tbuckley/cabot-search huggingface dataset:
Prognostic value of methylation status of MGMT gene promoter in patients with glioblastoma after combination treatment.
Authors: Stanislav G. Vlasov, Dmitry Yu. Gvaldin, Anton A. Pushkin, Oleg I. Kit, Marina A. Engibaryan, Pavel G. Sakun, Vitaliy I. Voshedskiy, Marina A. Gusareva, Maksim A. Komandirov, Yulia A. Kultysheva, Anna A. Solntseva, Olga G. Rodionova, Elena A. Karnaukhova, Vladislav E. Khatyushin, Maria A. Teplyakova, Takhmina M. Kecheryukova, Ekaterina S. Zbrailova, Tatiana S. Rogova
Journal: Journal of Clinical Oncology (2021)

e14025 Background: The effectiveness of radiation therapy in the classical and stereotactic treatment regimens of the primary glioblastoma multiforme was analyzed and compared. Methods: 87 patients with primary glioblastoma multiforme were hospitalized during the study period. 17 patients of them were in the treatment group (stereotactic radiotherapy, dose per fraction 2 Gy, 60 Gy total dose, CTV 2.0 cm, PTV 0.1 cm - group 1), and 70 patients were in the control group (conventionally fractionated radiotherapy, dose per fraction 2 Gy, 60 Gy total dose, CTV 2.0 cm, PTV 0.5 cm - group 2). Patients of both groups were treated with alkylating agents as the third stage of complex treatment. MGMT methylation was evaluated by pyrosequencing. Results: The use of stereotactic radiation therapy allowed to conduct a full course of treatment without interruption, whereas in the second group, due to the development of adverse reactions, the course was interrupted for 7 patients (10%). The advantage of stereotactic radiation therapy was a less pronounced increase and rapid regression of neurological deficits during treatment, manifested by better local control for 6 months. Hypermethylation of MGMT was detected in 39% of glioblastoma cases and was not detected in non-tumor tissue. The presence of promoter methylation disrupts DNA repair and is associated with longer survival in glioblastoma patients receiving alkylating agents. Note that the median survival of patients with MGMT hypermethylation in the group 1 was 285 days (IQR = 323.75), and in the group without hypermethylation was significantly more than 338.5 days (IQR = 476) (p = 0.045). A similar trend was observed in the second group: in patients with hypermethylated MGMT, the median survival was 271 days (IQR = 337), the result is different from patients without hypermethylated MGMT – 342 days (IQR = 493) (p = 0.039). Conclusions: As a result, the application of the stereotactic approach of radiation therapy in the complex treatment of patients with glioblastoma and their classification by the MGMT methylation status with a cut-off point of 10% has the basis for improving the effectiveness and tolerability of radiation therapy and contributes to the overall survival of patients.
Harvesting Endothelial Cells During Routine Invasive Coronary Procedures
Authors: Peter D. Zalewski, Zinaida Tvorogova, Adrian Abdo, Anna A. Wawer, Sandra Hodge, Chiara Murgia, Rosanna Tavella, Peter J. Psaltis, Christopher J. Zeitz, John F. Beltrame
Journal: Journal of the American College of Cardiology (2021)
Tumor mutational burden assessed by a targeted NGS assay to predict benefit from immune checkpoint inhibitors in non-small cell lung cancer.
Authors: Sacha Rothschild, Philip Jermann, Spasenija Savic, Kirsten Mertz, Alfred Zippelius, Luca Quagliata, Lukas Bubendorf
Journal: Journal of Clinical Oncology (2018)

e15075 Background: Immune checkpoint inhibitors (ICI) improve overall survival in non-small cell lung cancer (NSCLC) in the 2nd-line setting and lead to prolonged disease control in a subgroup of patients (pts). Robust predictive biomarkers for ICI are highly desired. In an exploratory analysis of the CheckMate 026 study, high tumor mutation burden (TMB) assessed by whole-exome sequencing was associated with improved outcome of pts treated with nivolumab. Methods: From our institutional database, 41 pts with metastatic NSCLC were included in this study and identified as either having clinical benefit (CB; defined as complete/partial response (CR/PR) or stable disease (SD)) or having no clinical benefit. TMB was assessed using a targeted NGS assay that simultaneously detects variants in all coding regions / sequences of 409 cancer-related genes (Oncomine Tumor Mutation Load Assay, Thermo Fisher Scientific, Waltham, MA, USA). TMB values were normalized to tumor cell content. The correlation between TMB and CB rate was assessed. Mann-Whitney test was used and differences were considered significant at a p-value < 0.05. Results: Of 41 pts (mean age 63.7 years), 73% were male, 87.8% smokers and 71% had adenocarcinoma histology. Nivolumab was the most frequently used ICI (70.7%), and it was most commonly used in the 2nd-line setting (61.0%). PR was observed in 29.2% of patients, and SD in 14.6%. CB rate was 43.8%. The median number of genomic mutations per Megabase (Mb) was 8.81. In pts with CB, median TMB with 11.52 mutations per Mb was significantly higher than in pts without response to therapy (7.71 mutations per Mb; p = 0.02). Conclusions: TMB as determined by a targeted NGS panel comprising the coding regions of 409 cancer-related genes can reliably predict clinical benefit from ICI. These results need further confirmation due to limited sample size of this study. We are currently analyzing a second independent cohort, and results will be presented during the meeting.
Trajectories of machine learning-predicted mortality risk among patients with cancer and associated end-of-life utilization.
Authors: Manqing Liu, Jinbo Chen, Eric Li, Runze Li, Ravi Bharat Parikh
Journal: Journal of Clinical Oncology (2021)

1553 Background: Machine learning (ML) algorithms outperform traditional tools used for prognostication and may facilitate earlier discussions between oncologists and patients (pts) about hospice enrollment and treatment modification. Identifying longitudinal trajectories of mortality risk may help clinicians and health systems understand which populations such algorithms are likely to benefit. Methods: We identified trajectories of mortality risk and their association with existing metrics of end-of-life care quality, using electronic health and registry data from a prospective cohort of 3,280 pts with cancer who were seen in 18 tertiary or community medical oncology practices within a large academic health system between January 2018 and May 2020 and died prior to November 2020. A validated ML algorithm (c-statistic 0.89; Parikh et al, JAMA Oncol, 2020) prospectively generated mortality risk predictions prior to all encounters. Functional principal component analysis (FPCA) identified modes of variation for all patient-level mortality risk predictions associated with encounters prior to death. Adjusted logistic regression analyses tested associations between mortality risk trajectory and metrics of high-quality end-of-life care. Results: FPCA revealed 2 trajectories that represented 36% and 64% of all pts in the cohort. The first cluster (“unpredictable”) consisted of pts whose ML-predicted mortality risk rose sharply within 30 days of death. The second cluster (“predictable”) consisted of pts whose ML-predicted mortality risk was higher at baseline and rose gradually until death. Individuals with predictable mortality risk trajectories were more likely to have worse performance status, high comorbidity burden, and gastrointestinal (GI) malignancies (Table). Predictable trajectories were associated with higher hospice enrollment (adjusted odds ratio [aOR] 1.87, 95% CI 1.48-2.37), less inpatient death (aOR 0.72, 95% CI 0.56-0.92), less end-of-life intensive care unit admissions in the last 30 days of life (aOR 0.74, 95% CI 0.57-0.95), and less chemotherapy in the last 14 days of life (aOR 0.77, 95% CI 0.55-1.08). Conclusions: Over one-third of deaths among pts with cancer follow an unpredictable trajectory. For pts with unpredictable trajectories, overreliance on ML predictions could perpetuate aggressive end-of-life care.[Table: see text]
A phase I/II study of TQ-B2450, a PD-L1 mAb, plus anlotinib in EGFR+ advanced NSCLC patients failed to prior EGFR TKI therapies.
Authors: Meiqi Shi, Li Wang, Shaorong Yu, Fei Yan, Wei Peng, Jifeng Feng
Journal: Journal of Clinical Oncology (2021)

e21062 Background: Platinum-based chemotherapy is the standard therapy for the patients(pts) with EGFR-mutation–positive advanced NSCLC failed to prior EGFR TKI therapies. However, the IMpower150 study subgroup analyses showed Atezolizumab (PD-L1) plus bevacizumab and chemotherapy improved overall survival in EGFR TKI treated NSCLC. This ongoing phase I/II study designed to assess the benefit of the chemo-free combination of TQ-B2450, a humanized PD-L1 mAb, plus anlotinib in EGFR+ advanced NSCLC pts failed to prior EGFR TKI therapies. Methods: Pts with EGFR+ advanced NSCLC who failed to prior EGFR TKI therapies were eligible. Pts with previous received platinum-based chemotherapy were excluded. Anlotinib was given orally at dose of 8mg to 12mg for 2 weeks of a 21-day cycle (days 1-14), with TQ-B2450 given at 1200mg every 3 weeks on day 1. Phase I determined RP2D. In the phase II part, pts were assessed for efficacy and tolerability. The primary endpoint for the phase II part is the progression free survival (PFS). Secondary endpoints were objective response rate (ORR) disease control rate (DCR), overall survival (OS), and safety. Assuming an expected the median PFS of 9 months (5 months in chemotherapy), and a loss to follow-up of 10%, a total of 54 pts were required to have 90% power at a two-tailed alpha of 0.05 at the phase II part. Results: As of 12 Jan 2021, 22 pts were enrolled (9 in phase 1, 14 in phase 2). 18 pts were included in efficacy and safety analysis. The median age was 64.5 years with 61% male. 50% pts harbored EGFR exon19 deletion, 44% pts had exon21 L858R mutation. While 39% pts had T790M mutation who progressed after osimertinib treatment. The dose escalation cohort included 9 pts, no dose limiting toxicity occurred. 13 pts in the phase II part were administered with dose of 12 mg for anolitinib and 1200mg for TQ-B2450. Of the evaluable pts(n = 18), ORR was 11.1%, DCR was 77.8%, median PFS was 8.0 months (95% CI 4.9 to 11.1). Most frequent TRAE included hypertension (27.8%), hand and foot skin reaction (22.2%) and proteinuria (16.7%). Grade 3 TRAE occurred in 16.7% pts(3/18 pts), all were hypertension, and no Grade 4/5 TRAE were observed. Dose delay due to TRAE occurred in 22.2% patients while no one discontinued treatment due to TRAE. Conclusions: The chemo-free combination of TQ-B2450, a PD-L1 mAb, plus anlotinib has shown a promising anti-tumor efficacy with a more favorable safety profile for pts with EGFR+ advanced NSCLC who failed to prior EGFR TKI therapies. Pts will be continuously monitored for safety and efficacy readouts (PFS, DOR and OS). Clinical trial information: ChiCTR1900026273. Clinical trial information: ChiCTR1900026273.
Preliminary results of the phase 2 study of zanubrutinib in patients with previously treated B-cell malignancies intolerant to ibrutinib and/or acalabrutinib.
Authors: Mazyar Shadman, Jeff Porter Sharman, Moshe Y. Levy, Ryan Porter, Syed Farhan Zafar, John M. Burke, Arvind Chaudhry, Benjamin Bruce Freeman, Jamal Ghazi Misleh, Habte Aragaw Yimer, Jennifer L. Cultrera, Troy H. Guthrie, Ed Kingsley, Subramanya S. Rao, Dih-Yih Chen, Aileen Cohen, Shibao Feng, Jane Huang, Ian Flinn
Journal: Journal of Clinical Oncology (2021)

e19506 Background: Many patients (pts) with B-cell malignancies require continuous treatment with Bruton tyrosine kinase inhibitors (BTKi). Adverse events (AEs) are a common reason for ibrutinib (ibr) or acalabrutinib (acala) discontinuation. Early data from BGB-3111-215 showed zanubrutinib (zanu) was well tolerated in pts with B-cell malignancies intolerant to ibr or acala. We report preliminary results with a median follow-up of 4.2 mo. Methods: Pts meeting protocol criteria for intolerance to ibr, acala or both (without documented progressive disease) were given zanu monotherapy (160 mg twice daily or 320 mg once daily). Recurrence of AEs that led to intolerance of prior BTKi and additional safety measures were assessed based on the Common Terminology Criteria for AEs v5.0. Investigators determined responses using disease status at study entry as baseline. Results: As of November 1, 2020 (cutoff), 44 pts (n=34 chronic lymphocytic leukemia/small lymphocytic lymphoma, n=6 Waldenström macroglobulinemia, n=2 mantle cell lymphoma, n=2 marginal zone lymphoma) were enrolled, received ≥1 dose of zanu, and analyzed for safety. Median age was 70.5 y (range, 49-91); median duration of treatment was 4.2 mo (range, 0.1-12.6). Median number of prior regimens was 2 (range, 1-12). Regarding prior BTKi, 39 pts received ibr only, 4 received ibr and acala, and 1 received acala only. The median number of ibr- or acala-intolerant AEs per pt was 2 (range, 1-5). 83% of ibr and 78% of acala intolerant events did not reccur on zanu; Table. At data cutoff, 43 pts remained on treatment; 1 withdrew consent due to zanu-unrelated grade 3 syncope. Overall, 34 pts (77.3%) reported any AE; most commonly reported AEs were myalgia (n=9; 20.5%), contusion (n=8; 18.2%), dizziness (n=7; 15.9%), fatigue (n=7; 15.9%), and cough (n=5; 11.4%). Grade ≥3 AEs were reported in 6 pts (13.6%), serious AEs in 1 pt (2.3%, febrile neutropenia and salmonella infection), AEs requiring dose interruptions in 6 pts (13.6%), and AEs leading to dose reduction in 2 pts (4.5%). No AEs led to zanu discontinuation. No deaths were reported. All efficacy evaluable pts (26/26 [100%]) maintained (10 [38.5%]) or achieved deepening (16 [61.5%]) of their response. Conclusions: Zanu provides an additional treatment option after intolerance to other BTKi, demonstrating tolerability and sustained or improved efficacy. Updated results will be presented. Recurrence and Severity Change of AEs Leading to Ibr or Acala Intolerance. Clinical trial information: NCT04116437. [Table: see text]
Yet Another Automated Gleason Grading System (YAAGGS) by weakly supervised deep learning
Authors: Yechan Mun, Inyoung Paik, Su-Jin Shin, Tae-Yeong Kwak, Hyeyoon Chang
Journal: npj Digital Medicine (2021)

The Gleason score contributes significantly in predicting prostate cancer outcomes and selecting the appropriate treatment option, which is affected by well-known inter-observer variations. We present a novel deep learning-based automated Gleason grading system that does not require extensive region-level manual annotations by experts and/or complex algorithms for the automatic generation of region-level annotations. A total of 6664 and 936 prostate needle biopsy single-core slides (689 and 99 cases) from two institutions were used for system discovery and validation, respectively. Pathological diagnoses were converted into grade groups and used as the reference standard. The grade group prediction accuracy of the system was 77.5% (95% confidence interval (CI): 72.3-82.7%), the Cohen's kappa score (κ) was 0.650 (95% CI: 0.570-0.730), and the quadratic-weighted kappa score (κ
Long-term adverse events (AE) in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving prostate-specific membrane antigen (PSMA)-based targeted radionuclide therapy (TRT).
Authors: Michael Sun, Charlene Thomas, Benedict Ho, Muhammad Junaid Niaz, Ana M. Molina, Cora N. Sternberg, David M. Nanus, Neil Harrison Bander, Scott T. Tagawa
Journal: Journal of Clinical Oncology (2021)

5055 Background: PSMA-TRT is a promising investigational treatment for patients with mCRPC. Expected short-term toxicities associated with PSMA-TRT include dose-dependent myelosuppression and xerostomia. However, there is a lack of information regarding long-term effects of PSMA-TRT on marrow, renal, and liver function. Additionally, potential organ dose limits for radiation are derived from studies of external beam radiation, which may not be applicable to TRT. Methods: Men treated on prospective clinical trials of PSMA-TRT, from 2003 through 2020 with at least six months of follow-up were included. Variables included treatment, co-morbidities, baseline and most recent renal, liver, and marrow function, along with respective short-term ( &lt; 6 months) and long-term toxicities. AEs were graded using CTCAE version 5 and attribution was assessed with most recent clinical follow up. Multivariable logistic regression was used to control for type of TRT, comorbidities, and subsequent therapies. Results: 71 (59.7%) patients who received 177Lu-J591, 30 (25.2%) 177Lu-PSMA-617, 11 (9.2%) 225Ac-J591, and 7 (5.9%) 90Y-J591 were included, with median follow up 18 months (range 6-133). Long-term (most recent) laboratory values and AEs are summarized in the table. A majority of AEs were attributed to alternate etiologies. 5 of 14 cases of grade (Gr) ≥2 creatinine increase, 3 of 36 cases of Gr ≥2 platelets, 2 of 14 cases of Gr ≥2 bilirubin, 1 of 15 cases of Gr ≥2 AST increase, and 1 of 5 cases of Gr ≥2 ALT increase were deemed possibly related to PSMA-TRT. Only two Gr ≥3 AEs were attributed to possibly being related to PSMA-TRT: one case of Gr 4 creatinine elevation and one case of Gr 3 ALT elevation. On multivariable analysis, alpha-TRT was associated with hepatic AEs (OR 4.38, p = 0.047), and there was a trend towards higher Charlson Comorbidity scores associating with hematologic AEs (OR 1.27, p = 0.095). Conclusions: This is the largest analysis to-date of long-term AEs in patients who have received PSMA-TRT. Long-term effects on renal, liver, and marrow function are infrequent.[Table: see text]
Visual dysfunction in a mouse model of chemotherapy-related neurotoxicity.
Authors: David Anderson, Sachin Kedar, Matthew J Van Hook, Deepta A Ghate, Shan Fan, Jennie C Smith, Toni L Goeser, Lisa M Reid, Ekta Rishi, Staci L Haney, Sarah A. Holstein
Journal: Journal of Clinical Oncology (2021)

e24059 Background: Chemotherapy-related neurotoxicity (CRNT) poses challenges to long-term outcomes of cancer survivors. Visual function remains relatively unexplored in CRNT. Preliminary clinical work from our group suggests contrast sensitivity may be impaired in patients receiving chemotherapy. Here, we sought to isolate effects of chemotherapy on visual dysfunction in a mouse model. Methods: 10-week old C57BL/6J mice received either 4, 7, or 10 weekly intraperitoneal injections of chemotherapy (CTX group; n=15) or physiologic saline (SAL group; n=12). CTX mice received cyclophosphamide (50 mg/kg) and doxorubicin (2 mg/kg). Contrast sensitivity was assessed using an optomotor response (OMR) chamber. Psychometric functions were fitted to OMR contrast response functions to derive measures of contrast sensitivity (K), stimulus responsivity (R max ), and stimulus selectivity (n). Electroretinography (ERG) waveforms, which measure light-evoked retinal neural activity, were recorded under scotopic (rod-driven) conditions and decomposed to isolate photoreceptor (a-wave), bipolar cell (b-wave), and interneuron amacrine cell (oscillatory potentials [OP]) activity. OMR and ERG were measured prior to and following treatment. Dependent- and independent-sample t-tests assessed within- and between-group changes, respectively, in outcome measures. Results: Outcome measures are reported in Table 1. SAL relative to CTX mice showed greater weight gain (p=0.004). OMR revealed increases in R max (p CTX =0.002; p SAL =0.11) and K (p CTX =0.80; p SAL =0.06) parameters in SAL but not CTX mice. ERG results revealed significant declines in OP peak frequency in CTX relative to SAL mice (p=0.006). Other OMR and ERG measures showed no within- or between-group differences (p&gt;0.10). Decreases in weight were associated with decreases in R max (R 2 =0.25, p=.008) and OP peak frequency (R 2 =0.20, p=.02). Conclusions: Our animal model showed chemotherapy-related visual dysfunction. Mice receiving chemotherapy showed relative declines in contrast sensitivity, stimulus responsivity, and oscillatory neural activity, suggestive of disrupted neuronal circuits within the visual pathway. Future studies will focus on understanding neuronal mechanisms of visual pathway dysfunction and translating findings to clinical studies. [Table: see text]
Interventions for Vitiligo
Authors: Khaled Ezzedine, Maxine Whitton, Mariona Pinart
Journal: JAMA (2016)

<h3>Clinical Question</h3> Which interventions are associated with highest efficacy and fewest adverse events for treating vitiligo? <h3>Bottom Line</h3> Combination therapies, particularly those involving some form of light (ie, narrowband UV-B) were associated with more improved repigmentation than monotherapies. There was limited evidence to support the association of UV-A alone and UV-B alone with repigmentation for vitiligo. There was moderate evidence to support the association of UV-A and UV-B, when used in combination with psoralens, topical corticosteroids, vitamin D analogues, fluorouracil, azathioprine, and oral prednisolone with improved outcomes for vitiligo. However, combination therapies were associated with more adverse effects.
First-line pembrolizumab monotherapy for PD-L1-positive (TPS ≥ 50%) advanced non-small cell lung cancer (aNSCLC) in the real world: A national French bispective multicentric cohort—ESCKEYP trial (GFPC 05-2018).
Authors: Renaud Descourt, Laurent Greillier, Maurice Perol, Charles Ricordel, Jean-Bernard Auliac, Lionel Falchero, Pierre Demontrond, Remi Veillon, Sabine Vieillot, Florian Guisier, Marie Marcq, Gregoire Justeau, Laurence Bigay Game, Marie Bernardi, Pierre Fournel, Helene Doubre, Julian Pinsolle, Karim Amrane, Christos Chouaid, Chantal Decroisette
Journal: Journal of Clinical Oncology (2021)

9091 Background: To determine real-world outcomes with first line pembrolizumab monotherapy, for aNSCLC with PD-L1 TPS ≥50%. Methods: Bispective, national and multicentric study including consecutively aNSCLC patients who initiated first-line pembrolizumab monotherapy from May 5, 2017 (marketing authorization of pembrolizumab monotherapy in France) to Nov 22, 2019 (marketing authorization of pembrolizumab-chemotherapy for non-squamous aNSCLC). Data were collected on medical charts. Responses were locally assessed according to RECIST v1.1; overall survival (OS) and real-world progression-free survival (rwPFS) were assessed by Kaplan-Meier method. Results: 845 patients (pts) were included by 33 centres: 67.8% were men, PS 0/1/≥2: 25.5%/46.9%/27.6%, active/former/nonsmokers: 39.1%/51.7%/6.4%, adenocarcinoma: 70.8%; stage IV at diagnosis: 91.6%; median number of metastatic sites at baseline: 2±1 (brain (20.8%), liver (13.9%) and bone (35%)); KRAS mutated: 27.7%, PDL1 TPS &gt; 75%: 53.7% At the cut off date (31 December 2020), on the 783/845 (92.7%) evaluable pts, CR, PR, disease stabilization and progression were reported on 4.7%, 42.6%, 24.1% and 28.6% of cases, respectively; 588 (69.6%) pts had discontinued pembrolizumab, 390 (66.4%) had a first disease progression; 320/390 (82.1%) received a second line treatment, mainly platinum-based chemotherapy (90.6%). With a median follow up of 25,8 [95%CI: 24,8-26,7] months, median rwPFS and median OS were 8,2 [95%CI: 6,9-9,5] and 22,6 [95%CI: 18,5-27,4] months, respectively; 6, 12, 18-months survival rates were 76,8%, 64,8% and 54,3%. 835 adverse events were reported in 48% of the patients, grade ≥3 in 13.8% of cases, mainly asthenia, colitis, pneumonitis. For evaluable patients receiving a platinum-based doublet in second line (266/290, 89%), CR, PR, disease stabilization and progression were reported on 1.9%, 41%, 35.3% and 21.8% of cases, respectively. Uni and multivariate analysis of factors related to OS will be presented at the congress. Conclusions: Despite a less stringent selection of patients, pembrolizumab as a single agent achieves similar tumor shrinkage, rwPFS and OS than those of pivotal clinical trials.