tbuckley/cabot-search huggingface dataset:
Safety of using hormone replacement therapy in breast cancer survivors: A systematic review and metanalysis.
Authors: Francesca Poggio, Lucia Del Mastro, Marco Bruzzone, Marcello Ceppi, Maria Grazia Razeti, Piero Fregatti, Maurizio Cosso, Paolo Pronzato, Claudia Massarotti, Maria Alice B Franzoi, Matteo Lambertini, Marco Tagliamento
Journal: Journal of Clinical Oncology (2021)

12067 Background: Improvements in breast cancer (BC) care have led to increased survival of patients; hence, more attention to long-term treatment-related adverse events and quality of life (QoL) is required. Symptoms of spontaneous and treatment-induced menopause significantly affect the QoL and adherence to endocrine therapy among BC survivors, with potential negative implications on outcome. Use of systemic hormone replacement therapy (HRT) to mitigate menopause-associated symptoms is not recommended to reduce the burden of these side effects being historically associated with an increased risk of disease recurrence. This systematic review and metanalysis aimed to estimate the effect of HRT on risk of disease recurrence in BC survivors. Methods: A systematic search of Pubmed and Embase libraries up to January 15, 2021, was conducted in order to identify randomized controlled trials (RCTs) investigating the risk of disease recurrence with the use of HRT in BC survivors. We used the random-effect model to calculate the overall risk of recurrence, reported as pooled hazard ratio (HR) with 95% confidence intervals (CI). Moreover, we performed a subgroup analysis to estimate the risk of recurrence according to hormone receptor status. The Higgins I 2 index was computed to assess the heterogeneity between studies. The likelihood of publication bias was assessed by Egger’s test. Results: Four RCTs were found and three were included in the metanalysis (n = 3.973 patients); one study (n = 100 patients) was excluded due to the impossibility to extract the HR for disease recurrence. Overall, 1.990 patients were randomized to receive HRT (estrogen-progesteron combination or tibolone), while 1.983 patients were included in control groups (placebo or no HRT). As compared to control group, HRT significantly increased the risk of BC recurrence (HR 1.49, 95% CI 1.15-1.93, p = 0.002). The heterogeneity between the studies was low (39%, p = 0.194), and no publication bias was found ( p = 0.537). Two studies reported the HR according to hormone receptor status. At the subgroups analysis, the risk of BC recurrence with the use of HRT was significantly increased in hormone receptor-positive patients (HR 1.8, 95% CI 1.15-2.82, p = 0.010) but not in those with hormone receptor-negative tumors (HR 1.25, 95% CI 0.83-1.88, p = 0.290). Conclusions: Use of HRT significantly increases the risk of recurrence in BC survivors, particularly in those with hormone receptor-positive disease. Therefore, this approach remains contraindicated in this setting. Alternative interventions to mitigate menopause-related symptoms should be proposed to these patients.
Hereditary breast cancer associated with the CHEK2 gene: Study through NGS in a Spanish cohort.
Authors: Natalia Alonso Marin, Maitane Ocáriz, Marta Gascon Ruiz, Andrea Sesma Goñi, Maria Zurera Berjaga, Maria Zapata-Garcia, Ines Ruiz Moreno, Alba Moratiel Pellitero, Maria Marti Pi, Ana Goas Gomez, Mara Cruellas, Maria Alvarez, Raquel Andrés, Dolores Isla, Rodrigo Lastra
Journal: Journal of Clinical Oncology (2021)

e22502 Background: Inherited mutations in the CHEK2 gene have been associated with an increased lifetimerisk of develop breast cancer (BC). The main objective of the study is to identify in our population the prevalence of mutations in the CHEK2 gene in diagnosed BC patients, as well as to evaluate the phenotypic characteristics of the tumour and family history. Methods: A genetic study was performed in 396 patients diagnosed of BC at the University Hospital Lozano Blesa of Zaragoza (Spain). We selected 9 patients with genetic variants in the CHEK2 gene and performed a descriptive analysis of the clinical variables, a bibliographic review of the genetic variants and a co-segregation study. Results: We identified 2 pathogenic variants ( CHEK2 c.349 A&gt;G and c.507delT) and 6 variants of uncertain significance (VUS). The genotypic characteristics of the VUS are summarized in the table. In all cases there was a family history of BC in first and /or second degree relatives. The variant cosegregated with the disease in one of the families. Conclusions: The pathogenic missense variant c.349A&gt;G was found in two families. This is a rare missense variant. Studies have shown that this variant had a significant impact on the protein based on in silico prediction and has been associated with BC. In our study, this variant was found in a patient with renal carcinoma and was identified in a proband with a strong family history of pancreatic and ovarian cancer (OC). However, there aren’t exist data about the risk of developing other cancer, different of BC, with this specific mutation. The other pathogenic variant detected was CHEK2 c.507delT in a family with history of BC and OC. This variant is a frameshift mutation, predicted to cause loss of normal protein function. CHEK2 507delT was reported in one of 12 BC families in one series and is possible its relation with OC. With regard to the VUS the cosegregation analysis in selected families may help understand if a variant could have played a role in developing cancer. In conclusion, CHEK2 mutations have been associated with increased risk for BC. However, the frequency of carriers may vary depending on the population, and different mutations may be associated with different cancer risks. More studies are needed to establish a complete range of risks associated with CHEK2 mutations. [Table: see text]
Combining radiation therapy with anti-PD-1 for patients with advanced hepatocellular carcinoma: An open-label, single-center, single-arm clinical study.
Authors: Jian-Xu Li, Ting-Shi Su, Xiao-Feng Lin, Yi-Tian Chen, Shi-Xiong Liang, Bang-De Xiang
Journal: Journal of Clinical Oncology (2021)

e16117 Combining radiation therapy with anti-PD-1 for patients with advanced hepatocellular carcinoma: an open-label, single-center, single-arm clinical study Jian-Xu Li, Ting-Shi Su, Xiao-Feng Lin, Yi-Tian Chen, Shi-Xiong Liang, Bang-De Xiang; Guangxi Medical University Cancer Hospital, Nanning, China Abstract Research Funding: Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai, China. Guangxi Medical and Health Appropriate Technology Development and Application Project (No. S2019039), Guangxi, China. Background: Based on the results of recent studies, the PD-1 monoclonal antibodies have been approved to treat the patients with advanced hepatocellular carcinoma (HCC) by the FDA. Radiation therapy (RT) can enhance responsiveness to PD-1 monoclonal antibody by potential mechanisms. A phase Ⅱa study was conducted to assess the safety and the efficacy of combining RT with anti-PD-1 for patients with advanced hepatocellular carcinoma. Methods: Patients with advanced HCC were eligible. Stereotactic body radiation therapy (SBRT) were adopted, and the dose of radiation were Dt-PGTV 30-50 Gy/10fractions. Camrelizumab (200mg) were given intravenously every 3 weeks since the first day of RT until disease progression, or intolerable toxicity. Adverse events (AEs) and objective response rate (ORR) were summarized to assess the safety and efficacy. Results: From April 2020 to November 2020, 17 patients were enrolled (median age 54, range 32-69). 15 (88%) patients were male. 14 (82%) had ECOG performance score of 0. All the patients had Child-Pugh score A. 16 patients staged as Barcelona Clinic Liver Cancer staging C or China Liver Cancer staging Ⅲ. Extrahepatic metastases were identified in 11 (65%) patients. 13 (77%) patients were Hepatitis B virus infected. 15 (88%) patients had previously 2 lines or more chemotherapy. 9 (53%) patients had Alpha-fetoprotein level≥400 ng/ml. The ORR was 47%. The best response assessed by RECIST 1.1 was partial response (8 patients). Four patients had grade 3 immune-related adverse events (irAEs), including increased aspartate aminotransferase and alanine transaminase (n =1)，decreased hemoglobin (n =1)，decreased platelet count (n =1)，decreased neutrophil count (n =1). All grade 3 irAEs were mitigated with proper treatment. None treatment-related deaths occurred. Conclusions: In this study, RT combined with anti-PD-1 had an acceptable safety profile and indicated an effective treatment option in patients with unresectable HCC. Clinical trial information: NCT04193696. Clinical trial information: NCT04193696.
Reappraisal of anticancer nanomedicine design criteria in three types of preclinical cancer models for better clinical translation
Authors: Xin Luan, Hebao Yuan, Yudong Song, Hongxiang Hu, Bo Wen, Miao He, Huixia Zhang, Yan Li, Feng Li, Pan Shu, Joseph P. Burnett, Nathan Truchan, Maria Palmisano, Manjunath P. Pai, Simon Zhou, Wei Gao, Duxin Sun
Journal: Biomaterials (2021)
Chronic kidney disease ten years after pediatric allogeneic hematopoietic stem cell transplantation
Authors: Gertjan Lugthart, Carlijn C.E. Jordans, Anne P.J. de Pagter, Dorine Bresters, Cornelia M. Jol-van der Zijde, Joell E. Bense, Roos W.G. van Rooij-Kouwenhoven, Ram N. Sukhai, Marloes Louwerens, Eiske M. Dorresteijn, Arjan C. Lankester
Journal: Kidney International (2021)

Chronic kidney disease (CKD) is an important sequela of hematopoietic stem cell transplantation (HSCT), but data regarding CKD after pediatric HSCT are limited. In this single center cohort study, we evaluated the estimated glomerular filtration rate (eGFR) dynamics, proteinuria and hypertension in the first decade after HSCT and assessed risk factors for CKD in 216 pediatric HSCT survivors, transplanted 2002-2012. The eGFR decreased from a median of 148 to 116 ml/min/1.73 m2 between pre-HSCT to ten years post-HSCT. CKD (KDIGO stages G2 or A2 or more; eGFR under 90 ml/min/1.73m2 and/or albuminuria) occurred in 17% of patients. In multivariate analysis, severe prolonged stage 2 or more acute kidney injury (AKI), with an eGFR under 60ml/min/1.73m2 and duration of 28 days or more, was the main risk factor for CKD (hazard ratio 9.5, 95% confidence interval 3.4-27). Stage 2 or more AKI with an eGFR of 60ml/min/1.73m2 or more and KDIGO stage 2 or more AKI with eGFR under 60ml/min/1.73m2 but recovery within 28 days were not associated with CKD. Furthermore, hematological malignancy as HSCT indication was an independent risk factor for CKD. One third of patients had both CKD criteria, one third had isolated eGFR reduction and one third only had albuminuria. Hypertension occurred in 27% of patients with CKD compared to 4.4% of patients without. Tubular proteinuria was present in 7% of a subgroup of 71 patients with available β2-microglobulinuria. Thus, a significant proportion of pediatric HSCT recipients developed CKD within ten years. Our data stress the importance of structural long-term monitoring of eGFR, urine and blood pressure after HSCT to identify patients with incipient CKD who can benefit from nephroprotective interventions.
Safety evaluation of combined PD-1+CTLA4 inhibition concurrently to chemoradiotherapy (CRT) in localized muscle invasive bladder carcinoma (MIBC).
Authors: Ben-Max de Ruiter, Jons Wouter van Hattum, Theo Maria De Reijke, Jorg Reinier Oddens, Maarten C.C.M. Hulshof, Adriaan Dirk Bins
Journal: Journal of Clinical Oncology (2021)

4531 Background: Neoadjuvant nivolumab (nivo) + ipilimumab (ipi) prior to radical cystectomy showed efficacy in localized MIBC. The safety of PD-1 and PDL-1+CTLA4 inhibition concurrent with CRT in localized MIBC has not been assessed. We present the first clinical trial data on concurrent 3 doses of q4w nivo 480mg (cohort1) and concurrent 4 doses of q3w nivo 3mg/kg + ipi 1kg/mg (nivo3+ipi1, cohort2) in combination with Mitomycin C/Capecitabin (MMC/Cape) CRT. Methods: We report the first 2 cohorts of a phase 1b, EC approved, study with nivo only or nivo3+ipi1 added to MMC/Cape CRT. CRT consists of MMC i.v. on day 1 with Cape 750mg/m2 on days of radiotherapy. Radiotherapy schedule comprises a 20x2Gy whole bladder irradiation with a simultaneous tumorboost of 20x0.75Gy. Patients with MIBC, T2-4N0-1, ECOG performance status &lt;2 were included. A dose escalation scheme, with a staggered enrollment is used. The first 10 patients received nivo 480mg on week 1, 5, 9. Cohort2 of 10 patients received nivo3+ ipi1 at week 1, 4, 7 and 10. Relevant severe Adverse Events (AEs) were registered as Dose Limiting Toxicity (DLT) when they occurred within 6 weeks after start of treatment. Clinical efficacy is evaluated by cystoscopy and CT at week 12 and 24. Results: Both cohorts enrolled 10 patients. Median age was 68 [IQR 61-75] and 70 [IQR 66-75] years in cohort1 and 2, respectively. In cohort1 no patients experienced DLT. No dose reductions were applied. In cohort2, 2 patients experienced DLT, 1 trombocytopenia (grade 4) and 1 asystole (grade 5). 50% of patients did not receive all 4 q3w nivo3+ipi1 infusions, due to AEs. Table 1 reports an overview of AEs. In cohort2 6 SAE’s occurred in 3 patients. Median follow up is 71 [IQR 59-86] and 30 weeks [IQR 12-45] in cohort1 and 2, respectively. 1year OS and DFS is 100% in cohort1. Conclusions: Concurrent 3 doses nivo 480mg q4w added to MMC/Cape based CRT is feasible with a favorable toxicity profile and shows promising efficacy in MIBC patients. An escalated regimen with 4 doses nivo 3mg/kg + ipi 1mg/kg q3w concurrent to CRT shows acceptable toxicity. Cohort3 with ipi 3mg/kg and nivo 1mg/kg is enrolling. Clinical trial information: NCT03844256. [Table: see text]
Plasma-derived DNA containing-extracellular vesicles induce STING-mediated proinflammatory responses in dermatomyositis
Authors: Yubin Li, Christina Bax, Jay Patel, Thomas Vazquez, Adarsh Ravishankar, Muhammad M Bashir, Madison Grinnell, DeAnna Diaz, Victoria P Werth
Journal: Theranostics (2021)

Objectives: Extracellular vesicles (EVs) are lipid bilayer membrane vesicles that are present in various bodily fluids and have been implicated in autoimmune disease pathogenesis. Type I interferons (IFN), specifically IFN-β, are uniquely elevated in dermatomyositis (DM). The stimulator of interferon genes (STING) works as a critical nucleic acid sensor and adaptor in type I IFN signaling with possible implications in autoimmune diseases such as DM. In the current study, we investigated whether circulating EVs contribute to proinflammatory effects in DM, whether these proinflammatory responses are mediated by the STING signaling pathway, and if so, by what mechanism STING is activated. Methods: We collected and characterized EVs from plasma of healthy controls (HC) and DM patients; analyzed their abilities to trigger proinflammatory cytokines release by ELISA, and explored STING signaling pathway activation using immunoblot and immunofluorescent staining. STING signaling pathway inhibitors and RNAi were used to further investigate whether STING was involved in EVs-triggered proinflammatory response. DNase/lipid destabilizing agent was utilized to digest EVs and their captured DNA contents to evaluate how EVs triggered STING-mediated proinflammatory response in DM. Results: EVs isolated from DM plasma triggered proinflammatory cytokines including type I IFN release with STING signaling pathway activation. The activated STING pathway was preferentially mediated by dsDNA captured by EVs. Suppression of STING or its downstream signaling proteins attenuated the EVs-mediated proinflammatory response. Conclusions: Plasma-derived, DNA containing-EVs induced STING-mediated proinflammatory effects in DM. Targeting the STING pathway may be a potential therapeutic approach for DM.
STAG2 loss rewires oncogenic and developmental programs to promote metastasis in Ewing sarcoma
Authors: Biniam Adane, Gabriela Alexe, Bo Kyung A. Seong, Diana Lu, Elizabeth E. Hwang, Denes Hnisz, Caleb A. Lareau, Linda Ross, Shan Lin, Filemon S. Dela Cruz, Melissa Richardson, Abraham S. Weintraub, Sarah Wang, Amanda Balboni Iniguez, Neekesh V. Dharia, Amy Saur Conway, Amanda L. Robichaud, Benjamin Tanenbaum, John M. Krill-Burger, Francisca Vazquez, Monica Schenone, Jason N. Berman, Andrew L. Kung, Steven A. Carr, Martin J. Aryee, Richard A. Young, Brian D. Crompton, Kimberly Stegmaier
Journal: Cancer Cell (2021)
Real-world outcomes of toripalimab (JS001) in advanced non-small cell lung cancer: A multicenter retrospective study.
Authors: Zhihua Ruan, Bo Zhu, Yi Na Wang, Baogang Liu, Mengxia Li, Guohao Xia, Xiaorong Dong, Jie Liu
Journal: Journal of Clinical Oncology (2021)

e21193 Background: In the past 3 years, immunotherapy has revolutionized the treatment paradigm of advanced non–small cell lung cancer (NSCLC). Checkpoint inhibitors showed promising results in the treatment of patients with advanced NSCLC with improved outcomes in clinical trials, but results from clinical trials can be difficult to generalize to real-world patient populations. Herein, we disclose the data of efficacy profile of toripalimab, a novel humanized IgG-4 mAb against programmed cell death protein 1 (PD-1), for NSCLC in a real-world setting in China. Methods: This retrospective study leveraged electronic health record (EHR) data collected during routine patient care in 8 cancer centers in China. The cohort included patients with mNSCLC who had received toripalimab for metastatic disease (n = 166) with &gt; 1 EHR-documented visit from January, 2019, to June, 2020. Patients (age ≥ 18yrs) with pathologically or histologically diagnosed advanced NSCLC receiving toripalimab treatment were enrolled in this retrospective, multicenter, real-world study. The endpoints included progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR) and duration of response (DOR). Results: Between January 2019 and June 2020, 166 patients from 8 centers were eligible. The median age was 60.6 years, 134(81.7%) male, 123(76.4%) diagnosed as stage IV lung cancer, 69(42.9%) squamous histology, 25 (21.9%) underwent prior surgery and 94 (57%) received prior chemotherapy. Toripalimab was administered as first, second, and further lines of therapy in 45(28.1%), 60(37.5%) and 55(34.4%) patients, respectively. Among them, 28(17.5%) patients received toripalimab as monotherapy. 22(13.8%) received in combination with antiangiogenic agent and 132(82.5%) in combination with chemotherapy. The 164 patients were eligible for efficacy evaluation. The ORR and DCR were 21.3% and 81.7% for all the evaluable patients. The median PFS was 15.0 months (95% CI 10.2 – NA). The median PFS of adenocarcinoma and squamous cell carcinoma were 15.4 months(95% CI 10.2-NA) and 13.4 months(95% CI 10.6-NA), respectively. The PFS in first line and further-line treatment were 15.4 months(95% CI 12.6-15.4) and 13.4 months(95% CI 7.0-NA). Stratified analysis revealed that the PFS of toripalimab monotherapy and combination treatment were 15.0 months(95% CI 12.6-15.0) and 15.4 months(95% CI 8-NA). The PFS were comparable between the patients received with or without anti-angiogenesis agents (11.5m vs 15.4m). Conclusions: Toripalimab monotherapy or in combination with chemotherapy and/or antiangiogenic agent in real world were effective in advanced NSCLC patients.
Tumor progress intercept by intervening in Caveolin-1 related intercellular communication via ROS-sensitive c-Myc targeting therapy
Authors: Xueqing Zhou, Xuan Liu, Xiqin Yang, Li Wang, Yiling Hong, Keke Lian, Guoxi Qiu, Xuwei Shang, Zhongjun Ma, Hong Yuan, Fuqiang Hu
Journal: Biomaterials (2021)
Risk factors for early-onset colorectal cancer in China.
Authors: Zhe Pan, Junfeng Huang, Mingkai Huang, Zhiyuan Yao, Jiongqiang Huang, Jingsong Chen, Rongchang Wang
Journal: Journal of Clinical Oncology (2021)

10542 Background: The incidence of colorectal cancer among persons aged &lt; 50 years (early-onset colorectal cancer, EOCRC) has increased since the early 1990s. However, the risk factors contributing to this trend remain largely unknown. Methods: We conducted a retrospective study of participants who were aged &lt; 50 years and without a previous cancer history, using the China Kadoorie Biobank cohort study. We analyzed data related to demographics, lifestyle habits, family history, and comorbidities of EOCRC cases with participants without colorectal cancer in this age group (controls). Univariate and multivariate-adjusted cox regression models were used to estimate the associations with risk factors. Results: We identified 225 EOCRC cases and 88842 controls that include the final analyses. Of the 225 EOCRC patients, 105 (46.7%) were colon cancers and 120 (53.3%) were rectum cancers. EOCRC cases were older, have more intake of fish and eggs, have higher BMIs, diabetes, and family history of cancer compared with controls (P &lt; 0.05). After adjustment for potential confounding factors, increasing age (HR 2.18, 95%CI 2.05-2.31), BMI (HR 1.06, 95%CI 1.01-1.11), family history of cancer (HR 1.41, 95%CI 1.00-1.98), and more intake of fish (HR 1.54, 95%CI 1.09-2.19) were significantly associated with a higher risk of EOCRC. In sensitivity analyses stratified by cancer site (colon and rectum), the results remained consistent. Conclusions: Based on the large Chinese cohort study, we found increasing age, higher BMI or obesity, family history of cancer, and more intake of fish were independent risk factors for EOCRC. Further studies are needed to identify factors that cause the increasing incidence of EOCRC in China and other countries, and explore the potential mechanism behind.[Table: see text]
Discovery of HBW-3-10: A potent, orally active, reversible Bruton’s tyrosine kinase (BTK) inhibitor with antitumor activity in mice.
Authors: Ning Lee, Yingfu Li, Chester Yuan, Guanfeng Liu, Chunchao Yue
Journal: Journal of Clinical Oncology (2021)

e15062 Background: The first generation irreversible BTK inhibitor ibrutinib has been approved for the treatment of B cell-related diseases, including chronic lymphocytic leukemia (CLL), for several years. However, CLL patients who used ibrutinib may develop drug resistance due to acquired mutations, in particular BTK C481S that directly impacts the binding of ibrutinib. In recent years, efforts have been made to develop the second generation reversible BTK inhibitors that are effective against both wild-type and C481S mutated B-cell malignancies. LOXO-305 and ARQ-531 are two examples of the second generation reversible BTK inhibitors in advanced clinical trials for ibrutinib-resistant CLL. Methods: New reversible BTK inhibitors were designed, synthesized and tested for enzymatic activities against wild-type and C481S-mutated BTK. Highly active compounds were confirmed for growth effects in diffuse large B-cell lymphoma derived TMD8 cells. Their microsomal stability and ADME properties were also assessed. Potent and bioavailable compounds were further evaluated in vivo efficacy using a TMD8 xenograft tumor model in mice. A 14-day toxicity study in rats was performed correspondingly. Results: As shown in the table, HBW-3-10 has greater potency and pharmacokinetic profile (rats, 10mg/kg PO) than ARQ-531. In a TMD8 mouse xenograft study, HBW-3-10, ARQ-531 and ibrutinib were compared directly, all dosed at 10mg/kg QD, and the resulting tumor growth inhibition rates (TGI) are 38.3%, 9.3% and 22.5%, respectively. Based on our data, HBW-3-10 is more efficacious than ARQ-531 and ibrutinib. In a 14-day preliminary toxicity experiment in rats, both HBW-3-10 and ARQ-531 were dosed 100mg/kg QD. Animals in ARQ531 group started showing signs of sickness on day 3, and all died on day 6 due toxicity; in contrast, no animal in HBW-3-10 group showed any sign of sickness or died during the entire course of study. Conclusions: We have discovered a novel second generation reversible BTK inhibitors HBW-3-10, that has a superior preclinical profile, efficacy and safety than other known ones. HBW-3-10 provides a valuable clinical candidate for treating Ibrutinib resistant CLL and beyond![Table: see text]