tbuckley/cabot-search huggingface dataset:
Autophagy (A) inhibition to enhance combined immunotherapy (I) and anti-EGFR treatment (E) in colorectal cancer (CRC).
Authors: Michalis Karamouzis, Evangelos Koustas, Chrysovalantou Mihailidou, Dimitrios Schizas, Athanasios G. Papavassiliou
Journal: Journal of Clinical Oncology (2017)

e14554 Background: Resistance to E impairs survival of metastatic CRC (mCRC) patients. The aim of this study is to assess the preclinical activity of triple inhibition of E, I and A in CRC. Methods: RKO and Colo-205 cell lines were treated with E [cetuximab (C) / panitamumab (P)] and/or I [pembrolizumab (PE) or nivolumab (NI) with/without ipilimumab (IPI)] and/or autophagy inhibitor 3-Methyladenine (3-MA). Phosphorylated EGFR (pEGFR), p62 (SQSTM1), MAP1LC3 (LC3B) and PARP protein levels were detected by Western blotting. Cell viability was determined by MTT Assay. Tumor volumes were determined from 3D cell culture on Corning Matrigel Matrix as well as the apoptotic cell death. Results: E+I combination compared to E alone decreased pEGFR and increased A activation through p62 downregulation and LC3II activation. Similar results were shown for cell viability/apoptosis. Cells were also treated with C or P combined with I plus 3-MA. Triple inhibition suppresses EGFR and blocks A. Compared to E+I, triple inhibition reduced more cell growth/viability. Caspase-3 activity was increased as well as proportion of apoptotic cells (Table). Conclusions: Τhese results indicate that the combinatorial inhibition of A, E and I represents a promising treatment strategy in mCRC that needs further testing. [Table: see text]
Clinicopathologic and prognostic features of hepatocellular carcinoma (HCC) due to metabolic syndrome (MS) compared to chronic liver disease (CLD) and cryptogenic causes (CC).
Authors: Matthew L Chase, Nikroo Hashemi, Stephanie Reyes, Kathleen E Corey, Joseph Misdraji, Andrew X. Zhu, Lipika Goyal
Journal: Journal of Clinical Oncology (2016)

e15616 Background: Nonalcoholic fatty liver disease (NAFLD) and MS-associated HCC are increasing in frequency. We compared the presentations and outcomes of patients undergoing resection for HCC due to MS/NAFLD, CC, CLD. Methods: We queried a pathological database for adults who had hepatectomy for HCC from January 2004 - April 2015. Resections at outside institutions and metastatic resections were excluded. Charts were reviewed for etiology of liver disease including viral and autoimmune hepatitis alcohol abuse, cholestatic disease, hemochromatosis, and MS/NAFLD. Data included: metabolic risk factors (diabetes, hypertension, and obesity), viral serologies, AFP, and pathologic tumor characteristics. Patients were classified as MS/NAFLD if they had evidence of diabetes or ≥3 ATP III criteria, as CLD for all other causes of chronic liver disease, and as CC when no cause was identified. Results: 263 patients were identified: MS/NAFLD (n=64), CLD (n=150), and CC (n=49). Baseline demographic characteristics and AFP did not significantly differ by group. Patients were largely Child-Pugh class A (92%). At the time of surgery, individuals with MS/NAFLD had significantly higher MELD scores than those with CLD or CC (7.93 vs 5.82 vs 7.33, P=0.032). Tumor size at diagnosis varied by etiology of liver disease. Those with CC had the largest tumors (8.5 cm), followed by MS/NAFLD (7.36cm) and CLD (5.61, P<0.001). There was no significant difference in the MS/NAFLD, CLD, and CC groups in recurrence free survival (RFS) (15.2, 12.4, 6.4 months, P=0.57) or overall survival (OS) (27.9, 28.8, 15.73 months, P=0.44). OS were associated with MELD at time of surgery, vascular invasion, and resection margin.(Table 1). Conclusions: Despite higher MELD scores at the time of surgery, individuals with MS/NAFLD had similar RFS and OS following resection when compared to those with CLD and CC. HR CI p MS/NAFLD ref. CLD 0.90 0.45 - 1.78 0.76 CC 1.18 0.48 - 2.88 0.72 Tumor Size >5cm 1.10 0.64 - 1.87 0.74 Child Pugh Score 2.19 0.90 - 5.35 0.08 MELD 1.10 1.02 - 1.18 0.01* Histologic Grade 0.77 0.46 - 1.29 0.31 Vascular Invasion 2.29 1.27 - 4.12 0.01* Resection Margin 1.89 1.28 - 2.79 <0.01*
A phase II open-label single-arm study of vandetanib in patients with advanced RET-rearranged non-small cell lung cancer (NSCLC): Luret study.
Authors: Takashi Seto, Kiyotaka Yoh, Miyako Satouchi, Makoto Nishio, Noboru Yamamoto, Haruyasu Murakami, Naoyuki Nogami, Kaname Nosaki, Yoshiko Urata, Seiji Niho, Atsushi Horiike, Takashi Kohno, Shingo Matsumoto, Shogo Nomura, Sakiko Kuroda, Akihiro Sato, Yuichiro Ohe, Takeharu Yamanaka, Atsushi Ohtsu, Koichi Goto
Journal: Journal of Clinical Oncology (2016)

9012 Background: RET fusions were identified as new driver oncogenes of NSCLC in 2012 and observed in 1-2% of all NSCLC. Vandetanib is a multi-targeted tyrosine kinase inhibitor having RET kinase activity. Methods: This was a multicenter, single-arm phase II study to evaluate the efficacy and safety of vandetanib in pts with advanced RET-rearranged NSCLC who failed at least one prior chemotherapy. Vandetanib was administered orally at 300 mg once daily in 28-day cycles. RET fusion positive-pts were screened by a nationwide genomic screening network with 196 institutions in Japan participating (LC-SCRUM-Japan). The primary endpoint was objective response rate by independent review committee (ORR). This study required 17 pts, with ORR of 30% considered non-promising and 60% promising (one-sided alpha = 0.05; beta = 0.2). Results: 1536 pts with advanced NSCLC without EGFR mutation were screened in the LC-SCRUM-Japan from February 2013 to March 2015 and 34 pts (2%) with RET-rearranged NSCLC were identified. A total of 19 pts (10 KIF5B-RET, 6 CCDC6-RET, and 3 unknown-RET) were enrolled in this study and 17 pts were eligible for efficacy analysis. The median age was 59 (range 41-80 years) and 74% were female. All pts had adenocarcinoma and 68% were never a smoker. 63% of pts had received 2 or more prior chemotherapy (range 1-12). Among 17 eligible pts, ORR was 53% (90% CI, 31 to 74) of which 9 partial responses met the primary endpoint, and disease control rate was 88%. The median progression-free survival (PFS) was 4.7 months (95% CI, 2.8 to 8.3). According to RET fusion subtypes, ORR and median PFS were 83% (5/6) and 8.3 months in pts with CCDC6-RET versus 20% (2/10) and 2.9 months in those with KIF5B-RET. The median overall survival was 11.1 months (95% CI, 9.4 to not reached). The safety profile of vandetanib was similar to that reported previously. The most common G3/4 toxicities were hypertension (58%), rash (16%), diarrhea (11%), and QTc prolongation (11%). Conclusions: Vandetanib showed marked antitumor activity in pts with advanced RET-rearranged NSCLC. In particular, it was indicated that CCDC6-RET subtype showed much higher sensitivity to vandetanib. Clinical trial information: UMIN000010095.
Association Between Physician Burnout and Patient Safety, Professionalism, and Patient Satisfaction
Authors: Maria Panagioti, Keith Geraghty, Judith Johnson, Anli Zhou, Efharis Panagopoulou, Carolyn Chew-Graham, David Peters, Alexander Hodkinson, Ruth Riley, Aneez Esmail
Journal: JAMA Internal Medicine (2018)

Physician burnout has taken the form of an epidemic that may affect core domains of health care delivery, including patient safety, quality of care, and patient satisfaction. However, this evidence has not been systematically quantified.To examine whether physician burnout is associated with an increased risk of patient safety incidents, suboptimal care outcomes due to low professionalism, and lower patient satisfaction.MEDLINE, EMBASE, PsycInfo, and CINAHL databases were searched until October 22, 2017, using combinations of the key terms physicians, burnout, and patient care. Detailed standardized searches with no language restriction were undertaken. The reference lists of eligible studies and other relevant systematic reviews were hand-searched.Quantitative observational studies.Two independent reviewers were involved. The main meta-analysis was followed by subgroup and sensitivity analyses. All analyses were performed using random-effects models. Formal tests for heterogeneity (I2) and publication bias were performed.The core outcomes were the quantitative associations between burnout and patient safety, professionalism, and patient satisfaction reported as odds ratios (ORs) with their 95% CIs.Of the 5234 records identified, 47 studies on 42 473 physicians (25 059 [59.0%] men; median age, 38 years [range, 27-53 years]) were included in the meta-analysis. Physician burnout was associated with an increased risk of patient safety incidents (OR, 1.96; 95% CI, 1.59-2.40), poorer quality of care due to low professionalism (OR, 2.31; 95% CI, 1.87-2.85), and reduced patient satisfaction (OR, 2.28; 95% CI, 1.42-3.68). The heterogeneity was high and the study quality was low to moderate. The links between burnout and low professionalism were larger in residents and early-career (≤5 years post residency) physicians compared with middle- and late-career physicians (Cohen Q = 7.27; P = .003). The reporting method of patient safety incidents and professionalism (physician-reported vs system-recorded) significantly influenced the main results (Cohen Q = 8.14; P = .007).This meta-analysis provides evidence that physician burnout may jeopardize patient care; reversal of this risk has to be viewed as a fundamental health care policy goal across the globe. Health care organizations are encouraged to invest in efforts to improve physician wellness, particularly for early-career physicians. The methods of recording patient care quality and safety outcomes require improvements to concisely capture the outcome of burnout on the performance of health care organizations.
TCT-819 Patent Foramen Ovale Closure versus Medical Therapy after Cryptogenic Stroke-A Systematic Review and Meta- Analysis
Authors: Safi Khan, Irbaz Bin Riaz, Adeel Arshad, Muhammad Husnain, Anum Riaz, Sandipan Bhattacharjee, Edo Kaluski, Aneel Ashrani
Journal: Journal of the American College of Cardiology (2018)
TCT-244 Percutaneous suture-mediated patent foramen ovale (PFO) closure with the NobleStitch EL system: center experience effect
Authors: None Achille Gaspardone, Antonella De Santis, Fabiana Piccioni, Maria Iamele, Emanuela D'Ascoli, Gaetano Gioffrè, Fabrizio D'Errico, Anthony Nobles, Francesco Summaria, Gregory Sgueglia
Journal: Journal of the American College of Cardiology (2018)
Ambiguity in End-of-Life Care Terminology—What Do We Mean by “Comfort Care?”
Authors: Anne M. Kelemen, Hunter Groninger
Journal: JAMA Internal Medicine (2018)

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P01.003 Botulinum toxin therapy to improve Tumor Treating Field (TTF) compliance: A case report
Authors: G H J Stevens, J Bucklan, A Vidimos, D M Peereboom
Journal: Neuro-Oncology (2018)

Glioblastoma therapy traditionally consists of maximal surgical debulking and radiation therapy with concomitant chemotherapy. Adjunctive therapy with TTF earned FDA approval in 2015. Transducer arrays are placed on a shaved scalp and emit low intensity (1–2 V/cm), intermediate frequency (200 Hz) wavelengths which interfere with mitotic microtubular assembly in rapidly dividing cancer cells, leading to apoptosis. The TTF must be worn for at least 18 hours/day for optimal results. However, use of this device is associated with local skin irritation. 57 year-old left-handed woman presented with left facial numbness and droop, slurred speech, and left hand numbness persisting over one day. Brain MRI demonstrated two ring-enhancing lesions in the right motor strip. The patient underwent a frontal craniotomy near-total resection. Pathology was consistent with glioblastoma (MGMT methylated, IDH1 negative). She underwent radiotherapy (6000 cGy in 30 fx) with concurrent temozolomide followed by 6 cycles of post-radiation chemotherapy. Two months later, she elected to pursue TTF. She developed progressive contact dermatitis/hyperhidrosis of the scalp at the sites of transducer array application. The hyperhidrosis interfered with the contact of the arrays to the scalp and became intolerable. Eleven months into TTF therapy, she began subcutaneous botulinum toxin injections of the scalp and forehead every 3–4 months. Her hyperhidrosis and tolerance of TTF improved significantly. She remains on TTF 22 months after beginning treatment. TTF is a novel therapy that may prolong progression-free and overall survival in glioblastoma when used as an adjunct to surgery, radiotherapy, and chemotherapy. However, tolerability may be limited by localized skin toxicity. Botulinum toxin therapy at TTF application site can improve patient comfort and quality of life.
A retrospective review of complication rates of Ommaya reservoir placement for intrathecal medication administration.
Authors: Raphael Bosse, Bently Doonan, Azka Ali, Jacob Barish, Preeti Narayan, Samantha Welniak, Grant Jester, Jess Delaune, Coy D. Heldermon
Journal: Journal of Clinical Oncology (2018)

e18532 Background: Intraventricular devices such as Ommaya reservoirs play a central role in the management of neuro-oncologic diseases. These devices are implanted under the scalp and are used to rapidly administer therapeutic agents into the cerebral ventricles. Despite their routine use, the placement of these devices can be associated with significant morbidity and mortality. In this study we aimed to recognize the different rates of complications from a large single institution database. Methods: We conducted a retrospective analysis of 936 patients who underwent insertion of a vascular device at the University of Florida between 1/2011 and 12/2016. Of those, 22 had placement of an Ommaya reservoir. Clinical data was obtained through a detailed review of electronic medical records, examining complications during the procedure and at several 6-month intervals during the post-operative period. Patients were grouped according to each interval. All data was stored in a HIPAA compliant online database and all collection protocols underwent approval by the local IRB. Results: The patients' age ranged at time of placement from 0 to 78. Out of 22 patients, 13 devices were placed for intrathecal chemotherapy and 11 for hydrocephalus. No patients died as a direct complication of placement. Two patients (9.1%) had a catheter obstruction complication during Ommaya placement. From discharge to 6 months post-op, 1 patient out of 16 (6.3%) had a catheter obstruction, and 4 (25%) had a catheter-related infection. From 6 months to 1 year post-op, 1 patient out of 13 (7.7%) had a catheter obstruction. After 1 year post-op, 1 patient out of 11 (9.1%) had a catheter obstruction and 1 (9.1%) had a ventricular hemorrhage. Conclusions: This study identified catheter-related infection and catheter migration as the most common complications of Ommaya reservoir placement during the post-operative period. Catheter obstruction was the most common complication during the surgical placement. Surgeons and clinicians should take these factors into account when caring for this patient population. Additional studies should be conducted to further analyze these factors and the possible benefits of prophylactic therapy.
Does aggressive treatment in pediatric melanoma improve survival? A comparison of melanoma treatment and prognosis by age.
Authors: Alicia Gingrich, Sarah Bateni, Richard J. Bold, Sepideh Gholami, Robert J. Canter, Amanda Kirane
Journal: Journal of Clinical Oncology (2018)

e21563 Background: As pediatric melanoma is rare, treatment strategies are largely influenced by adult guidelines despite known clinicopathologic and prognostic differences between pediatric and adult patients. We sought to evaluate the application of adult treatment algorithms to the very young melanoma patient and compare the impact of clinicopathologic differences on overall survival (OS) for pediatric and adult melanoma patients. Methods: We performed a retrospective analysis of 377,927 melanoma patients from the National Cancer Database from 2004-2015. Patients were categorized into four age groups (1-25, 26-40, 41-64 & ≥65 years old). Standard parametric, non-parametric, log-rank and cox regression analyses were performed to compare clinicopathologic characteristics, treatment, & OS. Due to the treatment implications for positive lymph node disease, subset analyses were performed on patients with stage III disease. Results: In this cohort, 3% (n = 9804) of patients were 1-25, 11% (n = 42,817) were 26-40, 47% (n = 176,472) were 41-64, and 39% (n = 148,768) were ≥65 years old. Children had higher rates of regional node evaluation (55% vs. 48%, 45% & 37%, p < 0.01) and node positive disease (27% vs. 24%, 22% & 10%, p < 0.01). Most patients ≤40 were female (63%), while most patients > 40 were male (58%) with female patients demonstrating better OS (p < 0.001). Pediatric patients had greater OS compared to stage-matched adults (p < 0.01). Among stage III disease, regional node dissection, immunotherapy, and chemotherapy were more common among younger cohorts, while radiation therapy was more common among the elderly (p < 0.05 all). However, among pediatric patients, immunotherapy was only associated with improved survival in stage IIIC disease (p = 0.01), while lymph node dissection, radiotherapy and chemotherapy were not associated with greater survival. Conclusions: Although nodal dissections, immunotherapy and chemotherapy were common in pediatric melanoma patients, except for immunotherapy in stage IIIC disease, these aggressive treatment approaches were not associated with improved overall survival, suggesting the need for more tailored treatment approaches for pediatric melanoma.
Transparency around disapproval reasons of early-phase trial proposals submitted to the National Cancer Institute (NCI).
Authors: Holly A. Massett, Amy Gravell, Brittany Waters, Grace Mishkin, Andrea Denicoff, S. Percy Ivy, Jeffrey Moscow, James A. Zwiebel, Michael Montello, Jeffrey S. Abrams
Journal: Journal of Clinical Oncology (2017)

6585 Background: NCI’s ETCTN accepts Letters of Intent (LOI) for a new clinical trial either from a response to a solicitation for studies, or via unsolicited LOIs, where investigators independently propose novel studies. While the LOI approval rate for the first two years of the ETCTN was 100% for solicited LOI’s, it was only 36% for unsolicited LOIs. Therefore, we analyzed all ETCTN LOI disapproval letters (DL) for unsolicited LOIs to identify the major reasons for disapproval. Methods: A content analysis was conducted on DLs issued between March 2014 and March 2016 (N = 50). Two coders independently scored disapproval reasons per letter using a code sheet with 22 categories identified from a sample of DLs (Intercoder Reliability = 97%). Results: All DLs were issued for unsolicited LOIs (44% = Ph 1; 26% = Ph 1/2; 30% = Ph 2); 271 reasons were identified across the 50 DLs (mean = 5.4/DL). High-level categories included concerns with study design, scientific rationale, feasibility, modality and administrative reasons. The top disapproval reasons were: Insufficient preclinical animal model data (54% of DLs); weak rationale/background (52%); inadequate information for biomarker correlative studies (46%); dose/scheduling plan absent or weak (36%); clinical data not adequately advanced (34%); and, patient population not described/inconsistent with treatment (34%). Top reasons for Phase 1 and 1/2 LOIs resembled the total but Phase 2 LOIs deviated slightly, with ‘weak objective/endpoint’ and ‘biomarker correlative studies’ as top DL reasons. Other common reasons were problems with combination study agents, company/drug collaboration, and competing trials. Conclusions: The reasons for LOI disapproval can be categorized and quantified. To increase transparency in the NCI ETCTN LOI review process, disapproval reasons for each DL are now collected on a standardized coding sheet, and will be reported quarterly to ETCTN PIs. NCI will also meet with all Grant PIs in Spring, 2017 to jointly discuss concerns and explore quality improvement solutions regarding the LOI submission process. The outcome of this meeting will be reported at ASCO as part of our findings.
Results of a phase II randomized controlled clinical trial comparing efficacy of cabazitaxel versus docetaxel as second-line or above therapy in recurrent head and neck cancer.
Authors: Amit Joshi, Vijay Maruti Patil, Vanita Noronha, Sachin Dhumal, Arun Chandrasekharan, Nikhil Pande, Chandrakanth MV, Vikas Talreja, Dilip Vallathol, Sujay Srinivas, Raajit Chanana, Kushal Gupta, Sangeetha Parthiban, Kumar Prabhash
Journal: Journal of Clinical Oncology (2017)

6018 Background: Cabazitaxel has shown activity in squamous cancer cell lines and in taxane resistant cell lines. Hence we planned a randomized phase 2 study to evaluate the efficacy and safety of cabazitaxel against docetaxel in recurrent head and neck cancer, post first line treatment. Methods: This was a phase 2 open label, investigator initiated, randomized controlled trial of Docetaxel (75 mg/m2) versus Cabazitaxel (20 mg/m2), in adult patients with head and neck cancer, ECOG performance status 0-2, with measurable disease, who have been exposed to at least one line of chemotherapy (CTRI/2015/06/005848). 1:1 central randomization was performed and chemotherapy was administered till progressive disease or until patient had intolerable side effects. The sample size of 92 (46 per group) was determined based on an assumption for a difference in disease control rate of 25%, an alpha of 0.05 and 80% power. The data was censored for analysis on 3rd March 2017. Primary analysis of disease control at 6 weeks (CR/PR/SD) was assessed and compared using the chi-square test. Progression free survival (PFS) and overall survival (OS) curves were estimated using the Kaplan-Meier method. Cox proportional hazard model was used for comparison of PFS and OS between the 2 arms. Results: 92 patients were accrued in the study with 46 in each arm. The disease control rate at 6 weeks was better in the docetaxel arm which was statistically significant over the cabazitaxel arm (13.6% versus 52.3%, p = 0.017). The median PFS was 21 days (95% CI 5.28-36.72 days) in the cabazitaxel arm versus 61 days (95% CI 16.21 to 105.79 days) in the docetaxel arm (HR = 1.466, 95% CI 0.923-2.328, p = 0.105). The median OS was 172 days (95% CI 111.78 to 232.22 days) in the cabazitaxel arm versus 188 days (95% CI 134.4 to 241.6 days) in the docetaxel arm (HR-1.408, 95% CI 0.738-2.688, p = 0.299). Conclusion: In this phase 2 study, docetaxel had a superior disease control rate at 6 weeks and PFS compared to cabazitaxel. Clinical trial information: CTRI/2015/06/005848.