bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of gene expression in 5-FU metabolic pathways in a phase III trial evaluating adjuvant S-1 therapy compared to surgery alone following curative resection for biliary tract cancer (JCOG1202A1).
Authors: Mitsunaga Shuichi , Ikeda Masafumi , Nomura Shogo , Morizane Chigusa , Todaka Akiko , Kamei Keiko , Yanagibashi Hiroo , Mizuno Nobumasa , Gotoh Kunihito , Kawamoto Yasuyuki , Shirakawa Hirofumi , Okano Naohiro , Nomura Tatsuya , Takahashi Amane , Makino Isamu , Anbo Yoshiyasu , Ohta Koji , Katayama Hiroshi , Konishi Masaru , Ueno Makoto
Published: January 2023

732

Background: S-1, an oral fluoropyrimidine derivative, is standard adjuvant therapy in Japanese patients with resected biliary tract cancer (BTC), based on the results of JCOG1202, a phase III trial evaluating adjuvant S-1 following curative resection for BTC compared to surgery alone. The efficacy of 5-FU-based therapy is related to the expression of enzymes involved in 5-FU metabolic pathways, such as thymidylate synthase (TS), thymidine phosphorylase (TP), orotate phosphoribosyltransferase (OPRT) and dihydropyrimidine dehydrogenase (DPD). The aim of this study was to evaluate the impact of messenger RNA (mRNA) levels of the four 5-FU metabolic pathway genes on the outcomes of patients enrolled in JCOG1202. Methods: Tumor cell RNA was isolated from formalin-fixed paraffin-embedded primary BTC specimens resected in 264 of 440 randomized patients in JCOG1202. The four 5-FU metabolic pathway genes were measured in 183 patients (surgery alone: n = 94; adjuvant S-1: n = 89) who were randomly divided to training (n = 96) or validation set (n = 87). The endpoints of interest were the predictive values of the four genes for the efficacy of adjuvant S-1 on overall survival and relapse-free survival (RFS), and we here report the results regarding RFS. Cut-off levels for mRNA expression were selected in the training set which minimized the bootstrap p-values (2,000 samples) of an interaction term of treatment (surgery alone or S-1) and mRNA expression in a Cox regression model. Results: There were no obvious differences in each mRNA level and clinical characteristics between surgery alone and adjuvant S-1 groups. RFS tended to be better with adjuvant S-1 (hazard ratio [HR] = 0.790, [95% confidence interval: 0.524-1.192]) compared to surgery alone, which was maintained in the low DPD population (HR = 0.440 [0.216-0.898] in training set and 0.748 [0.334-1.675] in validation set), in the low TP population (HR = 0.709 [0.388-1.296] and 0.602 [0.287-1.262]), and in the high OPRT population (HR = 0.520 [0.152-1.779] and 0.609 [0.161-2.304]). Conclusions: The efficacy of adjuvant S-1 on RFS was representative in BTC patients with intratumoral gene expressions of low DPD, low TP, and high OPRT, which was disappeared in the population with high DPD, high TP, and low OPRT. These biomarkers might be useful to predict therapeutic benefits with S-1 containing chemotherapy for BTC.
Comparison of precursor neoplasms at colonoscopic diagnosis of early-onset and later-onset colon cancer.
Authors: Emiloju Oluwadunni Eunice , Saberzadeh Ardestani Bahar , Sinicrope Frank A.
Published: January 2023

74

Background: Colorectal cancer (CRC) incidence has steadily increased in adults younger than 50 years (EO-CRC) since the 1990s, with a reported higher prevalence in the left colon and rectum. Established precursor lesions of CRCs are adenomas, including advanced adenomas, and sessile serrated polyps. We hypothesized that patients at diagnosis of early-onset colon cancer (EO-CC) would have fewer adenomas compared to patients with later-onset colon cancer (LO-CC). Methods: We performed a retrospective review of electronic health records and identified 58 patients diagnosed with EO-CC who had colonoscopy at Mayo Clinic or Mayo Health System who were then matched with 58 LO-CC patients based on gender and procedure indication (diagnostic in 76%, surveillance 16%, screening 8%)[2012 to 2021]. At colonoscopy where colon cancer was diagnosed, we recorded findings of adenomas, advanced adenomas (≥ 1 cm, villous histology, and/or high-grade dysplasia) and sessile serrated polyps. On CCs, limited molecular data were available [mismatch repair (MMR); BRAFV600E, KRAS]. Results: Among 116 patients included in the EO-CC and LO-CC study arms, the median age at cancer diagnosis were 42 and 74 years, respectively. No significant differences were found between study arms and risk factors for CRC including tobacco, alcohol, BMI, genetic syndromes, family history of CRC, and MMR, BRAFV600E or KRAS status (all p> 0.05). While no difference was found for polyp number by arm, patients with EO-CC had larger polyps (median of 10 mm vs 6 mm, p=0.001) compared with LO-CC. At least 1 adenoma was found in 50% and 52% of patients with EO-CC and LO-CC, respectively. Importantly, advanced adenomas were significantly more common in the EO-CC group compared with the LO-CC group (41% and 21%, p=0.027). Sidedness of all adenomas did not differ significantly for EO-CC vs LO-CCs. Conclusions: Patients found to have a primary EO-CC had a significantly higher likelihood of a synchronous advanced adenoma in the colon compared to those with a primary LO-CRC. Together, these data suggest accelerated carcinogenesis throughout the colorectum with increased risk of synchronous and metachronous patients with EO-CC. [Table: see text]
ATM or CHEK2 alterations: Potential biomarkers of improved outcomes with irinotecan-containing chemotherapy in advanced pancreatic ductal adenocarcinoma.
Authors: Mehdi Maahum , Thapa Bicky , Szabo Aniko , Ahmed Gulrayz , Shreenivas Aditya V. , Thomas James P. , Sriram Deepika , Evans Douglas B. , Tsai Susan , Christians Kathleen K. , Erickson Beth , Hall William A. , McFall Thomas , Patrick Steve , George Ben , Kurzrock Razelle , Kamgar Mandana
Published: January 2023

754

Background: ATM and CHEK2 mutations are linked to homologous recombination DNA repair deficiency, with the potential for improved therapeutic response to DNA damaging agents. To investigate our clinical observation of improved outcomes with irinotecan (IRI) based chemotherapy in advanced/metastatic pancreatic ductal adenocarcinoma (PDAC) patients (pts) with somatic or germline ATM/ CHEK2 mutations, we examined our institutional real world experience. Methods: Between 2015-2021, 33 pts with ATM or CHEK2 mutations treated with chemotherapy were identified, of which 16 pts had advanced/metastatic disease. Progression-free survival (PFS) was calculated and compared (Kaplan Meier, log-rank test) in several ways to assess the impact of IRI vs platinum or other regimens. The event for PFS was progression (or death), and pts without progression were censored at treatment end, or at last follow up if treatment was ongoing. Results: Among 16 pts with advanced/metastatic PDAC, 8 (50%) had ATM (5 germline, 3 somatic) and 8 (50%), CHEK2 alterations (4 germline, 4 somatic). Overall, pts received 48 lines of chemotherapy (platinum-based-(No-IRI) N=14; IRI-based-(No-Platinum) N=8; both N=4; none N=22). For best-PFS among pts analysis, median line of best-PFS therapy for IRI-Ever (N=9 pts) was 2nd line (range 1-7) and for IRI-Never (N=7 pts) was 1st (range, 1-1); median PFS was 13 vs 3 months (mo) (IRI-Ever vs IRI-Never; p=0.0076). For PFS analysis within lines of treatment of each pt, median therapy line for both IRI-containing and No-IRI lines was 2nd line (range 1-7); median PFS for IRI-containing (N=12 lines of therapy) vs No-IRI (N=36) was 12.1 vs 3 mo (p<0.001). Median PFS for best IRI-based-(No-Platinum) line (N=7) was 13 mo; for best platinum-based-(No-IRI) line (N=9) was 2.8 mo; and for best treatment containing no IRI or platinum (N=13) was 5.1 mo (P= 0.003) (median therapy line for each was 3, 2 and 1.5, respectively). Conclusions: Irinotecan is a topoisomerase 1 inhibitor that induces DNA strand breaks, potentially causing synthetic lethality in tumors with DNA damage repair deficits due to ATM or CHEK2 alterations. IRI-containing therapy out-performed other treatment types, including platinum-containing regimens, in pts with ATM or CHEK2-mutated advanced/metastatic PDAC. Prospective trials are warranted.
Trends in pancreatic cancer incidence and mortality in the United States from 2000 to 2019: A SEER-based study.
Authors: Abidoye Oluseyi , Cho Young Min , Ahoussougbemey Mele Ange , Bhushan Sheena , Ruiz Vega Ruben , Ghosh Aditya Kumar
Published: January 2023

755

Background: The annual incidence and mortality rates of pancreatic cancer has been rising. We analyzed pancreatic cancer trends by demographics and geographic location. Methods: Data obtained from the Surveillance, Epidemiology, and End Results (SEER) registry 17 were available to assess trends of pancreatic cancer incidence and mortality from 2000 to 2019. Results: The pancreatic cancer incidence and mortality rates consistently increased over time from 2000 to 2019. Incidence of pancreatic cancer was highest in males (14; 95% Cl, 13.9,14.1) and blacks (15.4 95% Cl,15.2, 15.6). The incidence was highest in Alaska (16.2; 95% Cl, 14.1, 18.5), and lowest in Utah (10.7; 95% Cl, 10.4, 11.0). Incidence increased at 0.85% per year (95% Cl, 0.76, 0.92; P < .001). Overall incidence increased significantly for all sex, race, stage sub-groups except for Blacks (APC of 0.04%; 95% Cl, -0.14, 0.22; P = 0.649), and American Indian/Alaska natives (APC of -0.22 %; 95% Cl, -1.33, 0.89; P = 0.679). There was an overall significant increase in incidence across all states except for Alaska. Incidence-based mortality of pancreatic cancer was highest in males (12.6; 95% Cl, 12.5,12.7) and blacks (14.1; 95% Cl, 13.9, 14.3). Mortality was highest in Alaska (15.1; 95% Cl, 13.1,17.3), and lowest in Utah (9.6; 95% Cl, 9.3,9.9). Mortality increased at 0.91% per year (95% Cl, 0.32, 1.50; P = .005). The overall incidence-based mortality increased significantly only in the males APC, 0.95% (95% Cl, 0.36, 1.54; P = 0.003), females APC 1.18 (95% Cl, 0.47, 1.89; P = 0.002) and whites APC 1.05% (95% Cl, 0.45, 1.66; P = 0.002). Furthermore, there was an overall significant increase in incidence-based mortality across all states except for Alaska, Hawaii and Washington. Conclusions: Pancreatic cancer incidence and mortality rates increased overall but differed by demographics and geographic location.
Spectrum of germline mutations among Mexican patients with colorectal cancer.
Authors: Aguilar Dione , Santuario Facio Sandra , Barraza Angélica , Villarreal-Garza Cynthia , Ortiz Lopez Rocio
Published: January 2023

78

Background: Colorectal cancer (CRC) is the third most common cancer in the world, and the second most frequent cause of death due to cancer. 5-10% of CRC cases are due to a hereditary predisposing syndrome, the most frequent being Lynch Syndrome (LS) followed by Familial Adenomatous Polyposis (FAP), characterized by loss of function of mismatch repair genes (MMR) and APC, respectively. The purpose of this study is to describe the spectrum of germline pathogenic variants among Mexican CRC patients using Next-generation sequencing (NGS). Methods: This study is original research approved by IRB; all patients signed the informed consent. 43 patients between 18-60 y/o with CRC were enrolled. NGS was performed using a panel which targeted a set of 94 genes and 284 SNPs known to play a role in cancer predisposing. Bioinformatics data analysis was carried out using Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE) and an in-silico analysis to classify variants according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Mean age 48.71 y/o, 62.6% men. Germline pathogenic and likely pathogenic variants (PV/LP) were identified in 69% of sample. A molecular diagnosis of LS (MLH1, MSH2, MSH6, and PMS2) was confirmed in 12 (28%), and FAP in 5 (11.6%). It is remarkably the presence of 5 PV in PRF1 (2 G149S; 3 A91V), among other unusual genes for CRC. Also 12 double heterozygotes were identified, including one with PRF1 and CHEK2 PV. Conclusions: NGS allow the discover of new pathogenic variants that would not be suspected in classic hereditary syndromes. The understanding of other genes involved in other pathways could expand our understanding in the heritability of CRC. PRF1 emerges as a new candidate gene associated with CRC, previous evidence supports the role of PRF1 in solid tumors beside hematologic malignancies.
The role of socioeconomic deprivation in gastrointestinal cancer clinical trial enrollment at an NCI-designated comprehensive cancer center.
Authors: Strebig Daniel , Al-Toubah Taymeyah E. , Coughlin Emily , Mhaskar Rahul , Lowery Sylea , Mathew Ebin , Capelli Mitchell , Pattnaik Aishwarya , Turner Kea , Kirtane Kedar , Dhahri Amina , Kim Richard D. , Permuth Jennifer B. , Vadaparampil Susan Thomas , Fleming Jason B. , Strosberg Jonathan R. , Powers Benjamin Daniel
Published: January 2023

785

Background: Socioeconomic deprivation has been described as a barrier to cancer clinical trial participation. However, few studies have examined socioeconomic deprivation using patient-level or granular geocoded designations. To overcome this challenge, the Area Deprivation Index (ADI) was used to assess neighborhood socioeconomic deprivation in a cohort of gastrointestinal cancer clinical trial patients at an NCI-Designated Comprehensive Cancer Center. Methods: Patients enrolled in a gastrointestinal cancer clinical trial from 2008 to 2019 with an identifiable ADI national rank were identified. Socioeconomic deprivation was assessed using the ADI, a publicly available, validated dataset that ranks census block groups into percentiles using variables such as income, education, employment, and housing characteristics. For this study, ADI was categorized as quintiles listed in the table. Statistical analyses included Chi-square and Kruskal-Wallis tests. Results: The median age of the cohort (N=1,334) was 62.0 years. Most patients were male (54.3%). Race included White (88.2%), African American (6.8%), and Asian (1.5%) patients. Hispanic/Latinx patients made up 6.7% of the cohort. The median ADI was 46. The proportion of enrollees from lowest to highest ADI quintile was 11.2%, 29.3%, 27.3%, 19.1%, and 13.1%. Trial enrollment differed by ADI and age (p=0.019), gender (p=0.042), race (p<0.001), and insurance (p=0.001). Conclusions: In this study, patients enrolled in gastrointestinal cancer clinical trials had lower neighborhood socioeconomic deprivation than the national or state average. African American, Hispanic/Latinx, female, and uninsured patients comprised a lower proportion of enrollees compared to catchment area estimates (10.6%, 17.7%, 51.3%, and 12.4%, respectively). These findings suggest inequity in clinical trial enrollment and warrant further studies to identify drivers of these disparities. [Table: see text]
Effect of tumor location on the efficacy of chemotherapy for gastrointestinal stromal tumors.
Authors: Sweeney Ryan , Shah Shivani , Wegner Rodney E.
Published: January 2023

790

Background: Gastrointestinal stromal tumors (GISTs) arise from multiple sites within the gastrointestinal tract. Since the introduction of imatinib in 2002, patients have seen improved overall survival. However, a recent National Cancer Database (NCDB) study suggested no survival benefit to adjuvant imatinib for colorectal GIST patients. Another recent study showed that small bowel GISTs have larger median tumor size and higher incidence of tumors with at least 5 mitoses compared to gastric GISTs. These findings suggest a differential tumor biology for GISTs arising from different primary tumor sites, potentially conferring differential response to imatinib. In this NCDB study, we compare overall survival outcomes with and without chemotherapy, stratifying by primary tumor site. Methods: We queried the NCDB from 2004-2018 for patients with GIST histology. We excluded patients with age <40, age>80, high comorbidity score, and patients who received additional therapy other than surgery or chemotherapy. Of the 22,846 patients meeting criteria for our study, 27 patients had tumors originating from the anus, 454 from the colon, 173 from the esophagus, 15,296 from the stomach, 556 from the rectum, 32 from the rectosigmoid junction, and 6,308 from the small intestine. 8,983 (39%) received chemotherapy. Treatment with chemotherapy was used to extrapolate response to imatinib, the mainstay of treatment. Results: Cox proportional hazards analysis demonstrated increased hazard of death for chemotherapy, increasing age, and comorbidity score of 1. Positive predictive factors for survival included female sex and later year of diagnosis. For anal, esophageal, gastric, and rectosigmoid GIST patients, there was no statistically significant overall survival benefit for any treatment modality. For colonic GISTs, neoadjuvant chemotherapy combined with surgery improved overall survival. For rectal GISTs, adjuvant chemotherapy with surgery also provided survival benefit. For small intestinal GISTs, surgery alone or surgery with neoadjuvant, adjuvant, or both neoadjuvant and adjuvant chemotherapy improved overall survival. Conclusions: While our study is retrospective and limited as a NCDB study, our Kaplan-Meier survival analysis demonstrated survival benefit for chemotherapy only in patients with colon, rectal, or small intestinal GIST tumors. Our Cox proportional analysis demonstrated an overall negative survival impact for chemotherapy. These findings lend further support to the idea that differential tumor biology at each primary site may lead to differential response to imatinib. Overall, our study provides rationale for further investigating the heterogeneity of GIST tumor microenvironments, as these differences could contribute to the differential treatment outcomes.
Improvement of a clinical colorectal cancer risk prediction model integrating polygenic risk.
Authors: Spaeth Tuff Erika Leigh , Gafni Aviv , Dite Gillian S. , Allman Richard
Published: January 2023

81

Background: Improving colorectal cancer risk prediction and stratification is pivotal for implementing better screening and prevention programs in public health and for enabling a personalised approach for assessing patients’ colorectal cancer risk. Methods: In this study, we used the UK Biobank to compare the performance of a risk prediction model incorporating two different polygenic risk scores – one comprising 45 SNPs and the other comprising 140 SNPs. The clinical component of the risk prediction model included a simple measure of first-degree family history. We used age- and sex-specific population incidence rates to calculate full-lifetime risks. Results: The model using the 140-SNP PRS showed an improvement in discrimination, calibration and risk stratification over the model using the 45-SNP PRS for full-lifetime risk: discrimination was 0.706 (95% CI 0.697–0.715) and 0.674 (95% CI 0.664–0.683), respectively, and the P for difference was < 0.001. The 140-SNP model was well calibrated and showed a small overestimation of risk 0.951 (95% CI 0.918–0.986). Standard incidence ratios compared to population incidence rates showed that, for the 140-SNP model, the top quintile of risk shows a 27% improvement compared to the 45-SNP model. Furthermore, there was a 3-fold difference in colorectal cancer incidence between adults identified in the top quintile compared to the bottom quintile of risk using the 140-SNP model versus the 45-SNP model. Conclusions: This updated risk prediction score with a 140–SNP PRS and a simple measure of family history, improves risk prediction and risk stratification in the general population compared with a similar model with a 45-SNP PRS, and will ultimately assist in colorectal cancer disease prevention in the clinic.
Randomized phase II trial of encorafenib and cetuximab with or without nivolumab for patients with previously treated, microsatellite stable, BRAFV600E metastatic and/or unresectable colorectal cancer: SWOG S2107.
Authors: Morris Van K. , Guthrie Katherine A , Kopetz Scott , Breakstone Rimini , Karasic Thomas Benjamin , Hu Zishuo Ian , Bellasea Shay , Fakih Marwan , Gholami Sepideh , Gold Philip Jordan , Philip Philip Agop
Published: January 2023

TPS265

Background: Patients with microsatellite stable (MSS), BRAFV600E metastatic colorectal cancer (mCRC) experience poor survival outcomes. Treatment with the BRAF inhibitor encorafenib (E) and anti-EGFR antibody cetuximab (C) is an approved treatment combination, with a reported overall response rate (ORR) of 20% and median progression-free survival (PFS) of 4.1 months. Anti-PD-1 antibodies like nivolumab (N) are ineffective as monotherapy for patients with MSS, BRAFV600E mCRC. In preclinical models of MSS, BRAFV600E CRC, inhibition of BRAF and EGFR induces a loss of expression of mismatch repair genes and promotes a microsatellite instability-high phenotype, which may prime these tumors for response to immunotherapy. In support of these findings, a single-institution clinical trial of E + C + N for 26 patients with MSS, BRAFV600E mCRC reported an ORR of 50% and median PFS of 7.2 months. We hypothesize that the addition of N to E + C will improve median PFS for patients with MSS, BRAFV600E mCRC. Methods: In this prospective phase II clinical trial (N = 75), patients with previously treated MSS, BRAFV600E mCRC will be randomized 2:1 into 2 arms, respectively: experimental treatment (E + C + N) or standard treatment (E + C). No prior BRAF, EGFR, or immunotherapy agents are allowed. All patients will receive E (300 mg PO daily) and C (500 mg/m2 IV every 14 days), and patients in the experimental arm will receive N (480 mg IV every 28 days). The primary endpoint is PFS. Secondary endpoints include overall survival, best overall response, duration of response, and safety/tolerability. Using a one-sided α = .10 and power 80%, we target an improvement in median PFS from 4.2 to 7.3 months and a hazard ratio of 0.57. Additional patient specimens will be collected for exploratory correlative research. The study activated across the United States in June 2022 and as of September 2022 has enrolled 2 of 75 planned participants. Funding: NIH/National Cancer Institute grants U10CA180888, U10CA180819, U10CA180820, U10CA180821, U10CA180868; and in part by The Hope Foundation for Cancer Research STrS award. Clinical trial information: NCT05308446 .
An open-label, multicenter study investigating RP3 oncolytic immunotherapy in combination with first- or second-line systemic atezolizumab and bevacizumab therapy in patients with locally advanced unresectable or metastatic hepatocellular carcinoma.
Authors: Bekaii-Saab Tanios S. , Yarchoan Mark , Ahmed Muneeb , Cohan David Michael , Ma Wen Wee
Published: January 2023

TPS623

Background: Despite advances in treatment for unresectable hepatocellular carcinoma (HCC), long-term survival rates remain poor. The combination of bevacizumab (Bev) and atezolizumab (Atezo) is the preferred frontline therapy for advanced HCC, but a minority of patients (pts) respond, and secondary resistance usually occurs within months. HCC has an immune-suppressed tumor microenvironment, mediated by activated immune checkpoint signaling and angiogenesis pathways, which may contribute to therapeutic resistance. RP3 is a genetically modified herpes simplex virus 1 (HSV-1) that expresses the fusogenic GALV-GP R- protein, an anti–CTLA-4 antibody-like molecule, CD40 ligand, and 4-1BB ligand. The direct oncolytic effect coupled with immune stimulation by RP3 in the tumor microenvironment is intended to provide systemic anti-tumor activity and reverse therapeutic resistance to anti-PD-1/PD-L1 agents. Pre-clinical data has demonstrated improved distribution of oncolytic HSV within tumors in combination with Bev supporting the clinical combination of RP3 with Bev. RP3 combined with anti-PD1 therapy has demonstrated clinical activity and safety in pts with various malignant solid tumors. This study will evaluate the safety and efficacy of RP3 combined with Atezo and Bev as 1st (1L) and 2nd (2L) line systemic therapies for inoperable and advanced HCC. Methods: The 1L and 2L cohorts will each enroll up to 30 pts with advanced, unresectable HCC. Pts in the 1L cohort may not have received prior systemic treatment; pts in the 2L cohort must have progressed on or following one prior line of systemic therapy, which must have included a PD-(L)1 directed agent. Key inclusion criteria include advanced unresectable HCC with at least 1 measurable tumor of ≥1 cm in longest diameter, Childs-Pugh Class A, and ECOG Score of 0 or 1. Important exclusion criteria include untreated esophageal and/or gastric varices with bleeding or at high risk for bleeding, and macroscopic invasion of tumor into major blood vessels and/or main bile ducts. Pts with a history of medically refractory hepatic encephalopathy and/or hepato-renal syndrome are also excluded. Pts in 1L cohort will receive 1200 mg Atezo and 15mg/kg Bev Q3W together with RP3 intratumorally (IT) Q3W for a total of up to 8 doses. In 2L pts will receive RP3 Q2W for 4 doses with Bev Q3W starting on C1D1, then RP3 and Bev Q3W for up to 4 more doses with Atezo Q3W being added on C4D1. The primary endpoint includes overall response rate (ORR) by RECIST v1.1. Secondary endpoints are safety, ORR using HCC mRECIST, duration of response, complete response rate, and progression-free survival.
A phase 1b, open-label, safety, pharmacokinetic, and pharmacodynamic study of an anti–super-enhancer triptolide analogue with nab-paclitaxel plus gemcitabine in patients with metastatic adenocarcinoma of the pancreas.
Authors: Park Joon Oh , Hong Jung Yong , Kim Seung Tae , Park Young Suk , Saluja Ashok
Published: January 2023

TPS769

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies and the leading cause of cancer-related death in the world, although recent advances in chemotherapies for metastatic PDAC provide better clinical outcomes. Triptolide (TPL), a natural compound isolated from the Chinese herb has shown promising antitumor activity though the inhibition of HSP70 in a number of preclinical models including pancreatic cancer. In addition, TPL disrupt super-enhancer networks in pancreatic cancer cells and cancer-associated fibroblasts to reprogram the cellular cross talk and signaling in tumor environment. Minnelide (ML), water soluble, novel prodrug of TPL, was recently reported to show promising activity in patients with gastrointestinal malignancies in phase I trial. Based on the strong synergism with nab-paclitaxel (A) plus gemcitabine (G), we designed this phase 1b study. Methods: Eligible patients will have histologically confirmed PDAC and have failed first-line FOLFIRINOX with adequate organ function and performance status. This study is composed of two parts; dose escalation and dose expansion. In the dose escalation part (phase 1b), different dose levels of ML (0.25 mg to 1.0 mg once a day) in combination with A plus G will be tested with 3+3 subjects recruited in each cohort. Patients in each cohort will receive ML 0.25 to 1.0 mg orally once a day on days 1-5, 8-12 and 15-19 with A 100-125mg/m2 intravenously plus G 800-1000mg/m2 IV on days 1, 8 & 15 of a 28-day cycle. The primary endpoint is to determine the safety of ML with A+G and to determine PFS by Independent Radiological Review (IRR). Once an MTD reaches, a total of 18 patients will be enrolled at MTD level in dose expansion part. The key secondary endpoints are to determine the pharmacokinetics, pharmacodynamics effect, the percentage of patients who achieve an objective confirmed overall response by IRR, maximum tolerated dose and recommended dose for phase 2 of ML in combination of A+G. As of September 2022, the study is just initiated for patient enrollment in first cohort. This study is prospectively registered on ClinicalTrials.gov, NCT05557851. Clinical trial information: NCT05557851 .
A phase II, open-label pilot study evaluating the safety and activity of liposomal irinotecan (Nal-IRI) in combination with 5-FU and oxaliplatin (NALIRIFOX) in preoperative treatment of pancreatic adenocarcinoma (NEO-Nal-IRI Study).
Authors: Rogers Sherise C. , Sahin Ilyas , Fabregas Jesus C. , Nassour Ibrahim , Ramnaraign Brian Hemendra , Hitchcock Kathryn , Hughes Steven J. , Lee Ji-Hyun , Kayaleh Omar Roger , Turk Anita Ahmed , Fan Z. Hugh , Russell Karen Bullock , DeRemer David L. , George Thomas J.
Published: January 2023

TPS778

Background: Neoadjuvant treatment for potentially curable pancreatic cancer (PDAC) is increasing in acceptability, but a standard regimen has yet to be established. Multiple studies have demonstrated feasibility and effectiveness of the FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen in the perioperative setting. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery when given neoadjuvantly. Liposomal irinotecan injection (Nal-IRI) is FDA approved with a well-tolerated safety profile in relapsed, refractory metastatic PDAC. The current study aims to substitute Nal-IRI for traditional irinotecan in the standard FOLFIRINOX regimen (NALIRIFOX) and to demonstrate safe and effective neoadjuvant delivery. Methods: This phase 2, open-label, multicenter single-arm study focuses on patients (pts) with operable PDAC without metastatic disease. Other key eligibility criteria include age ≥18 years, resectability confirmed by multidisciplinary GI tumor board (resectable vs. borderline), adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts receive NEO-N-IRI regimen as per Table every 2 weeks for four months followed by disease reassessment. Pts who remain surgical candidates will undergo surgical resection within 4 to 8 weeks following last dose of therapy. The primary endpoint is to assess safety and feasibility of regimen in perioperative setting. Secondary endpoints include R0 resection rate, clinical, biochemical and radiological response rate and patient-reported quality of life during treatment as measured by the NCI validated FACT-G scale. Enrollment continues to a maximum of 28 evaluable pts to demonstrate a reduction in historical 30-day postoperative complication rate. Microbiota specimens will be collected for exploratory analysis. Clinical trial information: NCT03483038 . [Table: see text]
Trial in progress: Phase II study of niraparib and dostarlimab for the treatment of germline or somatic homologous recombination repair mutated metastatic pancreatic cancer.
Authors: McWilliams Robert R. , Kasi Pashtoon Murtaza , Foster Nathan R. , Zhu Mojun , Carr Ryan Michael , Ma Wen Wee , Hartgers Mindy L. , Jones Kayla M. , Bartusiewicz Jacqueline M. , Dong Haidong , Markovic Svetomir , Alberts Steven R , Ahn Daniel H. , Babiker Hani M. , Bekaii-Saab Tanios S. , Couch Fergus
Published: January 2023

TPS780

Background: Pancreatic adenocarcinoma is an aggressive malignancy with a limited number of therapeutic options. One subset of patients (up to 15%) carries germline and/or somatic mutations in homologous recombination repair genes, most notably BRCA1, BRCA2 and PALB2 amongst others, that confer sensitivity to PARP inhibition. Combinations of PARP inhibitors with anti-PD1 immunotherapy have shown activity in breast and ovarian cancer and have not yet been thoroughly studied in pancreatic cancer. Methods: We designed a single-arm phase 2 investigator-initiated study utilizing the combination of niraparib, a highly selective PARP inhibitor and a dostarlimab, an anti PD1 antibody, in the subset of pancreatic cancer patients with germline or somatic mutations in BRCA1/2, PALB2, BARD1, RAD51C, or RAD51D. Additional inclusion criteria include metastatic pancreatic adenocarcinoma, receipt of a platinum agent in 1st or 2nd line unless contraindicated, and at least 1 but not more than 2 prior lines of systemic therapy not including maintenance. Prior PARP inhibition is allowed, but not immediately prior to enrollment. Exclusion criteria include active unstable autoimmune disease or prior malignancy requiring active treatment within 2 years. Patients are treated with niraparib 200 mg orally once daily on days 1 through 21 of a 21 day cycle. Dostarlimab is administered IV 500 mg every 3 weeks for the 1st 4 cycles and then 1000 mg IV every 6 weeks subsequently. The primary endpoint of the study is the disease control rate at 12 weeks using standard iRECIST criteria. Twenty patients will be enrolled to ensure 19 evaluable. The design has 80% power to detected improvement in disease control rate from 25-50% with significance level of 0.10. Descriptive factors include gene mutated for inclusion, germline/somatic, and platinum refractoriness. Given the size of the study along with genetic heterogeneity there will be no interim analysis. Patients are being enrolled at 3 Mayo clinic sites in Rochester Minnesota, Phoenix Arizona, Jacksonville Florida. To date, 13 patients have been enrolled across all 3 sites. Full accrual is anticipated by early 2023. Correlative studies include genomic characterization of baseline tumors, assessment of immune infiltration of tumor microenvironment, tumor collection for organoid/xenograft, and serial circulating cell-free DNA and immune biomarkers. Trial Identifiers: NCT04493060, Mayo: MC1841. Supported by Glaxo Smith Kline. Clinical trial information: NCT04493060 .
A phase II study of hypofractionated radiation therapy to augment immune response in patients with metastatic gastrointestinal malignancies progressing on immune therapy (ARM-GI).
Authors: Chang Hewitt , Andemicael Luchia , Anwar Moshiur Mekhail , Gordan John , Johnson Jamese , Keenan Bridget P , Kelley Robin Kate , Ko Andrew H. , Van Loon Katherine , Venook Alan P. , Fong Lawrence , Xu Melody Ju , Feng Mary Uan-Sian
Published: January 2023

TPS817

Background: Metastatic disease remains a consistent challenge for patients with gastrointestinal (GI) malignancies. Multiple immune checkpoint inhibitors (ICI) have been FDA approved for several GI indications. Still, patients will progress on these therapies, either immediately or after initial response. Palliative radiation therapy (RT) is an effective treatment that can be delivered to symptomatic metastases. It also has been reported to lead to an abscopal effect, which is an induction of response in a distant tumor. This is thought to result from increased tumor immunogenicity, tumor microenvironment modulation, and immune cell recruitment. Thus, palliative RT could not only relieve symptoms, but also potentially reinvigorate the immune response, prolong ICI efficacy, and delay next-line systemic therapy that carries risks of unknown efficacy and tolerability. Ongoing studies seek to elucidate prognostic and predictive biomarkers of the abscopal effect. However, cohorts of patients with GI malignancies are limited, so there remains a need for research in combining RT and immunotherapy in the context of metastatic GI cancer. ARM-GI aims to study the radiation-augmented immune response in patients with metastatic GI cancers progressing on immunotherapy. Methods: ARM-GI is a phase 2, single arm study. Key eligibility criteria include confirmed metastatic GI malignancy, progressive disease per RECIST v1.1 on any ICI, and at least 2 metastases, one of which can be safely left unirradiated. The target prescription dose is 30 Gy in 5 fractions to symptomatic sites through intensity modulated RT or stereotactic body RT. Patients will continue the same immunotherapy after RT and be evaluated per RECIST v1.1 longitudinally. The primary endpoint is overall response rate (ORR) per RECIST v1.1. Secondary endpoints include ORR per iRECIST, progression free survival, overall survival, local control in radiated lesion(s), effect of distant radiation on unirradiated target lesions, incidence of new metastatic lesions, safety by CTCAE v5.0, and time to new systemic therapy. The study will enroll 28 patients, with recruitment ongoing. Serial peripheral blood samples are collected for exploratory studies that will analyze for association with disease response and quantification of changes in circulating immune cell subsets after RT compared to baseline. Clinical trial information: NCT04221893 .
Phase 2, multicenter, open-label basket trial of nab-sirolimus for patients with malignant solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 genes (PRECISION I).
Authors: Deming Dustin A. , Rodon Ahnert Jordi , Demeure Michael J. , Federman Noah , McKean Meredith , Lee Elizabeth Katherine , Spira Alexander I. , Kwiatkowski David J. , Hussein Maen A. , Gordon Erlinda Maria , Crockett David G. , Ganjoo Kristen N. , Schulte Brian , Cranmer Lee D. , Schmid Anita N. , Navarro Willis H. , Itri Loretta Marie , Iyer Gopa
Published: January 2023

TPS818

Background: Albumin-bound ( nab)-sirolimus, a novel mTOR inhibitor (mTORi) that utilizes nanoparticle technology to preferentially target tumors, is approved in the US for the treatment of adults with malignant PEComa. In an exploratory analysis of the AMPECT registrational trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with TSC1 and TSC2 inactivating alterations, respectively, had confirmed response (Wagner, J Clin Oncol. 2021). Importantly, both TSC1 and TSC2 alterations have been observed in patients with various gastrointestinal cancers (Table). Overall, most treatment-related adverse events (TRAEs) in AMPECT were grade 1/2 and manageable for long-term treatment; no grade ≥4 TRAEs occurred. Methods: PRECISION I (NCT05103358) is a phase 2, open-label, multi-institutional basket trial evaluating efficacy and safety of nab-sirolimus in patients with alterations in TSC1 (Arm A) and TSC2 (Arm B). Patients ≥12 years old with malignant solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 (confirmed by central review of next generation sequencing reports) who have progressed on standard therapies and are mTORi-naïve are eligible. nab-Sirolimus 100 mg/m2 will be administered weekly as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate determined by independent review using RECIST v1.1; other endpoints include duration of response, disease control rate, time to response, progression-free survival by independent radiographic review, overall survival, patient-reported quality of life, and safety. Enrollment is ongoing. The most frequent tumor types expected in this tissue-agnostic trial are bladder, hepatobiliary, endometrial, soft tissue sarcoma, ovarian, and esophagogastric based on the prevalence of TSC1 or TSC2 alterations (Table). Clinical trial information: NCT05103358 . [Table: see text]
Threshold-free estimation of entropy from a Pearson matrix
Authors: Felippe H. , Viol A. , de Araujo D. B. , da Luz M. G. E. , Palhano-Fontes F. , Onias H. , Raposo E. P. , Viswanathan G. M.
Published: January 2023

There is demand in diverse fields for a reliable method of estimating the entropy associated with correlations. The estimation of a unique entropy directly from the Pearson correlation matrix has remained an open problem for more than half a century. All existing approaches lack generality insofar as they require thresholding choices that arbitrarily remove possibly important information. Here we propose an objective procedure for directly estimating a unique entropy of a general Pearson matrix. We show that upon rescaling the Pearson matrix satisfies all necessary conditions for an analog of the von Neumann entropy to be well defined. No thresholding is required. We demonstrate the method by estimating the entropy from neuroimaging time series of the human brain under the influence of a psychedelic.
Conserved currents for the gauge-field theory with Lorentz symmetry group and a composite theory of gravity
Authors: Öttinger Hans Christian
Published: January 2023

For the Yang-Mills–type gauge-field theory with Lorentz symmetry group, we propose and verify an explicit expression for the conserved currents in terms of the energy-momentum tensor. A crucial ingredient is the assumption that the gauge symmetry arises from the decomposition of a metric in terms of tetrad variables. The currents exist under the weak condition that the energy-momentum tensor and the Ricci tensor commute. We show how the conserved currents can be used to obtain a composite theory of gravity and discuss the static isotropic field around a point mass at rest.
Opposing Roles of Sphingosine 1-Phosphate Receptors 1 and 2 in Fat Deposition and Glucose Tolerance in Obese Male Mice
Authors: Asano Motochika , Kajita Kazuo , Fuwa Masayuki , Kajita Toshiko , Mori Ichiro , Akahoshi Noriyuki , Ishii Isao , Morita Hiroyuki
Published: January 2023

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that regulates fundamental cellular processes such as proliferation, migration, apoptosis, and differentiation through 5 cognate G protein–coupled receptors (S1P1-S1P5). We previously demonstrated that blockade of S1P2 signaling in S1P2-deficient mice attenuates high-fat diet-induced adipocyte hypertrophy and glucose intolerance and an S1P2-specific antagonist JTE-013 inhibits, whereas an S1P1/S1P3 dual antagonist (VPC23019) activates, adipogenic differentiation of preadipocytes. Based on those observations, this study examined whether an S1P1-specific agonist, SEW-2871, VPC23019, or their combination acts on obesity and glucose intolerance in leptin-deficient ob/ob mice. The oral administration of SEW-2871 or JTE-013 induced significant reductions in body/epididymal fat weight gains and epididymal/inguinal fat adipocyte sizes and improved glucose intolerance and adipocyte inflammation in ob/ob mice but not in their control C57BL/6J mice. Both SEW-2871 and JTE-013 decreased messenger RNA levels of tumor necrosis factor-α and CD11c, whereas they increased those of CD206 and adiponectin in the epididymal fats isolated from ob/ob mice with no changes in the levels of peroxisome proliferator activated receptor γ and its regulated genes. By contrast, VPC23019 did not cause any such alterations but counteracted with all those SEW-2871 actions in these mice. In conclusion, the S1P1 agonist SEW-2871 acted like the S1P2 antagonist JTE-013 to reduce body/epididymal fats and improve glucose tolerance in obese mice. Therefore, this study raises the possibility that endogenous S1P could promote obesity/type 2 diabetes through the S1P2, whereas exogenous S1P could act against them through the S1P1.
State-Level Trends in Lifespan Variability in the United States, 1960–2019: A Research Note
Authors: Brown Dustin C. , Lariscy Joseph T. , Walker Benjamin H.
Published: January 2023

State-level disparities in life expectancy are wide, persistent, and potentially growing in the United States. However, the extent to which differences in lifespan variability by state have changed over time is unclear. This research note describes trends in lifespan variability for the United States overall and by state from 1960 to 2019 using period life table data from the United States Mortality Database. Lifespan disparity at birth (e0†) decreased over time in the United States overall from 14.0 years in 1960–1964 to 12.2 in 2015–2019. Lifespan variability decreased in all states, but states differed in the level and pace with which these changes occurred. Southern states and the District of Columbia exhibited consistently higher (i.e., less equitable) levels of lifespan variability than the nation overall. Conversely, lifespan variability was lower among several states in the Northeast (e.g., Connecticut and Massachusetts), Upper Midwest (e.g., Iowa, Minnesota, and Wisconsin), and West (e.g., California, Oregon, Utah, and Washington). We observe a particularly worrisome trend of increasing lifespan variability for the United States overall and for most states from 2010–2014 to 2015–2019. Monitoring state-level trends in lifespan variability has the potential to inform policies designed to ameliorate population health disparities.
State Courts, State Legislatures, and Setting Abortion Policy
Authors: Kim Jeong Hyun , Gunderson Anna , Lane Elizabeth A. , Bauer Nichole M.
Published: January 2023

On June 24, 2022, the US Supreme Court decided in Dobbs vs. Jackson Women's Health Organization (597 U.S. (2022)) to overturn the constitutional right to abortion, a seismic shift in abortion policy that makes the states key battlegrounds in fights over abortion and broader reproductive rights. This article focuses on the role of state supreme courts in setting state abortion policies. Using an original data set of state court decisions surrounding abortion from the past 20 years, the authors investigate how two overarching factors affect state supreme court decision-making on abortion. First, they track how states' political environments affect the decisions courts make about access to abortion. Second, the authors consider the scope of the abortion policy considered by the courts. The authors find that the partisan makeup of state legislatures does not influence the direction of state supreme courts' rulings on abortion issues, but it does affect the scope of abortion regulation being considered by the courts. Additionally, they find that elected judges tend to be more responsive to constituent preferences when ruling on abortion policies. Overall, these findings illustrate the multifaceted dynamics involved in state supreme courts' rulings on abortion.
Frizzled 7 modulates goblet and Paneth cell fate, and maintains homeostasis in mouse intestine
Authors: Gu Nai-Xin , Guo Yu-Ru , Lin Sey-En , Wang Yen-Hsin , Lin I.-Hsuan , Chen Yi-Fan , Yen Yun
Published: January 2023

Intestinal homeostasis depends on interactions between the intestinal epithelium, the immune system and the microbiota. Because of these complicated connections, there are many problems that need to be solved. Current research has indicated that genes targeted by Wnt signaling are responsible for controlling intestinal stem cell fate and for modulating intestinal homeostasis. Our data show that loss of frizzled 7 (Fzd7), an important element in Wnt signaling, interrupts the differentiation of mouse intestinal stem cells into absorptive progenitors instead of secretory progenitors (precursors of goblet and Paneth cells). The alteration in canonical Wnt and Notch signaling pathways interrupts epithelial homeostasis, resulting in a decrease in physical protection in the intestine. Several phenotypes in our Fzd7-deleted model were similar to the features of enterocolitis, such as shortened intestines, decreased numbers of goblet cells and Paneth cells, and severe inflammation. Additionally, loss of Fzd7 exacerbated the defects in a chemical-induced colitis model and could initiate tumorigenesis. These findings may provide important information for the discovery of efficient therapeutic methods to treat enterocolitis and related cancers in the intestines.