tbuckley/cabot-search huggingface dataset:
Resectability, conversion and resections rates, and outcomes in <i>RAS</i>&amp;<i>BRAF</i> wildtype (wt), <i>RAS</i> mutant (mt) and <i>BRAF</i>mt metastatic colorectal cancer (mCRC) subgroups in the prospective Finnish RAXO-study.
Authors: Pia J. Osterlund, Emerik Osterlund, Aki Uutela, Päivi Halonen, Raija S. Kallio, Annika Ålgars, Tapio Salminen, Annamarja Lamminmäki, Leena-Maija Soveri, Raija Ristamäki, Kaisa I Lehtomäki, Hanna Stedt, Eetu Heervä, Arno Nordin, Ali Ovissi, Jari Sundström, Lasse Nieminen, Markus J Mäkinen, Ari Ristimäki, Helena Isoniemi
Journal: Journal of Clinical Oncology (2021)

3532 Background: Outcomes of metastasectomy varies with RAS and BRAF-status, but the effect on resectability, conversion and resection rates has not been extensively studied. Methods: The prospective Finnish RAXO study (NCT01531621) included 1086 patients 2011-2018 (Osterlund et al TLRHE 2021, Isoniemi et al BJS 2021) of which 906 were included in this secondary endpoint analysis. Excluded had missing KRAS/ NRAS/ BRAF-V600E test, were untreatable or had an atypical BRAF mutation. We studied repeated centralized resectability assessment, conversion and resectability rates in mCRC, and overall survival (OS) after resection and/or local ablative therapy (LAT) and systemic therapy. Results: Included were 289 RAS&amp; BRAFwt, 529 RASmt (overrepresented) and 88 BRAFmt, with median age 65.8/66.1/66.9 years. Demographics per RAS&amp; BRAFwt, RASmt and BRAFmt showed significant differences in male proportion (68/61/39%), ECOG PS 2-3 groups (16/14/25%), primary tumour location (right colon 16/30/69%, left colon 47/34/17%, rectum 38/36/14%), but not for Charlson comorbidity index, BMI, resection of primary, synchronous presentation or adjuvant therapy (Bonferroni corrected Chi-square). Metastatic profile was different for liver (78/74/61% per RAS&amp; BRAFwt, RASmt and BRAFmt), lung (24/35/28%) and peritoneal (15/15/32%) metastases, but not for lymph nodes or other sites, nor for number of metastatic sites (1 in 53/54/52%). Upfront resectability rates were different with 32/29/15% for RAS&amp; BRAFwt, RASmt and BRAFmt, respectively, as were conversion rates with 16/13/7%, and resection/LAT rates with 45/37/17%, respectively. Kaplan-Meier median OS estimate in R0/1/2-resected and/or LAT group (n = 342) was 83/69/30 months for RAS&amp; BRAFwt, RASmt and BRAFmt groups, respectively and 5-year OS-rates 67/60/24%, with Cox HR ref/1.53 (95% CI 1.04-2.25)/3.11 (1.49-6.49). In the “systemic therapy only” (n = 564) OS was 29/21/15 months and 5-year OS-rates 11/6/2% respectively, with HR ref/1.43 (1.15-1.76)/2.34 (1.73-3.17). Resection/LAT patients had improved OS over “systemic therapy only” patients in all subgroups, HR 5.74 (3.90-8.44)/5.06 (3.92-6.55)/2.89 (1.43-5.86). Conclusions: There were significant differences in resectability, conversion and resection/LAT rates according to RAS&amp; BRAFwt, RASmt and BRAFmt status. OS was also significantly longer for RAS&amp; BRAFwt versus either mutant. Resected/LAT had better OS than “systemic therapy alone” patients in all subgroups. Clinical trial information: NCT01531621.
Origami Folding by Multifingered Hands with Motion Primitives
Authors: Akio Namiki, Shuichi Yokosawa
Journal: Cyborg and Bionic Systems (2021)

Origami, a traditional Japanese art, is an example of superior handwork produced by human hands. Achieving such extreme dexterity is one of the goals of robotic technology. In the work described in this paper, we developed a new general-purpose robot system with sufficient capabilities for performing Origami. We decomposed the complex folding motions into simple primitives and generated the overall motion as a combination of these primitives. Also, to measure the paper deformation in real-time, we built an estimator using a physical simulator and a depth camera. As a result, our experimental system achieved consecutive valley folds and a squash fold.
Camrelizumab combined with paclitaxel and nedaplatin as neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma (ESPRIT): A phase Ⅱ, single-arm, exploratory research.
Authors: Jianqun Ma, Jinfeng Zhang, Yingnan Yang, Dayong Zheng, Xiaoyuan Wang, Hao Liang, Luquan Zhang, Yanzhong Xin, Xiaodong Ling, Chengyuan Fang, Hao Jiang, Wei Zheng
Journal: Journal of Clinical Oncology (2021)

e16033 Background: Camrelizumab has been approved as a standard therapy in the second-line treatment of esophageal squamous cell carcinoma (ESCC). This study aimed to explore the efficacy and safety of camrelizumab combined with commonly used neoadjuvant chemotherapy (paclitaxel and platinum) in neoadjuvant treatment of ESCC. Methods: In this single-arm, phase Ⅱ study, patients with advanced ESCC who were expected to receive neoadjuvant therapy followed by radical surgery were recruited. The patients received 2-4 cycles of camrelizumab (200mg, iv, q3w) in combination with paclitaxel (155mg/m 2 , iv, q3w) and nedaplatin (80mg/m 2 , iv, q3w) as neoadjuvant therapy, and the therapeutic effects were determined every 2 cycles. The radical surgery was performed on patients whose tumors were evaluated as resectable. The primary endpoint was pCR, and the secondary endpoints were objective response rate (ORR) and disease control rate (DCR). Results: From May 2020 to January 2021, 24 patients with a median age of 60.5 years (50-73) were enrolled. Among them, 21 patients were available for efficacy analysis, of which 1 achieved complete response (CR), 7 achieved partial response (PR), and 13 had stable disease (SD). The ORR was 38.1% and DCR was 100%. The tumor in 10 patients shrank significantly after neoadjuvant therapy and these patients preferred radiotherapy instead of surgery as the radical therapeutic method. 2 patients abandoned surgery because of personal reasons. 2 patients were in the process of neoadjuvant therapy and had not undergone surgery yet. The remaining 7 patients underwent radical surgery and 4 patients (57.14%) achieved pCR (pT0N0M0). The main treatment-related grade 3/4 adverse event (AE) was neutropenia (1/21). All the AEs were manageable. The average intraoperative blood loss was 221mL and the average hospitalization time after operation was 12.7 days (range 8-19 days). No anastomotic leakage and treatment-related death occurred. Conclusions: Camrelizumab in combination with paclitaxel and platinum as a neoadjuvant therapy was well tolerated. The pCR rate of 57.14% was higher than the expected 40%. This encouraging result promoted us to continue this phase Ⅱ study. Clinical trial information: ChiCTR2000033761.
IGF1 receptor inhibition amplifies the effects of cancer drugs by autophagy and immune-dependent mechanisms
Authors: Qi Wu, Ai-Ling Tian, Bei Li, Marion Leduc, Sabrina Forveille, Peter Hamley, Warren Galloway, Wei Xie, Peng Liu, Liwei Zhao, Shuai Zhang, Pan Hui, Frank Madeo, Yi Tu, Oliver Kepp, Guido Kroemer
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Pharmacological autophagy enhancement constitutes a preclinically validated strategy for preventing or treating most major age-associated diseases. Driven by this consideration, we performed a high-content/high-throughput screen on 65 000 distinct compounds on a robotized fluorescence microscopy platform to identify novel autophagy inducers. Results Here, we report the discovery of picropodophyllin (PPP) as a potent inducer of autophagic flux that acts on-target, as an inhibitor of the tyrosine kinase activity of the insulin-like growth factor-1 receptor (IGF1R). Thus, PPP lost its autophagy-stimulatory activity in cells engineered to lack IGF1R or to express a constitutively active AKT serine/threonine kinase 1 (AKT1) mutant. When administered to cancer-bearing mice, PPP improved the therapeutic efficacy of chemoimmunotherapy with a combination of immunogenic cytotoxicants and programmed cell death 1 (PDCD1, better known as PD-1) blockade. These PPP effects were lost when tumors were rendered PPP-insensitive or autophagy-incompetent. In combination with chemotherapy, PPP enhanced the infiltration of tumors by cytotoxic T lymphocytes, while reducing regulatory T cells. In human triple-negative breast cancer patients, the activating phosphorylation of IGF1R correlated with inhibited autophagy, an unfavorable local immune profile, and poor prognosis. Conclusion Altogether, these results suggest that IGF1R may constitute a novel and druggable therapeutic target for the treatment of cancer in conjunction with chemoimmunotherapies.
Abstract NT-114: CATALYTIC SUBUNITS SWITCH DRIVES RESISTANCE TO EZH2 INHIBITORS IN ARID1A-MUTATED CELLS
Authors: Shuai Wu, Nail Fatkhutdinov, Takeshi Fukumoto, Benjamin G. Bitler, Pyoung Hwa Park, Andrew V. Kossenkov, Marco Trizzino, Alessandro Gardini, David W. Speicher, Rugang Zhang
Journal: Clinical Cancer Research (2019)

Abstract The SWI/SNF chromatin remodeling complex is altered in ~20% of human cancers. ARID1A, a component of the SWI/SNF chromatin-remodeling complex, is the most frequently mutated epigenetic regulator in human cancers. Inactivation of the SWI/SNF complex is synthetically lethal with inhibition of EZH2 activity. EZH2 inhibitors are entering clinical trials for specific tumor types with SWI/SNF mutations. However, mechanisms of de novo or acquired resistance to EZH2 inhibitors in cancers with inactivating SWI/SNF mutations are unknown. Here we show that the switch of the SWI/SNF catalytic subunits from SMARCA4 to SMARCA2 drives resistance to EZH2 inhibitors in ARID1A-mutated ovarian cancer cells. SMARCA4 decease dominates over SMARCA2 increase in the switch. SMARCA4 loss leads to suppression of apoptotic pathways through upregulating anti-apoptotic genes such as BCL2 in the EZH2 inhibitor resistant cells. EZH2 inhibitor resistant ARID1A-mutated cells are hypersensitive to BCL2 inhibitors such as ABT263. ABT263 is sufficient to overcome resistance to EZH2 inhibitor and synergistic with EZH2 inhibitor in vivo in ARID1A-inactivted ovarian tumour mouse models. Together, these data establish that the switch of the SWI/SNF catalytic subunits from SMARCA4 to SMARCA2 underlies the acquired resistance to EZH2 inhibitors and BCL2 inhibition alone or in combination with EZH2 inhibition represents a novel strategy to overcome and/or prevent EZH2 inhibitor resistance in ARID1A-mutated cancers. Given that the SWI/SNF subunits are among the most frequently mutated genes in human cancers and EZH2 inhibitors are in the clinical trials for tumor with mutations in the SWI/SNF complex, we expect our findings to have far-reaching implications for developing cancer epigenetic therapeutics. Citation Format: Shuai Wu, Nail Fatkhutdinov, Takeshi Fukumoto, Benjamin G. Bitler, Pyoung Hwa Park, Andrew V. Kossenkov, Marco Trizzino, Alessandro Gardini, David W. Speicher, Rugang Zhang,. CATALYTIC SUBUNITS SWITCH DRIVES RESISTANCE TO EZH2 INHIBITORS IN ARID1A-MUTATED CELLS [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-114.
Predictors of hypomethylating agent discontinuation among patients with higher-risk myelodysplastic syndromes.
Authors: Amer Methqal Zeidan, Namita Joshi, Hrishikesh Kale, Wei-Jhih Wang, Shelby Corman, Kala Hill, Tehseen Salimi, Robert S. Epstein
Journal: Journal of Clinical Oncology (2021)

7043 Background: Real-world studies have shown that persistence with intravenous (IV) and subcutaneous (SC) hypomethylating agents (HMAs) among patients (pts) with higher-risk myelodysplastic syndromes (MDS) is poor, with over one-third of treated pts receiving &lt;4 cycles or having a ≥90-day gap in therapy, despite recommendations for at least 4-6 cycles to elicit response in absence of progression/unacceptable toxicity. Survival outcomes have also been shown to be worse, and direct medical costs higher, among HMA non-persistent vs persistent pts. We explored factors associated with early discontinuation of HMA therapy in this population. Methods: This was a retrospective cohort study among pts from the 2010-2016 SEER-Medicare linked database with a diagnosis of refractory anemia with excess blasts (RAEB; a surrogate for higher-risk MDS) from 2011-2015. Included pts had to have received HMA therapy and have ≥12 months’ continuous follow-up after diagnosis. Discontinuation was defined as stopping HMA therapy before 4 cycles. Multivariable logistic regression was used to assess predictors of HMA discontinuation. Results: In total, 664 pts with RAEB and treated with HMAs were included. Overall, 193 (29%) discontinued before 4 cycles; of these, 91 (47%) discontinued after 1 cycle, 57 (30%) 2 cycles, and 45 (23%) 3 cycles. Compared with pts continuing for ≥4 cycles, pts discontinuing before 4 cycles were generally older and more likely to be single/separated/divorced/widowed, have more comorbidities, and have poor performance status (PS) (Table). These trends were most pronounced among pts discontinuing HMA therapy after only 1 cycle vs ≥4 cycles (Table). In multivariable analysis, age 71-75 vs ≥80 y (odds ratio [OR] 0.556, p=0.017) and poor PS (OR 1.585, p=0.019) remained significant predictors of HMA discontinuation. Among treatment-related factors, the most statistically significant association with HMA discontinuation was observed for GCSF use (OR 0.453, p&lt;0.001). Number of pills/day was not a predictor of HMA discontinuation (OR 1.009, p=NS). Conclusions: In this real-world study, almost one-third of RAEB pts treated with IV/SC HMAs discontinued before 4 cycles, with almost half of these pts discontinuing after only 1 cycle. Predictors of HMA discontinuation included older age and poor PS. Novel approaches are needed to improve persistence with HMA therapy, particularly among these higher-risk groups.[Table: see text]
A new staging system for radiotherapy-based treatment of hepatocellular carcinoma: A multicenter cohort study.
Authors: Ting-Shi Su, Shi-Xiong Liang, Li-Qing Li, Qiu-Hua Liu, Xiao-Fei Zhu, Ping Liang
Journal: Journal of Clinical Oncology (2021)

e16155 Background: External beam radiation therapy has been used as a palliative to radical treatment of hepatocellular carcinoma (HCC) depending on different tumor status, liver function and patient's general state of health. The existing models of HCC staging cannot perfectly predict the prognosis of radiotherapy. In this study, we aimed to set up a new staging system for radiotherapy-based treatment by incorporating bilirubin-albumin (ALBI) grade and tumor status for the prognostic classifications of HCC. Methods: This multicenter cohort study included 878 HCC patients who received radiotherapy-based treatment. A new staging system was established: stage I, solitary nodule without macrovascular invasion or 2-3 nodules with no more than 3.0 cm each other and PS 0-2 (Ia: ALBI-1 grade; Ib: ALBI-2 or 3 grade); stage II: 2-3 nodules with anyone more than 3.0 cm or ≥4 nodules and PS 0-2 (IIa: ALBI-1 grade; IIb: ALBI-2 grade); stage III: macrovascular invasion or regional lymph node metastasis or distant metastasis and PS 0-2 (IIIa: ALBI-1 grade; IIIb:ALBI-2 grade); stage IV: ALBI-3 grade without stage I patient or/and PS score 3-4. The new modified staging system and the existing staging systems, such as the BCLC, TNM, CNLC staging systems were used for prognostic analysis. All patients were separated into different stages and substages. The long-term overall survival outcomes and time-dependent receiver operating characteristic (ROC) were analyzed. Results: A training cohort of 595 patients underwent stereotactic body radiotherapy (SBRT) from 2011 to 2017 and an external validation cohort of 283 patients underwent intensity-modulated radiotherapy (IMRT) from 2000 to 2013 were included into establishing and validating the new staging system. In the training cohort, the median follow-up time was 55 months (range, 6–100 months), and the new staging system had a good discriminatory ability to separate patients into different stages with 4 notably different curves and substages with 7 notably different curves. BCLC staging could not differentiate stage 0 to A, and stage C to D in these selected patients. TNM staging could not completely distinguish stage IIIb to IV, but also stage Ia to Ib. CNLC staging could not differentiate among stage IIIa, IIIb, and IV. In the external validation, the median follow-up time was 95 months (range, 9–120 months), and the new staging system also had a good discriminatory ability to separate patients into different stages with 4 notably different curves and substages with 7 notably different curves. The new staging system had a better area under curve of time-dependent ROC than BCLC, TNM and CNLC staging in both SBRT and IMRT cohorts. Conclusions: The new modified (Su’s) staging system could provide a good discriminatory ability to separate patients into different stages and substages after radiotherapy treatment. It may be used to supplement the other HCC staging systems.
Minding the gap: Gynecologic oncology practices differ by gender.
Authors: Sarah Madhu Temkin, Eloise Chapman, Elise C. Kohn, Navya Nair, Stephanie V. Blank
Journal: Journal of Clinical Oncology (2021)

11011 Background: Although most gynecologic oncologists (GOs) are now women, gender differences in clinical practice and compensation persist. Practice characteristics and infrastructural support that may influence gender-based differences were explored. Methods: Every 5 years, the Society of Gynecologic Oncology (SGO) conducts a member survey that provides details on member demographics, practice characteristics, activities, and revenue. Between 8/15-9/30/19 SGO members received a direct link to the survey. Gender was self-identified. Differences in responses were evaluated by gender. Results: Of 1425 surveys delivered, 690 were completed (48% response rate). 312 (45%) identified as male; 367 (53%) as female; 1 nonbinary; 1 other; 7 no response. Male GOs were more likely white (75 vs 68%, p=0.048), married (91 vs 81%, p&lt;0.001), heterosexual (94 vs 90%, p=0.045), and hold an academic rank of professor (23 vs 12%, p&lt;0.001). Practice setting and number of partners were similar. Chemotherapy prescribing was more common for females (82 vs 73%, p=0.004), but other clinical activities were similar (Table). Female GOs had lower clinical volumes than males for cervical, ovarian, vaginal/vulvar cancer and benign gynecologic procedures. Females reported fewer medical assistants and transcriptionists supporting their clinical activities. Overall and practice support was higher for male GOs although hospital support was similar for both genders. Female GOs reported more time spent on research (26 vs 19%, p=0.005), but the same research support. Conclusions: Clinical activities, specifically chemotherapy prescribing, and support differ for male and female GOs and may explain gender inequities. Clinical support should be equalized to maximize workplace productivity regardless of gender. Coordination of support between the practice and hospital and standard compensation for chemotherapy prescribing could decrease the large gender wage gap in this specialty.[Table: see text]
Access to cancer care for Medicaid patients at cancer hospitals in the United States.
Authors: Victoria A. Marks, Walter R. Hsiang, James Nie, Matthew Buck, Patrick C Demkowicz, Waez Umer, Afash Haleem, Bayan Galal, Irene Pak, Dana Kim, Patrick Aloysius Kenney, Michael S. Leapman
Journal: Journal of Clinical Oncology (2021)

6548 Background: As the result of expansions associated with the Affordable Care Act (ACA), one in five Americans are now insured through Medicaid. Despite overall increases, access to care for Medicaid-insured patients with cancer may be limited by facilities due to lower reimbursement and administrative burden. We aimed to directly assess facility-level acceptance of Medicaid patients with a new diagnosis of cancer. Methods: We performed a cross-sectional secret shopper study to evaluate access to cancer care for colorectal, breast, urologic, and skin cancer at Commission on Cancer (CoC) accredited hospitals. We studied the relationship between Medicaid access and facility-level characteristics assessed through American Hospital Association and Center for Medicare and Medicaid Service data using univariable statistics and multivariable logistic regression. Results: Among 334 CoC facilities contacted, the overall rate of Medicaid acceptance for at least one investigated cancer type was 99% (n = 331). However, we identified hospital-level variation in Medicaid acceptance across cancer types, where Medicaid acceptance for colorectal, breast, urologic, and skin cancer was 90%, 96%, 87%, and 80%, respectively. Of the hospitals that accepted Medicaid, 2% accepted Medicaid for one cancer type, 8% for two, 21% for three, and 68% for all four cancer types. In multivariable logistic regression, odds of Medicaid acceptance were lowest in comprehensive community cancer centers (p &lt; 0.05 for colorectal and urologic cancer) and for-profit designated facilities (p &lt; 0.05 for urologic and skin cancer) (Table). Hospitals in states with Medicaid expansion were also more likely to accept Medicaid for urologic (OR: 2.5, 95% CI: 1.2-5.2) and breast (OR: 12.8, 95% CI: 2.7-60.2) cancer care. Conclusions: Access disparities persist for patients with Medicaid, with acceptance rates differing substantially within and between facilities. Facility-level differences in Medicaid access among CoC facilities are notable given the use of hospital registry data to estimate ACA-related effects.[Table: see text]