Clinical trials of neoadjuvant immune checkpoint inhibitors for early-stage operable colon and rectal cancer.

BACKGROUND: Immune checkpoint inhibitors (ICI) have become first-line treatment for metastatic colorectal cancer (CRC) with deficient mismatch repair (dMMR). Despite the remarkable response reported in preliminary trials, the role of ICI in patients with early-stage, operable CRC remains unclear. The aim of this study was to investigate trials on neoadjuvant ICI in operable CRC. MATERIALS AND METHODS: Scoping review of clinical trial registries (Clinicaltrials.gov and EU clinical trial registers) and PubMed/Medline database of trials on neoadjuvant ICI for operable CRC was done up to December 2022. RESULTS: Some 40 trials investigating neoadjuvant ICI for early-stage, operable CRC were identified, including five published trials and three conference abstracts. Preclinical phase I/II trial predominated with only three clinical phase III trials. Few trials investigated neoadjuvant ICI as the only intervention (monotherapy). Trials in rectal cancer were designed for combined ICI with chemo(radio)therapy, only 8 trials stating an MSI/dMMR status for inclusion, one designed for MSS/pMMR only and, the rest agnostic for MMR status. Thirty-eight (95%) trials investigated programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors. PD-1/PD-L1 inhibitors were combined with vascular endothelial growth factor (VEGF) inhibitor or with cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitor, in two trials each, respectively. Pathological complete response as primary outcome after surgery was the most frequently used study endpoint. In rectal cancer, six trials included a "watch and wait" strategy for patients with complete clinical response. No "watch and wait" study design for colon cancer after neoadjuvant ICI were identified. CONCLUSION: High response rates from neoadjuvant ICI in early-stage colon and rectal cancer are reported in phase I/II studies. Contemporary trial designs are heterogeneous, with few comparable inclusion criteria, use of several drug combinations and durations and, wide variation of endpoints reported. Harmonizing clinical and translational aspects including survival data is needed for improved future trial designs with clinical impact.

Neoadjuvant immunotherapy in colorectal cancer beyond immune checkpoint inhibitors: emerging from bench to bedside.

Colorectal cancer (CRC) is the second most frequent cancer in both men and women, and of concern increasing in the younger population. Despite the progress in treatment, still up to half of CRC patients will develop metastasis. Immunotherapy consists of an arsenal of different managements that in many aspects has revolutionized cancer therapy. Monoclonal antibodies, chimeric antigen receptor (CAR) T-cell receptor gene modified T-cells and immunization and/or vaccination are different immunotherapies used in cancer treatment. Large trials in metastatic CRC, such as CheckMate 142 and KEYNOTE-177, have proven the efficacy of immune checkpoint inhibitors (ICI). The ICI drugs, targeting the cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) are now part of first-line treatment of dMMR/MSI-H metastatic CRC. However, ICIs are gaining a novel role in management of primary operable CRC after preliminary results from early-phase clinical studies in both colon and rectal cancer. Neoadjuvant ICI in operable colon and rectal cancer is hence becoming a clinical reality, while not quite yet adopted as a routine use. However, with some answers comes more questions and challenges. In this review article we aim to give an overview over different modes of immunotherapy to treat cancer with an emphasis on ICIs and their relevance to CRC, describe some of the progresses made in immunotherapy overall, with potential mechanisms, some of the concerns and, some highlight for the way forward.

Histopathological Growth Pattern in Colorectal Liver Metastasis and The Tumor Immune Microenvironment.

Almost half of all patients with colorectal cancer present with or eventually develop metastasis, most frequently in the liver. Understanding the histopathological growth patterns and tumor immune microenvironment of colorectal liver metastases may help determine treatment strategies and assess prognosis. A literature search was conducted to gather information on cancer biology, histopathological growth patterns, and the tumor immune microenvironment in colorectal liver metastases, including their mechanisms and their impact on clinical outcomes. A first consensus on histopathological growth patterns emerged in 2017, identifying five growth patterns. Later studies found benefits from a two-tier system, desmoplastic and non-desmoplastic, incorporated into the updated 2022 consensus. Furthermore, the tumor immune microenvironment shows additional characteristic features with relevance to cancer biology. This includes density of T-cells (CD8+), expression of claudin-2, presence of vessel co-option versus angiogenesis, as well as several other factors. The relation between histopathological growth patterns and the tumor immune microenvironment delineates distinct subtypes of cancer biology. The distinct subtypes are found to correlate with risk of metastasis or relapse, and hence to clinical outcome and long-term survival in each patient. In order to optimize personalized and precision therapy for patients with colorectal liver metastases, further investigation into the mechanisms of cancer biology and their translational aspects to novel treatment targets is warranted.

Structured and Systematic Team and Procedure Training in Severe Trauma: Going from 'Zero to Hero' for a Time-Critical, Low-Volume Emergency Procedure Over Three Time Periods.

BACKGROUND: Resuscitative emergency thoracotomy is a potential life-saving procedure but is rarely performed outside of busy trauma centers. Yet the intervention cannot be deferred nor centralized for critically injured patients presenting in extremis. Low-volume experience may be mitigated by structured training. The aim of this study was to describe concurrent development of training and simulation in a trauma system and associated effect on one time-critical emergency procedure on patient outcome. METHODS: An observational cohort study split into 3 arbitrary time-phases of trauma system development referred to as 'early', 'developing' and 'mature' time-periods. Core characteristics of the system is described for each phase and concurrent outcomes for all consecutive emergency thoracotomies described with focus on patient characteristics and outcome analyzed for trends in time. RESULTS: Over the study period, a total of 36 emergency thoracotomies were performed, of which 5 survived (13.9%). The "early" phase had no survivors (0/10), with 2 of 13 (15%) and 3 of 13 (23%) surviving in the development and mature phase, respectively. A decline in 'elderly' (>55 years) patients who had emergency thoracotomy occurred with each time period (from 50%, 31% to 7.7%, respectively). The gender distribution and the injury severity scores on admission remained unchanged, while the rate of patients with signs on life (SOL) increased over time. CONCLUSION: The improvement over time in survival for one time-critical emergency procedure may be attributed to structured implementation of team and procedure training. The findings may be transferred to other low-volume regions for improved trauma care.

Elevated Microsatellite Alterations at Selected Tetranucleotides (EMAST) in Colorectal Cancer is Associated with an Elderly, Frail Phenotype and Improved Recurrence-Free Survival.

BACKGROUND: Elevated microsatellite alterations at selected tetranucleotides (EMAST) is a poorly investigated form of microsatellite instability (MSI) in colorectal cancer (CRC). OBJECTIVE: The aim of this study was to investigate the clinicopathological features of EMAST in CRC and its relation to outcome. METHODS: A population-based, consecutive cohort of surgically treated stage I-III CRC patients investigated for high-frequency MSI (MSI-H) and EMAST. Clinicopathological differences were reported as odds ratios (OR) and survival was presented as hazard ratios (HR) with 95% confidence intervals (CIs). RESULTS: Of 161 patients included, 25% were aged > 79 years. There was a large overlap in the prevalence of EMAST (31.7%) and MSI-H (27.3%) [82.4% of EMAST were also MSI-H]. EMAST had the highest prevalence in the proximal colon (OR 15.9, 95% CI 5.6-45.1; p < 0.001) and in women (OR 4.1, 95% CI 1.9-8.6; p < 0.001), and were poorly differentiated (OR 5.0, 95% CI 2.3-10.7; p < 0.001). Compared with EMAST-negative patients, EMAST-positive patients were older (median age 77 vs. 69 years; p < 0.001), leaner (median weight 67.5 vs. 77 kg; p = 0.001), had significantly higher rates of hypoalbuminemia (24% vs. 6%; OR 2.3, 95% CI 1.5-3.6; p = 0.002) and anemia (45% vs. 20%; OR 3.3, 95% CI 1.6-6.8; p = 0.001), and had elevated preoperative C-reactive protein (CRP) levels (51% vs. 34%; OR 1.9, 95% CI 1.0-3.9; p = 0.046). Improved recurrence-free survival was found in both MSI-H and EMAST subtypes. In multivariable analysis, node status (pN +), together with elevated CRP and MSI-positive, were the strongest prognostic factors for recurrence-free survival. CONCLUSIONS: EMAST in CRC is associated with an older, leaner, and frailer phenotype with a lower risk of recurrence. The relevance of, and putative mechanisms to, EMAST warrants further investigation.