Cancer Medicine

BackgroundDespite the role of pathogenic variants (PVs) in cancer predisposition genes conferring significantly increased risk of breast cancer (BC), uptake of genetic testing (GT) remains low, especially among ethnic minorities. Our prior study identified that a patient decision aid, RealRisks, improved patient-reported outcomes relative to standard educational materials. This study examined patients GT experience and its influence on subsequent actions. We also sought to identify areas for improvement in RealRisks that would expand its focus from improved GT decision-making to understanding results. MethodsWomen enrolled in the parent randomized controlled trial were recruited and interviewed. Demographic data was collected from surveys in the parent study. Interviews were conducted, transcribed, and coded to identify recurring themes. Descriptive statistics were generated to compare the interviewed subgroup to the original study cohort of 187 women. ResultsOf the 22 women interviewed, 11 (50%) had positive GT results, 2 (9.1%) with a BRCA1/2 PV, and 9 (40.9%) with variants of uncertain significance (VUS). Median age was 40.5 years and 15 (71.4%) identified as non-Hispanic. Twenty (90.9%) reported a family history of BC, and 2 (9.1%) reported a family history of BRCA1/2 PV. The emerging themes included a preference for structured communication of GT results and the need for more actionable knowledge to mitigate BC risk, especially among patients with VUS or negative results. Few patients reported lifestyle changes following the return of their results, although they did understand that their behaviors can impact their BC risk. ConclusionsPatients preferred a structured explanation of their GT results to facilitate a more personal testing experience. While most did not change lifestyle behaviors in response to their GT results, there was a consistent call for further guidance following the initial discussion of GT results. Empowering patients, especially those with negative or VUS results, with the knowledge and context to internalize the implications of their results and form accurate risk perception represents a powerful opportunity to mediate subsequent risk management strategies. Informed by this study, future work will expand RealRisks to foster an accurate perception of GT results and include decision support to navigate concrete next steps.

BackgroundWe previously reported the 16A antibody, which binds to the abnormally glycosylated tandem repeat region of the MUC1 glycoprotein, and developed 16A-MMAE as an antibody-drug conjugate. However, its antitumor efficacy as an antibody-drug conjugate with DNA topoisomerase Iinhibitors remains unknown. MethodsWe humanized the 16A antibody and conjugated it to DXd and MF6, two DNA topoisomerase I inhibitors. The antitumor efficacy of the conjugates was evaluated in vitro and in vivo. ResultsThe humanized 16A-DXd conjugate showed potent antitumoral efficacy, with an IC50 in the nM range against CFPAC1 cells. In vivo, h16A-DXd and h16A-MF6 inhibited tumor growth in asubcutaneous mouse tumor transplantation model using CT26-COSMC KO-hMUC1 cells, administered at a dose of 10 mg/kg. ConclusionsThe high antitumor efficacy of h16A-conjugated DNA topoisomerase I inhibitors supports further clinical development. The relatively low toxicity of h16A-DXd and h16A-MF6 may enable a higher therapeutic window, since MUC1-positive cells internalize the antibody-drug conjugate more efficiently.

BackgroundEnhanced Recovery After Surgery (ERAS) optimizes perioperative management for colorectal cancer (CRC), improving short-term outcomes, but its impact on long-term outcomes remains inconclusive, supporting the need for this meta-analysis. This study evaluates the effect of perioperative ERAS (therapy-focused) on 1-, 2-, 3-, and 5-year postoperative survival in patients with CRC. MethodsWe conducted a systematic review and meta-analysis following a pre-registered protocol in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Web of Science, Embase, Medline Ovid, and Cochrane Library Wiley were searched up to December 31, 2025, for clinical studies reporting long-term postoperative survival outcomes of patients with CRC undergoing ERAS implementation. Of 1,063 retrieved reports, 10 studies (5,876 patients) were included in Kaplan-Meier-based meta-analyses and eight studies (5,556 patients) in aggregated data meta-analyses. Data extraction was performed independently by two reviewers, with study quality and risk of bias assessed using the Newcastle-Ottawa Scale (NOS) and RevMan software. Effect sizes were pooled using fixed- or random-effects models according to heterogeneity, with cross-validation and subgroup analyses examining the influence of tumor stage and ERAS adherence. The pre-specified primary outcome was postoperative overall survival (OS) [&ge;]12 months, and the secondary outcome was disease-free survival (DFS). ResultsERAS significantly improved OS at 1 year (93.2%, 95% CI: 92.3-94.2 vs. 90.2%, 95% CI: 89.1-91.2), 2 years (86.7% vs. 81.3%), 3 years (81.1% vs. 72.4%), 5 years (70.9% vs. 60.6%) (all P<0.01). The pooled HR for mortality was 0.72 (95% CI: 0.63-0.83, P<0.01), indicating a 28% reduction in long-term mortality. Stage I-II tumors and ERAS adherence [&ge;]70% conferred the greatest benefits. DFS did not show a statistically significant improvement (HR=0.90, 95% CI: 0.68-1.19, P=0.45). Included studies were of moderate to high quality (NOS score 6-9). ConclusionsPerioperative ERAS significantly improves 1- to 5-year OS and reduces long-term mortality in patients with CRC, with the greatest benefits in early-stage disease and high adherence. These findings support ERAS as a critical component of comprehensive CRC care.

PURPOSETo synthesize adherence rates to colorectal cancer medications and identify predictors of nonadherence. METHODSFollowing PRISMA, we searched PubMed, Embase, PsycINFO, and Web of Science through August 13, 2024. Observational studies reporting adherence or predictors were eligible. Two reviewers independently screened and extracted data and assessed risk of bias using JBIs Checklist for Cohort Studies. Adherence was grouped by measurement approach: claims-based PDC/MPR, chart/clinical record review, or patient-reported. Random-effects meta-analyses were performed within clinically and methodologically homogeneous subgroups. RESULTSThirteen studies (n = 13) met inclusion, with adherence ranging from 33% to 100%. In claims-based analyses using PDC/MPR thresholds, pooled adherence was about 40% [95% CI, 0.36-0.44] with substantial heterogeneity (I2 = 84.6%). Pooled adherence was about 83% in both chart/record [95% CI, 0.44-0.97] (I2 = 71.4%) or patient-reported measures [95% CI, 0.68-0.92] (I2 = 93.8%), also with substantial heterogeneity. Nonadherence was more likely with advanced stage, ECOG [&ge;]1, multiple prior regimens, female sex, and treatment-related adverse events. The overall risk of bias was low, although some included studies lacked complete follow-up or strategies to address it. CONCLUSIONWe synthesized adherence to CRC medications and identified consistent predictors of nonadherence. Adherence was lowest with claims-based PDC/MPR and higher with chart or patient-reported measures. These findings support targeted interventions for patients at higher risk of non-adherence, including those in the advanced stage of the disease, those with multiple regimens, and those experiencing adverse events. Future work should use standardized adherence definitions and metric-specific reporting to enable valid pooling.

BackgroundIdentification of minimally invasive biomarkers of different stages of cachexia (Ca), and precachexia (PCa) in particular, might help clinicians in treating patients with pancreatic ductal adenocarcinoma (PDAC) at high risk of progressing to a more severe cachectic stage. In this work, we developed a machine-learning (ML) model optimized to blood biomarkers data that identifies precachectic and cachectic patients. MethodsBlood and clinical data was collected from treatment-naive patients with PDAC through the Florida Pancreas Collaborative (FPC), a multi-institutional cohort study and biobanking initiative. Blood was processed into serum and assayed for a total of 35 candidate biomarkers. Participants were classified as having noncachexia (NCa), precachexia, or cachexia according to modified criteria by Vigano and colleagues which consider unintentional weight loss and biochemical data. Using these data, we designed ML algorithms to: (i) pre-select predictive blood biomarker candidates using a combination of mutual information method together with the leave-one-feature-out (LOFO) feature importance approach; (ii) identify the minimal combination of predictive biomarkers using the forward feature selection method; (iii) determine the optimal classification hyperparameters for the support vector machine using a cross-validation technique; and (iv) adjust the decision-boundary threshold for imbalanced data using the Matthews correlation coefficient. Three ML-based binary predictors were designed to determine patients cachexia status: NCa vs. Ca; PCa vs. Ca; and PCa vs. NCa. ResultsThe biomarker levels from 184 patients (28 NCa, 53 PCa, and 103 Ca) were used in this study. The NCa vs. Ca predictor identified a set of 6 biomarkers and yielded area under the curve (AUC) of 0.835. The PCa vs. Ca predictor identified a set of 6 biomarkers and yielded AUC of 0.810. The PCa vs. NCa predictor identified a set of 5 biomarkers and yielded AUC of 0.771. ConclusionsThe developed ML models that use blood biomarker data provided effective predictions of patients cachexia stage that can help clinicians to diagnose PCa.

BackgroundGastric cancer (GC) continues to be among the most commonly identified cancers worldwide. This study integrates glycosylation and inflammation-related gene features for the first time to construct a prognostic model for gastric cancer, providing new theoretical basis for revealing immune escape mechanisms and personalized treatment strategies. MethodsTranscriptomic and clinical data derived from GC samples were meticulously examined, utilizing resources from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Through differential expression analysis, we successfully identified glycosylation and inflammatory-related differentially expressed genes (GANDIRDEGs). To construct a prognostic gene signature, we applied least absolute shrinkage and selection operator (LASSO) analysis in conjunction with Cox regression analysis. Additionally, we performed somatic mutation (SM) along with copy number variation (CNV) analyses, alongside gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Furthermore, we conducted gene set enrichment analysis (GSEA) along with a comprehensive evaluation of immune infiltration and drug sensitivity. ResultsWe identified and validated a six-gene (INHBA, OLR1, ROS1, EPHA5, TACR1, and IL6) signature, termed GANDIRDEGs, which showed excellent performance in distinguishing overall survival (OS) between high-risk (HR) and low-risk (LR) cohorts. Moreover, we developed a prognostic nomogram utilizing this six-gene signature that provides highly accurate predictions of GC patient outcomes.SM and CNV analyses revealed that MSR1 had the highest mutation rate among the GANDIRDEGs, with a mutation rate of 5%. GO, KEGG, and GSEA revealed significant associations of each pivotal gene with pathways, including cytokine signaling, the inflammatory response, and apoptosis mediated by CDKN1A through TP53, among various biological functions and signal transduction pathways. Our findings offer a novel gene signature, GANDIRDEGs, that correlated with prognosis, immune infiltration, and therapeutic sensitivity in patients with GC. ConclusionThis study establishes a prognostic signature integrating glycosylation and inflammatory pathways in GC, providing valuable insights into the mechanisms of immune evasion and potential personalized treatment approaches.

ObjectiveGemcitabine (GEM) is commonly chosen for treating pancreatic cancer. However, its use is limited by toxicity. Earlier in vitro studies with GEM in combination with Bromelain (Brom) and Acetylcysteine (Ac) indicated a substantial reduction in IC50. Here, we investigated the efficacy and safety of Brom and Ac (BromAc) in the pancreatic cancer model in vivo. DesignBoth low dose and high dose studies for safety and efficacy of BromAc and GEM were conducted in nude mice. Body weight, wellbeing and tumor volume were monitored. At autopsy, tumor weight, tumor density, percentage of tumor necrosis, expression of Ki67 antigen, and immunohistological evaluation of vital organs were compared between the treatment groups. ResultsThe low and high doses of BromAc alone and with chemotherapy agents were safe. A very significant reduction in pancreatic tumor volume, weight, and ki67 were seen with BromAc therapy and was equal to treatment with GEM alone and better than treatment with 5-FU. In addition, tumor density was significantly reduced by BromAc. ConclusionThese encouraging results are the first in vivo evidence of the efficacy of BromAc in pancreatic cancer and provide some mechanistic leads.

BackgroundTo comprehensively assess and validate the associations between insulin-like growth factor 2 (IGF2) gene methylation in peripheral blood leukocytes (PBLs) and colorectal cancer (CRC) risk and prognosis. MethodsThe association between IGF2 methylation in PBLs and CRC risk was initially evaluated in a case-control study and then validated in a nested case-control study and a twins case-control study, respectively. Meanwhile, an initial CRC patient cohort was used to assess the effect of IGF2 methylation on CRC prognosis and then the finding was validated in the EPIC-Italy CRC cohort and TCGA datasets. A propensity score (PS) analysis was performed to control for confounders, and extensive sensitivity analyses were performed to assess the robustness of our findings. ResultsPBL IGF2 hypermethylation was associated with an increased risk of CRC in the initial study (ORPS-adjusted, 2.57, 95% CI: 1.65 to 4.03, P<0.0001), and this association was validated using two independent external datasets (ORPS-adjusted, 2.21, 95% CI: 1.28 to 3.81, P=0.0042 and ORPS-adjusted, 10.65, 95% CI: 1.26 to 89.71, P=0.0295, respectively). CRC patients with IGF2 hypermethylation in PBLs had significantly improved overall survival compared to those patients with IGF2 hypomethylation (HRPS-adjusted, 0.47, 95% CI: 0.29 to 0.76, P=0.0019). The prognostic signature was also observed in the EPIC-Italy CRC cohort, although the HR did not reach statistical significance (HRPS-adjusted, 0.69, 95% CI: 0.37 to 1.27, P=0.2359). ConclusionsIGF2 hypermethylation may serve as a potential blood-based predictive biomarker for the identification of individuals at high risk of developing CRC and for CRC prognosis. FundingThis work was supported by the China Postdoctoral Science Foundation (grant number 2018M641875 to YPL); the Natural Science Foundation of Heilongjiang Province (grant number YQ2019H021 to YPL); the National Natural Science Foundation of China (grant number 81473055 to YSZ), and by grant from the SCORE Foundation (Y-MX2016-045 to YLL). Clinical trial numberNot applicable.

BackgroundAppendiceal tumors comprise a heterogeneous group of tumors which may be localized or disseminate throughout the peritoneum. Limited high quality clinical data exists and many practices have been extrapolated from colorectal cancer without validation in appendiceal cohorts. Many controversies exist regarding their treatment, and practices vary widely between centers and care settings. A national consensus update of best management practices for appendiceal malignancies was performed to better standardize care. MethodsThe 2018 Chicago consensus guideline was updated via modified Delphi consensus, performed over two rounds using nationally circulated surveys. Supporting evidence was evaluated using rapid systematic reviews. Key systemic therapy concepts were summarized by content experts. ResultsMost supporting literature consists of observational studies, but increasingly high-quality studies are becoming available to drive management. Two consensus-based pathways were generated for localized appendiceal tumors, one for epithelial mucinous neoplasms and another for appendiceal adenocarcinoma. Of 138 participants responding in the first round, 133 (96%) engaged in the second round. Over 90% consensus was achieved for all pathway blocks. Key points include minimizing intervention invasiveness where permitted by pathologic classification and margin status, and determining what margin and pathologic findings are indications for consideration of cytoreduction with or without intraperitoneal chemotherapy. Surveillance and systemic therapy recommendations are also presented. ConclusionWith growing but still primarily observational evidence currently dictating care, these consensus recommendations provide expert guidance in the treatment of appendiceal tumors without peritoneal involvement.

PurposeTumor genomic testing (TGT) is standard-of-care for most patients with advanced/metastatic cancer. Despite established guidelines, patient education prior to TGT is frequently omitted. The purpose of this study was to evaluate the impact and durability of a concise 3-4 minute video for patient education prior to TGT in community versus academic sites and across cancer types. Patients and MethodsPatients undergoing standard-of-care TGT were enrolled at a tertiary academic institution in three cohorts: Cohort 1-breast cancer; Cohort 2-lung cancer; Cohort 3-other cancers. Cohort 4 consisted of patients with any cancer type similarly undergoing SOC TGT at one of three community cancer centers. Participants completed survey measures prior to video viewing (T1), immediately post-viewing (T2), and after return of TGT results (T3). Outcome measures included: 1) 10-question objective genomic knowledge/understanding (GKU); 2) 10-question video message-specific knowledge (VMSK); 3) 11-question Trust in Physician/Provider (TIPP); 4) perceptions regarding TGT. ResultsA total of 203 participants completed all survey timepoints. Higher baseline GKU and VMSK scores were significantly associated with higher income and greater years of education. For the primary objective, there was a significant and sustained improvement in VMSK from T1:T2:T3 (Poverall p<0.0001), with no significant change in GKU (p=0.41) or TIPP (p=0.73). This trend was consistent within each cohort (all p[&le;]0.0001). Results for four VMSK questions significantly improved, including impact on treatment decisions, incidental germline findings, and insurance coverage of testing. ConclusionsA concise, 3-4 minute, broadly applicable educational video administered prior to TGT significantly and sustainably improved video message-specific knowledge in diverse cancer types and in academic and community settings. This resource is publicly available at http://www.tumor-testing.com, with a goal to efficiently educate and empower patients regarding TGT while addressing guidelines within the flow of clinical practice.

BackgroundCancer survivors and secondary malignancy risk have increased following early diagnosis and advanced cancer treatments; however, secondary malignancy risk in cancer survivors and possibility of genetic susceptibility among young individuals with multiple cancers have scarcely been evaluated. We evaluated the risk of secondary malignancies in cancer survivors by primary cancer type, and the combination of cancer types frequently observed in young patients with multiple cancers. Methods and FindingsPatients diagnosed with cancer, from Korea Health Insurance Review and Assessment database, between January 2009 and December 2010, were followed-up until December 2019. Cancer survivors and those with secondary cancers were defined as having lived >5 years without developing other cancers; and being newly diagnosed with cancer at another site, respectively. To identify possible hereditary multiple cancer syndrome (HMCS), combinations of multiple cancers frequently observed in young individuals compared to older adults were evaluated. Of the 371,181 patients in 3,008,274 person-years of follow-up, 266,241 were cancer survivors; of these 7,348 had secondary cancers (2.76%; 2,759.9 persons/100,000 population), higher than primary cancer risk in general population. The common primary cancer types were those mainly observed as secondary cancer in cancer survivors. Contrarily, higher-risk cancers among those with secondary cancers compared to those in the general population varied by sex and primary cancer type, suggesting the need for tailored cancer screening for cancer survivors. Combinations of well-known hereditary cancer syndrome-related cancer types were mainly observed in younger compared to older patients with multiple cancers, which could be HMCS, including cancer combinations those may be caused by a novel cancer predisposition gene. ConclusionsCancer survivors harbor high and distinctive secondary cancer risk than the general population, necessitating tailored cancer screening in survivors. Genetic screening should be considered for young patients with multiple cancers to validate genetic predisposition.

Background and AimsThere is limited evidence on the link between ultra-processed food (UPF) intake and the risk of lung cancer (LC). This study examined the association between UPF and LC risk using data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer trial. MethodsThis study involved PLCO participants (n = 96,607, aged [&ge;] 55 years) who were followed between 1998 and 2009. Food items were categorized based on the NOVA classification. Cox regression models with inverse probability of censoring weighting (IPCW) were utilized to estimate the association between UPF intake and LC risk. The joint effect of UPF and diabetes was explored using additive hazard models to calculate the additional number of LC cases. ResultsDuring a median follow-up period of 9.4 years, 1,596 incident LC cases were identified. UPF consumption (in %gram/day) showed no significant association with the overall risk of LC. However, adults with diabetes in the highest quintile of UPF intake had a significantly higher risk of LC (HR = 2.44; 95% CI: 1.27, 4.67) compared to participants without diabetes. A small excess risk due to the interaction between UPF and diabetes (0.13; 95% CI -0.32, 0.58) was observed, resulting in an additional 201 cases of LC per 105 person-years (95% CI: 70, 332) attributed to the highest UPF intake and diabetes interaction. Furthermore, a 10% increment in UPF intake (%kcal/day) increased the risk of LC by 32%. ConclusionsWhile UPF, in terms of weight contribution, is associated with a higher risk of LC in participants with diabetes, UPF (in %kcal/day), is associated with an increased risk of LC in all participants. Lowering UPF intake may help reduce the risk of LC in both diabetic patients and the general population.

BackgroundCancer death rates are declining, in part due to smoking cessation, better detection and new treatments; nevertheless, a large fraction of metastatic cancer patients die soon after diagnosis. Few studies and interventions focus on these patients. Our study aims characterize early mortality in a wide range of metastatic solid tumors. MethodsWe retrieved data on adult patients diagnosed with pathologically confirmed de-novo metastatic solid tumors between the years 2004-2016 from the Surveillance, Epidemiology, and End Results database (SEER). Our primary outcome was cancer specific early death rate (defined as death within two months of diagnosis). Additional data extracted included socio-demographical data, tumor primary, sites of metastases, and cause of death. Results109,207 (20.8%) died of cancer within two months of diagnosis. The highest rates of early death were found in hepatic (36%), pancreato-biliary (31%) and lung (25%) primaries. Factors associated with early death included primary site, liver and brain metastases, increasing age and lower income. Cancer was the cause of death in 92.1% of all early deaths. Two-month mortality rates have improved during the study period (from 22.4% in 2004 to 18.8% in 2016). ConclusionA fifth of metastatic cancer patients die soon after diagnosis, with little improvement over the last decade. Further research is required to better classify and identify patients at risk for early mortality, which patients might benefit from faster diagnostic tracks, and which might avoid invasive and futile diagnostic procedures.

BackgroundCancer Centers offer a comprehensive approach to cancer prevention, diagnosis, and treatment through tertiary services and by providing coordinated, personalized care. We investigated whether this approach results in significantly better patient outcomes at an NCI-designated Comprehensive Cancer Center (NCI-CCC), City of Hope (COH), versus the U.S. Surveillance, Epidemiology, and End Results (SEER) national database. MethodsPatient-level data were abstracted from the COH Cancer Registry and SEER*Stat software, respectively. The cohort included patients diagnosed with incident cancer from 2004 to 2020. Overall survival was analyzed using multivariable Cox proportional hazards models. To reduce confounding from baseline differences, propensity score matching (PSM) methods were employed in a 1:5 ratio between COH and SEER, respectively, using age group at diagnosis category, gender, race, ethnicity, stage (for solid tumors), and diagnosis year. FindingsPatients treated at COH had significantly superior overall survival (OS) compared with those in the SEER cohort across all examined cancer types after multivariable adjustment for key baseline characteristics and in the PSM analyses. Median OS (when reached) was uniformly longer in the COH cohort compared with the SEER cohort in the full population adjusted model and in the PSM analyses. For the PSM analyses: non-small cell lung cancer (NSCLC) hazard ratio (HR) 0.73 (95% confidence interval [CI]: 0.70-0.76), breast cancer HR 0.83 (95% CI: 0.78-0.86), prostate cancer HR 0.62 (95% CI: 0.58-0.65), colorectal cancer HR 0.74 (95% CI: 0.69-0.79), pancreatic cancer HR 0.75 (95% CI: 0.70-0.81), acute myeloid leukemia HR 0.79 (95% CI: 0.75-0.84), acute lymphoid leukemia HR 0.7 (95% CI: 0.69-0.87), and multiple myeloma HR 0.70 (95% CI: 0.66-0.76) (all p<0.001). In addition, notable findings included substantially lower mortality risk for patients with any of the studied advanced solid cancers, including stage IV NSCLC (HR 0.71, 95% CI: 0.67-0.75, p<0.001) and stage IV breast cancer (HR 0.78, 95% CI: 0.69-0.87, p<0.001). ConclusionsOur results revealed patient care at an individual NCI-CCC employing state-of-the-art therapies and modern care is associated with survival benefits for cancer patients. Patients had significantly superior OS in the COH cohort compared with the SEER cohort for most of the analyzed solid tumors assessed for each stage (I-IV) and for 3 major hematologic malignancies assessed by age group. Until randomized comparisons studies are possible and the SEER data becomes more comprehensive, the specific causes of the observed benefit and identifying patients that benefit most may be subject to considerable debate. Additional research can help determine with greater granularity the drivers of the survival benefit and highlight an opportunity to make adjusted survival outcomes more accessible to patients, complementing the data currently available because of price transparency mandates. Such efforts may help ensure that all patients benefit from precision medicine approaches.

BackgroundLiver metastasis is a frequent and serious complication of pancreatic cancer, contributing to its high mortality rate. Identifying risk factors and understanding the timing of liver metastasis may improve early detection and support more effective treatment planning. MethodA cohort of 12,955 incident pancreatic cancer patients was assembled from the Truveta platform. A subgroup of cases and controls that met the inclusion/exclusion criteria was analyzed using logistic regression and was reported as the primary analysis for this study. Effects on time to liver metastasis were also analyzed using univariate and multivariate Cox regression models. The primary outcome was the occurrence of liver metastasis within 1 year of diagnosis. Subjects were categorized as having baseline metastasis ([&le;] 30 days from pancreatic cancer diagnosis) or post-baseline metastasis (>30 days). Demographic characteristics and comorbidities were evaluated for their potential role as risk factors. ResultAmong 7,858 patients in the case-control cohort, 2,920 (37%) developed liver metastasis within one year, while 2,066 (70%) subjects were diagnosed with metastasis at baseline. Male sex, older age, and a history of Type 2 diabetes mellitus, depression, obesity, anemia, abdominal pain, and distant metastasis were significantly associated with a higher risk of liver metastasis. Lower odds of liver metastasis were observed among Black or African American and Hispanic or Latino subjects. In the subgroup analysis after removing baseline metastasis, surgery and radiotherapy were protective, while tumors located in the head of the pancreas showed a higher risk for metastasis in this cohort. ConclusionsThis study identified key clinical and demographic risk factors for liver metastasis in pancreatic cancer, emphasizing the importance of using real-world data, analyzing the timing of disease progression, and highlighting opportunities for earlier intervention and personalized care.

BackgroundThe peritoneum is a common site of metastases from colorectal cancer (CRC), yet controversy exists regarding optimal treatment strategies. These guidelines describe the results of a national consensus addressing the management of CRC with peritoneal metastases (CRC-PM). MethodsAn update of the 2018 Chicago Consensus Guidelines was conducted using a modified Delphi technique. Two rounds of voting were performed to assess agreement levels on two clinical management pathways regarding synchronous and metachronous CRC-PM. Supporting evidence was evaluated via rapid literature reviews. ResultsThe overall level of evidence was low in existing literature. Of 145 participants in the first round, 136 (96.8%) responded in the second round. Over 90% consensus was achieved in most pathway blocks. For both pathways, early referral to a peritoneal surface malignancy (PSM) center should be made for patients with CRC-PM. For the synchronous pathway, upfront cytoreductive surgery was de-emphasized in favor of systemic therapy. For the metachronous pathway, risk stratification via clinical and pathologic features was revised. For both pathways, surveillance strategies were added, including only a weak recommendation for circulating tumor DNA (ctDNA) testing given limited evidence of its utility in detecting and monitoring PM. ConclusionThe consensus-driven clinical pathways provide valuable guidance for the management of CRC-PM. There remains a need for high-quality evidence and prospective multicenter trials in this domain. SYNOPSISWe developed two consensus-driven clinical pathways for the management of colorectal cancer with peritoneal metastases (CRC-PM), using a modified Delphi approach. Rapid reviews evaluating the optimal systemic therapy and the role of plasma-based liquid-biopsy for CRC-PM were conducted.

Background and aimsDNA repair deficiency is a common feature of cancer. Homologous recombination (HR) and nucleotide excision repair (NER) are the two most frequently disabled DNA repair pathways in solid tumors. HR deficient breast, ovarian, pancreatic and prostate cancers respond well to platinum chemotherapy and PARP inhibitors. However, the frequency of DNA repair pathway deficiency in gastric and esophageal adenocarcinoma (GEA) still lacks diagnostic and functional validation. Furthermore, whether DNA repair deficient GEA have enhanced responsiveness to platinum chemotherapy and sensitivity to PARP inhibitors is not well characterized. MethodsUsing whole exome and genome sequencing data, we measured various HR deficiency-associated mutational signatures in patient specimen of gastric, esophageal and colorectal cancer specimens and gastric cancer cell lines. Gold-standard immunofluorescence assays were used to confirm HR and NER deficiency in cancer cell lines. The relationship between PARP inhibitor treatment and tumor response was evaluated in patients with gastric cancer. Drug sensitivity was determined using standard in vitro cell culture assays. Single-cell RNA-sequencing was performed to evaluate gastric cancer response to commonly used chemotherapeutics. ResultsWe found that a significant subset of GEA, but very few colorectal tumors, show evidence of HR deficiency by mutational signature analysis (HRD score). Gastric cancer cell lines with high HRD mutational signature scores demonstrated functional HR deficiency by RAD51 assay and increased sensitivity to platinum and PARP inhibitors. There was a positive association between HRD scores and tumor response in patients with gastric cancer treated with a PARP inhibitor on a clinical trial. A gastric cancer cell line with strong sensitivity to cisplatin showed HR proficiency but exhibited NER deficiency by DDB2 proteo-probe assay. Single-cell RNA-sequencing revealed that, in addition to inducing general apoptosis, cisplatin treatment triggered ferroptosis in a NER-deficient gastric cancer, which may explain the outlier sensitivity. ConclusionA subset of upper gastrointestinal tumors have genomic features of HR and NER deficiency and therefore may be more likely to benefit from platinum chemotherapy and PARP inhibition.

BackgroundPharmacogenomics has emerged as a crucial tool in precision medicine, offering the potential to personalise cancer treatments by predicting and managing therapy-induced toxicities. This systematic review examined the genetic basis of toxicities associated with radiotherapy, chemotherapy, and immunotherapy in solid tumours. MethodsA comprehensive literature search was conducted across PubMed, Google Scholar, and PharmKB databases, covering the period from December 2019 to July 2024. This review focused on genetic variants linked to different treatment-related toxicities, including chemotherapy, radiotherapy, and immunotherapy, across various solid tumour types. ResultsThe review primarily assessed immune-related adverse events and dermatologic, haematologic, neurological, and organ-specific toxicities (e.g. ototoxicity, hepatotoxicity, nephrotoxicity, and cardiotoxicity). This review highlights single-nucleotide variants (SNVs) as essential genetic markers for identifying treatment-related toxicities. However, data on many SNVs remains limited, highlighting the need for further research and clinical validation. These findings suggest that the understanding of genetic factors that contribute to toxicity may support treatment decisions, optimise patient outcomes, and promote advances in the field of precision oncology. ConclussionThe identification of specific genetic variants could prevent the use of expensive and ineffective treatments and guide the selection of patients most likely to benefit from a specific therapy. Here, we provide valuable insights into the current state of knowledge regarding the genetic basis of toxicity in solid tumour treatments and emphasise the importance of integrating pharmacogenomics into personalised cancer care. To enhance patient outcomes and reduce the economic burden of cancer treatment, further research must validate these genetic markers and integrate the findings into clinical practice, thereby avoiding ineffective treatments for patients.

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.

BackgroundIn this Phase II randomized clinical trial, we evaluated a medically supervised ketogenic diet (MSKD) compared to a usual diet (non-MSKD) when combined with the triplet chemotherapy regimen of gemcitabine, nab-paclitaxel with cisplatin in patients with treatment-naive advanced pancreatic ductal adenocarcinoma (PDAC). MethodsPatients with treatment-naive metastatic PDAC were randomized 1:1 to MSKD or non-MSKD while receiving gemcitabine, nab-paclitaxel, cisplatin on Days 1, 8 of a 21-day cycle. The MSKD was guided by tracking of daily ketone (beta-hydroxybutyrate, BHB) and glucose levels, a web-based application, education, and communication with a remote care team to maintain nutritional ketosis, targeting BHB 0.5-3.0mM. Patients with BMI < 18 kg/m2, type 1 diabetes or history of diabetic ketoacidosis were excluded. The primary endpoint was progression-free survival (PFS), tested using a one-sided alpha level of 0.20. Secondary endpoints included overall survival (OS), disease control rate (DCR; partial response + complete response + stable disease at 9 weeks), incidence and severity of adverse events (AEs) and changes in CA 19-9, fasting insulin, HbA1c, BHB, body weight, and quality of life (QLQ-C30). FindingsFifty-six patients with untreated metastatic PDAC were consented, of which 41 were eligible and 36 were enrolled and randomized. Among 32 evaluable patients (median age 65.9 years; 53% male), 16 were randomized to each arm. In the MSKD arm, 15 of 16 patients achieved nutritional ketosis at any point during the study, with mean BHB of 0.49 mM (95% CI 0.36-0.63) and median proportion of days in ketosis of 39.4% (range 0-95.8%). The study met its primary endpoint. Patients on the MSKD had a PFS by RECIST or clinical progression of 8.5 months, compared to non-MSKD of 5.5 months, HR (95% CI) = 0.53 (0.20 - 1.36) p = 0.092 (one-sided). Patients in the MSKD arm had a median OS of 13.7 months versus 10.2 months in the non-MSKD arm, HR (95% CI) = 0.58 p = 0.107 (one-sided). All MSKD-related AEs were Grade 1-2 and included fatigue, constipation, weight loss, decreased appetite, dehydration, dizziness and nausea. None of the patients stopped the MSKD due to related AEs. There were no significant differences in grade [&ge;]3 chemotherapy-related AEs between the arms. ConclusionsA medically supervised ketogenic diet is feasible in patients with treatment-naive metastatic pancreatic adenocarcinoma, and when combined with gemcitabine, nab-paclitaxel, and cisplatin, demonstrates significant improvements in progression-free and overall survival, without added toxicity or detriment to quality of life. Larger studies are required to definitively establish the value of ketogenic diet in pancreatic cancer treatment.