tbuckley/cabot-search huggingface dataset:
A phase II study of pemetrexed and carboplatin as front-line chemotherapy in patients with malignant pleural mesothelioma (MPM)
Authors: G. L. Ceresoli, P. A. Zucali, A. Favaretto, M. Marangolo, G. Del Conte, F. Grossi, A. Ceribelli, P. Bidoli, A. Bearz, A. Santoro
Journal: Journal of Clinical Oncology (2005)

7172 Background: The combination of pemetrexed (P) and carboplatin (C) was found to be active and well tolerated in MPM in a phase I trial (Hughes, JCO 2002). Aim of our study was to explore this combination in a Phase II setting in patients affected by MPM. Methods: From 11/02 to 10/04, 87 chemo-naive patients (pts) with unresectable MPM were enrolled from 8 Italian institutions. Therapy consisted of P 500 mg/m2 given as a 10-minute intravenous infusion, followed by C AUC 5 administered as a 30-minute intravenous infusion. Treatment was repeated every 21 days for a maximum of 6 cycles or until progression or unacceptable toxicity. All pts received folic acid and vitamin B12 supplementation, and steroid prophylaxis. Results: All pts had unresectable disease; 10 had relapses after radical surgery. Their characteristics were: M/F 65/22; PS 0/1/2 27/52/8; median age 65 years (range:38–79). Histology was epithelial in 69 (79%), sarcomatoid in 5 (6%), mixed in 8 (9%), unclassified in 5 (6%). Seventy-eight pts were evaluable for response, toxicity and survival; the remaining 9 are still on treatment. Response rate was 20% (95% CI 12–31%), with 1 CR and 15 PR; SD was observed in 34 pts (44%, 95% CI 32–55%), PD in 28 (36%, 95% CI 25–48%). A total of 368 cycles were delivered. Grade (G) 3–4 hematological toxicity consisted of neutropenia in 14 pts (18%, febrile neutropenia in 1 case only), anemia in 10 (13%), thrombocytopenia in 5 (6%). Non-hematological toxicity was generally mild: G 3–4 diarrhea in 3 pts (4%), G 1–2 conjunctivitis in 12 (15%),G 1–2 asthenia in 27 (35%). With a median follow-up of 5.2 months (range 0.8–21.9), 25 pts died and 53 are still alive. Median time to progression was 6 months (range 0.3–11.3). Conclusions: This Phase II trial confirms the encouraging activity of the combination of P and C in MPM. The excellent toxicity profile of this regimen strongly supports its use as front-line therapy as well as in the neoadjuvant setting of MPM. No significant financial relationships to disclose.
Abstract 1923: Distinct evolutionary and mutational patterns in oncogenes and tumor suppressor genes
Authors: Li Liu, Yung Chang, Jieping Ye, Sudhir Kumar
Journal: Cancer Research (2015)

Abstract Oncogenes and tumor suppressor genes play different roles in carcinogenesis and tumor progression. However, very little attention has been paid to compare their mutational and evolutionary patterns. As such, these two groups of genes are often mingled together in computational modeling and analysis. To bridge this gap, we examined the evolutionary profiles of 150 oncogenes and 102 tumor suppressor genes and their somatic mutations recorded in the COSMIC database. We found that these two groups of genes display distinct evolutionary and mutational patterns. In general, oncogenes are more conserved than tumor suppressor genes, as revealed by multiple-species comparisons. The stronger purifying selection on oncogenes is also reflected at positions harboring somatic missense mutations. Thus, somatic mutations disrupting oncogenes tend to have higher functional impact than those disrupting tumor suppressor genes. However, the mutational landscape of oncogenes is often dominated by one or very few hotspots, while multiple hotspots and frequent sporadic mutations are found in tumor suppressor genes. Furthermore, CpG hypermutations contribute to 58% of highly recurrent mutations in tumor suppressor genes, but only 4% to those in oncogenes. These patterns indicate that most random somatic mutations in oncogenes are also under stronger purifying selection as compared to those in tumor suppressor genes. However, once an advantageous mutation in an oncogene arises, it tends to increase the fitness significantly such that a hard sweep pursues, which eventually reduces the mutational diversity of the tumor. On the contrary, the relatively mild selection on tumor suppressor genes allows more neutral mutations to accumulate. When eventually the deactivation of both copies of a tumor suppressor gene triggers positive selection, the mutational diversity of the tumor has increased significantly. These distinct evolutionary and mutational patterns warrant independent modeling of oncogenes and tumor suppressor genes in studies that incorporate these features in the analysis, such as prediction of driver mutations or inference of evolutionary paths for cancers. Citation Format: Li Liu, Yung Chang, Jieping Ye, Sudhir Kumar. Distinct evolutionary and mutational patterns in oncogenes and tumor suppressor genes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1923. doi:10.1158/1538-7445.AM2015-1923
Abstract 19353: Decrease in Matrix Gla Protein Level is Associated with Faster Progression of Aortic Valve Stenosis in a Substudy of ASTRONOMER: Relationship with Age
Authors: Nancy Cote, Romain Capoulade, Dominique Fournier, Philippe Pibarot, Jean-Guy Dumesnil, Kwan L Chan, Koon Teo, James Tam, Jean-Pierre Despres, Pierre Moreau, Patrick Mathieu
Journal: Circulation (2010)

Background: Matrix Gla protein (MGP) is an inhibitor of cardiovascular calcification. The objective of this substudy was to examine, in a large prospective multicenter study, the relationship betwe...
Bevacizumab in the first-line treatment of elderly patients with metastatic colorectal cancer: Mature results from a large community-based observational study.
Authors: Ralf Hofheinz, Wilfried Grothe, Dirk Tummes, Manfred Kindler, Volker Petersen, Stefanie Boszeit-Luft, Joerg Seraphin, Axel Hinke, Dirk Arnold
Journal: Journal of Clinical Oncology (2012)

566 Background: In most patients (pts) with metastatic colorectal cancer, a 3-drug combination of a fluoropyrimidine, oxaliplatin (ox) or irinotecan (iri), and a monoclonal antibody is considered standard 1st-line treatment. However, in elderly pts this choice remains controversial. After registration of bevacizumab (bev) in Germany in 2005, this observational study was initiated in pts receiving bev with various first-line chemotherapy (CT) regimens to evaluate the disease profile and efficacy of bev in patients with metastatic colorectal cancer. Methods: Eligibility criteria focused on M1 disease without prior palliative CT. The choice of CT regimen was at the physician’s discretion. Predefined efficacy endpoints were: response rate (RR), progression-free survival (PFS) and overall survival (OS). Pts were followed for up to 6 years (y). Two pt subgroups were analyzed: ≥70 y and ≥75 y; the ≥75 y group is the focus of this abstract. Results: 1777 eligible pts were enrolled at 261 sites from Jan 2005 to June 2009, 206 (12%) of whom were aged ≥75 y. These elderly pts did not differ greatly vs younger pts in time from initial diagnosis or time to first relapse, pT, pN and M stage, site of metastasis, grading, CEA, WBC, blood pressure, or prior adjuvant therapy. However, fewer elderly pts had &gt;1 involved organ site (28% of pts ≥75 y vs. 32% of pts ≥70 y) and elderly pts had significantly poorer performance status (ECOG 0 in 29% of pts ≥75 y vs. 39% of pts ≥70 y). Bev treatment duration was similar in elderly and younger pts, but differences in CT usage were observed (Table). Response and survival outcomes were significantly worse in those aged ≥75 y. Conclusions: Bev-based treatment combinations can be used successfully in pts aged ≥75 y. However, PFS and OS are significantly shorter in pts aged ≥75 y vs younger pts, probably because of greater comorbidity and possibly because of less intensive treatment in the elderly. [Table: see text]
Determinants of Racial/Ethnic Disparities in Incidence of Clinical Diabetes in Postmenopausal Women in the United States: The Women’s Health Initiative 1993-2009
Authors: Yunsheng Ma, James R Hebert, JoAnn E Manson, Raji Balasubramanian, Simin Liu, M Lamonte, Chloe E Bird, Judith K Ockene, Yongxia Qiao, Barbara Olendzki, K L Schneider, M C Rosal, Deidre M Sepavich, J Wactawski-Wende, M Stefanick, L S Phillips, Ira S Ockene, R C Kaplan, G E Sarto, L Garcia, Barbara V Howard
Journal: Diabetes Care (2012)
The evaluation of the complementary role of pre and postoperative PET/CT fusion imaging in the detection of regional lymph node metastatic disease in malignant melanoma
Authors: B. Singh, H. J. Biersack, H. Ahmadzadehfar, H. Palmdeo
Journal: Journal of Clinical Oncology (2005)

7560 Background: Although,the sensitivity of PET for detecting subclinical regional lymph node/s metastatic disease in malignant melanoma is reported to be high but recent studies undermine its role. Methods: We evaluated the comparative role of 18F-FDG-PET/CT and lymphatic mapping (LM) in 55 (40M: 15F; mean age 53.32± 16.76 years) melanoma patients (stage IIA-V, mean Breslow depth = 3.46 ± 2.57mm; range 1.0mm- 12.0 mm, Clarks level III-V) having no evidence of regional lymph node metastatic disease. PET imaging was performed preoperatively in 46 and postoperatively in 9 patients respectively. Results: Preoperative lymphoscintigraphy (LS) detected 116 SLNs (average 2.10 SLN per patient) and demonstrated a single and multiple (2–5) drawing nodal basin in 16 and 39 patients respectively. Histologically, only 22% (26/116) of the nodes detected by LS/LM, were positive for malignant melanoma. Peoperative and postoperative PET imaging was true positive for 1 SLN each respectively. Additionally, PET demonstrated 1 more SLN postoperatively in the left knee. False PET positivity was demonstrated for 4 SLNs, 1 each in the axilla, submandibular region & 2 in the supraclavicular region, preoperatively. The other 2 false positive metastatic lesions were the primary tumor sites. The preoperative PET sensitivity was 4%, specificity 94%, PPV 17%, NPV 75% and diagnostic accuracy (DA) 71%. However, the isolated statistical analysis in 9 patients in whom PET imaging was performed postoperatively, revealed a sensitivity of 100%, specificity of 87.5%, PPV of 50%, NPV of 100% and DA of 89%. On the contrary, the preoperative LS and intraoperative LM had an overall sensitivity of 93%, specificity of 100%, positive predictive value (PPV) of 100%, negative predictive value (NPV) of 83% and DA of 95% for the detection of subclinical nodal metastases. Conclusions: Postoperative PET imaging is a useful modality in localizing recurrent distant metastatic disease during the follow up of malignant melanoma patients. No significant financial relationships to disclose.
Testicular Disease in Childhood B-Cell Non-Hodgkin’s Lymphoma: The French Society of Pediatric Oncology Experience
Authors: Jean-Hugues Dalle, Françoise Mechinaud, Jean Michon, Jean-Claude Gentet, Lionel de Lumley, Hervé Rubie, Claudine Schmitt, Catherine Patte
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To investigate whether testicular disease in childhood B-cell lymphoma should continue to be considered a sanctuary site, as it is with other lymphoid malignancies such as acute lymphoblastic leukemia. PATIENTS AND METHODS: Seven hundred forty-two children with B-cell non-Hodgkin’s lymphoma were included in the LMB protocols of the French Society of Pediatric Oncology from February 1981 to May 1994. Thirty patients (5.3%) had testicular involvement at diagnosis. We describe the clinical presentation and outcome of these 30 patients, who were treated without local radiation therapy. RESULTS: Five patients underwent diagnostic orchidectomy. The median patient age was 8.5 years (range, 2 to 14 years), and their cancers were stage III (18 patients), stage IV (five patients), and B-cell acute lymphoblastic leukemia (seven patients). Five patients had central nervous system involvement. Twenty-eight patients (95%) achieved complete remission. Twenty-six patients are alive without progressive disease (median follow-up, 6.5 years). CONCLUSION: Testicular disease does not seem to confer a poor prognosis, and it is curable with intensive combination chemotherapy alone. Local treatment (surgery or radiation) is avoidable; therefore, gonadal function can be preserved.
Paclitaxel gemcitabine (P-G) for patients (pts) with advanced urothelial cancer (UC) age &gt; 70 years (yrs): SWOG 0028.
Authors: D. Raghavan, C. M. Tangen, C. Moinpour, C. Gotay, K. S. Albain, S. Louie, H. Lenz, D. I. Quinn, M. Hussain, I. Thompson
Journal: Journal of Clinical Oncology (2010)

4569 Background: Pts age ≥ 70 yrs are under-represented in cancer trials. Primary aim: to assess feasibility of enrolling pts age ≥ 70 yrs with advanced UC to phase II trial of P-G with PK and PD sampling. Secondary aims: assess toxicity, response, feasibility of self-report measures of comorbidity, depression and functional status, and study of genetic polymorphisms. Methods: Key eligibility included: histologic confirmation; age ≥70 yrs, or < 60 yrs; previously untreated advanced, measurable or evaluable UC; standard biochemical and hematologic parameters; Zubrod performance status 0-2; agreement to undergo PK and PD tests; written informed consent. Pts treated with P 175mg/m2 day1 (d1) and G 1000mg/m2 d1&8, with standard anti-emetic Rx, repeat q21 days, 6 cycles. Pts completed Medical Conditions Questionnaire, Instrumental Activities of Daily Living Form, and the Feelings Questionnaire. Nurses assessed same issues. Toxicity assessed via standard SWOG parameters. PK and gene polymorphisms for P and G metabolism measured. Results: 51 eligible pts ≥ 70 years and 10 eligible pts aged < 60 years were treated. Males 73%; median ages 76 years and 53.8 years in 2 cohorts. Metastases: nodes (58%), liver (29%), lung (33%), bone (22%). Common self-report co-morbidities: myocardial infarct 22%, renal disease 20%, diabetes mellitus 16%, lung disease 16%, heart failure 8%. Compliance with self assessment forms > 90%. In older group, CR 2%, PR 20%, unconfirmed PR 14%, SD 27%, PD 16%, symptomatic PD 4%, early death in 2%; inadequate assessment in 16%, none with sustained response. Median PFS 6 mos and OS 11 mos. In younger pts, 0 CR, 4 PR, 2 SD, 2 PD, 1 symptomatic PD without restaging, and 1 with inadequate assessment. 50% & 32% of pts, respectively, sustained any grade III and IV toxicity, one toxic death (dehydration) in elderly pt (2%), no toxic deaths in younger pts. Major toxicities: gastrointestinal, myelosuppression and infection. Conclusions: P-G tolerable, but efficacy and toxicity do not justify routine use in very elderly. Accrual slower than anticipated. Patterns of PK and PD will be presented. Supported by NCI 5UO1 CA 58882-06, CA32102, CA38926 and Bristol-Myers Squibb, and Eli Lilly & Company. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly
Phase I/randomized phase II trial of either dasatinib or placebo combined with standard chemoradiotherapy for newly diagnosed glioblastoma multiforme (GBM): Final results of phase I study.
Authors: Nadia N. Laack, Evanthia Galanis, Clinton Leinweber, Jan C. Buckner, Caterina Giannini, Francois J. Geoffroy, Kurt A. Jaeckle, Jann Nagina Sarkaria
Journal: Journal of Clinical Oncology (2012)

2032 Background: Dasatinib is a potent oral ATP competitive multi-targeted kinase inhibitor of multiple members of the Src kinase family, known to be involved in gliomagenesis and invasion. N0877 is a phase I/randomized phase II trial evaluating the combination of dasatinib, radiation (RT) and temozolomide (TMZ) in newly diagnosed GBM. The phase I portion has been completed and is the focus of this report. Methods: A cohorts-of-3 design was used to assess the safety of dasatinib in combination with RT and concomitant TMZ, and establish the phase II dose of the combination. Dasatinib was given orally for 42 days, beginning with the first day of RT (total dose 60 Gy) and first dose of TMZ (75 mg/m2/d). A 24 - 42 day rest (cycle 2) followed the RT/TMZ/dasatinib. Patients (pts) were observed for DLT to the end of cycle 2. Patients then received 6 cycles (28 day cycles) of dasatinib (once daily) and TMZ (days 1-5). At the completion of 6 cycles of TMZ + dasatinib, pts stay on dasatinib only (28 day cycles) until progressive disease. Results: Phase I component is complete with 13 patients (3 at dose level 0, 3 at dose level 0-A, 7 at dose level 1). One patient in dose level 1 had to be replaced due to the development of unrelated medical issues. One DLT (grade 4 pancytopenia) was observed in 1 patient at dose level 0 (50mg bid) and one DLT (grade 3 rash) was observed in 1 patient at dose level 1 (150mg qd). MTD of dasatinib was determined to be 150mg daily. Most common adverse events throughout the entire study period were hematologic with the most common toxicity being lymphopenia (grade 3 in 69% of patients, grade 4 in 8%). Other toxicities attributed to treatment and occurring in &gt; 10% of patients included anemia (31%), neutropenia (15%), and fatigue(15%). Best response was stable disease in 10 patients, progressive disease in 1 patient, and not evaluable in 2. Conclusions: MTD for dasatinib in combination with TMZ and RT in newly diagnosed GBM patients is 150mg daily. Toxicity was primarily hematologic with minimal non-hematologic events. This dose is currently being used in the ongoing placebo-controlled, randomized phase II trial.
Association of increase in thymidine uptake relative to tumor cell proliferation in indolent NHLs and DNA repair
Authors: M. E. Juweid, A. K. Buck, L. L. Ponto, F. M. Mottaghy, S. Syrbu, P. Moller, J. M. Vose
Journal: Journal of Clinical Oncology (2009)

11116 Background: Uptake of radiolabeled thymidine (tdR) or its analogs is frequently used to assess tumor cell proliferation as well as tumor DNA repair synthesis after inhibition of tumor cell proliferation with certain drugs. We determined whether the relationship between thymidine (td) uptake and tumor cell proliferation may be different between indolent and aggressive NHLs. Methods: Twenty-four patients with histologically confirmed aggressive (n=16; all DLC) or indolent NHLs (n=8; 7 FL gr I-II, 1 MZL) underwent pretherapy imaging with the td analog 18 F-fluorothymidine (FLT) and biopsy to determine the proliferative cell fraction by the Ki-67 index. Tumoral FLT uptake was determined by the maximum standardized uptake values (SUVmax) and correlated with the Ki-67 index. The FLT-SUV to Ki-67 ratio was also compared between indolent and aggressive NHLs. Results: Disproportional increase in FLT-SUVmax relative to tumor cell proliferation was found in indolent NHLs: median %Ki-67 was 5% in indolent vs. 80% in aggressive NHL whereas median FLT-SUVmax was 3.6 vs. 9.4, respectively. The disproportional increase in FLT-SUV in indolent NHLs could not be explained by nonspecific FLT uptake in tumor extracellular space estimated to account for &lt;0.2 SUV unit. Difference in the ratio of FLT-SUVmax to Ki-67 index between indolent and aggressive NHLs was highly significant (1.21 ± 0.77 vs. 0.18± 0.20; P=0.006). These data are in line with a previous study using tdR where the ratios of median tdR (in cpm) to median %-Ki-67 or %-S phase cells in indolent were ∼1.5x those in aggressive NHLs which was associated with relatively increased expression of DNA repair proteins (PCNA) in indolent NHLs (Holte et. al. Acta Oncologica, 1999) Conclusions: Disproportional increase in td uptake relative to %proliferating tumor cells in indolent NHLs likely reflects enhanced DNA repair in quiescent cells or, less likely, constitutively increased Tk 1 expression. Studies are underway to determine expression of proteins that, unlike Ki-67, are associated with both DNA repair and replication (e.g., RFA, PCNA). If enhanced DNA repair is confirmed in indolent NHLs this could have major implications with respect to understanding their natural course and treatment options. No significant financial relationships to disclose.
The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) expanded access trial in North America: Safety and efficacy
Authors: J. J. Knox, R. A. Figlin, W. M. Stadler, D. F. McDermott, N. Gabrail, W. H. Miller, J. Hainsworth, C. W. Ryan, L. Cupit, R. M. Bukowski
Journal: Journal of Clinical Oncology (2007)

5011 Background: A prior phase III trial (TARGETs) demonstrated that sorafenib (SOR) doubled median progression-free survival versus placebo in previously treated clear cell renal cell cancer (RCC) patients (pts). The ARCCS trial made SOR available to a broader range of RCC pts through an expanded access program. Methods: This open-label, nonrandomized trial enrolled pts with advanced RCC not eligible for, or without access to, other SOR clinical trials; ECOG PS 0–2 with waivers granted for pts with ECOG PS 3–4; age =15 yrs; and adequate prior treatment of brain metastases. Major exclusion criteria included treatment &lt;4 wks prior, life expectancy &lt;2 mos, uncontrolled hypertension, and severe renal impairment requiring dialysis. Objectives were to analyze the safety and efficacy (response by RECIST) of 400 mg bid SOR in a community-based setting. Enrollment ceased on 12/20/05 when SOR became commercially available in the US, and those with no prior therapy or non-clear cell RCC continued in an extension protocol. Enrollment completed in Canada in 8/06. Results: A total of 2488 pts were valid for safety: 69% male with median age 63 yrs and most (83%) had prior nephrectomy; histologies included 78% clear-cell, 7% papillary, 1% chromophobe, and &lt;1% collecting duct and oncocytoma. Median time from diagnosis for all pts was 1.4 yrs (range &lt;1–34). Of those pts receiving prior therapy (n=1249), treatments included interferon alfa (54%), interleukin 2 (43%), bevacizumab (23%), thalidomide (12%), and sunitinib (2%). Grade 3 and 4 adverse events occurring in &gt; 2% pts were hand- foot skin reaction 7.2%, fatigue 5.3%, hypertension 4.4%, rash/desquamation 4%, dehydration and dyspnea 2.7%, and diarrhea 2.5%. Efficacy assessment, mainly PFS, was limited by the short median time (14 wks) on study due to many pts enrolling during the last 2 months of the study. Of 1,850 pts evaluable for response, 17.5% had unconfirmed PR. One (0.1%), 67 (3.6%), 1479 (79.9%) and 303 (16.4%) had CR, PR, SD, and PD, respectively. Conclusions: ARCCS pts were representative of the broader range of RCC pts in the community including those excluded from previous SOR trials. Toxicity and response rates were similar to those reported previously, supporting the generalizability of the phase III trial data. [Table: see text]