tbuckley/cabot-search huggingface dataset:
Whole-exome sequencing on circulating tumor cells explores platinum-based chemotherapy resistance in advanced non-small cell lung cancer.
Authors: Rong Li, Shuangxiu Wu, Yuanyuan Chang, Yin Wang, Boyi Li
Journal: Journal of Clinical Oncology (2021)

e21021 Background: Circulating tumour cells (CTCs) have important applications in clinical practice on early tumour diagnosis, prognostic prediction and treatment evaluation. Platinum-based chemotherapy is the first-line treatment for non-small cell lung cancer (NSCLC) patients without targeted drugs. But most patients progressed after a period of treatment. Therefore, to dissect the genetic information contributing to drug resistance and tumour progression in CTCs is valuable for guidance of treatment adjustment. Methods: In this study, we enrolled 9 NSCLC patients treated with platinum-based chemotherapy. For each patient, 10 CTCs were isolated after progression to perform a single cell-level whole-exome sequencing (WES). Meanwhile the patients’ paired primary-diagnosed FFPE sample and progressive biopsy specimens were also performed WES. Results: Comparisons of WES data between primary and progressive specimens, as well as CTCs revealed that more than half patients’ tumour mutation burden (TMB) increased after progression. Dozes to hundreds of single-nucleotide variants (SNVs) and insertions or deletions (Indels) were detected in the CTCs. Slightly more proportion of SNVs/Indels in CTCs shared with paired primary tumours (1.2%-23.1%) than with progressive samples (0.6%-11.7%). Conclusions: Functional annotation on SNVs/Indels showed that CTCs not only harboured cancer driver gene mutations, such as EGFR and TP53, shared with primary and/or progressive tumours, but also harboured chemotherapy-resistance and stem cell-related gene mutations, including SHKBP1, NUMA1, ZNF143, MUC16, ORC1, PON1, PELP1, etc. which have crucial roles in drug resistance and poor prognosis for NSCLCs. Thus, detection of genetic information in CTCs was necessary for guidance of individual therapy and drug resistance study.
Clinical outcomes in HER2-positive and triple-negative breast cancer: Assessing racial disparities.
Authors: Maithreyi Sarma, Ashwini Ronghe, Samar Nasir, Ankita Kapoor, Kristopher Attwood, Shipra Gandhi
Journal: Journal of Clinical Oncology (2021)

e18624 Background: Triple negative breast cancer (TNBC) &amp; HER2 positive breast cancer (Her2BC), are aggressive breast cancer subtypes. Both are associated with higher mortality in Non-Hispanic Black (NHB) compared to Non-Hispanic White women (NHW). Factors attributed to this racial disparity include socioeconomic status, insurance status, diagnosis(dx)/ treatment delays &amp; comorbidities. We examined the association between race &amp; clinical outcomes (pathological complete response, pCR; recurrence free survival, RFS &amp; overall survival, OS) in patients (pts) dxed with TNBC/Her2BC treated with neoadjuvant chemotherapy (NAC) at Roswell Park Comprehensive Cancer Center. Methods: Pts dxed with Stage I-III TNBC/Her2BC who received NAC from 2000-2018 were included. pCR was defined as absence of residual invasive cancer in the breast &amp; lymph nodes after NAC. Association of race with pCR &amp; survival outcomes was evaluated using logistic &amp; Cox regression models, respectively. Multivariate (MV) models were used to evaluate the association between race &amp; pCR or survival while controlling for relevant confounders including age, BMI, insurance, comorbidities, clinical stage, grade &amp; time from dx to chemotherapy(chemo)/surgery. Analysis was conducted using SAS v9.4 at a significance level of 0.05. Results: 174 TNBC (49 NHB, 125 NHW) &amp; 80 Her2BC (13 NHB, 67 NHW) pts were analyzed. Among TNBC pts, NHB pts had higher baseline BMI(34.3 vs 28.6 kg/m2; p&lt;0.001), higher incidence of hypertension (HTN) (45% vs. 24%; p&lt;0.01), diabetes mellitus (20% vs 8%; p&lt;0.05) &amp; higher Medicare/Medicaid use (M/M) (55% vs. 28%; p&lt;0.01). Among Her2BC pts, NHB pts had higher incidence of HTN (54% vs 25%; p&lt;0.05). There was no statistically significant difference in mean chemo relative dose intensity by race. Among TNBC pts, those with pCR were younger (47 vs 53 yrs; p=0.002) &amp; had more grade 3 tumors (96% vs 80.5%; p&lt;0.05) at dx compared to pts without pCR. Similarly, among Her2BC pts, those with pCR had more grade 3 tumors (64% vs 36%; p&lt;0.05) at dx compared to pts without pCR. Among TNBC pts, advanced age, higher clinical stage &amp; longer time from dx to surgery were associated with worse RFS &amp; OS (p&lt;0.05). Among Her2BC pts, M/M use &amp; advanced clinical stage were associated with worse RFS &amp; OS (p&lt;0.05). There were no significant associations between race &amp; pCR/RFS/OS on MV analysis (table below). Conclusions: Similar outcomes were noted between races for TNBC/Her2BC pts treated at a single academic center in Buffalo, NY. Given the known genetic diversity of African American ancestry in the US, further studies investigating the interplay between race, geography &amp; clinical outcomes are warranted.[Table: see text]
High expression of ferroptosis-sensitizer ACSL4 as an indicator of good response to immune checkpoint inhibitors and preferable survival with increased TIICs in skin cutaneous melanoma.
Authors: Jinchun Wu, Zhengxi He, Xianyu Liu, Yanhua Mou, Jingchen Lu, Chaojun Duan, Bin Li
Journal: Journal of Clinical Oncology (2021)

e21594 Background: Skin cutaneous melanoma (SKCM) has a high incidence and mortality. Immune checkpoint inhibitors (ICIs) are promising but show heterogeneous efficacy in the SKCM treatment. T cell-promoted tumor ferroptosis is a vital anti-tumor mechanism of ICIs. Acyl-CoA synthetase long chain family member 4 (ACSL4) can sensitize ferroptosis by facilitating lipid peroxidation. So we proposed that ACSL4 is a positive predictor for ICIs efficacy and correlated with tumor-infiltrating immune cells (TIICs) in SKCM. Methods: The responses of SKCM patients to ICIs were evaluated from Tumor Immune Dysfunction and Exclusion (TIDE) using the gene expression data of The Cancer Genome Atlas (TCGA)-SKCM downloaded from UCSC Xena browser and datasets within TIDE. The correlation between ACLS4 expression and survival was obtained from the Online consensus Survival webserver for Skin Cutaneous Melanoma (OSskcm) and TIDE databases. The relationships between ACSL4 and TIICs were evaluated using the database of Tumor Immune Estimation Resource 2.0 (TIMER2.0). Results: ACSL4 expression was positively correlated with the predicted responder of ICIs in TCGA dataset (R = 0.12, p = 0.0093) and therapy outcomes of ICIs in Gide2019_PD1+CTLA4 (Progression-free survival(PFS), contimuous z = -2.39, p = 0.0169) and Lauss2017_ACT (PFS, contimuous z = -2.08, p = 0.0371; overall survival(OS), contimuous z = -2.96, p = 0.00309). Favorable OS was observed in the patients with high ACSL4 expression in the TCGA (HR = 0.6567, 95% CI = 0.5015̃0.8599, p = 0.0022) and GSE19234 (HR = 0.4135, 95% CI = 0.1748̃0.9784, p = 0.0445) from OSskcm and the GSE8401 (contimuous z = -2,24, p = 0.025) and GSE54467 (contimuous z = -2.26, p = 0.0239) from TIDE database. TIICs including CD8+ T cells, CD4+ T cells (memory, Th2), B cells, neutrophils, monocytes, M1 macrophages, and cancer-associated fibroblasts (CAFs) were positively associated with the expression level of ACSL4. Conclusions: High ACSL4 expression maybe indicates a good response to ICIs and long survival in SKCM. The increased T cells within the tumor microenvironment correlated with high ACSL4 expression possibly implied the synergism effects of ferroptosis and ICIs, deserving further investigation. Keywords: ACSL4, ICIs, TIICs, SKCM.
Corrected QT prolongation among chemotherapy: Treated patients, a study of a Romanian center.
Authors: Cristina Crisan
Journal: Journal of Clinical Oncology (2021)

e24053 Background: Chemotherapy cardiotoxicity sometimes occurs as QTc prolongation, which may lead to ventricular arrhythmia. We assessed incidence of QTc prolongation among chemotherapy-treated patients. Methods: We enrolled 396 consecutive patients receiving chemotherapy in the Oncology Institute of Cluj-Napoca, Romania. 870 ECGs were performed at baseline and every 2 months, for 5 assessments, during 2016. Results: Most patients were diagnosed with gastro-intestinal tumors and received regimens containing more than one drug. Maximum QTc was recorded after 4 months, when we also found the maximum incidence of increased QTc (&gt;470msec), of 3,73% and of increased ΔQTc (&gt;60msec), of 4%. Female gender was associated with a higher baseline QTc=421 msec, ± 26,9 (p=0.02). No particular chemotherapy regimen was proved to significantly increase QTc. Age was associated with higher QTc and is also an independent variable predicting QTc prolongation (for QTc &gt;480msec, p=0.02), as well as increase of ΔQTc (p&lt;0.001). The number of prior chemotherapy lines correlates with baseline QTc (p&lt;0.0001), with QTc prolongation after 2 months (p=0.01) and predicts higher ΔQTc after 2 months (p=0.01), although within normal range. There was no additive effect during all the 5 assessments. Conclusions: Our results confirm QTc prolongation with chemotherapy and a special attention should be paid to previously treated patients and to elderly patients. Key words: chemotherapy, cardiotoxicity, QTc prolongation.
Is shift-work associated with increased risk of rectal cancer? A meta-analysis.
Authors: Chenyu Sun, Ce Cheng, Kelly Kozma, Gopika Chandra, Na Hyun Kim, Chandur Bhan
Journal: Journal of Clinical Oncology (2021)

e15600 Background: Globally, more than 1.8 million people were diagnosed of colorectal cancer (CRC) in 2018, with over 30% of CRC in the rectum. Shift-work, involving circadian disruption, sleep deprivation and lifestyle changes, was designated as a probable cause of cancer by The International Agency for Research on Cancer. Previous studies investigating the impact of permanent night-shift work and rotating shift-work on rectal cancer risk showed controversial results. Thus, this meta-analysis was conducted. Methods: A comprehensive literature search on PubMed was conducted to identify all relevant studies published prior to January 2021 according to the established inclusion criteria. The quality assessment was performed by the Newcastle-Ottawa Scale (NOS). The pooled odds ratio (OR) and 95% confidence intervals (CI) were calculated to estimate the association between the shift-work and rectal cancer risk. Based on heterogeneity significance, random-effect or fixed-effect model was used. Subgroup analyses were conducted to explore the night-shift and rotating-shift, respectively. Sensitivity analysis and publication bias detection were performed, and trim and fill analysis was also conducted. All statistical analyses were performed using RevMan software (version 5.3; Cochrane library) and STATA 15.0 statistical software (Stata Corp., College Station, TX), and all P values were two-tailed, the test level was 0.05. Results: Thirty-seven articles were obtained from database searching. Three articles involving 1,063 rectal cancer cases were included. All studies were considered moderate to high quality. All included studies investigated on the association between shift-work and rectal cancer risk. A statistically significant association between shift-work and increased rectal cancer risk was found (OR 1.53, 95%CI: 1.31, 1.79, P&lt; 0.00001, I 2 = 35%). In subgroup analyses, night-shift work was associated with a non-statistically significant increased risk of rectal cancer (OR 1.25, 95%CI: 0.47, 3.32, P = 0.66, I 2 = 93%). In contrast, Rotating-shift was associated with a statistically significant increased rectal cancer risk (OR 1.35, 95%CI: 1.10, 1.65, P = 0.004, I 2 = 6%). Sensitivity analysis confirmed the stability of the result. Funnel plot, Egger's test (t = 1.69, P = 0.341), and Begg's test (z = 1.04, P = 0.296) found no publication bias of analysis. Trim and fill analysis on fixed-effect model showed the pooled OR kept stable after adding two “missing” studies (OR 1.403, 95%CI: 1.224, 1.609, P &lt;0.05). Conclusions: The current meta-analysis demonstrates that shift-work is associated with increased rectal cancer risk. However, no association between night-shift work and rectal cancer risk was found. In contrast, association between rotating-shift work and increased rectal cancer risk was found. More original studies on this topic are needed to further explore shift-work impacts on rectal cancer risk.
Nivolumab/ipilimumab primed immunotransplant in post-CAR-T and post-ASCT DLBCL.
Authors: Bailey Gleason Fitzgerald, Thomas Urban Marron, Dana Ostrowski, Jonah Shulman, Matko Kalac, Netonia Marshall, Joshua Brody
Journal: Journal of Clinical Oncology (2021)

2593 Background: Patients with refractory diffuse large b cell lymphoma (DLBCL) have poor outcomes with &lt; 30% surviving for 12 months and especially poor outcomes for those who progress after chimeric antigen receptor T cells (CAR-T) or autologous stem cell transplant (ASCT). These therapies utilize lymphodepleting chemotherapy which induces homeostatic T cell proliferation. We have demonstrated these expanding T cells express high levels of PD1 and CTLA4. In pre-clinical models, addition of dual checkpoint blockade (DCB) with anti-PD1/anti-CTLA-4 to adoptive T cell transfer after lymphodepletion achieved a synergistic anti-tumor effect. Based on these studies, we developed a phase Ib/II study of Nivolumab/Ipilimumab primed “immunotransplant” for relapsed/refractory (R/R) DLBCL (NCT03305445). Methods: Phase Ib of the trial enrolled 6 patients with progressive disease following at least one line of standard therapy. Patients received two cycles of DCB with ipilimumab (1mg/kg) and nivolumab (3mg/kg) given at three-week intervals followed by immunotransplant (i.e. peripheral blood T cell harvest, lymphodepletion with fludarabine/cyclophosphamide, T cell reinfusion), followed by two further cycles of DCB and nivolumab maintenance. Results: Five patients received at least two cycles of DCB and the autologous T cell transfer, while one patient had progressive disease during initial DCB and required salvage chemotherapy. Treatment emergent AE (TEAE) occurred in 100% of patients. As expected with lymphodepleting chemotherapy, the most common TEAE were neutropenia (66.7% grade 1, 66.7% grade ≥ 3), fatigue (83.3%, 16.7%), fever (66.7%, 0%), and dyspnea (66.7%, 0.0%). One patient (16.7%) died during the intervention period (grade 5 TEAE), though relation to study drug is unclear. Three patients (50.0%) experienced clinical benefit with immunotransplant. One patient (a 58yo M with progression after seven lines of therapy including ASCT and CAR-T) is experiencing partial metabolic response after 4 months on protocol. One 77yo F with multiple prior lines of therapy including ASCT has experienced an extended complete metabolic response, currently 31 months post immunotransplant. A third (a 50yo F) experienced mixed radiographic response, and has not received subsequent therapy 30 months following immunotransplant. Conclusions: Nivolumab/Ipilimumab primed immunotransplant is well tolerated in patients with R/R DLBCL for whom there are few treatment options. Preliminary results demonstrate remissions in heavily pre-treated patients, including prior ASCT and CAR-T. Pre-clinical models in melanoma, non-small cell lung cancer, and T cell lymphoma all demonstrate synergy when DCB is administered with lymphodepletion and autologous T cell transfer. These data support further investigation of DCB-primed immunotransplant. Clinical trial information: NCT03305445.
Switching Kogenate FS® to Kovaltry® for the Treatment of Severe Haemophilia A Patients: A Successful Single Center Experience
Authors: Teresa Álvarez-Roman, Nora Butta, Mónica Martín, María Isabel Rivas Pollmar, Ihosvany Fernandez-Bello, Miguel A. Canales, Victor Jimenez-Yuste
Journal: Blood (2017)
Thromboprophylaxis in active cancer patients: Is it a controversial clinical issue or not? Preliminary results of ACT4CAT study.
Authors: Nikolaos Tsoukalas, Athina Christopoulou, Christos N. Papandreou, Anna Koumarianou, Ilias Athanasiadis, Stavros Peroukidis, Georgios Samelis, Amanda Psyrri, Nikolaos Kapodistrias, Achilleas Nikolakopoulos, Charalampos Andreadis, Alexandros Ardavanis, Epaminondas Samantas, Alexandros Bokas, Barbounis Vassilios, Nikolaos K. Kentepozidis, Dimitrios Mavroudis, Athanasios Athanasiadis, Pavlos Papakotoulas, Ioannis Boukovinas
Journal: Journal of Clinical Oncology (2021)

e18803 Background: Cancer Associated Thrombosis (CAT) is an increasing challenge for oncology patients since oncologists sometimes are reluctant to mitigate the risk with thromboprophylaxis. Active cancer patients while receiving chemotherapy have a 7fold risk of thrombosis compared with no cancer patients. Anticoagulation holds a prominent place in prevention of CAT usually with Low Molecular Weight Heparins (LMWHs). Methods: ACT4CAT is prospective observational study conducted by HeSMO across Greece, aiming to record the clinical practice of CAT prophylaxis in patients with solid tumors. Ambulatory, high thrombotic risk, active cancer patients who received thromboprophylaxis enrolled after signing informed consent. Results: Preliminary results collected from 18 oncology departments. From 431 enrolled patients 322 (65.4%) had completed the study. Tumor types included: lung 28.8%, gastrointestinal 39.8%, gynecological 7.0%, breast 4.4%, urological 7.0% and others 20%. Majority of patients (88.2%) received High-Risk for Thrombosis Chemotherapy Agents (HRTCAs) such as platinum agents (55.9%), antimetabolites (44.7%) and immunotherapy (12.6%). In 1 st line were 62.1%, 2nd line 18.4%, adjuvant 8.9% and neoadjuvant 2.4%. The following table depicts: age, gender, metastatic disease, Khorana score ≥2 and HRTCAs. All patients received thromboprophylaxis for 5.3±3.6 months with: tinzaparin 90.8%, fondaparinux 5.5%, bemiparin 1.5%, enoxaparin 1.2%, apixaban 0.5% and rivaroxaban 0.5%. Intermediate doses received 70.9% of patients regardless clinical setting (1 st , 2 nd , adjuvant &amp; neoadjuvant: 70.2%, 79.2%, 51.3% and 70.0% respectively, p = 0.0254), although intermediate doses were used more in metastatic stages (OR:2.4 95%CI: 1.4-4.2, p = 0.0028). Nine thrombotic events reported (2.1%, 95%CI: 1.1-3.9%), irrespective of clinical setting but with a trend towards prophylactic doses. Eleven grade 1 bleedings reported (2.6%, 95%CI: 1.4-4.5%), despite clinical setting or dose used. Conclusions: Thromboprophylaxis in ambulatory active cancer patients with high thrombotic risk is safe and effective. Oncologists are alerted about CAT negative influences in cancer patients’ prognosis. Apart from Khorana score, factors such as metastases, use of HRTCAs and drug-drug interactions influence the clinical decision of thromboprophylaxis in active cancer patients mainly with LMWHs and quite often with intermediate doses regardless clinical setting. Clinical trial information: NCT03909399. [Table: see text]
Rh Hemolytic Disease
Authors: Diane K. Wysowski
Journal: JAMA (1979)

Nationwide surveillance of Rh hemolytic disease of the newborn showed that associated infant mortality decreased from 941 deaths in 1968 to 269 deaths in 1975, or from 2.7 to 0.9 per 10,000 live births. The incidence of Rh hemolytic disease declined from 45 per 10,000 total births in 1970 to 21 per 10,000 in 1975. In 1970, an estimated 16,000 infants were affected, whereas in 1975, the number was 6,000. Several state-based Rh disease surveillance programs reported declining mortality and incidence and increasing use of Rh immune globulin. Rh immune globulin was administered to an estimated 80% of eligible Rh-negative women in 1974, eighty-one percent in 1975, and 82% in 1976. More concerted efforts are needed to determine the frequency of maternal sensitization and to identify and correct gaps in postpartum and postabortion use of Rh immune globulin. (<i>JAMA</i>242:1376-1379, 1979)
The surgical oncology clinical trial landscape: A cross-sectional analysis of ClinicalTrials.gov from 2008-2020.
Authors: Nirosha D. Perera, Brandon E. Turner, Jolie Z. Shen, Bonnie O. Wong, Henry K. Litt, MaKenna A. Stavins, Tiffany R. Bellomo, Massoud Saleki, Alexander Bell, Ruxandra Ionescu, Margaret Shyu, Max M. Wang, Jacqueline Tao, Nadeen Sarsour, Ryan M O'Keefe, Jordan M. Takasugi, Jecca R. Steinberg, Roderick King, Amit Mahipal, Sherry M. Wren
Journal: Journal of Clinical Oncology (2021)

1561 Background: Surgical interventions are studied less often than medical or radiation interventions in oncology clinical trials. We characterized surgical oncology trials registered on ClinicalTrials.gov, analyzed funding sources and identified features associated with early discontinuation and results reporting. Methods: We employed a cross-sectional study design with descriptive, logistic regression, cox regression, time series and survival analyses. We downloaded all 270,172 studies registered on the Aggregate Analysis of the ClinicalTrials.gov database from October 1, 2008 to March 9, 2020. After excluding non-interventional trials, applying cancer/oncology specific Medical Subject Heading terms to the remaining trials and excluding phase 1 trials, 27,915 trials were identified for manual review. Primary exposure variables were trial focus: neoplasia site and treatment modality (surgical interventions included investigations of outcomes from surgical resection or intra-operative/peri-operative changes), and funding: industry, U.S. government, academic. Results: 26,815 trials were found to have true oncology content; 1,661 (6.2%) involved surgical oncology, representing 311,789 patients. Funding sources were: 82.7% by academic institutions, 10.9% by industry, and 6.2% by U.S. government. The most studied neoplasia sites were colorectal (17.4% of trials), breast (10.7%), gastric (10.5%), hepatic (8.6%), lung (7.5%), brain/CNS (6.7%) and cervical (6.6%). U.S. government funded surgical oncology trials had the lowest risk of early discontinuation (adjusted HR 0.50, 95% CI: 0.26-0.99, p&lt;0.047) and the highest odds of results reporting (adjusted OR 1.08, 95% CI: 0.55-2.11, p=0.83) (Table 1). Conclusions: There is a paucity of surgical oncology clinical trials compared to other treatment modalities, especially in context of surgery’s role in overall cancer care. From 2008-2020 only 6.2% of trials focused on surgical oncology, and U.S. government funded trials displayed the lowest hazard of early discontinuation and highest odds of results reporting. Stakeholders should look to government funded trials as models of improvement, but must increase representation and results dissemination of surgical oncology trials to guide treatment recommendations. Surgical oncology trial features and associated early discontinuation/results reporting. [Table: see text]