tbuckley/cabot-search huggingface dataset:
Surgical resection and intraoperative radiation therapy for locally recurrent rectal carcinoma.
Authors: David Furfaro, Zhi Ven Fong, Paul C. Shellito, David L. Berger, Jackie Szymonifka, Jennifer Yon-Li Wo, Theodore S. Hong, James C. Cusack
Journal: Journal of Clinical Oncology (2014)

3643 Background: Surgical resection with intraoperative radiation therapy (IORT) has been used to treat locally recurrent rectosigmoid adenocarcinoma (LRRSA). We present the experience at Massachusetts General Hospital (MGH) with resection and IORT for LRRSA. Methods: We retrospectively evaluated patients with LRRSA referred for IORT. Charts were evaluated for TNM staging, treatment regimen, IORT, resection margins, complications, recurrences, and current status. For the purpose of this study, R0 resection was defined as margins > 1mm from tumor. We evaluated the prognostic impact of treatment and resection margins on local control (LC), 5-year overall survival (OS) and disease-free survival (DFS). Results: Between 1995 and 2010, 51 patients with LRRSA were referred for IORT. Pre-operative radiation therapy was delivered to 88.2% of patients—for 5.9% this was re-irradiation—and 27.5% received post-resection radiation. IORT was delivered to 42 patients. Neoadjuvant chemotherapy was given to 96.1% of patients, and 76.5% had adjuvant chemotherapy. The resection margins achieved, measured as R0, clear margins with tumor within 1 mm (R<1mm), R1 and R2, were 49.0%, 7.8%, 25.5%, and 17.6%, respectively. The overall 5-year LC, OS and DFS were 52.3%, 60.9% and 36.4% respectively. The patients who received resection and IORT vs resection alone did not have improved DFS (HR 1.07, p=0.896), LC (HR 1.40, p=0.590) or OS (HR 0.52, p=0.247). R0 resection predicted favorable LC (HR 0.34, p=0.017), DFS (HR 0.22, p<0.001) and OS (HR 0.32, p=0.043). Patients with R0 margins vs R<1mm had improved LC (HR 0.20, p=0.024) and DFS (HR 0.12, p=0.004). On multivariate regression, margins of R0 or R<1mm (vs. R1 or R2) improved OS (HR 0.31, p=0.028), patients with worse resection margin status had worse DFS (HR 5.19, p<0.001), and R0 resections improved LC (HR 0.34, p=0.017). Conclusions: For patients with LRRSA optimal 5-year DFS, LC and OS were achieved with a margin negative surgical resection. Patients with R<1mm resections had the same OS as patients with R0 resections, but had worse DFS and LC. IORT in addition to surgical resection did not improve DFS, LC, or OS; however, the results are limited due to small sample size and patient selection bias.
Effects of Treadmill Exercise on Advanced Osteoarthritis Pain in Rats
Authors: Joshua Allen, Ian Imbert, Joshua Havelin, Terry Henderson, Glenn Stevenson, Lucy Liaw, Tamara King
Journal: Arthritis & Rheumatology (2017)

Exercise is commonly recommended for patients with osteoarthritis (OA) pain. However, whether exercise is beneficial in ameliorating ongoing pain that is persistent, resistant to nonsteroidal antiinflammatory drugs (NSAIDs), and associated with advanced OA is unknown.
A phase I and pharmacokinetic study of multiple schedules of ganetespib (STA-9090), a heat shock protein 90 inhibitor, in combination with docetaxel for subjects with advanced solid tumor malignancies.
Authors: John S. Kauh, R Donald Harvey, Taofeek Kunle Owonikoko, Bassel F. El-Rayes, Dong Moon Shin, Sujatha Murali, Colleen Margaret Lewis, Michael D. Karol, Florentina Teofilovici, Yuhong Du, Haian Fu, Fadlo Raja Khuri, Suresh S. Ramalingam
Journal: Journal of Clinical Oncology (2012)

3094 Background: Ganetespib is a next-generation Hsp90 inhibitor unrelated to the first-generation ansamycin class of Hsp90 inhibitors and has superior activity to these agents in preclinical studies. Ganetespib is well tolerated with promising antitumor activity. Based on synergy between ganetespib (G) and docetaxel (D), a phase I study evaluating preclinical dosing models was performed. Methods: Patients (pts) with advanced solid tumor malignancies and ECOG performance status (PS) 0-2 were eligible. Sequential cohorts of pts were treated (3+3 design) with increasing doses of D (day 1) and G (days 1, 8) (A) Q 21 days. Following MTD determination, safety and exploratory cohorts of D day 1 with G days 1, 15 (B); or G days 1, 4, 15 (C) were completed. PK sampling was performed during schedule A. The primary endpoint was determination of optimal doses and schedule of the two agents for combination therapy. Results: Twenty-seven patients were enrolled in schedules A (n=12), B (n=8), and C (n=7). Median age-64 (44-75); 11-M, 16-F; ECOG PS: 0 (n=5), 1 (n=21), 2 (n=1). Most pts had NSCLC (n=9), others were head/neck (n=4), and SCLC (n=3). The defined MTD was level 2 (D-75 mg/m2, G-150 mg/m2), as 2 of 4 pts at level 3 (D-75 mg/m2, G-200 mg/m2) had DLTs (febrile neutropenia and one g4 neutropenia of &gt; 7 days), requiring expansion of level 2. The median number of cycles received is 2 (1-11), with 3 pts in schedule C still on study. Among 22 pts evaluable for response, 1 had a PR (head/neck), 12 had SD following 6 weeks evaluation, 10 pts for 12 weeks and 6 pts for 18 weeks. Common AEs included neutropenia, diarrhea, anemia, fatigue, nausea, and febrile neutropenia. Prophylactic filgrastim/pegfilgrastim was not used at any time. PK data indicates similar G exposure alone compared to G administered prior to D. No accumulation was observed following once-weekly dosing, consistent with studies of G alone. Conclusions: The combination is well tolerated at the recommended doses of D 75 mg/m2 and G 150 mg/m2. Promising anti-cancer activity was noted, and a randomized phase 2b/3 study with D day 1 and G days 1, 15 regimen is ongoing in advanced NSCLC (NCT01348126).
Secondary primary malignancy risk among patients with gastric cancer: A nationwide population-based study in Taiwan.
Authors: San-Chi Chen, Jin-Hwang Liu, Cheng-Hwai Tzeng, Tzeon-Jye Chiou, Po-Min Chen, Chia-Jen Liu
Journal: Journal of Clinical Oncology (2015)

e15104 Background: Several studies have reported an increase in secondary primary malignancies (SPMs) among gastric cancer patients. Methods: Newly diagnosed gastric cancer patients between 1997 and 2011 were recruited from the Taiwan National Health Insurance database. Those who had antecedent malignancies or gastrointestinal stromal tumor were excluded. Standardized incidence ratios (SIRs) of SPMs were calculated. Risk factors for cancer development were analyzed by Cox proportional hazards models. Effects of treatments for gastric cancer were treated as time-dependent variables. Results: During the 15-year study period, 47,729 gastric cancer patients were recruited. Overall, 2,110 SPMs developed with a follow-up of 137,798 person-years. The SIR for all cancers was 1.46. The SIRs of follow-up periods were 1.43, 1.41, and 1.21 at >10 years, 5–10 years, and 1–5 years, respectively. After exclusion of SPM developed within 1 year, significant higher SIRs were seen in cancers of the head and neck (1.34), esophagus (2.16), colon and rectum (1.37), bones and soft tissues (1.95), ovaries (2.89), bladder (1.47), kidneys (1.44), as well as non-Hodgkin's lymphoma (5.56). Multivariate analysis showed that age ≥70 years (hazard ratio [HR] 1.19), being male (HR 1.37), diabetes mellitus (HR 1.30), chronic obstructive pulmonary disease (HR 1.17) and liver cirrhosis (HR 1.94) were independent risk factors. According to the treatments, radiotherapy (HR 1.24) and chemotherapy (HR 1.87) were independent risk factors, but surgery (HR 0.67) was not. Conclusions: Patients with gastric cancer are at increased risk of developing SPM. Close and longer surveillance for patients with risk factors should be considered. Taipei Veterans General Hospital-National Yang-Ming University Excellent Physician Scientists Cultivation Program, No. 104-V-B-029
Preliminary analysis of the phase II study of pemetrexed plus carboplatin as first-line chemotherapy for elderly patients with advanced nonsquamous, non-small cell lung cancer.
Authors: Naoki Omachi, Motohiro Tamiya, Akihiro Tamiya, Tomoya Kawaguchi, Hiroyasu Kaneda, Kazuhiko Nakagawa, Koichi Goto, Yuichiro Ohe, Hiroaki Okamoto, Tetsuya Abe, Akira Yokoyama, Haruko Daga, Koji Takeda, Tomonori Hirashima, Shinji Atagi
Journal: Journal of Clinical Oncology (2014)

e19162 Background: We previously reported a phase I study that recommended a dose of carboplatin (Cb, area under the curve = 5) plus pemetrexed (PEM, 500 mg/m2) for elderly (≥75-years-old) patients with non-squamous non-small cell lung cancer (NSCLC). This phase II trial assessed the efficacy and safety of this recommended dose in these elderly patients. Methods: Treated patients received 4 courses of Cb plus PEM, followed by PEM, without showing disease progression or severe toxicities. We preliminary analized the progression free survival (PFS), response rate (RR), and safety. Results: 34 patients were enrolled between June 2012 and May 2013. The median observation time was 7.4 months. The overall RR was 41.2%, and the disease control rate was 85.3%. No patient showed a complete response, 14 showed partial responses, 15 showed stable disease, 4 showed disease progression, and 1 was not evaluated. The maintenance therapy rate was 58.8%. The median PFS for all patients was 6.4 months (95% confidence interval, 2.7–10.3 months). Hematological adverse events ≥grade 3 included leucopenia (in 23.5% of patients), neutropenia (55.9%), anemia (32.4%), and thrombocytopenia (20.6%), and major non hematological adverse events ≥grade 3 were febrile neutropenia (in 8.8% of patients), increased levels of aminotransferase (5.8%), infection (23.5%), and anorexia/fatigue (5.9%). There was 1 treatment-related death due to interstitial lung disease. Adverse events during the maintenance phase were mild and well tolerated. Conclusions: The combination of Cb plus PEM was reasonably well tolerated in chemotherapy-naïve elderly patients with non-squamous NSCLC. Clinical trial information: UMIN000004810.
A first-in-human phase Ib study to evaluate the MEK inhibitor GDC-0973, combined with the pan-PI3K inhibitor GDC-0941, in patients with advanced solid tumors.
Authors: Patricia LoRusso, Geoffrey Shapiro, Shuchi Sumant Pandya, Eunice Lee Kwak, Cheryl Jones, Marcia Belvin, Luna C. Musib, Alex de Crespigny, Meghan McKenzie, Mary R. Gates, Iris Tan-Chi Chan, Johanna C. Bendell
Journal: Journal of Clinical Oncology (2012)

2566 Background: Both RAS/RAF/MEK and PI3K/Akt signaling pathways are deregulated in many tumor types. Targeting both pathways may be more efficacious than targeting either pathway alone. In preclinical models, concurrent administration of GDC‑0973, a potent, selective, MEK1/2 inhibitor and GDC-0941, a potent class I PI3K inhibitor, shows improved efficacy compared to either agent alone dosed continuously or intermittently. Methods: A phase Ib dose-escalation study with 3+3 design was initiated in patients (pts) with advanced solid tumors to evaluate the safety and pharmacokinetics (PK) of oral dosing of GDC-0973 and GDC-0941. Pts received: concurrent GDC-0973 + GDC-0941 once daily (qd) on a 21 day on/7 day off (21/7) schedule; intermittent GDC-0973 on Days 1, 4, 8, 11, 15, 18 of a 28 day cycle + GDC-0941 qd on a 21/7 schedule (MEK int); or GDC-0973 + GDC-0941 qd on a 7 day on /7 day off schedule (7/7). Starting doses were 20 mg GDC-0973 + 80 mg GDC-0941 (21/7), 100 mg GDC-0973 + 130 mg GDC-0941 (MEK int); 40 mg GDC-0973 + 130 mg GDC-0941 (7/7). Serial plasma PK samples, FDG-PET, and CT scans were obtained. Results: 78 pts have enrolled. DLTs were G3 lipase (n=1), G4 CPK elevation (n=1). Compared to the 21/7 MTD of 40 mg GDC-0973 + 100 mg GDC-0941, higher doses of GDC-0973 + GDC-0941 were tolerated on the MEK int schedule. Overall, adverse events related to the study drug combination in ≥ 20% pts were diarrhea, rash, nausea, fatigue, vomiting, decreased appetite, dysgeusia, and elevated CPK. Preliminary analysis indicated PK of GDC-0973 and GDC-0941 are not altered when dosed in combination. Of 46 evaluable pts, 26 had an FDG-PET partial metabolic response (≥ 20% decrease in mean SUV max from baseline) at ≥1 time points. Partial responses were observed in 3 pts (mBRAF melanoma, mBRAF pancreatic ca, mKRAS endometrioid ca); 5 pts had stable disease ≥ 5 months. Conclusions: Combination dosing of GDC‑0973 and GDC-0941 is generally well tolerated, with toxicities similar to those observed in single agent GDC-0973 and GDC-0941 phase 1 trials. There are early signs of anti-tumor activity. Dose escalation on MEK int and 7/7 schedules continues and updated data will be presented.
Should research ethics committees police reporting bias?
Authors: Simon E Kolstoe, Daniel R Shanahan, Janet Wisely
Journal: BMJ (2017)

Ethics review bodies are well placed to check trial reporting, say <b>Simon E Kolstoe</b> and <b>Daniel R Shanahan,</b> but <b>Janet Wisely</b> worries about resourcing and the lack of sanctions available once approval has been granted
Management of antiangiogenics’ renovascular safety in breast cancer subgroup and intermediate results of the MARS study.
Authors: Catherine Daniel, Nicolas Janus, Jean-Baptiste Rey, Philippe Beuzeboc, Isabelle Ray-Coquard, Joseph Gligorov, Jean-Philippe Spano, Jean Christophe Thery, Christelle Jouannaud, Francois Goldwasser, Olivier Mir, Jean F. Morere, Stephane Oudard, Michel Azizi, Richard Dorent, Gilbert Deray, Vincent Launay-Vacher
Journal: Journal of Clinical Oncology (2012)

1095 Background: Hypertension (HTN) and proteinuria (Pu) are class-side-effects of anti-VEGF drugs (AVD), related to the inhibition of the VEGF pathway. The MARS study has been conducted to assess the renovascular tolerance of AVD in the clinical setting. Methods: The MARS study is a multicentric prospective observational study of the renovascular safety of AVD in AVD-naive pts. 7 centres from 2009 to 2011. Data collected included: gender, age, serum creatinine (SCr), diabetes, HTN, hematuria (Hu) and Pu. This sub-group analysis presents the intermediate results for the 1st 155 pts with breast cancer (BC) receiving bevacizumab who completed the 1-year follow-up (f/u) (out of 337 BC pts in total). Results: Median age at inclusion: 62 years. Bone, visceral and cerebral metastasis frequencies were 74.2, 51.6 and 5.2%, respectively. Diabetes and HTN prevalences were 3.9% and 10.3%, respectively. Baseline renal assessment retrieved: Pu 14.2%, Hu 8.4%, aMDRD 98.2 ml/min/1.73m 2 and 2 pts with aMDRD&lt;60. The incidence of de novo Pu during f/u was 15% (Table). 59.1% of pts with Pu at inclusion improved. Among pts with de novo Pu, 40.0% afterwards improved/normalized. No grade 3/4 Pu has been reported and no hematuria. 12.9% developed HTN. Moreover, renal function decreased by -3.2 ml/min/1.73m 2 /year and 4 pts had aMDRD&lt;60 at the end of f/u. 32.2% increased their SCr: 27.1% grade 1, 4.5% grade 2, and 0.6% grade 3. All pts with grade 2-3 returned to normal or grade 1. No thrombotic micro-angiopathy (TMA) has been reported. Conclusions: These results show that 1) TMA remains rare, 2) Pu developed in 15% of pts, with no grade 3/4, 3) less than 13% developed HTN and 4) renal function was only slightly impaired with transient elevations in SCr. Furthermore, in case of a renovascular effect, investigators followed the recommendations from the French Society of Nephrology (Halimi JM. Nephrol Ther 2008) and no treatment withdrawal for unmanageable renovascular toxicity occurred. [Table: see text]
Free Fatty Acid Receptor 1 (FFAR1) as an Emerging Therapeutic Target for Type 2 Diabetes Mellitus: Recent Progress and Prevailing Challenges
Authors: Zheng Li, Xue Xu, Wenlong Huang, Hai Qian
Journal: Medicinal Research Reviews (2017)

Abstract The free fatty acid receptor 1 (FFAR1/GPR40) amplifies glucose‐dependent insulin secretion; therefore, it has attracted widespread attention as a promising antidiabetic target. Current clinical proof of concept also indicates that FFAR1 agonists achieve the initially therapeutic endpoint for the treatment of type 2 diabetes mellitus (T2DM) without the hypoglycemic risk. Thus, many pharmaceutical companies and academic institutes are competing to develop FFAR1 agonists. However, several candidates have been discontinued in clinical trials, often without reporting the underlying reasons. Herein, we review the challenges and corresponding strategies chosen by different medicinal chemistry teams to improve the physicochemical properties, potency, pharmacokinetics, and safety profiles of FFAR1 agonists, with a brief introduction to the biology and pharmacology of related targets.
Molecular staging of gastric cancer with a novel panel of prognostic microRNAs.
Authors: Yanghee Woo, Carolyn E. Behrendt, Yuman Fong
Journal: Journal of Clinical Oncology (2017)

52 Background: Molecular heterogeneity of gastric cancer discerns patient survival in ways that clinically-based prediction models cannot. To date, individual microRNAs(miRs) expressed by gastric tumors have been associated with survival. We offer a unique molecular-based method of prognosticating the survival of gastric cancer patients with an efficient panel of miRs. Methods: From The Cancer Genome Atlas(TCGA), we studied subjects with gastric adenocarcinoma, who had undergone R0-R1 resection and had data on clinical characteristics, overall survival (OS), and miR expression. Of miRs quantified by TCGA, miRs expressed by at least 15% of subjects’ tumors were evaluated as continuous variables. From 10 replicate samples, each containing 80% of current subjects, miRs were selected using proportional hazards regression adjusted for age with stepwise selection. Cross-validated miRs were retained for the panel if they optimized an accelerated failure-time model of OS using the full cohort. Results: Among subjects (n=254, age 64.7+10.9 years), median OS was 2.38 (95% Confidence Interval: 2.09-3.85) years. Of the 913 evaluable miRs, 10 distinct miRs (miR-373, miR-548ay, miR-659, miR-891a, miR-1243, miR- 4685, miR-6718, miR-6733, miR-6808, and miR-8072) were cross-validated as being prognostic and retained for the age-adjusted panel. Panel-predicted survival estimates, grouped into tertiles, distinguished progressively worse survival at 2 years, OS was 81.0%+5.1% for upper tertile, 61.5%+6.3% for middle tertile, and 29.6%+6.3% for lower tertile. As shown in Table 1, each tertile included subjects at all levels of TNM stage, and tertile was not significantly associated with stage (chi-square test, p=0.26). Conclusions: This unique miRs panel represents a molecular staging system for gastric cancer that has the potential to prognosticate patients' survival more accurately than existing clinical systems can. [Table: see text]
Gender associations in head and neck squamous cell carcinoma (HNSCC).
Authors: Tien Hoang, Chong Zhang, Heather M Geye, Tod Speer, Menggang Yu, Peggy A Wiederholt, Jennifer C Kakuske, Anne M. Traynor, James F. Cleary, Seth H Dailey, Charles N Ford, Timothy M McCulloch, Gregory K Hartig, Paul M. Harari
Journal: Journal of Clinical Oncology (2012)

e16010 Background: The primary objective of this analysis was to examine the association of gender with various presentation and outcome parameters in HNSCC. Methods: We queried the head and neck cancer (HNC) database at the University of Wisconsinand examined selected clinical, treatment and outcome data for all patients (pts) treated consecutively during the 10-year period (1/01-12/10). Results: From a total of 1,108 HNC pts, we identified 965 with SCC histology, including 252 women (26.1%) and 713 men (73.9%). Women were slightly older at presentation (mean age 62 vs. 60, p = 0.03); 29.6% of women vs. 19.6% of men were 70 years or older. There were no differences in race distribution. Smoking and drinking habits were frequently reported in both sexes, although seen more frequently in men. 74.1% of women vs. 83.1% of men had smoked cigarettes (p=0.003), while 74.9% and 90.6% respectively had consumed alcohol (p&lt;0.0001). 16.3% women never smoked or drank in comparison to 4.6% in men (p&lt;0.0001). There was a difference in primary tumor site distribution between genders (p=0.0003). Oral cavity (41.3%) and larynx (23%) were the most common sites in women vs. oropharynx (31.1%) and larynx (24.8%) in men. There appeared to be no difference in tumor T stage. However, more men presented with N2/3 (51.7% vs. 39.9%, p=0.01) and stage IV (63.1% vs. 53.2%, p=0.04). For initial treatment, more men received multi-modality therapy (56.2% vs. 48.4%, p=0.009) while more women received surgery as sole therapy (37.3% vs. 27.1%). Overall, 72.7% of men vs. 62.3% of women received radiation (XRT); 36.5% and 26.2% respectively received concurrent chemoradiation. There were no differences in baseline performance status, total XRT dose (mean 65.8 Gy), fractionation (mean 33), XRT technique (3D conformal, linac-based IMRT or tomotherapy), or chemotherapy delivered. Recurrence free outcome was achieved equally in both genders at the primary tumor site (~80%), neck (~84%) and distant sites (~88%). Median survival was 89.5 months in women and 84.2 months in men (p=0.65). Conclusions: Although there were no differences in overall survival,our analysis suggests that some gender differences may exist in risk factors and clinical presentation for HNSCC pts. Further study is warranted.
A study on thromboembolism of patients with pancreatic cancer.
Authors: Kwan Yu LAM, Kirsty Lee, Charing Chong, Anthony WH Chan, Tony Mok, Stephen Lam Chan
Journal: Journal of Clinical Oncology (2017)

262 Background: There have been studies on the association between thromboembolism (TE) and pancreatic cancer in Caucasian patients. This study aims to study the TE in Chinese patients with pancreatic cancer. Methods: This study retrospectively reviewed consecutive patients with confirmed diagnoses of pancreatic cancers from 2010-2015 in the Prince of Wales Hospital in Hong Kong. Patients with radiologically confirmed TE were identified. Corresponding information related to the type and site of TE were recorded. Predictive factors for the TE were studied by multivariate analysis. Results: Total 372 patients with pancreatic cancer were identified. In the cohort, the diagnoses of cancers were made by histology in 225 (60.5%) of them while others were made by radiology. The stage was as follows: 15 (4.1%) stage I; 113 (30.4%) stage II; 47 (12.7%) stage III and 196 (52.7%) stage IV. Total 55 (14.7%) patients had TE after diagnosis of pancreatic cancer. Of these 55 patients, 33 (60%) and 18 (32.7%) had venous and arterial events, respectively. For patients with TE, 27 (49.1%) were treated with anti-coagulants, and 13 (23.6%) had surgery within 2 years. The median time from surgery to the development of TE was 1.06 years. Patients with ECOG ≥2 and metastatic disease (HR 2.92, 95% CI 1.58-5.37; HR 6.90, 95% CI 3.63-13.14 respectively) had a higher risk of developing TE. Patients with venous, arterial, or both types of TE did not have significantly different overall survival. Poor prognostic factors for overall survival include ECOG ≥2 (HR 2.80, 95% CI 2.18-3.60) and tumour stage (stage II disease HR 1.36, 95% CI 0.70-2.62; stage III disease HR 1.85, 95% CI 0.92-3.70; stage IV disease HR 4.92, 95% CI 2.58-9.36). The presence of TE equated to a worse overall survival (median overall survival 148 vs. 228 days, HR 1.03, 95% CI 0.75-1.40, P=0.87), which was statistically insignificant. Conclusions: TE was similarly high in Chinese patients with pancreatic cancer. Patients with poorer performance status and metastatic disease had a greater risk of developing TE. Patients with TE had a worse overall survival (which was statistically insignificant) compared to patients without TE.