Investigating the WNT and TGF-beta pathways alterations and tumor mutant burden in young-onset colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer in the United States. Recent epidemiological evidence demonstrates an increasing incidence of young-onset CRC cases, defined as CRC cases in individuals 50 years old or younger. Studies have established that alterations in both the WNT and TGF-Beta signaling pathways have contributed to CRC development. While this is well understood, the comprehensive analysis of WNT and TGF-Beta pathway alterations in young-onset CRC cases has yet to be investigated. Here, we conducted a comprehensive bioinformatics analysis of mutations associated with each of the WNT and TGF-Beta signaling pathways according to age (≤ 50 years old versus > 50 years old) utilizing published genomic data from the cBioPortal. Chi-square results demonstrated no significant difference in WNT alterations between young-onset CRC and those > 50 years old. However, across all age groups, WNT alterations were frequently found in rectal cancers. We also found that WNT alterations were associated with better outcomes. The mutations associated with TGF-beta were observed at a higher rate in older CRC patients when compared to those ≤ 50 years old. Additionally, these mutations were found more frequently in colon primaries.

Expert opinion on screening, diagnosis and management of diabetic peripheral neuropathy: a multidisciplinary approach.

The proposed expert opinion aimed to address the current knowledge on conceptual, clinical, and therapeutic aspects of diabetic peripheral neuropathy (DPN) and to provide a guidance document to assist clinicians for the best practice in DPN care. The participating experts consider the suspicion of the disease by clinicians as a key factor in early recognition and diagnosis, emphasizing an improved awareness of the disease by the first-admission or referring physicians. The proposed "screening and diagnostic" algorithm involves the consideration of DPN in a patient with prediabetes or diabetes who presents with neuropathic symptoms and/or signs of neuropathy in the presence of DPN risk factors, with careful consideration of laboratory testing to rule out other causes of distal symmetric peripheral neuropathy and referral for a detailed neurological work-up for a confirmative test of either small or large nerve fiber dysfunction in atypical cases. Although, the first-line interventions for DPN are currently represented by optimized glycemic control (mainly for type 1 diabetes) and multifactorial intervention (mainly for type 2 diabetes), there is a need for individualized pathogenesis-directed treatment approaches for DPN. Alpha-lipoic acid (ALA) seems to be an important first-line pathogenesis-directed agent, given that it is a direct and indirect antioxidant that works with a strategy targeted directly against reactive oxygen species and indirectly in favor of endogenous antioxidant capacity for improving DPN conditions. There is still a gap in existing research in the field, necessitating well-designed, robust, multicenter clinical trials with sensitive endpoints and standardized protocols to facilitate the diagnosis of DPN via a simple and effective algorithm and to track progression of disease and treatment response. Identification of biomarkers/predictors that would allow an individualized approach from a potentially disease-modifying perspective may provide opportunities for novel treatments that would be efficacious in early stages of DPN, and may modify the natural course of the disease. This expert opinion document is expected to increase awareness among physicians about conceptual, clinical, and therapeutic aspects of DPN and to assist them in timely recognition of DPN and translating this information into their clinical practice for best practice in the management of patients with DPN.

The Role of Circulating Tumor DNA for Management of Patients With Rectal Cancer: Challenges and Opportunities.

ABSTRACT: Recently, organ preservation with total neoadjuvant therapy resulted in substantial progress in the management of locally advanced rectal cancer (LARC). The PROSPECT trial showed noninferiority of de-escalation of radiotherapy for patients with low-risk LARC who do not need abdominoperineal resection. Although these escalation and de-escalation approaches offer more personalized therapeutic approaches, the current state of care for patients with rectal cancer is far from individualized management. Circulating tumor DNA (ctDNA) is known to be one of the most powerful prognostic factors for early relapse and has been investigated in several interventional clinical trials to offer more precise treatment algorithms. In this review article, we discuss recent updates from studies examining the role of ctDNA for the prediction of treatment response and recurrence for patients with rectal cancer. We also elaborate on the future potential use of ctDNA in treatment escalation and de-escalation approaches for more personalized therapeutic interventions.

Which Treatment for Which Patient: Rectal Cancer Management After PROSPECT Trial.

Determining treatment options for patients with locally advanced rectal cancer after the PROSPECT trial data readout adds an important level to the decision-making process.

Targeting KRAS Oncogene for Patients With Colorectal Cancer: A New Step Toward Precision Medicine.

KRAS mutations are common driver oncogenes associated with the development of several solid tumors. KRAS oncogene has been considered a highly challenging target for drug development because of structural features, including the lack of deep groove on its catalytic unit. However, by leveraging cysteine residues, covalent KRAS inhibitors irreversibly trap KRAS G12C mutants in their inactive GDP-bound state. These agents have resulted in significant clinical responses among patients with KRAS G12C-mutant solid tumors, including patients with colorectal cancer (CRC). Other allele-specific inhibitors of KRAS oncogene and panKRAS and panRAS inhibitors are also currently being investigated in clinical trials. This review article overviews recent clinical progress on KRAS G12C targeting for the management of patients with KRAS G12C-mutant CRC and provides an update on other RAS targeting approaches. We also discuss the unique biological features of RAS-mutant CRC, which require the combination of KRAS inhibitors and anti-epidermal growth factor receptor therapy, and elaborate on resistance mechanisms and novel therapeutic avenues that may define future treatment paradigms of patients with RAS-mutant CRC.

The Efficacy of Immune Checkpoint Inhibitors in Microsatellite Stable Colorectal Cancer: A Systematic Review.

The use of immune checkpoint inhibitors (ICIs) has revolutionized cancer care, particularly in immune-inflamed tumors and tumors with a high mutational burden, like microsatellite instable colorectal cancer (CRC). However, their effectiveness in microsatellite stable (MSS) CRC is limited. This systematic review aims to evaluate the efficacy of ICIs in MSS CRC and explore promising combination strategies. A comprehensive search from the Web of Science, Medline, and Embase databases, for studies published until 14 November 2022, identified 53 clinical trials included in the review. ICI monotherapy or ICI-ICI combinations demonstrated limited clinical activity for patients with MSS CRC, with overall response rates below (ORR) 10% in most studies. The ICI and tyrosine kinase inhibitor (TKI) garnered ORRs ranging from 10% to 40% and indicated a higher benefit for patients, particularly those without active liver metastases. The combination of ICIs with anti-VEGF agents showed modest ORRs, especially in the earlier treatment lines and in combination with chemotherapy. While these combinations could lead to modest improvements, well-defined biomarkers for long-term benefit are yet to be delineated. Combinations involving BRAF inhibitors with ICIs were studied, showing promising responses with combination approaches in molecularly defined subgroups. In conclusion, while ICI monotherapy has limited efficacy in MSS CRC, combination strategies hold promise to enhance survival outcomes. Further research is necessary to identify optimal combination approaches, predictive biomarkers for treatment response, as well as enrollment according to tumor molecular characteristics.

Who Should Receive Immunotherapy for Advanced Gastroesophageal Cancer?

OPINION STATEMENT: This paper shines a light on the exciting progress being made in using immunotherapy to treat advanced gastroesophageal cancers. The positive results from trials using drugs like Pembrolizumab and Nivolumab are certainly encouraging and open new possibilities for treating this challenging disease. However, it is clear that we still have a lot to learn about how to predict which patients will benefit most from these treatments. The exploration of combining therapies and using machine learning to guide treatment shows promise. Moving forward, it is crucial that researchers and healthcare professionals continue to work together, sharing knowledge and findings to continue the advancements in this important area.

Differential Responses to Immune Checkpoint Inhibitors are Governed by Diverse Mismatch Repair Gene Alterations.

PURPOSE: The response to immune checkpoint inhibitors (ICI) in deficient mismatch repair (dMMR) colorectal cancer and endometrial cancer is variable. Here, we explored the differential response to ICIs according to different mismatch repair alterations. EXPERIMENTAL DESIGN: Colorectal cancer (N = 13,701) and endometrial cancer (N = 3,315) specimens were tested at Caris Life Sciences. Median overall survival (mOS) was estimated using Kaplan-Meier. The prediction of high-, intermediate-, and low-affinity epitopes by tumor mutation burden (TMB) values was conducted using R-squared (R2). RESULTS: Compared with mutL (MLH1 and PMS2) co-loss, the mOS was longer in mutS (MSH2 and MSH6) co-loss in all colorectal cancer (54.6 vs. 36 months; P = 0.0.025) and endometrial cancer (81.5 vs. 48.2 months; P < 0.001) patients. In ICI-treated patients, the mOS was longer in mutS co-loss in colorectal cancer [not reached (NR) vs. 36 months; P = 0.011). In endometrial cancer, the mOS was NR vs. 42.2 months; P = 0.711]. The neoantigen load (NAL) in mutS co-loss compared with mutL co-loss was higher in colorectal cancer (high-affinity epitopes: 25.5 vs. 19; q = 0.017, intermediate: 39 vs. 32; q = 0.004, low: 87.5 vs. 73; q < 0.001) and endometrial cancer (high-affinity epitopes: 15 vs. 11; q = 0.002, intermediate: 27.5 vs. 19; q < 0.001, low: 59 vs. 41; q < 0.001), respectively. R2 ranged from 0.25 in mutS co-loss colorectal cancer to 0.95 in mutL co-loss endometrial cancer. CONCLUSIONS: Patients with mutS co-loss experienced longer mOS in colorectal cancer and endometrial cancer and better response to ICIs in colorectal cancer. Among all explored biomarkers, NAL was higher in mutS co-loss and may be a potential driving factor for the observed better outcomes. TMB did not reliably predict NAL.

Ablative 5-Fraction Stereotactic MRI-Guided Adaptive Radiotherapy for Oligometastatic Pancreatic Adenocarcinoma.

INTRODUCTION: Metastatic pancreatic ductal adenocarcinoma (PDAC) carries a poor prognosis and significant morbidity from local tumor progression. We investigated outcomes among oligometastatic PDAC patients treated with stereotactic magnetic resonance image-guided ablative radiotherapy (SMART) to primary disease. METHODS: We performed a retrospective multi-institutional analysis of oligometastatic PDAC at diagnosis or with metachronous oligoprogression during induction chemotherapy treated with primary tumor SMART. Outcomes of interest included overall survival (OS), progression-free survival (PFS), freedom from locoregional failure (FFLRF), and freedom from distant failure (FFDF). Acute and late toxicity were reported and in exploratory analyses patients were stratified by the number of metastases, SMART indication, and addition of metastasis-directed therapy. RESULTS: From 2019 to 2021, 22 patients with oligometastatic PDAC (range: 1-6 metastases) received SMART to the primary tumor with a median follow-up of 11.2 months from SMART. Nineteen patients had de novo synchronous metastatic disease and three had metachronous oligoprogression. Metastasis location most commonly was liver only (40.9%), multiple organs (27.3%), lungs only (13.6%), or abdominal/pelvic nodes (13.6%). All patients received either FOLFIRINOX (64%) or gemcitabine/nab-paclitaxel (36%) followed by SMART (median 50 Gy, 5 fractions) for local control (77%), pain control (14%), or local progression (9%). Additionally, 41% of patients received other metastasis-directed treatments. The median OS from diagnosis and SMART was 23.9 months and 11.6 months, respectively. Calculated from SMART, the median PFS was 2.4 months with 91% of patients having distant progression, and 1-year local control was 68. Two patients (9%) experienced grade 3 toxicities, gastric outlet obstruction, and gastrointestinal bleed without grade 4 or 5 toxicity. CONCLUSION: There was minimal morbidity of local disease progression after SMART in this cohort of oligometastatic PDAC. As systemic therapy options improve, additional strategies to identify patients who may derive benefits from local consolidation or metastasis-directed therapy are needed.

Higher TP53 somatic mutation prevalence from liquid biopsy analysis in ever smoker non-small-cell lung cancer patients.

OBJECTIVE: Cigarette smoking is a primary risk factor, linked to 80% of LC deaths. TP53, a key gene, is implicated in various cancers, with TP53 alterations in 36.7% of cancers. This research aims to investigate TP53 mutations detected in NSCLC patients by liquid biopsy and explore the relationship between these mutations and smoking history. MATERIAL AND METHOD: The study enrolled a total of 340 patients diagnosed with non-small cell lung cancer (NSCLC). For sequencing, the Illumina NextSeq 500 system was utilized. The oncogenicity of the variants was assessed according to the ClinGen/CGC/VICC SOP and the variants were categorized into four tiers according to AMP/ASCO/CAP. RESULTS: The most common mutations were in TP53 (48.7%), followed by EGFR, PIK3CA, and PTEN. Missense mutations were frequent, with TP53 and EGFR having higher rates in ever-smokers. No indels or complex mutations were found in ever-smokers. Patient age ranged from 20 to 86 years. Tier I-II variants were more common in ever-smokers, while Tier III variants were prevalent in never-smokers. TP53 mutations were more frequent in ever-smokers, showing a strong association with smoking. Domain distribution showed differences in PIK3CA. Transversion/transition ratios varied by gene and smoking status. DISCUSSION: The presence of TP53 mutations is strongly associated with both cigarette smoking and elevated Tv/Ti ratios. The tier status of TP53, EGFR, and PTEN variants does not show a specific domain distribution, but interesting associations are observed between the tier status and domain distribution in PIK3CA variants. Therefore, further comprehensive investigations are needed to explore this entity, as well as the underlying factors contributing to the increased Tv/Ti rates in the TP53 gene. Such research will provide deeper insights into the genetic alterations associated with smoking and tumor heterogeneity, ultimately aiding in the development of targeted therapies.

A Meta-Analysis to Assess the Efficacy of HER2-Targeted Treatment Regimens in HER2-Positive Metastatic Colorectal Cancer (mCRC).

Recent trials provide evidence that HER2 is a potential new target for patients with colorectal cancer. While HER2-positive tumors do not show a very encouraging response to anti-HER2-positive agents like trastuzumab alone, promising results have been observed when combined with other synergistically acting tyrosine kinase inhibitors (TKIs). Our meta-analysis was conducted following the Cochrane Handbook and written following the PRISMA guidelines. The protocol was registered on PROSPERO with the registration number CRD42022338935. After a comprehensive search for relevant articles, 14 CTs were identified and uploaded to Rayyan, and six trials were ultimately selected for inclusion. The meta-analysis revealed that a median of three prior lines of therapy was used before enrolling in the six trials comprising 238 patients with HER2-positive metastatic colorectal cancer (mCRC). The pooled objective response rate (ORR) and disease control rate (DCR) were 31.33% (95% confidence interval [CI] 24.27-38.39) and 74.37% (95% CI 64.57-84.17), respectively. The pooled weighted progression-free survival (PFS) was 6.2 months. The pooled ORR and DCR meta-analysis indicate a significant response to HER2-targeted therapy in this patient in HER2-positive mCRC. Additionally, a pooled PFS of 6.2 months suggests that HER2-targeted treatment regimens are associated with a meaningful improvement in survival outcomes in this population.

Investigation of germline variants in Bahraini women with breast cancer using next-generation sequencing based-multigene panel.

Germline variants in BRCA1 and BRCA2 (BRCA1/2) genes are the most common cause of hereditary breast cancer. However, a significant number of cases are not linked to these two genes and additional high-, moderate- and low-penetrance genes have been identified in breast cancer. The advent of next-generation sequencing (NGS) allowed simultaneous sequencing of multiple cancer-susceptibility genes and prompted research in this field. So far, cancer-predisposition genes other than BRCA1/2 have not been studied in the population of Bahrain. We performed a targeted NGS using a multi-panel covering 180 genes associated with cancer predisposition to investigate the spectrum and frequency of germline variants in 54 women with a positive personal and/or family history of breast cancer. Sequencing analysis revealed germline variants in 29 (53.7%) patients. Five pathogenic/likely pathogenic variants in four DNA repair pathway-related genes were identified in five unrelated patients (9.3%). Two BRCA1 variants, namely the missense variant c.287A>G (p.Asp96Gly) and the truncating variant c.1066C>T (p.Gln356Ter), were detected in two patients (3.7%). Three variants in non-BRCA1/2 genes were detected in three patients (1.85% each) with a strong family history of breast cancer. These included a monoallelic missense variant c.1187G>A (p.Gly396Asp) in MUTYH gene, and two truncating variants namely c.3343C>T (p.Arg1115Ter) in MLH3 gene and c.1826G>A (p.Trp609Ter) in PMS1 gene. Other variants of uncertain significance (VUS) were also detected, and some of them were found together with the deleterious variants. In this first application of NGS-based multigene testing in Bahraini women with breast cancer, we show that multigene testing can yield additional genomic information on low-penetrance genes, although the clinical significance of these genes has not been fully appreciated yet. Our findings also provide valuable epidemiological information for future studies and highlight the importance of genetic testing, and an NGS-based multigene analysis may be applied supplementary to traditional genetic counseling.

A Comprehensive Review on Cancer Vaccines and Vaccine Strategies in Hepatocellular Carcinoma.

HCC, the most prevalent form of primary liver cancer, presents a substantial global health challenge due to its high mortality and limited therapeutic options. This review delves into the potential of cancer vaccines as a novel therapeutic avenue for HCC. We examine the various categories of cancer vaccines, including peptide-based, dendritic cell-based, viral vector-based, DNA, and mRNA vaccines, and their potential application in HCC management. This review also addresses the inherent challenges in vaccine development, such as tumor heterogeneity and the need for identifying tumor-specific antigens. We underscore the role of cancer vaccines in reshaping the immune environment within HCC, fostering durable immune memory, and their potential in combination therapies. The review also evaluates clinical trials and emphasizes the necessity for more extensive research to optimize vaccine design and patient selection criteria. We conclude with future perspectives, highlighting the significance of personalized therapies, innovative antigen delivery platforms, immune modulatory agents, and predictive biomarkers in revolutionizing HCC treatment. Simple Summary: This review explores the potential of cancer vaccines as a promising therapeutic strategy for hepatocellular carcinoma (HCC), a prevalent and deadly liver cancer. The authors discuss various types of cancer vaccines, their challenges, and their role in modulating the immune response within HCC. They also highlight clinical trials and future perspectives, emphasizing the importance of personalized therapies, novel antigen delivery platforms, and predictive biomarkers. The findings from this research could significantly impact the research community by providing a comprehensive understanding of the current state of cancer vaccines for HCC, thereby guiding future research and potentially transforming HCC treatment strategies.

Neoadjuvant Immunotherapy for Patients with dMMR/MSI-High Gastrointestinal Cancers: A Changing Paradigm.

Immune checkpoint inhibitors have revolutionized the management of mismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) gastrointestinal cancers, particularly colorectal cancer. Cancers with the MMR-D/MSI-H genotype often carry a higher tumor mutation burden with frameshift alterations, leading to increased mutation-associated neoantigen (MANA) generation. The dramatic response seen with immune checkpoint inhibitors (ICIs), which are orchestrated by MANA-primed effector T cells, resulted in the rapid development of these novel therapeutics within the landscape of MSI-H gastrointestinal cancers. Recently, several clinical trials have utilized ICIs as potential neoadjuvant therapies for MSI-H gastrointestinal cancers and demonstrated deep clinical and pathological responses, creating opportunities for organ preservation. However, there are potential challenges to the neoadjuvant use of ICIs for certain disease types due to the clinical risk of overtreatment for a disease that can be cured through a surgery-only approach. In this review article, we discuss neoadjuvant management approaches with ICI therapy for patients with MSI-H gastrointestinal cancers, including those with oligometastatic disease. We also elaborate on potential challenges and opportunities for the neoadjuvant utilization of ICIs and provide further insight into the changing treatment paradigm of MMR-D/MSI-H gastrointestinal cancers.

Return to intended oncologic therapy after colectomy for stage III colon adenocarcinoma: Does surgical approach matter?

AIM: Return to intended oncologic treatment (RIOT) is an important paradigm for surgically resected cancers requiring multimodal treatment. Benefits of minimally invasive colectomy (MIC) may allow earlier initiation of adjuvant chemotherapy (ACT) and have associated survival benefits. We sought to determine if operative approach affects RIOT timing in resected stage III colon cancer. METHODS: NCDB identified pathological stage III colon adenocarcinoma patients who underwent resection and received ACT. Propensity score matching and kernel density estimation compared operative approaches and conversion impact on intervals to RIOT. RESULTS: A total of 15,132 open colectomies (OC) versus 14,107 MIC were included. MIC patients had two-days shorter median length of stay (LOS) (4 vs. 6 days; p < 0.001), one-week shorter median time to RIOT (6 vs. 7 weeks; p = 0.015) comparing 12,867 matched pairs. There was no difference in time interval to RIOT between the LC versus RC, converted MIC vs. OC groups. MIC was a favourable predictor of earlier RIOT (HR 1.14 [1.07-1.22]; p < 0.001). CONCLUSION: MIC in stage III colon cancer is associated with a shorter time to RIOT when compared to OC. Since timely initiation of ACT may influence cancer outcome, MIC may be oncologically preferable. Prospective studies are needed to assess RIOT and survival outcomes in stage III colon cancer.

Next generation immuno-oncology biomarkers in gastrointestinal cancer: what does the future hold?

INTRODUCTION: Gastrointestinal (GI) cancers pose a significant health burden worldwide, necessitating advancements in diagnostic and treatment approaches. One promising avenue is the utilization of next-generation biomarkers, which hold the potential to revolutionize GI cancer management. AREAS COVERED: This review explores the latest breakthroughs and expert opinions surrounding the application of next-generation immunotherapy biomarkers. It encompasses various aspects of the currently utilized biomarkers of immunotherapy in the context of GI cancers focusing on microsatellite stable cancers. It explores the promising research on the next generation of biomarkers addressing the challenges associated with integrating them into clinical practice and the need for standardized protocols and regulatory guidelines. EXPERT OPINION: Immune profiling, multiplex immunohistochemistry, analysis of immune cell subsets, and novel genomic and epigenomic markers integrated with machine-learning approaches offer new avenues for identifying robust biomarkers. Liquid biopsy-based approaches, such as circulating tumor DNA (ctDNA) and exosome-based analyses, hold promise for real-time monitoring and early detection of treatment response.

The role of immune checkpoint inhibitors for patients with advanced stage microsatellite stable colorectal cancer and high tumor mutation burden: quantity or quality?

INTRODUCTION: The US Food and Drug Administration (FDA) approved pembrolizumab for patients with unresectable or metastatic solid tumors with tumor mutational burden (TMB) of ≥ 10 mutations/megabase. However, the clinical implications of this universal cutoff of TMB ≥ 10 for patients with microsatellite stable (MSS) metastatic colorectal cancer (CRC) remain debatable. AREAS COVERED: In this review, we discuss the tissue agnostic approval of pembrolizumab, its efficacy, and clinical relevance in the management of patients with MSS CRC patients with high TMB (defined as TMB ≥ 10). We also elaborate on molecular subgroups of MSS CRC that influence the immune checkpoint inhibitor (ICI) response for patients with MSS CRC, including pathogenic POLE and POLD1 mutations associated with ultramutated tumors. EXPERT OPINION: Patients with microsatellite stable CRC with TMB ≥ 10 without POLE and POLD1 mutations may not significantly benefit from immune checkpoint inhibitors therapy. Predetermined cutoff TMB ≥ 10 mutation per MB does not seem to define a universal cutoff for the benefit of disease-agnostic ICI therapy, particularly for patients with MSS CRC. Patients with POLE/POLD1 mutations with MSS CRC represent a unique biological subgroup of MSS CRC with favorable responses to ICI therapy.

An Investigation of Latex Sensitivity and Respiratory Complaints in Workers in a Rubber-Based Material Manufacturing Industry.

OBJECTIVE: To present study aimed to investigate the prevalence of latex sensitivity in a workplace that produced rubber-based vehicle seals. METHOD: The serum latex-specific IgE levels, respiratory complaints, PFT, serum interleukin (IL)-4, IL-5, IL-8, IL-10, IL-13 levels of all male workers (n = 108) exposed to latex in the workplace, which produced rubber seals, were compared with the control group (n = 52). RESULTS: The rates of latex-specific IgE >0.10 kU/L in the workers and control group were 12.3% and 4.1%, respectively ( P = 0.147). There was no difference in IL-4, IL-5, IL-10, and IL-13 levels between latex-specific IgE-positive, and -negative participants. CONCLUSION: Latex sensitivity was higher in workers who used rubber as a raw material than in the control group but it was not statistically significant.

Neoadjuvant Immune Checkpoint Inhibitor Therapy for Patients With Microsatellite Instability-High Colorectal Cancer: Shedding Light on the Future.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigm of mismatch repair-deficient/microsatellite instability-high (MMMR-D/MSI-H) colorectal cancer (CRC). Unique molecular features of MMR-D/MSI-H CRC with frameshift alterations, which result in mutation-associated neoantigen (MANA) generation, create an ideal molecular framework for MANA-driven T-cell priming and antitumor immunity. These biologic characteristics of MMR-D/MSI-H CRC resulted in rapid drug development with ICIs for patients with MMR-D/MSI-H CRC. Observed deep and durable responses with the use of ICIs in advanced-stage disease have stimulated the development of clinical trials with ICIs for patients with early-stage MMR-D/MSI-H CRC. Most recently, neoadjuvant dostarlimab monotherapy for nonoperative management of MMR-D/MSI-H rectal cancer and neoadjuvant NICHE trial with nivolumab and ipilimumab for MMR-D/MSI-H colon cancer resulted in groundbreaking results. Although nonoperative management of patients with MMR-D/MSI-H rectal cancer with ICIs will potentially define our current therapeutic approach, therapeutic goals of neoadjuvant ICI therapy for patients with MMR-D/MSI-H colon cancer may differ given that nonoperative management has not been well established for colon cancer. Herein, we overview recent advancements in ICI-based therapies for patients with early-stage MMR-D/MSI-H colon and rectal cancer and elaborate on the future treatment paradigm of this unique subgroup of CRC.

Betatrophin, elabela, asprosin, glucagon and subfatin peptides in breast tissue, blood and milk in gestational diabetes.

We investigated the presence of asprosin (ASP), betatrophin, elabela (ELA), glucagon and subfatin (SUB) in the milk of mothers with gestational diabetes mellitus (GDM) and compared their levels with blood levels. We also investigated whether these peptides are synthesized by the breast. We investigated 12 volunteer mothers with GDM and 14 pregnant non-GDM control mothers. The peptides were measured using ELISA and their tissue localization was determined using immunohistochemistry. Breast milk contains ASP, betatrophin, ELA, glucagon and SUB. The amount of the peptides ranged from highest to the lowest in colostrum, transitional milk and mature milk. The amount of peptides in the milk was greater than for blood. The peptides, except for ELA, were increased in milk and blood by GDM. Betatrophin and ELA are synthesized in the connective tissue of the breast. ASP, glucagon and SUB are synthesized in the alveolar tissue of the breast. These peptides in breast milk may contribute to the development of the gastrointestinal tract of newborns and infants.