tbuckley/cabot-search huggingface dataset:
Phase II study of atezolizumab and bevacizumab combination therapy for patients with advanced hepatocellular carcinoma who previously received systemic treatment.
Authors: Takeshi Terashima, Tatsuya Yamashita, Makoto Yamamoto, Masahiro Yanagi, Hidetoshi Nakagawa, Akihiro Seki, Kouki Nio, Kuniaki Arai, Tadashi Toyama, Taro Yamashita
Journal: Journal of Clinical Oncology (2024)

495 Background: Atezolizumab plus bevacizumab (AteBev) has been established as a standard of care for patients with untreated advanced hepatocellular carcinoma (HCC). Lenvatinib was once the first choice and remains a treatment option for such patients; however, no subsequent treatment to date has proven a similar level of efficacy. This study aimed to evaluate the efficacy of AteBev in patients with HCC previously treated with lenvatinib. Methods: In this single-center, open-labeled, single-arm, phase II study, patients with advanced HCC previously treated with at least one systemic treatment were enrolled to receive 1,200 mg of atezolizumab and 15 mg/kg of bevacizumab intravenously every 3 weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, response rate, tumor control rate, and frequency of adverse events. The threshold and expected PFS were 3 months and 6.8 months, respectively, at a one-sided significance level of 0.05, and statistical power of 80%. Based on these data, the number of patients required was estimated to be 26. Results: Among 29 patients enrolled between November 2020 and October 2022, 26 previously treated with lenvatinib were included in the primary efficacy analysis. Median PFS was 9.70 [90% confidence interval (CI), 5.10–14.24] months. Median overall survival was 17.23 (90% CI, 3.18–27.85) months, and response rate and tumor control rate were 34.6% and 69.2%, respectively. Severe adverse events were observed in six patients (23.1%), six patients (23.1%) discontinued treatment because of immune-related adverse events or treatment-refractory ascites, and 10 patients (38.5%) required the withdrawal of treatment mainly because of proteinuria. There were no treatment-related deaths. Conclusions: AteBev for patients with advanced HCC previously treated with lenvatinib had a comparable efficacy to that in patients with no prior treatment. It may therefore be a treatment option for patients with advanced HCC previously treated with lenvatinib. Clinical trial information: jRCT1041200068 .
Clinical Prediction Models Combining Routine Clinical Measures Have High Accuracy in Identifying Youth-Onset Type 2 Diabetes Defined by Maintained Endogenous Insulin Secretion: The SEARCH for Diabetes in Youth Study
Authors: Angus G. Jones, Beverley M. Shields, Richard A. Oram, Dana M. Dabelea, William A. Hagopian, Eva Lustigova, Amy S. Shah, Julieanne Knupp, Amy K. Mottl, Ralph B. D’Agostino, Adrienne Williams, Santica M. Marcovina, Catherine Pihoker, Jasmin Divers, Maria J. Redondo
Journal: Diabetes Care (2024)

OBJECTIVE With high prevalence of obesity and overlapping features between diabetes subtypes, accurately classifying youth-onset diabetes can be challenging. We aimed to develop prediction models that, using characteristics available at diabetes diagnosis, can identify youth who will retain endogenous insulin secretion at levels consistent with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS We studied 2,966 youth with diabetes in the prospective SEARCH for Diabetes in Youth study (diagnosis age ≤19 years) to develop prediction models to identify participants with fasting C-peptide ≥250 pmol/L (≥0.75 ng/mL) after &amp;gt;3 years’ (median 74 months) diabetes duration. Models included clinical measures at the baseline visit, at a mean diabetes duration of 11 months (age, BMI, sex, waist circumference, HDL cholesterol), with and without islet autoantibodies (GADA, IA-2A) and a Type 1 Diabetes Genetic Risk Score (T1DGRS). RESULTS Models using routine clinical measures with or without autoantibodies and T1DGRS were highly accurate in identifying participants with C-peptide ≥0.75 ng/mL (17% of participants; 2.3% and 53% of those with and without positive autoantibodies) (area under the receiver operating characteristic curve [AUCROC] 0.95–0.98). In internal validation, optimism was very low, with excellent calibration (slope 0.995–0.999). Models retained high performance for predicting retained C-peptide in older youth with obesity (AUCROC 0.88–0.96) and in subgroups defined by self-reported race/ethnicity (AUCROC 0.88–0.97), autoantibody status (AUCROC 0.87–0.96), and clinically diagnosed diabetes types (AUCROC 0.81–0.92). CONCLUSIONS Prediction models combining routine clinical measures at diabetes diagnosis, with or without islet autoantibodies or T1DGRS, can accurately identify youth with diabetes who maintain endogenous insulin secretion in the range associated with T2D.
Design, synthesis, and evaluation of (1E,4E,6E)-1,7-diphenyl hepta-1,4,6-trien-3-one analogues-inspired <i>o</i>-methoxy phenyl group as potential anti–gastric cancer agents.
Authors: Fatehi Rashad Abdulwahab Khushafah
Journal: Journal of Clinical Oncology (2024)

292 Background: Gastric cancer (GC) is a major global malignancy causing significant mortality. Most diagnoses occur at advanced stages. Current treatments involve surgery, chemotherapy, and targeted therapies. Targeted drugs face resistance and side effects. Curcumin, derived from Curcuma longa, shows promise against GC. Improved analogs addressing bioavailability have been developed. Some curcumin-based compounds with o-methoxy phenyl groups exhibit enhanced anticancer activity. We designed and synthesized (1E,4E,6E)-1,7-diphenyl hepta-1,4,6-trien-3-one analogs inspired by o-methoxy phenyl for anti-gastric cancer evaluation in vitro and in vivo. Methods: We designed and synthesized a series of analogs named (1E,4E,6E)-1,7-diphenyl hepta-1,4,6-trien-3-one analogues inspired by the o-methoxy phenyl group based on association theory. Anti-tumor activity was evaluated in vitro using gastric cancer cell lines BGC-823 and SGC-7901. Compound 2 was selected as a prime candidate based on its potency. Results: Compound 2 demonstrated potent anti-tumor effects in vitro by suppressing growth, migration, and invasion of SGC-7901 and BGC-823 cells. Impressively, it prompted cell cycle arrest at the G2/M phase and initiated apoptosis through Bax activation and caspase 3 inhibition. Moreover, in vivo trials on xenograft model nude mice validated the compound's substantial anti-gastric cancer potential while maintaining a favorable safety profile. Conclusions: A group of curcumin analogs exhibiting strong anti-gastric cancer activity was developed. The active compound 2 is capable of inhibiting the growth, colony formation, migration, and invasion of gastric cancer cells. It also arrests the cell cycle at the G2/M phase and stimulates the expression of apoptosis-related proteins, showcasing a powerful anti-gastric cancer effect in vitro. Furthermore, it demonstrates significant anti-gastric cancer activity in vivo while maintaining a favorable safety profile. Our research underscores the potential of (1E, 4E, 6E)-1,7-diphenylheptyl-1,4,6-trien-3-one analogs with o-methoxyphenyl in combatting tumors and highlights their promise as a secure anti-tumor candidate drug.
Factors associated with resolution of ultrasound subclinical synovitis in anti-CCP-positive individuals with musculoskeletal symptoms: a UK prospective cohort study
Authors: Leticia Garcia-Montoya, Jing Kang, Laurence Duquenne, Andrea Di Matteo, Jacqueline L Nam, Kate Harnden, Rahaymin Chowdhury, Kulveer Mankia, Paul Emery
Journal: The Lancet Rheumatology (2024)

Subclinical synovitis occurs in a third of individuals at risk of rheumatoid arthritis. The objective of this study was to assess the reversibility of subclinical synovitis in individuals at risk of rheumatoid arthritis who are positive for anti-cyclic citrullinated peptide (CCP) antibody with musculoskeletal symptoms and investigate factors associated with its resolution within 12 months.
Actionable molecular alterations in veterans with advanced cholangiocarcinoma.
Authors: Ethan Samuel Lin, Eric G. Mehlhaff, Colin P Bergstrom, Dyan M. Lesnik, Noelle K. LoConte, Sam Joseph Lubner, Kristina A. Matkowskyj, Monica Arun Patel, Sean Ronnekleiv-Kelly, Nataliya Volodymyrivna Uboha, Megan Wachsmann, David H. Wang, Albert Y. Lin, Jeremy D. Kratz
Journal: Journal of Clinical Oncology (2024)

548 Background: Cholangiocarcinoma (CCA) requires integrated efforts to understand the heterogeneity in available molecular targets. Chemotherapy remains a non-selective standard of care, however defining distinct populations with molecular actionability remains a critical need. The Veteran Health Administration’s (VHA) National Precision Oncology Program (NPOP) was established to characterize comprehensive genomic profiles across the integrated VHA network. Methods: Veterans with CCA underwent next-generation sequencing (NGS) with FoundationOne CDx, which enhanced sensitivity in the reporting of gene fusions. Analysis included dedicated chart review for date of diagnosis and survival utilizing the VHA’s Corporate Data Warehouse. Molecular alterations included mutations(mut), amplifications (amp) and fusion/rearrangements (fus). Log-rank Kaplan-Meier survival analysis was stratified by primary tumor location, and actionable driver alterations defined by VA Clinical Pathways. Results: Veterans diagnosed with CCA (07/2008-04/2023) underwent tissue-based NGS (n=483) including 96 unique VHA sites with male predominant population (96.9%). There was a predominance of localized disease at clinical presentation (55.3%). A summary of common pathogenic variants is provided (see table). Actionable alterations defined as IDH1mut, FGFR2fus, ERBB2amp, BRAFmut (V600E), and MSI-H collectively represented 21.1% of all Veteran CCA. The largest population was intrahepatic CCA (n=327) with actionable alterations including IDH1mut (13.5%), ERBB2amp (4.3%), and FGFR2fus (4.3%). Data suggested improved overall survival (OS) in IDH1mut Intrahepatic CCA including median OS 19.8 months (mo) v. 10.7 mo (p&lt;0.03). ERBB2amp (n=32) was enriched in extrahepatic (8.1%) and gallbladder cancer (17.2%), however did not improve OS including 7.1 mo in ERBB2amp v. 13.2 mo in wildtype (p=0.15). PIK3CAmut CCA (n=35) was found to confer inferior OS across the population with median OS of 7.5 mo v. 13.2 mo in wildtype (p&lt;0.02). Additional pathologic mutations in genes of homologous recombination deficiency (31.7%), PIK3CA (7.2%), and amplifications in MDM2 (5.0%). Conclusions: Across an integrated healthcare system of Veterans, actionable molecular alterations from VA Pathways were seen in 21.1% of the population. Further data is needed to clarify the prognostic versus predictive value of integrated precision-based strategies in clinical practice. The Veteran population includes important molecular subtypes to consider in future prospective trial design. [Table: see text]
Short course immunotherapy as curative-intent treatment in stage I-III dMMR rectal cancer.
Authors: Per Pfeiffer, Per Vadgaard Andersen, Søren Salomon, Nadia Øgaard, Christina Demuth, Claus Lindbjerg Andersen, Ismail Gögenur, Tobias Freyberg Justesen, Vinicius Araujo de Lima, Line Schmidt Tarpgaard
Journal: Journal of Clinical Oncology (2024)

121 Background: Neoadjuvant chemo-radiation followed by resection is standard treatment for patients with locally advanced rectal cancer (RC). A subset of RC are mismatch repair deficient (dMMR). Check-point inhibitors (CPI) are the standard of care in dMMR colorectal cancer (CRC) in the metastatic setting, and recent trials have demonstrated impressive efficacy in early CRC, even with a limited number of cycles. In the NICHE-II trial (Chalabi et al, ESMO 2022) 72 of 107 patients (67%) with colon cancer obtained pathological complete response (pCR) after short course CPI. In patients with RC, Cercek et al (NEJM 2022) showed that 12 patients (100%) obtained pCR after 6 months of dostarlimab. The efficacy of CPI in dMMR RC has only been evaluated in few studies. Here we report data from a Danish trial with early dMMR RC. EU CT number 2022-500646-14-00. Methods: The purpose was to evaluate the efficacy and tolerability of 1 cycle of nivolumab (3 mg/kg days 1 and 15 - nivo) and ipilimumab (1 mg/kg day 1 - ipi) in patients with early stage dMMR RC. The primary endpoint was number of patients with clinical complete response (cCR - no visible or palpable tumor) evaluated 4 weeks after nivo-ipi. Patients achieving a clinical, radiological, pathological (representative biopsy without viable tumor cells), and molecular complete response was offered a thorough watchful waiting strategy without surgery. Results: 5 patients were treated, 4 patients received a single cycle of nivo-ipi and 1 patient received 2 cycles of nivo-ipi, as the tumor was still visible at the first endoscopy (Table). All 5 patients were evaluated 4 weeks after completing nivo-ipi and all 5 patients (100%) achieved cCR. All 5 patients were ctDNA positive (Jensen et al, Clin Chem 2020) at diagnosis, 4 patients turned negative after therapy (1 pending). No patient needed radiotherapy and all patients agreed to non-surgical watchful waiting. No patient has had progression or recurrence (1-42 months follow-up). Conclusions: Short-course nivo-ipi is very effective in locally advanced dMMR rectal cancer and may become an alternative to resection. Clinical trial information: 2022-500646-14-00 . [Table: see text]
Efficacy and safety of LY3537982, a potent and highly selective KRAS G12C inhibitor in KRAS G12C-mutant GI cancers: Results from a phase 1 study.
Authors: Antoine Hollebecque, Yasutoshi Kuboki, Yonina R. Murciano-Goroff, Rona Yaeger, Philippe Alexandre Cassier, Rebecca Suk Heist, Yutaka Fujiwara, Dustin A. Deming, Natraj Ammakkanavar, Amita Patnaik, Toshio Shimizu, Justin Call, Sae-Won Han, Aaron Alan Fink, Aaron Chen, Melinda D Willard, Arjun Vasant Balar, Takafumi Koyama
Journal: Journal of Clinical Oncology (2024)

94 Background: LY3537982 is an oral, potent, and highly selective inhibitor of GDP-bound KRAS G12C with unique pharmacologic properties that achieve high target occupancy at low absolute exposures. Here we present results of GI tumors treated on LOXO-RAS-20001, a phase 1 study of LY3537982 in patients (pts) with a KRAS G12C mutation. Methods: Dose escalation followed a mTPI-2 method. Dose expansion included a combination with cetuximab in colorectal cancer (CRC). All pts were KRAS G12C inhibitor naïve. Key objectives were to determine the RP2D, safety, PK, and antitumor activity per RECIST v1.1. Results: As of 24 July 2023, 73 pts with CRC (32), PANC (24), BTC (10), and other GI tumors (7) were treated with 50-200 mg BID LY3537982. Median age was 62 yrs (range, 36-85) and median number of prior lines of therapies was 3 (range, 0-11). No DLTs were observed. Grade 1 diarrhea was the highest frequency TEAE regardless of attribution (33%). At a median time on treatment of 4 months (range, 0.1-18), 20 pts are ongoing and 53 discontinued treatment. In the combination cohort, 46 pts with CRC were treated with 100 or 150 mg BID LY3537982 and cetuximab. Median age was 57 yrs (range, 35-77) and median number of lines of prior therapies was 3 (range, 1-8). 1 pt at 100 mg BID had a DLT (ALT/AST increased) and required a dose reduction. TEAEs ≥30% were dermatitis acneiform (59%), diarrhea (44%), dry skin (44%), hypomagnesemia (33%), and fatigue (30%). Vomiting, pruritus, skin fissures, headache, nausea, pyrexia, and rash were mostly grade 1 with 20-24% occurrence. At a median time on treatment of 6 months (range, 0.6-11), 37 pts are ongoing and 9 discontinued treatment (none due to AE). Table shows efficacy data. Conclusions: In pts with GI tumors, LY3537982 alone or in combination with cetuximab demonstrated preliminary efficacy and a favorable safety profile. Clinical trial information: NCT04956640 . [Table: see text]
Amivantamab monotherapy in relapsed/refractory metastatic colorectal cancer: OrigAMI-1, an open-label, phase 1b/2 study.
Authors: Paul Eliezer Oberstein, Victor Moreno, Kanwal Pratap Singh Raghav, Yong Sang Hong, Sae-Won Han, Yu-Li Su, Ying Yuan, Filippo Pietrantonio, Eric Van Cutsem, Cathy Eng, Joshua C Curtin, Sanjib Chowdhury, Rianka Bhattacharya, Raymond Scott Maul, Ryota Iwasawa, Robert W. Schnepp, Roland Elmar Knoblauch, Meena Thayu, Gwo Fuang Ho, Han Sang Kim
Journal: Journal of Clinical Oncology (2024)

135 Background: Amivantamab (ami), an EGFR-MET bispecific antibody with immune cell-directing activity, has shown preclinical activity in colorectal cancer (CRC) models. MET amplification is implicated in driving resistance to anti-EGFR therapies in metastatic CRC (mCRC). We hypothesize that dual, co-inhibition of EGFR and MET with ami could improve outcomes in relapsed/refractory mCRC. Methods: OrigAMI-1 (NCT05379595) is assessing the safety and efficacy of ami as monotherapy in patients (pts) with refractory mCRC in 3 separate cohorts (Table). Eligible pts were wild-type for KRAS, NRAS, BRAF, and EGFR ectodomain by ctDNA testing, without ERBB2/ HER2 amplification. Cohorts A and B included pts with left-sided mCRC without/with prior exposure to anti-EGFR monoclonal antibodies, respectively, and cohort C included pts with right-sided mCRC. Safety population included all pts receiving the recommended phase 2 dose (RP2D; 1050 mg [1400 mg, ≥80kg]). Investigator-assessed response per RECIST v1.1 is reported for evaluable pts with post-baseline disease assessment(s) or who discontinued for any reason. Ami plus FOLFOX or FOLFIRI is being explored in additional cohorts. Results: As of September 4, 2023, 93 pts were treated at RP2D; 89 were response evaluable (median follow-up: 4.4 mo). Median age was 60 years, 66% were male, and median prior lines of therapy were 2, with 94% receiving prior bevacizumab and 69% prior anti-EGFR therapy. Best timepoint responses were: Cohort A: 7/17, 41.2%; Cohort B: 13/54, 24.1%; Cohort C: 1/18, 5.6%. Disease control rates (DCR) were 88.2%, 72.2%, and 77.8% for Cohorts A, B, and C, respectively. Median duration of response (mDoR) for confirmed responders was 7.5 and 7.4 mo for Cohorts A and B, respectively. Treatment is ongoing for the responder in Cohort C. 10/13 responders (77%) remain on treatment. Preliminary biomarker data suggest ami may be active in alterations associated with anti-EGFR antibody resistance (eg, EML4-ALK fusion, PTEN). The most frequent treatment-emergent adverse events were rash (84%) and infusion-related reactions (53%). No new safety signals were observed. Updated results will be presented at the meeting. Conclusions: Ami monotherapy demonstrated promising, durable antitumor activity in refractory mCRC, including pts treated with prior anti-EGFR therapy and pts with right-sided disease. The safety profile of ami in mCRC is manageable and consistent with prior NSCLC experience. Clinical trial information: NCT05379595 . [Table: see text]
Therapeutic effectiveness of high-intensity focused ultrasound (HIFU) ablation in patients with unresectable hepatocellular carcinoma.
Authors: Jin Il Kim
Journal: Journal of Clinical Oncology (2024)

490 Background: High-intensity focused ultrasound (HIFU) ablation is a new therapeutic method for treatment of solid tumor. To determine the efficacy and safety of HIFU, we report our experience for local therapy of primary or metastatic hepatocellular carcinoma (HCC). Methods: From January 2015 to December 2022, forty- eight patients with unresectable HCC underwent single or two therapeutic sessions of HIFU under general anesthesia. Ten patients with liver metastasis from colon cancer and three patients with liver metastasis from stomach cancer were included. We used HIFU, ultrasound-guided extracorporeal system (HIFU Technology Company, Chongqing, China). Thirty-three patients received transarterial embolization before HIFU. Thirteen patients were treated with chemotherapy before HIFU. Technical effectiveness per patient and per masses was assessed according to clinical findings and MR imaging at follow-up. Complications were also recorded. Results: We treated total 78 tumors in 48 patients. The tumor size ranged from 1.3 cm to 12 cm in diameter. Small (&lt; 3 cm), intermediate (3-5 cm) and large tumors (&gt;5 cm) are 44, 24 and 10 patients, respectively. Average procedure time was 4 hours 10 minutes with 68 minutes treatment time. We made the artificial pleural effusion to get treatment field in 25 patients. Mean follow-up period was 52 weeks. For the technical effectiveness per patient as follows: complete ablation with no evidence of recurrence on follow up in 18%, apparent complete ablation of target mass with progression of new lesions on follow up in 29%, recurrence after apparent complete ablation in 26%, and incomplete ablation at 2 week follow up in 27%. Average post-procedure hospital day was 5.4 days. No severe complication except mild right upper quadrant pain was observed after treatment. Conclusions: HIFU is an effective and safe treatment option for local image-guided tumor ablation in patients with unresectable HCC. Although further study is necessary, these results show that HIFU may be helpful in treating unresectable HCC.
Outcomes with immunotherapy between Lynch syndrome vs non-Lynch syndrome microsatellite instability-high colorectal cancer.
Authors: Cody Eslinger, Alyssa McGary, Daniel Walden, Oluwadunni Eunice Emiloju, Daniel H. Ahn, Bassam Bassam Sonbol, Tanios S. Bekaii-Saab, Mojun Zhu, Joleen M. Hubbard, Christina Wu
Journal: Journal of Clinical Oncology (2024)

175 Background: Alterations to mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, and PMS2, can lead to microsatellite instability-high (MSI-H) tumors. MMR mutations can be inherited in Lynch syndrome (LS) but can also be a result of de novo alterations resulting in MSI-H malignancies. Treatment with immune checkpoint inhibitors (ICIs) have been shown to improve survival in such patients (pts) compared to systemic chemotherapy. However, there is a paucity of information in the literature with respect to outcomes of pts with germline vs somatic MMR mutations in MSI-H colorectal cancer (CRC). Furthermore, the presence of underlying BRAF mutation confers resistance to chemotherapy in pts with CRC, however data regarding outcomes with immunotherapy in such pts with MSI-H CRC is lacking. Methods: Pt records from the Mayo Clinic (AZ, MN, FL) between 2008-2023 denoted as MSI-H CRC, were included for retrospective review. Pt demographics, treatment courses, and genomic profiles were collected. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Outcome differences between sub-groups were accessed with the log rank test and univariate analyses were assessed with Cox-regression. Results: A total of 81 pt records were identified (n = 18 LS, n = 63 non-LS). Stage IV disease was found in 28% of LS pts vs 59% of non-LS pts at diagnosis. Pembrolizumab was the most common ICI selected for metastatic CRC pts for both LS and non-LS pts (65% vs 94%) with median treatment duration for each group 11.7 vs 8.8 months. There were no differences in OS or PFS for any stage between LS vs non-LS. Median OS for all patients was 82 months. For all stage IV patients, median OS was 44 months, and median PFS was 19 months. Interestingly, for stage IV pts treated with immunotherapy, tumors that harbored BRAF V600E mutation (n = 21) vs BRAF wild type (n = 20) had a significantly lower median OS 19 vs 113 months (HR = 2.69, p = 0.043) as well as median PFS 12 vs 95 months (HR = 2.48, p = 0.041). Conclusions: In this study, we found that patient treated with ICIs have similar outcomes in the presence of germline vs. somatic MMR mutations in MSI-H CRC. The presence of an associated BRAF V600E mutation, which occurs in non-LS MSI-H CRC conferred worse outcomes.