogenase complex (SDH) may underlie kindreds with GIST and paraganglioma, particularly in GISTS of the pediatric/wild-type histology. We are conducting a multicenter study to ascertain the prevalence of hereditary GIST. Methods: Individuals ≥ age 18 years with confirmed GIST are recruited through sarcoma specialty clinics at the Memorial Sloan-Kettering Cancer Center and the Dana-Farber Cancer Institute, or a web recruitment tool. Participants are stratified to high- and low-hereditary risk groups based on questionnaire and family history review. Germline analysis of KIT and PDGFRA is ongoing at Oregon Health & Science University on specimens from all high-risk subjects; SDHX analysis is in process for a subset. Results: Thus far we have enrolled 512 participants. Specimens from 92 high-risk and 41 low-risk subjects have been analyzed to date. Eight mutations were found in KIT, zero in PDGFRA. In-frame deletion of KIT D579 was found in 5 families, two of which report a common ancestor, and W557R, K642E, and K509I were identified each in one family. Two of these families, one segregating D579del and the second W557R, were reported previously by other groups, and one, K642E, was reported in the course of this study. Germline analysis of KIT exons 8, 9, 11, 13, 17 and PDGFRA 12, 14, 18 is negative in four families. KIT mutations were identified only in individuals with family history of GIST in relatives. Two individuals with SDHB mutations, identified by other investigators in the course of this study, are included. Germline analysis of the SDH family of genes in five individuals with pediatric/wild-type GIST and/or family history of pheochromocytoma or paraganglioma is in progress. Conclusions: The hereditary form of GIST constitutes a small fraction of all GISTs. Individuals with GIST and without a family history of GIST in other relatives are unlikely to carry inherited susceptibility linked to the KIT or PDGFRA protooncogenes.
Evaluating Chemotherapy at the End of Life
Authors: Anthony F. Provenzano, Richard D. Carvajal
Journal: JAMA Oncology (2016)

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Cost-effectiveness of denosumab (Dmab) versus zoledronic acid (ZA) for prevention of skeletal-related events (SREs) in patients (pts) with castrate-resistant prostate cancer (CRPC) and bone metastases (BM).
Authors: Michael E. Rader, Mark Danese, Ze Cong, Marc Halperin, Yi Qian, Carsten Dietrich Goessl, Karen Chung
Journal: Journal of Clinical Oncology (2012)

59 Background: It has become more important to understand the incremental cost/benefit of new medicines as healthcare costs rise. Subcutaneous Dmab is superior to intravenous ZA for prevention of SREs in pts with CRPC and BM (Fizazi, 2011). In addition, a lower proportion of pts receiving Dmab progressed to moderate/severe pain than those receiving ZA (Brown, 2011). Dmab can be used in pts regardless of renal status or concomitant use of nephrotoxic drugs. These analyses assess the lifetime, real world cost-effectiveness of Dmab vs ZA in pts with CRPC and BM from a US managed care perspective. Methods: A lifetime Markov model was developed to estimate SREs, quality adjusted life-years (QALYs), and costs. The relative rate reduction in SREs for Dmab vs ZA was based on a large head-to-head phase 3 trial (N=1,901). The real world SRE rate in ZA pts was derived from a large commercial claims database analysis (Hatoum, 2008). SRE QALY decrements were estimated using the time trade-off method (Matza, 2011). SRE costs were estimated from a nationally representative commercial claims database (Barlev, 2010). Wholesale acquisition drug cost (Analysource, 2011), drug administration, and renal monitoring costs (National Fee Analyzer, 2011) were included. Compliance and mortality were assumed to be the same in both groups. Costs and QALYs were discounted at 3% annually. Results: With a median pt survival of 1.7 years, Dmab reduced the number of SREs and increased pts’ QALY vs ZA. The lifetime cost/pt on Dmab was $7,430 higher than ZA. Cost/QALY gained was $65,134, commonly considered good value based on oncologists’ implied threshold in the US (Nadler, 2006). Cost/SRE avoided was $9,212. Conclusions: Dmab is cost-effective in preventing SREs in pts with CRPC and BM compared with ZA in the US. The overall value of Dmab is based on superior efficacy and more efficient administration. [Table: see text]
Phase || Study of Pemetrexed + Carboplatin + Bevacizumab As First-Line Therapy for Nonsquamous Non-Small Cell Lung Cancer with Egfr Mutation, Result of Induction Therapy: Central Japan Lung Study Group (Cjlsg) 0910 Trial
Authors: T. Kimura, H. Taniguchi, T. Ogasawara, R. Suzuki, M. Kondo, J. Shindoh, N. Yoshida, E. Kojima, Y. Yamada, O. Hataji, M. Ichikawa, H. Saito
Journal: Annals of Oncology (2014)
Domino-Style Cerebral Bleeding in a Patient With Immune Thrombocytopenic Purpura
Authors: Hiroaki Kitamura, Takero Shindo, Yusuke Yakushiji, Mari Yoshihara, Makoto Eriguchi, Yasushi Kubota, Tomoyuki Noguchi, Shinya Kimura
Journal: JAMA Neurology (2016)

This case report describes a patient (who previously received a diagnosis of immune thrombocytopenic purpura) admitted to the hospital with disturbed activity, ataxic gait, and subacute onset of apathy.
From Loci to Biology
Authors: Sylvia T. Nurnberg, Hanrui Zhang, Nicholas J. Hand, Robert C. Bauer, Danish Saleheen, Muredach P. Reilly, Daniel J. Rader
Journal: Circulation Research (2016)

Genome-wide association studies have provided a rich collection of ≈ 58 coronary artery disease (CAD) loci that suggest the existence of previously unsuspected new biology relevant to atherosclerosis. However, these studies only identify genomic loci associated with CAD, and many questions remain even after a genomic locus is definitively implicated, including the nature of the causal variant(s) and the causal gene(s), as well as the directionality of effect. There are several tools that can be used for investigation of the functional genomics of these loci, and progress has been made on a limited number of novel CAD loci. New biology regarding atherosclerosis and CAD will be learned through the functional genomics of these loci, and the hope is that at least some of these new pathways relevant to CAD pathogenesis will yield new therapeutic targets for the prevention and treatment of CAD.
From Lipids to Inflammation
Authors: Michael D. Shapiro, Sergio Fazio
Journal: Circulation Research (2016)

The introduction of statins ≈ 30 years ago ushered in the era of lipid lowering as the most effective way to reduce risk of atherosclerotic cardiovascular disease. Nonetheless, residual risk remains high, and statin intolerance is frequently encountered in clinical practice. After a long dry period, the field of therapeutics targeted to lipids and atherosclerosis has entered a renaissance. Moreover, the demonstration of clinical benefits from the addition of ezetimibe to statin therapy in subjects with acute coronary syndromes has renewed the enthusiasm for the cholesterol hypothesis and the hope that additional agents that lower low-density lipoprotein will decrease risk of atherosclerotic cardiovascular disease. Drugs in the orphan disease category are now available for patients with the most extreme hypercholesterolemia. Furthermore, discovery and rapid translation of a novel biological pathway has given rise to a new class of cholesterol-lowering drugs, the proprotein convertase subtilisin kexin-9 inhibitors. Trials of niacin added to statin have failed to demonstrate cardiac benefits, and 3 cholesterol ester transfer protein inhibitors have also failed to reduce atherosclerotic cardiovascular disease risk, despite producing substantial increases in HDL levels. Although the utility of triglyceride-lowering therapies remains uncertain, 2 large clinical trials are testing the influence of omega-3 polyunsaturated fatty acids on atherosclerotic events in hypertriglyceridemia. Novel antisense therapies targeting apolipoprotein C-III (for triglyceride reduction) and apo(a) (for lipoprotein(a) reduction) are showing a promising trajectory. Finally, 2 large clinical trials are formally putting the inflammatory hypothesis of atherosclerosis to the test and may open a new avenue for cardiovascular disease risk reduction.
Influence of smoking dose on the outcome of Japanse patients with non-small cell lung cancer who had gefitinib treatment
Authors: K. Asami, M. Kawahara, S. Atagi, T. Kawaguchi, A. Kubo, K. Okishio, Y. Yagi, Y. Matsuda, T. Kagawa, M. Kitaichi
Journal: Journal of Clinical Oncology (2009)

e19004 Background: Non-smoking history and epidermal growth factor receptor (EGFR) mutation are associated with increased sensitivity to gefitinib in non-small cell lung cancer (NSCLC). However, it is still unclear how much smoking dose is associated with survival and response to gefitinib among smokers. Methods: NSCLC patients (pts) with detailed smoking history who received gefitinib at our institution between 9/02 and 9/04 were reviewed. An analysis was conducted to the pts for association between smoking dose, EGFR mutations, performance status (PS), response and overall survival using multivariate analysis. Results: Data were available for 100 pts including 30 females and 70males. We expressed smoking dose as pack year (Py).The median dose of smoking was 32 Py (0.1–100 Py). We defined the group of &lt;10 Py as light smokers(17 pts) and the other group of 10 Py or more as heavy smokers(83 pts). We detected 31(31%) EGFR mutation (median 14 Py 0.1–75 Py) with exon 18 / 19 /21 mutation;3/17/11 pts .Cox survival analysis showed that overall survival was preferably associated with small dose of smoking(&lt;10 Py)(HR=0.505; [95% CI 0.277–0.921; P=0.013]), EGFR mutation(HR=0.452[95% CI 0.235–0.87;P=0.035])and PS;0–1(HR=0.347 [95% CI 0.207–0.583 P&lt;0.001]). EGFR mutations were significantly more frequently observed in light (12/17:71%) than heavy smokers(19/83:23%) (p&lt;0.001). Disease control rate(DCR) was significantly higher in light (13/17;76%;PR 6, SD 7) than heavy smokers(29/83;35%;PR 15, SD 14)(P=0.002), but there was not significant difference between those groups in terms of response rate (RR)(P=0.187). There were significant differences between pts with EGFR mutations (PR 13 SD 14; RR 42%,DCR 87%) and pts without EGFR mutations (PR 8 SD 15; RR 12%, DCR 33%) in terms of RR(P&lt;0.001) and DCR(P&lt;0.001). In pts with EGFR mutation, there was no significant difference between light and heavy smokers in terms of RR (light smokers 5/10, heavy smokers 8/21; P=0.701) and DCR (light smokers 10/10, heavy smokers17/21; P= 0.277). Conclusions: EGFR mutations were predictive factor and prognostic factor. Small dose of smoking (&lt; 10 Py) was prognostic factor, however it was not a predictive factor of smokers with NSCLC. No significant financial relationships to disclose.
The anti-dementia drug candidate, (−)-clausenamide, improves memory impairment through its multi-target effect
Authors: Shifeng Chu, Shaolin Liu, Wenzhen Duan, Yong Cheng, Xueying Jiang, Chuanjiang Zhu, Kang Tang, Runsheng Wang, Lin Xu, Xiaoying Wang, Xiaoming Yu, Kemei Wu, Yan Wang, Muzou Wang, Huiyong Huang, Juntian Zhang
Journal: Pharmacology & Therapeutics (2016)
Phase II study of capecitabine (X) as palliative treatment for patients (p) with squamous head and neck cancer (HNC) with locoregional and/or metastatic relapse after previous platinum-based treatment (PBT): An interim analysis
Authors: J. Martínez-Trufero, D. Isla, J. C. Adansa, R. Hitt, J. J. Cruz
Journal: Journal of Clinical Oncology (2007)

6074 Background: PBT is the standard therapy for HNC and is widely used as first line treatment. Nevertheless the incidence of relapse remains still high. Therefore, new non-platinum drugs need to be asses as second line treatment options. Taking into account the results obtained with X in HNC, we proposed this study to evaluate activity and tolerability of X when used as palliative monotherapy for relapsed HNC p previously treated with PBT. Methods: Patients aged 18–75 years, ECOG PS 0–2, with advanced squamous HNC with locoregional and/or metastatic relapse previously treated with PBT and adequate bone marrow, renal and hepatic functions were included. X (1,250 mg/m 2 BID) during 14 days was administered every 21 days, for at least 2 cycles. Objective response rate (ORR) was assessed according RECIST criteria and toxicity following NCI-CTC v2 criteria. Results: Sixteen patients with median age 57 years old, all of them male, ECOG 0/1 (33.3% / 66.7%) and with squamous HNC, were analyzed. Twelve p had local disease, 4 p adenopathies and 6 p lung metastases. Median time since HNC diagnosis was 30.4 months and since disease extension diagnosis, 1.8 months. All p received a total of 58 cycles of X (median 3, range 1–6) and the median relative dose intensity was 92%. Four p were not evaluable for response (1 is still on treatment; 3 died, 2 due to unknown reasons and 1 due to an infection). ORR was 16.7%.The median follow-up time was 3.3 months, median TTP was 4.2 months and median OS was 4.7 months. Hematological toxicity G3/4 was reported in 2 p. The only grade 4 non-hematological toxicity was dysphagia in 1 p; grade III toxicities were: asthenia (2 p), anorexia (1 p), dehydratation (1 p), diarrhea (1 p), mucositis (1 p), weight loss (1 p) and palmar-plantar erythrodysesthesia (1 p). The most common grade II toxicity was asthenia (2 p). Conclusions: Capecitabine seems to be an active, feasible and well tolerated palliative treatment for advanced HNC patients that have previously received platinum-based schedules. No significant financial relationships to disclose.