tbuckley/cabot-search huggingface dataset:
Moral distress, organizational climate, and the risk of burnout among oncology physician assistants.
Authors: Eric Daniel Tetzlaff, Heather Marie Hylton, Karen Ruth, Zachary Hasse, Michael J. Hall
Journal: Journal of Clinical Oncology (2021)

11018 Background: Moral Distress (MD) is the result of barriers or constraints that prevent providers from carrying out what they believe to be ethically appropriate care and has been associated with burnout. Advances have been made in our understanding of burnout in the oncology (Onc) workforce but our understanding of MD remains limited. This study was initiated to explore associations between moral distress, burnout, and the organizational climate (OC) for Onc Physician Assistants (PAs). Methods: A national survey of onc PAs was conducted in 2020. MD and Burnout were assessed with the Maslach Burnout Inventory and the Measure of MD – Healthcare Professionals (MMD-HP). To assess OC, the Nurse Practitioner Primary Care OC Questionnaire (NP-PCOCQ) was revised for Onc PAs and assessed professional visibility (PV), administrative relations (AR), physician relations (PR), and professional autonomy and support (PAS). A robust Poisson regression model was used to estimate risk ratios (RR) for burnout associated with MD and OC variables. Results: Respondents who completed the survey included 146 Onc PAs that were mostly female (90%), White/Caucasian (84%), married/partnered (78%), and in medical Onc (73%). Mean MMD-HP score was 71.5 and burnout was reported by 39.7% of PAs. MMD-HP scores did not differ based on specialty, practice setting or practice type. PCOCQ subscale scores were lower for PAs with burnout vs. without burnout (p=0.003 to p &lt; 0.001). Increasing levels of MD were associated with increased levels of emotional exhaustion (p&lt;0.001), depersonalization (p&lt;0.001) and a higher overall rate of burnout. For Low, Medium and High MMD, burnout rates were 10%, 44% and 66% respectively (p&lt;0.001). Risk of burnout was associated with increasing levels of MD, which remained when adjusted for the PCOCQ subscales. An interaction model with the PCOCQ subscales and the association between burnout and MD was not significant. Conclusions: Higher levels of MD and unfavorable organizational climate are associated with Onc PA burnout. The relationship between MD and burnout does not appear to be moderated by organizational climate. Additional research is needed to identify potential moderators of the MD/Burnout relationship. Risk Ratio estimate for Burnout.[Table: see text]
Clinical trial testing superiority of combination plinabulin (Plin) and pegfilgrastim (Peg) versus peg alone in breast cancer treated with high-risk febrile neutropenia risk chemotherapy (chemo): Final results of the phase 3 protective-2 in chemo-induced neutropenia (CIN) prevention.
Authors: Douglas W. Blayney, Yuankai Shi, Hryhorii Adamchuk, David Feng, Qingyuan Zhang, Lihua Du, Lan Huang, Ramon Mohanlal
Journal: Journal of Clinical Oncology (2021)

533 Background: Peg is standard of care (SoC) for the prevention of CIN. Peg’s mechanism of action leaves patients vulnerable to FN in week 1 of the chemo cycle(C), as the absolute neutrophil count (ANC) does not normalize until week 2. Plin is a first-in-class, non-G-CSF small molecule agent, which received breakthrough designation from FDA in CIN. It prevents CIN by protecting progenitor cells in bone marrow from chemo assault and has normal ANC in week 1 (Blayney JAMA Onc 2020). Phase 2 testing showed the combination of Plin and Peg achieved CIN protection throughout the entire cycle vs Peg alone (Blayney: St Gallen 2019, ASCO 2019). Methods: Plin is given on Day (D)1 after Chemo, has a favorable safety profile, and also has anticancer activity. A separate phase 3 study evaluating Plin as an anticancer agent (DUBLIN-3; NCT02504489) in NSCLC pts is underway, with anti-cancer results in OS expected in 2021. In PROTECTIVE-2 (Study 106; NCT0329457), we added Plin (on D1) to Peg (on D2), testing superiority of the combination for CIN prevention vs Peg alone. Study 106, is a global multicenter randomized (1:1) double-blind study to evaluate Plin 40 mg + Peg 6mg (Arm 1) versus Peg 6mg + Placebo (Plac) (Arm 2) in preventing Severe Neutropenia (N), (defined as ANC &lt;0.5 cells × 10E9/L) in early-stage BC (node positive or node negative with a high risk of recurrence) pts. 221 pts with ECOG status 0 or 1 received Docetaxel (75 mg/m2), Doxorubicin (50 mg/m2), and Cyclophosphamide (500 mg/m2) (TAC) on D1 for four 21 D cycles and study treatment. Central laboratory ANC was assessed at Covance in Cycle 1 (C1) on D 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, and 15. Primary objective was to compare the percentage (%) of pts with a Duration of Severe Neutropenia (DSN) of 0 days [that is % of pts with no Grade (Gr) 4 neutropenia (N)] in C1 in each arm. Key secondary endpoints were DSN and ANC Nadir in C1. We also evaluated safety (AE frequency and Grade). Conclusions: Adding Plin to Peg offers superior CIN protection compared to Peg alone and also has a superior safety profile by lowering over 20% of grade 4 AE. The effect size of the CIN protection in the combination is also correlated to clinical meaningful FN reduction compared to peg alone. Clinical trial information: NCT03531099. [Table: see text]
High CXCR4 expression in pancreatic ductal adenocarcinoma as characterized by an inflammatory tumor phenotype with potential implications for an immunotherapeutic approach.
Authors: Andreas Seeber, Florian Kocher, Andreas Pircher, Alberto Puccini, Yasmine Baca, Joanne Xiu, Kai Zimmer, Johannes Haybaeck, Gilbert Spizzo, Richard M. Goldberg, Axel Grothey, Anthony Frank Shields, Mohamed E. Salem, John Marshall, Michael J. Hall, Wolfgang Michael Korn, Chadi Nabhan, Francesca Battaglin, Heinz-Josef Lenz, Dominik Georg Friedrich Wolf
Journal: Journal of Clinical Oncology (2021)

4021 Background: Immunotherapy is considered ineffective in the majority of patients with pancreatic ductal adenocarcinoma (PDAC), a consequence of a highly immunosuppressive tumor microenvironment (TME). However, treatment induced inhibition of CXC chemokine receptor 4 (CXCR4) and programmed cell death protein-1 (PD-1) in the COMBAT trial caused T cell infiltration and tumor regression in a subset of PDAC patients. Elucidating a phenotype that predicts response is clinically relevant. We performed a comprehensive molecular landscape study in PDAC evaluating CXCR4 RNA expression. Methods: 3,647 PDAC specimens were centrally analysed. NextGen DNA sequencing (NextSeq, 592 gene panel or NovaSeq, whole-exome sequencing), whole-transcriptome RNA sequencing (NovaSeq) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ) were performed. Gene expression is reported as TPM (Transcripts per million). Pathway gene enrichment analyses were done using GSEA (Subramaniam 2015, PNAS). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). The cohort was stratified in quartiles according to CXCR4 RNA expression status. Results: Overall, CXCR4 expression was higher in primary tumors compared to distant metastasis (38 vs. 28 TPM, p &lt; 0.0001). CXCR4-high (top quartile: &gt; 59 TPMs), when compared to CXCR4-low (bottom quartile: &lt; 17 TPM) PDACs, were characterized by a high prevalence of mutations in signal transduction pathway genes (e.g. GNAS: 3.6 vs. 0.5%), an increased infiltration of immune cells (e.g. CD8 + T cells, M1 macrophages), and a higher expression of HLA-DRA and HLA-E (all p &lt; 0.0001). We detected an upregulation of CXCL9, CXCL10, CXCL12, CCL5, IDO1 and LAG3 in CXCR4-high compared to CXCR4-low tumors. In contrast, lower PD-L1 expression (17.4 vs. 13.1%, p = 0.02), genomic loss of heterozygosity (17.4 vs. 10.8%), and a lower frequency of gene amplifications in ERBB2 (2.1 vs. 0.1%), TNFRSF14 (2.0 vs. 0.1%), and TP53 (82 vs. 73%, all p &lt; 0.0001) were observed. Moreover, CXCR4-high expression was associated with a better survival (HR: 1.417, 95% CI [1.168-1.72], p &lt; 0.001). Conclusions: This is the first study comprehensively investigating the molecular landscape of PDACs according to CXCR4 RNA expression. High CXCR4 expression is associated with an improved survival and a pro-inflammatory phenotype that may identify a subset of tumors with greater responsiveness to immunotherapeutic approaches.
Do differences in baseline clinical severity of ovarian cancer patients with thrombosis predict treatment with rivaroxaban versus low molecular-weight heparin?
Authors: Christine G. Kohn, Jonathan T. Caranfa, Molly Brewer, Meghana Singh, Craig I. Coleman, Olivia S. Costa
Journal: Journal of Clinical Oncology (2021)

e18748 Background: Prescribers use direct oral anticoagulants and low molecular-weight heparin (LMWH) for the acute treatment and secondary prevention of cancer-associated thrombosis (CAT). We sought to identify predictors impacting the use rivaroxaban versus LMWH for CAT in patients with ovarian cancer. Methods: Using US Surveillance, Epidemiology and End Result-Medicare linked data from 2013-2016, we evaluated adults with ovarian cancer, undergoing hospitalization/emergency department admission for CAT and prescribed rivaroxaban or LMWH for outpatient anticoagulation. Univariate analysis was performed to examine the association between covariates and clinicians’ choice to use rivaroxaban or LMWH. Variables with a p-value &lt; 0.20 upon univariate analysis were deemed significant and subsequently included into a stepwise, backwards multivariable logistic regression model to obtain adjusted odd ratios (ORs) of treatment assignment. Results: Of the 125 ovarian cancer patients included in our analysis, 26% received rivaroxaban and 74% LMWH. All patients had stage 3 or 4 ovarian cancer, 36% were ≥75 years-of-age, 78% were white, and 18% were below the poverty line (p ≥ 0.25). Upon univariate analysis, rural community, time between cancer diagnosis and VTE ≥ 1 year, index VTE without evidence of pulmonary embolism, and CKD ≥ stage 3 were found to be significant predictors of rivaroxaban use when compared to LMWH (p ≤ 0.14 for all). Upon multivariable regression, CKD ≥ stage 3 (OR = 3.13) was shown to be independently associated with rivaroxaban versus LMWH use (p≤0.01). Conclusions: In routine practice, patients were more likely to receive rivaroxaban if they had CKD and lived in a rural area. These differences in prescribing practices may be due to less availability of LMWH in rural areas and less tolerance of injections in CKD patients. Univariate analysis also suggest that low VTE burden (i.e., DVT only) and VTE event ≥ 1 year after cancer diagnosis were also associated with rivaroxaban use over LMWH, which may be due to LMWH therapy as the long-established standard of care for patients with cancer. Large observational studies are needed to confirm these results. [Table: see text]
Increased risk of immune-related hepatitis among adolescent and young adults (AYAs) with melanoma during immunotherapy with checkpoint inhibitors (ICIs).
Authors: Alicia Darwin, Damon R. Reed, Tawee Tanvetyanon
Journal: Journal of Clinical Oncology (2021)

9584 Background: Melanoma is the second most common malignancy affecting AYA patients after lymphoma. Nevertheless, AYA melanoma does constitute a minority of all melanoma cases. Additionally, the AYA population is not well represented in prospective clinical trials, including immunotherapy trials. While previous research has demonstrated the efficacy of ICIs across age groups, it remains unclear if toxicity profiles will be similar. In the general population, age-related changes in the immune milieu result in differential incidences of autoimmune diseases by age. This study aims to compare the toxicity profile between a cohort of AYA melanoma versus elderly melanoma patients receiving ICI therapy. Methods: In this single NCCN institutional study, electronic medical records of melanoma patients treated with ICIs between 01/2007-01/2019 were reviewed. Subjects receiving concurrent investigational agents or chemotherapy were excluded. The AYA cohort included those aged 15-40 years. The elderly cohort included those aged ≥65 years. Adverse events were coded according to CTC-AE version 5.0. Multivariable logistic regression analyses were performed. Results: Analyses included 184 treatment courses. In the AYA cohort (N = 57), median age at ICI initiation was 28.8 years (range: 17.9-39.3). In the Elderly cohort (N = 127), median age at ICI initiation was 72.3 years. More AYA patients (28.1% AYA vs. 7.9% Elderly) received ICI combination regimens. The most common adverse events amongst both cohorts were transaminitis (23.4%), rashes (49.5%), and diarrhea/colitis (20%). Incidences of pneumonitis, colitis, hypothyroidism, and hypophysitis did not differ significantly between cohorts. However, the AYA cohort experienced a higher incidence of transaminitis (38.6% AYA vs. 16.5% Elderly, p =0.001 ) and increased occurrence of treatment related hospitalization (26.3% AYA vs. 7.1% Elderly, p &lt;0.001 ). Moreover, a higher proportion of severe grade ≥3 transaminitis occurred in the AYA group (27.3% AYA vs. 9.5% Elderly, p =0.004). While occurrence of transaminitis was significantly associated with combination ICIs, the association between AYA status and transaminitis remained significant after adjusting for ICI regimen (OR 2.75, 95% CI: 1.3-5.8). There was a trend toward shorter time to transaminitis onset among the AYA than Elderly cohort (median 53.0 vs. 74.5 days [non-parametric p= 0.28]). To date, median survival has not been reached in both groups ( p= 0.09). Conclusions: In this large cohort of AYA melanoma patients treated with ICI, we found a significantly higher incidence of immune-related transaminitis than in the Elderly cohort. Other immune-related AEs were comparable between cohorts. This finding was independent of ICI regimen. Further investigation will be needed to understand these differences between the AYA and Elderly cohorts.
Early COVID-19 pandemic’s toll on tuberculosis services, WHO European Region, January to June 2020
Authors: Masoud Dara, Giorgi Kuchukhidze, Askar Yedilbayev, Ihor Perehinets, Tanja Schmidt, W. Leif Van Grinsven, Martin J. Boeree
Journal: Eurosurveillance (2021)

BackgroundEssential health services, including for tuberculosis (TB), are being affected by public health and social measures (PHSM) introduced to control COVID-19. In many settings, TB resources, facilities and equipment are being redirected towards COVID-19 response.AimWe sought to assess the COVID-19 pandemic's impact on TB services in the World Health Organization (WHO) European Region.MethodsThe fifty-three European Region Member States were asked to report qualitative and quantitative data in quarter one and two (Q1 and Q2) 2020. TB notifications were triangulated with the severity score on domestic movement restrictions to assess how they may have influenced TB detection.ResultsTwenty-nine countries reported monthly TB notifications for the first half of 2019 and 2020. TB notifications decreased by 35.5% during Q2 2020 compared with Q2 2019, which is six-fold more than the average annual decrease of 5.1% documented during 2015-2019. The number of patients enrolled in rifampicin-resistant/multidrug-resistant TB treatment also decreased dramatically in Q2 2020, by 33.5%. The highest movement restriction severity score was observed between April and May 2020, which coincided with the highest observed decrease in TB notifications.ConclusionA decrease in TB detection and enrolment to treatment may cause increases in TB burden and threatens the Region's ability to reach the TB targets of the 2030 Sustainable Development Goals, still this might be mitigated with rapid restoration of TB services and the implementation of targeted interventions during periods with severe PHSM in place, such as those introduced in response to the COVID-19 pandemic.
A randomized phase III study of immune checkpoint inhibition with chemotherapy in treatment-naive metastatic anal cancer patients: A trial of the ECOG-ACRIN cancer research group (EA2176).
Authors: Marc Thomas Roth, Paul J. Catalano, Kristen Keon Ciombor, Al Bowen Benson, Xin Yao, Rona Yaeger, Mohamed E. Salem, Van K. Morris, David H. Henry, Jennifer G. Whisenant, Peter J. O'Dwyer, Cathy Eng
Journal: Journal of Clinical Oncology (2021)

TPS3614 Background: Anal cancer is growing in annual incidence globally and human papillomavirus (HPV) remains the predominant risk factor underlying its development. Due to its relative rarity, clinical trials in anal cancer have historically been difficult to conduct and treatment options for metastatic disease remain limited. Carboplatin/paclitaxel (CP) was compared to cisplatin/5-fluorouracil (historical standard of care) in a recent randomized phase II clinical trial (InterAACT; EA2133) in treatment-naïve metastatic anal cancer, finding that response rates were equivocal, but that overall survival (OS) was significantly longer in the CP arm (20 months vs 12.3 months, p = 0.014). Additionally, reduced grade 3/4 toxicities were seen in the CP arm. NCI9673, a single-arm phase II study, established safety and efficacy of nivolumab in previously-treated metastatic anal cancer. Progression-free survival (PFS) was 4.1 months (95% CI 3.0-7.9) and OS was 11.5 months (95% CI 7.1-not estimable). Multiple randomized trials in lung cancer have demonstrated efficacy of platinum-based chemotherapy combined with checkpoint inhibitors. Together these studies form the rationale behind combining CP and nivolumab in treatment-naïve metastatic anal cancer. Methods: EA2176 (NCT04444921) is the first NCTN phase III randomized clinical trial in treatment-naïve metastatic anal cancer. Stratification factors include HIV status and history of chemoradiation for curative intent. Patients will be randomized to carboplatin (AUC = 5, Day 1) plus paclitaxel (80mg/m2, Days 1, 8, 15) +/- nivolumab 240mg IV (Cycle 1 = Days 1, 15; Cycle ≥2 = Day 1, 480mg) q 28-days until disease progression or treatment intolerance. CP will be given for up to 6 cycles, while nivolumab will be continued as maintenance for up to 2 years. The primary endpoint is PFS. Secondary objectives include OS, response rate, and toxicity. Goal enrollment is 205 patients and the study continues accrual. This sample size will provide 80% power at a two-sided α of 0.05 to detect a 4.8-month improvement in PFS assuming 8 months in the control arm. Novel correlative studies include sequential quantitative tumor-derived cell-free HPV ctDNA levels (serotypes 16 and 18; Sysmex-Inostics SafeSEQ NGS assay). Correlative funding provided in part by the Farrah Fawcett Foundation and Sysmex Inostics, Inc. Clinical trial information: NCT04444921.
Tumor-agnostic precision immuno-oncology and somatic targeting rationale for you (TAPISTRY): A novel platform umbrella trial.
Authors: Alexander E. Drilon, Haiying Liu, Felice Wu, David Chen, Timothy Richard Wilson, Brian P. Simmons, Fabrice Barlesi
Journal: Journal of Clinical Oncology (2021)

TPS3154 Background: Actionable genomic alterations are found in many solid tumors in pediatric and adult populations. Identifying such alterations can match patients (pts) to genome-driven therapies. Although TRK and immune checkpoint inhibitor therapies have tumor-agnostic approval for NTRK-rearranged and tumor mutational burden (TMB)-high cancers, respectively, similar approvals remain an unmet need for other genome-driven cancers, limiting pt access to potentially active therapies. Platform master protocol studies leveraging comprehensive next-generation sequencing (NGS) are a pragmatic means of evaluating multiple genome-driven therapies in rare biomarker-selected populations. Contemporary study designs include adult and pediatric pts to expand care across age groups. Methods: TAPISTRY (NCT04589845) is a phase 2, global, open-label, multi-cohort study evaluating the efficacy and safety of targeted therapy or immunotherapy, as single agents or in combination, in pts with unresectable, locally advanced/metastatic solid tumors. Eligible pts have tumors that harbor genomic alterations or are TMB-high by NGS (Foundation Medicine or CLIA/equivalent-certified laboratory). General inclusion criteria: PD on prior treatment/no available acceptable treatment; measurable disease (by RECIST v1.1, RANO, INRC), adequate ECOG/equivalent PS and end organ function. Pts will be assigned to treatment according to eligibility criteria for biomarker-defined cohorts (Table). Pediatric pts may be enrolled if age-appropriate formulations/dosages are established. Samples will be taken for central NGS biomarker testing at baseline (tissue/blood), tumor assessments (blood) and at response/PD (optional tissue/blood). Tumor assessments (CT, MRI, PET) will be completed at baseline then every 6–8 weeks, depending on cohort. Primary endpoint: confirmed ORR by independent review committee (IRC; RECIST v1.1). Key secondary endpoints: ORR (by investigator [INV], per RECIST/INRC); DoR, CBR, PFS, time to CNS PD (by IRC and INV, per RECIST/INRC); intracranial efficacy (Cohorts A–D; per RANO [primary brain tumors]/RECIST [baseline CNS mets]); OS; patient-reported outcomes; safety; pharmacokinetics and immunogenicity (Cohorts D and F). Treatment will continue until PD, loss of clinical benefit, unacceptable toxicity, discontinuation or death. Target enrollment is 650 pts at 100+ sites based on screening 40,000+ pts; 3 pts enrolled as of 9 Feb 2021. Clinical trial information: NCT04589845. [Table: see text]
Regorafenib plus PD-1 inhibitors in Chinese patients with microsatellite stable/mismatch repair proficient metastatic colorectal cancer: A real-world study.
Authors: Kaili Yang, Lu Han, Yun-Bo Zhao, Yang Ge, Qin LI, Yusheng Wang, Shikai Wu, Yan Zhang, Chuanhua Zhao, Jing Zhou, Lin Zhao
Journal: Journal of Clinical Oncology (2021)

e15585 Background: A previous phase 1b trial has shown encouraging efficacy of regorafenib plus nivolumab in patients with microsatellite stable/mismatch repair proficient (MSS/pMMR) metastatic colorectal cancer (mCRC). We aimed to evaluate the efficacy and safety of this regimen in Chinese patients in the real world. Methods: We retrospectively identified patients with MSS/pMMR mCRC who received at least one dose of programmed cell death-1 (PD-1) inhibitors plus regorafenib from 5/2019 to 2/2021 in 10 Chinese medical centers. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and the safety. Results: Fifty-two patients were identified. Liver metastases were presented in 35 patients (67%). A total of 48 patients (92%) received regorafenib plus a PD-1 inhibitor as the third or later line treatment. At the data cut-off, 11 patients (21%) were still on treatment. Other patients terminated treatment because of progressive disease (45%), treatment-related adverse events (TRAEs) (14%) or treatment-unrelated deaths (6%). The median treatment cycle was 3 (range, 1-18). At a median follow-up of 4.9 months, the median OS was 17.3 months (95% CI, 10.2-NR) and the median PFS was 3.1 months (95%CI, 2.5-6.0). Baseline liver metastases were associated with inferior PFS (2.7 versus 6.3 months, p &lt;0.05), but not OS (17.3 months versus NR, p =0.6). Among 38 patients evaluable for response, two patients (5%) achieved partial response, and 17 patients (45%) experienced stable disease as the best response. The DCR was 50% (95%CI, 5.0-NR) and was similar among different PD-1 inhibitors (Table). TRAEs were observed in 30 patients (58%). Fatigue (21%), hand-foot syndrome (19%) and rash (13%) were the most common TRAEs. Eight patients (15%) experienced grade 3-4 TRAEs, including rash (n=3), hand-foot syndrome (n=2), hypertension (n=1), myocardial enzyme elevation (n=1) and visual field loss (n=1). No treatment-related death occurred. Conclusions: The combination of regorafenib plus PD-1 inhibitors was generally tolerated and exhibited potential benefit in terms of OS and DCR. The presence of baseline liver metastases was predictive for shorter PFS but requires further investigation. Disease control rate of different PD-1 inhibitors.[Table: see text]