Ben Boursi

Background: Mucinous phenotype has been associated with an immune-cold microenvironment in dMMR/MSI-H CRC. Here, we investigated the impact of mucinous histology on resistance to ICIs in patients with dMMR/MSI-H mCRC. Patients and methods: We collected data on patients with dMMR/MSI-H mCRC receiving anti–PD-1 alone or with anti-CTLA-4 agents in any line from a multinational dataset. Mucinous histology was defined locally as ≥50% mucinous component. The occurrence of progression or death of disease within or after 6 months from ICIs initiation were considered innate (IR) and acquired resistance (AR). Progression-free survival (PFS)-1 and overall survival (OS)-1 were calculated using the 6-month landmark from the start of ICIs in patients without IR. Results: Among 929 patients, 316 (34%) had mucinous tumors and had inferior PFS and OS. At a median follow-up of 44.7 months, the 6-month PFS rate was similar in patients with mucinous and non-mucinous tumors (71.5% and 73.0%) and a subsequent divergence of the PFS and OS curves was observed beyond this timepoint. In patients without IR, mucinous histology was independently associated with shorter PFS-1 (multivariable model HR 2.10, 95%CI 1.56–2.82; p < 0.001), while OS-1 was non-significantly shorter (HR 1.36, 95%CI 0.91–2.02, p = 0.130). Dual anti-CTLA4/PD-1 blockade was associated with longer PFS and OS regardless of mucinous histotype, but the worst outcomes were observed in patients with mucinous histology receiving single-agent anti-PD-1 (3-year PFS and OS: 39.7% and 56.1%). Conclusion: Mucinous histology is associated with ICIs resistance, particularly AR, in dMMR/MSI-H mCRC. These findings may be useful to guide the management of this disease in practice.

BackgroundImmune checkpoint blockers (ICBs) are front-line therapy for mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). Poor ECOG performance status (PS) is widely recognized as a negative prognostic factor, often leading physicians to avoid treatment. We aimed to assess the effect of ECOG PS on patient outcomes in dMMR/MSI-H mCRC receiving ICBs.MethodsAn international multicenter retrospective cohort study of ICBs-naïve dMMR/MSI-H mCRC patients who received ICBs between 2014–2024. Exposure variables included best treatment response and patient characteristics including line of treatment, RAS/BRAF status, single-agent versus doublet ICBs, and metastatic sites. The main outcome was overall survival. Kaplan-Meier analysis was used to analyze the association of best treatment response with overall survival according to ECOG PS of 2-3 and 0-1.ResultsThe study cohort included 51 dMMR/MSI-H mCRC patients with ECOG PS of 2-3 and 633 patients with ECOC PS of 0-1 that were treated with ICBs. Median follow-up time was 35.3 months (IQR 23.9 – 54.9) and 49.9 months (IQR 46.7-53.8), respectively. For patients with ECOG PS of 2-3 ORR and DCR rates were 37.3% and 60.8%. Median overall survival (mOS) was 14.4 months - not reached for those who achieved CR/PR and 1.7 months for those whose best response was PD. For patients with ECOG PS of 0-1, mOS was not reached, and ORR was 60.0%.ConclusionsPatients with dMMR/MSI-H mCRC and ECOG PS 2-3 derive durable benefit from ICBs, mainly among those who achieved CR/PR, and should therfore be considered candidates for this therapy.

Introduction: Space travel exposes crew to substantial stressors, which may potentially alter their microbiome and be detrimental to their health and safety. We hypothesize that urinary microbiota is altered during a short-duration spaceflight to the International Space Station (ISS). Methods: Urine samples were collected from 4 male crew members. One crew member provided samples while on orbit on the ISS using a urine collection kit (UCK) designed for low-gravity environments. This crew member also provided paired mid-stream and UCK samples on Earth prelaunch and on return for direct comparison of collection methods. Three additional crew members provided mid-stream samples prelaunch and on return, and also for follow-up timepoints to serve as ex post facto control samples. Urine was stored at −80℃ and sent for 16s next-generation sequencing (MicroGenDX, Lubbock, TX). Results: Bacterial load ( P = .52), species richness ( P = .64), and differences in microbiota composition ( P = .26) did not significantly vary by the collection method (mid-stream vs UCK). Significant differences in species richness, load, and microbial composition among preflight, orbital, and return mission samples were detected ( P = .047, F = 1.8092, df = 2.9, R2 = 0.34076). Orbital microbial composition significantly differed from preflight ( P = .03) and return ( P = .03), whereas preflight and return samples did not differ ( P > .05). Comparison with the limited follow-up ex post facto Earth-bound samples serving as controls showed no significant differences among preflight or return mission samples, but preflight ( P = .04) and return ( P = .05) did significantly differ compositionally from orbital samples. Continuous temporal effects on composition were evaluated through which bacterial load ( P = .05) was statistically significant, peaking during the orbital period. Conclusions: Results are consistent with an effect of space travel altering the urinary microbiota. Further studies are needed to confirm this result and to better understand whether such changes may be detrimental to the health and safety of space travelers and professional astronauts.

Background: Patients with deficient mismatch repair (dMMR) and/or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) show marked sensitivity to immune checkpoint inhibitors (ICIs). Dual PD-1/CTLA-4 blockade with nivolumab and ipilimumab showed superior progression-free survival (PFS) over chemotherapy and anti-PD-1 monotherapy, but data on treatment-naïve patients is not available yet. Methods: This international multicenter study included patients with dMMR/MSI-H mCRC receiving either chemotherapy with or without biologics, or anti-PD-1 monotherapy, or dual PD-1/CTLA-4 blockade as a first-line treatment. Data were adjusted using inverse probability of treatment weighting (IPTW) to account for baseline imbalances. IPTW-adjusted survival and subgroup analyses were conducted. Results: Among 711 patients, 51.2% received chemotherapy with or without biologics, 37.1% anti-PD-1 monotherapy, and 11.7% dual checkpoint blockade. Anti-CTLA-4 combination therapy significantly improved PFS (HR: 0.14; p < 0.001) and OS (HR: 0.13; p < 0.001) versus chemotherapy. In first-line IPTW-adjusted analyses (median follow-up: 29.2 months), dual blockade showed superior PFS over PD-1 monotherapy (HR: 0.58, 95%CI 0.35-0.97, p = 0.037), with a favorable OS trend (HR: 0.61, 95%CI 0.33-1.14, p = 0.12), and higher objective response rate (ORR) (71.5% vs 55.5%; OR: 1.15; 95%CI 1.03-1.29; p = 0.016) and disease control rate (DCR) (93.7% vs 75.8%; OR, 1.18; 95%CI 1.08-1.28; p < 0.001). Subgroup analyses suggested greater benefit in patients with left-sided and BRAF mutated tumors, while those with right-sided BRAF wild-type status showed no incremental benefit from dual ICI. Toxicity profile was manageable for both ICI regimen, with grade 3 or 4 immune-related adverse events registered in 11.9% and 15.7% cases in anti-PD-1 monotherapy and anti-CTLA-4 combination groups, respectively. Conclusions: First-line dual PD-1/CTLA-4 blockade demonstrated superior efficacy over anti-PD-1 monotherapy in dMMR/MSI-H mCRC regardless of clinical variables. Compared to previous published data across treatment lines, the prognostic impact of several clinical features does not seem to be retained in patients treated upfront with ICIs combination.

Background: Li–Fraumeni syndrome (LFS) is a rare autosomal‐dominant cancer‐predisposition syndrome caused by germline pathogenic or likely pathogenic variants (P/LPVs) in the TP53 gene. Classical autosomal‐dominant inheritance predicts a 50% transmission rate of TP53 P/LPV from each carrier parent to their offspring. However, clinical observations suggest higher‐than‐expected carrier proportions, indicating a potential transmission ratio distortion (TRD). The objective of this study was to investigate TRD in Israeli LFS families.Methods: Data from families with an LFS diagnosis who were followed at Sheba Medical Center between 2015 and 2024 were reviewed. Families that had complete clinical data and offspring were included. Pedigree analyses classified carriers as confirmed, obligate, or probable. Observed carrier proportions were compared with the expected 50% rate using one‐sample t‐tests.Results: Among 171 individuals from 20 families, 100 (58.5%) were identified as TP53 P/LPV confirmed or obligatory carriers, significantly exceeding the expected 50% inheritance rate (p = .027). A second analysis, which included 11 probable carriers, resulted in a carrier proportion of 64.9% (p < .001). TRD was observed across all phenotypic groups. No significant differences in TRD were observed by sex or variant type.Conclusions: This study revealed significant TRD in TP53 P/LPV inheritance among Israeli LFS families. A potential mechanism involves the role of TP53 in the cell cycle, in which reduced TP53 function may enhance embryonic cell proliferation, offering a survival or implantation advantage. TRD in LFS has implications for genetic counseling, reproductive decision making, and clinical management. These findings underscore the need for further research to validate TRD across diverse populations and elucidate the underlying mechanisms.

Mitochondrial DNA (mtDNA) is highly polymorphic, and host mtDNA variation has been associated with altered cancer severity. To determine the basis of this mtDNA–cancer association, we analyzed conplastic mice with the C57BL/6J (B6) nucleus but two naturally occurring mtDNA lineages, mtDNA ^B6 and mtDNA ^NZB , where mtDNA ^NZB mitochondria generate more oxidative phosphorylation (OXPHOS)-derived reactive oxygen species (mROS). In a cardiac transplant model, mtDNA ^B6 Foxp3+ T regulatory (Treg) cells supported long-term allograft survival, whereas mtDNA ^NZB Treg cells failed to suppress host T effector (Teff) cells, leading to acute rejection. When challenged with melanoma or colon cancer cells, the mtDNA ^NZB mice exhibited strikingly impaired tumor growth while mtDNA ^B6 mice showed Treg-dependent inhibition of Teff cells and allowed rapid tumor growth. Transcriptional analysis showed that activation of mtDNA ^NZB Teff cells increased mitochondrial gene expression while activation of mtDNA ^NZB Treg cells impaired mitochondrial gene expression and resulted in mtDNA ^NZB Treg cell exhaustion. Induction of the mitochondrially targeted catalytic antioxidant, mCAT, in hematopoietic cells normalized mtDNA ^NZB Treg function in both transplant and tumor models, indicating a key role for mROS in promoting Treg dysfunction. Anti-PD-L1 therapy did not modulate these effects, indicating that modulation of host mitochondrial function provides an independent approach for enhancing tumor cell destruction.

Introduction Recently, Narunsky-Haziza et. al. showed that fungi species identified in a variety of cancer types may have prognostic and diagnostic signficane. We used that data in order to better understand the effects of demographic factors (age, sex, BMI, and race) on the intratumor mycobiome composition. Materials and Methods We first tested the data in view of recent critiques of microbiome data processing procedures, and concluded that the batch correction and transformation used on it may produce false signals. Instead, we explored 14 combinations of data transformation and batch correction methods on data of 224 fungal species across 13 cancer types. Propensity scores were utilized to adjust for potential confounders such as histological type and tumor stage. To minimize false outcomes, we identified as positive results only those fungi species that showed significant difference in abundance across a demographic factor within a particular cancer type, using data normalized according to all 14 combinations. Results and Discussion We observed significant differences in fungal species abundance within tumors for certain demographic characteristics. Most differences were among races in specific cancers. The findings indicate that there are intricate interactions among the mycobiome, cancer types, and patient demographics. Our study highlights the need for accounting for potential confounders in order to further understanding of the mycobiome’s role in cancer, and underscores the importance of data processing techniques.

Our understanding of how the microbiota affects the balance between response to and failure of cancer treatment by modulating the tumour microenvironment and systemic immune system has advanced rapidly in recent years. Microbiota-targeting interventions in patients with cancer are an area of intensive investigation. Promisingly, phase I–II clinical trials have shown that interventions such as faecal microbiota transplantation can overcome resistance to immune checkpoint blockade in patients with melanoma, improve therapeutic outcomes in treatment-naive patients and reduce therapy-induced immunotoxicities. Here, we synthesize the evidence showing that the microbiota is an important determinant of both cancer treatment efficacy and treatment-induced acute and long-term toxicity, and we discuss the complex and inter-related mechanisms involved. We also assess the potential of microbiota-targeting interventions, including bacterial engineering and phage therapy, to optimize the response to and recovery from cancer therapy.