tbuckley/cabot-search huggingface dataset:
A phase I expansion study of trifluridine and tipiracil (FTD/TPI) in combination with irinotecan (IRI) and bevacizumab (BEV) in patients with metastatic colorectal cancer (mCRC).
Authors: Anna M. Varghese, Dana Backlund Cardin, Jonathan Hersch, Al Bowen Benson, Howard S. Hochster, Robert E. Winkler, Fabio Benedetti, Kensuke Hamada, Jordan Berlin, Leonard B. Saltz
Journal: Journal of Clinical Oncology (2018)

3546 Background: FTD/TPI is an oral antineoplastic agent that was developed to overcome resistance to fluoropyrimidines. FTD/TPI is approved for use in previously treated patients with mCRC. This Phase I expansion study investigated the safety, pharmacokinetics (PK), and preliminary efficacy of FTD/TPI and IRI with BEV. The dose-escalation phase determined the maximum tolerated dose of FTD/TPI and IRI to be FTD/TPI 25 mg/m2 and IRI 180 mg/m2. Methods: Patients aged ≥18 years with mCRC with disease progression following ≥1 line of chemotherapy were included. Patients who had required any prior IRI dose reductions, dose delay, or growth factor support in the first 8 weeks of treatment with IRI were excluded. FTD/TPI was administered at 25 mg/m2 twice daily on days 1-5 of 14-day cycles with IRI 180 mg/m2 preceded by BEV 5 mg/kg on day 1 of each 14-day cycle. PK samples were collected on days 1-3 of cycle 1. Results: Twenty-four patients with mCRC were enrolled; 67% were female and the median age was 55.5 years (range 19-73). The median number of prior regimens was 4; all patients had received prior fluoropyrimidine and oxaliplatin treatment, 3 patients were IRI-naïve, and 5 patients were BEV-naïve. Grade ≥3 adverse events were reported in 20 patients (83%); the most common were neutropenia (33%), leukopenia (25%), diarrhea (13%), and hypertension (13%). Based on RECIST v1.1 of the 24 evaluable patients, 3 had a partial response and 17 experienced stable disease. Median progression-free survival was 7.9 months (95% CI 5.1, 13.4). PK analysis did not show any significant correlation between the plasma concentrations of FTD/TPI and IRI or their metabolites. Conclusions: No new safety findings or cumulative adverse events were reported with the addition of BEV to FTD/TPI and IRI. Preliminary efficacy results indicate promising anti-tumor activity using FTD/TPI and IRI with BEV for patients who had failed a median of 4 prior regimens with most having had prior IRI. This triple chemotherapy combination warrants further evaluation in patients with mCRC. Clinical trial information: NCT01916447.
TCT-836 Unique Calcification Patterns in the Left Main Bifurcation in Patients After Coronary Artery Bypass Grafting
Authors: Rafal Wolny, Gary Mintz, Mitsuaki Matsumura, Masaru Ishida, Akiko Fujino, Tetsumin Lee, Evan Shlofmitz, Alec Goldberg, Allen Jeremias, Elizabeth Haag, Richard Shlofmitz, Akiko Maehara
Journal: Journal of the American College of Cardiology (2018)
Development of a web-based DrAV tool for comprehensive genomic profiling interpretation.
Authors: Amit Verma, Peeyush Tuli, Jatinder Kaur
Journal: Journal of Clinical Oncology (2018)

e18568 Background: Comprehensive genomic profiling (CGP) has provided insights into cancer genomic landscape, aiding Precision Oncology. Clinical translation is challenging due to time consuming interpretation and lack of consensus in treatment strategy. A web-based tool DrAV (cgpeasy.com) was designed to provide a platform for extracting genomic data and clinical information into clinical decision making user friendly format. Methods: Validation was done on 123 FoundationMedicine (FM) cases. Tool integrates COSMIC, ClinVar, IARC databases and proprietary algorithm to calculate genomic complexity score (GCS), immunotherapy (IT) response score and heterogeneity score. Tool classifies Genomic alterations (GA) into driver mutations, 12 signaling pathways and 3 core cellular processes. Tool predicts potentially germline GA prompting clinical features associated with genetic syndromes and recommends final treatment strategy and reflex germline-testing. Results: In 123 cases, 653 GA were identified in 183 genes. 100% concordance was observed between FM and DrAV for classifying pathogenic mutations. However, of the 1724 VUS reported by FM, 149 (8.6%) were re-classified as pathogenic, 131 single nucleotide substitutions (avg pathogenic score 0.93, 0.7-1.0) and 18 amplifications. 39/149 (26.2%) were driver mutations of which 13 were actionable. DrAV predicted 22 patients with potentially germline GA, of which germline information was available in 2 cases that were in agreement. Target therapy (TT) alone was recommended in 15 cases which were concordant with FM report. Concordance for recommendation for use of IT was observed in 3/9 (33%) cases. Discordance in 6 cases was attributed to unproven markers used by FM, intermediate TMB levels ( 6-19 muts/Mb) and PDL1/2 genes amplification. In addition, chemotherapy (CT) was recommended along with TT in 105 cases based on high GCS. Conclusions: DrAV tool is a user-friendly, validated web-based tool for CGP analysis. It identifies more actionable targets in comparison to FM and simplifies GA into clinically-relevant user-friendly objective information, recommending personalized treatment strategy including CT thus unifying the physician to reach a consensus.
Cadherin Combinations Recruit Dendrites of Distinct Retinal Neurons to a Shared Interneuronal Scaffold
Authors: Xin Duan, Arjun Krishnaswamy, Mallory A. Laboulaye, Jinyue Liu, Yi-Rong Peng, Masahito Yamagata, Kenichi Toma, Joshua R. Sanes
Journal: Neuron (2018)

Distinct neuronal types connect in complex ways to generate functional neural circuits. The molecular diversity required to specify this connectivity could be supplied by multigene families of synaptic recognition molecules, but most studies to date have assessed just one or a few members at a time. Here, we analyze roles of cadherins (Cdhs) in formation of retinal circuits comprising eight neuronal types that inform the brain about motion in four directions. We show that at least 15 classical Cdhs are expressed by neurons in these circuits and at least 6 (Cdh6–10 and 18) act individually or in combinations to promote specific connectivity among the cells. They act in part by directing the processes of output neurons and excitatory interneurons to a cellular scaffold formed by inhibitory interneurons. Because Cdhs are expressed combinatorially by many central neurons, similar interactions could be involved in patterning circuits throughout the brain.
Ultrasound examination in monitoring chemotherapy for retroperitoneal tumors in children.
Authors: Natalia A. Maksimova, Oleg Ivanovich Kit, Yuliya Yu. Kozel, Maria G. Ilchenko
Journal: Journal of Clinical Oncology (2016)

e22007 Background: Nephroblastoma (N) is registered in 20% of children with solid tumors, neuroblastoma (NB) – in 14%. However, about 2/3 of children and adolescents come to initial treatment with locally advanced and generalized processes, i.e., in stage III-IV of disease. The purpose of the study was optimization of complex ultrasound (US) in monitoring the treatment of retroperitoneal neuroblastoma NB and N in children. Methods: 152 children aged 1-15 years with retroperitoneal tumors (NB, n = 86; N, n = 66) were examined at the primary hospital admission and in dynamics of polychemotherapy (PCT). Complex US was performed before each PCT course by our original technique using Philips IU22 ultrasound scanner with 2-5 MHz convex transducers in B-mode, color and power Doppler (CD, PD). The method sensitivity was assessed according to the standard methods. Results: Increase in the tumor size, progression of angioarchitectonics with an increase in the number of tumor vessels in the control volume in CD and PD, increase in the maximum arterial velocity of intratumoral hemodynamics by 20% and more compared to the initial values correlated with resistance to treatment and negative dynamics of the process. Stabilization or low sensitivity to the therapy was registered in unchanged tumor size and volume after treatment, stable indices of angioarchitectonics and intratumoral hemodynamics. Tumor sensitivity to the therapy and positive dynamics was registered in reduction of the tumor size and volume, hypovascularization, decreased parameters of arterial intratumoral hemodynamics by 20% and more or tumor devascularization. Conclusions: The method of US examination allows assessment of the treatment effectiveness in children with retroperitoneal tumors which contributes to choosing the further treatment tactics. The method sensitivity was 95%.
TCT-271 Drug Eluting Stents Compared With Bare Metal Stents in High Risk Patients Undergoing Percutaneous Coronary Interventions: A Meta-analysis
Authors: Saroj Neupane, Owais Khawaja, Sushruth Edla, Hemindermeet Singh, Hussein Othman, None eduardo bossone, Hiroshi Yamasaki, Thomas Lalonde, Howard Rosman, Holger Eggebrecht, Rajendra Mehta
Journal: Journal of the American College of Cardiology (2018)
Organisational barriers to and facilitators for female surgeons’ career progression: a systematic review
Authors: Megumi Hirayama, Senaka Fernando
Journal: Journal of the Royal Society of Medicine (2018)

Objective To identify organizational barriers to and facilitators for female surgeons' career progression. Design Systematic review of qualitative and quantitative studies relating to organizational barriers to and facilitators for female Surgeons' career progression. After the quality assessment of the peer-reviewed journal articles, twelve articles were selected for full review. Thematic analysis was used to identify key themes in these selected articles. Setting The studies solely focused on organizational factors linked to female physicians' career progression in surgical specialties. Partcipants Female surgeons. Main outcome measures Organizational barriers and facilitators Results Twelve peer-reviewed journal articles were included in the study which focused on barriers to female surgeons' career progression, ways of facilitating female surgeons' career progression, and female surgeons' job satisfaction. Conclusion The major organisational factors contributing to the lack of career progression for female surgeons are (1) organizational culture which promotes rigid career structure that is inclined to support male surgeons than female surgeons and also male domination in which male surgeons feel superior to female surgeons (2) work family conflict whereby women feel that they have to make a family sacrifice by being women; they experience the difficulty in securing a work-life balance in the masculine career structure in surgical specialties. This implies that policy makers and healthcare organizations need to pay significant attention to organizational facilitators for female surgeons' career progression such as flexible career pathways and work patterns, a variety of different viable career progressions, more family-friendly working conditions, and the promotion of female mentors and role models in surgical specialties to support female surgeons in dealing with the organizational barriers in the male-dominated organizational culture and the lifestyle issues as well.
Association of increased T cell infiltrates in the invasive margin with relapse-free survival in patients with cholangiocarcinoma (CCA).
Authors: Petra Prins, Noah Collins, Andrew Yang, Emily Lu, Hongkun Wang, Nadim G Haddad, John Marshall, Aiwu Ruth He
Journal: Journal of Clinical Oncology (2018)

e15001 Background: CCAs are often aggressive tumors of the bile duct system with a poor prognosis. Immune cells that infiltrate these tumors might have a prognostic value for patients who have had surgically resected CCAs. Methods: We took clinical outcome measures from 44 patients with surgically resected CCA and correlated them with the presence of total (CD3+) and cytotoxic (CD8+) T lymphocytes in the tumor interior (TI) and their invasive tumor margin (IM). The immune cell density was converted to a binary score (1, high; 0, low) and correlated with recurrence and relapse-free survival (RFS). In addition the expression of T-regulatory cells (Fox3P) was correlated with CD3+ and CD8+ density and recurrence, overall survival (OS) and RFS. Results: Our cohort consisted of 48% males and 52% females. Forty-eight percent of patients were Caucasian, 25% were African American, and the remainder were of other origin. Fifty percent of patients had intra-hepatic CCA, 18% had extra-hepatic CCA, and the remainder had CCA of mixed origin. Median OS for our cohort was 26 months (m) from diagnosis and 23m from surgery. The presence of a high density of CD8+ cells in the IM correlated with significantly improved OS (48m versus 18m; p = 0.013) as well as survival after surgery (48m versus 12m; p = 0.009). Median RFS was 11 months from date of surgery, and again the presence of a high density of CD8+ in the IM correlated with a significant survival benefit (19m versus 6m; p = 0.013). In addition we observed a trend toward better RFS for high density CD3+ in the IM, although significance was not reached (19m versus 7.5m; p = 0.094). High density of either CD3+ or CD8+ in the TI was nog significant for either OS or RFS. Expression of Fox3P was not significantly relevant for either OS or RFS. Conclusions: The presence of cytotoxic CD8+ T lymphocytes in the invasive margin predicts significantly increased survival and prolonged RFS. Immunoscore of tumor infiltrate in CCA’s can have a prognostic value for patients who have undergone primary tumor resection.
Type-specific data on human papillomavirus infection in squamous cell carcinomas of the head and neck across anatomic sites and world regions.
Authors: Liga Bennetts, Monika Wagner, Danielle Badgley, Glorian P. Yen, Edith Morais, Smita Kothari
Journal: Journal of Clinical Oncology (2018)

e18055 Background: Each year, > 550,000 cancers of the head and neck are diagnosed globally, resulting in around 300,000 deaths. About 90% of head and neck cancers are squamous cell carcinomas (HNSCC), of which a subset have HPV-related etiology. Human papillomavirus (HPV) detection in HNSCC varies across anatomic sites and geographically. As HPV-positive SCC have distinct clinical and pathological features, up-to-date information is needed to inform management and prevention options. Objectives: To assess global availability of recent type-specific data on HPV infection in HNSCC and report on type-specific HPV prevalence in HNSCC in the US. Methods: PubMed/Medline and EMBASE databases were systematically searched for full publications reporting type-specific HPV DNA detection in histologically-confirmed HNSCC (oral cavity, oropharynx, larynx, hypopharynx). Bibliographies were also searched. Original studies reporting on HPV 16 and 18 and ≥1 other high-risk type were included. Exclusion criteria were: publication before 2012, not English, special populations (e.g., HIV-infected only), N < 25. Key information, i.e., study type, country, population characteristics, sample type, HPV assay, HPV types detected, p16INK4a and E6/E7 mRNA positivity, was extracted. Results: 134 publications were included: 69 on oropharyngeal, 44 on oral cavity, 23 on laryngeal, 11 on hypopharyngeal SCC and 31 studies on pooled HNSCC sites. By region, 62 studies originated from Europe (42 of which were from Western/Southern Europe), 43 from Asia-Pacific, 17 from Northern America, 8 from Latin America and the Caribbean, 2 from Africa. Countries with the largest number of studies were the US (15 studies), Germany (11) and Italy (10). In the US (N = 3,875 cases), HPV was detected in 74.4% of oropharyngeal, 16.6% of oral cavity, and 16.6% of laryngeal SCC. HPV 16 was detected in 86% of HPV-positive HNSCC and was the dominant type across all subsites. Conclusions: Most evidence on HPV in HNSCC focuses on oropharyngeal SCC. Substantial data exists for Europe, particularly Western and Southern Europe. There is a scarcity of published HPV type-specific data for Africa and Latin America and the Caribbean.
Predictive factors of carcinoid syndrome among patients with gastrointestinal neuroendocrine tumors (GI NETs).
Authors: Beilei Cai, Michael Broder, Eunice Chang, Tingjian Yan, David C. Metz
Journal: Journal of Clinical Oncology (2017)

e15690 Background: Carcinoid syndrome (CS) is associated with a significant symptom burden and deleterious impacts on quality of life. Patients may experience delays in CS diagnosis of 5 to 7 years from initial onset of symptoms, as symptoms may be mistaken for other diseases, such as irritable bowel syndrome or menopause. The current study attempts to detect factors predictive of CS prior to CS diagnosis among patients with GI NETs. Methods: Using a US administrative claims database (IMS PharMetrics) and a retrospective case-control study design, patients (≥18 years) who were newly diagnosed with GI NETs without CS (controls) were exactly matched to patients with CS (cases) based on NET diagnosis date (month and year) at a 3-to-1 ratio. For CS patients, the study index date was the first CS diagnosis date. Each control patient was assigned to have the same index month and year as the matched case patient. The most frequently observed conditions other than symptoms/diagnoses known to be associated with CS during the 1 year prior to the index date were assessed. These conditions were entered into a forward-stepwise logistic regression model to derive predictive factors. Similar methods were applied to another administrative claims database (Truven Health Analytics MarketScan) to validate these predictors. Results: In the development database 1,004 patients with GI NETs were identified, among whom 251 (25%) had CS and 753 (75%) were controls. In both databases, three factors prior to CS diagnosis were found consistently associated with higher risks for CS, including liver disorder [odds ratio (95% CI): 3.38 (2.07 - 5.51)], enlargement of lymph nodes [2.13 (1.10 - 4.11)], and abdominal mass [3.79 (1.87 - 7.69)]. Conclusions: By assessing patients with GI NET from two independent US claim databases, this study suggested that patients diagnosed with CS were 2-3 times more likely to be diagnosed with liver disorder, enlargement of lymph nodes, or abdominal mass, than those without CS during the one year prior to CS diagnosis. Future studies using patients’ medical charts are warranted to validate and interpret the findings. These findings, when validated, may aid physicians to diagnose CS patients earlier.
Association of androgen receptor (AR) status in plasma DNA with outcome on enzalutamide (enza) or abiraterone (abi) for castration resistant prostate cancer (CRPC).
Authors: Vincenza Conteduca, Daniel Wetterskog, Mansour Taghavi Azar Sharabiani, Anuradha Jayaram, Samanta Salvi, Alessandro Romanel, Cristian Lolli, Valentina Casadio, Giorgia Gurioli, Dino Amadori, Delila Gasi Tandefelt, Anna Wingate, David P. Dearnaley, Francesca Demichelis, Ugo De Giorgi, Enrique González-Billalabeitia, Gerhardt Attard
Journal: Journal of Clinical Oncology (2017)

5060 Background: There is an urgent need to identify biomarkers to guide personalized therapy in CRPC. We aimed to clinically qualify the association of AR status in plasma DNA with worse outcome in pre- and post-docetaxel (doc) CRPC. Methods: We used droplet digital (dd)PCR to assess AR copy number (CN) and mutations (mut) (2105T &gt; A (p.L702H) and 2632A &gt; G (p.T878A) status in plasma DNA from 171 patients (pts) treated with abi/enza in biomarker protocols at 2 institutions. The aim to evaluate plasma AR was defined after sample collection but prior to analysis. Results: We first optimised multiplex ddPCR to accurately define AR status and identified an AR CN cutpoint = 2.01 as having the greatest likelihood to split pts into 2 prognostic groups. We confirmed a strong agreement between ddPCR and NGS for quantitating AR CN and mut allelic frequency (Bland-Altman test: mean difference -0.02 95%CI -2.45 to 2.41; mean difference -0.01 95%CI -0.015 to 0.016 respectively). AR CN gain was observed in 10 (14%) pre- and 33 (34%) postdoc pts and associated with a worse OS (HR 3.98 95%CI 1.74-9.10 p &lt; 0.001; HR 3.81 95%CI 2.28-6.37 p &lt; 0.001 respectively), PFS (HR 2.18 95%CI 1.08-4.39 p = 0.03; HR 1.95 95%CI 1.23-3.11 p = 0.01 respectively) and PSA decline ≥50% (OR 4.7 95%CI 1.17-19.17 p = 0.035; OR 5.0 95%CI 1.70-14.91 p = 0.003 respectively). AR mut were observed in 8 (11%) postdoc but no pre-doc abi-treated pts and also associated with worse OS (HR 3.26 95%CI 1.47-not reached p = 0.004). There was no interaction between AR and doc status (p = 0.83 for OS, p = 0.99 for PFS). Multivariate analysis, adjusting for AR CN and mut, previous doc, double stranded DNA concentration, LDH, confirmed AR status was independently associated with OS (HR 3.77 95%CI 2.42-5.88 p &lt; 0.001 and HR 2.76 95%CI 1.26-6.07 p = 0.011 for AR CN and mut respectively) and PFS (HR 1.96 95% CI 1.32-2.93 p = 0.001). Conclusions: Plasma AR status assessment using multiplex ddPCR identifies CRPC with worse outcome to enza/abi in pre/postdoc CRPC. Additional clinical qualification is available from the PREMIERE study (Grande et al;ASCO2017;Abstract#). Prospective evaluation of treatment decisions based on plasma AR is now required.
Hypercalcemia in malignancy: An inpatient analysis.
Authors: Divya Asti, Saqib Abbasi, Bindu Madhavi Mudduluru, Abhishek D Polavarapu, Avinash Boddapati, Gautam Valecha, Alisa Sokoloff
Journal: Journal of Clinical Oncology (2018)

e20517 Background: Hypercalcemia is a common electrolyte abnormality and is known to occur in 20-30% of patients with underlying malignancy. The presence of hypercalcemia in malignancy indicates a poor prognosis with increased mortality. We evaluated NIS data of patients who were admitted to the hospital with a primary diagnosis of hypercalcemia associated with malignancy, to look at inpatient trends to get a better understanding of the condition. Methods: National Inpatient Sample (NIS) for years 2002-2014 has been utilized to identify patients with a primary admission diagnosis of hypercalcemia (ICD-9-CM :275.42) in conjunction with a diagnosis of malignancy. Total number of patients were sub-categorized based on the type of underlying malignancy. The associated incidence and in-hospital outcomes were determined. Linear regression analysis assessed for annual trends in in-hospital mortality, length of stay (LOS), and total charges. A univariate logistic regression analysis was employed to calculate odds ratios (OR) for the effect on in-hospital mortality of the five most common associated cancers. Results: The most common malignancies associated with admissions for hypercalcemia of malignancy included breast cancer (16.51%), lung cancer (16.50%), multiple myeloma (12.39%), non-Hodgkin lymphoma (8.15%), renal cell cancer (6.53%). In-hospital mortality was higher in patients admitted with hypercalcemia associated with cancer (6%) compared to patients who did not have an underlying malignancy (2%) (p < 0.001). Among those with cancer, in-hospital mortality has decreased from 6% in 2002 to 3% in 2014. In comparing the five most commonly associated cancers, mortality was the highest among patients with a diagnosis of lung cancer (OR 2.45), and lowest among breast cancer (OR 0.98). Conclusions: Although, hypercalcemia of malignancy is associated with increased mortality this seems to be even higher in patients with lung cancer. Previous reviews indicate that treating hypercalcemia of malignancy did not improve mortality. However, based on the observed trends, it would be interesting if further studies could shed light if aggressive treatment of hypercalcemia would improve mortality.