tbuckley/cabot-search huggingface dataset:
Molecular epidemiology of gastrointestinal stromal tumors (GISTs): comparison of North and South American patient populations
Authors: M. Chacon, C. L. Corless, E. Roca, A. Harlow, M. Galich, C. Le, M. C. Heinrich
Journal: Journal of Clinical Oncology (2008)

22142 Background: KIT or PDGFRA mutations are found in 80–90% of gastrointestinal stromal tumors (GIST) arising in North American, western European, or Asian populations. OBJECTIVE: To compare kinase genotypes of GIST tumors obtained from Argentinian patients to those obtained from North American patients (pts). Methods: 302 Argentinian (ARG) pts with a histological diagnosis of GIST were included in a prospective clinical database (Grupo Argentino de Tumores del Estroma Gastrointestinal- Digestivos). Paraffin blocks of tissue from 97 of these pts were analyzed using high performance liquid chromatography (HPLC) and DNA sequencing for KIT (exon 9, 11, 13, 17) and PDGFRA gene mutations (exons 12, 14, 18). The ARG genotyping results were compared to our previously genotyped group of 1354 North American pts (NA). Results: GIST mutations were found in 83.8% and 82.5% of NA and ARG GISTs, respectively. 1027 NA (75.8%) and 70 ARG (72%) patients had KIT gene mutations–exon 11 was mutated 63% and 65% of cases, respectively. There was a slightly greater frequency of PDGFRA gene mutations in the ARG group (8.05 vs. 10.5%). The percentage of wild-type GISTs was similar between the two populations (16.2% NA and 17.5% ARG). Overall, there was no statistically significance in the spectrum or frequency of NA and ARG GIST mutations. Clinical response data (RECIST) was available for 24 pts with exon 11-mutant GIST and 6 patients with wild-type GIST treated with imatinib (IM) for advanced disease. CR/PR was observed in 42% of IM-treated patients with exon 11-mutant GIST compared with 17% of patients with WT-GISTs. The clinical benefit rate (CR+PR+SD) of IM was 100% for patients with exon 11-mutant GIST. Ongoing studies will further correlate clinical features with molecular genotype in the ARG patients (e.g. post-resection recurrence risk; progression-free and overall survival during IM therapy). In addition, analysis of a cohort of ARG pediatric GIST patients is underway. Conclusions: molecular epidemiology of GISTs appears similar between ARG and NA populations. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Novartis, Pfizer
Phase 1 study of picoplatin (pico) in combination with 5-fluorouracil (FU) and leucovorin (LV) as initial therapy in subjects with metastatic colorectal cancer (CRC)
Authors: O. Gladkov, G. Manikhas, M. Biakhov, S. Tjulandin, D. Karlin
Journal: Journal of Clinical Oncology (2007)

14510 Background: Pico is a platinum analogue designed to overcome platinum resistance with improved safety and efficacy compared with conventional platinum agents. FOLFOX (FU, LV, oxaliplatin) has emerged as the standard of care in first and second-line therapy of advanced -stage CRC but significant neurotoxicity limits long-term use of oxaliplatin in this regimen. Pico has been well tolerated in &gt;600 patients with rare clinically significant nephro-, oto-, or neurotoxicity (∼2% grade 3 and 0% grade 4), even in platinum pretreated patients. Pico has demonstrated synergy with FU in vitro and is thus an attractive candidate to replace oxaliplatin in the FOLFOX regimen. The objective of this Phase 1 study is to identify the maximum tolerated dose (MTD) of pico administered either every 2 wks or every 4 wks with FU and LV administered every 2 wks. Methods: Each patient receives q 2 wk FU and LV: LV, 400 mg/m 2 , 2-hr infusion, followed by 5- FU bolus, 400 mg/m 2 and then 5-FU, 2,400 mg/m 2 , 46 hr continuous infusion. Subjects are randomized to pico administered either every 2 or every 4 wks. Starting dose of pico for q 2 weekly regimen was 45 mg/m 2 and in subsequent cohorts pico increases by 15 mg/m 2 . Starting dose of pico for q 4 wk regimen was 60 mg/m 2 and in subsequent cohorts pico increases by 30 mg/m 2 until dose limiting toxicity (DLT) establishes the MTD. Results: 23 pts have been treated to date, the first have received 32 wks of therapy. Therapy has been well tolerated, with infrequent dose delays from non-cumulative platelet and ANC toxicity and 1 episode of mild diarrhea. No DLT has been seen through the first 3 cohorts, i.e. with picoplatin, 75 mg/m 2 with every dose of FU-LV or120 mg/m 2 with every other dose of FU-LV. Dose escalation continues. Response assessments for 12 patients in the first 2 cohorts (6 on each pico schedule, all below the MTD) after 16 wks show 4 partial responses, 5 stable disease and 3 progressive disease. Conclusions: Picoplatin can be safely administered with 5FU and LV. A phase 2 study of FU, LV and pico will begin as soon as the MTD is identified and a safe dose and schedule are defined. No significant financial relationships to disclose.
Ten-year results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trial evaluating the use of L-phenylalanine mustard (L-PAM) in the management of primary breast cancer.
Authors: B Fisher, E R Fisher, C Redmond
Journal: Journal of Clinical Oncology (1986)

Between 1972 and 1974, patients were entered into a National Surgical Adjuvant Breast and Bowel Project (NSABP) trial to evaluate L-phenylalanine mustard (L-PAM) as an adjuvant to mastectomy in patients with primary breast cancer and pathologically positive axillary nodes. Overall, findings through 10 years of observation indicate an 8% difference in disease-free survival (DFS) (P = .06) and a 5% difference in survival (P = .4). Women less than or equal to 49 years of age who received L-PAM demonstrate a significant (P = .03) prolongation of DFS and a significant (P = .05) survival benefit compared with those who received a placebo. There is a 37% reduction in their mortality and a cumulative odds of survival of 1.67. In that age group, both those with one to three and greater than or equal to 4 positive nodes benefited, but the advantage was greater when there were fewer positive nodes. There was a significant (P = .009) reduction in mortality (64%) and a cumulative odds of survival of 3.25 in patients less than or equal to 49 years old with one to three positive nodes. No advantage from L-PAM was observed in patients greater than or equal to 50 years old. When L-PAM response is related to nuclear grade, a marker of tumor differentiation, there is a highly significant improvement in DFS (less than .001), distant DFS (.001), and survival (.004) through 10 years of observation for all patients with tumors classified as nuclear grade poor (poorly differentiated), regardless of age and nodal status. Mortality was reduced by 32% and the cumulative odds of survival was 2.10 at 10 years. Of singular importance is the observation of a benefit in those greater than or equal to 50 years of age as well as in those less than or equal to 49 years of age with poorly differentiated tumors. There is a significant (P = .003) survival benefit for those in the older age group with a 37% reduction in mortality, and a cumulative odds of survival of 2.75. Patients in both age groups with well-differentiated tumors demonstrated no benefit from L-PAM. Those who are older seem to do less well following chemotherapy. We conclude that tumor differentiation is a better discriminant of response to chemotherapy than is age, and that both younger and older women are responsive to adjuvant chemotherapy when they have poorly differentiated tumors.
Alloreactive T Cell Clonotypes Identified By In Vitro Mixed Lymphoid Reaction and High-Throughput Sequencing Exhibit Increased Frequency In Peripheral Blood Samples From Patients Following Allogeneic Hematopoietic Cell Transplantation For Chronic Lymphocytic Leukemia
Authors: Aaron C. Logan, Mark R. Krampf, Mark Klinger, Martin Moorhead, Jianbiao Zheng, Randall Armstrong, Malek Faham, Kenneth I Weinberg, David B. Miklos
Journal: Blood (2013)
Factors associated with willingness to participate in an acupuncture clinical trial for arthralgia among breast cancer patients
Authors: K. Desai, A. DeMichele, D. Bruner, N. Vapiwala, C. Hughes Halbert, C. Stricker, J. J. Mao
Journal: Journal of Clinical Oncology (2009)

6596 Background: Many breast cancer patients use complementary and alternative medicine (CAM), which warrant rigorous evaluation of the safety and efficacy of these therapies. As with conventional cancer treatment studies, researchers face challenges in accruing patients to CAM trials. This study aims to identify the factors associated with willingness to participate (WTP) in a trial evaluating use of acupuncture for arthralgia among breast cancer patients. Methods: We conducted a cross-sectional survey study among outpatient postmenopausal breast cancer patients who were receiving aromatase inhibitors. Self-reported WTP in an acupuncture trial was used as the main outcome variable. Expectation towards acupuncture efficacy was measured using a previously validated Acupuncture Expectancy Scale. Multivariate logistic regression was used to identify factors associated with WTP. Results: 300 patients participated (92% response rate), with a mean age of 61 ± 10 years, 252 (84%) White, and 38 (13%) Black. Of the participants, 148 (49.8%) reported WTP in an acupuncture trial should they be offered an opportunity for such research. In a multivariate model, higher likelihood of WTP was associated with having a college education, adjusted odds ratio (95% confidence interval), 3.78 (1.83–7.81); having previous radiation therapy 2.02 (1.13–3.62); and current experience of arthralgia 2.36 (1.11–4.98). Positive expectancy of acupuncture outcome was also associated with greater likelihood of WTP 1.20 (1.12–1.28). Age and race were not predictors of WTP in the multivariate model. Conclusions: Almost half of the outpatient breast cancer patients expressed WTP in an acupuncture clinical trial for arthralgia. Higher education, previous radiation therapy, current experience of arthralgia, and positive expectancy related to acupuncture may affect breast cancer patients’ willingness to participate in an acupuncture trial for arthralgia. No significant financial relationships to disclose.
Sorafenib (S) in patients (pts) with advanced hepatocellular carcinoma (HCC): Safety and efficacy in Child-Pugh (CP) class A and B patients.
Authors: Tiziana Pressiani, Corrado Boni, Lorenza Rimassa, Roberto Labianca, Stefano Fagiuoli, Andrea Ardizzoni, Paolo Foa, Enrico Cortesi, Laura Giordano, Armando Santoro
Journal: Journal of Clinical Oncology (2012)

306 Background: S is the first systemic agent that has been shown to prolong survival in pts with CP A advanced HCC. However, its safety and efficacy have not been extensively evaluated in pts with CP B cirrhosis. Methods: We performed a descriptive analysis on pts with histologically documented advanced HCC and CP A/B cirrhosis, enrolled in a multicenter phase II randomized, open-label trial (data reported elsewhere), in order to assess the feasibility and efficacy of treatment with S in CP B pts. Written informed consent was obtained from all pts. Results: From April 2007 to July 2008, 297 pts were prospectively treated with S 400 mg bid, 234 (78.8%) CP A, 63 (21.2%) CP B. 232 pts were male (76%), median age was 68.3 yrs (range 19.8-89.2 yrs), 217 pts had no extra hepatic disease (73.1%). The two subgroups, according to CP class A or B, were homogeneous for all considered parameters. Median treatment duration was &gt;3 months (mos) for 59.4% of CP A pts and for 27% of CP B pts (p &lt;0.001). Median PFS for the total population was 3.9 mos, 4.3 mos for CP A pts and 2.1 mos for CP B pts (p&lt;0.001). Median OS was 10 mos for CP A pts and 3.8 mos for CP B pts (p&lt;0.001). Adverse events (all grades) were similar in type and incidence for CP A and B pts, with fatigue, stomatitis, diarrhea and weight loss having the highest incidence (44%, 41%, 38% and 38%, respectively). Specifically, no differences in terms of grade 3-4 events have been documented between the two groups. Conclusions: This study supports the feasibility of S also in advanced HCC pts with CP B status. Tolerability data suggest that pts with CP B status might potentially be treated safely with S for its potential survival benefits. Further prospective trials, specifically designed to investigate S in CP B pts, are eagerly advocated.
Utilization of Oncotype DX to predict chemotherapy use in an inner-city population.
Authors: A. A. Guth, S. Fineberg, K. Fei, R. Franco, N. Bickell
Journal: Journal of Clinical Oncology (2011)

e11131 Background: Oncotype Dx is a 21 gene array analysis to help guide chemotherapy treatment decision-making for women with ER+ tumors. There is little data on its effect on treatment decisions in an inner-city population. At the time of this study, Genomic Health did not have a contract with Medicaid, but did not charge individual patients. Methods: 374 women with a early-stage breast cancer surgically treated between 2006-2010 participated in a randomized controlled trial of patient assistance to reduce disparities in treatment. Of 347 with completed data, 206 had ER+ tumors stage 1B or greater eligible to undergo Oncotype Dx testing. Bivariate comparisons done with chi square/t tests; logistic models done for multivariate comparisons. Results: 23% (47/206) women underwent Oncotype Dx. Women tested vs nontested were: 54y vs 57y (NS). 79% of stage 1B vs 17% of stage 2A and 4% of 2B (p<0.0001), 68% white vs 11% black and 19% Hispanic (p=0.02) women were tested. 13% of women living in poverty were tested compared to 30% of those not (p<0.01). 1 of 36 (3%) women treated at municipal hospitals compared to 30% at academic referral centers was tested (p=0.002). In non-municipal hospitals 33% of white compared to 19% of nonwhite women (p<0.05) were tested. Insurance did not affect likelihood of testing. Multivariate analysis revealed tested women were more likely to have stage 1B (OR=5.4; 95%CI: 2.4-12.1) and be white (OR=2.8; 95%CI: 1.31-5.86); model c=.75; p<0.0001. 21/47 women tested (45%) with low recurrence risk; 18/47 (38%) intermediate risk and 8/47 (17%) high risk, with no racial difference. 100% at high risk were treated with chemotherapy; 65% at intermediate risk and only 5% at low risk were treated with chemotherapy. Conclusions: Oncotype Dx influences treatment with chemotherapy, particularly at high and low risk of recurrence. However, only a small percentage of eligible women who could benefit were tested; minority women and those treated at municipal hospitals were less likely to undergo testing. As Oncotype Dx influences treatment and can reduce overuse of chemotherapy, it is imperative to expand testing to those who could benefit yet experience underuse of this test, namely, minority women and women treated at safety-net hospitals.
Altered expression of prostaglandin synthases in NSCLC: Therapeutic strategies and targets for intervention
Authors: M. Cathcart, K. Gatley, E. Kay, G. P. Pidgeon, K. J. O’ Byrne
Journal: Journal of Clinical Oncology (2007)

18083 Background: Prostacyclin Synthase (PGIS) and Thromboxane synthase (TXS) metabolize PGH(2) into prostacyclin and thromboxane respectively. PGIS over-expression inhibits cancer growth in a mouse model, while over-expression of TXS caused opposite effects. TXS is expressed in a variety of tumours, associated with poor prognosis and increased metastasis. The aim of this study was to examine the expression of PGIS and TXS in NSCLC, the effect of targeted TXS inhibition, and the mechanisms regulating these effects. Methods: A panel of resected human lung tumours were stained for PGIS and TXS expression by IHC and by western analysis. A 170- core tissue microarray was stained for TXS and intensity correlated with tumour grade. Cell survival was examined by BrdU assay in A-549 (adenocarcinoma) and SKMES-1 (squamous cell carcinoma) cells following 24h selective TXS inhibition with Ozagrel (500nM) alone, or in combination with chemotherapy. Multi-parameter apoptosis signalling was examined after TXS inhibition using In Cell Analyser and confirmed by DNA laddering and cell death ELISA. PCR arrays were used to examine genes involved in tumourigenesis following TXS inhibition. Results: PGIS was absent in lung cancer sections. TXS was over-expressed in lung cancer relative to matched normal, with significantly increased expression in lower grade tumours. PGIS was down-regulated or absent, while TXS expression was up-regulated in tumours v’s normal tissue. Ozagrel significantly reduced cell survival and induced apoptosis, determined by both DNA laddering and Cell Death ELISA. Multi-parameter apoptosis analysis revealed enlarged nuclei, decreased f-actin staining and decreased mitochondrial mass potential, while PCR arrays confirmed upregulation of the pro-apoptotic gene BAX following TXS inhibition. Ozagrel in combination with Doxorubicin (10nM) showed greatest efficacy compared to a number of other chemotherapy drugs. Conclusions: Expression of PGIS and TXS are altered in NSCLC. Overexpression of TXS may regulate tumour survival as its inhibition induces apoptosis, potentially through upregulation of pro- apoptotic proteins. Targeting TXS, alone or in combination with chemotherapy is a potential therapeutic strategy for the treatment of NSCLC. No significant financial relationships to disclose.
Osteonecrosis of the maxilla and mandible in patients treated with bisphosphonates: A retrospective study
Authors: C. L. Estilo, C. H. Van Poznak, T. Williams, E. Evtimovska, L. Tkach, J. L. Halpern, S. J. Tunick, J. M. Huryn
Journal: Journal of Clinical Oncology (2004)

8088 Background: Bisphosphonates (BP) inhibit osteoclast activity and decrease the risk of skeletal complications. Hence, intravenous BPs have been incorporated into the therapy of patients (pts) with osseous metastases of various tumor types. Anecdotal reports of osteonecrosis (ON) in the maxilla and mandible have raised concerns regarding BP toxicity. To further explore this potential drug complication, we preformed a retrospective chart review of pts with multiple myeloma and metastatic breast cancer who were receiving intravenous BP therapy. Methods: The medical and dental records of all pts with multiple myeloma or breast cancer who were treated in the Dental Service of Memorial Sloan-Kettering Cancer Center between 1/1/00 and 12/10/03 were reviewed. Pts who presented with exposed bone or ON of the maxilla or mandible and were previously treated with BP were further evaluated for various clinical and pathological characteristics. Results: 124 pts were identified within the time frame and disease type of interest. 13 pts were found to have ON of the maxilla or mandible. Of these pts, 9 pts had a history of breast cancer with bony metastases and 4 had multiple myeloma. There were 4 men and 9 women, with a median age of 56 years. All of the pts received intravenous BP, with a median duration of 39 months. 9/14 pts (69%) had been treated with corticosteroid. 6/13 pts (46%) had a history of tobacco smoking. 9/14 (69%) pts presented with symptoms. ON was noted in the maxilla in 5, mandible in 6, and both maxilla and mandible in 2 pts. 9 pts had a history of dental extraction in the region of ON. 4 pts presented with spontaneous ON. Conservative sequestrectomy was performed in 6 pts. 1 patient underwent surgical debridement. 6 pts were managed conservatively with chlorhexidine rinse and/or antibiotics. Conclusions: The clinically relevant cancer literature on BPs is almost uniformly positive demonstrating a decrease in skeletal complications. Contributing causes of these pts' ON may include advanced cancer, chemotherapy, comorbidities, steroids, and possibly BP. Clinicians caring for pts with advanced cancer should be aware of ON as a possible treatment complication. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis
Polymorphisms of GSTP1, GSTT1, GSTM1, MTHFR, TS, ERCC1, and ERCC2 in metastatic colorectal cancer treated by first-line mFOLFOX6 chemotherapy
Authors: K. Ishibashi, N. Okada, T. Ishiguro, M. Yokoyama, T. Miyazaki, M. Sano, H. Yamada, H. Ishida
Journal: Journal of Clinical Oncology (2009)

e14628 Background: It was reported that determining functional polymorphisms of genes involved in drug-metabolising pathways and DNA repair may be useful for predicting the response to 5-FU/oxaliplatin chemotherapy in Caucasian patients with metastatic colorectal cancer. This study was performed to examine whether determining these polymorphisms had any clinical value in Asian patients with colorectal cancer receiving 5-FU/oxaliplatin therapy. Methods: Genomic DNA was extracted from peripheral blood lymphocytes (n=25) or colonic mucosa (n=47) in Japanese patients with metastatic colorectal cancer who were receiving first-line therapy with the modified FOLFOX6 regimen followed by FOLFIRI (n=42). Polymorphisms of 5 genes involved in drug metabolism (glutathione S-transferase (GST) P1 (IIe 105 Val), GSTT1 deletion, and GSTM1 deletion, methylenetetrahydrofolate reductase (MTHFR) (Ala 677 Val), and a 6-base pair (bp) deletion in the 3’-untranslated region (UTR) of thymidylate synthase (TS)), and polymorphisms of two DNA repair genes (excision repair cross complementing group 1 (ERCC1): Asp 118 Asn and ERCC2: Lys 751 Gln) were assessed in these patients by PCR-RFLP or the invader technique. Correlations between polymorphisms of these genes and the response to therapy were evaluated. Results: The distribution of the genotypes of GSTP1, GSTT1, TS, ERCC1, and ERCC2 in the present Japanese patients (but not that of GSTM1 or MTHFR), differed significantly from the distribution of these genotypes in a Caucasian population. The response rate and progression-free survival were not correlated with any of the functional polymorphisms investigated. However, patients who had both alleles containing the 6-bp nucleotide fragment in the 3’UTR of TS showed significantly shorter overall survival than those who had at least one allele without the 6-bp nucleotide fragment (p=0.03). Conclusions: These results suggest that 3’UTR polymorphism of TS may be an important predictor of overall survival for Japanese patients with metastatic colorectal cancer receiving first-line 5-FU/oxaliplatin therapy. No significant financial relationships to disclose.