tbuckley/cabot-search huggingface dataset:
<i>BRCA</i> reversion mutations in a pan-cancer cohort to reveal <i>BRCA-</i>dependence in select noncanonical <i>BRCA-</i>mutant histologies.
Authors: Yonina R. Murciano-Goroff, Alison M. Schram, Ezra Rosen, Yelena Y. Janjigian, Michael F. Berger, Mark Donoghue, Chaitanya Bandlamudi, Alexander E. Drilon
Journal: Journal of Clinical Oncology (2021)

3012 Background: Loss of BRCA1/2 function leads to homologous recombination deficiency (HRD) and can enhance platinum and PARP inhibitor sensitivity in breast, pancreas, prostate, and ovarian cancers. In BRCA-associated cancers, resistance can result from the development of BRCA1/2 reversion mutations, which restore BRCA1/2 function. By contrast, a BRCA mutation may be an incidental finding in other tumor histologies. Methods: To determine the distribution of reversion mutations in a pan-cancer cohort, the MSK-IMPACT clinical sequencing cohort was mined to identify patients who had both a germline BRCA1/2 mutation and a frameshift somatic reversion mutation that restored BRCA1/2 function. Whole exome resequencing was used to detect HRD signatures. Chart review enabled collection of data on treatment history in patients consented to germline testing. Results: Of the 33,277 patients with matched tumor and normal sequencing profiled in this study, 861 patients were found to have germline pathogenic BRCA1/2 alterations, including 347 (40%) in BRCA1 and 514 (60%) in BRCA2. Somatic BRCA1/2 driver alterations were also found in tumor tissue from an additional 447 patients, with 156 (35%) having BRCA1 mutations, and the remainder having alterations in BRCA2 (65%) . Among the 1,308 germline or somatic BRCA1/2 mutant tumors, we identified reversion mutations in 12 patients, all of whom were germline carriers of BRCA1/2, comprising 3 BRCA1 and 9 BRCA2 tumors. 7 patients consented to germline testing enabling review of clinical characteristics and treatment history, 5 of whom received PARP inhibitor or platinum-therapy prior to reversion detection. Ten of 12 tumors with reversion mutations were in canonical BRCA-associated cancers. Interestingly, reversion mutations were also found in patients with lung adenocarcinoma (n=1) and gastroesophageal junction adenocarcinoma (n=1). In both these non-canonical histologies, the reversion was detected following progression on platinum-based therapy. Whole exome resequencing of the lung tumor revealed the classic somatic molecular phenotypes of HRD that are characteristic of BRCA-dependent tumors, including in terms of large-scale transitions, HRD-loss of heterozygosity, signature 3, and the number of telomeric allelic imbalance score. Conclusions: Matched tumor and normal sequencing from a large cohort of patients with diverse cancer histologies reveals that reversion mutations are found across BRCA-associated cancer types. In rare cases, reversion mutations in BRCA1/2 following platinum-based therapy may be indicative of prior BRCA-dependence in select non-canonical tumor histologies.
Racial and ethnic disparities in inpatient health care utilization for mycosis fungoides: A cross-sectional analysis of the 2012-2017 National Inpatient Sample
Authors: Justin Choi, Nishadh Sutaria, Youkyung Sophie Roh, Zachary Bordeaux, Ronald J. Sweren, Yevgeniy R. Semenov, Shawn G. Kwatra
Journal: Journal of the American Academy of Dermatology (2021)
Age-related amyloidosis outside the brain: A state-of-the-art review
Authors: Masayoshi Tasaki, Francesca Lavatelli, Laura Obici, Konen Obayashi, Takeshi Miyamoto, Giampaolo Merlini, Giovanni Palladini, Yukio Ando, Mitsuharu Ueda
Journal: Ageing Research Reviews (2021)
The diagnostic value of core needle biopsy in cervical cancer: A retrospective analysis.
Authors: Massimiliano Lia, Lars-Christian Horn, Paulina Sodeikat, Michael Höckel, Bahriye Aktas, Benjamin Wolf
Journal: Journal of Clinical Oncology (2021)

e17512 Background: The aim of this retrospective study was to evaluate the accuracy, sensitivity, specificity, and predictive values of preoperative core needle biopsy (CNB) assessment of histological characteristics in primary cervical cancer. Methods: We reviewed 318 cases of primary cervical carcinoma with available pathology reports from preoperative CNB assessment and from final postoperative evaluation of the hysterectomy specimen. Setting the postoperative comprehensive pathological evaluation as reference, we analysed CNB assessment of histological tumor characteristics. In addition, we performed multivariable logistic regression to identify factors influencing the accuracy in identifying lymphovascular space invasion (LVSI) and tumor grade. Results: CNB was highly accurate in discriminating histological subtype. Sensitivity and specificity were 98.8% and 89% for squamous cell carcinoma (SCC), 92.9% and 96.6% for adenocarcinoma (AC), 33.3% and 100% in adenosquamous carcinoma respectively. Neuroendocrine carcinoma was always recognized correctly. The accuracy of the prediction of lymphovascular space invasion (LVSI) was 61.9% and was positively influenced by tumor size in preoperative MRI and negatively influenced by strong peritumoral inflammation. High tumor grade was diagnosed accurately in 73.9% of cases and was influenced by histological tumor type. Conclusions: CNB is an accurate sampling technique for histological classification of cervical cancer and represents a reasonable alternative to other biopsy techniques. Factors such as peritumoral inflammation, tumor size or tumor subtype may influence the accuracy of histologic Evaluation and should be taken into account when interpreting the results.
Eruptive xanthoma model reveals endothelial cells internalize and metabolize chylomicrons, leading to extravascular triglyceride accumulation
Authors: Ainara G. Cabodevilla, Songtao Tang, Sungwoon Lee, Adam E. Mullick, Jose O. Aleman, M. Mahmood Hussain, William C. Sessa, Nada A. Abumrad, Ira J. Goldberg
Journal: Journal of Clinical Investigation (2021)

Although tissue uptake of fatty acids from chylomicrons is primarily via lipoprotein lipase (LpL) hydrolysis of triglycerides (TGs), studies of patients with genetic LpL deficiency suggest additional pathways deliver dietary lipids to tissues. Despite an intact endothelial cell (EC) barrier, hyperchylomicronemic patients accumulate chylomicron-derived lipids within skin macrophages, leading to the clinical finding eruptive xanthomas. We explored whether an LpL-independent pathway exists for transfer of circulating lipids across the EC barrier. We found that LpL-deficient mice had a marked increase in aortic EC lipid droplets before and after a fat gavage. Cultured ECs internalized chylomicrons, which were hydrolyzed within lysosomes. The products of this hydrolysis fueled lipid droplet biogenesis in ECs and triggered lipid accumulation in cocultured macrophages. EC chylomicron uptake was inhibited by competition with HDL and knockdown of the scavenger receptor-BI (SR-BI). In vivo, SR-BI knockdown reduced TG accumulation in aortic ECs and skin macrophages of LpL-deficient mice. Thus, ECs internalize chylomicrons, metabolize them in lysosomes, and either store or release their lipids. This latter process may allow accumulation of TGs within skin macrophages and illustrates a pathway that might be responsible for creation of eruptive xanthomas.
Abstract NT-119: TARGET DISCOVERY OF NATURAL PRODUCT INSPIRED PHYLLANTHUSMINS FOR TREATMENT OF HIGH GRADE SEROUS OVARIAN CANCER
Authors: Alexandria N. Young, Steven Kurina, Andrew Huntsman, Rathnayake A. Rathnayake, Melissa Korkmaz, A. Douglas Kinghorn, Leslie Aldrich, Stephanie Cologna, James R. Fuchs, Joanna E. Burdette
Journal: Clinical Cancer Research (2019)

Abstract BACKGROUND: High grade serous ovarian cancer (HGSOC) is a lethal gynecological malignancy with a need for new therapeutic agents. Many of the most widely used chemotherapeutic drugs are either derived from or are semi-synthetic derivatives of natural products. We developed potent synthetic analogs (PHYs) of the phyllanthusmin class inspired by prior natural product isolated from Phyllanthus poilanei Beille. MATERIALS &amp; METHODS: HGSOC cell lines, OVCAR3 and OVCAR8, and non-tumorigenic controls, IOSE80 and FT33, were used in this study. Cytotoxicity assays included sulforhodamine B assay, and annexin X/PI staining and Western blotting for confirmation of apoptosis induction. A photo affinity labeling method was used to attach PHY analogs to solid phase support. Targets were isolated using a pulldown technique and mass spectrometry. CRISPR-Cas9 genome editing was used to knockout and confirm putative targets. RESULTS: The most potent analog, PHY34, has nanomolar potency in HGSOC cell lines in vitro and displayed cytotoxic activity through late-stage autophagy inhibition and activation of apoptosis. PHY34 was readily bioavailable through intraperitoneal administration in vivo where it significantly reduced HGSOC tumor burden. Targets were identified using photo affinity labeling-aided protein pulldown and mass spectrometry, and confirmed by generating knockout cell lines of targets. CONCLUSIONS: This class of compounds holds promise as a potential, novel chemotherapeutic approach and demonstrates the effectiveness of pleiotropically targeting autophagy and apoptosis as a viable strategy for combating high grade serous ovarian cancer. Citation Format: Alexandria N. Young, Steven Kurina, Andrew Huntsman, Rathnayake A. Rathnayake, Melissa Korkmaz, A. Douglas Kinghorn, Leslie Aldrich, Stephanie Cologna, James R. Fuchs, Joanna E. Burdette. TARGET DISCOVERY OF NATURAL PRODUCT INSPIRED PHYLLANTHUSMINS FOR TREATMENT OF HIGH GRADE SEROUS OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-119.
Adverse events in non-small cell lung cancer patients receiving immune checkpoint inhibitors: A single center, real-world study in China.
Authors: Chongrui Xu, Hai-Yan Tu, Yueli Sun, Yang-Si Li, Bingfei Xu, Binchao Wang, Hua-Jun Chen, Zhen Wang, Qing Zhou, Jinji Yang, Qi Yang, Yi-Long Wu
Journal: Journal of Clinical Oncology (2021)

e21081 Background: Immune checkpoint inhibitors (ICIs) have improved clinical outcomes in non-small cell lung cancer (NSCLC), whereas they also can cause various adverse events (AEs). We reported the incidences, spectrum and severity of AEs in real-life practice after the approval of ICIs in Chinese NSCLC patients. Methods: In this single center, retrospective study, anonymized electronic medical record data were collected from the dedicated lung cancer immunotherapy outpatient clinic of Guangdong Provincial People’s Hospital through the LinkDoc database. The patients (≥18 years old) with pathologically diagnosed metastatic NSCLC who receiving ICIs between 1 June 2019 and 31 December 2020 were included. The immune-related adverse events (irAEs) were diagnosed and assessed by oncologists. All AEs were classified and graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE V5.0). Results: A total of 203 patients with a median age of 60.5 years were included in this study. Most patients were male (81.8%), smokers (49.8%), non-squamous histological type (51.7%). 61.1% of patients visited the outpatient clinic more than once. Pembrolizumab and Nivolumab were given to the majority of patients (80.8%). 114 patients (56.2%) received single-agent and 89 patients (43.8%) received combination therapy. The median duration of ICIs therapy was 271.2 days. In our study, 68.0% of patients experienced any-grade AEs, and 19.7% experienced grade≥3 AEs. The most commonly AEs were abnormal laboratory findings (57.1%), blood and lymphatic system disorders (25.1%), and respiratory disorders (19.7%). All of 93 patients (45.8%) experienced irAEs and 6 patients (8.4%) developed grade≥3 irAEs. The most frequent irAEs included blood and lymphatic system disorders (25.1%), hepatobiliary disorders (17.7%), and cardiac disorders (9.9%). Cough (3.4%), sputum (2.5%), and pain (2.0%) were the most frequent AEs which received treatment. Conclusions: Our results showed 68.0% and 45.8% patients experienced AEs and irAEs, respectively. The AEs and irAEs were primarily low grade. This study also demonstrated the information of AEs could be well collected and managed through our dedicated lung cancer immunotherapy outpatient clinic. [Table: see text]
Resolving driver events in MLL-r negative high-risk infant ALL.
Authors: Jennifer Seelisch, Matthew Zatzman, Federico Comitani, Fabio Fuligni, Ledia Brunga, Patrick A. Brown, Adam Shlien, Sumit Gupta
Journal: Journal of Clinical Oncology (2021)

10030 Background: Infant acute lymphoblastic leukemia (ALL) is the only subtype of childhood ALL whose outcome has not improved over the past two decades. The most important prognosticator is the presence of rearrangements in the Mixed Lineage Leukemia gene (MLL-r), however, many patients present with high-risk clinical features but without MLL-r. We recently identified two cases of infant ALL with high-risk clinical features resembling MLL-r, but were negative for MLL-r by conventional diagnostics. RNA sequencing revealed a partial tandem duplication in MLL (MLL-PTD). We thus aimed to determine if MLL-PTD, other MLL abnormalities, or other genetic or transcriptomic features were driving this subset of high-risk infant ALL without MLL-r. Methods: We obtained 19 banked patient samples from the Children’s Oncology Group (COG) infant ALL trial (AALL0631) from MLL wildtype patients as determined by FISH and cytogenetics. Utilizing deep RNA-sequencing, we manually inspected the MLL gene for MLL-PTD, while also performing automated fusion detection and gene expression profiling in search of defining features of these tumors. Results: 3 additional MLL-PTDs were identified, all in patients with infant T-cell ALL, whereas both index cases were in patients with infant B-cell ALL. Gene expression profiling analysis revealed that all five MLL-PTD infants clustered together. Eight infants (7 with B-cell ALL) were found to have Ph-like expression. Five of these 8 infants were also found to have an IKZF1/JAK2 expression profile; one of these five had a PAX5-JAK2 fusion detected. Two infants (including the one noted above) had novel PAX5 fusions, known drivers of B-cell leukemia. Additional detected fusions included TCF3-PBX1 and TCF4-ZNF384. Conclusions: MLL-PTDs were found in both B- and T-cell infant ALL. Though Ph-like ALL has been described in adolescents and young adults, we found a substantial frequency of Ph-like expression among MLL-WT infants. Further characterization of these infants is ongoing. If replicated in other infant cohorts, these two findings may help explain the poor prognosis of MLL-WT ALL when compared to children with standard risk ALL, and offer the possibility of targeted therapy for select infants.
Four-year survival follow-up of toripalimab (JS001) as salvage therapy in Chinese melanoma patients.
Authors: Bixia Tang, Zhihong Chi, Yingbo Chen, Xiufeng Liu, Di Wu, Jing Chen, Xin Song, Weifeng Wang, Lihou Dong, Haifeng Song, Hai Wu, Shukui Qin, Jun Guo, Xiaoshi Zhang, Sheng Yao, Hui Feng
Journal: Journal of Clinical Oncology (2021)

e21522 Background: Toripalimab, a PD-1 monoclonal antibody received conditionally approval in China as a salvage therapy for metastatic melanoma in 2018 based on a phase II trial with confirmed objective response rate of 17.3%. With four-year survival follow-up, here we report long-term survival results and related predictive biomarkers (NCT03013101). Methods: Patients with advanced melanoma who had failed prior systemic treatments were given toripalimab at 3 mg/kg i.v. Q2W until disease progression, intolerable toxicity or 2-year of treatment. Pts were followed for survival every 3 mo after discontinuation of treatment. Pts were transferred to an extension study after 2-year treatment. The Primary endpoint for the extension study was overall survival (OS). Results: 127 pts were enrolled, including50 (39.4%) acral, 22 (17.3%) mucosal, 29 (22.9%) nonacral cutaneous, and 26 (20.5%) unknown primary subtypes. After a median follow-up of 16.5 mo (range, 0.9-48.8), 74 (58%) pts had died. Median duration of response was 25.6 mo (95%CI:12.8-NE). Median OS was 22.0 mo (95%CI: 15.3-32.5). The OS rates for year 1 to 4 were 67.1%, 48.2%, 38.0% and 31.7% respectively. The median OS of complete response (CR)/ partial response (PR) (n = 22), stable disease (SD) (n = 51), progression disease (PD) (n = 54) were not reached, 34.0 mo and 9.7 mo, respectively. The median OS of non-acral cutaneous, unknown primary, acral and mucosal melanoma subtypes were 46.1, 37.3, 16.9 and 10.3 mo, respectively. The median OS of PD-L1+ (n = 26) and PD-L1- (n = 84) patients were 46.1 and 14.4 mo (P = 0.026, HR = 0.45, 95%CI 0.26-0.76). The median OS of TMB high (n = 20), TMB low (n = 78) was 16.0 and 22.3 mo with no statistically significance (P = 0.49, HR = 1.28, 95%CI 0.63-2.58). Conclusions: Salvage treatment with toripalimab leads to long-term survival benefit in advanced melanoma patients, especially for those with non-acral cutaneous and unknown primary subtypes, CR/PR/SD as best response or PD-L1+.
Regorafenib in recurrent glioblastoma patients: A large real-life experience.
Authors: Mario Caccese, Giulia Cerretti, Marta Padovan, Vittorina Zagonel, Giuseppe Lombardi
Journal: Journal of Clinical Oncology (2021)

e14024 Background: Regorafenib (REG), an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases showed encouraging benefit in recurrent GBM patients enrolled in the randomized, phase 2 REGOMA trial. We investigated the clinical outcome and safety of REG in a real-life population of recurrent glioblastoma patients treated at Veneto Institute of Oncology as off-label use. Methods: The clinical data of patients receiving REG at Veneto Institute of Oncology (Padua, Italy) were entered prospectively into clinical records and were retrospectively analyzed. The primary endpoints of the study were overall survival (OS) and safety. The major inclusion criteria were: histologically confirmed diagnosis of GBM, disease progression as defined by RANO criteria after surgery followed by radiochemotherapy with temozolomide, ECOG PS ≤ 2; PTS with ≥ 2 prior lines of therapy were excluded. According to original schedule, patients received REG 160 mg once daily for the first 3 weeks of each 4-week cycle until disease progression, death, unacceptable toxicity, or consent withdrawal. Kaplan-Meier method was used to estimate the survival curves, RANO criteria for radiological assessment, CTCAE v5.0 for drug related adverse events. Results: From February 2018 to September 2020, 54 consecutive patients were treated with REG and enrolled in this study: median age was 56, ECOG PS 0-1 in 91% of patients, MGMTmet in 53%, second surgery at the time of relapse were performed in 30% of enrolled patient, 41% of patients underwent steroids at baseline. At the time of analysis, median follow-up was 11.1 ms, 30 PTS (56%) had died and 50 PTS (93%) had progressed. Median OS was 10.2 ms (95%CI, 6.4-13.9), 12m-OS was 43%; median PFS was 2.3ms (95%CI, 1.3-3.3) and 6m-PFS was 18%. All patients were evaluable for response: disease control rate (DCR) was 46.3%; stable disease was reported in 38.8% and partial response in 7.4%. Age, MGMT status and corticosteroid use at baseline were not statistically significant on multivariate analysis for OS. Grade 3 drug-related adverse events (AEs) occurred in 10 patients (18%) and the most frequent were hand-foot skin reaction, asthenia and increased lipase and transaminases; 1 PT (2%) reported a grade 4 AE (rash maculo-papular). AEs led to REG dose reductions in 37% of patients and, it was permanently discontinued in 5%. No death was considered to be drug-related. Conclusions: We reported a large, mono-institutional “real world” experience of REG in recurrent glioblastoma patients. Overall, results are close to those reported in REGOMA trial although, we showed a longer OS. Toxicity was moderate and manageable. Encouraging clinical benefits of REG in recurrent GBM population were confirmed.
Radiological response as a predictor of pathological response to combined tyrosine kinase inhibitor (TKI) and anti-PD-1 antibodies in hepatocellular carcinoma (HCC).
Authors: Hui-Chuan Sun, Cheng Huang, Xiao-Dong Zhu, Ying-Hao Shen, Dong Wu, Yuan Ji, Ning-Ling Ge, Yi Chen, Chang-Jun Tan, Jian Zhou, Jia Fan
Journal: Journal of Clinical Oncology (2021)

e16144 Background: Pathological complete response (CR) and major pathological response (MPR) are associated with long-term survival after neoadjuvant/conversion surgery of HCC. The relationship between imaging and histopathological evaluations of response to combined TKI plus anti-PD-1 antibody treatment is unclear. Methods: This retrospective analysis included 23 patients with an initial diagnosis of unresectable HCC who underwent resection after combined TKI/anti-PD-1 antibody treatment between March 2019 and December 2020 at Zhongshan Hospital of Fudan University. MRI was performed before and after treatment and objective response rate (ORR; CR or partial response [PR]) was evaluated using RECIST 1.1 and mRECIST by investigator assessment (INV) and independent imaging review (IIR). Histopathological response was evaluated in resected tumor tissue using residual viable tumor (RVT; RVT area/total tumor bed surface area under 100X microscopy). MPR was defined as &lt;10% RVT. The relationship between radiological reduction in tumor size and MPR was investigated using a receiver operating characteristic (ROC) curve. Results: Patients had a median age of 54.0 years, 91% were male and the average pre-treatment tumor diameter was 11.5±4.6 cm. Three had Barcelona Clinic Liver Cancer (BCLC) Stage A disease (China Liver Cancer Stage [CNLC] Ib, n=3), six had BCLC Stage B (CNLC IIa, n=1 and IIb n=5) and 14 had BCLC Stage C (CNLC IIIa, n=10 and IIIb, n=4). Patients received lenvatinib (n=19) or apatinib (n=4) plus anti-PD-1 antibodies (pembrolizumab [n=5], sintilimab [n=5], camrelizumab [n=10], treprizumab [n=2] or nivolumab [n=1]) followed by resection. Radiological responses are summarized in Table. An MPR or pathologic CR was achieved by 52.2% (12/23) and 39.1% (9/23) of patients, respectively. A correlation was observed between radiological responses using RECIST 1.1 and mRECIST and MPR (Fisher’s exact test; P=0.089 and 0.037, respectively). Using RECIST 1.1, the optimum diagnostic cutoff for MPR was a 26% reduction in tumor size, by both INV (area under ROC (AUC)=0.780, 95% CI: 0.580–0.981, sensitivity 83.3%, specificity 72.7%) and IIR (AUC=0.739, 95% CI: 0.527–0.951, sensitivity 75.0%, specificity 72.7%). Using mRECIST, the optimum cutoff for MPR was a 78% reduction in tumor size by INV (AUC=0.746, 95% CI: 0.538–0.954, sensitivity 58.3%, specificity 90.9%) and IIR (AUC=0.742, 95% CI: 0.532–0.953, sensitivity 66.7%, specificity 81.8%). Conclusions: Radiological response showed a degree of correlation with MPR in patients with advanced HCC receiving combined TKI and anti-PD-1 antibody therapy. Therefore, imaging evaluation may be used to predict a pathological response and further guide clinical treatment decisions. Response rates (n=23).[Table: see text]