tbuckley/cabot-search huggingface dataset:
Phase I safety and pharmacokinetic (PK) study of veliparib in combination with whole brain radiation therapy (WBRT) in patients (pts) with brain metastases.
Authors: Minesh P. Mehta, Walter J. Curran, Ding Wang, Fen Wang, Lawrence Kleinberg, Anthony M. Brade, Nael Mostafa, Xiangdong Zhou, Jiang Qian, Terri Leahy, Bhardwaj Desai, Vincent L. Giranda
Journal: Journal of Clinical Oncology (2012)

2013 Background: Veliparib is an oral PARP-1 and -2 inhibitor that enhances the antitumor activity of DNA damaging agents including radiation therapy in vivo. In pre-clinical models, veliparib crosses the blood-brain barrier. This ongoing phase I dose-escalation study evaluates the safety, PK, and provides preliminary antitumor activity of veliparib in combination with WBRT in pts with brain metastases. Methods: Pts with brain metastases from non-CNS primary solid malignancy, adequate organ function, RPA Class 2, and KPS ≥70 were treated with WBRT (37.5 Gy in 15 fractions or 30 Gy in 10 fractions) QD with veliparib BID with every fraction of WBRT in escalating doses of 10, 20, 30, 50, 100, 150, and 200 mg; the final WBRT fraction was followed by 1 extra day of veliparib. Safety, PK, and tumor response by RECIST were assessed. Results: At the time of reporting 59 pts (M/F, 21/38; median age 57 y) had been treated. Baseline KPS was 70, 80, 90, and 100 in 6.8, 32.2, 40.7, and 20.3% pts, respectively; primary tumor types were breast (n=20), NSCLC (n=20), melanoma (n=9), colorectal (n=2), and others (n=8); 71.2% pts had multiple lesions; and 18.6% had prior brain SRS. Grade 3/4 treatment-emergent adverse events (TEAEs; ≥5%) were fatigue (6.8%), anemia (5.1%), hyponatraemia (5.1%), and thrombocytopenia (5.1%); other TEAEs (≥20%) were fatigue (57.6%), headache (42.4%), nausea (40.7%), alopecia (28.8%), vomiting (22%), radiation skin reactions (22%), and decreased appetite (22%). PK of veliparib were approximately dose-proportional, with oral clearance of 21.6 ± 14.2 L/h (mean ± SD, n=45), minimal drug accumulation at day 15, and no significant effect of food on bioavailability. Tumor response was evaluable in 48 pts. Best tumor response and median survival were 37.5% and 10 months (m) for NSCLC, and 52.9% and 12.5 m for breast cancer (excluding pts with leptomeningeal disease). Conclusions: Addition of veliparib up to 200 mg BID was well tolerated with concurrent WBRT and dose escalation ongoing. The PK of veliparib was dose proportional with no food effect. Preliminary antitumor activity is encouraging and informative for the design of more definitive trials.
Dosimetric effects of deep inspiration breath hold for radiation treatment of esophageal cancer based on tumor location.
Authors: Kaleigh Doke, Rajeev Badkul, Nathan Aguilera, Melissa Pulfer Mitchell, Xinglei Shen, Chris Lominska
Journal: Journal of Clinical Oncology (2017)

173 Background: Deep inspiration breath hold (DIBH) has been shown to reduce heart and lung doses in radiation treatment of breast cancer and lymphoma. We investigated its application for treatment of esophageal cancer. Methods: Five patients who had DIBH simulation for diagnoses with chest scans were studied. Patients were simulated supine with 2 CT scans each: free breathing (FB) and DIBH using surface infrared markers. The patients were contoured using standard volumes as per RTOG 1010, including a 45 Gy planning target volume (PTV). Both a mid-esophagus and distal PTV were created for each of the model patients, by contouring 5 cm tumor volumes at the level of the carina and gastroesophageal junction. Normal structures were contoured as well. For distal tumors, the celiac nodes were covered electively as per RTOG 1010. Uniform three dimensional conformal radiotherapy plans were generated and normalized to provide 100% dose coverage to 95% of the PTV. Dose volume histograms were generated and evaluated. A 2-tailed paired student’s T-test was used to evaluate statistical significance. Results: When comparing the changes in dose to the normal structures with breath hold, a contrasting trend was seen between proximal and distal tumors. The mean heart dose and V40 decreased with breath hold for proximal tumor plans, however the heart dose metrics increased with breath hold for distal tumors. For the proximal tumor plans, the lung mean, V20, V10 and V5 decreased with breath hold in all patients. For distal tumors, mean lung doses trended towards an increase. Conclusions: Dosimetric parameters uniformly improved for proximal tumors with DIBH. By contrast, distal tumors often showed worsening of heart and lung dosimetry with DIBH. This appeared to be related to entry of the lung volume into the celiac nodal field, among other factors. [Table: see text]
Patterns of surveillance testing in commercially insured patients with breast cancer across provider types: A regional study.
Authors: Julia Rose Walker, Catherine R. Fedorenko, Stuart Greenlee, Laura Panattoni, Mikael Anne Greenwood-Hickman, Sarah Barger, Karma L. Kreizenbeck, Ted Conklin, Bruce Smith, Sibel Blau, Richard A. McGee, Gary H. Lyman, Scott David Ramsey
Journal: Journal of Clinical Oncology (2017)

4 Background: Oncologists, primary care physicians (PCPs), and other clinicians provide care for breast cancer patients following active treatment. Clinical practice guidelines are largely consistent in recommended number of clinic visits and annual mammograms. However, surveys of oncologists and PCPs have found variation in attitudes toward surveillance intensity, perceptions of care responsibility, and adherence to Choosing Wisely guidelines. This study examined if surveillance of patients with early stage breast cancer varied by whether they obtained follow up care with oncologists, PCPs or both. Methods: Cancer registry records for patients in Western Washington from 2007 to 2015 were linked with claims from two regional commercial insurers. Patients were selected if they had been diagnosed with stage I/II breast cancer and treated with mastectomy or lumpectomy + radiation. The surveillance period starts at the first 4 month gap in treatment (surgery, chemo, radiation) through 13 months from gap start or restart of treatment. Evaluation and Management (E&amp;M) codes for visits and procedure codes for biomarker and advanced imaging (PET, CT, bone scan) were identified in claims. Specialty codes were used to determine type of provider seen. Physician visits were matched to tests using E&amp;M codes in the ± 7 days around each test. Results: During surveillance, 2046 patients averaged 12.2 physician visits per patient [median: 10, IQR: 7-15]. Oncologists (92%) and PCPs (82%) were the most common specialties with an average of 4.0 and 4.2 visits respectively. 73% of patients received mammography (avg # exams = 1.6) , 37% biomarkers (avg = 2.7) and 16% advanced imaging (avg = 1.5). The majority of biomarkers and the largest proportion of advanced imaging occurred near an oncology visit. Conclusions: Patients frequently see oncologists and PCPs during early surveillance. Targeting oncologists for intervention on potentially inappropriate biomarker testing could have the largest impact on aligning practice with Choosing Wisely recommendations. [Table: see text]
Feasibility and efficacy study of gemcitabine plus cisplatin combination therapy after curative resection for biliary tract cancer.
Authors: Osamu Kainuma, Fumihiko Miura, Daisuke Furukawa, Hiroshi Yamamoto, Akihiro Cho, Toshio Nakagori, Keiji Sano, Takehide Asano
Journal: Journal of Clinical Oncology (2015)

e15148 Background: Gemcitabine plus Cisplatin (CDDP) combination therapy (GC therapy) has become a standard chemotherapy for advanced biliary tract cancer (BTC). The aim of this study was to assess the feasibility and the efficacy of GC therapy in adjuvant setting. Methods: Eligible patients between January 2008 and January 2013 were enrolled. GC therapy at a dose of 1,000mg/m2, d1, 8 of gemcitabine and 25mg/m2, d1, 8 of CDDP every 3 weeks was performed for 6 months (8 cycles). The primary endpoint was the feasibility and the adverse events. The secondary endpoints were recurrence-free survival (RFS) and overall survival (OS). The study was registered at UMIN Clinical Trials Registry (UMIN000001294) . Results: Totally 30 patients were enrolled, however one withdrew consent prior to chemotherapy. Among the 29 evaluable patients, 20 men and 9 women with a median age of 66 years (range, 49-79 years) were included. All patients had undergone curative resection (R0-1) including 16 with major hepatectomy and 13 without. The protocol was completed in 21 (72%) patients, 8 of whom patients needed dose modification of gemcitabine. The main reason for the treatment discontinuation was adverse events. No one discontinued the treatment with the reason of recurrence. Relative dose intensity (RDI) of gemcitabine and CDDP was 77% and 81%, respectively. There was no difference in completion rate and RDI between with and without major hepatectomy. Grade 3-4 toxicities, leukopenia (14%), neutropenia (27%), thrombocytopenia (7%), fatigue (10%), pneumonia (7%) and anorexia (3%) were observed. Eighteen patients were alive at the time of analysis with a median follow-up period of 38.1 months. Recurrence occurred in 16 patients. Two-year and four-year RFS and OS was 59%, 44% and 90%, 60% respectively. Conclusions: Standard dose of GC therapy can be employed safely even in patients who had undergone major hepatectomy. This regimen is promising for the treatment of BTC in adjuvant setting. Clinical trial information: 000001294.
Tumor-infiltrating lymphocytes (TILs) and expression of PD-L1 in melanoma brain metastases (BM).
Authors: Anna Sophie Berghoff, Barbara Kiesel, Georg Widhalm, Orsolya Rajky, Gerda Ricken, Karin Dieckmann, Peter Birner, Rupert Bartsch, Christoph Zielinski, Christoph Hoeller, Johannes A. Hainfellner, Matthias Preusser
Journal: Journal of Clinical Oncology (2014)

9055 Background: The brain is considered as an immuno-privileged organ and little is known about the inflammatory response to melanoma BM. Methods: Patients with neurosurgical resected and histologically verified melanoma BM were identified. Investigation of PD1, PD-L1, CD3, CD8, CD45RO and BRAF V600E were performed by immunohistochemistry and analyzed using previously published semiquantitative evaluation criteria. Results: Forty-six specimens (28/46; 60.9% BRAF V600E positive) were available. Forty-one/46 (89.1%) specimens presented with TIL infiltration. CD3+ TILs were evident in 35/46 (76.1%), CD8+ TILs in 28/46 (60.9%), CD45RO+ TILs in 32/46 (69.6%) and PD1+ TILs in 28/46 (60.9%) specimens. The Table lists details of TIL infiltration density. PD-L1 expression on melanoma BM tumor cells was observed in 21/46 (45.7%) specimens. Median H-score for PD-L1 was 3 (range 1–90). Eight/21 (38.1%) PD-L1 positive specimens presented with an H score over 5 %. PD-L1 expression on tumor cells was associated with higher density of PD1+ (p=0.002), CD3+ (p=0.024) and CD8+ (p=0.050) TIL infiltration. Furthermore, density of CD3+ TILs was associated with density of CD8+ (p<0.001), PD1+ (p<0.001) and CD45RO+ (p<0.001) TILs, respectively. No association of previous systemic antineoplastic therapy (including chemotherapy and interferon) and expression of PD-L1, PD1, CD3 or CD45RO could be observed (p=n.s). Expression of PD-L1 on tumor cells or density of PD1+, CD3+, CD8+ or CD45RO+ TILs did not correlate with BRAF V600E status (p=n.s.) or survival from first diagnosis of BM (p=n.s.). Conclusions: Melanoma BM show considerable inflammatory infiltrates and expression of PD1 and PD-L1. Clinical studies should investigate the value of checkpoint inhibitors in patients with melanoma brain metastases. CD3+ TILs CD8+ TILs CD45RO+ TILs PD1+ TILs Sparse infiltration 11/46 (23.9%) 13/46 (28.3%) 12/46 (26.1%) 13/46 (38.3%) Moderate infiltration 12/46 (26.1%) 12/46 (26.1%) 11/46 (23.9%) 11/46 (23.9%) Dense infiltration 8/46 (17.4%) 11/46 (23.9%) 7/46 (15.2%) 4/46 (8.7%) Very dense infiltration 4/46 (8.7%) 5/46 (10.9%) 2/46 (4.3%) 0/46 (0.0%)
Randomized, open-label, phase II trial of gemcitabine with or without bavituximab in patients with nonresectable stage IV pancreatic adenocarcinoma.
Authors: Shuchi Sumant Pandya, Lucas Wong, Andrea J. Bullock, Stephen A. Grabelsky, Merrill Kingman Shum, Joseph Shan, Kerstin B. Menander, Tony R. Reid
Journal: Journal of Clinical Oncology (2013)

4054 Background: Despite advances in the treatment of metastatic pancreatic cancer (PC), there is critical need to develop novel therapies.Median survival with combination chemotherapy is limited to less than one year and only the optimally conditioned patients can tolerate these therapies. Bavituximab (B) is a monoclonal antibody (mAB) directed againstphosphatidylserine (PS) that causes vascular shutdown and reactivation of the innate and adaptive immunity in animal models. Preclinical data in mouse PC models indicate that gemcitabine (G) increases PS exposure and the addition of a mAb targeting PS reduces tumor burden, visible liver metastases, microvessel density, and increases tumor macrophage infiltration compared to G alone (Beck et al. 2006). The purpose of this trial is to evaluate and compare the efficacy and safety of the combination of G+B vs. G alone as first line therapy in pts. with nonresectable Stage IV PC. Methods: Seventy patients were randomized (1:1) to receive G 1000 mg/m 2 on days 1, 8, and 15 every 28Edays with or without weekly B 3mg/kg IV until disease progression or unacceptable toxicities. Key eligibility criteria were Stage IV PC, ECOG ≤2, measurable disease, age≥18 years, total bilirubin ≤1.5xULN, and adequate renal, hematologic, and hepatic function. The primary efficacy endpoint was overall survival (OS) and secondary endpoints included overall response rate (ORR) and progression free survival (PFS). Results: Of the 70 (G/G+B 34/36) patients randomized, 67 (G/G+B 33/34) received study treatment and 63 (G/G+B 31/32) were evaluable. No significant difference was seen in age, gender, race or ECOG. At analysis 87% deaths had been reported in G and 72% in G+B group. Median OS estimate is 5.2 months for G and 5.6 months for G+B. No difference between groups was observed in PFS (median 3.9 months for G and 3.7 months for G+B). ORR was 13% for G and 28% for G+B. Most AEs were grade 1-2 and typical of exposure to G. Conclusions: In this patient population with extensive disease burdens and limited treatment options, G+B was well tolerated and demonstrated moderate activity in tumor response and survival. Clinical trial information: NCT01272791.
Could tumor growth rate provide useful information to predict the efficacy of eribulin?
Authors: Eleonora De Maio, Florence Dalenc, Henri Hubert Roche, Laurence Gladieff, jean-Louis Lacaze, Jean-Pierre Delord, Thomas Filleron, Carlos Alberto Gomez-Roca
Journal: Journal of Clinical Oncology (2015)

e12028 Background: Eribulin is approved for the treatment of patients (pts) with advanced or metastatic breast cancer, after at least two regimens including an anthracycline and a taxane. Influence of Eribulin on kinetics of tumor growth has not been investigated. We analyzed tumor growth rate (TGR) dynamics before and during treatment with Eribulin and the utility of using TGR variation to improve evaluation of treatment efficacy. Methods: Records of 110 pts treated with Eribulin from March 2011 to January 2014 were retrospectively analyzed. The TGR was computed for the pre-Eribulin-treatment period (reference) and for the Eribulin-treatment (treatment). Tumor response was evaluated according to RECIST 1.1. We studied the relationship between TGR variations, RECIST tumor response, PFS and OS. Results: Histological sub-types were: ductal carcinomas 86%, lobular carcinomas 9 % and other 5%. Hormonal receptor status was positive in 87.7% of pts, 13.6% were HER2-overexpressed/amplified and 22.7% triple negative. OR at the time of first evaluation was 19.2%. Median PFS and OS were 3.8 and 9 months, respectively. Sixty- one of 110 pts had at least one CT-scan evaluation before treatment, at baseline and after starting Eribulin treatment, allowing TGR evaluation. No significant demographic differences were observed between pts with and without pre-treatment CT-scan. At first CT-scan evaluation under treatment responses by RECIST were: 21.3% partial response (PR), 45.9% stable disease (SD) and 32.8% progressive disease (PD). No patient with PD showed a significant reduction in TGR between reference and treatment period (39 vs 34, variation -8.7; p 0.23). Pts with SD exhibited a significant TGR reduction between both periods (24.7 vs -14.3, variation -42.7; p < 0.001). Disease control rate at 4 months in patients classified as SD and showing TGR reduction was 88%. The analysis of association between TGR, PFS and OS is ongoing. Conclusions: As previously observed for targeted agents, evaluation of TGR in patients treated with Eribulin could provide a better characterization of drug activity at the time of first CT-scan evaluation beyond RECIST criteria.
A novel strategy for axitinib dosing in the treatment of metastatic renal cell carcinoma.
Authors: Gary Doherty, Deirdre Lynskey, Athena Matakidou, Kate Fife, Tim Eisen
Journal: Journal of Clinical Oncology (2017)

464 Background: The AXIS trial established axitinib as an effective second line treatment for patients with metastatic renal cell carcinoma (mRCC). The dosing schedule of axitinib in this trial begins at 5mg twice daily, with escalation of individual doses to 7mg and 10mg after consecutive 2 week intervals if tolerated. We observed significant drug-related toxicity using this dosing strategy, particularly after dose escalations, while clinical responses were often observed at the starting dose. We therefore switched to a pragmatic strategy where dose escalations were made only after disease progression or where a rapid response was deemed clinically pertinent. Methods: We performed a retrospective review of electronic health records and radiology of all patients with mRCC treated with axitinib for greater than 2 weeks at Addenbrooke’s Hospital, Cambridge, UK (a tertiary referral center), over a 40 month period to determine the clinical and radiological effects of dose escalations made according to the above strategy. Results: 42 patients fitting these criteria were identified; of these, 29 had at least one dose escalation event (DEE). A total of 58 DEEs were identified, with a median of 2 per patient, and the objective radiological consequences of 50 of these could be determined. The disease control rate (partial response or stable disease) after the first DEE instituted for disease progression was similar to that after the second DEE (68.8% versus 70%). 56% of all DEEs, and 62.5% of DEEs made as a result of disease progression, resulted in disease control. The median overall survival from the commencement of axitinib for all dose-escalated patients was 19.9 months, and 6.7 months for non-dose-escalated patients. The median survival for dose-escalated patients with a higher than median time on a prior tyrosine kinase inhibitor has not been reached at the time of data cut-off. The mean dose (for all patients) at 90 days after starting axitinib was 5.92 mg. Conclusions: These data suggest that dose escalation of axitinib after disease progression may be an effective dosing strategy for patients with mRCC, and may reduce toxicity through lower drug exposure. Our survival data compares favourably to the AXIS trial in a real practice population.
Association between visceral adiposity, BMI, and clinical outcomes in postmenopausal women with operable breast cancer.
Authors: Shalini Dalal, David Hui, Sai-ching J. Yeung, Gary B. Chisholm, Ijeoma Stephanie Ihenacho, Richard Ogunti, Maxine De la Cruz, Marieberta Vidal, Deepak Bedi, Rony Dev, Eduardo Bruera, Jennifer Keating Litton
Journal: Journal of Clinical Oncology (2014)

513 Background: High body mass index (BMI), an indicator of excess body fat, has been shown to negatively impact clinical outcomes in breast cancer. Metabolic dysfunction associated with high visceral fat may be contributory. Since BMI provides no information on the anatomical distribution of stored fat, we conducted this retrospective study to examine the association between visceral adiposity parameters and clinical outcomes. Methods: 1,237 postmenopausal women with stage I-III invasive breast cancer, diagnosed between 1997 to 2012, and who received neoadjuvant chemotherapy (NC) were included. Computed tomography images were used to quantify visceral fat (VFA) and subcutaneous fat area (SFA). The VFA/SFA Ratio was used as a metric of regional fat distribution. We conducted univariate and multivariate analyses to examine the association between body composition parameters (VFA, SFA, VFA/SFA Ratio, BMI) and key outcomes (pathologic complete response [pCR], relapse-free [RFS], disease-specific [DSS] and overall survival [OS]), adjusting for demographics and known prognostic factors, including stage, tumor grade, receptor status and type of NC. Results: Median age was 58 years; 63% white. A majority were overweight (32%) or obese (44%). Median VFA was 110 cm2, SFA 239 cm2and VFA/SFA Ratio 0.41. In multivariate analysis, higher VFA (odds ratio [OR]=0.52; 95% CI, 0.36-0.75; p< 0.001) and lower SFA (OR=0.56; 95% CI, 0.39-0.81; p=0.002) were independently associated with lower likelihood of achieving pCR. Higher VFA/SFA Ratio was an independent predictor of lower RFS (hazard ratio [HR]=1.41; 95% CI 1.05-1.89; p=0.02), DSS (HR=1.71; 95% CI, 1.20-2.44; p=.003) and OS (HR=2.18; 95% CI, 1.52-3.13; p<0.001). Conclusions: Our study suggests fat-depot specific differences in breast cancer outcomes. Higher visceral fat and lower subcutaneous fat were independently associated with lower likelihood of pCR. Higher visceral to subcutaneous fat ratio predicted worse RFS, DSS and OS. The predisposition to accumulate fat viscerally versus subcutaneously may be a novel prognostic factor independent of BMI, absolute fat stores and tumor characteristics.
Review: In AF, direct oral anticoagulants reduce all-cause and vascular mortality compared with warfarin
Authors: Eric R. Bates
Journal: Annals of Internal Medicine (2017)

ACP Journal Club21 March 2017Review: In AF, direct oral anticoagulants reduce all-cause and vascular mortality compared with warfarinEric R. Bates, MDEric R. Bates, MDUniversity of Michigan, Ann Arbor, Michigan, USA (E.R.B.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJC-2017-166-6-028 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationGómez-Outes A, Lagunar-Ruíz J, Terleira-Fernández AI, et al. Causes of death in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol. 2016;68:2508-21. https://pubmed.ncbi.nlm.nih.gov/27931607Clinical Impact RatingsGIM/FP/GP: Cardiology: Hematology: References1 January CT, Wann LS, Alpert JS, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64:e1–76. [PMID: 24685669] Google Scholar2 Connolly SJ. Anticoagulant-related bleeding and mortality [Editorial]. J Am Coll Cardiol. 2016;68:2522-4. [PMID: 27931608] Google Scholar Author, Article, and Disclosure InformationAffiliations: University of Michigan, Ann Arbor, Michigan, USA (E.R.B.)This article was published at Annals.org on 7 March 2017. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 21 March 2017Volume 166, Issue 6Page: JC28KeywordsAnticoagulantsAtrial fibrillationDeath ratesHeart failureHemorrhageHypertensionIschemic strokeMortalityNumber needed to treatStroke ePublished: 21 March 2017 Issue Published: 21 March 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...