bluuebunny/crossref_metadata_2025 huggingface dataset:
Does detection of microsatellite instability-high (MSI-H) by plasma-based testing predict tumor response to immunotherapy (IO) in patients with pancreatic cancer (PC)?
Authors: Chakrabarti Sakti , Bucheit Leslie A. , Starr Jason S. , Innis-Shelton Racquel , Shergill Ardaman , Resta Regina , Wagner Stephanie Ann , Kasi Pashtoon Murtaza
Published: January 2022

607

Background: Immunotherapy (IO) is known to have robust anti-tumor activity in patients with MSI-H solid tumors. However, clinical trials investigating IO activity have used tissue-based testing to determine MSI-H status. Pancreatic tumor biopsy often does not provide sufficient tumor tissue for MSI testing. We investigated if the MSI-H status detected by plasma-based circulating tumor DNA (ctDNA) testing predicts robust response to IO in patients with PC. Methods: Genomic results from a well-validated plasma-based ctDNA assay (Guardant360[G360]) performed as part of routine clinical care between October 1, 2018 and September 7, 2021 in patients with PC were queried to identify patients with MSI-H tumors. Patient characteristics, tumor characteristics, treatment details, and outcomes were reported by ordering clinicians where available. The data cut-off date was September 1, 2021. Results: A total of 52 patients with PC who had MSI-H tumors on G360 were identified. Clinical outcomes data were available for 10/52 (19%) patients who were included for analysis. This patient cohort had a median age of 68 years (range: 56-82); 80% were male and 80% of patients had metastatic disease. 9/10 patients received IO: 3 in the first-line, 3 in the second-line, 3 in the third-line setting; most received pembrolizumab (8/9) while 1 received ipilimumab plus nivolumab. The median duration of IO was 8 months (range: 1-24). The overall response rate was 77% (7/9) and 6 of the 7 responders continue to show response at the time of data cut-off after a median follow-up of 21 months (range:11-33). The median progression-free survival and overall survival were not reached in the IO-treated cohort. Tissue-based MSI testing results were concordant with plasma-based G360 results in 5 of 6 patients (83%) who had tissue-based test results available. The patient with the discordant result was MSI-H by G360 but had intact mismatch repair protein expression by immunohistochemistry. This patient received neoadjuvant IO followed by surgery and the resected specimen confirmed pathological complete response. Conclusions: The detection of MSI-H status by plasma-based ctDNA testing is highly concordant to tissue-based testing and predicts robust and durable response to IO in patients with PC. The use of a well-validated plasma-based ctDNA analysis may expand the identification of MSI-H tumors in patients with PC and enable treatment with IO resulting in improved outcomes.
Homologous recombination repair pathway alterations and their relationship to homologous recombination deficiency in advanced pancreatic cancer patients.
Authors: Patel Hitendra , Barrett Alex , Mauer Elizabeth , Kato Shumei , Leibowitz Benjamin D. , Singhi Aatur D. , Javle Milind M. , Lowy Andrew M.
Published: January 2022

609

Background: Homologous recombination repair (HRR) is critical for limiting DNA damage arising from double strand breaks. Disrupting HRR has emerged as a therapeutic strategy in pancreatic cancer given the development of PARP inhibitors that can specifically target tumors with homologous recombination deficiency (HRD). While HRD is strongly associated with loss-of-function mutations in BRCA1/2, a broad range of pathogenic alterations have been identified in other HRR genes. Identification of pathogenic alterations that predict response to PARP inhibition remains a critical knowledge gap in the field. Methods: We retrospectively analyzed de-identified records from 895 patients with advanced pancreatic cancer that underwent next generation sequencing (NGS) with the Tempus|xT assay (DNA-seq of 648 genes at 500x coverage, matched normal, full transcriptome RNA-seq). HRD-positivity and genome-wide loss of heterozygosity (LOH) were compared across groups, which were defined based on alterations to BRCA1/2 or other HRR pathway genes. Results: We identified 293/895 (33%) pancreatic cancer patients to be HRD-positive. Among HRD positive patients, 23/895 (2.6%) tumors harbored two alterations in BRCA1/2 (BRCA++), 179/895 (20%) harbored a single alteration in BRCA1/2 (BRCA+), 25/895 (2.8%) harbored two alterations in at least one other non-BRCA HRR gene (other HRR++), 367/895 (41%) harbored a single alteration in one other HRR gene (other HRR+), and 143/895 (16%) had pathogenic alterations in neither BRCA1/2 nor other HRR genes. In terms of HRD status, 23/23 (100%) of BRCA++ cases, 179/337 (53%) of BRCA+ cases, 4/25 (16%) of other HRR++ cases, and 87/367 (24%) of other HRR+ cases were HRD-positive. We observed no cases that were HRD-positive without an alteration in either BRCA1/2 or other HRR gene. Within the other HRR+ group, we found that single alterations in CHEK1/2, FANCA/L, MRE11, PALB2, and RAD51B were all significantly associated with HRD-positivity whereas CDK12, for instance, was not (Table). Conclusions: Comprehensive genomic profiling demonstrates that approximately 1 in 4 patients without BRCA alterations may potentially benefit from PARP inhibition due to alterations in other HRR genes. Future studies may examine the role of PARP inhibition in this population of HRR+ pancreatic cancer patients.[Table: see text]
KRAS mutation methylation clonality in early-stage pancreatic cancer.
Authors: Kowalski Jeanne , Xu Qi , Chao Hsueh Ping , Gandhi Heta , Aung Kyaw Lwin , Matsui William H.
Published: January 2022

614

Background: KRAS is mutated in 90% of pancreatic cancers making it a seemingly ideal target for treatment and yet, with the exception of the rare G12C mutation, KRAS is undruggable for the vast majority of pancreatic patients. Herein, we characterize, in silico, KRAS methylation-derived mutation clonal and subclonal diversity in PDAC and examine their impact upon clinical outcomes. Methods: We developed a mutation methylation (MM) clonality workflow for gene mutation assignment as clonal versus subclonal and applied it genome-wide to TCGA data. For comparison, we used the cancer cell fraction (CCF) clonality prediction. We examined clinical outcomes by comparing in months (mos), Kaplan-Meier estimated overall survival (OS) using a log-rank test and a cox model for testing several features. We performed differential gene expression, differential gene correlation, and gene set enrichment analyses (GSEA) between KRAS MM clonal versus subclonal early stage pancreatic patients. Results: Using 104 TCGA early stage pancreatic cancer patient tumors from TCGA with mutation, methylation and clinical outcomes data, we defined KRAS MM clonality (n = 70 clonal, n = 34 subclonal) and CCF clonality (n = 74 clonal, n = 28 subclonal) tumors. Clonality assignment between methods was 53% clonal and 17% subclonal concordant, and 19% discordant among samples. KRAS MM clonality was associated with significantly (p = 0.046) shorter OS (median OS = 11.5 mos) as compared to the KRAS subclonal group (median OS = 15 mos). By comparison, KRAS CCF clonal and subclonal patient groups did not differ in their OS. When RNA-Seq derived subtypes for pancreatic cancer were included in a model with our KRAS MM clonality marker, only our marker remained as significantly associated with OS. Median KRAS gene expression was significantly (p = 0.01) higher in the KRAS MM clonal versus subclonal group. A GSEA showed enrichment of MYC targets in the KRAS clonal group. We identified 72, mostly protein coding genes residing on chromosomes 5q, 7p and 8p that correlated with KRAS gene expression only in the subclonal group. Conclusions: Our analyses shows a potential clonality dissection of the established 90% KRAS mutation rate in pancreatic cancer, which based on our MM workflow, may be dissected into 61% KRAS clonal and 30% KRAS subclonal. By assigning clonality based on another DNA data type using CCF, we obtain 65% KRAS clonal and 25% KRAS subclonal. Thus, regardless of which DNA-based workflow, overall, the KRAS clonality rates are similar. There is a notable difference however in patient-level assignment of KRAS clonality as only our workflow showed poor OS associated with KRAS clonality. The introduction of a methylation-based mutation clonality marker could prove invaluable when used in combination with methylation-based circulating tumor DNA assays for patient and treatment selection, and clinical trial monitoring of tumor responses.
Disparities in comprehensive genomic profiling in older patients with gastrointestinal malignancies.
Authors: Elias Rawad , Kuang Zheng , Murphy Jo-Ellen , Yu Peter Paul
Published: January 2022

646

Background: Limited data guides the management of older adults with cancer, a patient population that continues to be under-represented in clinical trials. Comprehensive Genomic Profiling (CGP) drives the enrollment on biomarker-based trials and may inform treatment selection. This analysis aims to evaluate the use of CGP in older patients with gastrointestinal (GI) malignancies and to compare results of genomic profiling across age groups. Methods: Clinical CGP results derived from Next Generation Sequencing (NGS) of tumor tissue (n=92802) were reviewed for patients with GI malignancies. Genomic alterations (GAs) and complex signatures were identified, based on hybridization-captured, adapter ligation-based sequencing. Association between age group (< 65: n=51652; 65-74: n=28972; 75+: n=12178) and biomarkers of interests was evaluated using Chi-square test, adjusting for multiple testing using Bonferroni correction. Delay-adjusted incidence rates in populations included in the study were acquired from SEER Databases. Results: The majority of patients in the CGP cohort were <65 yrs (55.7%). Patients aged 75 and above were underrepresented as compared to the SEER database incidence rates (15.2% vs. 31.6%, p <0.0005). Overall, the incidence of known or likely pathogenic GAs was similar across all age groups (>99%). An analysis of specific GAs among all the GI cancers analyzed showed an age-associated increase of high tumor mutational burden (≥10 mut/Mb) (TMB-H) (5.6% vs 6.6% vs 10.7% for respective age groups, p<0.0005). The overall incidence of mismatch repair deficiency or microsatellite instability (dMMR/MSI) (3.6% vs 4.0% vs 7.5%, p<0.0005) and DNA damage repair mutations (DDR mut) (13.2% vs 13.9% vs 16.4%, p<0.0005) also increased with age. The magnitude of the CGP findings varied by GI cancer type, as summarized for select significant findings (p <0.0005) in Table. Detailed results for each GI subtype and relevant biomarkers will be presented. Conclusions: This large scale analysis of CGP done for patients with GI cancers showed that genomic profiling is under utilized in older adults who constitute the majority of patients with GI malignancies. These findings may improve access to clinical trials and guide the development of older adult-specific studies.[Table: see text]
Poorly differentiated histology as a predictive biomarker in patients with advanced gastrointestinal (GI) cancers treated with immunotherapy.
Authors: Draper Amber , Jung Emily , Cao Yichun , Atallah Rami , Switchenko Jeffrey M. , Alese Olatunji B.
Published: January 2022

664

Background: Checkpoint inhibitors (CPI) have significantly improved survival among patients with various cancer types. Prior studies have showed a correlation between immune cell infiltration and poorly differentiated cancers. We evaluated the impact of poorly differentiated histology on survival in patients with advanced GI malignancies treated with immunotherapy. Methods: We performed a retrospective, single institution analysis of patients with poorly differentiated GI tumors treated with CPI between 2016 and 2021. Univariate (UVA) and multivariable analyses (MVA) were performed to identify factors associated with patient outcome. Kaplan-Meier analysis and Cox proportional hazards models were used to assess the association between tumor/patient characteristics, progression free survival (PFS) and overall survival (OS). Results: A total of 123 patients were included. Median age was 66years. Majority had stage IV disease (88.2%), were White (65.5%) and male (64.5%). Most common diagnoses were HCC (28.5%), gastric (15.4%) and esophageal (14.6%) adenocarcinomas. About 32% were MSI-H, with 10% BRAF mutation rate. About 25% received CPI as initial treatment and 35.5% received 2 or more prior lines of therapy. Compared with well and moderately differentiated histology, poorly differentiated tumors had shorter mPFS (3.4 vs 2.5 vs. 2.2months; p = 0.29) and mOS (not reached [NR] vs. 20.9 vs. 14.2 months; p = 0.14) respectively. On UVA, the degree of tumor differentiation did not correlate with mPFS or mOS. Female patients (HR: 0.55, CI: 0.34-0.90, p = 0.018) and ECOG of 1 vs. ≥2 had significantly longer mPFS (HR: 0.58, CI: 0.35-0.97, p = 0.036). ECOG 1 correlated with better mOS (HR: 0.47, CI: 0.23-0.94, p = 0.034). Microsatellite stable (MSS) tumors had significantly shorter mPFS (HR: 5.74, CI: 2.41-13.63, p < 0.001) and mOS (HR: 5.45, CI: 1.64-18.12, p = 0.006). Number of prior systemic therapies was also associated with shorter mPFS (HR: 1.19, CI: 1.03-1.39, p = 0.022) and mOS (HR: 1.23, CI: 1.01-1.50, p = 0.045). On MVA, ECOG status of 0/1 vs. ≥2 and MSI-H vs. MSS remained significantly associated with longer mPFS and mOS. There was no correlation with race or mutations such as BRAF or KRAS. Conclusions: Poorly differentiated histology did not predict for PFS or OS. Treatment naïve patients, female gender, ECOG 1 and MSI-H were most likely to benefit from CPI.
A proof-of-concept formative trial evaluating the interest of multiple connected devices for the early detection of hand-foot skin reactions in patients treated with regorafenib therapy (FACET).
Authors: Coriat Romain , Sibaud Vincent , Dochy Emmanuelle , Leturgez Thibaut , Arvis Pierre , Kremliovsky Michael , Reeves John A. , Di Palma Mario
Published: January 2022

TPS207

Background: Hand-foot skin reaction (HFSR) is a common skin toxicity associated with regorafenib that may lead to drug withdrawal, dose reduction, or drug interruption. Predicting or recognizing early symptoms of HFSR could allow for better care. Digital solutions for ambulatory monitoring of patients provide an opportunity for monitoring and early detection of HFSR in home conditions. Methods: FACET is a phase 4, prospective, open-label, multicenter, interventional trial designed to assess the clinical utility, technical feasibility and usability of a system including a camera, FeetMe Connected insoles for gait assessment, ePRO questionnaires (HFS-14, EQ-5D-5L, FAS and VAS), and educational materials to detect and grade the severity of HFSR. During the study, enrolled patients developing an HFSR will be assigned to the HFSR group and patients without any sign of HFSR, they will be assigned to non-HFSR group. Study registration number at ANSM (French Authority): ID-RCB 2020-A03080-39. Patients will have metastatic colorectal cancer requiring initiation of regorafenib in accordance with clinical practice standard. Other key inclusion criteria are ECOG Performance Status 0-2, ability to understand the instructions and complete the ePRO questionnaires, ability to understand and communicate in French language, familiarity in using mobile communication devices and mobile application software, no previous episode of HFSR or HFS. The primary objective is to explore fit-for-purpose, and usability of the ePRO instruments and the data collecting devices. The primary endpoint is participants’ compliance with data collection measured by ePRO questionnaires completion, use of camera to take images vs expected and number of device days of insoles usage vs expected. Secondary objectives are to characterize variables exhibiting significant associations with development of HFSR. Secondary endpoints include summary statistics of ePRO questionnaires scores at the HFSR worst grade event in the HFSR group vs at 3 weeks in the non-HFSR group; Summary statistics for Feetme Connected insoles variables; Regorafenib dose modifications and treatment discontinuation; Participant’s device daily use to generate data; Participants ability to reach a hotline for technical issues or usability complaints. For HFSR related secondary endpoints, a blinded and independent Preliminary Adjudication Committee (PAC) will retrospectively assign participants to two groups (HFSR vs. no-HFSR) based on a case-by-case blinded assessment. An independent Final Adjudication Committee will compare the PAC assessment and investigators’ assessments done on site. It is planned to include a total of 38 participants from 4 centers. As of September 2021, all sites are open and ready to enroll. Study funded by Bayer.
Prevention of colorectal cancer through multiomics blood testing: The PREEMPT CRC study.
Authors: Putcha Girish , Xu Chuanbo , Shaukat, MD, MPH Aasma , Levin Theodore R.
Published: January 2022

TPS208

Background: The USPSTF recently recommended colorectal cancer (CRC) screening for adults aged 45 to 49 years in addition to those aged 50 to 75 years. This guideline update, which increases the number of screen-eligible individuals by ̃19 million, is similar to the recommendation in 2018 by the American Cancer Society (ACS) and is based on the modeling studies that reflect rising CRC incidence rates in younger adults. Currently, only 67% of average-risk individuals over the age of 50 years are up-to-date on CRC screening, and adherence to screening is lower in younger individuals (e.g., 50-54 years). Despite the non-invasive nature of existing stool-based CRC tests, barriers remain to adoption, including a dislike for manipulating stool and a requirement for substantial navigational support. Blood tests may overcome these barriers through ease of sample collection and integration into routine blood work. Methods: Here we describe our prospective, multi-center registrational study for validating a blood-based multiomics test for average-risk CRC screening: PREEMPT CRC. Eligible participants include those aged 45-85 with no known history of CRC or colorectal adenomas who are undergoing CRC screening by colonoscopy. The target enrollment is 25,000 participants, and primary outcome measures are sensitivity for CRC and specificity for advanced colorectal neoplasia, which includes CRC and advanced adenomas. Secondary outcome measures include positive predictive value for CRC, negative predictive value for advanced colorectal neoplasia, and sensitivity for advanced adenomas. Novel recruitment methods have been implemented by combining traditional, site-based recruitment and virtual recruitment using an online web portal, coupled with mobile phlebotomy, to make participation broadly accessible, especially during the COVID-19 pandemic. Participants have been enrolled from 40 states as of August 2021, and virtual recruitment has enabled widespread participation, potentially from any zip code in the continental US. To ensure adequate representation of the intended use population, community organizations, federally qualified health centers (FQHCs), and universities have been engaged to reach underserved and minority patient populations. The study was initiated in May 2020 and to our knowledge will be the largest prospective, multi-center registrational validation study of an average-risk CRC screening test to date. Clinical trial information: NCT04369053.
Neoadjuvant chemoradiotherapy with or without Pd-1 antibody sintilimab for pMMR/MSS/MSI-L locally advanced rectal cancer: A randomized controlled study (cohort B).
Authors: Xiao Weiwei , Lin Jun-zhong , Chen Gong , Wu Xiao-Jun , LU Zhen-Hai , Wang Qiaoxuan , Cai Peiqiang , Liu Min , He LongJun , Xi ShaoYan , Wang Feng , Zhang Huizhong , Gao Yuan-Hong , Pan Zhi-Zhong , Xu Rui-hua
Published: January 2022

TPS210

Background: Neoadjuvant chemoradiotherapy (NACRT) could bring tumor downstaging and pathological response (pCR), and also survival benefit for locally advanced rectal cancer (LARC) patients. Several single arm prospective clinical trials have investigated combination effect of immunotherapy (PD-1 or PD-L1 antibody) and NACRT in LARC patients, such as the VOLTAGE clinical trial. A randomized trial is needed to confirm the benefit of immunotherapy in this setting and explore predictive biomarkers. This is a clinical trial with two cohorts according the MMR/MSI status (clinicalTrials.gov, NCT04304209). Methods: In this study, LARC patients with pMMR/MSS/MSI-L tumor will enter cohort B and be randomized into two arms. Main inclusion criteria include: cT3-4N0M0 or cTxN+M0 rectal adenocarcinoma, pMMR/MSS/MSI-L confirmed by immunohistochemistry or gene test, aged 18-75y; ECOG performance 0-1; no previous anti-tumor treatment for rectal adenocarcinoma. Main exclusion criteria include: active autoimmune diseases or a history of autoimmune diseases, and inadequate main organ functions. Patients in the experimental arm will receive four cycles of neoadjuvant PD1 antibody Sintilimab, Capeox chemotherapy and concurrent radiotherapy, followed by curative surgery or watch and wait, then four cycles of adjuvant Capeox chemotherapy. Patients in the control arm will receive four cycles of neoadjuvant Capeox chemotherapy and concurrent radiotherapy, followed by curative surgery or watch and wait, then four cycles of adjuvant Capeox chemotherapy Primary outcome measure is pCR rate. Secondary outcome measures include acute toxicity, tumor regression grade, R0 resection rate, local recurrence, distant metastasis. Sample size for this cohort is 134. Whole exome sequencing, RNA sequencing and immunohistochemistry of the rectal primary tumor are planned for biomarker searching and synergy effect mechanism investigation. The first patient has been enrolled in June, 2020. Clinical trial information: NCT04304209.
REVERCEII (ACCRU-GI-1809): A randomized phase II study of regorafenib followed by anti-EGFR monoclonal antibody therapy versus the reverse sequencing for metastatic colorectal cancer patients previously treated with fluoropyrimidine, oxaliplatin and irinotecan.
Authors: Ahn Daniel H. , Ou Fang-Shu , Sonbol Bassam Bassam , Wender Donald , Klute Kelsey , Jin Zhaohui , Jones Jeremy Clifton , Ulrich Angela , Waechter Blake , Young Heather , Weinberg Benjamin Adam , Lenz Heinz-Josef , Strickler John H. , Bekaii-Saab Tanios S.
Published: January 2022

TPS213

Background: Regorafenib (R) is an oral multikinase inhibitor that blocks several protein kinases involved in angiogenesis and oncogenesis; it has a survival benefit in refractory metastatic colorectal cancer (mCRC). The current standard (std) treatment in patients (pts) with RAS wildtype (WT) mCRC is sequential treatment with an anti-EGFR antibody (AEA) followed by R. However, R, which is orally administered once daily, may be more convenient and thus preferable for pts than AEA. REVERCE, a Japanese trial, demonstrated a significant 5.8 month (mo.) survival benefit with regorafenib administered prior to AEA compared to the std sequence. Based off these findings, the proposed phase II trial is to confirm the observed survival benefit from regorafenib sequencing prior to anti-EGFR monoclonal antibody therapy in REVERCE in a US patient population. Methods: REVERCEII is an Academic and Community Cancer Research United (ACCRU) network-led randomized phase II study of R (dose escalation from 80mg to 160mg based on tolerance) prior to AEA (R+AEA) compared to standard sequencing (AEA+R) in pts with refractory RAS WT mCRC. Patients are randomized 1:1 to receive R (Arm A) vs. AEA (with or without irinotecan per investigator choice) (Arm B). At the time of disease progression or intolerance, patients will receive sequential treatment until disease progression. Eligibility criteria include histologically confirmed mCRC, ECOG ≤ 2, acceptable organ function, and patients must have had prior fluoropyrimidine, oxaliplatin and irinotecan, and no prior AEA nor R. The primary objective is to compare the overall survival (OS), the primary endpoint, between evaluable patients (eligible, consented, started protocol treatment) who were randomized to R+AEA (arm A) and AEA+R (arm B). With 83 OS events, we have 87% power to detect an improvement in median OS from 9 months to 14.5 mo., assuming 1-sided significance level of 0.15, and exponential distribution. The total sample size is 124 patients. Secondary endpoints include progression-free survival, objective response, and adverse events. The total study duration is expected to be 3 years. Clinical trial information: NCT04117945. Clinical trial information: 04117945.
REGINA: A phase II trial of neoadjuvant regorafenib (Rego) in combination with nivolumab (Nivo) and short-course radiotherapy (SCRT) in intermediate-risk, stage II-III rectal cancer (RC).
Authors: Bregni Giacomo , Senti Chiara , Acedo Reina Elena , Gkolfakis Paraskevas , Moretti Luigi , Veron Ana , Demetter Pieter , Liberale Gabriel , Carrasco Javier , Geboes Karen Paula , Gokburun Yeter , Peeters Marc , Van Den Eynde Marc , Van Laethem Jean-Luc , Vergauwe Philippe , Buyse Marc E. , Deleporte Amélie , Hendlisz Alain , Sclafani Francesco
Published: January 2022

TPS226

Background: Despite recent improvements, management of locally advanced rectal cancer (LARC) remains challenging, and many patients (pts) still experience recurrence. In preclinical models, combining Rego with an anti-PD-1 inhibitor led to superior tumour growth suppression as compared with either treatment alone. In a phase I clinical trial, remarkable results were reported for the combination of Rego and Nivo in advanced MSS colorectal cancer. This synergistic effect is thought to be secondary to the anti-angiogenic effects of Rego and its potential to reduce TAMs, promote M1 macrophage conversion, and down-regulate expression of immunosuppressive factors. Building on these data, we designed a trial of Rego-Nivo with standard SCRT in the neoadjuvant setting of RC. Methods: REGINA is an academic, multicentre, single-arm, phase II trial sponsored by Institut Jules Bordet. Eligible patients are treated according to the following plan: induction phase (Nivo 240 mg IV D1&15, and Rego 80 mg PO D1-14), SCRT (D22-26), consolidation phase (Nivo 240 mg IV D29,43&57, and Rego 80 mg PO D29-49), and surgery (7-8 weeks after SCRT). Key eligibility criteria include age ≥18 years, ECOG PS ≤1, adenocarcinomas below the peritoneal reflection, intermediate-risk, stage II-III tumour (ie, cT3/T4aNany or cT1-2N+, no involvement/threatening of the mesorectal fascia, no involvement of lateral pelvic lymph nodes) irrespective of microsatellite instability status. The primary endpoint is pathological complete response (pCR). Secondary endpoints include, among others, toxicity, compliance to treatment, pathological tumour regression grade, event-free survival, and overall survival. Subjects will be followed for recurrence and survival for 5 years after end of treatment visit. The study follows a Simon’s two-stage design (null hypothesis pCR = 12%, alternative hypothesis pCR = 24%; α= 5%, β= 20%) with a maximum of 60 pts to be enrolled. A safety interim analysis is planned after the first 6 pts have completed treatment. Serial collection of tumour, blood, and stool samples is mandatory at pre-specified time points for exploratory correlative biomarker analyses. The trial is planned to be run at 8-10 centres across Belgium. Study recruitment started in Q1 2021 and is anticipated to complete in Q3 2023. The study is funded by Bayer. Clinical trial information: NCT04503694.
A prospective trial to evaluate the performance of the multitarget hepatocellular carcinoma blood test (mt-HBT) for screening at-risk patients: The Altus study.
Authors: John Binu , Porter Kyle , Dahman Bassam , Parikh Neehar , Silva Alvin C. , Yang Ju Dong , Joseph Patrick , Strong Laura E. , Limburg Paul J.
Published: January 2022

TPS486

Background: Hepatocellular carcinoma (HCC) is a major cause of cancer-related death in the U.S. HCC surveillance is associated with improved early detection and receipt of curative treatment. However, current surveillance strategies suffer from low adherence and suboptimal sensitivity. The multi-target HCC blood test (mt-HBT) is a novel early detection assay that provides a qualitative result based on a multiparametric algorithm that incorporates information from methylation markers ( HOXA1, TSPYL5, and B3GALT6), AFP, and patient sex. Here, we describe the protocol for a prospective, multicenter clinical trial designed to investigate the performance of the mt-HBT in patients at risk for HCC. Methods: ALTernative to U/S (ALTUS) is a longitudinal, multicenter, prospective study with a targeted enrollment of 3,000 participants. The main inclusion and exclusion criteria are described in the table. Participants will receive HCC surveillance imaging (either U/S or CT/MRI) and blood collection for the mt-HBT. Those with positive U/S are anticipated to receive standard-of-care imaging follow-up with a multiphase CT or MRI, and those with a negative U/S will receive a study CT/MRI within 30 days of blood collection. Imaging interpretation is based on the CT/MRI LI-RADS (LR) v2018 categories. The primary endpoints are the overall sensitivity and specificity of the mt-HBT to detect HCC, defined as pathology-confirmed HCC or hepatocellular cholangiocarcinoma (cHCC-CCA), LR-4/5, or LR-TIV/M plus definite/probable HCC or cHCC-CCA. The secondary endpoints are mt-HBT early-stage sensitivity, and performance in a) participants with LR-5 or biopsy-confirmed HCC and b) participants confirmed non-HCC. Participants not diagnosed with a liver malignancy at visit one will continue to receive HCC surveillance, returning for a second visit ̃6 months from first blood collection. Blood will be collected after the second visit for the mt-HBT. Data on treatment will be collected for those diagnosed with HCC. Study participants and providers will be blinded to the mt-HBT results. Participants are currently enrolling across the U.S., with 60 targeted sites and an anticipated 12-month enrollment window. Clinical trial information: NCT05064553. [Table: see text]
Randomized, parallel arm, phase II study of telotristat (Xermelo) in combination with lutetium Lu 177 dotatate (Lutathera) in well-differentiated neuroendocrine tumors (NETs).
Authors: Chauhan Aman , Kunos Charles , Yan Donglin , Khurana Aman , Khouli Riham , Cavnar Michael J. , Pandalai Prakash , Kim Joseph , Anthony Lowell Brian
Published: January 2022

TPS516

Background: PRRT using Lutetium Lu 177 Dotatate, has been approved by the FDA for metastatic, progressive gastroenteropancreatic neuroendocrine tumors (GEPNETs). Despite an impressive progression-free survival noted in NETTER-1 study, most patients will eventually progress after PRRT treatment. Increased serotonin secretion is found in a number of slow-growing NETs of the diffuse neuroendocrine system. Serotonin stimulates proliferation in cell lines of a typical (NCI-H727), an atypical (NCI-H720) bronchopulmonary NET, a small intestinal NET (KRJ-I), and a functioning human pancreatic carcinoid cell line (BON). This stimulation of growth by serotonin can be performed in an autocrine manner. Telotristat ethyl is a novel oral inhibitor of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis. In 2017, results of placebo-controlled phase III study (Telestar) evaluating Telotristat ethyl confirmed that among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with Telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in bowel movement frequency and urinary 5- hydroxy indoleacetic acid (u5-HIAA). Based on results of the Telestar trial, FDA approved 250 mg PO TID dosage of Telotristat for control of carcinoid syndrome diarrhea. Of note, 500 mg TID arm showed increased decline in urinary 5-HIAA as compared to 250 mg TID arm. Study Hypotheses: We hypothesize that inhibition of serotonin production will lead to cytostatic effect on neuroendocrine tumors and will complement anti-tumor activity of lutetium 177 dotatate. We anticipate our proposed combination will result in improved treatment efficacy as reflected by improved 20-month PFS as compared to historical control (NETTER-1). Methods: This is a single center, open label, randomized, parallel arm, phase II study evaluating two dose levels of Telotristat (Xermelo; 250 mg vs 500 mg) in combination with Lutetium Lu 177 Dotatate (Lutathera) in 70 well-differentiated neuroendocrine tumor patients. Study is currently enrolling patients and is expected to complete accrual in 3 years. Clinical trial information: NCT04543955.
A multi-institutional, single-arm, phase II trial of neoadjuvant modified-FOLFIRINOX for resectable pancreatic ductal adenocarcinoma.
Authors: Lee Choong-kun , Hwang Ho Kyoung , Jeung Hei-Cheul , Chon Hongjae , Park Hyung Soon , Kim Min Hwan , Park Mi-Suk , Kang Chang Moo , Choi Hye Jin
Published: January 2022

TPS624

Background: Within the next decade, pancreatic ductal adenocarcinoma (PDAC) is expected to rise to the second leading cause of cancer-related mortality. To increase the survival, various peri-operative treatments have been tested, and adjuvant FOLFIRINOX or gemcitabine plus capecitabine is now standard of care after surgical resection for localized PDAC. Even with superior survival among various disease extent of PDAC, resectable PDAC still shows poor outcomes with surgery followed by adjuvant chemotherapy. This phase II study is investigating the role of modified-FOLFIRINOX as neoadjuvant treatment for resectable PDAC. Methods: This study is a phase II, multi-institutional, single-arm trial to evaluate the efficacy and safety of modified-FOLFIRINOX in resectable PDAC. The main inclusion criteria are histologically confirmed PDAC; resectable PDAC confirmed by both computed tomography (CT) and magnetic resonance imaging (MRI) according to NCCN guideline resectability criteria (no arterial tumor contact to celiac axis, SMA or CHA; no tumor contact with SMV or PV or ≤180° contact without vein contour irregularity); no previous treatment (surgery or chemotherapy); ECOG 0 or 1; and adequate organ function. Patients receive oxaliplatin 85 mg/m2 D1 + leucovorin 400mg/m2 D1 + irinotecan 150 mg/m2 D1 + 5-FU 2,000 mg/m2 46h continuous infusion, every other week for 6 cycles (12 weeks). Response assessments are performed every 6 weeks using the RECIST criteria version 1.1. Baseline MRI, PET-CT scan before treatment, and pre-surgery MRI after 6 cycles are mandatory. The primary endpoint was R0 resection rate. Secondary endpoints included progression-free survival, overall survival, disease-free survival, objective response rate, safety, resection rate, and correlative biomarker exploration. The study will enroll up to 27 patients and is currently recruiting at four sites in South Korea. As of September 2021, 20 patients have been enrolled. Clinical trial information: KCT0004421 (Registration ongoing for clinicaltrials.gov).
A phase 1, first-in-human (FIH) study of adenovirally transduced autologous macrophages engineered to contain an anti-HER2 chimeric antigen receptor (CAR) in subjects with HER2 overexpressing solid tumors.
Authors: Reiss Kim Anna , Yuan Yuan , Barton Debora , Cushing Daniel , Ronczka Amy , Klichinsky Michael , Dees Elizabeth Claire
Published: January 2022

TPS668

Background: Adoptive T cell therapies have led to remarkable advances among patients with hematologic malignancies, but not in those with solid tumors. Macrophages are actively recruited into, and are abundantly present in the solid tumor microenvironment (sTME). Tumor- associated macrophages typically display immunosuppressive behavior, but when engineered to be proinflammatory, may be an ideal vector to administer adoptive cellular therapy in solid tumors. Furthermore, insertion of a CAR on the macrophages allow them to selectively recognize and phagocytose antigen overexpressing cancer cells. CAR macrophages reprogram the sTME and present neoantigens to T cells, leading to epitope spreading and immune memory. Human Epidermal Growth Factor Receptor 2 (HER2) overexpression promotes tumorigenesis in many cancers (Table). CT-0508 is a cell product comprised of autologous monocyte-derived pro-inflammatory macrophages expressing an anti-HER2 CAR. Pre-clinical studies have shown that CT-0508 induced targeted cancer cell phagocytosis while sparing normal cells, decreased tumor burden and prolonged survival in relevant models. CT-0508 cells were safe and effective in a semi-immunocompetent mouse model of human HER2 overexpressing ovarian cancer. Methods: This is a FIH Phase 1 study to evaluate safety, tolerability, cell manufacturing feasibility, trafficking and preliminary evidence of efficacy of investigational product CT-0508 in 18 subjects with locally advanced (unresectable) or metastatic solid tumors overexpressing HER2, who have failed available therapies, including anti-HER2 therapies when indicated. Filgrastim is being used to mobilize autologous hematopoietic progenitor cells for monocyte collection by apheresis. The CT-0508 CAR macrophage product is manufactured, prepared and cryopreserved from mobilized peripheral blood monocytes. Group 1 subjects receive CT-0508 infusion split over D1, 3 and 5. Dose limiting toxicities will be observed and addressed by a Safety Review Committee. Group 2 subjects will receive the full CT-0508 infusion on D1. Pre and post treatment biopsies and blood samples will be collected to investigate correlates of safety (immunogenicity), trafficking (PCR, RNA scope), CT-0508 persistence in blood and in the tumor, target antigen engagement, TME modulation (single cell RNA sequencing), immune response (TCR sequencing) and others. Clinical trial information: NCT04660929. [Table: see text]
Tractography-Based Surgical Targeting for Thalamic Deep Brain Stimulation: A Comparison of Probabilistic vs Deterministic Fiber Tracking of the Dentato-Rubro-Thalamic Tract
Authors: Yang Andrew I. , Parker Drew , Vijayakumari Anupa A. , Ramayya Ashwin G. , Donley-Fletcher Melanie P. , Aunapu Darien , Wolf Ronald L. , Baltuch Gordon H. , Verma Ragini
Published: January 2022

BACKGROUND:

The ventral intermediate (VIM) thalamic nucleus is the main target for the surgical treatment of refractory tremor. Initial targeting traditionally relies on atlas-based stereotactic targeting formulas, which only minimally account for individual anatomy. Alternative approaches have been proposed, including direct targeting of the dentato-rubro-thalamic tract (DRTT), which, in clinical settings, is generally reconstructed with deterministic tracking. Whether more advanced probabilistic techniques are feasible on clinical-grade magnetic resonance acquisitions and lead to enhanced reconstructions is poorly understood.

OBJECTIVE:

To compare DRTT reconstructed with deterministic vs probabilistic tracking.

METHODS:

This is a retrospective study of 19 patients with essential tremor who underwent deep brain stimulation (DBS) with intraoperative neurophysiology and stimulation testing. We assessed the proximity of the DRTT to the DBS lead and to the active contact chosen based on clinical response.

RESULTS:

In the commissural plane, the deterministic DRTT was anterior (P < 10−4) and lateral (P < 10−4) to the DBS lead. By contrast, although the probabilistic DRTT was also anterior to the lead (P < 10−4), there was no difference in the mediolateral dimension (P = .5). Moreover, the 3-dimensional Euclidean distance from the active contact to the probabilistic DRTT was smaller vs the distance to the deterministic DRTT (3.32 ± 1.70 mm vs 5.01 ± 2.12 mm; P < 10−4).

CONCLUSION:

DRTT reconstructed with probabilistic fiber tracking was superior in spatial proximity to the physiology-guided DBS lead and to the empirically chosen active contact. These data inform strategies for surgical targeting of the VIM.
Duodenum inversum: a rare cause of nausea and epigastric pain
Authors: Yap Chin Harn , Coupland Danielle , Au John , Raju Smita
Published: January 2022

Duodenum inversum is a rare congenital anomaly of unknown aetiology characterised by the proximal duodenum travelling posteriorly and superiorly prior to crossing midline. Clinical presentations include epigastric pain, nausea, and abdominal distension. It can be associated with duodenitis, acute pancreatitis, peptic ulcer disease and functional biliary obstruction. In this case report, we discuss a 77-year-old male who presented with hematemesis and epigastric pain secondary to duodenitis, for which he had a CT scan of the abdomen which demonstrated duodenum inversum. Despite the rarity of the condition and its common omission from differential diagnoses, the ability to recognise duodenum inversum is important for radiologists, especially considering its implications in clinical management. If not diagnosed correctly, it may result in unnecessary hospital admissions, dietary restrictions, and perhaps even unnecessary surgery. In this case, the radiological diagnosis of duodenum inversum using CT allowed for conservative medical management and prevented surgical intervention.
The association between the lymph node ratio, surgical margin, and survival in patients with colon cancer receiving adjuvant chemotherapy
Authors: Fidan Evren , Merev Elif , Usta Arif , Alandağ Celal , Dişli Şafak , Özdöver Ali
Published: January 2022

Objectives: To investigate the prognostic significant of lymph node ratio and surgical margins in patients with colon cancer undergoing surgery.

Methods: This observational and retrospective study was conducted at Karadeniz Technical University Medical Faculty, between 1 January, 2010 and 31 November, 2020. A series of 137 patients who had undergone surgical resection of colon carcinoma were included in this study. mLNR, deﬁned as the ratio of the number of mLNs to the number of examined lymph nodes, was calculated in colorectal cancer cases with lymph node metastasis. Patients were divided into three groups; LNR1 (< 0.25), LNR2 (0.25-0.6) and LNR3 (> 0.6).

Results: Mean disease-free survival was 79.2 months (95% CI 71.0-87.4). The mean expected survival time was 73.5 months (95% CI: 65.9-81.0). As the metastatic LN ratio increased, the rate of local recurrence or distant metastasis increased statistically significantly (p=0.007). As the metastatic LN ratio increased, the death rate increased statistically significantly (p=0.036). Metastatic lymph node ratio did not have a statistically significant effect on overall survival in patients with stage-3 and more than 12 LNs removed (p=0.069). There was no statistically significant association between the closeness of the surgical margin and disease-free survival in stage 1 (p=0.505) and stage-2 (p=0.161). There was no statistically significant association between the closeness of the surgical margin and overall survival among patients with stage 1 (p=0.494) and stage 2 (p=0.265).

Conclusion: A high metastatic LNR is associated with poorer overall and disease-free survival.

doi: https://doi.org/10.12669/pjms.38.3.5085

How to cite this:Fidan E, Merev E, Usta A, Alandag C, Disli S, Ozdover A. The association between the lymph node ratio, surgical margin, and survival in patients with colon cancer receiving adjuvant chemotherapy. Pak J Med Sci. 2022;38(3):---------.  doi: https://doi.org/10.12669/pjms.38.3.5085

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Model and Pedagogical Conditions for Preparing a Future Teacher for the Implementation of Psychological and Pedagogical Support for Intellectually Gifted Schoolchildren
Authors: Nikitina E. , Bychkova O.
Published: January 2022

In this article, the authors consider the phenomenon of the future teacher's readiness to provide psychological and pedagogical support for intellectually gifted schoolchildren. The authors define the structural characteristics of the future teacher's readiness to provide psychological and pedagogical support for gifted schoolchildren.
Tożsamość i jej biograficzne (re)konstrukcje. Przyczynek do badań nad śląskością
Authors: Piechaczek-Ogierman Gabriela
Published: January 2022

Podjęta w artykule problematyka dotyczy tożsamości rozumianej w sposób procesualny, dialogiczny, zmienny w czasie, czyli tożsamości kształtowanej przez całe życie, zależnej od uwarunkowań kulturowych, ekonomicznych i politycznych. Zaprezentowana trajektoryjna rekonstrukcja tożsamości uczestniczącej w badaniach kobiety stanowi egzemplifikację doświadczeń tożsamościowych tych osób, które ze względu na warunki ekonomiczne osiedliły się w nowym regionie i z upływem lat doświadczyły zakorzenienia w nim. Przyjęty tu jakościowy paradygmat badań może stanowić propozycję metodologiczną dla szeroko pojętych badań nad śląską tożsamością.
Recepcja pojęcia nieświadomości w filozofii Johannesa Volkelta
Authors: Gmerczyński Marek
Published: January 2022

Artykuł przedstawia poglądy neokantysty Johannesa Volkelta na genezę i kształtowanie się pojęcia nieświadomości oraz przybliża czytelnikowi sam, raczej mało popularny w filozofii, termin. Trudności w intuicyjnym ujęciu nieświadomości i jej definicyjnym określeniu oznaczają wieloznaczność i mętność pojęcia jak i jego desygnatu, które okazują się zwielokrotnione wobec podobnych problemów dotyczących świadomości. Tekst, który jest streszczeniem myśli Volkelta, pokazuje ułomność lokowania nieświadomości w dziedzinie idealnej lub realnej i śmiałą próbę wyjścia z impasu zaproponowaną przez Eduarda von Hartmanna. Konkluzją pracy jest teza, że nieświadomość wymaga dalszych badań zarówno na płaszczyźnie historycznej jak i systematycznej.
La Universidad de Sevilla en el siglo XVIII Estudio sobre la primera reforma universitaria moderna
Authors: Aguilar Piñal Francisco
Published: January 2022

Este libro pretende analizar minuciosamente la reforma de la Universidad hispalense en el reinado de Carlos III -primera de una relativa modernidad- como medio eficaz de conocimiento de la política cultural de la Ilustración. Política que se caracteriza por su indecisión, su escasez de medios, su falta de realismo, de coordinación y de libertad. Su fracaso era, pues, inevitable. Los riquísimos fondos del Archivo Histórico Nacional y del Archivo Universitario de Sevilla, principalmente, han permitido realizar este trabajo con un copioso respaldo documental, cuya transcripción, ha sido imprescindible en muchos casos para dar el necesario "tono" de época que nos hace revivir casi gráficamente el pasado.
The Housing Movement in Seville. From "Dignified Housing" to 15M.
Authors: Candón-Mena Jose , Díaz-Parra Ibán , Montero-Sánchez David
Published: January 2022

In recent times, Spain has seen the emergence of a number of social movements advocating for decent housing. This has been in parallel with the deepening and generalization of this problem for an important part of the population. These movements integrate political ideas and forms of collective action that have developed and matured over the last two decades in markedly different situations. This article proposes that, rather than disconnected groups and movements, we can speak of a long sequence of on-going mobilization with various waves of urban protests, which reached their maximum relevance under the economic crisis. This narrative takes the city of Seville as a case study and depicts the main features of this cycle as observed from an investigation based on direct participant observation.