O'Donnell, C.

Background: Colorectal neuroendocrine carcinomas (NECs), including small cell (SCNEC) and large cell (LCNEC) subtypes, are rare but aggressive malignancies with limited population-level data. Moreover, prior studies have limited stratification by histologic subtype and anatomic location, despite evidence of disease heterogeneity in colorectal malignancies. This study aimed to characterize the clinical characteristics, treatment patterns, and outcomes of colorectal NEC by histologic subtype and tumor location, and to compare them with neuroendocrine tumors (NETs) and adenocarcinomas (ACs). Methods: A retrospective cohort review was conducted utilizing the SEER database from 2000 to 2022 to identify patients with colorectal SCNEC, LCNEC, NET, and AC. Demographic, clinical, therapeutic and survival data were analyzed and compared using Kaplan–Meier methods, log-rank tests, and Cox proportional hazards regression. Results: A total of 790 SCNEC, 498 LCNEC, 31,200 NET, and 638,898 AC cases were identified. SCNEC and LCNEC were associated with advanced stage at diagnosis (66% and 55% stage IV, respectively) and inferior survival outcomes compared to NET and AC (median OS (mOS) of 7 and 8 months for SCNEC and LCNEC, respectively, p = 0.0002). Stratified by location, colonic SCNEC had the poorest survival (mOS 5 months), worse than rectal SCNEC (mOS 9 months); this pattern was not observed in LCNEC. Surgical resection was associated with improved OS in both NEC subtypes (HR range 0.25–0.56, all p < 0.012). Radiation therapy was associated with improved survival in NEC overall (SCNEC HR 0.58; LCNEC HR 0.71, both p < 0.05), with the observed benefit appearing greatest in rectal NEC. Demographic factors were associated with survival in NET and AC but had no significant impact in NEC. Conclusions: Colorectal SCNEC and LCNEC are highly aggressive malignancies with poor outcomes, with SCNEC demonstrating modestly inferior outcomes compared to LCNEC. This study demonstrates that both histologic subtype and anatomic site of disease are important determinants of prognosis and treatment response. This supports the concept that colorectal NEC represents a biologically heterogeneous disease, with colonic SCNEC showing the worst outcomes and rectal NEC associated with a potential enhanced response to radiation. These findings support the need for further prospective and molecular studies to better define treatment approaches and targeted therapies for these rare malignancies.

Background/Objectives: Locoregional anal squamous cell carcinoma (ASCC) is usually cured with chemoradiotherapy; however, some patients relapse, require salvage abdominoperineal resection or develop metastatic disease. Approximately 90% of cases are driven by high-risk human papillomavirus, most commonly HPV16. Conventional surveillance using clinical examination and imaging may have limited sensitivity and specificity and is not individualized by recurrence risk. Circulating biomarkers (CBs), particularly circulating tumor DNA (ctDNA), have emerged as promising methods for real-time disease monitoring. We systematically reviewed available evidence evaluating CBs across treatment timepoints in localized ASCC. Methods: A PROSPERO-registered review (ID: 1133987) was conducted according to PRISMA guidelines. PubMed, EMBASE, Cochrane CENTRAL, Web of Science, and major conference proceedings (ASCO, ESMO, ASTRO) were searched on 30 November 2025. We included prospective or retrospective studies (≥10 patients) with stage I–III disease treated with curative-intent chemoradiotherapy that reported CBs, assay characteristics, and at least one clinical outcome. Studies with predominantly localized cohorts were included even if small proportions of metastatic patients were present, provided results relevant to curative-intent populations could be interpreted. Data were synthesized narratively by timepoint (baseline, mid-treatment, end of treatment, post-treatment/surveillance) and assay type given methodological heterogeneity. Results: Fifteen studies were included. CB assays comprised four categories: viral HPV ctDNA assays, tumor-informed ctDNA assays, non-specific total cell-free DNA (cfDNA) quantification, and circulating tumor cell (CTC)-based assays. Baseline detection rates varied by assay type. Viral HPV ctDNA assays demonstrated detection rates of 59–100%, while tumor-informed ctDNA assays showed rates of 79–89%. Across studies, higher CB detection rates and levels were generally associated with greater tumor burden, including more advanced T and N stage disease. Mid-treatment ctDNA clearance identified patients with excellent locoregional control and progression-free survival, whereas persistent ctDNA was associated with treatment failure. End-of-treatment and surveillance ctDNA positivity predicted recurrence within individual cohorts, with reported sensitivities of 80–90%, specificities of 95–99%, and molecular lead times preceding clinical or radiographic detection. In contrast, non-tumor-specific cfDNA dynamics showed more variable prognostic associations and were less consistently linked to tumor burden. Conclusions: Across heterogeneous assays, CB dynamics provide clinically meaningful prognostic information in localized ASCC, particularly when measured during treatment and early surveillance. Viral HPV and tumor-informed ctDNA may have the potential to guide follow-up intensity and inform future escalation or de-escalation strategies; however, prospective, standardized trials are needed to define actionable thresholds and test ctDNA-guided management.

PURPOSE For patients with advanced biliary tract cancer (BTC), cancer-related time spent in health care systems, time toxicity, represents a critical but understudied burden affecting quality of life. This study aimed to quantify time toxicity in patients receiving first-line systemic therapy and evaluate whether the addition of durvalumab to gemcitabine plus cisplatin (GC) increases health care contact time. METHODS This international, multicenter, retrospective cohort study included patients with advanced BTC seen between January 2019 and April 2024 at Mayo Clinic Enterprise (US), and between January 2021 and April 2024 at Kyorin University Hospital (Japan), and Hospital Israelita Albert Einstein (Brazil). Patients received GC plus durvalumab (GCD) or GC. Time toxicity was recorded from treatment initiation until discontinuation or last follow-up during first-line systemic therapy. Multiple regression analysis identified factors associated with high time toxicity. RESULTS Among 193 patients (102 GCD, 91 GC; median age 65 years; 50% male; 49% Eastern Cooperative Oncology Group performance status [PS] 0), median time on treatment (TOT) was 156 days (95% CI, 122 to 190). The median proportion of total time toxicity was 14.4% (IQR, 10.9-20.6). Planned visits accounted for 11.9%, while unplanned visits were infrequent (1.8%). Time toxicity strongly correlated with TOT ( r = 0.824) and progression-free survival ( r = 0.827). Despite longer treatment in the GCD group than the GC group (212 v 134 days; P = .027), total time toxicity was similar (27 v 18 days; P = .19). Younger age and poor PS were independent factors of higher time toxicity. CONCLUSION Time toxicity represents a meaningful metric that allows for more comprehensive integration of the net benefit in patients with advanced BTC with a limited lifespan.

Background: Metastatic squamous cell carcinoma of the anus (SCCA) carries a poor prognosis, with systemic therapy remaining the standard of care. While metastasis-directed therapy improves outcomes in select gastrointestinal malignancies, the role of liver-directed intervention in metastatic SCCA remains undefined. We evaluated clinicopathologic features and oncologic outcomes of patients with liver-limited metastatic SCCA treated with curative-intent hepatic local therapy at a tertiary academic center. Methods: We conducted a retrospective cohort study of adults with histologically confirmed SCCA and liver-only metastatic disease who underwent curative-intent hepatic resection or ablation at Mayo Clinic between 1993 and 2023. Patients with extrahepatic disease or incomplete records were excluded. Demographic, tumor, treatment, and outcomes data were abstracted from electronic medical records. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan–Meier method. Prognostic factors were assessed using univariate Cox proportional hazards models. Results: Twenty-five patients met inclusion criteria. Median age was 56.7 years, and 92% were female. Most patients had metachronous metastases (76%), a single hepatic lesion (56%), and unilobar disease (76%). Pre-intervention systemic therapy was administered in 52% of patients, with radiographic complete or partial responses observed in all treated patients. Liver-directed therapy consisted of surgical resection in 80% and thermal ablation in 20%. Among surgical patients, 90% achieved microscopically negative margins. With a median follow-up of 22 months, disease recurrence occurred in 80% of patients, most commonly within the liver. Median DFS was 7.27 months. Median OS from the date of liver-directed therapy was 51.3 months. On univariate analysis, poorly differentiated tumor histology was associated with inferior OS (hazard ratio 4.67, p = 0.018). No other clinicopathologic variables were significantly associated with DFS or OS. Conclusions: In this single-institution experience, carefully selected patients with liver-limited metastatic SCCA undergoing curative-intent hepatic-directed therapy achieved prolonged overall survival, substantially exceeding historical outcomes with systemic therapy alone. Despite frequent recurrence, the observed median OS exceeding four years supports consideration of liver-directed therapy within a multidisciplinary framework for patients demonstrating favorable disease biology and response to systemic treatment. Prospective studies are needed to better define patient selection and optimal integration of local and systemic therapies in the modern treatment era.

Liver transplantation has emerged as a curative treatment option for selected patients with unresectable hepatic malignancies beyond hepatocellular carcinoma, marking a paradigm shift in transplant oncology. For colorectal cancer liver metastases (CRLM), prospective trials have demonstrated that highly selected patients achieve 5-year OS rates of 60–83%, with the Oslo score identifying optimal candidates for transplantation. Perihilar cholangiocarcinoma (pCCA) has been successfully treated using strict patient selection criteria combined with neoadjuvant therapy, achieving 5-year OS rates of 50–68%, though emerging data suggests chemotherapy-based approaches may be preferable to radiation in selected cases. Intrahepatic cholangiocarcinoma (iCCA), previously considered a contraindication to transplantation, can now achieve excellent long-term outcomes (79.5% 5-year OS) in patients demonstrating sustained response to neoadjuvant chemotherapy and radioembolization, with metabolic tumor volume < 70 cm3 serving as an objective prognostic marker. Across these three emerging indications, successful outcomes depend on strict patient selection based on tumor biology, intensive multimodal neoadjuvant therapy, multidisciplinary evaluation in high-volume centers, and careful observation during treatment to exclude patients with aggressive disease. This evolution in transplant practice offers curative intent therapy to patients that previously only had palliative therapeutic options, fundamentally transforming hepatobiliary and oncologic surgery.

Anal squamous cell carcinoma (ASCC) is a rare malignancy of the lower gastrointestinal tract, with distant metastases typically involving the liver and lungs. Metastasis to the kidneys is uncommon, and only one prior case has been reported in the literature. Herein, we report a rare presentation of a patient with biopsy-confirmed metastatic ASCC presenting as bilateral renal lesions. We then provide a review of the literature for rare metastatic presentations of ASCC, highlighting all the cases described in the literature. Clinicians should maintain a high index of suspicion for unusual metastatic sites, perform targeted imaging and biopsy when indicated, and consider systemic therapies to optimize outcomes in rare metastatic presentations.

Background: Peritoneal metastasis represents an aggressive disease pattern in pancreatic ductal adenocarcinoma (PDAC), traditionally associated with poor survival and limited therapeutic options. Emerging intraperitoneal chemotherapy strategies—including hyperthermic intraperitoneal chemotherapy (HIPEC), normothermic intraperitoneal paclitaxel (NIPEC/IP-PTX), and pressurized intraperitoneal aerosol chemotherapy (PIPAC)—have been investigated to improve local tumor control and survival outcomes. Methods: We systematically reviewed published studies evaluating HIPEC, NIPEC/IP-PTX, and PIPAC in PDAC, including adjuvant, cytoreductive, and palliative settings. Study characteristics, feasibility, perioperative outcomes, oncologic outcomes, and risk of bias were analyzed. Results: Across modalities, intraperitoneal treatment strategies demonstrated acceptable feasibility and safety profiles in appropriately selected patients. Adjuvant HIPEC following pancreatectomy showed reduced local–regional recurrence signals in limited cohorts. CRS + HIPEC among patients with isolated peritoneal metastases yielded encouraging multi-year survival in highly selected candidates achieving complete cytoreduction. NIPEC/IP-PTX demonstrated favorable ascites control, symptom relief, and potential conversion to resection in select patients. PIPAC was primarily used in unresectable, heavily pretreated, palliative peritoneal metastasis settings, with goals centered on disease stabilization, histologic regression, and symptom control rather than curative intent. Conclusions: Intraperitoneal chemotherapy strategies in PDAC appear feasible with signals of meaningful clinical benefit in select settings. While CRS + HIPEC may benefit carefully selected metastatic patients, NIPEC/IP-PTX and PIPAC hold value primarily in symptom control and disease stabilization. Larger prospective trials are needed to define patient selection, optimize treatment protocols, and clarify survival benefit.

Objective: This study aimed to evaluate the characteristics, clinical outcomes, and resource use of patients with unresectable hepatocellular carcinoma (uHCC) treated with first-line (1L) atezolizumab plus bevacizumab (A+B) at five United States (US) institutions: the Mayo Clinic, Houston Methodist, Moffitt Cancer Center, Mays Cancer Center, and University of Arizona. Methods: Treating oncologists extracted data from medical charts of patients with uHCC who were treated with A+B after 1 January 2019. Real-world progression-free survival (rwPFS) and overall survival (OS) were assessed using the Kaplan–Meier method for the overall cohort and for a “trial-like” subgroup with characteristics similar to those in the IMbrave150 trial (Eastern Cooperative Oncology Group Performance Status [ECOG PS] 0–1, Child–Pugh [CP] class A, albumin–bilirubin grade 1–2). Results: Of the 300 patients in the overall cohort (median age of 68 years; 12% ECOG PS ≥ 2; 73% CP A; 26% CP B; median follow-up of 8.7 months), the median rwPFS was 6.8 (95% confidence interval [CI]: 5.8, 8.4) months, and the median OS was 14.4 (95% CI: 12.3, 18.2) months. In the trial-like subgroup (n = 194), the median rwPFS was 8.8 (95% CI: 7.6, 12.1) months and the median OS was 19.5 (95% CI: 14.6, 24.7) months. A significantly lower proportion of patients with CP A compared with CP B (39.7% vs. 73.4%) experienced hospitalization within one year of A+B initiation, whereas hospitalizations due to treatment-related adverse events were similar. Conclusions: This study provides insights into the real-world effectiveness of 1L A+B in a diverse US patient cohort, with results from trial-like patients supporting the reproducible efficacy of A+B in clinical practice.

Intrahepatic cholangiocarcinoma is an aggressive malignancy with rising incidence and poor outcomes. This review examines recent advancements in locoregional therapies for unresectable intrahepatic cholangiocarcinoma, focusing on external beam radiotherapy, transarterial radioembolization (TARE), hepatic artery infusion pump (HAIP) chemotherapy, and liver transplantation. Stereotactic body radiation therapy and proton beam therapy have shown promise in achieving local control and improving survival. TARE, with personalized dosimetry, has demonstrated encouraging results in select patient populations. HAIP chemotherapy, primarily studied using floxuridine, has yielded impressive survival outcomes in phase II trials. Liver transplantation, once contraindicated, is now being reconsidered for carefully selected patients with localized disease. While these locoregional approaches show potential, randomized controlled trials comparing them to standard systemic therapy are lacking. Patient selection remains crucial, with factors such as liver function, tumor burden, and molecular profile influencing treatment decisions. Ongoing research aims to optimize treatment sequencing, explore combination strategies with systemic therapies, and refine phenotype identification and patient selection criteria. As the landscape of intrahepatic cholangiocarcinoma management evolves, a multidisciplinary approach is essential to tailor treatment strategies and improve outcomes for patients with this challenging disease.

(1) Background: Local therapies offer a potentially curative approach for patients with oligometastatic colorectal cancer (CRC). An evidence-based consensus recommendation for systemic therapy following definitive locoregional therapy is lacking. Tumor-informed circulating tumor DNA (ctDNA) might provide information to help guide management in this setting. (2) Methods: A multi-institutional retrospective study was conducted, including patients with CRC that underwent curative-intent locoregional therapy to an isolated site of metastatic disease, followed by tumor-informed ctDNA assessment. The Kaplan–Meier method and log-rank tests were used to compare disease-free survival based on ctDNA results. ctDNA test performance was compared to carcinoembryonic antigen (CEA) test results using McNemar’s test. (3) Results: Our study cohort consisted of 87 patients treated with locoregional interventions who underwent ctDNA testing. The initial ctDNA test post-intervention was positive in 28 patients and negative in 59 patients. The median follow-up time was 14.0 months. Detectable ctDNA post-intervention was significantly associated with early disease recurrence, with a median disease-free survival (DFS) of 6.63 months compared to 21.30 months in ctDNA-negative patients (p < 0.001). ctDNA detected a numerically higher proportion of recurrences than CEA (p < 0.097). Post-intervention systemic therapy was not associated with improved DFS (p = 0.745). (4) Conclusions: ctDNA results are prognostically important in oligometastatic CRC, and further prospective studies are urgently needed to define its role in guiding clinical decisions.