tbuckley/cabot-search huggingface dataset:
Integrating clinical pharmacy services into patient care in an early-phase clinical trial clinic.
Authors: Dazhi Liu, Thu Oanh Dang, Stephen Harnicar, Katherine Kargus, Lauren A Evans, Yat Yee So-Kwan, David Michael Hyman
Journal: Journal of Clinical Oncology (2017)

e18228 Background: Early phase clinical trials have broadened treatment options for patients with cancer. Expert management of these new therapies is essential to positive patient outcomes. At Memorial Sloan Kettering Cancer Center, the Developmental Therapeutic Center (DTC) satisfies this need. Oncology clinical pharmacists collaborate with other healthcare professionals to maximize the benefits of drug therapy and minimize toxicities. The purpose of this project is to describe the interventions from a clinical pharmacist assigned to the DTC. Methods: A clinical pharmacist joined DTC to serve adult patients with cancer undergoing clinical trials. The clinical pharmacist acted as a liaison between pharmacy team and medical team, and sees patients during their trial eligibility screening and follow-up visits. The interventions were documented by the clinical pharmacist in patients’ medical charts and email communications. All interventions during 1 month were retrospectively collected and categorized into supportive care optimization, protocol violation prevention, and operational. Results: The oncology clinical pharmacist was involved in 115 patient visits for trial eligibility screening or protocol follow-up. A total of 769 interventions were addressed including supportive care optimization (40.2%), protocol violation prevention (24.7%), and operational (35.1%). Conclusions: The oncology clinical pharmacist is actively engaged in many aspects of cancer care at the early phase trial clinic. Our results demonstrate the vital role of an oncology clinical pharmacist. The impact of these categorized intervention areas would require a formal outcome and cost-saving analysis. [Table: see text]
Abstract 15201: Diastolic Pulmonary Gradient and Outcomes in Group 1 Pulmonary Hypertension (Analysis of the NIH Primary Pulmonary Hypertension Registry)
Authors: Sula Mazimba, Eliany Mejia-Lopez, Jamie L Kennedy, James Bergin, Jose A Tallaj, Elizabeth Gay, Mohammad Abuannadi, Andrew D Mihalek, Kenneth C Bilchick
Journal: Circulation (2015)

Introduction: The National Institute of Health (NIH) registry for primary pulmonary hypertension (PPH) established prognostic factors for PPH (now WHO group 1 PH). Diastolic pulmonary gradient {(DPG), Pulmonary artery diastolic pressure-mean Pulmonary capillary wedge pressure} ≥ 7 mmHg is associated with pulmonary vascular disease and a poor prognosis in heart failure (HF). The prognostic relevance of DPG in group 1 PH is uncertain. Methods: Using the NIH risk stratification equation for 239 patients in the NIH-PPH registry, the 5-year probability of death was calculated. The NIH model was then compared with DPG using a Cox proportional hazards model. Kaplan-Meier survival curves were determined for two cohorts using the median DPG of 30 mmHg as cutoff, and significance was tested using the logrank test. Results: The median age of patients was 38.1 ± 16.0 years old, 63% were female, and 72% had race reported as “white”. The mean DPG was 31.5 mmHg (± 13.6 mm Hg) and only 17.4% of patients had a DPG &lt; 7 mm Hg. In a Cox proportional hazards model, increasing DPG was significantly associated with 5-year mortality even after adjustment for the NIH risk equation (DPG HR 1.18 per 10 mm Hg increase [95% CI 1.05-1.32]), and the chi square statistic for DPG compared favorably with the NIH risk equation (15.6 versus 26.2). When DPG was dichotomized based on the median value of 30 mm Hg, the hazard ratio for DPG &gt; 30 mm Hg with respect to 5-year mortality was 1.91, 95% CI [1.34-2.75] (Figure). In a separate Cox model adjusted for pulmonary artery systolic pressure (PASP), increasing DPG remained significantly associated with decreased survival over 5 years (HR 1.45 for DPG &gt; 30 mm Hg, 95% CI [1.01, 2.10]). Conclusions: DPG has higher distribution in PH than previously reported in HF studies and is associated with survival in group 1 PH patients even after adjustment for the NIH risk equation or PASP. More studies are needed to evaluate the use of DPG in guiding treatment and prognosis in group 1 PH.
Phase 3, open-label, randomized study of first-line pembrolizumab (pembro) vs investigator-choice chemotherapy for mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal carcinoma (mCRC): KEYNOTE-177.
Authors: Luis A. Diaz, Dung T. Le, Takayuki Yoshino, Thierry Andre, Johanna C. Bendell, Minori Koshiji, Yinghua Zhang, S. Peter Kang, Bao Lam, Dirk Jaeger
Journal: Journal of Clinical Oncology (2017)

TPS3618 Background: About 5% of mCRCs are dMMR, leading to high levels of MSI. CRCs with MSI-H have abundant lymphocyte infiltrates and strong expression of immune checkpoints. In the phase 2 KEYNOTE-016 study, the anti-programmed death 1 (PD-1) antibody pembro provided an ORR of 40% in patients (pts) with progressive dMMR mCRC vs 0% in pts with MMR-proficient mCRC. KEYNOTE-177 (ClinicalTrials.gov, NCT02563002) is an international, randomized, open-label, phase 3 study designed to evaluate the efficacy and safety of pembro vs standard-of-care (SOC) chemotherapy in the first-line setting for dMMR or MSI-H mCRC. Methods: Key eligibility criteria include age ≥ 18 years, locally confirmed dMMR or MSI-H stage IV CRC, measurable disease per RECIST v1.1 by local site assessment, ECOG performance status 0-1, no active autoimmune disease or brain metastases, and no prior therapy for mCRC. Pts are to be randomized 1:1 to receive either pembro 200 mg Q3W or investigator’s choice of SOC chemotherapy, which must be chosen prior to randomization; options include mFOLFOX6 or FOLFIRI alone or in combination with bevacizumab or cetuximab. Treatment is to continue until disease progression, unacceptable toxicity, pt/investigator decision, or completion of 35 cycles (pembro only). Response is to be evaluated Q9W per RECIST v1.1 by central imaging vendor review and per RECIST adapted for immunotherapy response patterns. Pts in the SOC arm who have disease progression and meet crossover criteria may be eligible to receive pembro for up to 17 treatment cycles. Eligible pts may continue pembro beyond initial RECIST-defined progression. AEs are to be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and graded per NCI CTCAE v4.0. Pts are to be followed for survival Q9W. Primary end point is PFS per RECIST v1.1 by central imaging vendor review. Secondary end points include ORR per RECIST v1.1 by central imaging vendor review, OS, and safety and tolerability. Other end points include DOR and HRQoL. Planned enrollment in KEYNOTE-177 is 270 pts across 21 countries. Clinical trial information: NCT02563002.
MicroCT imaging reveals differential 3D micro-scale remodelling of the murine aorta in ageing and Marfan syndrome
Authors: Júlia López-Guimet, Lucía Peña-Pérez, Robert S. Bradley, Patricia García-Canadilla, Catherine Disney, Hua Geng, Andrew J. Bodey, Philip J. Withers, Bart Bijnens, Michael J. Sherratt, Gustavo Egea
Journal: Theranostics (2018)

Aortic wall remodelling is a key feature of both ageing and genetic connective tissue diseases, which are associated with vasculopathies such as Marfan syndrome (MFS).Although the aorta is a 3D structure, little attention has been paid to volumetric assessment, primarily due to the limitations of conventional imaging techniques.Phase-contrast microCT is an emerging imaging technique, which is able to resolve the 3D micro-scale structure of large samples without the need for staining or sectioning.Methods: Here, we have used synchrotron-based phase-contrast microCT to image aortae of wild type (WT) and MFS Fbn1 C1039G/+ mice aged 3, 6 and 9 months old (n=5).We have also developed a new computational approach to automatically measure key histological parameters.Results: This analysis revealed that WT mice undergo age-dependent aortic remodelling characterised by increases in ascending aorta diameter, tunica media thickness and cross-sectional area.The MFS aortic wall was subject to comparable remodelling, but the magnitudes of the changes were significantly exacerbated, particularly in 9 month-old MFS mice with ascending aorta wall dilations.Moreover, this morphological remodelling in MFS aorta included internal elastic lamina surface breaks that extended throughout the MFS ascending aorta and were already evident in animals who had not yet developed aneurysms.Conclusions: Our 3D microCT study of the sub-micron wall structure of whole, intact aorta reveals that histological remodelling of the tunica media in MFS could be viewed as an accelerated ageing process, and that phase-contrast microCT combined with computational image analysis allows the visualisation and quantification of 3D morphological remodelling in large volumes of unstained vascular tissues.
Tissue sampling for genomic testing in a community-based center.
Authors: Carol J. Farhangfar, Farhang Farhangfar, Meghan Schneider, Kathryn Finch Mileham, Chad Livasy, Will Ahrens, Edward S. Kim
Journal: Journal of Clinical Oncology (2017)

e18000 Background: Genomic testing requires greater quality than routine clinical diagnostic tests. As genomic testing proliferates and becomes more widespread, adjustments in processes may be needed by community-based pathology, radiology, and surgery groups. Both tissue quality and quantity parameters are essential for successful completion of next-generation sequencing (NGS) panels. Methods: A NGS genomic platform ( &gt; 600 genes) was implemented in a hybrid academic community-based cancer institute, with success/failure rates recorded.. Data were collected from the electronic medical records and biorepository data system. Descriptive statistics assessed success or failure rates by tissue quality or quantity with subgroup analyses by disease sites (primary/metastases), collection procedure, and specimen age. Results: From 6/2015-2/2017, 809 NGS tests yielded 143 (17%) failures [specimen quality (34%) and specimen quantity (66%)]. Of the failed tests, specimens were collected from 26 primary disease sites [lung (21%)] and 18 metastatic sites [liver (29%), lymph node (19%), and lung, omentum, brain, and peritoneal specimens (all &lt; 10%)]. Of the failed tests, all bronchoscopy, EBUS, and peritoneal fluid specimens and the majority of FNAs (78%) were due to insufficient tissue quantity, whereas surgical resection or excision had more issues with quality of the specimen (60%). Of note, surgical specimens ranged from 2005-2016; NGS quality initiatives were implemented system-wide in 2015, leading to substantially fewer failed tests. Cores biopsies had fewer quantity (24%) or quality (18%) issues. The number of tests failing due to insufficient quantity also declined due to education and communication processes implemented. Conclusions: The majority of NGS tests provided valuable information. Implementation of systematic tissue collection (core biopsies) and processing, for primary lung and lung and liver metastases using core biopsies consistently provided the fewest failures and implementing NGS-specific processes improved NGS success rates.
Impact of the type and modalities of preoperative chemotherapy on the outcome of liver resection for colorectal liver metastases: A LiverMetSurvey study.
Authors: Yuichi Goto, Pasquale F. Innominato, Marc Antoine Allard, Carlos Castro Benitez, Oriana Ciacio, Gabriella Pittau, Eric Vibert, Antonio Sa Cunha, Daniel Cherqui, Denis Castaing, Koji Okuda, Yoshito Akagi, Hiroyuki Tanaka, René Adam
Journal: Journal of Clinical Oncology (2018)

3529 Background: Prognostic factors of survival have been extensively reported after resection of colorectal liver metastases (CLM). However, a specific analysis of patients submitted to preoperative chemotherapy (PCT), with the real impact of type and modalities of PCT on patient outcome is lacking. Methods: The study population consisted of a multicentric cohort of patients who received PCT before resection of CLM within a 20-year period and whose data were prospectively collected in the LiverMetSurvey. Patients were analyzed in terms of intentions of PCT including neoadjuvant (N-CT) and conversion (C-CT) chemotherapy. Overall survival (OS) rates were analyzed by Kaplan-Meyer method and compared using the log-rank test. The distribution of potential prognostic factors for OS including age, sex, sidedness of primary tumor, timing of metastases, tumor number, diameter of largest CLM, CEA, bilaterality, and type and number of PCT cycles were analyzed by Cox regression model. Results: Of 7,202 eligible patients, N-CT was submitted in 4,422 (61.4%) for resectable and C-CT in 2,780 patients (38.6%) for unresectable CLM. In N-CT, 5-year OS of Irinotecan-based (Iri-) PCT was decreased compared to the oxaliplatin-based (Oxa-) PCT (40.9% vs. 47.8%, p < 0.01). The 5-year OS was not different with or without targeted therapy (41.1% vs. 47.0%, p = 0.12). As for C-CT, the 5-year OS was comparable between Iri- and Oxa-PCT (32.2% vs. 32.9%, p = 0.32), and also not different with regard to the use of targeted therapy (p = 0.47). On multivariate analysis, Iri-PCT was associated with worse OS in N-CT (HR = 1.46 [1.02-1.52], p = 0.02) but not in C-CT (p = 0.89). Use of targeted therapy was not associated with OS for both N-CT and C-CT (p = 0.53, p = 0.06, respectively). PCT > 6 cycles in N-CT (HR = 1.46 [1.23-1.76], p = 0.04) and > 8 cycles in C-CT (HR = 2.39 [1.73-3.30], p < 0.01) was associated with worse OS. Conclusions: For resectable CLM with N-CT, Oxa-PCT is associated with better survival compared to Iri-PCT. For unresectable CLM with C-CT, the type of PCT did not influence the outcome, provided that resection was achieved. For both, the shorter is the PCT, the best is the survival after surgery.
Value-based healthcare delivery models in oncology: A systematic review.
Authors: Emeline Aviki, Stephen Matthew Schleicher, Samyukta Mullangi, Konstantina Matsoukas, Deborah Korenstein
Journal: Journal of Clinical Oncology (2018)

6525 Background: With the rising cost of health care in the US has come increasing emphasis on optimizing value. Value-based healthcare delivery models are designed to maximize outcomes and minimize costs through changes in care delivery. Little is known about the impact of value-based interventions in cancer care. We performed a systematic review to describe the landscape of value-based interventions in cancer. Methods: This review included peer-reviewed and non peer-reviewed articles describing value-based interventions in cancer care. We identified articles through structured searches of PubMed/MEDLINE, EMBASE, CINAHL, and Cochrane Central Register of Controlled Clinical Trials since passage of the Affordable Care Act. We used the Effective Public Health Practice Project Quality Assessment Tool to evaluate the quality of studies reporting results. Results: Twenty-three articles describing 22 unique value-based interventions in cancer met inclusion criteria. Of the 23 articles, 12 were published in the peer-reviewed literature, and 13 reported outcomes and were assessed for quality. All were of moderate (n = 6, 46%) or weak (n = 7, 54%) quality. The 22 value-based interventions included 6 (27%) bundled payments, 4 (18%) accountable care organizations (ACOs), 9 (41%) patient-centered medical homes, and 3 (14%) other interventions. Most interventions were conducted in community settings (n = 16 of 21, 76%) and performed through commercial insurance contracts (n = 13 of 15, 87%), including all bundled payments and all cancer-specific ACOs. Of the 12 interventions with outcomes reported, the majority (n = 7, 58%) improved value, 4 had no impact on value, and 1 reduced value, though this effect was no longer significant after 2-3 years. Conclusions: This systematic review of value-based healthcare delivery models in cancer care found that reports of outcomes are often lacking and are of variable quality when available. Despite promising early signs, the efficacy of these interventions in cancer remains unclear. Moving forward, rigorous evaluations and increased outcome reporting will enable continued innovation to achieve the highest value of care for cancer patients.
Clinical support with integrated multimodality molecular profiling for colorectal tumors.
Authors: Vincent Anthony Funari, Wanlong Ma, Wayne Chen, Shiping Jiang, Sally Agersborg, Maher Albitar
Journal: Journal of Clinical Oncology (2016)

e15064 Background: Current recommendations for colorectal cancer testing include KRAS and NRAS for anti-EGFR therapy, and BRAF mutational analysis with microsatellite instability (MSI) testing for prognostic stratification and Lynch syndrome. We developed a multi-modality colorectal cancer profile useful for clinical management. Methods: 133 Colorectal cancer samples were profiled with our platform, which includes 1) 21 gene mutation analysis using deep sequencing (ca. 15K reads), 2) MSI status, 3) MLH1 Promoter Methylation, 4) MET amplification and PTEN deletion by FISH, and 5) PD-L1 expression (30% of samples) by IHC. Results: 99% of tumors contained at least 1 mutation found by NGS. The most commonly observed mutations were TP53(85%), KRAS (49%), PIK3CA(26%), BRAF(19%), EGFR(16.5%), NRAS(8%), FGFR3(6%), HRAS(5%), KIT (5%), SMO(5%), JAK3(5%), and ERBB2(5%). 39 patients had a TP53 mutation allele frequency consistent with germline mutations, raising the possibility of a Li–Fraumeni syndrome. Most tumors (51%) also had at least 1 abnormal non-sequencing result. The most common findings were PTEN deletion (25%), MLH1(17%) methylation, MSI(11%), PDL1 (17.5%) overexpression. PTEN/MET/PDL1 was anticorrelated to MSH/MLH status. (p < 0.05). Our integrated profile (NGS, FISH, MSI, MLH) robustly recapitulated hypermutation profiles that were associated with BRAF+/MLH+/MSH+ profiles using comprehensive WGS in a recent TCGA study. In addition, 25%(10) were KRAS-/MLH-/MSH-/BRAF- of unknown prognosis without PTEN deletion status. The integrated profile also identified ~2 percent (3/131) of patients as candidates for Lynch Syndrome testing (MSH+/MLH-/BRAF- and < 50 years). Conclusions: Multimodality Colorectal Cancer profiling identified patients with potential new targeted therapy. Specifically, we identified a significant number of cases that were PTEN, PI3KCA, HRAS, FGFR3, MET, KIT, ERBB2, and PDL1 positive that change treatment options. In addition, to identifying patients with prognostic status (e.g.BRAF+, MSI+/MLH+), we identified important candidates for Lynch syndrome testing or possibly Li-Fraumeni Syndrome who would benefit from alternative treatments and different management.
Real world study of afatinib in first-line or re-challenge setting for patients with EGFR mutant non-small cell lung cancer.
Authors: Hisashi Tanaka, Kageaki Taima, Masamichi Itoga, Yoshiko Ishioka, Keisuke Baba, Toshihiro Shiratori, Yoshihito Tanaka, Hideyuki Nakagawa, Junichiro Tsuchiya, Yukihiro Hasegawa, Hiroaki Sakamoto, Hideo Yasugahira, Koichi Okudera, Shingo Takanashi, Sadatomo Tasaka
Journal: Journal of Clinical Oncology (2018)

e21173 Background: Afatinib is the second generation epidermal growth factor receptor (EGFR) - tyrosine kinase inhibitor (TKI) for mutant non-small cell lung cancer (NSCLC), and approved in Japan in 2014. This study evaluated clinical outcomes of afatinib in real world practice. Methods: Patients who received afatinib for advanced EGFR-mutant NSCLC in 5 institutions in Aomori, Japan from October 2014 to January 2017 were included into the analyses. Results: In total, 128 patients were analyzed. Seventy-six patients received afatinib as first-line setting and 52 as re-challenge setting (i.e., prior first generation TKIs used and third generation TKI were not adapted). In first-line setting, patient characteristics were as follows: a median age 68 yrs (42- 88 yrs), 67% female, and 88.1% PS 0/1. The median progression-free survival (PFS) was 17.8 months (95% CI: 13.7- 21.5 months). The overall survival (OS) was 39.5 months (95% CI: 34.4- not reached). There was no difference in median PFS and OS according to age ( < 74, 75 ≦). Though 58 patients (76.3%) had to reduce the dose due to adverse events, it did not affect its efficacy in terms of OS (39.5 months in the reduction group vs. not yet reached in the no reduction group) (P = 0.37). Moreover, the reduction group showed even longer PFS than the no reduction group. (18.0 months in the no reduction group vs. 7.9 months in the reduction group) (P = 0.016). The response rate (RR) was 64% (CR/PR/SD/PD/NE: 1/48/16/1/10). Twenty-eight patients among 48 who had PD underwent re-biopsy, and 16 patients (57.1%) were T790M positive. In re-challenge setting, patient characteristics were as follows: a median age 65 yrs (37- 90 yrs), 78% female, and 90.3% PS 0/1. The median PFS was 8.0 months (95% CI: 4.9- 9.5 months). The RR was 24% (CR/PR/SD/PD/NE: 1/12/29/6/4). Most common adverse events leading to dose modification and treatment discontinuation were diarrhea, paronychia, and oral mucositis in both settings. Interstitial lung disease occurred in 5.4% (7/128). Conclusions: In the real practice in Japan, afatinib in first-line and re-challenge settings showed comparable or better efficacy compared with previous clinical trials.
Impact of somatic mutations on recurrence free survival (RFS) and overall survival (OS) for resected non-small cell lung cancer (NSCLC): results from the Japan Molecular Epidemiology for lung cancer study (JME).
Authors: Akihiro Tamiya, Yasuhiro Koh, Akihito Kubo, Masahiko Ando, Shun-ichi Isa, Hideo Saka, Naoki Yoshimoto, Masakuni Serizawa, Sadanori Takeo, Hirofumi Adachi, Tsutomu Tagawa, Osamu Kawashima, Motohiro Yamashita, Kazuhiko Kataoka, Yukito Ichinose, Yukiyasu Takeuchi, Katsuya Watanabe, Akihide Matsumura, Tomoya Kawaguchi
Journal: Journal of Clinical Oncology (2018)

8549 Background: We previously reported molecular profiling as a primary endpoint in a prospective multicenter molecular epidemiology study, collecting 876 surgically resected NSCLC and examining 72-gene somatic mutation status using the next-generation sequencing (JME study; Kawaguchi T, J Clin Oncol 2016). The secondary endpoint was OS and RFS analysis (UMIN 000008177). Here, we report follow-up data and clinical outcomes in the JME study and the impact of somatic mutations on RFS and OS. Methods: All the patients were enrolled from July 2012 to December 2013, and clinical and prognostic data were obtained until the end of November 2017. Cox proportional hazards model were applied to assess the impact of the gene mutations on RFS and OS, considering gender, smoking history, age, stage, histology, history of adjuvant chemotherapy, EGFR, KRAS, TP53, and number of coexisting mutations. Results: Median follow up time was 48.4 months, and 876 patients were analyzed: 419 were men; 734 were non-squamous carcinoma; 441 had smoking history; 450 were ≥70 years; 618/131/127 were stage I/II/III-IV, 309 received the adjuvant chemotherapy. Among these, 141 had ≥ two somatic mutations. Multivariate analysis showed the number of coexisting mutations (≥2 vs. 0 or 1, HR = 1.643, 95%CI: 1.126-2.373), age (≥70 vs. < 70, HR = 1.561, 95%CI: 1.201-2.035) and pathological stage (II vs. I, HR = 3.103, 95%CI: 2.217-4.304; ≥III vs. I, HR = 6.382, 95%CI: 4.641-8.758) were significantly associated with RFS, while in OS, EGFR mutations (yes vs. no, HR = 0.450, 95%CI: 0.277-0.715), adjuvant chemotherapy (yes vs. no, HR = 0.493, 95%CI: 1.406-2.967), age (≥70 vs. < 70, HR = 1.694, 95%CI: 1.201-2.415) and pathological stage (II vs. I, HR = 2.448, 95%CI: 1.581-3.723; ≥III vs. I, HR = 6.601, 95%CI: 4.498-9.665) were also significant prognostic factors. Conclusions: Our prospective study showed less number of coexisting mutations, earlier stage and younger age were associated with longer RFS, while in OS, EGFR mutation and adjuvant chemotherapy were significantly associated with improved OS as well as earlier stage and younger age in resected NSCLC.