tbuckley/cabot-search huggingface dataset:
Physician burnout costs US $4.6bn a year, study finds
Authors: Owen Dyer
Journal: BMJ (2019)

Healthcare organisations that don’t invest in prevention strategies to reduce physician burnout are making false economies, a study has found. 

The study, published in the Annals of Internal Medicine, estimated that the annual cost of physician turnover and reduced working hours caused by burnout was $4.6bn (£3.6bn; €4.1bn) (95% confidence interval $2.6bn to $6.3bn).1 In a country where more than half of physicians report at least one symptom of burnout, that represents about $7600 per working physician per year.

The incidence of suicide among US physicians is greater than among US combat veterans, noted Edward Ellison of the …
Therapeutic targeting of polyamines in malignant pleural mesothelioma xenograft models.
Authors: James C. M. Ho, Sheng Yan, Sze Kwan Lam
Journal: Journal of Clinical Oncology (2019)

e20060 Background: Although the use of asbestos has been restricted, the incidence of malignant pleural mesothelioma (MPM) is still rising. The US FDA approved a combination of pemetrexed with cisplatin for treatment of unresectable MPM. And development of novel adjuvant therapeutic options for resected early-stage disease is also urgently needed. From our preliminary data, ornithine decarboxylase (ODC) is highly expressed in MPM xenografts and clinical tumor samples. Upregulation of ODC increases polyamines production and enhances tumor growth. a-difluoromethylornithine (DFMO) is a specific ODC inhibitor. This study aims to disclose the adjuvant (minimal residual disease setting) and therapeutic (metastatic setting) effects of DFMO in MPM xenografts. Methods: In adjuvant therapy setting, nude mice were fed with DFMO in drinking water 7 days before subcutaneous inoculation of 200,000 tumor cells. In therapeutic setting, 10 7 corresponding cells were injected subcutaneously into nude mice which were randomized for treatment after established tumor growth. Mice with tumor size &gt; 600mm 3 were considered reaching humane endpoint. Spermidine levels, protein expression, cytokines concentration, and apoptosis were investigated by Dot plot, Western blot, ELISA, and TUNEL assay respectively. Results: In adjuvant therapy setting, DFMO suppressed tumor growth and increased median survival in both 211H and H226 xenografts. In H226 xenografts, 43% of treated mice have not yet reached humane endpoint, mimicking long-term survival. Upon DFMO treatment, decrease in spermidine level, increase in nitrotyrosine content, and activation of apoptosis were observed in both xenografts. In addition, increase in nitrosocysteine level, intratumoral IL-6, keratinocyte chemoattractant and TNFα, DNA lesions and inhibition of Akt/mTOR pathway were induced by DFMO in H226 xenografts, which may explain higher potency of DFMO in these xenografts. In therapeutic setting, DFMO also suppressed tumor growth in both xenografts with similar mechanisms. Conclusions: DFMO may have a potential role as adjuvant therapy in MPM especially epithelioid mesothelioma.
Ultrasound-guided dual-localization for axillary nodes before and after neoadjuvant chemotherapy with clip and activated charcoal in breast cancer patients: A feasibility study.
Authors: Yee Soo Chae, Soo Jung Lee, In Hee Lee, Jin Hyang Jung, Ho Yong Park, Jeeyeon Lee, Won Hwa Kim, Hye Jung Kim
Journal: Journal of Clinical Oncology (2019)

e12067 Background: We report on our experience of ultrasound (US)-guided dual-localization for axillary nodes before and after neoadjuvant chemotherapy (NAC) with clip and activated charcoal to guide axillary surgery in breast cancer patients. Methods: Between November 2017 and May 2018, a dual-localization procedure was performed under US guidance for the most suspicious axillary nodes noted at initial staging (before NAC, with clip) and restaging (after NAC, with activated charcoal) in 28 cytologically proven node-positive breast cancer patients. Patients underwent axillary sampling or dissection, which involved removing not only the sentinel nodes (SNs), but also clipped nodes (CNs) and tattooed nodes (TNs). Success (or failure) rates of biopsies of SNs, CNs, and TNs and inter-nodal concordance rates were determined. Sensitivities for the individual and combined biopsies were calculated. Results: SN biopsy failed in four patients (14%), whereas the CN biopsy failed in one patient (4%). All TNs were identified in the surgical field. Concordance rates were 79% for CNs–TNs, 63% for CNs–SNs, and 58% for TNs–SNs. Sensitivity for SN, CN, and TN biopsy was 73%, 67%, and 67%, respectively. Sensitivity was 80% for any combination of biopsies (SN plus CN, SN plus TN, SN plus CN plus TN). Conclusions: US-guided dual-localization of axillary nodes before and after NAC with clip and activated charcoal was a feasible approach that might facilitate more reliable nodal staging with less-invasive strategies in node-positive breast cancer patients.
Protocol-specified final analysis of the phase 3 KEYNOTE-048 trial of pembrolizumab (pembro) as first-line therapy for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC).
Authors: Danny Rischin, Kevin J. Harrington, Richard Greil, Denis Soulieres, Makoto Tahara, Gilberto de Castro, Amanda Psyrri, Neus Baste, Prakash C. Neupane, Ase Bratland, Thorsten Fuereder, Brett Gordon Maxwell Hughes, Ricard Mesia, Nuttapong Ngamphaiboon, Tamara Rordorf, Wan Zamaniah Wan Ishak, Yayan Zhang, Fan Jin, Burak Gumuscu, Barbara Burtness
Journal: Journal of Clinical Oncology (2019)

6000 Background: KEYNOTE-048 is a phase 3 study of P or P + chemo (C) vs EXTREME (E) as 1L therapy for R/M HNSCC (NCT02358031). At the second interim analysis (IA2), P significantly improved OS in the PD-L1 combined positive score (CPS) ≥20 and ≥1 populations and had noninferior OS in the total population with favorable safety; P+C significantly improved OS in the total population with comparable safety. We present the protocol-specified final results. Methods: 882 pts with locally incurable R/M HNSCC and no prior systemic therapy in the R/M setting who provided a tumor sample for PD-L1 testing were randomized to P 200 mg Q3W for 24 mo (n = 301), P for 24 mo + 6 cycles of C (cisplatin 100 mg/m 2 or carboplatin AUC 5 Q3W + 5-FU 1000 mg/m 2 /d for 4 d Q3W) (n = 281), or E (cetuximab 400 mg/m 2 loading/250 mg/m 2 QW + 6 cycles of chemo) (n = 300). OS superiority was tested sequentially for P+C vs E in the CPS ≥20 population, then the CPS ≥1 population, and for P vs E in the total population (superiority thresholds: one-sided P = .0023, .0026, and .0059, respectively). Data cutoff was 25 Feb 2019 (~25 mo after last pt randomized). Results: P+C significantly improved OS vs E in the CPS ≥20 (HR 0.60, 95% CI 0.45-0.82, P = .0004; median 14.7 vs 11.0 mo) and CPS ≥1 (HR 0.65, 95% CI 0.53-0.80, P &lt; .0001; median 13.6 vs 10.4 mo) populations. HR (95% CI) for PFS was 0.76 (0.58-1.01) for CPS ≥20 and 0.84 (0.69-1.02) for CPS ≥1. ORR (P+C vs E) was 42.9% vs 38.2% for CPS ≥20 and 36.4% vs 35.7% for CPS ≥1; median DOR was 7.1 vs 4.2 mo and 6.7 vs 4.3 mo, respectively. P did not significantly improve OS vs E in the total population (HR 0.83, 95% CI 0.70-0.99, P = .0199; median 11.5 vs 10.7 mo). HR (95% CI) for PFS was 1.29 (1.09-1.53). ORR (P vs E) was 16.9% vs 36.0%; median DOR was 22.6 vs 4.5 mo. All-cause gr 3-5 AE rates were 54.7% for P, 85.1% for P+C, and 83.3% for E. Conclusion: Overall, KEYNOTE-048 showed that compared with E, P+C had superior OS in the PD-L1 CPS ≥20, CPS ≥1, and total populations with comparable safety and P had superior OS in the CPS ≥20 and ≥1 populations, noninferior OS in the total population, and favorable safety. These results support pembrolizumab and pembrolizumab + platinum + 5-FU as new 1L standards of care for R/M HNSCC. Clinical trial information: NCT02358031.
Cctg MA.39 tailor RT: A randomized trial of regional radiotherapy in biomarker low-risk node-positive breast cancer (NCT03488693).
Authors: Wendy R. Parulekar, Tanya Berrang, Iwa Kong, Eileen Rakovitch, Valerie Theberge, Karen A. Gelmon, Stephen K. L. Chia, Jennifer Ruth Bellon, Reshma Jagsi, Alice Y. Ho, Julia R. White, Richard C. Zellars, Anita Bane, Jean-Francois Boileau, Julie Lemieux, Alexander Montenegro, Bingshu E. Chen, Timothy Joseph Whelan
Journal: Journal of Clinical Oncology (2019)

TPS602 Background: Biomarker low risk, ER positive (+), HER2 negative (-) breast cancer with low burden nodal involvement may be associated with good outcomes (Woodward 2016, Mamounas 2017). There is conflicting data regarding the efficacy of regional radiotherapy after breast conserving surgery (BCS) or mastectomy in these patients (Kyndi 2008, Whelan 2015, Poortmans 2015, Liu 2015). Our hypothesis is that the risk of recurrence in patients with biomarker low risk, ER+, Her2- breast cancer and involvement of 1-3 lymph nodes where regional RT is omitted will not be inferior to the risk of recurrence in patients treated with regional RT. Methods: MA39 is a Canadian Cancer Trials Group led, NCTN sponsored, randomized phase III study comparing breast cancer recurrence free interval (BCRFI) in patients with ER+, Her2-, LN 1-3+ breast cancer that is low risk as defined by Oncotype Dx Recurrence Score &lt; 18. Secondary objectives include a comparison of DFS, breast cancer mortality, OS, locoregional and distant recurrence free intervals, toxicity, arm volume and mobility measurements, patient reported outcomes and cost effectiveness. Key eligibility criteria include: age ≥ 40 years; BCS or mastectomy with axillary dissection and 1-3 positive axillary nodes; BCS and SLNB alone and 1-2 positive axillary nodes; mastectomy and SLNB alone and only 1 positive axillary node; planned endocrine therapy ≥ 5 years; adjuvant chemotherapy allowed. Statistical design: The primary analysis will be a test of non-inferiority (NI) in the intention to treat population. If the upper bound of a one-sided 95% interval for the hazard ratio for BCRFI is &lt; 1.4, NI will be declared. Using a one-sided α of 0.05 and a power of 87%, it is anticipated that 278 events are required. With an expected 5 years of accrual and 4.5 years of follow-up, 2140 patients are needed for the final sample size. Conduct to Date: Study activation May 30 2018. Participation as of February 2019: Registrations 64 Randomizations 26. CIRB approval for continuation of MA.39 was received on January 11 2019. Clinical trial information: NCT03488693.
Use of the Child-Pugh score in anticancer drug dosing decision making: proceed with caution – Authors' reply
Authors: Stefanie D Krens, Gerben Lassche, Frank G A Jansman, Ingrid M E Desar, Nienke A G Lankheet, David M Burger, Carla M L van Herpen, Nielka P van Erp
Journal: The Lancet Oncology (2019)
Prevalence of immunotherapy-related adverse events due to checkpoint inhibitors: First report in Mexico.
Authors: Elina Alexandra Rodriguez Melendez, J. Fabian Martinez Herrera, Guillermo Olivares, Alberto Villalobos, Juan Alberto Serrano, Fernando Perez-Zincer, Alvaro Aguayo, Samuel Rivera Rivera, Jesus Miguel Lazaro Leon, Ivonne Salcedo, Gabriela Olivia Regalado Porras, Jorge Alatorre Alexander, Christian Patricio Camacho Limas, Victoria Imaz, Raquel Gerson
Journal: Journal of Clinical Oncology (2019)

e14090 Background: Since 2010, immune checkpoint inhibitors (ICI) have been approved for the treatment of several neoplasms. Their immune-mediated toxicity profile, used as monotherapy (nivolumab [N], Ipilimumab [Ip], pembrolizumab [P]) or in combination (Nivolumab/Ipilimumab [N/Ip]) and their management is still being described, recently. Methods: A retrospective review of medical records, included all cancer patients treated, in our institution, with ICI from January 2014 to February 2018. Frequency, type and grade of immune related adverse events (irAE) by neoplasm, individual agent or combination were recorded. Time to first ir-AE (TTF-irAE) was estimated by Kaplan Meir Method and compared by Cox regression model. Results: 140 patients were evaluated, all in pretreated metastatic setting. Median age 65.8+/-11.8, men in 59.3%. The most frequent neoplasms treated with ICI were: lung (34%), melanoma (33%), genitourinary (17%), H&amp;NC (6%), and GI (6%). Ip alone was indicated in 11.4% cases; N, 30%; P, 54.29%; N/Ip 4.29%. Median number of cycles per drug: Ip: 3 cycles, N/Ip: 4; N: 6; and P: 4 cycles. Toxicity (G1-4) was seen in Ip: 62.5%, N/Ip: 50%, N: 40.5%, P: 31.6%, p &gt; 0.05. The most frequent irAE's were: dermatological 40%, gastrointestinal 18.3%, and endocrine 13.4%; other irAE´s were reported in: pulmonary 7.3%, ophthalmologic 6%, muscle-skeletal 6%, neurologic 2.4%, renal 1.2%, hematologic 1.2%. Severe toxicities (G3-4) were observed with N/Ip: 33.3%, P: 17.4%, Ip: 10%, N: 5.6%. TTF-ir-AE per drug: I: 1 st cycle (dermatitis, pruritus, colitis), N/Ip: 2 nd cycle (dermatitis, conjunctivitis), N: 3 rd cycle (dermatitis, thyroiditis, colitis, hepatitis), P: 1 st cycle (pruritus, neuritis, adrenalitis). Ipilimumab was an independent prognostic factor for developing severe ir-AE´s [OR = 12.8, p = 0.038], and any grade toxicity [OR = 1.9 (IC95% 0.92 - 4.1, p = 0.079)]. Conclusions: In this study, the dermatological, gastrointestinal and endocrine toxicities were the most frequent ir-AE´s, and they were observed in a low grade toxicity. The irAE´s profile is different among ICI or their combination and number of cycles administered. Ipilimumab alone or combined was associated to higher risk of severe irAEs.
Phase I/II study of oxaliplatin dose escalation via a laparoscopic approach using pressurized aerosol intraperitoneal chemotherapy (PIPOX trial) for nonresectable peritoneal metastases of digestive cancers (stomach, small bowel and colorectal).
Authors: Frederic Dumont, Michele Boisdron-Celle, Sandrine Hiret, Helene Senellart, Judith Raimbourg, Loic Campion, Francois J. L. Pein, Naoual Bakrin, Jean-Luc Raoul, Olivier Glehen, Emilie Thibaudeau
Journal: Journal of Clinical Oncology (2019)

e15027 Background: The pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new route of intraperironeal drug administration that enhances the absorption of oxaliplatin. The objectives were to determine the MTD and PK of Oxaliplatin administred via the PIPAC technic. Methods: This was a phase I two center study with standard 3 x 3 design for pts with extended peritoneal carcinomatosis from gastrointestinal cancer (gastric PCI&gt;4, small bowell PCI&gt;13, colorectal PCI&gt;15), ECOG PS≤1 and no organ dysfunction. The primary endpoint are dose determining dose limiting toxicity (DLT), maximum tolerable dose (MTD), recommandation dose for the phase 2 (RD2P) and PK of oxaliplatin. The dose escalation was in 50 mg/m 2 steps up to a maximum of 300 mg/m² and starting with 90 mg/m². Pts were monitored for DLT from the first PIPAC up to 4-6 weeks after the second PIPAC. Each patient who experiences good tolerance will be invited to receive two to five PIPAC procedures at 4–6 week intervals. A systemic chemotherapy was allowed between the PIPAC session. Adverse event (AEs) were defined according NCI-CTCAE toxicity scale version 4. Results: To date, 10 patients received 31 PIPACs procedures and were treated in 2 differents dl. Two DLTs (grade 4 allergic reaction and grade 3 neutropenia) occurred at second level dose of 140 mg/m 2 and no one at 90mg 2 . Frequent treatment related AE (TRAE) grade ≤ 2 during PIPACs sessions were nausea (9/31), abdominal pain (8/31) and fatigue (7/31). Nine patients were evaluable for response after at least 2 PIPACs. The histologic peritoneal regression grading score (PRGS) were 4 (no response), 3 (minor response), 2 (major response), and 1 (complete response) in respectively 0, 5, 2 and 2 pts. Pts with PRGS 1 underwent complete cytoreductive surgery and HIPEC. In this ongoing study, the PK profile is currently investigated. Conclusions: The RP2D of oxaliplatin during PIPAC was 90mg/m 2 with correct tolerance and some patient have experienced of major histological response allowing a secondary complete resection. The study was opened for phase II enrollement. Clinical trials informations: NCT03294252 .
Dynamic assessment of circulating tumor DNA in prediction of response to nab-paclitaxel-based first-line chemotherapy in metastatic pancreatic cancer.
Authors: Yan Shi, Shasha Guan, Quanli Han, Jie Li, Yao Lv, Huan Yan, Guanghai Dai
Journal: Journal of Clinical Oncology (2019)

e15769 Background: Emerging evidence showed circulating tumor DNA (ctDNA) may be used as biomarker for monitoring tumor response to chemotherapy in pancreatic cancer. This pilot study was to evaluate the clinical application of dynamic assessment ctDNA in MPC. Methods: From December 2016 to June 2018 in our center, 29 MPC patients treated with nab-paclitaxel based first-line chemotherapy (NS or N plus Gemcitabine, NG) had at least 2 ctDNA tests were included for analysis. Plasma samples were prospectively collected at baseline and periodical follow-ups until progression, death, or withdrawal of consent. Next-generation sequencing for a panel of 425 genes covering a wide range of cancer-related loci was performed to profile ctDNA. Progression of ctDNA was defined as increased mutation allelic frequency (MAF) of common mutant gene from baseline or nadir, or the presence of new gene alternations. The clinical relevance of the common alteration, and its dynamic changes in ctDNA were analyzed, and compared to conventional imaging response and survival. Results: In our patient cohort, the best overall response of partial response (PR) was 48.3% (14/29). By February 2019, 18 patients passed away with median follow-up of 9.7 months. At baseline, 22 patients (75.9%, N = 29) had at least one common driver gene alterations ( KRAS, TP53, CDKN2A, SMAD4) detected in ctDNA. Mutant KRAS and TP53 were identified in 72.4% and 62.1% patients with a median MAF of 5.8% and 4.7%, respectively. Of 14 patients achieved PR on image, MAF of the mutant driver genes found declined significantly or mutant gene disappeared. At the time of clinical progressive disease (PD), 24 patients had evaluable image and ctDNA results whereas both demonstrated PD in 23 (95.8%), including 9 found earlier progression of ctDNA with median time of 1.93 months compared to image findings. Among 22 patients with any of the above 4 mutant driver genes in ctDNA at baseline, 13 patients demonstrated significant reduction of MAF (reduction to &lt; 1% or undetectable) within 6 weeks, who had a longer progression free survival (PFS, reduction 6.6m vs no reduction 3.4m, P = 0.001) and overall survival (OS, reduction 12.6m vs no reduction 5.4m, P = 0.001), compared to those who had an increased or stable MAF. Conclusions: Our initial findings demonstrated the changes in MAF of 4 common driver genes in ctDNA was well correlated with treatment response to chemotherapy, PFS and OS in MPC. Peripheral ctDNA was a potential reliable alternative biomarker for efficacy and progression prediction in MPC.
Real-world treatment outcome of advanced Chinese NSCLC EGFR exon 20 insertion patients.
Authors: Yan Wang, Guangjian Yang, Jun Li, Haiyan Xu, Lu Yang, Fei Xu, Yaning Yang, Bing Xia, Viola Weijia Zhu, Weini Qiu, Sai-Hong Ignatius Ou
Journal: Journal of Clinical Oncology (2019)

9043 Background: Treatment outcome of advanced EGFR exon20 insertion (ex20ins) patients with 1 st - or 2 nd -line chemotherapy and EGFR TKIs remains limited. Methods: Retrospective real-world analysis of clinical, molecular, and treatment outcome of a web-based patient registry and hospital chart review. Results: Between 9/13/18-10/22/18, 165 EGFR ex20ins NSCLC patients treated in 99 hospitals from 26 different regions in China were registered. Data cutoff was 12/20/18. EGFR ex20ins were determined by commercial NGS (84%) or PCR (16%). 41 different molecular subtypes of EGFR ex20ins were identified. Ala767_Val769dupASV was the most common (23.0%) followed by Ser768_Asp770dupSVD (17.6%). 61% were females, 77% never-smokers, and CNS mets occurred in 22.4% of patients at time of diagnosis. Median PFS was significantly longer in patients who received 1 st -line platinum-based chemotherapy (N = 105) (6.4m; 95% CI:5.7-7.1) vs. EGFR TKI (all generations, N = 23) (2.9m; 95%CI:1.5-4.3; P &lt; 0.001) or vs. EGFR TKI (1G, N = 14) (2.6m; 95%CI:0.8-4.4; P &lt; 0.001). Median PFS was numerically longer in patients who received 2 nd -line paclitaxel-based chemotherapy (N = 34) (4.1m; 95%CI:3.3-4.9) versus patients who received 2 nd -line EGFR TKIs (N = 18) (2.0m; 95%CI:0.8-3.2; P = 0.342). Patients with CNS mets (N = 21) had shorter median PFS with 1 st -line chemotherapy than those without CNS mets (N = 84) (5.5m; 95%CI:0.7-10.3 vs. 6.4m; 95%CI:5.8-7.0; P = 0.694). Patients with CNS mets had numerically shorter median PFS with 1 st -line EGFR TKI (N = 7) than those without CNS mets (N = 16) (2.0m; 95%CI:0.8-3.2 vs. 2.9m; 95%CI:2.1-3.7; P = 0.077). Conclusions: Chemotherapy is superior to current approved EGFR TKIs as 1 st - or 2 nd -line treatment of EGFR ex20ins. Patients with CNS mets had numerically poorer PFS with chemotherapy and EGFR TKI treatment. Targeted therapy against EGFR ex20ins with CNS activity is needed.
Kratom-Related Deaths
Authors: Bridget Kuehn
Journal: JAMA (2019)

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