tbuckley/cabot-search huggingface dataset:
Androgen pathway manipulation and outcome in elderly men with non-small cell lung cancer: A population-based study from Ontario, Canada.
Authors: Marshall W. Pitz, Gregory Russell Pond, David Dawe, Grace Musto, Pascal J Lambert, Peter Michael Ellis
Journal: Journal of Clinical Oncology (2014)

e17662 Background: Non-small cell lung cancer (NSCLC) is the commonest cause of cancer-related mortality in the world. Despite a number of treatment options, these cancers remain resistant to therapy and novel approaches are needed. Previous work has found an association between exposure to androgen pathway manipulating agents (APM) and improved overall survival in men with NSCLC. Methods: We conducted a retrospective cohort study of males aged ≥65 years from Ontario, Canada diagnosed with NSCLC from 2000-2010 using data from the Ontario Cancer Registry. These data were linked to the outpatient prescription database to provide a record of patients exposed to APM. Survival was measured from diagnosis of NSCLC to death. The data were analyzed to assess APM exposure as a prognostic factor in NSCLC. Exposure to APM was categorized based on receiving an initial prescription and at least one subsequent refill. Time-dependent Cox regression and landmark analyses using log-rank tests were performed. Results: A total of 23 052 elderly males were diagnosed with NSCLC from 2000-2010 in Ontario, and were included in this cohort. Exposure to APM was found in 6.3% of patients, with 3.4% exposed within 2 years prior to diagnosis of NSCLC and 4.8% exposed after diagnosis. Landmark analysis at baseline and 180 days post-diagnosis did not find a statistical association between exposure to APM and survival (p=0.35 and p=0.54). Adjusting for stage of NSCLC, age, and histological type, exposure to APM was not associated with improved survival (p=0.70). In an analysis limited to stage IV disease (n=4474), a protective effect of APM was seen in patients exposed after diagnosis, after adjusting for age and histological type (HR 0.72, 95%CI 0.52 to 0.99, p=0.042). Conclusions: Exposure to APM was not independently associated with improved survival in elderly males from Ontario, controlling for age, stage, and histology. However, a protective effect was seen for exposure to APM following a diagnosis of stage IV NSCLC. A prospective study is required to clarify the effect of APM in NSCLC.
Consolidation chemotherapy for locally advanced mid- or low rectal cancer after neoadjuvant concurrent chemoradiotherapy: A multicenter, randomized controlled trial (KONCLUDE).
Authors: Chang Woo Kim, Ik Yong Kim, Suk-Hwan Lee
Journal: Journal of Clinical Oncology (2017)

TPS813 Background: Chemoradiotherapy (CRT) followed by total mesorectal excision (TME) has been a standard treatment option for locally advanced mid or low rectal cancer with improved local control. However, systemic recurrence after the standard therapy is the most important failure of treatment, and several efforts have been trying to overcome it. Consolidation chemotherapy is adding several cycles of chemotherapy between neoadjuvant CRT and TME. It could increase the proportion of pathologic complete response (pCR), subsequently could show better oncologic outcomes. Methods: Patients with advanced mid or low rectal cancer who received neoadjuvant CRT will be included after screening. They will be randomized and assigned to underwent TME followed by adjuvant chemotherapy of 8 cycles (control arm) or receive 3 cycles of chemotherapy before TME, and receive 5 cycles of chemotherapy (experimental arm). The primary endpoints are pathologic complete response and 3-year disease-free survival, and the secondary endpoints are radiotherapy-related complications, R0 resection, tumor response rate, surgery-related morbidity, and peripheral neuropathy 3 year after the surgery. The authors hypothesize that the experimental arm would show a 15% improvement in two primary endpoints, compared with the control arm. Based on the superiority design, an one-sided log-rank test with α-error of 0.025 and a power of 90% was conducted. Allowing for a drop-out rate of 10%, 316 patients (158 per arm) will need to be recruited. The accrual period is 2 years and the follow-up period is 3 years. Discussion: KONCLUDE (A Korean society of coloproctology trial: cONsolidation Chemotherapy for Locally advanced mid or low rectal cancer after neoadjUvant concurrent chemoraDiothErapy: A multicenter, randomized controlled trial) is expected to provide evidence to support clear treatment guidelines for patients with locally advanced rectal cancer. Clinical trial information: 02843191.
Phase I/II trial of induction chemotherapy with docetaxel, cisplatin, and fluorouracil (DCF) followed by concurrent chemoradiotherapy in locally advanced esophageal squamous cell carcinoma.
Authors: Hironaga Satake, Makoto Tahara, Satoshi Mochizuki, Sadamoto Zenda, Takashi Kojima, Hideaki Bando, Tomoko Yamazaki, Ken Kato, Satoru Iwasa, Yoshitaka Honma, Hiroki Hara, Tomoya Yokota, Satoshi Hamauchi, Naomi Kiyota, Takayuki Kii, Keisho Chin, Atsushi Ohtsu
Journal: Journal of Clinical Oncology (2013)

4074 Background: Standard of care for unresectable locally advanced esophageal squamous cell carcinoma (ESCC) is concurrent chemoradiotherapy (CRT). However, its survival remains limited. Neoadjuvant chemotherapy with docetaxel, cisplatin and 5-FU (DCF) demonstrated promising activity with pathological complete response (CR) of 22% for resectable stage II/III ESCC (Hara H et.al, ASCO 2012). This study was performed to assess the efficacy and safety of induction chemotherapy with DCF followed by CRT in patients with unresectable locally advanced ESCC. Methods: Eligibility criteria included clinically T4 and/or M1 lymph node (LYM) ESCC, PS 0-1, and 20-70 years old. Treatment consisted of docetaxel 70 mg/m 2 , cisplatin 70 mg/m 2 on day 1 and fluorouracil 750 mg/m 2 on days 1 to 5, repeated every 3 weeks for three cycles, followed by cisplatin 70 mg/m 2 on days 64 and 92, and fluorouracil 700 mg/m 2 on days 64 to 67 and 92 to 95 concurrently with radiotherapy (60Gy in 30 fractions, 5 days/week). Results: From August 2009 to November 2011, 33 patients were enrolled.There were 16 pts with T4M0 disease, 13 with nonT4M1 LYM, and 4 with T4M1 LYM.Most grade 3 or 4 toxicities were neutropenia (66%), leukopenia (39%), anorexia (18%), dysphasia (12%), nausea (9%), febrile neutropenia (6%), and hyponatremia (6%) during induction chemotherapy. Most grade 3 or 4 toxicities were leukopenia (27%), neutropenia (20%), dysphasia (17%), anorexia (13%), esophagitis (13%), nausea (10%), and febrile neutropenia (3%) during CRT. No treatment related death was observed. The completion rate of protocol treatment was 88% (29/33). The overall response rate after completion of induction chemotherapy was 61%. Eleven pts (38%) achieved CR after completion of protocol treatment. With a median follow-up period of 14 months, 1y-PFS and 1y-OS are 38.5 and 78.6 %, respectively. Of a total of 33 patients, eighteen patients (55%) received secondary treatment. Conclusions: Induction chemotherapy with DCF followed by CRT in unresectable locally advanced ESCC was well tolerated. Although these data are preliminay, this approach warrants further evaluation. Clinical trial information: UMIN000003370.
Effect of human OX40 ligand fusion protein (MEDI6383) on immune cells of the humoral and cell-mediated immune response in a non-human primate model.
Authors: Michael D Oberst, Steven Eck, Nicholas Buss, Andrew Pierce, Haesun Park, Hyewon Kim, Andrew Sylwester, Michael Axhelm, Louis Picker, Andrew Weinberg, Lolke De Haan, Scott A Hammond
Journal: Journal of Clinical Oncology (2015)

3052 Background: MEDI6383 is a human OX40 ligand fusion protein currently in clinical development for the treatment of advanced solid malignancies. In vitro, this OX40 agonist binds and activates the human OX40 receptor to potently induce activation and proliferation of OX40-expressing human T cells. Given that MEDI6383 binds and signals through non-human primate OX40 with similar potency as human OX40, we hypothesized that the fusion protein would mediate T cell activation in vivo in a non-human primate model. Methods: To test this hypothesis, a PK/PD study was conducted wherein non-human primates were administered MEDI6383, a vehicle control, or an agonist mouse anti-human OX40 monoclonal antibody (mAb). Pharmacodynamic changes in the peripheral blood were measured using flow cytometry-based immunophenotyping. Results: Peripheral CD4 and CD8 memory T cell activation and proliferation were observed after administration of MEDI6383, and differed quantitatively and qualitatively from that following treatment with the OX40 mAb. Likewise, MEDI6383 also induced the proliferation of peripheral B cells, suggesting an effect on T cell-to-B cell crosstalk in vivo. Other pharmacodynamic changes observed with OX40 agonism will also be presented. Conclusions: These findings suggest that MEDI6383 activates both humoral and cellular immune responses, activities that have the potential to boost anti-tumor immunity in the setting of human cancer.
5-year outcomes from a prospective multi-institutional trial of heterogeneous dosing stereotactic body radiotherapy (SBRT) for low- and intermediate-risk prostate cancer.
Authors: Donald B. Fuller, Brent L. Kane, Clinton A. Medbery, Kelly Underhill, James R. Gray, Anuj Peddada, Ronald C. Chen
Journal: Journal of Clinical Oncology (2017)

35 Background: SBRT is an emerging treatment for prostate cancer, but long-term reporting remains sparse. We present a prospective Phase II trial with 90% treated in community facilities. Methods: 14 institutions enrolled 259 patients - 112 low-risk; 147 intermediate-risk. The regimen emulated a high-dose rate brachytherapy (HDR) regimen - 38 Gy/4 fractions delivered by robotic SBRT. Androgen deprivation therapy was not allowed. HDR-like heterogeneous prostate dosing was used (Dmax &gt;57 Gy). Toxicities were assessed by CTCAE v3.0 and quality of life assessed by Expanded Prostate Cancer Index Composite (EPIC). Biochemical recurrence was defined by Phoenix criteria. Results: Median follow-up is 5 years. 5-yr Grade 2 GU toxicity was 13.7% and GI toxicity 4.5%, with Grade 3 rates of 3% (GU) and 0% (GI) (one Gd 4 GU event). 5-yr median PSA was 0.1 ng/mL with further subsequent decrease (7 y = 0.035 ng/mL). 5-yr biochemical disease-free survival (bDFS) = 100% for low-risk and 88.5% for int-risk. 6 patients developed distant metastasis and one died of disease. Median EPIC GU obstruction and GI scores were similar at baseline vs. 5 years. 2% of patients had baseline GU incontinence requiring pad use vs 10% at 5 yrs. Of baseline potent men, 46% remained so at 5 yrs (66.7% for those age ≤65 vs. 37.1% age &gt;65 at treatment). Conclusions: This is the first report of 5-year median follow-up outcomes post heterogeneous dosing SBRT for early prostate cancer. This treatment produces a low PSA nadir vs other forms of radiotherapy, with a favorable long-term result that appears reproducible in the community. Clinical trial information: 00643617. [Table: see text]
The BMJ Awards 2017: Clinical leadership
Authors: Nigel Hawkes
Journal: BMJ (2017)

Nigel Hawkes finds out how this year’s nominees are transforming practice

Oxygen deprivation during labour is universally recognised as a disaster in the making, but is enough done to prevent it? At St George’s University Hospitals NHS Trust in London, the answer was no. Edwin Chandraharan, consultant obstetrician and gynaecologist at the trust says: “Our rate of hypoxic ischaemic encephalopathy (HIE, the brain injury caused by oxygen deprivation) was above the national average. Our neonatal metabolic acidosis rate (a measure of oxygen deprivation) was 2.6%, and our emergency caesarean section rate was 15-17%. We reflected on our results and accepted they were worse than national data.”

The response was uncompromising and included mandatory retraining and testing on the interpretation of fetal heart monitoring (cardiotocography, CTG) for all midwives and obstetricians who worked in the labour wards. “CTG was introduced in 1968 with no clinical trials,” Chandraharan says. “Interpretation was based on recognising certain patterns, and it got into the culture that ‘this is good’ or ‘this is bad’ without real knowledge.”

The answer was to change the way CTG was interpreted, retrain staff, and then oblige them to achieve an 85% pass mark before being allowed to work in the labour wards. Since this was introduced in 2010, emergency caesareans have fallen to 6-8%, the acidosis rate to 0.6%, and the HIE rate to half the national average.

Since every baby with brain damage costs the NHS £8m-£10m, Chandraharan estimates that the measures have saved £30m—three fewer babies damaged at birth than would have happened had there been no improvement. “And the indirect social costs to parents having to lose their jobs to look after a brain damaged baby for life are immeasurable,” he adds.

Junior doctors work very hard, but not everything they do is really doctoring. At East …
Fast-Acting Insulin Aspart Improves Glycemic Control in Basal-Bolus Treatment for Type 1 Diabetes: Results of a 26-Week Multicenter, Active-Controlled, Treat-to-Target, Randomized, Parallel-Group Trial (onset 1)
Authors: David Russell-Jones, Bruce W. Bode, Christophe De Block, Edward Franek, Simon R. Heller, Chantal Mathieu, Athena Philis-Tsimikas, Ludger Rose, Vincent C. Woo, Anne Birk Østerskov, Tina Graungaard, Richard M. Bergenstal
Journal: Diabetes Care (2017)

OBJECTIVE This multicenter, treat-to-target, phase 3 trial evaluated the efficacy and safety of fast-acting insulin aspart (faster aspart) versus conventional insulin aspart (IAsp) in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS The primary end point was change from baseline in HbA1c after 26 weeks. After an 8-week run-in, subjects were randomized (1:1:1) to double-blind mealtime faster aspart (n = 381), IAsp (n = 380), or open-label postmeal faster aspart (n = 382)—each with insulin detemir. RESULTS HbA1c was reduced in both treatment groups, and noninferiority to IAsp was confirmed for both mealtime and postmeal faster aspart (estimated treatment difference [ETD] faster aspart–IAsp, mealtime, –0.15% [95% CI –0.23; –0.07], and postmeal, 0.04% [–0.04; 0.12]); mealtime faster aspart statistically significantly reduced HbA1c versus IAsp (P = 0.0003). Postprandial plasma glucose (PPG) increments were statistically significantly lower with mealtime faster aspart at 1 h (ETD –1.18 mmol/L [95% CI –1.65; –0.71], –21.21 mg/dL [–29.65; –12.77]; P &amp;lt; 0.0001) and 2 h (–0.67 mmol/L [–1.29; –0.04], –12.01 mg/dL [–23.33; –0.70]; P = 0.0375) after the meal test; superiority to IAsp for the 2-h PPG increment was confirmed. The overall rate of severe or blood glucose–confirmed (plasma glucose &amp;lt;3.1 mmol/L [56 mg/dL]) hypoglycemic episodes and safety profiles were similar between treatments. CONCLUSIONS Faster aspart effectively improved HbA1c, and noninferiority to IAsp was confirmed, with superior PPG control for mealtime faster aspart versus IAsp. Subjects randomized to postmeal faster aspart for all meals maintained HbA1c noninferior to that obtained with mealtime IAsp.
Phase I/Ib study of the PARP inhibitor (PARPi) olaparib (O) with carboplatin (C) in heavily pretreated high-grade serous ovarian cancer (HGSOC) at low genetic risk (NCT01445418).
Authors: Victoria L. Chiou, Elise C. Kohn, Christina M. Annunziata, Lori M. Minasian, Stan Lipkowitz, Minshu Yu, Nicolas Gordon, Nicole D. Houston, Jung-min Lee
Journal: Journal of Clinical Oncology (2015)

5514 Background: O is a FDA-approved PARPi for advanced ovarian cancer with germline BRCA mutation (gBRCAm). O and C each have shown single agent activity in HGSOC. We hypothesize that addition of O to C to stress DNA repair machinery is tolerable and of clinical benefit in HGSOC pts without gBRCAm. Methods: 3x3 dose escalation examined O capsules (400 mg q12h, d 1-7) with C AUC 3, 4, or 5 on d1 or 2 every 21d over 3 dose levels. No more than 8 O + C cycles were given, followed by daily O maintenance. Safety was assessed every cycle. Response was assessed every 2 cycles. PBMCs were collected at baseline, d3, and post-cycle 1 for PAR incorporation. Tumor biopsies were performed in a 15 patient (pt) expansion cohort at maximum tolerated dose (MTD) pre-and post-cycle 1 for proteomics and apoptosis endpoints. Results: 30 women (median age 65 [49-71]) were treated over 3 dose levels of O + C AUC3 (3 pts), AUC4 (MTD, 21 pts), and AUC5 (6 pts). 24 pts had negative gBRCAm testing and 6 had BRCAPRO score < 10% with negative family history. The median number of prior therapies was 7 (2-12). All pts received prior platinum (time from last platinum: median 17 mo [7-154]), with 11 platinum-sensitive and 19 platinum-resistant disease. Gr 3/4 AEs included neutropenia (23%), thrombocytopenia (20%), and anemia (13%). DLTs were gr 3 neutropenia/thrombocytopenia and gr 3 infection on AUC 5. 2 pts required C dose reduction and early discontinuation due to delayed marrow recovery. Of 28 evaluable pts, 5 PR (18%; median 4 [3-18] mo), and 10 SD ≥ 4 mo (36%; median 8 [4-11] mo) were observed, yielding a disease control rate of 54%. RR and median PFS were 36 % (4/11 pts) and 3.5 (1.5-10) mo in platinum-sensitive disease and 6% (1/17 pts) and 4 (1.5-18) mo in platinum-resistant disease. There was no significant difference in tissue apoptotic index pre-and post-cycle 1. PAR incorporation and proteomics results will be presented. Conclusions: Recommended phase 2 dose is O 400 mg capsules q12h d1-7 with C AUC4 on 21d cycles in heavily pretreated recurrent HGSOC pts without gBRCAm. Interactive marrow suppression was observed. Identification of biomarkers of response to O + C is needed in recurrent HGSOC without gBRCAm. Clinical trial information: NCT01445418.
Comparative effectiveness of erlotinib versus no treatment for advanced non-small cell lung cancer patients in the Veterans Administration.
Authors: Benjamin Kim, Ren He, Anna Liza M Antonio, Steven M Asch, Jennifer Malin
Journal: Journal of Clinical Oncology (2012)

6105 Background: Erlotinib (E) is FDA-approved for second-line treatment of unselected advanced non-small cell lung cancer (aNSCLC) patients. Clinical trials have shown increased response rates with E in aNSCLC patients having East Asian ethnicity, female gender, never-smoking history, or adenocarcinoma histology. The objective of this study was to compare the real-world effectiveness of E versus no treatment (NT) for first- and second-line treatment of aNSCLC patients in the Veterans Administration (VA). Methods: All incident aNSCLC cases diagnosed in the VA during 2007 were identified through the VA Central Cancer Registry, a subset of which underwent medical record abstraction through the VA External Peer Review Program. Abstracted records were then merged with national VA Decision Support System pharmacy and Corporate Data Warehouse encounters data through 2010. Treatment lines were determined through adaptation of a published algorithm. The impact of E versus NT on overall survival for each treatment line was then evaluated using 1:N greedy propensity score matching (PSM) and 2-stage residual inclusion (2SRI) estimation. Results: Among 1965 aNSCLC patients assessed for first-line treatment, 78 (4%) received E and 782 (40%) received NT; among 1124 assessed for second-line treatment, 128 received E (7%) and 638 (33%) received NT. 1:3 PSM of E cases to NT controls showed no difference in overall survival by Kaplan-Meier estimation in the first- (median 2.6 vs. 2.9 mos., p-value=0.86) and second-line (3.4 vs. 3.2 mos., p=0.85) settings. Chemotherapy use by Veterans Integrated Service Network was selected as the instrumental variable for 2SRI. Expected mean survival of E versus NT was similarly not statistically prolonged in the first- (E:NT survival time ratio 2.55, p=0.35) and second-line (2.49, p=0.32) settings. Conclusions: For a population with few aNSCLC patients having 3 out of the 4 clinicopathologic characteristics associated with improved response, E did not appear to confer a survival advantage over NT. Linking mutation results to observational datasets may improve comparative effectiveness research of personalized medicine in oncology.
Effect of anamorelin/ONO-7643, a selective ghrelin receptor agonist, on tumor growth in a lung cancer mouse xenograft model.
Authors: Robert Northrup, Ken Kuroda, Elizabeth Manning Duus, Sheri Routt Barnes, Tim Wiley, Claudio Pietra
Journal: Journal of Clinical Oncology (2012)

e19577 Background: Anamorelin/ONO-7643 is an orally-active ghrelin receptor agonist in development for non-small cell lung cancer (NSCLC)-related cachexia/anorexia. It displays both anabolic and orexigenic properties via its ghrelin and growth hormone (GH) secretagogue activity. However, increasing GH and insulin-like growth factor-1 (IGF-1) in cancer patients raises potential concerns of stimulating tumor growth. In this study, we investigated the effect of ghrelin and Anamorelin/ONO-7643 on tumor growth in a NSCLC xenograft model. Methods: On Day 1 (D1), 21 days after implanting A549 tumors, female nude mice were sorted into six groups (n=15/group) and administered ghrelin (2 mg/kg i.p.), Anamorelin/ONO-7643 (3, 10, or 30 mg/kg p.o.) or vehicles (saline i.p. or de-ionized water p.o.) for 28 days, starting on D3. Tumor growth, body weight, and food consumption were monitored. Mice used to assess plasma levels of murine GH (mGH) and IGF-1 (mIGF-1) were sorted into three groups (n=21/group) and treated for 28 days with ghrelin, the high dose of Anamorelin/ONO-7643 or vehicle (de-ionized water p.o.). Results: After 28 days of treatment, there was no difference in median tumor volumes (D30 values: 1008, 936, 1080, 666 and 847 mm 3 for vehicle, ghrelin and Anamorelin/ONO-7643 at 3, 10 and 30 mg/kg, respectively). Ghrelin significantly increased mGH compared to controls, while Anamorelin/ONO-7643 modestly increased mGH. Peak mIGF-1 levels were slightly higher in animals given ghrelin or Anamorelin/ONO-7643 compared to vehicle, although not significantly. Anamorelin/ONO-7643 at 10 and 30 mg/kg/day showed a statistically significant (p&lt;0.01) increase in body weight from D1 to D30 compared to control animals, with no change in food consumption. Ghrelin treatment had no effect on body weight or food consumption. Conclusions: Anamorelin/ONO-7643 or ghrelin treatment for 28 days had no effect on tumor growth in A549 tumor-bearing nude mice, despite increased mGH and a trend of increased mIGF-1. Anamorelin/ONO-7643 also significantly increased body weight at 10 and 30 mg/kg/day. These results support using ghrelin receptor agonist-based treatments in managing NSCLC-related cachexia/anorexia.