bluuebunny/crossref_metadata_2025 huggingface dataset:
Preliminary data from the phase I study of TCMCB07, a study to assess the safety, tolerability and pharmacokinetics of the melanocortin antagonist TCMCB07 in healthy subjects.
Authors: Qi LeAnn Kuhlmann , Zhu Xinxia , Gruber Kenneth , Roeland Eric J. , Potterfield Russell , Marks Daniel
Published: June 2023

e15195

Background: Cachexia is a complex wasting syndrome characterized by anorexia, an involuntary loss of adipose tissue and lean body mass, and a paradoxical increase in energy catabolism. TCMCB07 is an optimized peptide antagonist of the melanocortin type 3 and 4 receptors for the treatment of cachexia. Several studies have been completed on TCMCB07 including: primary efficacy studies in rodent models of cachexia, studies to assess off-target activities, PK/ADME studies, and a 28-day GLP tox program in rats and dogs. Pre-clinical animal trials show significant results in ameliorating cancer and chronic kidney disease-associated cachexia. Based on these data, a phase 1 dose escalation study was conducted in healthy volunteers. Methods: The Phase 1 study of TCMCB07 (NCT05529849) is a single center, double-blind, randomized, sequential assessment of 5 single ascending dose cohorts (SAD) and 3 multiple ascending dose cohorts of TCMCB07. Subjects received subcutaneous administration of TCMCB07 or placebo on each of 5 consecutive days. Primary endpoints were safety and tolerability. The secondary endpoint was characterization of pharmacokinetics. Results: 40 subjects completed the SAD and 36 subjects completed the MAD portions of the trial. In a preliminary analysis of the results, there were no subjects with abnormal vital signs, no subjects with abnormal electrocardiograms, and no drug-related serious adverse events. The most common study-related adverse event was injection site reaction, graded 1 mild, or 2 moderate out of 5 (NCI CTCAE). Analysis of pharmacokinetics yielded Cmax and AUC higher than what was expected based on rat and dog studies. This resulted in lowering the cohort 3 dose so that the CMax would not exceed the cohort 5 SAD CMax. A weight difference in MAD cohort 2 and 3 between placebo and control was observed with the change in weight from end-of-study to baseline of 1.07 kg (p = 0.0195). In the same groups, on a VAS hunger scale, subjects taking TCMCB07 indicated 15% greater ease in eating meals compared to controls. This measure reached significance at one time point (p = 0.0497) but not at another (p = 0.0892). Conclusions: CB07 was well tolerated by normal healthy volunteers. Though the Phase 1 study was not designed to study efficacy, a modest difference was observed between placebo and active for body weight change and hunger. Results warrant further examination in a randomized Phase 2 study in cancer patients experiencing cachexia. Clinical trial information: NCT05529849 .
Effect of melanocortin-4 receptor antagonist TCMCB07 on chemotherapy-induced anorexia and weight loss in rats.
Authors: Zhu Xinxia , Roeland Eric J. , Norgard Mason A. , Gruber Kenneth , Potterfield Russell , Marks Daniel
Published: June 2023

e15196

Background: We previously reported that peripheral administration of TCMCB07, a synthetic antagonist of the type 4 melanocortin receptor (MC4R), ameliorates cancer- and chronic kidney disease-associated cachexia in rats. In this study, we used a rat model of cisplatin and 5-FU to evaluate the efficacy of TCMCB07 in alleviating chemotherapy-induced anorexia, weight loss and muscle wasting. Methods: Two separate experiments were performed in a total of 58 rats. 1) Cisplatin (Cis)/TCMCB07 experiment with 3 groups: Cis/saline (n = 11), Cis/TCMCB07 (n = 11), Saline/saline (n = 6). 2) 5-FU/TCMCB07 experiment with 3 groups: 5-FU/saline (n = 12), 5-FU/TCMCB07 (n = 12), Saline/saline (n = 6). Rats were treated with Cis (2.5mg/kg), 5-FU (70 mg/kg), or saline via IP injection once weekly for 3 weeks. Rats were also treated with TCMCB07 (3 mg/kg/day) or saline via daily SC injection for 21 days. Food intake and body weight were measured daily. Body composition was analyzed pre- and post-treatment by MRI. Heart and gastrocnemius were dissected and weighed after euthanasia. Results: Total food intake over 21 days was significantly increased in Cis/TCMCB07 vs Cis/saline group (p = 0.0006) and 5-FU/TCMCB07 vs 5-FU/saline group (p = 0.0134), and decreased in Cis/saline vs Saline/saline group (p = 0.001), but was no significant change in Cis/TCMCB07 vs Saline/saline group and 5-FU/saline or 5-FU/TCMCB07 vs Saline/saline group. Body weight was robustly increased in Cis/TCMCB07 vs Cis/saline group (p = 0.0007) and 5-FU/TCMCB07 vs 5-FU/saline group (p = 0.0013), and decreased in Cis/saline vs Saline/saline group (p = 0.0001) and 5-FU/saline vs Saline/saline group (p = 0.0041), but was no significant change in Cis/TCMCB07 vs Saline/saline group and 5-FU/TCMCB07 vs Saline/saline group. Cardiac and skeletal muscle loss was markedly attenuated in Cis/TCMCB07 vs Cis/saline (cardiac: 3.12% vs -11.95%, p < 0.0001; skeletal: -3.88% vs -9.02%, p = 0.0259). Cardiac muscle loss was significantly attenuated in 5-FU/TCMCB07 vs 5-FU/saline group (1.40% vs -6.09%, p = 0.0131) and skeletal muscle was modestly changed (-4.17% vs -7.24%, p = 0.1782). While Cis/saline and 5-FU/saline groups lost 91.33% and 52.61% of fat mass respectively compared to Saline/saline group, Cis/TCMCB07 and 5-FU/TCMCB07 groups gained 37.68% (p = 0.0002) and 70.19% (p < 0.0001). Conclusions: This preclinical trial provides evidence supporting peripheral TCMCB07 antagonism of central melanocortin signaling, increasing food intake and anabolism, ultimately alleviating anorexia, weight loss and muscle wasting over multiple cycles of cisplatin or 5-FU chemotherapy.
Socioeconomic and demographic disparities in rectal cancer treatment.
Authors: Wu Vernon , Kobritz Molly , Kantarovich Diana , Sidiqi Baho , Tchelebi Leila , Whelan Richard L , King Daniel
Published: June 2023

e15512

Background: Early treatment (tx) improves survival in rectal cancer (ca). We explored whether socioeconomic and demographic attributes are associated with time to tx initiation for rectal ca patients (pts) in New York's largest and most diverse healthcare system. Methods: 283 rectal ca pts were identified from three multidisciplinary tumor boards from 2019-2022. Time to tx was calculated as time from biopsy to first tx (surgery, chemotherapy, or radiation). Social work assistance was defined as an intervention by a social worker for home care, housing, or transportation assistance. Reasons for tx delay were assessed from physician and social work notes. Results: Median time to tx for all pts was 41 days. Time to tx was longer for Black/African American (BAA) (56.5 days; p < 0.001) and Medicare only (46.5 days; p = 0.005) pts. No differences were seen in time to tx for all pts when stratified by first tx modality (surgery, chemotherapy, or radiation). In a univariable linear regression, BAA pts (vs Asian or White; p < 0.001), Medicare only pts (vs Medicaid, Medicare with Supplemental, or Commercial Insurance; p = 0.001), and pts requesting social work assistance (p = 0.001) predicted longer time to tx. Employed pts (vs unemployed or retired; p = 0.034) predicted shorter time to tx. In a multivariable model, BAA (p = 0.013), Medicare (p = 0.022), and social work assistance (p = 0.029) predicted longer time to tx. The most common reasons identified for tx delay in BAA and Medicare pts were hospitalization during diagnosis (9%), evaluation of metastatic disease (9%), and tx hesitancy (7%). The odds ratio of being hospitalized during initial workup was 2.8 times higher for BAA than Asian or White pts (p = 0.007). Conclusions: Analysis of time to tx in rectal ca showed a notable delay for BAA pts, Medicare only pts, and pts requesting social work assistance. These findings may empower further studies to assess which factors are causal and to implement interventions that promote equity in timely tx for rectal ca pts. Reasons for tx delay were also not well documented and should be further elucidated. [Table: see text]
Translationally controlled tumor protein as a prognostic marker in metastatic colon cancer.
Authors: Stoyanov Dragomir Svetozarov , Penkova Mariya , Conev Nikolay , Donev Ivan
Published: June 2023

e15513

Background: The translationally controlled tumor protein (TCTP) is a highly conserved protein present in virtually all eukaryotic organisms. TCTP is involved in a variety of normal cell functions and disease processes. Preclinical studies reveal that TCTP has anti-apoptotic properties, promotes cell growth and division, and is involved in cancer progression by promoting invasion and metastasis. Our study explores the potential value of TCTP as a prognostic marker in metastatic colon cancer. Methods: A retrospective analysis of 54 patients with primary metastatic colon cancer was performed. Using immunohistochemistry, TCTP levels in the primary tumor were assessed semiquantitatively via the calculation of cytoplasmic and nuclear H-score. Results: Cytoplasmic TCTP levels in the primary tumor had no statistically significant association with progression-free survival in first-line therapy (PFS1) and overall survival (OS) in our patient population. Patients whose primary tumors had a negative nuclear TCTP expression had significantly better clinical outcomes. The PFS1 for the negative nuclear TCTP expression group was 7.4 months (95% CI, 5.3-9.6) vs 4.5 months (95% CI, 3.4-5.6) in the group with positive nuclear expression (p = 0.023). Patients with a negative nuclear expression of TCTP had a significantly higher median OS (17.1 months; 95% CI, 13.5–20.6) compared to those with positive TCTP nuclear expression (median 11.5 months; 95% CI, 8.5-14.5) (p = 0.031). In Cox regression analyses, a positive nuclear TCTP H-score conferred a higher risk for worse PFS1 (HR 1.960; 95% CI, 1.086-3.537; p = 0.025) and OS (HR 1.882; 95% CI, 1.050-3.371; p = 0.034). The 1-year OS rate in the group with negative nuclear TCTP expression was 80.0% compared to 47.4% in patients with positive nuclear TCTP expression (p = 0.03). Conclusions: The present study suggests that semiquantitative H-score measurement of TCTP levels in the nuclei of tumor cells from the primary tumor is a potential prognostic marker for clinical outcomes in patients with metastatic colon cancer.
Microscopic residual disease (MRD) monitoring and time to disease recurrence across gastrointestinal (GI) malignancies: A single-institution, real-world study.
Authors: Winters Harrison David , Sackstein Paul , Weinberg Benjamin Adam , Debnath Dipanjan , Geng Xue , Wang Hongkun , Chintalacheruvu Saavan , Marshall John , He Aiwu Ruth , Noel Marcus Smith , Mukherji Reetu
Published: June 2023

e15518

Background: Circulating tumor DNA (ctDNA) is a powerful tool that can detect early evidence of cancer relapse, or MRD. While most GI MRD studies to date are in colorectal adenocarcinoma (AC), a limited but growing body of evidence supports its use in other GI cancers. We describe the outcomes of patients (pts) with various GI cancers who underwent real-world MRD testing at our institution. Methods: In this retrospective analysis, we identified GI cancer pts with at least 1 tumor-informed ctDNA test (Natera, Inc) ordered between June 2020-August 2022. Descriptive statistics were used to characterize clinicopathologic factors, clinical contexts of ctDNA testing, rates of ctDNA positivity (ctDNA+), and relapse rates. Median relapse-free survival (mRFS) and overall survival (mOS) were calculated using Kaplan-Meier methods, comparison between groups by log-rank test, and hazard ratios (HR) by Cox proportional hazard models. Results: In total, 228 GI cancer pts underwent ctDNA testing for MRD monitoring. Pts had stage I (20.6%), 2 (32.0%), 3 (38.2%), and 4 (9.2%) disease at diagnosis. Testing started after an initial curative therapy attempt in 82% of pts and after a repeat curative attempt for disease recurrence in 18% of pts. The median follow-up time was 15.0 months (mo). ctDNA testing was successful in 222 pts (97.4%). The cancer subtypes, ctDNA, and clinical outcomes are reported (table). Collectively, 61/222 of pts had at least 1 ctDNA+ test, and 59.0% of these pts had relapse on their next scan performed after a median interval of 40 days (IQR 22-70) from the first positive test. Of the 62/222 pts who relapsed, ctDNA detected relapse before imaging in 43 pts (69.4%) with a median lead time of 57 days (IQR 29-128). The relapse rates were 82.0% vs. 7.5%, mRFS 10.8 mo vs. not reached (NR) (HR 18.6; 95% CI 9.8-35.3), and mOS 43.1 mo vs. NR (HR 5.0; 95% CI 1.8-13.9) in anytime-ctDNA+ pts compared to never-ctDNA+ pts. Similar trends were observed in the colon, rectal, and pancreas AC subgroups. Conclusions: ctDNA was utilized successfully across GI cancers and detected relapse before imaging in most pts. Anytime-ctDNA+ status predicted worse outcomes. About 40% of pts had a ctDNA+ test with no evidence of disease on an immediate subsequent scan, highlighting a prevalent “new stage” of high-risk pts that may benefit from novel treatments. [Table: see text]
Efficacy of PD-1 inhibitors for colorectal cancer and polyps in patients with Lynch syndrome.
Authors: Yu Jiehai , Xiao Binyi , Tang Jinghua , Li Dandan , Wang Fang , Ding Ya , Han Kai , Kong Ling-Heng , Ling Yi-hong , Mei Wei-Jian , Hong Zhigang , Liao Leen , Yang Wanjun , Pan Zhi-Zhong , Zhang Xiao-Shi , Jiang Wu , Ding Pei-Rong
Published: June 2023

e15521

Background: Programmed death-1 (PD-1) inhibitor is effective for colorectal cancer (CRC) with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). We aimed to explore its effects on CRCs and colonic polyps in Lynch syndrome (LS) patients. Methods: LS patients with CRC who had evaluable tumors and received ≥2 cycles of PD-1 inhibitors were included. PD-1 inhibitors were given as a monotherapy or in combination with other therapies including anti cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) treatment, radiotherapy, chemotherapy, and targeted therapy. Correlations of treatment responses with clinicopathological characteristics and genomic profiles were analyzed. Results: A total of 75 LS patients were included, with a median age of 39 years. The median duration of follow-up was 27 months (range, 3 to 71). The objective response rate (ORR) was 70.7%, including 28.0% (n = 21) complete responses (CRs) and 42.7% (n = 32) partial responses (PRs). Three cases of LS CRCs displaying pMMR/MSS or discordant MMR/MSI status were not responsive even with a high tumor mutation burden (TMB). Mucinous/signet-ring cell differentiation was associated with a lower ORR ( P= 0.013). The 3-year OS and PFS was 91.2% and 81.0%, respectively. Colorectal polyp/adenoma was detected in 26 patients during surveillance. Seven adenomas disappeared after treatment and their maximum diameters were all larger than 7mm. Conclusions: PD-1 inhibitors are highly effective for dMMR/MSI-H LS CRCs, but not for pMMR/MSS LS CRCs or those displaying discordant MMR/MSI status or mucinous/signet-ring cell CRC. Some of the large LS adenomas may also be sensitive to anti-PD-1 treatment.
Colorectal cancer screening and treatment before and during the COVID-19 pandemic at a Southeast Texas community hospital.
Authors: Abdelhakeem Ahmed , Siddiqi Muhammad , Thaimuriyil Nigil , Peters Chelsey , Blevins Samantha , Naqvi Tahir A.
Published: June 2023

e15522

Background: The COVID-19 pandemic imposed significant restraints on healthcare systems, raising concerns regarding care delays and excess cancer-related deaths. We aimed to investigate the impact of COVID-19 on colorectal cancer (CRC) screening and the time to treatment initiation (TTI) for cases with a confirmed diagnosis of CRC. Methods: We conducted a retrospective study in which we included all patients who underwent screening colonoscopy between April 2019 and March 2021 at our hospital. Patients with a diagnosis of CRC have been confirmed with the data from our cancer center to check if they could continue cancer staging workup and start their treatment. Patients were stratified into pre-COVID-19 (April 2019-March 2020) and COVID-19 (April 2020-March 2021) groups. Descriptive statistics and multivariate regression analysis were applied using SAS software, version 9.4. Results: A total of 1439 patients underwent screening colonoscopies during the study period. 746 during pre-COVID-19 group, and 693 during COVID-19 group (p = 0.1624). In the pre-COVID-19 group, 47 patients were found to have CRC, and 25 patients (53%) continued cancer staging workup and started treatment in our cancer center. Among 36 patients with confirmed CRC diagnosis in the COVID-19 group, only five patients (14%) continued cancer staging workup and started treatment (p = 0.0003). All patients with confirmed CRC in the COVID -19 group had localized disease compared to 25 patients (96%) in the pre-COVID-19 group. TTI in the COVID-19 group (mean of 21 days ± 13.3) was shorter compared to the pre-COVID-19 group (mean of 33 days ± 46.7) (p = 0.025). Comparative analysis between the study groups didn’t show any statistically significant difference based on age, sex, race, or insurance status. Conclusions: In our hospital, the COVID-19 pandemic didn’t appear to affect the accessibility to CRC screening or delay in TTI. However, a limited number of patients with confirmed CRC during the COVID-19 pandemic were able to continue cancer staging workup and receive treatment.
Preliminary study of microRNA expression profiling in non-metastatic colorectal cancer.
Authors: Kluz Natalia , Petniak Alicja , Ciechański Aleksander , Kocki Janusz , Gil Kulik Paulina
Published: June 2023

e15528

Background: MicroRNAs (miRNAs) are non-coding single-stranded RNAs (18–25 nucleotides in length) that regulate gene expression at the posttranscriptional level by promoting the degradation of mRNAs or by blocking mRNA translation. However, the clinical significance in colon cancer is not yet determined. This study aims to identify differentially expressed miRNAs in colorectal cancer by comparing colon cancerous tissues with normal tissues, exploring the potential roles. Methods: The miRNA expression microarray was employed on tumors from patients diagnosed with adenocarcinoma of the colon. The pilot study included samples from 6 patients (3 women and 3 men), aged 55 to 72 years (mean 62.5±8.4 years). The tumour was located in the rectum, TNM status was as follows: cT (all patients at stage T3), cN (3 patients – N1, 3 patients – Nx), cM (all patients at stage M0). Average tumor size 4.6±2.5 cm. Normal colon tissue was used as a control. The studies were performed with the consent of the patient and according to the protocol accepted by the Bioethics Committee at the Medical University of Lublin No. KE-0254/12/2018. The material was collected during tumor removal surgery, then transported and stored in RNAlater. In the next step, microRNAs were isolated using the RNeasy Micro Kit (Qiagen). The quality and quantity of isolated RNA was assessed with NanoDrop 2000c followed by Bioanalyzer 2100 (Agilent), for the next step samples with RIN above 7. The microRNA expression profile was then evaluated using the GeneChip™ miRNA 4.0 Array (Applied Biosystems). Results: On the basis of a pilot microarray study, the profile of differentially expressed miRNAs was successfully screened. 1.39% of 36 222 tested genes showed a significant at least twofold increase in expression, while 1.75% showed a significant at least twofold decrease in expression. Three novel, not yet described in literature, miRNAs i.e. miR-3154 (p-value 0.015), miR-3921 (p-value 0.036), and miR-5006 (p-value 0.007) appeared to be involved in colorectal carcinogenesis. Conclusions: The present study suggests that mentioned miRNAs after confirmation on a greater group of patients may be used as diagnostic markers for the detection of early stage colon cancer in the general population. This paper was created as part of the project “The Best of the Best! 4. 0.” implemented under the Operational Programme: Knowledge Education Development 2014-2020 and co-financed by the European Social Fund.
Use of circulating tumor DNA analysis to predict recurrence and need for adjuvant chemotherapy in stage I-IV colorectal cancer.
Authors: Li Li-Ren , Fan Wenhua , Xia Zhiyuan , Chen Rongrong , Lin Dagui , Li Fang , Zheng Yang , Luo Jiongyong , Xiong Yuanyuan , Yu Pengli , Gao Wei , Gong Yuhua , Zhang Sen , Zhang Feiran
Published: June 2023

e15537

Background: Circulating tumor DNA (ctDNA) has emerged as a biomarker that can define the risk of recurrence after curative-intent surgery for patients with colorectal cancer (CRC). However, beyond the predictive power of postoperative ctDNA detection, the efficacy and potential limitations of ctDNA detection urgently need to be fully elucidated in a large cohort of CRC. Methods: We enrolled 309 patients with stages Ⅰ to Ⅳ CRC who underwent definitive surgery. Tumor tissues from those patients were sequenced by a custom-designed next-generation sequencing (NGS) panel to identify somatic mutations, and plasma was analyzed using ctDNA-based molecular residual disease (MRD) assay which integrated tumor genotype–informed and tumor genotype–naïve ctDNA analysis. Results: ctDNA was detected after surgery in 5.4%, 13.8%, 15% and 30% of patients with stage Ⅰ, Ⅱ, Ⅲ and Ⅳ disease, respectively, and in 17.5% of all longitudinal samples. Detection of MRD after surgery and in serial plasma samples during follow-up were associated with shorter disease-free survival (DFS) (hazard ratio [HR], 13.17; P < 0.0001 and HR, 14.44; P < 0.0001, respectively) independent of tumor site, stage, and MSI status. Within the population, only 13 patients (6.6%) with longitudinal undetectable MRD recurred, resulting in a negative predictive value of 93.4%. Correspondingly, the positive predictive value of longitudinal detectable MRD was 79.6%, with a median lead time of 10.1 months. Further subgroup analyses revealed that adjuvant therapy did not confer a superior survival for patients with undetectable or detectable MRD. Moreover, lung-only and peritoneal metastases were less detectable by MRD. Conclusions: Postoperative ctDNA status is a strong predictor of recurrence independent of stage and MSI status. Longitudinal undetectable MRD could be used to define the potentially cured population in CRC patients undergoing curative-intent surgery.
Assessment of genomic profiling in patients with colorectal cancer treated in community oncology practices.
Authors: Cosgrove David , Paul Emily , Harrell Robyn , Espirito Janet L. , Robert Nicholas J. , Oliver Robert J.
Published: June 2023

e15538

Background: Comprehensive genomic profiling is becoming the standard of care for oncology, though actionable biomarkers remain the focus. The value of expansion from single gene tests to large, next-generation sequencing (NGS) based tests can be seen in the application of precision medicine. Additionally, circulating tumor DNA (ctDNA) is becoming a key area of testing during and post treatment. In this study, we explored genetic testing rates in colorectal cancer (CRC) patients (pts). Methods: Pts were identified from the iKnowMedSM EMR data over 4 years (2018-2022) from 113 community oncology practices. Pts were required to have either primary colon or rectal cancer, be at least 20 yrs old at diagnosis, and have at least 2 office visits. All stages of disease were included. Genomic data was assessed from two sources: abstracted data from charts and genomics reports from clinical labs. Genomic tests included detection of mutations for relevant biomarkers, including but not limited to BRAF, KRAS, NRAS, NTRK, microsatellite instability (MSI), and tumor mutational burden (TMB), and entry of germline biomarkers relevant to Lynch syndrome. The use of ctDNA was also evaluated. Results: A cohort of 41,980 pts with CRC was identified. Median age was 66 yrs, 62% white. Of these, 18,782 pts (45%) had biomarker testing performed. Genomic testing rates were observed to have increased by 61% across all stages of disease over the four-year time span. The highest rate of biomarker testing was performed in pts with stage IV disease at diagnosis, representing 21% (n = 9021). Testing results were most often available for BRAF (n = 17576), with nearly 16% of the cohort showing a mutation, 35% of those with the V600E mutation (n = 967). MSI was observed in 14%. Increasing use of ctDNA observed, and 350 pts had multiple genetic reports (3+). Of the pts with genetic information, 245 were enrolled in clinical trials. Conclusions: In this study, we observed the increase of genetic profiling of CRC pts over time. Additional research into the use of targeted therapies and outcomes will be performed. The exploratory regions of the NGS-based assays tested may also provide new potential targets as the database of combined clinical and genetic information grows.
Circulating tumor DNA (ctDNA) dynamics in response to checkpoint inhibitor immunotherapy in colorectal cancer.
Authors: Patell Kanchi , Kurian Matthew , Booker Benjamin , Chung Michelle , Bennett Alexis , Bajor David L , Mohamed AMR , Mahipal Amit , Chakrabarti Sakti , Selfridge J. Eva
Published: June 2023

e15540

Background: Circulating tumor DNA (ctDNA) is emerging as a sensitive and specific non-invasive marker of active disease in patients (pts) with colorectal cancer (CRC) and may be used for monitoring response to immunotherapy (IO) in all solid tumors. However, the dynamics of ctDNA changes in response to IO and their correlation to radiographic response has not been well-established. Methods: We searched for all pts in our institution who received IO for a solid tumor diagnosis and who also received quantitative ctDNA testing using Signatera. We retrospectively evaluated radiographic treatment response using RECIST v1.1 and correlated radiographic response to time-matched changes in quantitative ctDNA. Objective response rate (ORR) was defined as the percentage of pts achieving radiographic partial response (PR) plus complete response (CR). Results: We identified 6 pts with advanced CRC who underwent serial ctDNA testing while receiving IO; all patients had loss of mismatch repair protein expressions. Median age was 70 years (range 35-90), and 50% of patients were female. All pts were actively receiving IO at the time of data cutoff. Two pts were receiving ipilimumab plus nivolumab, the other 4 pts were receiving pembrolizumab; 1 pt had only received 1 cycle of IO at time of cutoff, thus did not have on-treatment imaging and was excluded from further analysis. For the response evaluable patients, ORR was 100%, with all pts (5/5) achieving PR after median of 3 cycles (range 1-3 cycles) of treatment. Quantitative ctDNA decreased by 83-100% in all pts analyzed. 1 pt had radiographic (pseudo-)progression at time of first radiographic assessment, however at this timepoint, ctDNA had decreased by 60%; this pt continued on immunotherapy based on clinical benefit including ctDNA data. Subsequent radiographic assessment of this pt confirmed partial response and ctDNA response decreased by total of 95% after a total of 3 cycles of IO. Conclusions: In this small patient population, we show that quantitative ctDNA directly corresponds to radiographic response to IO, and may guide treatment decisions by differentiating pseudoprogression from true progression. Further longitudinal studies will show if ctDNA changes correlate to duration of response, early identification of treatment resistance, and ultimately survival.
Analysis of patients at the Memphis VA Medical Center with positive FIT testing and incomplete GI evaluation during the COVID-19 pandemic.
Authors: Mitchell Mark , Huynh Richard , Lands Lindsey , Weir Alva B
Published: June 2023

e15542

Background: In 2020, colorectal cancer was the second leading cause of cancer death in the United States 1. In March 2020, the COVID pandemic began which led to widespread disparities in health care, such as surveillance colonoscopies 2. A Veterans Health Administration large data review revealed completion rates of colonoscopy for high risk individuals, including positive fecal immunochemical test (FIT) to be unchanged pre-pandemic and during the pandemic at 27% vs 26.5% 3. Another study reports a non-VA population completion rate within 360 days pre-COVID compared to COVID was 53.9% vs 44% 4. This research sought to analyze data through a retrospective chart review from the Memphis VA Medical Center, the timing of screening colonoscopies after a positive FIT and reasons for delay in obtaining these. Thereby, evaluating effectiveness in completing the procedures and change effected by the COVID pandemic. Methods: A retrospective cohort study designed to detect rates of completed colonoscopy during and before the COVID pandemic after a positive FIT. Records were reviewed of all positive FIT from 2 specified time frames at the Memphis VA to evaluate completion of colonoscopy after a positive FIT. The charts of 157 VA patients with positive FIT during the pandemic were compared to the charts of 115 VA patients with positive FIT pre-pandemic for colonoscopy completion, evaluating both completion rates within 180 days and chart identified reasons for lack of completion. Both community (CITC) and VA procedures for veterans were included. One tailed Fisher’s exact test was applied to calculate the completion rate difference. Results: Overall completion rate of colonoscopy was 46% in the pre-COVID and rose to 56% in the COVID period [p-value < .05 (.0665)]. Percentage of timely completion ( < 180 days) was 26% pre-COVID, compared to 47% during COVID. Percentage of delay ( > 180 days) in pre-Covid was 74%, compared to 53% during COVID. [p-value < .05 (.0004)]. Reasons for delay both pre-COVID and during COVID are listed below. Conclusions: It can be concluded that there is a statistically significant increase in timely colonoscopy completion during the studied COVID period when compared to the pre-COVID period. The total completion rate was higher at our institution than in the literature, likely due to our inclusion of community colonoscopies and our aggressive case management system. A common reason for delay in all groups was delay/lack of referral. This cause for delay should be improved with additional steps in our case management policy. [Table: see text]
Genomic analysis of RAS and BRAF mutation in an oncology reference hospital in Brazil.
Authors: Amorim Guilherme , Medeiros Maria Clara Rodrigues Lima , Ferreira Mariana , Medeiros Ana Maria Rodrigues Lima , Bighetti Bruna , Forones Nora Manoukian , Tadokoro Hakaru
Published: June 2023

e15545

Background: Colorectal cancer (CRC) is a common malignancy worldwide and a leading cause of cancer-related deaths. The molecular basis of CRC can guide patient prognosis and therapy. Unfortunately, knowledge on the CRC mutation landscape is limited. In this study, we investigated the mutation profile of related genes by next-generation sequencing and associated with microsatellite instability (MSI) in a series of 43 Brazilian CRC patients from 2016 to 2022, of a Public Oncology Hospital. This study aimed to analyze the frequency of mutation covariates of the KRAS and BRAF genes and their correlation with survival data in patients diagnosed with metastatic RCC. Methods: We conducted a retrospective, observational and descriptive study in 43 patients diagnosed with CRC treated at an Oncology Reference Hospital in Brazil. DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tumor tissues. Targeted sequencing was performed using a customized panel for CRC-related genes. The mutation data was analyzed in relation to clinicopathological features, MSI status and survival, using the Kaplan-Meier method and log-rank test. Results: RAS mutations were found in 37.2% of patients and BRAF mutations in 9.3%. The analysis of most secondary clinicopathological features did not show statistical prognostic impact. In general analysis, the age and presence of BRAF mutation were related to the increased risk of death HR-0.31 (0.11-0.82). However, among patients with BRAF mutations exclusively, the age did not represent an increased risk of death. Concerning our RAS mutations, as we already knew from previous literature data, the variety is diverse. We noticed nine different RAS alterations, in which the most prevalent was the G12D (33%), followed by G13D, Q61K and G12A. The distribution of our RAS alteration and prevalence is summarized in the table below: Conclusions: Our findings are consistent with previous studies concerning frequency and patterns of RAS and BRAF mutations in CRC. The identification of MSI and the evaluation of genetic ancestry may help to guide treatment decisions in CRC patients. At present, it is already known that some of RAS mutations are targets for selective RAS drugs and may have better outcomes the pan-RAS drugs. Our study provides important insights into the mutation profile of related genes in Brazilian CRC patients and these findings have implications in clinical management of CRC. Further studies with larger cohorts are needed to validate our findings. [Table: see text]
ScRNA-seq to examine heterogeneity of transcriptional regulation of CAFs between left-sided and right-sided CRC.
Authors: Fan Tongqiang , Wang Qian , Wang Tao , Xiao Shanshan
Published: June 2023

e15548

Background: Cancer-associated fibroblasts (CAFs) play prominent and diverse tumor-promoting function roles in tumor microenvironment (TME) and influence cancer hallmarks, but without systematic investigation between left-sided and right-sided CRC (colorectal cancer). Methods: We collected a public scRNA-seq dataset (Pelka et al., 2021) with 21 samples from left-sided CRC and 79 from right-sided CRC. Only CAFs were extracted for downstream analysis. Seurat (Stuart et al., 2019), Monocle2 (den Berge et al., 2020) and pySCENIC (Aibar et al., 2017) were used to perform dimensionality reductions, differential analysis, pseudo-time trajectory analysis, and the transcriptional regulation analysis, respectively. Results: Firstly, we performed differential analysis on 2,049 cells from 62 of 100 samples that contained CAFs. The results showed that highly expressed genes including IGFBP1, IGFBP2, LCN2, ALDH1A1 and CASP1 in left-sided CRC were mainly enriched in immune response pathway, while up-regulated genes in right-sided CRC were neutrophil-migration-chemotaxis-related such as PPBP1, PF4V1, CCL7, CXCL3 and CXCL8. Then, we classified 2,049 CAFs into four subclusters based on the markers of CCL8+ CAF, CXCL14+ CAF, GREM1+ CAF and MMP3+ CAF. The proportion of CXCL14+ CAF was higher in left-sided CRC while MMP3+ CAF was preferentially enriched in right-sided CRC, which was also independently validated by 33 TCGA cohorts. Further investigation on those subclusters showed that CXCL14+ CAF was myCAF, while the rest (CCL8+ CAF, MMP3+ CAF and GREM1+ CAF) were iCAF. After investigating the heterogeneity of CAFs, we focused on the transcriptional regulatory networks (TRNs). The results showed that the dominant regulons in left-sided CRC ( HOXD9, HSF2, MYBL1, HES6, XRCC4, and ZNF585B) and right-sided CRC ( CREB5, ZNF274, IRF7, TFEC, NR2F1, and PITX3) were distinct, which highlighted the heterogeneity and plasticity of CAF-based TRNs between left-sided and right-sided CRC. Conclusions: Collectively, although further experimental verification is required to establish the functional roles of each CAF cluster and the diverse origins of CAFs, this study may facilitate better understanding molecular mechanism of CAF-targeted therapy strategies in CRC.
Trends of colorectal cancer and associated factors in the United States: A SEER registry analysis.
Authors: Fatima Ifrah , Ponvilawan Ben , Grover Dheera , Kahn Adriana Matutino , Shrestha Anuj , Dharan Murali
Published: June 2023

e15553

Background: Colorectal cancer (CRC) is the fourth most common type of cancer diagnosed in the US, accounting for 8% of new cancers diagnosis in 2022. Despite advancements in the screening and diagnostic methods, CRC still contributes significantly to cancer-related healthcare burden ($24.3 billion/year). Several factors including wider demographic reach, socioeconomic equity, age at screening, CRC awareness, and social media platforms have contributed to this changing landscape. We conducted a Surveillance, Epidemiology, and End Results Program (SEER) based analysis to determine the trends of CRC diagnosis and potential risk factors. Methods: Individual data was acquired from SEER 9 registry from 1975-2018. R was used for the statistical analyses. Univariate logistic regression was performed to evaluate the relation between year of diagnosis and each variable (year of diagnosis, household income, household location, sex, and race) at the time of diagnosis. Multivariate regression was performed for individuals in all age group and less than 45 years of age. P-value less than 0.05 was considered significant. Results: In total 550,221 CRC patients were retrieved. 91.7% (504,709) were ≥50 years and 4.5% (24,674) were < 45. Over the years, there was a notable increase in percentage of patients with age < 45 years amongst all CRC patients (3.3% in 1975-1979 vs. 7.4% in 2015-2018) with females increasing faster than males. A remarkable drop in percentage of CRC case in individuals ≥50 years amongst all gastrointestinal cancers (63.0% in 1975-1979 vs. 44.8% in 2015-2018) with females decreasing faster than males. There were no interactions between the year of diagnosis and above variables. Multivariate logistic regression exhibited lower odds of CRC diagnosis in all non-white races and males, but higher odds in lower household income and non-metropolitan areas (Table 1). Subgroup analysis of age group < 45 years pertained similar odds. Conclusions: The striking drop in number of CRC cases above 50 years of age can be attributed to earlier detection with screening methods, and other socioeconomic factors like healthcare literacy and awareness. Increased representation of younger population over the years reaffirms the recent change in guidelines for screening. Further studies focusing on determining the impact in outcomes of screening methods in younger population and equality of implementation in disadvantaged population are highly warranted. [Table: see text]
Efficacy of vemurafenib based regimens in colorectal cancer: A systematic review of clinical trials.
Authors: Aiman Wajeeha , Qirem Murad , Alkhlaifat Osama , Garcia Jose , Asfeen Ummul , Jumean Samer , Rayad Mohammad Nabil , Veeraballi Sindhusha , DaCosta Theodore , Guron Gunwant K. , Shaaban Hamid Salim
Published: June 2023

e15566

Background: Colorectal cancer (CRC) is the 3rd most common cancer worldwide, and BRAF gene mutation is present in almost 10% of these cancers. It results in constitutive activation of the mitogen-activated protein kinase pathway (MAPKP). Abnormal activation of MAPKP leads to uncontrolled mitotic activity and inhibition of apoptosis. In this systematic review, we will assess the efficacy of vemurafenib (BRAF inhibitor) based regimens in CRC. Methods: We followed PRISMA guidelines to conduct this systematic review. A literature search was performed on PubMed, Clinicaltirals.gov, and Embase with mesh terms, ‘’Colorectal Neoplasms’’ and “Proto-Oncogene Proteins B-raf” from the inception of data till 01/05/2023. We screened 4572 articles and included 1 randomized clinical trial (RCT, N = 100), and 4 non-randomized trials (nRCTs, N = 85), measuring the efficacy of vemurafenib (V) based regimens in BRAF V600E-mutated CRC. Results: In 5 clinical trials (N = 185), 90 patients were treated with triple therapy, 45 with dual therapy, and 50 were in the control arm. In triple therapy, 69 patients were treated with V plus irinotecan (I) and cetuximab (C), overall response rate (ORR) was 17% and 35%, and progression-free survival (PFS) was 4.2 and 7.7 months in the randomized and the non-randomized study, respectively. PFS was improved significantly with a hazard ratio (HR) of 0.50 (95% CI, 0.32 to 0.76, P = .001) in favor of V+I+C compared to C+I. Among combinations of V+C, adding 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) as third combination showed the highest ORR of 81% and overall survival (OS) and PFS of 15.4 and 9.7 months, respectively. In two drug regimens, V was combined with Cobimetinib (Co) and Panitumumab (P) in two non-randomized studies, and partial response (PR) was 26% and 13%, respectively. (Table 1). Conclusions: BRAF + EGFR inhibitor combination is showing promising antitumor effects, and the addition of the FOLFIRI regimen was more effective than adding irinotecan alone while comparing treatment regimens in BRAF V600E-mutated CRC patients with metastasis. V+Co showed antitumor effects in CRC BRAF mutated patients who were heavily pre-treated. More randomized trials needed. [Table: see text]
Efficacy and safety of regorafenib plus biweekly TAS-102 for refractory metastatic colorectal cancer (REGTAS): A multicenter single-arm phase II trial.
Authors: Wang Xiangling , Li Zhen , Sha Dan , Ren Haipeng , Yi Cuihua , Li Shuguang , Wang Peng , Chu Yunxia , Wang Jian , Yang Xiaorong , Hao Jing
Published: June 2023

e15567

Background: Both regorafenib and TAS-102 have shown significant, but limited survival benefits for metastatic colorectal cancer (mCRC) patients who progressed after standard treatments. Due to their unique mechanisms of action and non-overlapping toxicities, a preliminary phase I study (REMETY) has demonstrated that regorafenib combined with TAS-102 in a four-week standard schedule was feasible and safe, but at the cost of recommended phase II dose of TAS-102 being 25 mg/m2 BD. This study aimed to evaluate the efficacy and safety of biweekly TAS-102 plus regorafenib in refractory mCRC. Methods: REGTAS is a multicenter phase II trial involving patients with chemo-refractory mCRC. Prior treatment with 5-FU, oxaliplatin, irinotecan, anti-VEGF antibody and anti-EGFR antibody for RAS wild type was required. Regorafenib was administered at 120 mg/day for 21 days in a four-week cycle, or a dose-escalation strategy (80 mg/day, followed by weekly increase of 40 mg to 120 mg/day). TAS-102 was given biweekly (30mg/m2 BD, on Day 1-5). The primary endpoint was progression-free survival (PFS). The secondary endpoint included safety, disease control rate (DCR) and overall survival (OS). Results: From March 1st 2022 to December 31st 2022, 16 patients were enrolled form five centers. All patients received at least one cycle of treatment, and 13 patients had at least one evaluation. The median age was 56.5 years old including 9 (52.9%) males. 11 (68.7%) patients were enrolled within 18 months from diagnosis of mCRC. RAS and BRAF mutation were detected in 8 (50.0%) and 1 (6.3%) patients. Among 13 evaluable patients, 11 achieved SD and 2 had PD, with the DCR of 84.6% (95% CI: 54.6%-98.1%). The median PFS was 4.9 months (95% CI: 2.8-7.0). Twelve patients were alive, and the median OS was not reached. All patients experienced treatment-related adverse events (TRAEs) and 4 (25.0%) had grade 3 or higher TRAEs. No grade 5 TRAE occurred. The most common TRAEs of any grade were hand-foot syndrome (62.5%), hypertension (68.8%), fatigue (50.0%), neutropenia (43.8%), thrombocytopenia (31.3%) and alanine aminotransferase increased (25.0%). Conclusions: Regorafenib plus biweekly TAS-102 exhibited promising benefits in terms of DCR and PFS, and could be a novel treatment option for patients with refractory mCRC. The adverse events were generally tolerable and manageable. Further studies are needed to confirm these preliminary findings. Clinical trial information: The registration number is still under approval .
Total neoadjuvant therapy for locally advanced rectal cancer: A western Australian experience.
Authors: Oey Oliver , Khattak Adnan , Ferguson Tom , Theophilus Mary , Tiong Siaw Sze , Ali Sayed , Khan Yasir
Published: June 2023

e15582

Background: Despite the widespread application of standard chemoradiotherapy (CRT) followed by total mesorectal excision with adjuvant chemotherapy, the mortality reduction for locally advanced rectal cancer (LARC) has slowed in recent years. Total neoadjuvant therapy (TNT) is a novel therapeutic strategy in LARC which incorporates both systemic chemotherapy and neoadjuvant CRT prior to surgery. Recent studies have associated TNT with better treatment adherence, decreased toxicity, improved complete clinical response and anal sphincter preservation rates. However, real-world experience with TNT in the management of LARC remains limited. Methods: Records from patents with LARC who underwent TNT at two oncology centres in Western Australia since 2018 were screened. Patient demographics, diagnostic workup, treatment regimens, surgical, pathological reports, post-operative surveillance scans and adverse effects’ documentation were reviewed. TNT regimens included neoadjuvant chemotherapy (NAC) with oxaliplatin in combination with either 5-FU (FOLFOX) or capecitabine (CAPOX) with chemoradiation given prior or after NAC, which is then followed by surgery. Patients who had radiological complete response (rCR) were given the option of “watch and wait (W&W)” instead of proceeding to surgery. Outcomes assessed included radiological complete response (rCR), pathological complete response (pCR) rate, proportion of patients with progressive disease, type of surgery, rate of R0 resection, proportion of patients who completed planned cycles of chemotherapy and radiotherapy and treatment-related adverse effects. Results: 29 patients with LARC have thus far have completed TNT followed by surgery. The mean age was 59 years (range 34-84), 58% and 42% of patients were male and female respectively. 11 (38%), 16 (55%) and 2 (7%) patients were ECOG 0, 1 and 2 respectively. The majority of patients were stage 3 (90%), with the remaining 3 patients at stage 1, 2 and 4 at time of presentation. 3 (10%) and 7 (24%) patients had pCR and rCR respectively, of which 4 opted for W&W approach. Treatment was well-tolerated with 86% and 96% of patients completing the planned total course of chemotherapy and radiotherapy respectively although dose reductions and/or delay were required for many. Common adverse effects included neuropathy, neutropenia, anaemia and fatigue, most of which were grade 1. Of the 22 patients who underwent surgery, 19 (82%) and 4 (18%) patients had R0 resection and R1 resection respectively. Majority of the patients who underwent surgery had an anterior resection with temporary loop ileostomy (64%) while the remaining had an abdominoperineal resection (36%). After a median follow up time of 27 months, 10 (34%) patients had progressive disease. Conclusions: TNT is a well-tolerated, effective and promising strategy for the management of LARC. Further data is needed to determine the standard TNT protocol.