tbuckley/cabot-search huggingface dataset:
Real-world experience of dacomitinib in EGFR mutated advanced NSCLC: A single center experience from India.
Authors: Bivas Biswas, Sandip Ganguly, Joydeep Ghosh, Somnath Roy, Rupsa Bakshi, Deepak Dabkara
Journal: Journal of Clinical Oncology (2021)

e21043 Background: Dacomitinib is an irreversible tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) approved in advanced non-small cell lung cancer (NSCLC) with mutated EGFR. Literature on real world experience of dacomitinib is lacking, especially in patients (pts) with brain metastasis and uncommon EGFR mutation. Methods: This is single center retrospective study of EGFR mutated advanced NSCLC patients treated with dacomitinib between July’19 and Dec’20. All patients received dacomitinib at 45 mg once oral dose except few with Eastern Cooperative Oncology Group performance status (ECOG PS) of 2-3 and elderly received 30 mg once daily. Clinicopathologic features, treatment details, toxicity and treatment outcome were recorded. Progression free survival was calculated from start date of dacomitinib till date of progression. All pts underwent re-biopsy with evaluation for EGFR T790M at progression. Results: Total 43 pts were treated with median age of 63 years (range:43-81) and M: F ratio of 22:21. 26 pts accessed the drug through early access program, 6 pts through clinical trial and rest through commercially available product. ECOG PS was 1 in 29 pts, 2 in 13 pts and 3 in 1 patient. Ten patients had brain metastasis (out of evaluated 38) and 9 received whole brain radiotherapy. Type of mutations was Del 19 in 27 pts, L858R in 12 pts, G719X in 2pts, and Del 19 + L858R, L861Q in one patient each. Histopathology types were – adenocarcinoma in 39 pts, adenosquamous in 2 pts, NSCLC-not otherwise specified and squamous histology in one patient each. Starting dose of dacomitinib was 45 mg in 34 pts and 30 mg in 9 pts. 39 pts had any grade of toxicity and 20 pts (47%) had any grade 2 &amp; 3 toxicity- mostly diarrhea and acneiform skin rash. Total 18 pts (42%) required dose modification (all from 45 mg to 30 mg). 38 pts have evaluable response: complete response in 2, partial response in 34 and stable disease in 2 pts. 8 out of 10 pts with brain metastases had partial response. All three pts with uncommon EGFR mutation had partial response. Five pts underwent re-biopsy on subsequent progression (4 had Del 19 and one had L861Q) and two developed EGFR T790M mutation. Six patients died (5 died of infection and one died of acute myocardial infarction). After a median follow-up of 13.8 months (range: 1.2-20.1), the median PFS not reached (95% confidence interval [CI]: 17.9, not reached) and 2-yr PFS was 57.5%. Conclusions: This is the largest experience of dacomitinib in EGFR mutated advanced NSCLC from Indian subcontinent. This is first reported activity of dacomitinib in pts with brain metastasis and uncommon EGFR mutation. Response rate was high and durable. 42% pts on 45 mg oral daily dose required dose modification due to toxicity. 30 mg once daily may be an optimum dose of dacomitinib in Indian pts.
No Association between Relapse Risk and Thiopurine Methyltransferase Activity By Either Geno- or Phenotype in the NOPHO ALL-2008 Protocol
Authors: Stine Nygaard Nielsen, Kathrine Grell, Jacob Nersting, Jonas Abrahamsson, Bendik Lund, Jukka A. Kanerva, Ólafur G Jónsson, Goda Vaitkeviciene, Kaie Pruunsild, Malin Lindqvist Appell, Lisa Hjalgrim, Kjeld Schmiegelow
Journal: Blood (2017)
The epidemiological trend of esophageal cancer in Mumbai, India over the past two decades.
Authors: Anbarasan Sekar, Akhil Rajendra, Vanita Noronha, Smruti Mokal, Vijay Maruti Patil, Nandini Menon, Sunil Chopade, Rajesh Dikshit, Shripad Dinanath Banavali, Kumar Prabhash
Journal: Journal of Clinical Oncology (2021)

e16095 Background: There has been a definite histopathological shift in esophageal cancer in the West over the past few decades, with adenocarcinoma overtaking squamous cell carcinoma as the commonest type. Asian countries with a high human development index like China have also reported an increased incidence of esophageal adenocarcinoma. Data on the epidemiology of esophageal cancer in India are limited. Methods: We retrospectively evaluated the data of all patients with histologically proven esophageal cancer at Tata Memorial Hospital, from 2003 to 2018. We excluded non-squamous and non-adenocarcinoma histologies. Results: Of a total of 7,874 patients with esophageal cancer, 5,092 (64.7%) were men, for a male to female ratio of 2.5:1. The median age was 57 years (IQR, 50-65); 4,465 (56.7%) were below 60 years old. Of the 4912 patients in whom a history of tobacco or alcohol use had been elicited, there were 1,360 (27.7%) patients with no history of substance use. The site of the primary was the upper third in 906 (12.8%), middle third esophagus in 2,942 (41.5%), lower third in 2,331 (32.8%) and gastroesophageal junction in 917 (12.9%) patients. The predominant histology was squamous cell carcinoma in 6,413 (81.4%) patients and adenocarcinoma in 1461 (18.6%). There was no change in the histologic pattern over the period of the study; squamous cell carcinoma constituted 78.5% of the cases in 2003, and 85.5% in 2018; Chi square test for the year wise trend in histologic patterns was not significant, p=0.143. Evaluation of the histologic subtype according to sex revealed that in the male patients, there were 3890 (76.4%) squamous and 1202 (23.6%) adenocarcinoma cases, while in female patients, there were 2523 (90.7%) squamous and 259 (9.3%) adenocarcinoma cases. On a uni variate analysis, male sex (p&lt;0.001), a history of tobacco or alcohol use (p&lt;0.001), and the presence of comorbidity (p&lt;0.007) were associated with an increased risk of squamous cell carcinoma. Multivariate analysis by logistic regression model revealed that female sex and use of tobacco or alcohol were positively associated with squamous cell carcinoma, while the presence of comorbities and primary in lower esophagus/GEJ were positively associated with adenocarcinoma. Conclusions: Squamous cell carcinoma continues to be the commonest esophageal cancer histologic subtype in over 80% Indian patients. The mid esophagus is the most common site (42%). There is no evidence of an epidemiological shift or an increase in the occurrence of adenocarcinoma or of lower esophageal/GEJ malignancy over the past two decades.
2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease
Authors: Donna K. Arnett, Roger S. Blumenthal, Michelle A. Albert, Andrew B. Buroker, Zachary D. Goldberger, Ellen J. Hahn, Cheryl Dennison Himmelfarb, Amit Khera, Donald Lloyd-Jones, J. William McEvoy, Erin D. Michos, Michael D. Miedema, Daniel Muñoz, Sidney C. Smith, Salim S. Virani, Kim A. Williams, Joseph Yeboah, Boback Ziaeian
Journal: Journal of the American College of Cardiology (2019)
Impact of androgen deprivation therapy on mortality of prostate cancer patients with COVID-19: A propensity score-based analysis.
Authors: Mateus Bringel Oliveira Duarte, Frederico Leal, Juliana Luz Passos Argenton, Jose Barreto Campello Carvalheira
Journal: Journal of Clinical Oncology (2021)

5067 Background: Previous studies suggested that androgen deprivation therapy (ADT) may reduce severe acute respiratory syndrome coronavirus 2 (SARS-COV2) infectivity. However, it is unknown whether there is an association between ADT and a higher survival in prostate cancer patients with COVID-19. Methods: We performed a retrospective analysis of prostate cancer (PC) patients hospitalized to treat COVID-19 in Brazil’s public health system. We compared patients with the active use of ADT versus those with non-active ADT, past use. We constructed propensity score models of patients in active versus non-active use of ADT. All variables were used to derive propensity score estimation, and for the outcome analysis we performed a multivariate backward elimination process to select variables to add to the propensity score model. Results: We analyzed 109 PC patients with COVID-19 that presented past or current use of ADT. In total, 52.8% of our patients were less than 75 years old, 44.0% (48/109) were in active ADT, and most were using a GnRH analog (73%, 35/48). Also, 63.3% of our cohort died from COVID-19. ADT active use were protective factor in our logistic regression model (OR 0.28, 95% CI 0.12–0.66, P = 0.0036). We noticed a significant imbalance in the propensity score of patients in active and those in non-active ADT. Then, when we performed a propensity score-based inverse weight double robust estimation model, we observed that ADT remained statistically associated with improved overall survival (average treatment effect [ATE] -0.26, 95% CI -0.45 to -0.08, P = 0.0058). Conclusions: The active use of ADT was associated with a reduced risk of death in patients with COVID-19.
Impact of bodyweight (BW)-based starting doses on safety and efficacy of lenvatinib (LEN) in patients (pts) with hepatocellular carcinoma (HCC).
Authors: Takuji Okusaka, Masatoshi Kudo, Kenji Ikeda, Masafumi Ikeda, Kiwamu Okita, Toshiyuki Tamai, Min Ren, Kenichi Saito, Hiromitsu Kumada
Journal: Journal of Clinical Oncology (2021)

e16119 Background: In Study 202, pts received LEN 12 mg/d for treatment of unresectable (u)HCC, irrespective of BW. Correlations between early dose adjustments and BW in Study 202 led to BW-adjusted dosing in the phase 3 REFLECT study of LEN in uHCC. In REFLECT, pts &lt;60 kg received LEN 8 mg/d and pts ≥60 kg received LEN 12 mg/d. While improvements in safety were expected by reducing the LEN starting dose to 8 mg/d in pts &lt;60 kg, any differences in safety and efficacy of BW-adjusted dosing vs standard dosing among pts with lower BW have yet to be determined. Herein, we compare safety and efficacy of LEN based on pts’ BW (&lt;60 kg vs ≥60 kg) in Study 202 (LEN 12 mg/d irrespective of BW) and in Japanese pts in REFLECT (dose adjusted by BW). Methods: This ad hoc analysis included all pts from Study 202 (n=46; all Asian, 43 Japanese) and Japanese pts from REFLECT (n=81). Safety and efficacy were assessed in Study 202 and REFLECT according to pt BW (&lt;60 kg vs ≥60 kg). Tumors were assessed using mRECIST, by independent radiologic review. Results: In Study 202, pts in the &lt;60 kg group had a median treatment duration of 5.8 mos and received 57% of the LEN planned starting dose (PSD); pts in the ≥60 kg group had a median treatment duration of 9.4 mos and received 78.6% of the LEN PSD. Among Japanese pts in REFLECT, median treatment duration was 5.7 mos in both treatment groups; pts in the LEN 8 mg group received 79.1% of the PSD and pts in the LEN 12 mg group received 70.7% of the PSD. In Study 202, treatment-related adverse events (TRAEs) led to dose reduction in 80.8% of pts in the &lt;60 kg group and 55% of pts in the ≥60 kg group. In REFLECT, TRAEs led to dose reductions in 52.5% of pts in the LEN 8 mg group and 70.7% of pts in the LEN 12 mg group. Serious TRAEs occurred at incidences of 46.2% and 10.0% in Study 202 in the &lt;60 kg and ≥60 kg groups, and 15.0% and 22.0% in REFLECT in the LEN 8 mg and LEN 12 mg groups, respectively. Efficacy results are in the Table. Conclusions: Despite the small sample size, this comparison of Study 202 pts and Japanese pts from REFLECT indicates that BW-adjusted LEN dosing in pts with uHCC yielded comparable efficacy between pts &lt;60 kg who received LEN 8 mg and pts ≥60 kg who received LEN 12 mg. The safety profile was favorable in pts &lt;60 kg who received LEN 8 mg in REFLECT vs those who received LEN 12 mg in Study 202. Fewer serious TRAEs and dose reductions due to TRAEs were observed in pts with lower BW who received the LEN 8 mg starting dose in REFLECT. These data suggest that by reducing the starting dose from LEN 12 mg to 8 mg in pts with uHCC and lower BW (&lt;60 kg), safety is improved without compromising efficacy. Clinical trial information: NCT00946153; NCT01761266. [Table: see text]
CDK7 Inhibitor THZ1 Inhibits Glycolytic Metabolism By Suppressing HIF1α Activity in Chronic Lymphocytic Leukemia
Authors: Shuchao Qin, Austin Young Shull, Qimei Han, Lirong Pei, Farrukh T. Awan, Wei Xu, Jianyong Li, Huidong Shi
Journal: Blood (2017)
Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19
Authors: Aaron J. Wilk, Madeline J. Lee, Bei Wei, Benjamin Parks, Ruoxi Pi, Giovanny J. Martínez-Colón, Thanmayi Ranganath, Nancy Q. Zhao, Shalina Taylor, Winston Becker, Thanmayi Ranganath, Nancy Q. Zhao, Aaron J. Wilk, Rosemary Vergara, Julia L. McKechnie, Lauren de la Parte, Kathleen Whittle Dantzler, Maureen Ty, Nimish Kathale, Giovanny J. Martinez-Colon, Arjun Rustagi, Geoff Ivison, Ruoxi Pi, Madeline J. Lee, Rachel Brewer, Taylor Hollis, Andrea Baird, Michele Ugur, Michal Tal, Drina Bogusch, Georgie Nahass, Kazim Haider, Kim Quyen Thi Tran, Laura Simpson, Hena Din, Jonasel Roque, Rosen Mann, Iris Chang, Evan Do, Andrea Fernandes, Shu-Chen Lyu, Wenming Zhang, Monali Manohar, James Krempski, Anita Visweswaran, Elizabeth J. Zudock, Kathryn Jee, Komal Kumar, Jennifer A. Newberry, James V. Quinn, Donald Schreiber, Euan A. Ashley, Catherine A. Blish, Andra L. Blomkalns, Kari C. Nadeau, Ruth O’Hara, Angela J. Rogers, Samuel Yang, David Jimenez-Morales, Andra L. Blomkalns, Ruth O’Hara, Euan A. Ashley, Kari C. Nadeau, Samuel Yang, Susan Holmes, Marlene Rabinovitch, Angela J. Rogers, William J. Greenleaf, Catherine A. Blish
Journal: The Journal of Experimental Medicine (2021)

Our understanding of protective versus pathological immune responses to SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses revealed widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, including prominent hyperactivation signatures in neutrophils and NK cells. We also identified chromatin accessibility changes at NF-κB binding sites within cytokine gene loci as a potential mechanism for the striking lack of pro-inflammatory cytokine production observed in monocytes in severe and fatal COVID-19. We further demonstrated that emergency myelopoiesis is a prominent feature of fatal COVID-19. Collectively, our results reveal disease severity-associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention.
Metastatic site-specific utilization and outcome of immunotherapy in stage IV melanoma: A national perspective.
Authors: Lifen Cao, Jonathan T. Bliggenstorfer, Christopher W. Towe, Ankit Mangla, Megan E. Miller, Luke Rothermel
Journal: Journal of Clinical Oncology (2021)

e21525 Background: Metastatic melanoma is an aggressive disease with a rapid systemic dissemination. We evaluated the effect of metastatic sites on the utilization immunotherapy and survival outcomes in stage IV melanoma. Methods: The National Cancer Database from 2010-2017 was queried for stage IV melanoma. Those with missing relevant data were excluded. Patients were grouped into five categories based on metastatic sites: lung metastasis only, brain metastasis only, liver metastasis only, bone metastasis only and multiple sites metastasis. Multivariable logistic regression was used to predict use of immunotherapy. Effects of immunotherapy on overall survival were assessed using Kaplan-Meier curves and Cox proportional hazards model. Results: A total 12, 315 were included in the study, among whom 2206 (17.9%) had lung metastasis only, 1,873 (15.2%) had brain metastasis only, 785 (6.4%) had liver metastasis only, 662 (5.4%) had bone metastasis only and 5,983 (48.6%) presented with multiple metastatic sites. Surgery at primary site was performed in 34.3% of patients with bone metastasis (p&lt;0.001), and radiation therapy was delivered to 69.2% patients with brain metastasis (p&lt;0.001). Site of metastatic disease was associated with immunotherapy utilization, with multiple sites (OR = 1.149, p=0.012), and distant lymph nodes (OR=2.867, p&lt;0.001) demonstrating the strongest association, while patients with oligo brain metastasis were less likely to receive immunotherapy (OR = 0.486, p&lt;0.001). Immunotherapy is associated with superior survival among metastatic melanoma patients (HR=0.433, P&lt;0.001). The Kaplan-Meier curves showed the median overall survival among the immunotherapy group was 33.7 months for lung metastasis (vs. 13.4 months without immunotherapy, HR=0.633, p&lt;0.001), 25 months for brain metastasis (vs. 6.7 months without immunotherapy, HR=0.447, P&lt;0.001), 16.8 months for liver metastasis (vs. 4.2 months without immunotherapy, HR=0.449, P&lt;0.001), 18.3 months in bone metastasis (vs. 7.6 months without immunotherapy, HR=0.615, p&lt;0.001) and 12.1 months in multiple metastasis (vs. 3.8 months without immunotherapy, HR=0.338, p&lt;0.001). Conclusions: Utilization of immunotherapy is influenced by location of metastatic disease in stage IV melanoma. Overall survival is improved for patients treated with immunotherapy.[Table: see text]
<i>RECQL5</i> mutations as a potential efficacious predictor of immunotherapy in melanoma patients.
Authors: Yun Zhao, Dandan Fan, Xiaochun Huang, Mengli Huang, Yaoxu Chen, Ting Bei
Journal: Journal of Clinical Oncology (2021)

e21547 Background: Gene mutations in DNA damage repair (DDR) pathway were reported to affect the clinical response to immune checkpoint inhibitors (ICIs) by driving mutagenicity. Previous studies showed that RECQL5 is involved in RAD51-mediated strand invasion for homologous recombination DNA damage repair (HR-DDR). RECQL5 encoding RecQ protein-like 5 (RECQL5) is a member of RecQ helicase family and was discovered to play a tumor-suppressive or oncogenic role in various cancers. However, the association between RECQL5 mutation and ICI efficacy has not been revealed. Methods: Data of nine publicly independent cohorts of NSCLC, melanoma, and pan-cancer were retrieved (Rizvi, MSKCC, OAK/POPLAR, Van Allen, Hugo, Synder, Miao and Samstein cohorts) to investigate the correlation between RECQL5 mutations and clinical events including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). Wilcoxon test was used for comparing tumor mutational burden (TMB) between RECQL5-mutated patients and their wild-type counterparts. In addition, the correlation between infiltration of immune cells and RECQL5 mutation status was also analyzed by QUANTISEO using data of SKCM cohort (n=466) from TCGA database. Statistical significance was set at P = 0.05. Results: RECQL5 mutations were most commonly seen in melanoma patients and the detection rate was 4%-8% in melanoma patients from cohort Van Allen, Hugo, Synder, and Miao. RECQL5 mutation was not detected in other cancers except for one lung cancer case. In the three melanoma cohorts (Van Allen, Synder, Miao) with OS data available, the OS of the RECQL5-mutated patients was 2 to 3 times longer than that of the RECQL5-wt patients. In Synder cohort, the difference in OS between these two subsets was statistically significant (53.9 months vs 25.0 months, P = 0.045). In addition, the occurrence of RECQL5 mutations was correlated with higher CBR both in Miao ( P = 0.017) and Synder cohorts ( P = 0.011). No difference was observed in the PFS or ORR between these two subsets. Notably, RECQL5 mutations were associated with higher TMB levels both in Miao (32.6 mut/Mb vs 7.9 mut/Mb, P = 0.016) and Synder cohorts (1124 mut/Mb vs 358 mut/Mb, P = 0.033). Moreover, RECQL5 mutations were found to be correlated with increased infiltration of CD4 + T cells (no-regulatory) ( P = 0.037), B cells ( P = 0.13) and decreased infiltration of regulatory CD4 + T cells ( P = 0.02) in RECQL5-mutated tumors over RECQL5-wt tumors. Conclusions: RECQL5 mutations can serve as a potential predictor for a durable response to ICIs in melanoma. Moreover, the occurrence of RECQL5 mutations was correlated with higher TMB level as well as infiltration of immune cells, indicating the underlying mechanism of its predictive effect.
Potential determinants of radiation-induced lymphocyte decrease and lymphopenia in breast cancer patients by machine learning approaches.
Authors: Hao Yu, Fang Chen, Li Yang, Jian-Yue Jin, Feng-Ming Spring Kong
Journal: Journal of Clinical Oncology (2021)

e12567 Background: Radiation-induced lymphopenia accompanied with radiation therapy is associated with inferior clinical outcomes in a wide variety of solid malignancies. This study aimed to examine the potential determines of radiation-induced lymphocyte decrease and radiation-induced lymphopenia in breast cancer patients who underwent radiotherapy. Methods: Patients with breast cancer treated who underwent radiotherapy were enrolled in University of Hong Kong-Shenzhen Hospital (our cohort). Circulating lymphocyte levels were evaluated within 7 days prior to and end of radiation therapy. Feature groups including clinical data, tumor characteristics, radiotherapy dosimetrics, treatment regiments were also collected. We applied machine learning algorithms (Extreme Gradient Boosting, XGboost) to predict the ratio of lymphocyte level after radiotherapy to baseline lymphocyte level and the event of lymphopenia and compared with Lasso regression approaches. Next, we used Shapley additive explanation (SHAP) to explore the directional contribution of each feature for lymphocyte decrease and lymphopenia. For the purpose of model validation and proof-of-concept validation, an independent cohort of patients enrolled in prospective trial was eligible (IP cohort). Results: A total of 589 patients were enrolled in our cohort and 203 patients in IP cohort. XGboost models which trained in our cohort with performances of a mean RMSE: 0.157 and R2: 53.9% for the ratio of lymphocyte levels; a mean accuracy: 0.757 and ROC-AUC: 0.733 for the lymphopenia events, separately. These models can predict the ratio of lymphocyte levels with a mean RMSE: 0.175 and R2: 47%; predict the lymphopenia events with a mean accuracy: 0.739 and ROC-AUC: 0.737 in the totally independent IP cohort. The feature group of dosimetrics had the largest predictive power with RMSE: 0.192, R2: 29.8%, accuracy: 0.678 and ROC-AUC: 0.667; followed by the group of baseline blood cells with predictive power as RMSE: 0.207, R2: 18.9%, accuracy: 0.669 and ROC-AUC: 0.645. Next, by SHAP value analysis, we investigated that integral dose of the total body, V5 dose, mean lung dose and V20 dose of ipsilateral lung/bilateral lungs were in consequence important promote factors for lymphocyte decrease and for the event of lymphopenia, while the features of baseline monocyte, mean heart dose and tumor size played a role of protection at some extend. Conclusions: In this study, we constructed robust XGboost models for predicting the lymphocyte decrease and the event of lymphopenia in breast cancer patients who underwent radiation therapy. We also applied SHAP analysis for revealing the directional contribution of features. These results are important either for the understanding the contributions of dosimetrics on immune response or for the refine of radiation dosimetrics before treatment in future clinical usages.