tbuckley/cabot-search huggingface dataset:
A systematic evaluation of models predicting short-term mortality for cancer patients to highlight uncertainty about model performance and high risk of bias.
Authors: Sheng-Chieh Lu, Cai Xu, Chandler Nguyen, Larissa Meyer, Chris Sidey-Gibbons
Journal: Journal of Clinical Oncology (2021)

e13559 Background: Short-term cancer mortality prediction has many implications concerning care planning. An accurate prognosis allows healthcare providers to adjust care plans and take appropriate actions, such as initiating end-of-life conversations. Machine learning (ML) techniques demonstrated promising capability to support clinical decision-making via providing reliable predictions for a variety of clinical outcomes, including cancer mortality. However, the evidence has not yet been systematically synthesized and evaluated. The objective of this review was to examine the performance and risk-of-bias for ML models trained to predict short-term (≤ 12 months) cancer mortality. Methods: We identified relevant literature from five electronic databases: Ovid Medline, Ovid EMBASE, Scopus, Web of Science, and IEEE Xplore. We searched each database with predefined MeSH terms and keywords of oncology, machine learning, and mortality using AND/OR statements. Inclusion criteria included: 1) developed/validated ML models for predicting oncology patient mortality within one year using electronic health record data; 2) reported model performance within a dataset that was not used to train the models; 3) original research; 4) peer-reviewed full paper in English; 5) published before 1/10/2020. We conducted risk of bias assessment using prediction model risk of bias assessment tool (PROBAST). Results: Ten articles were included in this review. Most studies focused on predicting 1-year mortality (n = 6) for multiple types of cancer (n = 5). Most studies (n = 7) used a single metric, the area under the receiver operating characteristic curve (AUROC), to examine their models. The AUROC ranged from .69 to .91, with a median of .85. Information on samples (n = 10), resampling methods (n = 6), model tuning approaches (n = 9), censoring (n = 10), and sample size determinations (n = 10) were incomplete or absent. Six studies have a high risk of bias for the analysis domain in the PROBAST. Conclusions: The performance of ML models for short-term cancer mortality appears promising. However, most studies report only a single performance metric that obfuscates evaluation of a model’s true performance. This is especially problematic when predicting rare events such as short-term mortality. We found little-to-no information on a given model’s ability to correctly identify patients at high risk of mortality. The incomplete reporting of model development poses challenges to risk of bias assessment and reduces the confidence in the results. Our findings suggest that future studies should report comprehensive performance metrics using a standard reporting guideline, such as transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD), to ensure sufficient information for replication, justification, and adoption.
The prognostic performance of PREDICT+ in patients (pts) with HER2-positive (HER2+) early-stage breast cancer (EBC).
Authors: Elisa Agostinetto, Lieveke Ameye, Samuel Martel, Philippe Georges Aftimos, Noam Ponde, Christian Maurer, Sarra El-Abed, Yingbo Wang, Maria Lourdes Vicente, Saranya Chumsri, Judith Bliss, Judith R. Kroep, Marco Colleoni, Fausto Petrelli, Lucia Del Mastro, Alvaro Moreno-Aspitia, Martine J. Piccart-Gebhart, Marianne Paesmans, Evandro de Azambuja, Matteo Lambertini
Journal: Journal of Clinical Oncology (2021)

524 Background: PREDICT+ is a widely used, free, online tool based on traditional clinico-pathological features, including HER2, developed to predict individual mortality of EBC pts and to aid clinical decision making for adjuvant therapy. However, its prognostic role in HER2+ EBC pts treated with chemotherapy (CT) and anti-HER2 therapies remains unclear. We aimed to investigate the prognostic performance of PREDICT+ in HER2+ EBC pts enrolled in the ALTTO trial. Methods: ALTTO is a phase III study evaluating adjuvant lapatinib (L) +/- trastuzumab (T) vs. T alone in pts with HER2+ EBC. Pts enrolled in the ALTTO trial and receiving T-based therapy started concurrently with CT were eligible for this analysis. We calculated PREDICT+ estimates using variables extracted from ALTTO database, blinded to pts outcomes. The prognostic performance of PREDICT+ was evaluated by assessing its calibration and discriminatory accuracy. For calibration, median predicted 5-year (5-yr) overall survival (OS) was compared to observed 5-yr OS. For discriminatory accuracy, the area under the receiver-operator characteristic (AUC under the ROC) curve and corresponding 95% confidence intervals (CI) for predicted 5-yr OS were calculated. Subgroup analyses were performed according to type of anti-HER2 therapy, type of CT, age, hormone receptor (HR) status, nodal status and tumor size. Results: This analysis included 2,794 pts. After a median follow-up of 6.0 years (IQR, 5.8-6.7), 182 deaths were observed. Overall, PREDICT+ underestimated 5-yr OS by 6.7% (95% CI, 5.8-7.6): observed 5-year OS was 94.7% vs. predicted 88.0%. The underestimation was consistent across all subgroups (Table). For discriminatory accuracy, AUC under the ROC curve was 73.7% (95%CI 69.7-77.8) in the overall population, ranging between 61.7% and 77.7% across the analysed subgroups. Conclusions: In HER2+ EBC pts enrolled in the ALTTO trial, the PREDICT+ score highly underestimated OS. The low performance of this prognostic tool was consistent across all pts subgroups. PREDICT+ should be used with caution to give prognostic estimation in HER2+ EBC pts treated in the modern era with effective chemotherapy and anti-HER2 targeted therapies.[Table: see text]
Targeted ctDNA sequencing analysis reveals concurrent genomic alterations and its impact on TKI and immune checkpoint inhibitor therapy in advanced NSCLC from Asian population.
Authors: Wei Wu, Jing Shan Lim, Jonathan Poh, Trever G. Bivona
Journal: Journal of Clinical Oncology (2021)

3042 Background: For advanced non-small cell lung cancer (NSCLC), liquid biopsy followed by targeted DNA sequencing is used in the clinical setting for driver-gene identification in circulating tumor DNA (ctDNA), tumor evolution and treatment monitoring. To understand the complexity and diversity of genetic alterations in advanced NSCLC, we examined the genetic landscape of late-stage NSCLC from an Asian population and its association with tyrosine kinase inhibitor (TKI) or immune checkpoint inhibitor (ICI) treatment. Methods: Plasma cell-free DNA (cfDNA) from 142 Asian patients with advanced NSCLC underwent real-world testing in a CAP-accredited and CLIA-certified central laboratory. We analyzed genetic alterations in cfDNA using an amplicon-based next-generation sequencing assay that covers 61 NSCLC related genes. 88 patients (62%) had received one or more lines of treatment. A similar cohort from Caucasian NSCLC was used for comparison (Blakely et al. Nat Genet 2017). Systematic co-mutation analysis, functional annotation and pathway enrichment analysis were performed. Results: The top 10 mutated genes in the Asian cohort were EGFR (66.2%), TP53 (48.6%), KRAS (11.3%), BRCA2 (7%), CTNNB1 (6.3%), PIK3CA (6.3%), SMAD4 (5.6%), BRCA1 (4.9%), MET (3.5%) and RB1 (3.5%). EGFR mutations occurred at hotspots in exons 18 – 21, with exon19 deletion, L858R, T790M, C797S, and G719A being the top-ranking alleles, similar to the Caucasian NSCLC cohort. Concurrent KRAS and EGFR mutations were higher in Asian cohort (8.5%) than in Caucasian cohort (0.56%). A rare PD-L1 structural variant (1.1%), reported to be related to immune evasion in other cancers (Kataoka et al. Nature 2016), was detected in the EGFR-mutated subgroup. Within the first line TKI-treated group, responders (CR+PR) harbored more alterations than non-responders (p &lt; 0.017). Among ICI-treated NSCLC patients (anti-PD-1/PD-L1 mono- or polytherapy), responders from 1st line or 2nd line ICI treatment harbored fewer mutations than non-responders, but the distribution of mutational allele frequency (MAF) in responders was shifted to the right (more clonal than subclonal mutations). Functional annotation suggests that concurrent mutated genes and copy number alterations in advanced EGFR-mutant NSCLC were enriched in cell cycle, DNA repair, PI3K-AKT signaling pathways. Conclusions: We characterized the ctDNA-derived genetic landscape of advanced NSCLC from an Asian population and dissected mutated genes with the outcome of TKI or ICI treatment. We also report a rare PD-L1 structural variant in the EGFR mutated subgroup, which could be associated with immune evasion. Our analyses support the occurrence of clonal and subclonal driver co-alterations in EGFR-driven NSCLC, underlining the clinical utility of ctDNA detection for NSCLC diagnosis and treatment selection.
Multiple Roles of IL6 in Hepatic Injury, Steatosis, and Senescence Aggregate to Suppress Tumorigenesis
Authors: Anat Shriki, Tali Lanton, Amir Sonnenblick, Orr Levkovitch-Siany, Dana Eidelshtein, Rinat Abramovitch, Nofar Rosenberg, Orit Pappo, Sharona Elgavish, Yuval Nevo, Rifaat Safadi, Amnon Peled, Stefan Rose-John, Eithan Galun, Jonathan H. Axelrod
Journal: Cancer Research (2021)

Hepatocellular carcinoma (HCC) typically develops on a background of chronic hepatitis for which the proinflammatory cytokine IL6 is conventionally considered a crucial driving factor. Paradoxically, IL6 also acts as a hepatoprotective factor in chronic liver injury. Here we used the multidrug-resistant gene 2 knockout (Mdr2-/-) mouse model to elucidate potential roles of IL6 in chronic hepatitis-associated liver cancer. Long-term analysis of three separate IL6/Stat3 signaling-deficient Mdr2-/- strains revealed aggravated liver injury with increased dysplastic nodule formation and significantly accelerated tumorigenesis in all strains. Tumorigenesis in the IL6/Stat3-perturbed models was strongly associated with enhanced macrophage accumulation and hepatosteatosis, phenotypes of nonalcoholic steatohepatitis (NASH), as well as with significant reductions in senescence and the senescence-associated secretory phenotype (SASP) accompanied by increased hepatocyte proliferation. These findings reveal a crucial suppressive role for IL6/Stat3 signaling in chronic hepatitis-associated hepatocarcinogenesis by impeding protumorigenic NASH-associated phenotypes and by reinforcing the antitumorigenic effects of the SASP. SIGNIFICANCE: These findings describe a context-dependent role of IL6 signaling in hepatocarcinogenesis and predict that increased IL6-neutralizing sgp130 levels in some patients with NASH may herald early HCC development.See related commentary by Huynh and Ernst, p. 4671.
Phase II study of the IDH2-inhibitor enasidenib in patients with high-risk IDH2-mutated myelodysplastic syndromes (MDS).
Authors: Sangeetha Venugopal, Courtney Denton Dinardo, Koichi Takahashi, Marina Konopleva, Sanam Loghavi, Gautam Borthakur, Amy Elizabeth Dezern, Lucia Masarova, Naval Guastad Daver, Nicholas James Short, Yesid Alvarado, Farhad Ravandi, Guillermo Montalban-Bravo, Koji Sasaki, Ricardo Delumpa, Mikkael A. Sekeres, Bhumika J Patel, Gail J. Roboz, Hagop M. Kantarjian, Guillermo Garcia-Manero
Journal: Journal of Clinical Oncology (2021)

7010 Background: Isocitrate dehydrogenase 2 ( IDH2) mutations occur in 5% of patients (pts) with MDS. Enasidenib (ENA) is a selective oral inhibitor of the mutant IDH2 enzyme with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We report the results of the open label phase II study designed to evaluate the efficacy and tolerability of ENA, as monotherapy or in combination with azacitidine (AZA) in pts with higher-risk IDH2-mutated MDS (NCT03383575). Methods: Pts with higher-risk [Revised International Prognostic Scoring System risk &gt; 3 or high molecular risk (HMR)] MDS/CMML or LB AML naïve to hypomethylating agents (HMA) received ENA100 mg orally daily for 28 d of each 28-d cycle + AZA 75 mg/m2 IV or SC on d 1-7 of each cycle (ENA+AZA), and pts with refractory or progressive MDS to prior HMA therapy received ENA alone (ENA), in 28-d cycles until unacceptable toxicity, relapse, transformation to AML, or progression. The primary endpoint was overall response rate (ORR) [complete remission (CR), marrow CR (mCR), partial remission (PR) and hematologic improvement (HI)]. Other endpoints include safety, and survival outcomes. Results: 48 pts received ENA+AZA (n = 26) or ENA (n = 22). The median age was 73 yrs (range, 46-83). Most pts (72%) had HMR: ASXL1 (39%), and RUNX1 (17%). Median number Tx cycles was 4 (2–32) in the ENA+AZA, and 7 (1–23) in the ENA arm. Common Tx-related grade 3–4 AEs in the ENA+AZA arm were neutropenia (64%), thrombocytopenia (28%), and anemia (8%); these occurred in 10%, 0%, and 5%, in the ENA arm. Grade 3–4 infections occurred in 32% (ENA+AZA) and 14% (ENA). IDH differentiation syndrome occurred in 3 pts (12%) in the ENA+AZA and 5 pts (24%) in the ENA arm. Two deaths occurred during the initial 60 d, both unrelated to study and due to COVID. In response-evaluable pts (n=46), ORR was 84% (n = 21/25; 24% CR + 8% PR+44% mCR+ 8% HI] in the treatment naïve ENA+AZA and 43% (n = 9/21; 24% CR+5%PR+5% mCR+10% HI) in the HMA failure ENA arm (Table). Most common reason for Tx discontinuation was disease progression (ENA+AZA 20%, ENA 33%).5 pts (20%) received HCT in the ENA+AZA and 1 (5%) in the ENA arm. 7 pts in the ENA+AZA and 5 in the ENA arm were ongoing at data cutoff (Dec 31, 2020). After a median follow up of 12.6 mo, median OS was 32.2 mo in the ENA+AZA and 21.3 mo in the ENA arm. Conclusions: ENA is well tolerated and shows promising efficacy in IDH2-mutated higher risk MDS. Follow up and accrual is ongoing to better define duration and biomarkers of response. Clinical trial information: NCT03383575. [Table: see text]
Abnormal Movements in Bickerstaff Brainstem Encephalitis Mimicking Anti–<i>N</i>-Methyl-<scp>d</scp>-Aspartate Receptor Encephalitis
Authors: Masamune Kimura, Hajime Yoshimura, Nobuo Kohara
Journal: JAMA Neurology (2021)

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Complex fracture reduction by exact identification of the fracture zone
Authors: Adrián Luque-Luque, Francisco Daniel Pérez-Cano, Juan José Jiménez-Delgado
Journal: Medical Image Analysis (2021)

Planning of a fracture reduction is important in order to reduce the surgery time, with the consequent improvement of the recovery process. There are no fully automatic methods that solve an adequate fracture reduction without the intervention of a specialist. Usually there are parameters that must be supervised or adjusted by the specialist, in order to obtain a satisfactory reduction. Furthermore, most of the studies in the literature focus on a certain type of bone and area on it. This paper presents an approach that tries to reduce to some extent the intervention of the specialist, so that it can be closer to an automatic approach. The proposed method can be applied to a wide variety of bones and areas, based on the identification of the complete fracture zone and the use of an ICP algorithm modified to work with the distance between fragments. The cases in which it has been tested are clinical cases of real fractures obtained from CT scan. This method allows working with a wide range of fractures, as well as complex fractures or deformed fragments. Unfortunately, all possible cases and situations could not be obtained and proved, but the method can be successfully applied to cases that meet a set of characteristics. The proposed technique has been validated by experts, both visually and empirically, using a framework based on virtual reality (VR). This VR framework has allowed comparing the reduction performed by the method with a reduction made virtually by specialists. This technique has also been compared with other existing techniques, obtaining a significant improvement over these.
PRC2 loss of function confers a targetable vulnerability to BET proteins in T-ALL
Authors: Guillaume P. Andrieu, Milena Kohn, Mathieu Simonin, Charlotte L. Smith, Agata Cieslak, Marie-Émilie Dourthe, Guillaume Charbonnier, Carlos Graux, Françoise Huguet, Véronique Lhéritier, Hervé Dombret, Salvatore Spicuglia, Philippe Rousselot, Nicolas Boissel, Vahid Asnafi
Journal: Blood (2021)
TCOG T5217 trial: A phase II randomized study of SLOG versus modified FOLFIRINOX as the first-line treatment in locally advanced or metastatic pancreatic ductal adenocarcinoma.
Authors: Nai-Jung Chiang, Yan-Shen Shan, Li-Yuan Bai, Chung-Pin Li, Jen-Shi Chen, Shih-Hung Yang, Yung-Chia Kuo, Yee Chao, Yao-yu Hsieh, Hsiang-fong Kao, Chin-Fu Hsiao, Li-Tzong Chen
Journal: Journal of Clinical Oncology (2021)

4143 Background: The triplet regimen of S-1, leucovorin, oxaliplatin and gemcitabine (SLOG) has shown promising efficacy for metastatic pancreatic ductal adenocarcinoma (PDAC) in our previous study. Current multicenter randomized, phase II study compared the efficacy and safety of SLOG versus modified FOLFIRINOX (mFOLFIRINOX) in patients with advanced/metastatic PDAC. Methods: Patients with chemo-naïve, histologically confirmed advanced/metastatic PDAC, were randomly assigned to either SLOG (gemcitabine 800 mg/m 2 , fixed-rate infusion and oxaliplatin 85 mg/m 2 on day 1, plus daily 40/50/60 mg of S-1 based on BSA and 30 mg of oral leucovorin, twice daily, on days 1-7, every 2 weeks) or mFOLFIRINOX (oxaliplatin 85 mg/m 2 , irinotecan 150 mg/m 2 and leucovorin 400 mg/m 2 on day 1 plus 5-FU 2400 mg/m 2 for 46 hrs, every 2 weeks). Patients were stratified according to disease extent, ECOG PS and primary tumor location. The primary endpoint was 6-month progression-free survival (PFS) rate. The secondary endpoints were objective response rate (ORR), disease control rate (DCR), PFS, and overall survival (OS) and safety profile. Tumor response was assessed by CT/MRI every 8 weeks according to RECIST v1.1. As an exploratory trial, 130 (65 per arm) patients were estimated to detect a two-sided 15% difference in 6-month PFS (60% in SLOG and 45% in mFOLFIRINOX) with a significant level of α = 0.1 and β = 0.25. Results: Between March 2018 and October 2019, 130 patients were accrued. One patient who was assigned to mFOLFIRINOX arm didn’t receive assigned treatment. Of them, 62.3% were male, 45.4% were ECOG PS0, 81.5% had metastatic diseases, and 16.9% had prior surgery. The 6-month PFS rate was 55.4% in SLOG arm (n = 65) and 50% in mFOLFIRINOX arm (n = 64) (p = 0.850). The ORR and DCR in the SLOG and the mFOLFIRINOX arms were 40% versus 26.6% (p = 0.135) and 76.2% versus 71.9% (p = 0.550), respectively. The median PFS was 7.5 months in SLOG arm and 6.5 months in mFOLFIRINOX arm (p = 0.395); while the median OS was 12.9 months in SLOG arm and 12.1 months in mFOLFIRINOX arm (p = 0.88). Ten patients underwent conversion surgery, of whom 7 had SLOG and 3 had mFOLFIRINOX. The incidence of grade 3/4 neutropenia was significantly higher in mFOLFIRINOX arm (53.2% vs. 16.9% in SLOG arm, p &lt; 0.0001). Conclusions: SLOG could achieve comparable but numerically better ORR, and median PFS and OS as compared to mFOLFIRINOX in patients of advanced PDAC. SLOG can be an alternative first-line regimen for advanced PDAC patients. Clinical trial information: NCT03443492.
Efficacy of sorafenib in heavily pretreated adult patients with metastatic osteosarcoma.
Authors: Nail Paksoy, Izzet Dogan, Meltem Ekenel, Mert Basaran
Journal: Journal of Clinical Oncology (2021)

e23511 Background: Osteosarcoma is a rare tumor and is commonly seen in young people. It arises from bone and rarely from soft tissue. Surgery is the primary treatment option for osteosarcoma. Osteosarcoma is radioresistant, except for rare variants. The choices of chemotherapy are limited in the treatment of metastatic osteosarcoma. The efficiency data of targetted therapies in metastatic osteosarcoma is limited. This study aimed to evaluate sorafenib's efficacy in adult patients with heavily pretreated metastatic osteosarcoma. Methods: We evaluated the patients aged over 18 years with metastatic osteosarcoma retrospectively. The clinical, pathological, and treatment data of the patients were recorded. We used SPSS 25. version for statistical analysis. Kaplan-Meier and Cox-regression analysis were used for survival analysis. Results: Fifteen patients were included in the study. Ten (66.7%) of the patients were male, and the median age was 25 (range,19-64). The primary localization of the tumor was the lower extremity (53.4%), head and neck (20%), upper extremity (13.3%), and other sites (13.3%), respectively. The most common metastatic sites were lung (93.3%), bone (46.7%,) and other (33.3%), respectively. Before sorafenib, fourteen (93.3%) patients had received at least two different cytotoxic chemotherapy regimens, six (40%) patients palliative radiotherapy. In addition, metastasectomy had performed on eight (53.3%) patients. The median progression-free survival was 5.5 (95% CI, 1.3-9.7) months with sorafenib. The stable response was observed in 8 (50%) patients and progressive disease 8 (50%) patients. Grade 1-2 toxicities were observed in 50% of the patients, and grade 3-4 toxicities in 14.3% of the patients. Conclusions: In the study, we showed real-life outcomes of sorafenib for disease control in heavily pretreated adult patients with metastatic osteosarcoma. Sorafenib was effective and well-tolerated in the patients. Sorafenib may be considered as a treatment option after chemotherapy in patients with metastatic osteosarcoma.