tbuckley/cabot-search huggingface dataset:
Simplified/same day (s)-GOLF as first-line treatment of metastatic carcinoma of unknown primary (CUP).
Authors: Wasif M. Saif, Yvelisse Suarez, Douglas W Hackenyos, Martin D. Goodman, Melissa H Smith, Lisa Ralph, Antonia Maloney, Sanjay Hegde, Valerie Relias, Mark Bankoff, Barbara Weinstein, Kevin Daly
Journal: Journal of Clinical Oncology (2016)

e15665 Background: CUP represents a therapeutic challenge in oncological practice. Evidence lacks to support particular chemotherapy selection and empirical therapies are commonly extrapolated from data on pts where primary tumor site is known. GOLF (Gemcitabine, Oxaliplatin, Leucovorin and 5-Fluorouracil) was initially developed to treat pancreatic cancer. These agents have also demonstrated activities in other GI malignancies. Considering promising anti-tumor effects of GOLF, we performed a retrospective study to investigate anti-tumor activity and safety of s-GOLF in pts with CUP with IHC stains suggestive of upper GI origin. Methods: This retrospective study included pts recorded to have a diagnosis of CUP between Aug 2010-Dec 2015. IHC stains were positive for CK7, CK20, CA19.9; negative for TTF1, napsin-A, calretinin, Pax5/8, mammaglobin, hepar, glypican-3; focal for epcam, B72.3, CDX-2, CA125, ER. This staining pattern favored upper GI origin, including stomach, bile duct or pancreas. Endoscopy and CT/PET did not show primary. Molecular profiling was available in 4 pts; also favoring GI origin. 18 pts with chemo-naïve metastatic CUP were identified who received biweekly G 1000 mg/m2, O 85 mg/m2, L 200 mg/m2 and F 2400 mg/m2over 46-h on day 1 with pegfilgrastim on day 3 every 14 days. Tumor assessments were repeated every 8 weeks. Results: Median age was 67 years (range: 46-76), with ECOG PS < 2, and 50% were women. The most common sites of metastases were liver (11), peritoneum (9) and lungs (3). Median number of cycles was 4 (range: 3-14). 7 partial responses were obtained (RR: 39%) and 7 achieved stable disease with overall disease control of 78%. Median time to disease progression was 4 mths (range: 2-9). 7 (38%) pts received liver-directed therapy (SIRT, RFA), 10 had second-line and 5 had third-line chemotherapy. Median survival time was 10.5 mths (range: 6.7-14.5) and 1-year overall survival rate was 35%. Grade 3-4 toxicities included neutropenia (2), febrile neutropenia (1), thrombocytopenia (3), nausea (1), diarrhea (2), mucositis (2) and oxaliplatin neuropathy (4). Conclusions: s-GOLF regimen appears to be feasible with promising activity for CUP and deserves to be evaluated in future trials.
The advantage of pemetrexed combined with platium chemotherapy treatement for advanced nonsquamous non-small-cell lung cancer (NSCLC) patients without drive oncogene.
Authors: Haiyan Xu, Yan Wang
Journal: Journal of Clinical Oncology (2017)

e20527 Background:Platinum-based chemotherapy is the standard first-line treatment for non-squamous NSCLC patients without driver oncogene (EGFR, KRAS, and ALK mutations). However, it remains unknown that from which chemotherapy regimens can those patients get more benefit. Therefore, the study explore whether pemetrexed combined with platinum chemotherapy is superior to the other platinum-based chemotherapy regimens.Methods:We performed a retrospective study on 114 histologically or cytologically advanced IIIB-IV NSCLC patients admitted to Cancer Hospital from 1 Jan 2013 to 30 Dec 2015. The primary endpoint was the median progression free survival (PFS) and the disease control rate (DCR). And objective response was evaluated every two cycles by imaging according to the Response Evaluation Criteria In Solid Tumors (RECIST version 1.0). The multivariate logistic analyses were carried out by SPSS version 16.0. Results:114 patients received platinum-base doublet as first-line treatment. Among them, 59 patients underwent pemetrexed-containing regimens, and 55 patients received non-pemetrexed-containing regimens (38 patients for paclitaxel-containing regimens, 13 patients for gemcitabine-containing regimens, and 4 patients for other regimens.). The baseline characteristics between two groups were comparable ( p&gt;0.05). The median PFS of pemetrexed-containing regimens was significantly longer compared with that of non-pemetrexed-containing regimens (7.2 months [95% CI: 5.3–9.1] vs. 4.9 months [95% CI: 3.2–6.6], p%0.05). DCR of pemetrexed-containing regimens was better than that of non-pemetrexed-containing regimens in the multivariate logistic analysis (89.8% vs.74.5%, p%0.05).Conclusions:Pemetrexed-containing regimens displayed more benefit than the other chemotherapy regimens for non-squamous NSCLC patients without driver oncogene. However, large scale perspective study is warranted in the future.
TCT-621 Comparison of Quantitative Flow Ratio and Instantaneous Wave-Free Ratio for Immediate Assessment of Non-Culprit Lesions in Patients With ST-Segment Elevation Myocardial Infarction An iSTEMI Substudy
Authors: Martin Sejr-Hansen, Jelmer Westra, Troels Thim, Evald Christiansen, Ashkan Eftekhari, Steen Dalby Kristensen, Lars Jakobsen, Matthias Götberg, Ole Frobert, Nina van der Hoeven, Niels Holm, Michael Maeng
Journal: Journal of the American College of Cardiology (2018)
SM-88 efficacy across multiple high-risk factors.
Authors: Xinhua Zhu, Marcus Smith Noel, Patricia Zawisny, Zachary Gostout, Douglas Decorato, Maria Loushin, Giuseppe Del Priore
Journal: Journal of Clinical Oncology (2018)

e14535 Background: SM-88 is a relatively non-toxic novel combination therapy of dysfunctional tyrosine, CYP3a4 inducer, mTOR inhibitor and oxidative stress catalyst. Early testing with over 100 subjects has shown potential efficacy in 13 different cancer types (JCO 2013, e2209) with manageable toxicity (no grade 3-5 drug-related AEs). We now report tumor agnostic activity across multiple high-risk factors. Methods: Retrospective chart review of subjects treated with SM-88 (aka SMK) under Phase I or compassionate use. All subjects received SM-88 5 days/week. Results: 83 evaluable subjects were identified from 107 subjects treated with SM-88 between 2012–7. Mean age was 53 (7 – 82); 95% white; median prior systemic therapies: 1 (0 – 8), and baseline ECOG: 1 (0 – 4). At diagnosis: 7% Stage I, 13% Stage II, 14% Stage III, 37% Stage IV, and 28% unknown. At time of SM-88 treatment: 47% refractory, 33% recurrent, 2% stable, and 18% unknown. Primaries included: 30% breast, 12% pancreatic, 10% lung, and 6% prostate. Overall RR (CR+PR) was 41% (34/83); 14% (12/83) were CRs, 27% PRs, 40% SD, with 19% PD or unknown. Median PFS by response was CR - 16 months, PR - 12 mo, SD - 8 mo, and PD/UNK - 0 months. Median OS by response was 49, 14, 17, and 4 months, respectively. Responses were seen in 11/25 breast (44%), 3/10 pancreas (30%), 1/8 of lung (13%), and 3/5 of prostate (60%). Other outcomes included overall improvement of ECOG PS in 55% and 47% of EORTC QLQ-C30 “overall health” and “overall quality of life” plus pain reduction (NRS-11) in 40%. Responses were not affected by typical high risk factors (see table, * X2p<0.05). Conclusions: SM-88 has demonstrated potential efficacy in various cancer types with a favorable safety and QOL profile. There was no indication of cross-resistance based on prior treatments, metastatic site or other poor prognosis indicators. Low Risk Factor ORR Median PFS mo High Risk Factor ORR Median PFS mo 1L Prior Systemic n=28 43% 13 >1L Prior Systemic (median 3, 2-8) n=24 42% 4 Visceral Disease Only n=39 26% 7 Visceral & Bone Metastases n=17 41% 4 ECOG PS <= 1 n=36 39% 10 ECOG PS >1 n=30 47% 6 Duration > 6 mo. n=23 74%* 16 Therapy Duration 2-6 mo. n=60 28% 4 Weight < BMI 30 n=52 44% 9 Weight > BMI 30 n=8 50% 14 Monotherapy n=58 43% 13 Combination Therapy n=23 39% 5
Risk factors for the development of atrial fibrillation on ibrutinib treatment.
Authors: Robert William Lentz, Shuo Ma, Nausheen Akhter
Journal: Journal of Clinical Oncology (2018)

10059 Background: Ibrutinib is a Bruton’s tyrosine kinase inhibitor used for treating B-cell malignancies. The incidence of atrial fibrillation/flutter (AF) while on ibrutinib is reported to be 6-16%. The risk factors for incident AF while on ibrutinib are poorly defined. Methods: Charts were retrospectively reviewed to include patients treated with ibrutinib for any indication between July 2012 and July 2016. Those with existing AF were excluded. ECGs were manually reviewed to document AF. Patients were followed until incident AF, end of the medical record, end of ibrutinib treatment, or August 2017. Statistical analysis used chi-square and t-tests. Results: Of the 168 patients included, median age was 65.7 years, 70.2% were men, 68.5% were white, 60.7% had chronic lymphocytic leukemia, 13.1% had Waldenstrom macroglobulinemia, 11.3% had mantle cell lymphoma, and 14.9% had other cancer types. The incidence of AF was 11.9% after a median of 153 days of ibrutinib treatment. The median follow-up time for those without incident AF was 489 days. Age, coronary artery disease (CAD), heart failure (HF; systolic, diastolic, or either), and moderate/severe mitral regurgitation (M/S MR) were significantly different between patients with and without incident AF. Table 1 includes all evaluated parameters. Of those with HF or M/S MR, 45% and 100%, respectively, developed incident AF. Conclusions: In this large retrospective study, the incidence of AF on ibrutinib was higher in patients with older age, CAD, systolic or diastolic HF, and M/S MR. Every patient with M/S MR developed AF. Patients with these risk factors should be counseled on the risk of AF and monitored closely. An echocardiogram to evaluate for structural heart disease prior to initiating ibrutinib should be considered. Risk factors for incident AF. No incident AF (n = 148) Incident AF (n = 20) p value Body mass index, kg/m2 27.9 28.3 0.758 Age, years, median 65.4 69.1 0.038 Male (n = 118) 68.9% 80.0% 0.309 CAD (n = 27) 13.5% 35.0% 0.014 Hypertension (n = 78) 45.3% 55.0% 0.413 Hyperlipidemia (n = 92) 52.7% 70.0% 0.145 Diabetes mellitus (n = 35) 20.3% 25.0% 0.625 HF (n = 20) 7.4% 45.0% 1.12x10-6 Systolic HF (n = 10) 3.4% 25.0% 0.0001 Diastolic HF (n = 10) 4.1% 20.0% 0.005 M/S MR (n = 3) 0% 15.0% 1.99x10-6
Targeting alpha fetoprotein with TCR engineered T cells in HCC.
Authors: Andrew Gerry, Joe Sanderson, Miguel Maroto, Tiago Ferronha, Sulabha Ranganathan, Elliot Norry, Lini Pandite, Rafael G. Amado, Bent K Jakobsen
Journal: Journal of Clinical Oncology (2016)

3051 Background: Alpha fetoprotein (AFP), an oncofetal protein, is transcriptionally repressed after birth. Reappearance of AFP in adult circulation indicates liver regeneration, hepatitis, chronic liver diseases, or malignant growth. When AFP positive, expression in HCC tends to be very high and homogeneous, making it an attractive immunotherapy target. Methods: A TCR specific for the HLA-A2-resricted peptide AFP158-165 (FMNKFIYEI) was identified and engineered to generate a panel of 12 affinity-enhanced TCRs (KD: 79.5-0.31mM). One clone (10mM KD), demonstrating enhanced potency against AFP-expressing liver tumor cell lines and no response to normal hepatocytes, was selected. Molecular mapping of each position of the target peptide was performed; the generated binding motif was searched against the human genome, identifying 165 potentially reactive peptides, which were synthesized, loaded onto T2 cells, and tested for reactivity by AFP TCR engineered T cells (AFP-T). Results: No safety concerns were identified. 126 normal cells and 42 tumor cell lines from various organ systems were screened for AFP-T reactivity; AFP-T showed cytokine secretion and cytotoxic activity against HCC cell lines in 2D culture and 3D microtissues, but no relevant response to any other HLA-A*0201-expressing cells. Alloreactivity was detected against a subset of HLA-A*0202 primary cells. A full alloreactivity screen performed using a panel of 51 EBV- transformed B cell lines covering 38 HLA-A, 63 HLA-B and 28 HLA-C alleles, demonstrated enhanced responses against HLA-C*0404 and HLA-B*5103. AFP-T did not recognize the AFP peptide in the context of HLA-A*0203. Patients with HLA-C*0404 and -B*5103 and -A*0202 will be excluded. Conclusions: A Phase I study will evaluate preconditioning- and cell- dose escalation to investigate the safety and anti-tumor activity of AFP-T in HLA-A*0201+ patients with AFP+ HCC and good residual liver function. Clinical safety measures for mitigating treatment-related hepatotoxicity include pre-treatment biopsy evidence of low AFP expression in non-cancerous liver, and monitoring/management strategies within the protocol. Three cell-dose cohorts at 1x108, 1x109, 5x109 total transduced cells will be investigated.
Abstract 14126: Development of a Novel Shock Wave Catheter Ablation System -The Validation Study in Pigs in vivo
Authors: Michinori Hirano, Hiroaki Yamamoto, Yuhi Hasebe, Koji Fukuda, Susumu Morosawa, Hirokazu Amamizu, Kazuma Ohyama, Hironori Uzuka, Kazuyoshi Takayama, Hiroaki Shimokawa
Journal: Circulation (2016)

Background: The radio-frequency catheter ablation (RFCA) therapy has 3 Achilles’ heels caused by the joule heat as an energy source. First, limited lesion depth due to heat transfer results in ineffectiveness for the treatment of ventricular arrhythmias of epicardial origin. Second, myoendocardial injury causes resultant thromboembolic complications. Third, post-procedural inflammation responses are sustained with subsequent early phase recurrences. In order to overcome these limitations of RFCA, we have been developing a shock wave catheter ablation (SWCA) system as a novel non-thermal therapy (Fig. A). We have previously demonstrated that we are able to create persistent AV block in pigs in vivo with a prototype catheter. In this study, we further examined the lesion effects of the SWCA. Methods and Results: We applied the newly-improved SWCA system to ventricular muscle of pigs in vivo. A total of 22 pigs were used for the following 3 protocols. (1) Epicardial approach: the lesion depth by the SW appli...
Re: Pooja Ghatalia, Matthew Zibelman, Daniel M. Geynisman, Elizabeth Plimack. Approved Checkpoint Inhibitors in Bladder Cancer: Which Drug Should Be Used When? Ther Adv Med Oncol 2018;10:1758835918788310
Authors: Pontus Eriksson, Gottfrid Sjödahl, Fredrik Liedberg
Journal: European Urology (2018)
Response and durability of anti-PD-(L)1 therapy in never- or light-smokers with non-small cell lung cancer (NSCLC) and high PD-L1 expression.
Authors: Justin F. Gainor, Hira Rizvi, Elizabeth Jimenez Aguilar, Meghan Mooradian, Christine A. Lydon, Danyon Anderson, Megan Tenet, Jennifer L. Sauter, Mari Mino-Kenudson, Alice Tsang Shaw, Mark M. Awad, Matthew David Hellmann
Journal: Journal of Clinical Oncology (2018)

9011 Background: PD-1 blockade is now standard first-line therapy for patients (pts) with advanced NSCLC and a PD-L1 tumor proportion score (TPS) ≥50%. Tumor mutation burden (TMB) is also a biomarker of response to PD-1 blockade and correlates with smoking status in patients with NSCLC. Never/minimal smokers usually have low TMB and diminished response to PD-1 blockade. The impact of high PD-L1 expression on response to PD-1 blockade among never- or light-smokers has not been well studied. Methods: We retrospectively identified pts with NSCLC at 3 centers who were never- or light-smokers (≤10 pack years) and had received PD-(L)1 blockade. High PD-L1 expression was determined using commercially-available (22C3 or 28-8) or institutional laboratory developed tests (E1L3N) and defined as TPS ≥50%. A subset of pts underwent hybrid-capture NGS of 341-468 genes (MSK-IMPACT) to determine TMB. Results: We identified 52 light- (56%) or never-smokers (44%) with TPS ≥50% who received PD-(L)1 blockade in the first- (63%), second- (21%) or ≥third-line (15%) setting. Oncogenic driver mutations included KRAS (21%), EGFR (12%), BRAF (7%), RET/HER2/MET (4% each). Among 21 pts with MSK-IMPACT testing, median TMB was expectedly low (4.1 mutations/Mb). Objective responses were observed in 16 (ORR 31%) pts, including 6 (ORR 26%) never-smokers. The median duration of response (DOR) was 5.6 months (range 1-23+). Median progression-free survival and overall survival were 3.0 months (95% CI 2.2-5.1 months) and 16.4 months (95% CI 10.7-18.7 months), respectively. Conclusions: In never- or light-smokers with advanced NSCLC and high PD-L1 expression, PD-(L)1 blockade is associated with a moderate objective response rate; however, the durability of this activity appears diminished compared to historical controls. The immunobiologic features determining initial response versus durability of benefit to PD-(L)1 blockade may be distinct.
ADAM trial: A multicenter, randomized, double-blinded, placebo-controlled, phase 3 trial of adjuvant avelumab (anti-PD-L1 antibody) in merkel cell carcinoma patients with clinically detected lymph node metastases; NCT03271372.
Authors: Shailender Bhatia, Andrew Scott Brohl, Isaac Brownell, Sunandana Chandra, Sumia Dakhil, Marc S. Ernstoff, Leslie Anne Fecher, Ted Gooley, Glenn J. Hanna, Reina Hibbert, Ciara Marie Kelly, Samantha M. Kiriluk, Paul Nghiem, Vivian Nguyen, Nichole Pelz, Aubrey A. Poisson, Katharine Andress Rowe Price, Vernon K. Sondak, John A. Thompson, Scott S. Tykodi
Journal: Journal of Clinical Oncology (2018)

TPS9605 Background: Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. MCC with clinically detected lymph node (LN) metastases is associated with high risk of systemic recurrence despite initial surgical therapy and/or radiation therapy (RT). Adjuvant cytotoxic chemotherapy is not associated with overall survival benefit in stage III MCC and there is a strong unmet need for effective adjuvant systemic therapy. Clinical investigation of PD-1/PD-L1 blockade in patients with metastatic MCC is associated with remarkable improvement in clinical outcomes with response rates > 50% in a chemotherapy-naïve setting. This notable benefit from PD-1 blockade in stage IV MCC, along with the recent success with adjuvant PD-1 blockade in stage III melanoma, together provide strong rationale for investigating avelumab, an anti-PD-L1 antibody, for adjuvant systemic therapy in MCC patients with high risk of recurrence. Methods: The ADAM (Adjuvant Avelumab in Merkel) trial is an investigator-sponsored, phase 3, multi-center, double-blinded and placebo-controlled study. We plan to enroll 100 MCC patients with clinically or radiologically detected LN metastases treated definitively with surgery (with or without adjuvant RT). Patients will be randomized (1:1) to receive either avelumab or placebo administered IV at a dose of 10mg/kg every 15 days for the first 4 months, then once monthly for the next 4 months, and then once every 4 months. Treatment will end 2 years after starting the study drug, or upon recurrence of disease, unacceptable toxicity, or study withdrawal. The primary endpoint is relapse-free survival. Secondary endpoints include overall survival, disease-specific survival, distant metastasis-free survival, and safety and tolerability. Exploratory endpoints include tissue and blood-based biomarkers and AMERK (Anti-Merkel polyomavirus) serology as a recurrence predictor in a prospective, multi-center setting. The ADAM trial represents the first-ever phase 3 trial in MCC and is a major academic collaboration across several US cancer centers. Clinical trial information: NCT03271372.
Prognostic significance of microsatellite instability (MSI) and mismatch repair status (MMR) in African American (AA) patients with colorectal cancer (CRC) and its impact on therapy with 5Fluorouracil.
Authors: Shahla Bari, Shuba Balan, Paula Adamson, Ambreen Merchant, Snigdha Nutalapati, Taiwo Ajose, Suaka Kagbokue, Sanjay R Jain
Journal: Journal of Clinical Oncology (2018)

e15634 Background: MSI status remains an important clinical and prognostic marker and has been associated with better outcomes in CRC. AA patients are known to have more aggressive CRC at diagnosis and worse survival. The significance of MSI in this population is not well characterized. We analyzed effect of MSI status in AA patients, its effect on survival and response to 5-FU. Methods: We retrospectively analyzed 143 AA patients with CRC, who had MSI/MMR testing performed and were treated at Grady Memorial Hospital. We examined MSI status and expression of KRAS, BRAF V600, MLH1, MSH2, MSH6 and PMS2 in surgical specimens. Results: 19 patients had MSI-H. One presented with stage 1, 13 (68%) with stage 2, 3 (16%) with stage 3 and 2 with stage 4 disease. In this group 3 had Node positive disease, 1 had LVI, while 13 (68%) were stage 1 or 2 with no high-risk features. In the MSS group, 10 patients were stage 1, 38 stage 2 (30%), 42 stage 3 (33%) and 34 (27%) had stage 4 disease. In the MSI-H group 10 patients received 5-FU (including 6 stage 2 patients). The MSS group had 19 stage 2 patients out of a total of 86 patients treated with 5-FU. At the time of analysis 3 patients (15%) had died in the MSI-H group and 13 (10%) in the MSS group. Median OS was 26 months in the MSI-H and 28.5 months in the MSS group (not statistically significant). Similarly, progression free survival (p = 0.3) and overall survival (p = 0.6) was not affected by MSI status in all stages of. Patients treated with 5-FU (10 in MSI-H and 86 in MSS group) showed no difference in OS (p = 0.693) in the entire group or when stage 2 disease was analyzed separately (p = 0.403). Conclusions: We present the largest analysis of AA population with CRC and look at the impact of MSI status on survival and effect of therapy with 5-FU. Our study showed that in the AA population, MSI status had no impact on PFS or OS. At the same time, we saw similar benefit of 5-FU, regardless of the presence of MSI-H or MSS in this patient population. Since the AA patient population has historically had worse outcomes and is underrepresented in CRC clinical trials, further studies are needed in these patients to better tailor therapy
Medicare Bundled Payment Programs for Joint Replacement
Authors: Andrew M. Ryan
Journal: JAMA (2018)

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Impact of Lymph Node Dissection on Thymic Malignancies: Multi-Institutional Propensity Score Matched Analysis
Authors: Yoohwa Hwang, Chang Hyun Kang, Samina Park, Hyun Joo Lee, In Kyu Park, Young Tae Kim, Geun Dong Lee, Hyeong Ryul Kim, Se Hoon Choi, Yong-Hee Kim, Dong Kwan Kim, Seung-Il Park, Sumin Shin, Jong Ho Cho, Hong Kwan Kim, Yong Soo Choi, Jhingook Kim, Jae Il Zo, Young Mog Shim, Chang Young Lee, Jin Gu Lee, Dae Joon Kim, Hyo Chae Paik, Kyung Young Chung
Journal: Journal of Thoracic Oncology (2018)