Cancer Medicine

Background Emerging evidence suggests irreversible electroporation (IRE) with standard-of-care (SOC) chemo-therapy may improve survival in patients with Stage 3 pancreatic ductal adenocarcinoma (PDAC) when compared to SOC alone. This study evaluates the overall survival (OS) and progression-free survival (PFS) of Stage 3 PDAC patients treated with SOC plus IRE with the NanoKnife System versus SOC alone. Methods This prospective, multicenter study included two cohorts from the DIRECT registry: an IRE cohort from sites offering IRE as part of clinical care, and a comparator SOC cohort of prospectively enrolled and contemporaneous retrospective patients. Enrollment spanned 08/05/2019 to 02/05/2023, with follow-up through at least 24 months, death, or loss to follow-up. Included were 137 patients (99 IRE; 38 SOC), aged [&ge;]18 years with Stage 3 PDAC and no progression after three months of SOC therapy. Results Median (interquartile range) time from diagnosis to enrollment was 8 (6-10) months for IRE and 4 (3-6) for SOC (p<0.0001). Median OS and PSF from enrollment were 18 (95% confidence interval [CI]: 15-24) months and 9 (95% CI: 7-12) months for IRE, and 10 (95% CI: 8-14) months and 6 (5-8) months for SOC, respectively (p<0.0001 and p=0.009). Adverse events occurred in 80% (79/99) of IRE patients and 95% (36/38) of SOC patients; 29% (29/99) of the IRE cohort experiencing an IRE-related adverse event. Conclusions IRE was associated with improved OS versus SOC alone and may be an effective consolidative treatment for Stage 3 PDAC after three months of induction chemotherapy.

Gallbladder cancer (GBC) is a highly lethal malignancy with limited experimental models to study disease biology or evaluate therapeutic responses. Although canonical Wnt activation is commonly used for patient-derived organoid (PDO) development and expansion, gallbladder PDOs has also been generated under Wnt-inhibitory conditions. No comparative assessment has determined how Wnt pathway modulation influences gallbladder PDO development, phenotype or drug response. This study systematically compared the impact of canonical Wnt activation (WNTAct medium containing CHIR99021) versus inhibition (WNTInh medium containing DKK1) on the establishment, propagation, molecular features and therapeutic responses of PDOs generated from malignant or non-malignant gallbladder tissues derived from the same patient. Both media supported successful PDO generation with comparable efficiency, preserving biliary epithelial functions and marker expression. Transcriptomic profiling confirmed selective enrichment of canonical Wnt target genes in PDOs generated in WNTAct cultures. WNTAct conditions enabled markedly superior long-term propagation, whereas WNTInh cultures more consistently retained the dysplastic features in malignant samples. Gemcitabine response assays demonstrated significantly greater drug sensitivity in PDOs grown in WNTAct medium, a phenotype reversible upon media switching but requiring extended adaptation, indicating a dynamic and context-dependent influence of Wnt signaling on chemotherapeutic vulnerability. Collectively, the findings reveal a trade-off between long-term propagation and histological fidelity in gallbladder PDOs and show that Wnt signaling modulates gemcitabine sensitivity in a reversible manner. This comparative framework provides practical guidance for selecting culture conditions for gallbladder PDO based disease modelling and precision oncology applications.

BackgroundFOLFIRINOX is a cornerstone regimen for eligible patients with pancreatic ductal adenocarcinoma (PDAC), but its clinical benefit is limited by substantial toxicity and frequent dose modification. In real-world practice, dose modifications are often individualized, and the clinical factors associated with these decisions remain incompletely characterized. ObjectiveTo develop and evaluate an electronic medical record (EMR)-based machine-learning framework for modeling cycle-specific FOLFIRINOX dose modification decisions in patients with PDAC. MethodsWe included patients with PDAC who received FOLFIRINOX at UCSF oncology clinics between November 2011 and December 2023. Predictors included demographic, clinical, laboratory, and treatment variables derived from the EMR. Logistic regression, random forest, and XGBoost models were trained using group-based 5-fold cross-validation to predict cycle-specific dose modifications for 5-fluorouracil, irinotecan, and oxaliplatin. Model performance was evaluated using area under the receiver operating characteristic curve. ResultsThe cohort included 514 patients receiving FOLFIRINOX across 5,041 treatment cycles. The mean age was 59 years, 60% of patients were White, 41% had a history of smoking, and patients received a median of 6 chemotherapy cycles. More than 60% of patients required at least one dose modification during treatment. XGBoost demonstrated the highest performance across component drugs, with AUCs ranging from 0.53 to 0.70. Clinically plausible predictors of irinotecan and oxaliplatin dose modification included hepatic and renal function markers, cumulative drug exposure, treatment-related symptoms, and demographic or behavioral characteristics. ConclusionWe developed an EMR-based machine-learning framework to model real-world FOLFIRINOX dose modification and identified clinically plausible, routinely available predictors, particularly for irinotecan and oxaliplatin. Variable model performance suggests that dosing decisions are only partially captured by structured EMR data, highlighting both the limitations of current data-driven approaches and clinical domains where ML-based models may support individualized dosing and toxicity surveillance. Future informatics efforts should incorporate dose-modification rationale, patient-reported and functional outcomes, and validation across diverse practice settings.

ObjectiveThis study aimed to investigate the anti-gastric cancer effect of Patchouli alcohol (PA), especially its influence on PD-L1-mediated immune evasion, and to elucidate the underlying molecular mechanisms. MethodsA CCK-8 assay was used to evaluate the effects of PA on the viability of the gastric cancer cell lines HGC-27 and MKN-45. RT-qPCR and western blotting were performed to analyze the mRNA and protein levels of NF-{kappa}B and PD-L1, respectively. In a coculture system of gastric cancer cells and peripheral blood mononuclear cells (PBMCs), the effect of PA pretreatment on the PBMC-induced apoptosis of cancer cells was analyzed by flow cytometry, and the cytotoxic activity of the PBMCs was assessed by a lactate dehydrogenase (LDH) release assay. Flow cytometry was also used to determine the proportions of CD3CD8 T cells and IFN-{gamma}CD8 T cells. ELISA was used to measure the levels of IFN-{gamma}, TNF-, and granzyme B in the coculture supernatants. Immunofluorescence staining was conducted to assess NF-{kappa}B nuclear translocation. In a mouse xenograft model, tumor volume and weight were measured after 14 days of PA treatment. Histopathological changes and apoptosis were analyzed by HE and TUNEL staining. A luciferase reporter assay was used to examine the transcriptional regulation of PD-L1 by NF-{kappa}B. ResultsPA inhibited the viability of HGC-27 and MKN-45 cells in a dose- and time-dependent manner and significantly downregulated the expression of NF-{kappa}B and PD-L1 at both the mRNA and protein levels. In a PBMC coculture model, PA pretreatment enhanced the ability of PBMCs to induce apoptosis and directly kill gastric cancer cells. Furthermore, PA pretreatment increased the proportions of CD3CD8 T cells and IFN-{gamma}CD8 T cells in a dose-dependent manner. Consistent with this immunostimulatory effect, PA increased the levels of IFN-{gamma}, TNF-, and granzyme B in the coculture supernatants. Mechanistically, western blotting analysis demonstrated that PA significantly reduced the protein levels of AKT, NF-{kappa}B, and PD-L1 in gastric cancer cells. Immunofluorescence staining further indicated that PA suppressed the nuclear translocation of NF-{kappa}B. In a mouse xenograft model, PA treatment significantly inhibited tumor growth, induced apoptosis, and downregulated NF-{kappa}B and PD-L1 protein expression in tumor tissues. Flow cytometry of tumor-infiltrating lymphocytes revealed increased proportions of CD3CD8 and IFN-{gamma}CD8 T cells following PA treatment. Finally, luciferase reporter assays demonstrated that NF-{kappa}B directly regulates PD-L1 transcription by binding to its promoter region. ConclusionPA exerts antitumor effects in gastric cancer by suppressing the NF-{kappa}B/PD-L1 axis, thereby enhancing CD8 T-cell-mediated cytotoxicity and inhibiting immune evasion.

Purpose In resource-limited settings, locally advanced rectal cancer (LARC) often presents at advanced stages. Long-course chemoradiotherapy (LCCRT) remains a cornerstone of neoadjuvant therapy, yet outcome data from such settings remain limited. This study assessed tumor resectability, pathologic response, and factors associated with resectability following neoadjuvant LCCRT at Ethiopias largest tertiary oncology center. Methods A retrospective cohort study was conducted among patients with stage II-III rectal adenocarcinoma (cT3-4 and/or cN+) who completed neoadjuvant LCCRT at Tikur Anbessa Specialized Hospital between 2018 and 2023. Tumor resectability was determined by multidisciplinary team (MDT) assessment. Multivariable logistic regression was used to identify factors associated with post-LCCRT resectability, adjusting for initial T stage, circumferential resection margin (CRM) status, histologic subtype, radiotherapy technique, and neoadjuvant regimen. Results Among 58 eligible patients (median age 45 years; 62% male), 62% had cT4 tumors, 53% had cN2 disease, and 84.5% had involved CRM. The median diagnosis-to-LCCRT interval was 64 weeks (interquartile range [IQR], 37-82). After LCCRT, 27 patients (46.6%) were deemed resectable by MDT assessment; 19 patients (32.8%) ultimately underwent curative-intent surgery (median interval from LCCRT to surgery, 10 weeks; IQR, 7-15). Initial cT3 stage was associated with higher odds of resectability (adjusted odds ratio [AOR], 6.2; 95% CI, 1.06-36.37), whereas receipt of total neoadjuvant therapy was associated with lower odds (AOR, 0.10; 95% CI, 0.02-0.49). No pathologic complete responses were observed. Conclusion In this cohort characterized by advanced disease at presentation and treatment delays, neoadjuvant LCCRT resulted in low resectability and limited pathologic response. To enhance curative potential, concerted efforts are needed to expedite the timely initiation of radiotherapy, optimize multidisciplinary team assessment, and increase surgical capacity.

PurposeTreatment options of advanced oral squamous cell carcinomas (OSCC) are limited, and cisplatin toxicity and drug resistance are major clinical issues. Src is a central kinase that integrates multiple oncogenic pathways and a promising therapeutic target. However, Src inhibitors have shown suboptimal efficacy as monotherapies and their sensitivity in OSCC remains elusive. Experimental DesignWe examined the activation of major oncogenic signaling pathways and the antitumor effects of six Src inhibitors (dasatinib, ponatinib, vandetanib, saracatinib, PP2, bosutinib) in seven human OSCC cell lines (HSC-2, HSC-3, HSC-4, SAS, HO-1-u-1, CAL27, SCC-25). BALB/cAJcl nu/nu mice bearing CAL27 xenografts received dasatinib (30 mg/kg, intraperitoneally, daily), bosutinib (50 mg/kg, intraperitoneally, daily), cisplatin (2 mg/kg or 4 mg/kg, intraperitoneally, weekly), or combinations. Tumor volume, bioluminescence imaging, and body weight were monitored for 17 or 21 days, followed by histopathological assessment. ResultsThe activation of the key pathways, including Src and MAPK, considerably differed among the cell lines and was linked to heterogeneous sensitivity to Src inhibitors. Effective growth suppression required Src dephosphorylation and downstream MAPK pathway inhibition, which vary depending on the cell line. Additionally, combination treatment with a Src inhibitor and cisplatin showed additive antitumor effects, allowing the reduction of cisplatin doses by half without efficacy loss. Notably, dasatinib alone and in combination with cisplatin decreased tumor burden with characteristic internal tumor death in vivo. ConclusionsThese findings elucidate Src signaling dependency on OSCC and the potential of Src inhibition to decrease cisplatin toxicity, paving way for Src targeted therapeutic strategies.

BackgroundThe MDM2-p53 signaling pathway plays a central role in tumor suppression, and genetic variants that disrupt this pathway may influence breast cancer (BC) susceptibility. However, data from South Asian populations, particularly Bangladesh, remain limited. MethodsA case-control study was conducted in Bangladeshi women, including BC patients and healthy controls (HCs). Genotyping of MDM2 polymorphisms was performed using PCR-based methods. Circulating MDM2 and p53 protein levels were measured using enzyme-linked immunosorbent assays (ELISA). Associations between genotype, protein levels, BC status, and clinicopathological features were evaluated using appropriate statistical models. ResultsA strong and genotype-specific association was observed for MDM2 rs2279744. Women carrying the heterozygous TG genotype had a markedly increased risk of BC across additive, dominant, and over-dominant models, whereas the GG genotype showed a protective effect under the recessive model. In contrast, rs937282 did not show a significant association with BC risk. Circulating MDM2 levels were significantly elevated in patients compared with controls and varied by rs2279744 genotype, while circulating p53 levels showed an opposite trend. A strong inverse correlation was observed between serum MDM2 and p53 levels, supporting dysregulation of the MDM2-p53 feedback loop. Elevated MDM2 levels were also noted in HER2-positive and triple-positive BC subtypes. ConclusionTogether, these findings indicate that the MDM2 rs2279744 polymorphism contributes to BC susceptibility in a genotype-specific manner, likely through disruption of the MDM2-p53 regulatory balance. However, the absence of functional validation limits direct causal inference.

BackgroundImmune checkpoint inhibitors (ICI) have improved outcomes in Merkel cell carcinoma (MCC). Population analyses suggest improved survival following the 2017 approval of ICI, but registry data lack treatment-level information including type of systemic therapy and initiation timepoint to directly estimate the benefit attributable to immunotherapy. This study compared Merkel Cell Carcinoma-specific survival between patients treated with first-line ICI versus cytotoxic chemotherapy. MethodsPatients were identified from the Seattle Merkel Cell Carcinoma Registry. Among 1,517 patients with MCC, 463 received first-line systemic therapy with either ICI or chemotherapy. Propensity scores were estimated using logistic regression including AJCC 8th stage, age, sex, MCPyV status, and immunosuppression. One-to-one nearest-neighbor matching produced balanced cohorts of 133 ICI-treated and 133 chemotherapy-treated patients. Merkel Cell Carcinoma-specific survival from therapy initiation was analyzed using Kaplan-Meier and Cox proportional hazards models with follow-up administratively censored at five years. ResultsBaseline clinical characteristics were comparable between matched cohorts. ICI therapy was associated with significantly improved Merkel Cell Carcinoma-specific survival compared with chemotherapy (log-rank p<0.0001). Five-year Merkel Cell Carcinoma-specific survival was 56.8% (95% CI 46.8-65.6) for ICI versus 23.9% (95% CI 16.9-31.6) for chemotherapy. In multivariable stage-stratified Cox analysis, ICI remained independently associated with improved Merkel Cell Carcinoma-specific survival (HR 0.32, 95% CI 0.21-0.50; p<0.0001), while immunosuppression was associated with worse Merkel Cell Carcinoma-specific survival (HR 2.03, 95% CI 1.10-3.74; p=0.0228). ConclusionsICI therapy was associated with substantially improved MCC-specific survival compared with chemotherapy.

Colonic adenocarcinoma (COAD) is a major cause of cancer-related mortality worldwide. Various tumors are linked to metastasis-associated in colon cancer 1 (MACC1). This study aimed to analyze public datasets to examine MACC1 expression, signaling pathways, copy number variations, and associations with immune cell subsets in COAD employing bioinformatics. MACC1 expression was elevated in COAD, especially in Wnt signaling and chromatin modifier pathways. Analysis of somatic copy number alterations in The Cancer Genome Atlas-COAD dataset revealed a link between MACC1 and DNA damage repair. MACC1 also showed a negative correlation with genes involved in immune cell infiltration in patients with COAD, including cluster of differentiation (CD)8+ T cells, activated dendritic cells, CD8 T cells, and cytotoxic cells. Collectively, these findings suggest MACC1 as a potential prognostic biomarker and therapeutic target for COAD.

ObjectiveThe purpose of the present study is to describe the survival outcomes of patients with low-grade serous ovarian cancer (LGSOC) in the post-operative setting from a tertiary gynecologic oncology referral centre in Quebec, including evaluation of patient characteristics, clinical outcomes and prognostic factors. MethodsThe study included 25 patients: 1) with a post-surgical histopathologic diagnosis of a low-grade serous tumour of the ovary, 2) underwent primary cytoreductive surgery prior to adjuvant therapy, and 3) for whom clinical data was available. Clinical and demographic features were characterized by descriptive statistics. Clinical endpoints of progression-free survival (PFS) and overall survival (OS) were assessed, utilizing the Kaplan-Meier method for estimating survival probabilities. ResultsThe median age of this cohort was 61 years (range, 26-81). Median OS was 140.6 months in patients with no residual disease (R0), 71 months in patients with microscopic residual disease (R1), and 27.7 months in patients with macroscopic residual disease (R2) (p=.001). Residual disease was also found to significantly impact PFS (p=.008). Administration of adjuvant chemotherapy failed to improve survival outcomes altogether (PFS, p = .270; OS, p = .300). ConclusionsThis study supports the shifting consensus that optimal cytoreductive surgery, where feasible, is paramount for successful treatment of LGSOC. Furthermore, treatment with adjuvant chemotherapy may lead to worse survival outcomes.

BackgroundFor pancreatic cancer, practical blood-based tests for early detection and postoperative surveillance remain elusive. We sought to develop a qPCR-measurable serum microRNA (miRNA) panel that robustly discriminates pancreatic cancer from non-cancer controls and other malignancies. MethodsWe profiled 255 serum miRNAs in batch 1 (n=72) and selected 27 candidates. Candidates were refined in batch 2 (n=552) and cross-batch evaluation was performed with batch 3 (n=391) to derive a miRNA model. Independent validation used batch 4 (n=616). Clinical relevance was assessed in an independent clinical cohort of resection patients with samples obtained preoperatively and at 1 and 12 months postoperatively. ResultsThe miRNA model trained on batches 2 and 3 achieved an area under the curve (AUC) of 0.91 and 0.83 for pancreatic cancer versus non-cancer controls and non-cancer plus other cancers, respectively, when independently validated in batch 4. Stage-wise AUCs in batch 4 were 0.91 (I), 0.94 (II), 0.86 (III) and 0.90 (IV). In the clinical batch, the score decreased postoperatively (preoperative vs month 1; p<0.01) and was higher in recurrence than non-recurrence (p<0.001). ConclusionsThe developed compact miRNA qPCR assay discriminated pancreatic cancer across independent assay batches and showed clinical relevance for postoperative surveillance. Clinical Trial RegistrationNot applicable.

Background: Rectal cancer (RC) is traditionally grouped within colorectal cancer (CRC), despite growing evidence of distinct epidemiologic features. However, global comparative assessments of lifetime risks of RC relative to CRC remain limited. We aimed to estimate lifetime risks of developing and dying from RC and CRC worldwide and to examine geographic, socioeconomic, and temporal variations in the proportional contribution of RC within CRC. Methods: Age-specific incidence and mortality estimates for RC and CRC across 185 countries were obtained from GLOBOCAN 2022, together with population and all-cause mortality data from the United Nations. Lifetime risks of incidence (LRI) and mortality (LRM) were calculated using the adjusted-for-multiple-primaries (AMP) method by sex, country, region, and Human Development Index (HDI). The RC-to-CRC lifetime risk ratio quantified the proportional contribution of RC. Temporal trends were assessed in 42 countries using Cancer Incidence in Five Continents Plus (CI5plus) data and average annual percent change (AAPC). Results: In 2022, the global lifetime risk of developing RC was 1.61% and dying from RC was 0.95%, accounting for approximately 35% of the corresponding CRC lifetime burden (4.61% and 2.68%). Absolute lifetime risks of both RC and CRC increased with HDI. In contrast, the proportional contribution of RC varied markedly, peaking at 41%-43% in Central and South-Eastern Asia but falling below 20% in the Caribbean and Central America, and showed a negative association with HDI. The LRI/LRM ratio increased with socioeconomic development. Temporal analyses showed increasing LRI trends in 17 of 42 countries for CRC versus 9 for RC, while declines occurred in 14 countries for RC and 11 for CRC. Conclusions: RC constitutes a substantial yet epidemiologically distinct component of the global CRC burden. Its proportional contribution varies across regions and does not parallel absolute risk patterns, supporting the need for subsite-specific surveillance and prevention strategies.

BackgroundPrecision oncology is predominantly focused on nuclear genomic alterations, while mitochondrial DNA (mtDNA) variation remains largely excluded from routine pharmacogenomic testing. However, mitochondria regulate oxidative phosphorylation (OXPHOS), reactive oxygen species (ROS) production, apoptosis, and metabolic reprogramming pathways central to chemotherapy response. Methods468 Complete mitochondrial genomes from Kenyan individuals representing diverse ethnolinguistic groups were analyzed. Seven variants associated with effect on cancer treatment were identified. These include; m.310T>C(D-loop), m.10398A>G (MT-ND3), m.13708G>A (MT-ND5), m.16189T>C, m.13928G>C, m9055G>A and m.16519T>C (D-loop). Allele frequencies and distribution were assessed. ResultsThe coding-region variants (m.10398A>G and m.13708G>A) occur in Complex I subunits and are associated with altered oxidative phosphorylation efficiency and ROS production. The control-region variants (m.16189T>C and m.16519T>C) influence mtDNA replication and copy number. These variants have been implicated in differential response to chemotherapeutic agents including platinum-based therapies and anthracyclines. m.13928G>C sits in the MT-CYB gene and could possibly affect mitochondrial respiratory function; this variant could influence how tumors respond to therapies that rely on apoptosis or ROS generation.m.9055G>A is a MT-ATP6 variant classified as benign in mitochondrial disease but may represent a marker of haplogroup background rather than a direct cancer driver. While m.310T>C itself does not encode a protein, its location in the regulatory D-loop influences mitochondrial function, which can affect how tumor cells respond to chemotherapies that rely on mitochondrial-mediated apoptosis or oxidative stress. ConclusionPharmacogenomics relevant mitochondrial variants are present in the Kenyan population. With the rise of cancer burden in Kenya there is a need carry out more studies to understand the impact of these variations on cancer treatment. This can inform the integration of mtDNA analysis into precision oncology strategies in African populations.

Background. The European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT) ranks genomic alterations by the evidence supporting the predictive value of the molecular target for response to targeted therapies. No openly available, systematically curated set of standard care biomarkers mapped to the ESCAT framework exists to support clinical decision-making or harmonize biomarker interpretation. Methods. We mapped all OncoKBTM Level 1 biomarkers to ESCAT tiers using evidence cited by OncoKBTM, excluding abstract-only data. Eight board-certified oncologists and hematologists independently assigned ESCAT tiers, with discrepancies resolved through structured consensus meetings. Recurring evidence scenarios that did not correspond to any existing ESCAT tier informed a set of a priori defined modifications, which were subsequently applied to biomarkers that could not be classified using native ESCAT criteria. Results. Of 188 OncoKBTM Level 1 biomarkers, 16 were excluded due to abstract-only evidence. Using native ESCAT criteria, 51% of the remaining biomarkers were classified as Tier 1, 3% Tier 2, 18% Tier 3, 6% Tier X and 22% could not be assigned to any tier. Applying the modified ESCAT criteria resolved all previously unclassifiable biomarkers and increased Tier 1 assignments to 73%. Inter-rater reliability (Krippendorffs alpha) was moderate (0.586) and 62% of classifications required consensus discussions. Comparison with ESCAT tiers reported in ESMO Clinical Practice Guidelines showed improved concordance when using the modified criteria. Conclusions. The native ESCAT criteria are highly stringent, resulting in many FDA-recognized, clinically validated biomarkers that are currently assigned level 1 by OncoKBTM not mapping to any existing tier. Our predefined modifications improved alignment with OncoKBTM Level 1 designations and with published ESMO clinical practice guidelines. The mapped set of standard care biomarkers are provided on the OncoKBTM website, offering a practical resource that harmonizes ESCAT tiers of evidence with a widely adopted levels of evidence schema.

Immune checkpoint inhibitors such as anti-PD1 antibodies are essential in cancer therapy. Emerging data suggest that lower doses may be effective and more economical, though further evidence is needed. We conducted a retrospective study at Centre Leon Berard to assess the efficacy and safety of low-dose nivolumab (20 mg every three weeks) in patients with advanced cancer, mainly squamous cell carcinomas (SCC). Between 2023 and 2024, 53 patients were treated, with a median age of 74 years; 39.6% were over 80. Most were male (64%) and had ECOG >1 (69.9%). Primary tumor sites included cutaneous SCC (34%), head and neck SCC (32%), and soft tissue sarcoma (15%). After a median follow-up of 8.3 months, median overall survival was 7.5 months. The objective response rate (ORR) was 20.8% overall, rising to 35.3% in cutaneous SCC and 23.5% in head and neck SCC-comparable to standard-dose nivolumab. Toxicity was manageable: 18.7% experienced immune-related adverse events, with only 3.7% grade 3. Low-dose nivolumab demonstrates encouraging efficacy and tolerability in a frail population, supporting its potential role in resource-limited settings. Prospective trials are warranted to confirm these findings in broader populations.

PurposeEarly detection of cancer can improve survival following diagnosis. However, routine screening is limited to a few cancer types. Multi-cancer early detection (MCED) tests could substantially expand cancer screening by simultaneously detecting multiple cancer types. This modeling study evaluates the potential impact of an MCED test on cancer outcomes in the US general population. MethodsWe developed a microsimulation model of 14 solid tumor cancer types which account for nearly 80% of cancer incidence and mortality. The model was calibrated to reproduce annual incidence rates reported in the Surveillance, Epidemiology, and End Results database. Cancer diagnosis could arise from standard-of-care (SoC) procedures or annual MCED testing. MCED sensitivities were derived from a case-control clinical validation study. We simulated the 10-year life course of 5 million US adults aged 50-84 years. The primary outcome was cancer mortality reduction due to MCED testing. ResultsIn the best case with perfect uptake and adherence, MCED testing added to the SoC led to a 23% decrease in 10-year cancer mortality relative to the SoC alone, translating to 668,600 cancer deaths averted over 10 years. The largest mortality reductions, in absolute terms, were observed for lung (160; 802 versus 962 per 100,000), colorectal (118; 168 versus 284), and pancreatic (50; 238 versus 288) cancer. The largest relative reductions were in cervical (52%), colorectal (41%), and breast (34%) cancer. The population-level life-year gain was 7,158 years per 100,000. ConclusionMCED testing has the potential to substantially reduce cancer-related deaths, improve outcomes across multiple cancer types.

IntroductionPathogenic germline variants in the BRCA1 and BRCA2 genes confer a markedly increased risk of breast and ovarian cancer, for which effective preventive strategies are available. Although national and international guidelines recommend BRCA testing and cascade screening of relatives, implementation in Italy remains highly heterogeneous across regions. This study estimates the potential population health and cost impact of achieving full nationwide implementation of BRCA1/2 cascade screening in Italy and identifies key organisational barriers and priority actions for implementation. MethodsWe conducted a Health Impact Assessment integrating literature review, simulation modelling, and stakeholder consultation. A decision tree and Markov model compared the current heterogeneous implementation of BRCA screening in Italy with an ideal scenario reflecting full adherence to national guidelines, optimal cascade screening, and uptake of preventive strategies. Outcomes included breast and ovarian cancer incidence and mortality, healthcare costs over a lifetime horizon (80 years). Key barriers affecting organisational feasibility, acceptability, and patient well-being were assessed, and a set of priority action recommendations was developed. ResultsIn the ideal scenario, 25,626 eligible cancer patients would undergo BRCA testing annually, identifying 4,254 mutation carriers and enabling cascade testing of 27,650 relatives, of whom 8,682 would be BRCA-positive. Under the current implementation, only 8,807 patients and 2,168 relatives are tested, identifying 948 carriers. Over 30 years, full implementation would prevent 821 cancer cases (-27.9%) and 1,282 deaths (-49.7%) compared with the current scenario. While initial expenditures increase due to expanded testing and preventive interventions, cumulative costs decrease over time, resulting in net savings of {euro}5.8 million at 30 years and a saving per event avoided (-{euro}2,779). Major implementation barriers include fragmented governance, limited access to genetic counselling, heterogeneous laboratory practices, insufficient professional training, and weak referral pathways. ConclusionFull implementation of BRCA1/2 cascade screening in Italy would yield substantial population health benefits and long-term cost savings. Coordinated national governance, standardized pathways, investment in counselling and workforce capacity, and robust monitoring systems are essential to ensure equitable access and sustainable delivery of personalized cancer prevention. This study demonstrates the value of the HIA methodology for evaluating and guiding genomic prevention policies.

Background: The European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines on nutrition for cancer patients provides evidence based dietary recommendations that is routinely deployed by dieticians in oncology settings. Although these can be culturally adapted, they do not adequately address inter individual variability in treatment related gastrointestinal symptoms and appetite, issues that increase malnutrition risk in cancer patients. Ayurveda, on the other hand, lacks nutrient based guidelines but offers a well grounded dietary framework to assess digestive function and personalise diets. This study investigated the feasibility of combining the two approaches in a clinical setting. Methods: Consenting adult cancer patients diagnosed with any type and stage of cancer were recruited. At baseline, digestive strength, dietary intake, quality and frequency and Patient Generated Subjective Global Assessment (PGSGA) score were recorded. Based on this, personalised meal plans (MPs) that combine nutrient guidelines from ESPEN and traditional food concepts to support digestive strength were provided to participants. Follow ups ranged from 4 weeks to 6 months, at which digestive strength and PGSGA was noted. To evaluate against a benchmark, meal plans were theoretically constructed using Ayurveda concepts (traditional MP) or ESPEN guidelines (Standard MP) alone. Results: Data is presented for 33 participants, of which 52% had weak digestive strength. Baseline intake averaged 879 kcal/day, well below the recommended 1400 to 1600 kcal/ day level. Traditional MPs improved energy intake but were protein insufficient, aspects that were addressed in the standard MPs. Diet quantity (1417 kcal/day), quality and frequency improved on the integrated MP, with 3 patients achieving optimal digestive strength. Personalised counselling reduced malnutrition risk, as reported by PGSGA score. Conclusion: Customising dietary advice by overlaying nutrient guidelines with Ayurveda dietary concepts is feasible. The evaluation of digestive strength holds promise for personalising nutrition therapy. Trial Registration: CTRI/2023/07/055657

IntroductionColorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide, despite advances in conventional oncological therapies. In recent years, various studies have made advances in integrative oncology, such as investigating the use of Chinese Herbal Medicine (CHM) as a complementary therapy alongside conventional oncological therapies to alleviate treatment-related adverse effects, improve quality of life, and potentially enhance therapeutic outcomes. Despite this, clinical practice in this area remains highly heterogeneous, with limited standardized guidelines on key areas of concern such as (1) optimal intervention, (2) recommended stage and duration of intervention, (3) safety considerations, and (4) possible herb-drug interactions. Hence, this study aims to establish expert consensus on the usage of CHM as a complementary therapy in the management of CRC, to support safe, consistent, and evidence-informed clinical practice. Methods and AnalysisWe will employ a modified Delphi technique to achieve consensus amongst a panel of international experts in various fields related to integrative oncology. Prior to the study, a list of questionnaire items was developed based on a systematic review of existing clinical practice guidelines on CRC. An international panel will be invited based on established international profile in integrative oncology research and clinical practice, and by peer referral. Two rounds of Delphi will be conducted using anonymous online questionnaires. Consensus will be considered reached if at least 50% of the panel strongly agree/disagree that an item should be included or excluded while strong consensus will be set at 76%. Items which achieve strong consensus after Round 1 will be removed, before being sent out for Round 2 with a summary of Round 1 responses for a final consensus. Ethics and DisseminationEthics approval has been obtained from the Institutional Review Board of Nanyang Technological University (IRB-2025-1222). Our findings will be disseminated through peer-reviewed publications and conference presentations. Strengths and limitations of this studyO_LIThis study will develop an expert consensus which aims to guide future integration of Chinese Herbal Medicine (CHM) as a complementary therapy into colorectal cancer (CRC) management. C_LIO_LIKey concerns in areas such as determining the (1) optimal intervention, (2) recommended stage and duration of intervention, (3) safety considerations, and (4) possible herb-drug interactions, thereby laying the groundwork for potential future incorporation of CHM into CRC treatment protocols alongside conventional oncology approaches has been identified, thus limiting implementation in clinical practice. C_LIO_LIDesigning a study e-guide, followed by the consensus rounds study online will facilitate participants responses and the dissemination of information from previous rounds. C_LI

BackgroundMesonephric-like adenocarcinoma has been recently classified as a rare type of ovarian carcinoma. Description of these tumours have been rare and mostly covered in case reports. In some cases, molecular characterization by sequencing has been employed for guided therapy recommendations, however, functional chemosensitivity testing of targetable pathways using advanced in vitro cellular models such as organoids has not been reported so far. Here, we report on a case of ovarian cancer that was later identified as mesonephric-like adenocarcinoma at an advanced stage. MethodsThe tumour was characterized by molecular techniques including immunohistochemistry and whole-exome sequencing. At the same time, ovarian cancer organoids were established by adapting existing protocols for high-grade serous ovarian carcinoma. The organoids were subsequently used for functional in vitro chemosensitivity testing by treatment with standard-of-care chemotherapeutics cisplatin, paclitaxel, and the Poly (ADP-Ribose) Polymerase 1-inhibitor olaparib. Based on molecular characteristics, we also applied the inhibitor binimetinib, to target Mitogen-Activated Protein Kinase downstream of the KRAS Proto-Oncogene. Additionally, chemotoxicity testing with healthy fallopian tube organoids and high-grade ovarian cancer organoids was applied to determine the therapeutic window. ResultsImmunohistochemical analysis showed characteristic PAX8+, GATA3+, TFF1+, ER-, PR-, WT1- staining while the sequencing revealed mutations in 31 genes of which KRAS G12V and DYNC1H1 G4072S were annotated as (likely) pathogenic. The tumour was mismatch-repair proficient. Tumour-derived organoids proved to be highly resistant to standard-of-care chemotherapeutics cisplatin, paclitaxel, and olaparib, but sensitive to inhibition by binimetinib, which aligned well with the molecular characteristics. Direct comparison to healthy fallopian tube organoids and high-grade ovarian cancer organoids confirmed low cytotoxic potential underlining a feasible therapeutic window for binimetinib. ConclusionsFor the first time, we show that existing protocols for high-grade serous ovarian carcinoma can be used for the generation of organoids derived from mesonephric-like adenocarcinoma. These organoids could be used as an essential tool for functional precision medicine purposes. This functional data could be applied as an additional layer for molecular tumour boards diagnostics by supporting molecular datasets and even identify targetable pathways beyond genetic variations, thus offering novel therapeutic options particularly for rare and aggressive tumours.