tbuckley/cabot-search huggingface dataset:
Degradation of Janus kinases in <i>CRLF2</i>-rearranged acute lymphoblastic leukemia
Authors: Yunchao Chang, Jaeki Min, Jamie A. Jarusiewicz, Marisa Actis, Shanshan Yu-Chen Bradford, Anand Mayasundari, Lei Yang, Divyabharathi Chepyala, Lisa J. Alcock, Kathryn G. Roberts, Stanley Nithianantham, Dylan Maxwell, Lauren Rowland, Randolph Larsen, Aman Seth, Hiroaki Goto, Toshihiko Imamura, Koshi Akahane, Baranda S. Hansen, Shondra M. Pruett-Miller, Elisabeth M. Paietta, Mark R. Litzow, Chunxu Qu, Jun J. Yang, Marcus Fischer, Zoran Rankovic, Charles G. Mullighan
Journal: Blood (2021)
Clinical characteristics and outcome of mycosis fungoides among children, adolescents, and young adults: Single institution study.
Authors: Eric Taylor, Yumeng Zhang, Madeline Hooper, Lucia Seminario-Vidal, Lubomir Sokol
Journal: Journal of Clinical Oncology (2021)

e19576 Background: Mycosis fungoides (MF) is the most common subtype of cutaneous T cell lymphoma (CTCL) [1]. MF is characterized by the skin infiltrate of small to medium size T lymphocytes with cerebriform nuclei. The incidence of MF increases significantly with age, with a median age at diagnosis of 60 years, and predominantly in white males [2]. The clinical outcome has not been evaluated among children, adolescents, and young adults. This study aimed to evaluate the characteristics and outcomes in this population. Methods: We retrospectively reviewed clinical data on 90 patients with MF at Moffitt Cancer Center between 2000 and 2020. Fifteen patients were diagnosed before the age of 20 years. Our cohort was compared to the largest US epidemiological report by Nath et al. using SEER database, which consists of 4892 patients from 1998-2008 [2]. The Chi-square test was used for comparison. Overall survival (OS) was calculated from diagnosis until death or last contact. OS between different groups was compared using the Kaplan-Meier curve. Hazard ratio and p-value were calculated using the log-rank test. Results: Of 90 patients, the median age at diagnosis was 32 years (range 6-39). The male to female ratio was 1.3:1. White and black races account for 57% and 27% of the patients. Compared to historical control, black patients were significantly higher in the current cohort (27% vs. 13%, p &lt; 0.001). The difference widened in children and adolescents. More patients present with early stage MF in the current cohort (95.6% vs. 83%, p = 0.003). Clinical characteristics, including stage, LDH, WBC, ferritin level, were similar between children/adolescents and young adults. However, our cohort had significantly higher CD8 positive MF, and nearly half of children and adolescents were CD8 positive. Young adults had a higher rate of coexisting skin malignancy; however, this was not statistically significant due to small patient size. Time to diagnosis remained long, especially in children and adolescents’ group. However, the outcome is excellent. At a median follow-up of 4.9 years, four patients deceased, and the median OS was not reached. The prognosis remains poor in patients with advanced disease (HR = 39, p &lt; 0.001) and large cell transformation (LCT) (HR = 8.5, p = 0.009). Conclusions: Compared to historical cohorts, higher proportion of black and female patients were noted in our young cohort with more early-stage and CD8 positive disease. This observation likely represents the different underlying biology of the disease [3]. Clinical outcome in young patients was excellent. However, patients with LCT or advanced stage carry a poor prognosis and need better therapies.
Predicting the Risk of Pulmonary Arterial Hypertension in Systemic Lupus Erythematosus: A Chinese Systemic Lupus Erythematosus Treatment and Research Group Cohort Study
Authors: Jingge Qu, Mengtao Li, Yanhong Wang, Xinwang Duan, Hui Luo, Cheng Zhao, Feng Zhan, Zhenbiao Wu, Hongbin Li, Min Yang, Jian Xu, Wei Wei, Lijun Wu, Yongtai Liu, Hanxiao You, Juyan Qian, Xiaoxi Yang, Can Huang, Jiuliang Zhao, Qian Wang, Xiaomei Leng, Xinping Tian, Yan Zhao, Xiaofeng Zeng
Journal: Arthritis & Rheumatology (2021)

Pulmonary arterial hypertension (PAH) is a life-threatening complication of systemic lupus erythematosus (SLE). However, there is no algorithm to identify those at high risk. This study was undertaken to develop a prediction model for PAH in patients with lupus that provides individualized risk estimates.A multicenter, longitudinal cohort study was undertaken from January 2003 to January 2020. The study collected data on 3,624 consecutively evaluated patients diagnosed as having SLE. The diagnosis of PAH was confirmed by right-sided heart catheterization. Cox proportional hazards regression and least absolute shrinkage and selection operator were used to fit the model. Model discrimination, calibration, and decision curve analysis were performed for validation.Ninety-two lupus patients (2.54%) developed PAH during a median follow-up of 4.84 years (interquartile range 2.42-8.84). The final prediction model included 5 clinical variables (acute/subacute cutaneous lupus, arthritis, renal disorder, thrombocytopenia, and interstitial lung disease) and 3 autoantibodies (anti-RNP, anti-Ro/SSA and anti-La/SSB). A 10-year PAH probability-predictive nomogram was established. The model was internally validated by Harrell's concordance index (0.78), the Brier score (0.03), and a satisfactory calibration curve. According to the net benefit and predicted probability thresholds, we recommend annual screening in high-risk (>4.62%) lupus patients.We developed a risk stratification model using routine clinical assessments. This new tool may effectively predict the future risk of PAH in patients with SLE.
Cell dynamics in human villous trophoblast
Authors: John D Aplin, Carolyn J P Jones
Journal: Human Reproduction Update (2021)

Abstract BACKGROUND Villous cytotrophoblast (vCTB) is a precursor cell population that supports the development of syncytiotrophoblast (vSTB), the high surface area barrier epithelium of the placental villus, and the primary interface between maternal and fetal tissue. In light of increasing evidence that the placenta can adapt to changing maternal environments or, under stress, can trigger maternal disease, we consider what properties of these cells empower them to exert a controlling influence on pregnancy progression and outcome. OBJECTIVE AND RATIONALE How are cytotrophoblast proliferation and differentiation regulated in the human placental villus to allow for the increasing demands of the fetal and environmental challenges and stresses that may arise during pregnancy? SEARCH METHODS PubMed was interrogated using relevant keywords and word roots combining trophoblast, villus/villous, syncytio/syncytium, placenta, stem, transcription factor (and the individual genes), signalling, apoptosis, autophagy (and the respective genes) from 1960 to the present. Since removal of trophoblast from its tissue environment is known to fundamentally change cell growth and differentiation kinetics, research that relied exclusively on cell culture has not been the main focus of this review, though it is mentioned where appropriate. Work on non-human placenta is not systematically covered, though mention is made where relevant hypotheses have emerged. OUTCOMES The synthesis of data from the literature has led to a new hypothesis for vCTB dynamics. We propose that a reversible transition can occur from a reserve population in G0 to a mitotically active state. Cells from the in-cycle population can then differentiate irreversibly to intermediate cells that leave the cycle and turn on genes that confer the capacity to fuse with the overlying vSTB as well as other functions associated with syncytial barrier and transport function. We speculate that alterations in the rate of entry to the cell cycle, or return of cells in the mitotic fraction to G0, can occur in response to environmental challenge. We also review evidence on the life cycle of trophoblast from the time that fusion occurs, and point to gaps in knowledge of how large quantities of fetal DNA arrive in maternal circulation. We critique historical methodology and make a case for research to re-address questions about trophoblast lifecycle and dynamics in normal pregnancy and the common diseases of pre-eclampsia and fetal growth restriction, where altered trophoblast kinetics have long been postulated. WIDER IMPLICATIONS The hypothesis requires experimental testing, moving research away from currently accepted methodology towards a new standard that includes representative cell and tissue sampling, assessment of cell cycle and differentiation parameters, and robust classification of cell subpopulations in villous trophoblast, with due attention to gestational age, maternal and fetal phenotype, disease and outcome.
Surufatinib in combination with toripalimab in patients with advanced neuroendocrine carcinoma: Results from a multicenter, open-label, single-arm, phase II trial.
Authors: Lin Shen, Xianjun Yu, Ming Lu, Xing Zhang, Ying Cheng, Yanqiao Zhang, Zhiping Li, Jianming Xu, Desheng Weng, Chunjiao Wu, Yue Ma, Ke Cheng, Wenquan WANG, Heli Gao, Yi Li, Jinghong Zhou, Haiyan Shi, Panfeng Tan, Weiguo Su
Journal: Journal of Clinical Oncology (2021)

e16199 Background: Patients with advanced neuroendocrine carcinoma (NEC) have a poor prognosis and limited treatment option after first-line treatment. Surufatinib, a multi-kinase inhibitor of VEGFR 1-3, FGFR 1 and CSF-1R, has been approved in patients with advanced or metastatic extra-pancreatic neuroendocrine tumors in China. Toripalimab is a monoclonal humanized IgG4 PD-1 antibody. Surufatinib modulates tumor immune microenvironment and has shown promising antitumor activity in combination with toripalimab in solid tumors, including neuroendocrine tumor and neuroendocrine carcinoma. Herein, we reported the efficacy and safety of surufatinib in combination with toripalimab in a cohort of advanced NEC patients. Methods: The multicenter, open-label, single-arm phase II clinical trial enrolled advanced NEC patients refractory to first-line chemotherapy, and received surufatinib 250 mg once a day orally plus toripalimab 240 mg intravenously on day 1 of a 21-day cycle. The primary end point is objective response rate (ORR) per RECIST 1.1. Results: Twenty-one patients enrolled and received combination therapy. At data cut-off (December 31, 2020), the average treatment cycles were 5.1±3.69 for surufatinib and 5.0±3.68 for toripalimab. Among 20 tumor evaluable patients, 4 patients achieved confirmed PR and 10 patients achieved stable disease. The ORR and disease control rate (DCR) are 20 % (95%CI: 5.7%-43.7%) and 70% (95%CI: 45.7%-88.1%) respectively. The median PFS is 3.94 months (95%CI: 1.31- unknown). OS is not mature till data cut-off. Adverse events (AEs) reported as related to treatment (TRAE) occurred in 100% of patients, of which Grade≥3 TRAEs occurred in 33.3% of patients. The reported Grade≥3 TRAEs were hypertension in 2 (9.5%) patients, and upper abdominal pain, oral mucositis, neutrophil count decreased, leukocyte count decreased, dermatitis, anemia and backache in 1 (4.8%) patient each. Immune related Grade ≥3 AEs, Gamma-glutamyl transpeptidase increased and dermatitis, occurred in 2 (9.5%) patients, respectively. TRAE caused surufatinib or toripalimab interruption occurred in 6 (28.6%) and 4 (19%) patients respectively. There were neither serious AEs nor AEs inducing treatment discontinuations or deaths. Conclusions: As there is no standard second-line treatment, this combination of surufatinib and toripalimab might offer a new promising choice to treat NEC as second-line treatment due to good efficacy and manageable treatment related toxicities. Clinical trial information: NCT04169672.
Impact of clonal hematopoiesis to tumor-targeted liquid biopsy in a Chinese pan-cancer cohort.
Authors: Enwu Xu, Yang Zhou, Zhao Yi, Longlong Gong
Journal: Journal of Clinical Oncology (2021)

e18700 Background: Somatic mutations through detecting circulating cell-free DNA (cfDNA) in plasma samples have been used to diagnose tumor, administer drugs and monitor tumor recurrence. However, cfDNA is not only derived from tumor, but also from clonal hematopoiesis. Thus, the mutations from clonal hematopoiesis impact accuracy of somatic mutation detection using plasma cfDNA in tumor patients. Methods: We screened clonal hematopoiesis using a bioinformatics pipeline in 11,725 Chinese pan-cancer cohort. To evaluate the impact of clonal hematopoiesis for somatic mutations, Fisher’s exact test was used. Results: In this study, we identified clonal hematopoiesis mutations using a bioinformatics pipeline in a Chinese cohort included 11,725 pan-cancer patients. In order to enhance the detection accuracy of clonal hematopoiesis mutations, we performed a statistical framework to compare the distribution of alteration-supporting reads in cfDNA and matched peripheral blood lymphocyte (PBL) samples. The result indicated that 5,933 clonal hematopoiesis mutations in 301 genes for 5,100 patients. In particularly, 48 of 5,933 clonal hematopoiesis mutations carried by 92 of 5,100 tumor patients were actionable somatic mutations. Seven oncogenes (including EGFR, ERBB2, FGFR3, IDH1, KIT, KRAS and NRAS) and 10 tumor suppressor genes (including BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, PTEN, RB1, SMAD4 and TP53) were contained in the 48 clonal hematopoiesis mutations. The frequency of TP53 gene was 32.6% (30 of 92 tumor patients) and KRAS which was considered as targeted therapy was 16.3% (15 of 92 tumor patients). Conclusions: Taken together, we exhibited characteristic of clonal hematopoiesis mutations in a Chinese pan-cancer cohort and explored effect of clonal hematopoiesis mutations on liquid biopsy for tumor patients.
Pilocytic astrocytoma 再発の１例
Authors: 晋一 吉村, 昭雄 淺井, 正博 埜中, 孝昌 亀井, 裕美子 染野, 英樹 二宮, 亮一 岩田, 哲也 大石, 純一 武田, 英行 大重
Journal: Neuro-Oncology (2017)
Final report of Breast Cancer Care Registry at the Kenyatta National Hospital, Nairobi.
Authors: Nicholas Anthony Othieno-Abinya, Alice Musibi, Catherine Nyongesa, Benjamin Njihia, Andrew Gachii, Gladwell Wanjiru Kamere Kiarie, Beatrice Nyawira, Ochieng' Noel Onyango
Journal: Journal of Clinical Oncology (2021)

Retraction The abstract by Othieno-Abinya et al entitled, “Final report of Breast Cancer Care Registry at the Kenyatta National Hospital, Nairobi,” published in the Journal of Clinical Oncology 39, no. 15 suppl (May 20, 2021) e12552-e12552, was retracted by the authors as it did not meet the study sponsor's prior scientific verification and approval. This abstract was retracted on June 29, 2021. e12552 Background: Breast cancer is the commonest cancer among women in Kenya. We wanted to examine breast cancer seen at the Kenyatta National Hospital in relation to local factors that influence prognosis and quality of life, local variations in treatment and outcomes; describe the clinical care patterns, monitor the safety of the therapies provided to patients in a routine clinic setting. Methods: A prospective study of patients with breast cancer between 11.08.2011 and 11.09.2014 inclusive. Data included demographic details, diagnostic and staging procedures, stage, treatment and outcome. Estimates of relative survival used period approach. hi-square tests and analysis of variance (ANOVA) were utilised to make comparisons. Cross sectional data are presented in proportions, means and medians. Results: Four hundred patients were included, age range 20 to 83, median 49 years. Out 312, 65 (20.8%) were obese. Eight of 397 (2%) were smokers and 22(5.5%) took alcohol. Early disease was diagnosed in 269 out of 354 (76%) and metastatic disease in 85(24%). Breast lump presented in 388 out of 400 (97%), breast pain in 104 out of 388 (26.8%). Fifteen of 394 (3.8%) had second breast cancer, 4 (1%) had had ovarian cancer and 9 (2.3%) had had had other malignancy. History of breast cancer in first and second-degree relative was elicited in 41 out of 394 (10.4%). Ductal carcinoma NOS was commonest in 343 (88.2%), lobular carcinoma in 9(2.5%). Cases by T stage were T 1 - 25(7.2%), T 2 -130(37.4%), T 3 - 96(27.6%), T 4 - 87(25%). Of 322 cases, 187(58.1%) were ER positive and 175 (54.4%) PR positive. Her2 positive cases were 78 out of 322 (24.2%). Neo adjuvant and adjuvant chemotherapy mainly consisted of combinations of cyclophosphamide and doxorubicin [AC] +/- a taxane[AC→T] ( mainly by medical oncologists) or AC+ 5-FU [CAF] (mainly by clinical oncologists). Of 305 cases 272 (89.2%) completed adjuvant therapy, 8(2.6%) died during treatment. Median overall survival was 57.1 months (95% CI; 55.6 to 59.5 months). For metastatic disease, median PFS was worse for patients &lt; 40 years. Conclusions: Pathology and biology mirrored global situation, over 75% of patients had non metastatic disease. A significant proportion of early disease patients did not complete treatment.
Progression pattern and post-progression treatment of furmonertinib (AST2818) in EGFR T790M mutation positive NSCLC patients: A post-hoc analysis from a multicenter, single-arm study.
Authors: Xingsheng Hu, Shucai Zhang, Dongqing Lv, Lin Wu, Qitao Yu, Yiping Zhang, Li Liu, Xiang Wang, Ying Cheng, Zhiyong Ma, Hongrui Niu, Dong Wang, Jifeng Feng, Cheng Huang, Chunling Liu, Hui Zhao, Jingzhang Li, Xiaodong Zhang, Yong Jiang, Yuankai Shi
Journal: Journal of Clinical Oncology (2021)

e21071 Background: Furmonertinib (AST2818) is a selective third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), which can irreversibly inhibit both EGFR sensitizing and T790M resistant mutations. However, like other EGFR-TKIs, progression is still unavoidable when treated with furmonertinib. Methods: In a multi-center, single-arm phase IIb study (NCT03452592), non-small cell lung cancer (NSCLC) patients with EGFR T790M mutation received furmonertinib 80mg/d treatment until disease progression, death or treatment cessations for other reasons. This is a post-hoc analysis of the progression pattern and post-progression treatment. Results: A total of 220 patients were enrolled in this study. At baseline, 105 (48%) patients had central nervous system (CNS) metastases, 84 (38%) were EGFR L858R mutated and 9 (4%) were ECOG performance status 2. At data cut-off (December 31, 2020), 179 out of 220 (81%) patients had progressed assessed by investigators (patients who died before assessed as progression were excluded). The most frequent progression site was lung (n = 106，48%), followed by CNS (n = 33, 15%), lymph node (n = 22, 10%), liver (n = 20, 9%) and bone (n = 16, 7%). CNS progression rate were 3%, 8%, 13% and 15% at 3, 6, 12 and 18 months, respectively. After progression, 52% (93/179) patients continued furmonertinib monotherapy based on the judgement of continuous benefit by investigators which was permitted in the protocol. The median post-progression treatment time of furmonertinib was 3.02 months (range 0.03-18.27). Overall, 48% (86/179) patients discontinued furmonertinib and later-line treatments were decided by investigators. The post-progression survival (PPS) was 17.3 months in the furmonertinib-continued group and 12.4 months in the furmonertinib-not-continued group (HR 0.57 [95%CI 0.40-0.80], p = 0.0048). Conclusions: Although about half patients had CNS metastases at baseline, CNS progression rate was relatively low in this study. Post-progression continuous treatment of furmonertinib monotherapy might still bring survival benefit to certain NSCLC patients with EGFR T790M mutation which need further exploration. Clinical trial information: NCT03452592.
Proteotoxicity in Cardiac Amyloidosis: Amyloidogenic Light Chains Affect the Levels of Iintracellular Proteins in Human Heart Cells
Authors: Esther Imperlini, Massimiliano Gnecchi, Paola Rognoni, Eduard Sabidò, Maria Chiara Ciuffreda, Giovanni Palladini, Guadalupe Espadas, Giuseppina Palladini, Stefania Orrù, Paolo Milani, Stefano Perlini, Francesco Salvatore, Giampaolo Merlini, Francesca Lavatelli
Journal: Blood (2017)
Evaluation of proband adherence and satisfaction with a prospective cascade testing protocol.
Authors: Maria Smith, Kristina Hwang, Julia Anne Smith, Bhavana Pothuri
Journal: Journal of Clinical Oncology (2021)

10593 Background: We sought to evaluate the feasibility of a Cascade Testing (CT) protocol for family members of probands with actionable germline mutations associated with endometrial or ovarian cancer. Here, we characterize proband compliance with contacting family members for CT and proband satisfaction/regret. Methods: In this prospective study, consenting patients with pathogenic germline mutations associated ovarian or endometrial cancer completed a demographic survey and were asked to contact first- and second-degree relatives with genetic testing results. After a 1–3-month period, probands completed a survey indicating how many relatives had been contacted. At 3 months following consent, probands were asked to complete the validated Impact of Event Scale (IES) and Decision Regret Scales (DRS). Characteristics of probands who contacted relatives and those who did not were compared. Results: The study has accrued 57 probands since opening in March 2019. Germline mutations identified in the 57 probands include 27 BRCA1 (47.4%); 21 BRCA2 (36.8%); 3 BRIP1 (5.3%); 2 MLH1 (3.5%); 2 MSH2 (3.5%); 3 MSH6 (5.3%); 3 PMS2 (5.3%); 1 EPCAM (1.8%); 1 RAD50 (1.8%). Twenty-four (42.1%) probands had a history of cancer (breast 12; ovarian 8; uterine 2; other 5). Of the probands, 32 (56.1%) completed follow-up questionnaires and 29 (50.9%) had contacted relatives about participating in CT. In total, 67 relatives were contacted. Probands contacted an average of 1 relative, ranging from 1-20. Of the 29 probands who contacted relatives, 13 (44.8%) completed IES and DRS questionnaires. The median IES score was 0 out of 75 (IQR 0.0-4.5) and the median DRS score was 0 out of 100 (IQR 0.0-11.3). When comparing characteristics of probands who contacted relatives with those who did not, those with annual household incomes &lt;$75,000 were more likely to contact relatives vs those with incomes ≥$75,000 (77.8% vs 39.5%; p=0.01). There was no association between contacting relatives and personal cancer history, race/ethnicity, education status, or age (Table). Conclusions: Half of probands enrolled in this study contacted relatives about CT, and those with household incomes &lt;$75,000 were more likely to contact relatives than those with higher incomes. Overall, probands reported little/no regret or distress after contacting relatives about genetic testing results.[Table: see text]