Gastrointestinal cancers account for approximately one-fourth of all cancer cases and one-third of all tumor-related deaths worldwide. For the most frequent gastrointestinal tumor entities including colorectal, gastric, esophageal, and liver cancer, the incidence is expected to increase by more than 50% until 2040. While most gastrointestinal cancers are diagnosed beyond the age of fertility and predominantly in men, the increasing incidence of gastrointestinal malignancies in patients below the age of fifty suggests a growing importance in women of childbearing age. While localized cancers in pregnant women can either be monitored or treated surgically, more advanced stages might require radio- or chemotherapy to control tumor growth until delivery. Under these circumstances, critical decisions have to be made to preserve maternal health on the one side and minimize harm to the infant on the other side.

Here we summarize data from case reports, meta-analyses, and registries of women undergoing radio- or chemotherapy during pregnancy and provide guidance for therapeutic decision-making in pregnant women suffering from gastrointestinal cancers.

After the first trimester, most chemotherapeutic regimens can be safely administered to pregnant patients with gastrointestinal cancers. With appropriate safety measures, both radiotherapy and radiochemotherapy can be applied to pregnant patients with rectal cancers.

Cholangiocarcinoma (CCA) is a serious public health issue due to its insidious onset and dismal prognosis. The past few years have witnessed and highlighted the development of understanding and management of CCA. The combination of gemcitabine and cisplatin (GP) chemotherapy regimen with immunotherapy using immune checkpoint inhibitors has been considered the new standard first-line treatment alternative for advanced CCA. Notably, the proportion of patients with advanced CCA with targetable genetic mutations is approximately 40 %, and these patients may be considered for molecularly targeted therapy in the second-line treatment. In this review, we highlight the advances and progress in targeted therapies for advanced CCA, with special attention to data from Asian populations, including Chinese. In addition, we present in detail the phosphatase tension homolog (PTEN), a novel biomarker for both of first-line chemotherapy and second-line targeted therapy in advanced CCA, and its ability to forecast prognosis in patients with CCA. The mechanisms of rapid resistance to targeted agents warrant further investigation and address in light of the development of new targeted therapies. Precision medicine is gradually playing an increasing role in achieving optimal therapeutic outcomes.

Randomized data suggest improved survival with adjuvant chemotherapy for biliary tract cancers; however, subset analyses of intrahepatic cholangiocarcinoma (IHC) show limited survival benefit. This study evaluated the impact of adjuvant chemotherapy on recurrence patterns and overall survival (OS) in patients with resected IHC.

Patients who underwent curative-intent resection for IHC were identified within a bi-institutional dataset and the National Cancer Database (NCDB). Patients were stratified by receipt of adjuvant chemotherapy. Site of first recurrence was categorized as liver only, regional, distant, or multifocal. Survival outcomes within each dataset were compared using Kaplan-Meier methods.

In the bi-institutional dataset, 347 patients underwent resection for IHC, and 149 (43%) patients received adjuvant cytotoxic chemotherapy. Recurrence was observed in 222 (64.0%) patients. OS was similar between groups (adjuvant vs. observation: 42 vs. 49 months; p = 0.13), and did not differ in patients who received capecitabine specifically (p = 0.09) or in a risk-adjusted multivariable analysis. Recurrence-free survival was worse in those who received adjuvant chemotherapy (p = 0.04), although the liver was the most common site of recurrence in both groups (0.63). A similar analysis of 1159 resected IHCs from the NCDB also demonstrated no association between adjuvant chemotherapy and OS (49 vs. 57 months; p = 0.1).

Adjuvant chemotherapy may not be associated with improved OS in IHC and did not have an impact on hepatic recurrence in this retrospective analysis. Future investigation to identify more effective adjuvant systemic regimens and/or explore the potential role of adjuvant liver-directed therapies to reduce hepatic recurrence that may improve OS for IHC is warranted.

Although the prognosis for gallbladder cancer (GBCA) improves with early diagnosis and aggressive surgical treatment, the management of patients with muscle layer invasion (T1b) remains controversial. This study aimed to analyze the optimal surgical approach for these patients.

A database was queried for patients with early T1b GBCA treated at four Chilean hospitals. Patients were prospectively treated and registered by the same surgical team at each hospital. Clinical outcomes, including survival rates according to the type of surgery, were analyzed.

Between 1988 and 2023, 129 Chilean patients were pathologically diagnosed with T1b GBCA. Simple cholecystectomy (SC) was performed in 86 patients (66.7 %), while extended cholecystectomy (EC) was performed in 43 patients. The overall 5-year survival rate was 83 %, with no significant difference between SC and EC patients.

Simple cholecystectomy demonstrated survival rates comparable to extended cholecystectomy for patients with T1b GBCA. More extensive resections did not improve the prognosis.

The prognostic value of the preoperative cachexia index for patients with perihilar cholangiocarcinoma remains unclear.

We retrospectively evaluated 236 patients who underwent radical resection for perihilar cholangiocarcinoma from September 2002 to December 2020. The cachexia index was calculated as follows: (skeletal muscle index × albumin level)/neutrophil-to-lymphocyte ratio, with sex-specific cutoff values determined via receiver operating characteristic curves on the basis of 3-year survival data. Clinicopathologic characteristics and survival outcomes were compared between the low-cachexia index (n = 95) and high-cachexia index (n = 141) groups. Multivariable analyses were performed to identify prognostic factors for overall survival and relapse-free survival.

The low-cachexia index group was characterized by greater carbohydrate antigen 19-9 level (56 vs 31 U/mL, P = .024) and greater proportion of preoperative biliary drainage (84% vs 70%, P = .013). The low-cachexia index group underwent vascular resection and reconstruction more frequently (47% vs 29%, P = .006) and had a greater rate of lymph node metastasis (54% vs 35%, P = .005). The median overall survival and relapse-free survival times of the low-cachexia index group were significantly worse than those of the high-cachexia index group (overall survival, 29.0 vs 47.4 months, P < .001; relapse-free survival, 17.2 vs 33.1 months, P < .001). Multivariable analysis revealed that a preoperative cachexia index (hazard ratio for overall survival, 0.95, P = .008; hazard ratio for relapse-free survival, 0.95, P = .017) and high preoperative carbohydrate antigen 19-9 level (hazard ratio for overall survival, 1.01, P = .002; hazard ratio for relapse-free survival, 1.01, P = .012) were prognostic factors.

The cachexia index may be a useful biomarker for the prediction of tumor aggressiveness and prognosis before perihilar cholangiocarcinoma resection.

Differences between the biological sexes have long been observed in cancer incidence and prevalence, and in treatment outcomes including efficacy and toxicity. Ideally, there should be sufficient information to improve the individualization of cancer treatment by incorporating sex into treatment decisions. Necessary information should include: the nature and source of these differences; whether inherent to the specific cancer (such as molecular profiles, metabolic behaviors, and immune responses); the pathophysiological mechanisms of the specific cancer; or the pharmacokinetic and pharmacodynamic profiles of different cancer drugs. The influence of gender, which is defined as the sociocultural construct that determines societal norms for males and females, should also be included in personalized decision-making. This review aimed to describe the current evidence on the impact of sex and gender on treatment effects, outcomes, and toxicity profiles in cancer patients. Data for the influence of gender were negligible, whereas clinical studies and meta-analyses in different cancer types have identified differences between males and females in the effectiveness on survival outcomes of immunotherapy, chemotherapy, targeted therapy, and radiotherapy. Similarly, toxicity profiles of different cancer treatments varied between sexes. Based on these observed differences, it seems clear that sex should be included as an important variable when individualizing treatment; however, more research into sex- and gender-related differences in cancer treatment efficacy and toxicity, and the causes for these differences, is required before this can be fully incorporated into individualized treatment programs in real-world clinical practice.

The role of recurrence-free survival (RFS) as a validated surrogate endpoint for overall survival (OS) among patients undergoing upfront surgery for intrahepatic cholangiocarcinoma (ICC) has not been defined. We sought to evaluate the correlation between RFS and OS after surgical resection for ICC. We hypothesized that RFS was a reliable surrogate endpoint for OS among patients with ICC.

Patients who underwent upfront curative-intent surgery for ICC between 2000 and 2023 were identified from an international, multi-institutional database. The correlation between RFS and OS was assessed using rank correlation. Landmark analysis evaluated concordance between survival at 5 years and recurrence status at 6, 12, 24, 36, 48, and 54 months postoperatively.

Among 1541 patients who underwent curative-intent hepatic resection, the median RFS and OS were 22.6 months and 41.5 months, respectively. A moderately strong correlation between RFS and OS was identified (ρ = 0.79, 95% CI 0.76 to 0.82). In the landmark analysis, the concordance between 5-year OS after surgery and recurrence status at different time points (6, 12, 24, 36, 48, and 54 months) was 60.7%, 72.0%, 81.4%, 83.1%, 83.0%, and 82.5%, respectively. Restricted cubic spline analysis indicated that the prediction of OS based on RFS increased with time and plateaued 3 years after surgery.

Among patients undergoing curative-intent resection of ICC, there was a moderately strong correlation between RFS and OS. Three-year RFS may be a reliable surrogate endpoint to predict 5-year OS and should be considered in future trial design.

Hepatobiliary cancers are heterogeneous and molecularly complex. Recent advances in next-generation sequencing (NGS) have enhanced the understanding of their molecular landscape and enabled deployment of biomarker-based gene- and immune-targeted therapies. This review examines the role of molecular testing and targeted therapies in these malignant neoplasms.

Patients with hepatobiliary cancers have poor outcomes. Precision oncology studies have shown that while many common molecular alterations are not currently targetable in hepatocellular carcinoma (HCC), a large number of actionable alterations characterize biliary tract cancers (BTCs), with several therapies now approved by the US Food and Drug Administration. Immunotherapy is increasingly adopted in clinical practice, either as monotherapy or combined with cytotoxic chemotherapy, for both HCC and BTCs. Moreover, multiple solid cancer tumor-agnostic therapies are approved (larotrectinib, entrectinib, and repotrectinib for NTRK fusions; selpercatinib for RET fusions; dabrafenib and trametinib combination for BRAF V600E mutations; dostarlimab or pembrolizumab for tumors with high microsatellite instability and pembrolizumab for tumor mutation burden ≥10 mutations/megabase), highlighting the need for NGS as well as ERBB2 (formerly HER2) immunohistochemistry (IHC) (with the recent approval of solid tissue-agnostic deruxtecan trastuzumab for ERBB2-positive [IHC 3+] cancer) across cancers. N-of-1 clinical trials using customized drug combinations matched to the tumor's molecular profile have yielded encouraging results and provide a promising framework for future clinical trial design.

Molecular testing and gene- and immune-targeted therapies are transforming hepatobiliary cancer treatment. Tumor-agnostic and N-of-1 clinical trials have challenged traditional clinical trial paradigms and provide the foundation for truly personalized oncology for patients with these aggressive cancers. Further work is needed to determine how to leverage these novel approaches into the management of operable disease.

The prognostic value of the resection margin (RM) status and the efficacy of adjuvant therapy (AT) in distal cholangiocarcinoma (CCC) are unclear. RM status appears particularly impactful in lymph node-negative distal CCC, representing early-stage disease. The prognostic value of RM status was investigated, and subpopulations of patients with lymph node-negative distal CCC who might benefit from AT were identified. Overall, 139 patients with distal CCC who underwent surgical resection between March 2006 and December 2023 were analyzed. RM status was categorized as wide (>5 mm) in 65 patients (46.8%), close (≤5 mm) in 32 patients (23.0%), or positive in 42 patients (30.2%). AT was administered to 48 patients (34.5%). Patients with close or positive RMs achieved significantly lower locoregional control (LRC) than those with wide RMs. However, overall survival (OS) did not differ across the three RM groups. The impact of RM status was more evident in patients not receiving AT. Patients with wide RMs exhibited better 3-year LRC, progression-free survival (PFS), and OS rates (79.0%, 66.5%, and 69.1%, respectively) than those with close (21.7%, 15.7%, and 34.4%) or positive RMs (44.3%, 25.3%, and 50.2%, respectively). No significant differences were found between close and positive RM groups. AT appears to have improved LRC and PFS in patients with close or positive RMs but not in those with wide RMs. Close RMs were associated with poor outcomes comparable to those with positive RMs. These results indicate that achieving adequate RM width is crucial for improving survival. Moreover, AT may improve survival when adequate RMs cannot be achieved. Nonetheless, larger studies are needed to validate these findings.

Cholangiocarcinoma (CCA) is a unifying title granted to epithelial adenocarcinomas specific to the bile ducts making up 10-25% of all hepatobiliary malignancies. CCA is more appropriately classified based on anatomic site of origin within the biliary tract into intrahepatic cholangiocarcinoma (iCCA), peri-hilar (pCCA) cholangiocarcinoma, and distal cholangiocarcinoma (dCCA). Intrahepatic cholangiocarcinoma makes up 10-20% of CCA and originates within and/or proximal to the second order bile ducts. The incidence of iCCA has been rising overtime with up to 1.26 per 100,000 persons, per year in the United States and up to 3.3 per 100, 000 persons, per year affected globally. Risk factors include chronic hepatic inflammation secondary to viral hepatitis, alcohol/NASH cirrhosis, biliary cystic lesions, and endemic causes, among other less common genetic drivers. Given its rarity, the recognition and diagnosis of cholangiocarcinoma, iCCA specifically, remains challenging resulting in delays in treatment initiation or any treatment at all. Median overall survival (mOS) for iCCA remains low. Early diagnosis, and stage-based treatment approaches have evolved and are associated with improved survival. To this goal, a multi-disciplinary treatment approach has been demonstrated to improve patient outcomes by providing expert evaluation as it pertains to an accurate imaging and histologic diagnosis, staging, radiologic and surgical review for resectability, operative expertise, post operative care, as well as comprehensive knowledge and implementation of systemic/targeted or liver directed therapies. Here, we discuss the central role of imaging in the diagnosis of intrahepatic cholangiocarcinoma to implement a comprehensive treatment plan that frequently involves multiple disciplines to achieve the best outcome for each patient.

In the TOPAZ-1, patients with biliary tract cancers (BTC) and recurrence within 6 months after surgery were excluded, even if this event is frequently observed in clinical practice. Our study aimed to assess if the efficacy of cisplatin-gemcitabine-durvalumab (CGD) in this population is comparable to that reported in the phase 3 trial.

The study cohort included patients with BTC who underwent surgery on the primary tumor, experienced disease recurrence occurring ≤6 months or >6 months after surgery or after the end of adjuvant therapy and started CGD. The primary objectives were overall survival (OS) and progression free survival (PFS).

A total of 178 patients were enrolled. No significant differences were observed between early and late relapse groups in OS (23.4 months vs not reached; HR 1.26; 95% CI, 0.67-2.37; P = .45) and PFS [7.0 months vs 9.8 months; HR 1.3(95% CI, 0.9-2.1) P = .13]. Overall response rate and disease control rate (P = .33 and P = .62) were comparable between the 2 groups, as the overall safety profile. In addition, we compared survival outcomes between the selected population and a historical cohort of patients with BTC treated with cisplatin-gemcitabine (CG) and found that despite the absence of statistical significance, CGD showed an outcome trend compared with CG regardless of the time of recurrence after surgery or adjuvant chemotherapy [(CG ≤ 6 vs CGD ≤ 6 months: HR 0.59, 95%CI, 0.35-1.01, P = .05; HR 0.70; 95%CI, 0.46-1.06, P = .09, OS and PFS, respectively) and (CG > 6 vs. CGD > 6 months: HR 0.50; 95%CI, 0.29-0.88, P = 0.0165; HR 0.54; 95%CI, 0.35-0.84, P = .0068, OS and PFS, respectively)].

Our analysis suggests that CGD retains its efficacy independently of the timing of relapse after surgery or completion of adjuvant treatment in patients with advanced BTC.

A limited number of randomized controlled trials (RCTs) investigated adjuvant chemotherapy in biliary tract cancers (BTCs). Recurrences and deaths are common in the first 2 years and survival remains poor despite adjuvant treatment.

Phase-III RCTs were included comparing adjuvant chemotherapy and observation in resected BTCs. The primary endpoints were recurrence-free (RFS) and overall survival (OS). Proportional hazard results were used for trial-based analyses. Patient data was curated from published Kaplan-Meier curves to analyze short-term (2-year) hazards. The Parmar and generic inverse variance methods were used.

1308 patients in 4 trials (BILCAP, ASCOT, BCAT, PRODIGE-12) were included. Capecitabine (BILCAP) and S-1 (ASCOT) were grouped as 5-FU-based, gemcitabine (BCAT) and gemcitabine-oxaliplatin (PRODIGE-12) were grouped as gemcitabine-based chemotherapy. Adjuvant 5FU-based chemotherapy improved RFS [HR: 0.80 (95 % CI:0.68-0.95), p = 0.012] and OS [HR: 0.78 (95 % CI:0.65-0.94), p = 0.009]. However, gemcitabine-based chemotherapy did not provide benefit in RFS [HR: 0.90 (95 % CI:0.70-1.15), p = 0.428] and OS [HR: 1.03 (95 % CI:0.78-1.36), p = 0.794]. The benefit of 5-FU-based chemotherapy was more apparent in the short-term (2-year hazards) (RFS: [HR: 0.67 (95 %CI:57-0.79), p < 0.001] and OS: [HR: 0.61 (95 % CI:59-0.64), p < 0.001]). However, gemcitabine-based chemotherapy did not provide RFS benefit in the short term either [HR: 0.80 (95 % CI:0.64-0.1.01), p = 0.067] and seemed to be even detrimental for OS [HR: 1.22 (95 % CI:1.14-1.31), p < 0.001] in the first 2 years.

This study confirms using 5FU-based monotherapy in the adjuvant treatment of resected BTCs. The more prominent benefit in the first 2 years emphasizes that more effective adjuvant treatments with sustained long-term benefits are needed. Two-year proportional hazards OS and RFS are proposed here as an additional secondary end-point to consider in future clinical trials. in this setting. Registration ID (PROSPERO): CRD42024614444.

Resection outcomes for perihilar cholangiocarcinoma differ between Western and Eastern centres, but reasons behind these disparities remain unclear. This study aimed to compare current outcomes between a Western and an Eastern expert centre to identify prognostic factors.

Patients who underwent hepatobiliary resection for perihilar cholangiocarcinoma between 2010 and 2022 at Karolinska University Hospital (Stockholm, Sweden) and Cancer Institute Hospital (Tokyo, Japan) were retrospectively included. Primary outcome was overall survival. Secondary outcomes were disease-free survival, postoperative complications and 90-day mortality rate.

Two hundred and forty-nine patients were included (Cancer Institute Hospital n = 159, Karolinska n = 90). Median overall survival was 20.4 months at Karolinska and 52.0 months at Cancer Institute Hospital (P < 0.001). Median disease-free survival was 11.9 months at Karolinska and 32.4 months at Cancer Institute Hospital (P < 0.001). Advanced tumours, ASA class ≥III, poor differentiation and radial margin positivity were more common in the Western cohort. Treatment centre, T-status, N1-status, resection side, R1-status, age and carbohydrate antigen 19-9 were prognostic for overall survival. The Eastern cohort had a lower rate of postoperative complications (24.5%) and a lower mortality rate (2.5%) compared with the Western cohort (51.1% and 10.0%).

Advanced tumour stage and radial margin positivity contributed to poor long-term survival in the Western cohort. A higher burden of co-morbidity and a higher rate of extended resections with smaller remnant liver volume influenced the Western postoperative mortality rate.

The prognosis of perihilar cholangiocarcinoma (PHC) is poor even after curative resection, highlighting the need for effective adjuvant chemotherapy. The efficacy of adjuvant S-1 chemotherapy following major hepatectomy for PHC is unclear, and thus the aim of this study was to elucidate this.

Consecutive patients with PHC who underwent major hepatectomy (hemihepatectomy or trisectionectomy extending to segment 1 with extrahepatic bile duct resection) at three high-volume centers in Japan from 2007 to 2020 were retrospectively evaluated. Patients with Clavien-Dindo grade V complications, pStage 0, I, or IVB disease, and those who underwent adjuvant radiation therapy were excluded from analysis. Propensity score matching analysis was performed to compare the disease-specific survival (DSS) of patients who underwent adjuvant S-1 chemotherapy with those who underwent observation.

Overall, 373/480 patients were eligible, of whom 81 underwent adjuvant S-1 chemotherapy and 146 underwent observation. In the global cohort, DSS was similar in the S-1 and observation groups (p = 0.18), while in the matched cohort (S-1, n = 44; observation, n = 44), DSS was similar between the S-1 and observation groups (p = 0.09). On multivariate analysis, percutaneous biliary drainage (PTBD), CA19-9 levels of ≥ 300 U/mL at operation, and lymph node (LN) metastasis were independent predictors of poor survival following major hepatectomy for PHC. In subgroup analysis of patients with LN metastasis, DSS was better in the S-1 group than in the observation group (p = 0.001).

Adjuvant S-1 chemotherapy following major hepatectomy might be effective in PHC patients with LN metastasis.

To determine effectiveness of radiofrequency ablation for treatment of intrahepatic cholangiocarcinoma (iCCA) using a population-based database.

Data were extracted from Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2020 to include 194 patients who underwent ablation for iCCA. Data on patient demographics, overall survival (OS), and cancer-specific survival were retrieved. Factors associated with survival were evaluated. Comparison between ablation and surgical resection (n = 2,653) or external beam radiotherapy (n = 1,068) was performed.

In the ablation group, patients diagnosed and treated after 2010 demonstrated improved OS than that in the 2000-2009 subgroup (median OS, 32 vs 21 months; hazard ratio, 0.50; 95% CI, 0.33-0.75; P = .001). Additional factors associated with OS included tumor size (≤3 cm vs >3 cm; P = .049) and tumor stage (P < .001). For patients diagnosed after 2010, the 1-, 3-, and 5-year OS were 82.8% (95% CI, 74.8%-88.4%), 43.5% (95% CI, 33.5%-53.1%), and 23.7% (95% CI, 15.3%-33.5%), respectively. Patients with local disease (1-year OS, 87.8%; 95% CI, 78.6%-93.3%) demonstrated improved OS compared with patients with regional (1-year OS, 81.3%; 95% CI, 52.5%-93.5%) and distant disease (50.2%; 95% CI, 34.0%-78.8%; P < .001). For tumors ≤3 cm, ablation and surgical resection offered comparable survival benefits (P = .561), although both were better than radiotherapy (P < .0001).

Survival of patients with iCCA who underwent thermal ablation has improved over the last 10 years. For tumors ≤3 cm, ablation could be as effective as resection with careful candidate selection, and may be considered front-line compared with radiotherapy in certain patient populations. Patient selection based on tumor size and disease stage could improve survival outcomes.

Perihilar cholangiocarcinoma (phCCA) has excellent outcomes following liver transplantation (LT). Neoadjuvant radiation-based locoregional therapy is standard-of-care. Gemcitabine and cisplatin (gem/cis) combination systemic therapies have improved outcomes in advanced settings, but their efficacy pre-LT has not been studied.

We review our experience following neoadjuvant gem/cis alone versus radiation-based approaches. Patients with phCCA undergoing LT at a single center between January 2008 and February 2023 were identified retrospectively. Neoadjuvant therapy was categorized as gem/cis systemic therapy (ST) alone, or any ST and radiotherapy (RT). Outcomes were posttransplant overall survival (OS), recurrence-free survival (RFS), waitlist time, and pathologic tumor response.

During study period, 27 phCCA patients underwent LT. One patient decompensated with neoadjuvant therapy and was excluded. Median age was 61 y (interquartile range, 53-68 y) and 14 (54%) were male. Of 26 patients, 12 (46%) received ST and 14 (54%) RT. Six RT patients received gem/cis ST. Median waitlist time was 199 d (interquartile range, 98-405 d) and did not differ by neoadjuvant regimen. Explanted tumors were predominantly T1 stage, without lymphovascular invasion or nodal involvement. Neither pathologic features nor percent tumor necrosis differed by regimen. OS probabilities at 1 and 3 y were 84% and 55% for the cohort. There was no significant difference in OS and RFS when stratified by regimen.

Post-LT OS, RFS, waitlist time, and tumor response were similar in the 2 groups. Patients with phCCA who do not undergo RT may still be considered for LT under appropriate institution-based protocols that adhere to other established criteria.

Cholangiocarcinoma (CCA) has rising incidence and mortality rates. Outcomes from combination systemic, loco-regional therapy (LRT) and liver transplantation (LT) are improving, but more granular data are needed to inform evidence-based management, including patient selection and immunosuppression.

Patients with peri-hilar (PH) and intrahepatic (IH) CCA who underwent LT at a single center between January 2008 and February 2023 were reviewed retrospectively. Primary outcomes were overall survival (OS) and recurrence-free survival (RFS) with significance determined by Cox proportional hazards model.

During the study period, 53 patients underwent LT for either PH (n = 27), or IH (26). Cohort had mean age 58.5 years old (IQR, 47.0-63.0), body mass index (BMI) 25.9 (IQR, 22.9-30.0) kg/m2, and mean biologic MELD 9 (IQR, 7-17). Most frequent etiology was PSC (n = 12, 22.6%). Forty-nine patients (92.5%) received neoadjuvant therapy, including systemic (n = 48, 90.6%) and locoregional therapy (LRT) (n = 22, 41.5%), to which PH tumors were both most and least responsive (P = .03). On explant pathology, tumor were a median size of 3.5 cm and lympho-vascular invasion (LVI) was present in 13 (24.5%) cases. Median follow-up post-transplant was 910 days (IQR, 407-1509). Probabilities of OS and RFS at 3-years post-LT were 69.2% (95% CI, 56.9%-84.2%) and 57.4% (95% CI, 43.7%-75.4%). In multivariable analysis, OS was associated with tumor type and LVI, and RFS with age, BMI, PSC and LRT. After a median post-LT period of 38 days (IQR, 27-79.5), 39 (71.7%) patients started mTOR inhibition with lowered tacrolimus goal. Cox proportional hazard model showed significant association of OS with mTOR inhibition, though this was not validated by a time-dependent co-variate approach.

In this single center cohort of CCA, post-LT outcomes were significantly greater for patients with IH tumors and no LVI. Immunosuppression with mTOR inhibition was not consistently associated with outcomes.

A histologically involved surgical margin (R1) is often observed after resection for cholangiocarcinoma. Compared with a negative margin (R0), R1 with invasive carcinoma (R1inv) markedly worsens survival, whereas the prognostic effect of R1 with carcinoma in situ (R1cis) remains controversial.

Patients who underwent resection for perihilar cholangiocarcinoma between 2002 and 2019 were retrospectively reviewed. According to the pathological assessment, the duct margin was classified as R0, R1cis, or R1inv; radial margin positivity was treated as R1inv. Recurrence and survival were compared.

Among the 681 patients, 457 had R0, 69 had R1cis, and 155 had R1inv. The overall five-year recurrence rate was 82.8 % with R1inv, 67.8 % with R1cis, and 47.6 % with R0 (P < 0.001); the local recurrence rate also significantly differed among these groups (P < 0.001). The five-year survival rate was significantly worse with R1cis than with R0 (37.3 % vs. 56.7 %, P < 0.001) and better than that with R1inv (20.9 %, P = 0.007). Multivariate analysis revealed that R1cis was an independent predictor of survival (hazard ratio, 1.65; P < 0.001).

Compared with R0, R1cis significantly deteriorated overall survival in the whole resection subset of patients with perihilar cholangiocarcinoma. However, the prognostic impact of R1cis was milder than that of R1inv.

Given the high mortality associated with gallbladder cancer (GBC), the efficacy of adjuvant therapy (AT) remains controversial. We audited our data over an 11-year period to assess the impact of AT.

This study included all patients who underwent curative resection for GBC from 2007 to 2017. Analyses were conducted of clinicopathological characteristics, surgical details, and postoperative therapeutic records. The benefits of adjuvant chemotherapy (CT) or chemoradiotherapy (CTRT) were evaluated against surgery alone using SPSS version 20 for statistical analysis.

The median age of patients (n = 142) was 50 years. The median overall survival (OS) was 93, 34, and 30 months with CT, CTRT, and surgery alone respectively (p = 0.612). Multivariate analysis indicated that only disease stage and microscopically involved margins significantly impacted OS and disease-free survival (DFS). CT showed increased effectiveness across all prognostic subsets, except for stage 4 and margin-positive resections. Following propensity score matching, median DFS and OS were higher in the CT group than in the CTRT group, although the differences were not statistically significant (p > 0.05).

Radically resected GBC patients appear to benefit more from adjuvant CT, while CTRT should be reserved for cases with high-risk features.

Absorption and permeability are critical physicochemical parameters that must be balanced to achieve optimal drug uptake. These key factors are closely linked to the maximum absorbable dose required to provide appropriate plasma levels of drugs. Among the various strategies employed to enhance drug solubility and permeability, prodrug design stands out as a highly effective and versatile approach for improving physicochemical properties and enabling the optimization of biopharmaceutical and pharmacokinetic parameters while mitigating adverse effects. Prodrugs are compounds with reduced or no activity that, through bio-reversible chemical or enzymatic processes, release an active parental drug. The application of this technology has led to significant advancements in drug optimization during the design phase, and it offers broad potential for further development. Notably, approximately 13% of the drugs approved by the U.S. Food and Drug Administration (FDA) between 2012 and 2022 were prodrugs. In this review article, we will explore the application of prodrug strategies to enhance permeability, describing examples of market drugs. We also describe the use of the prodrug approach to optimize PROteolysis TArgeting Chimeras (PROTACs) permeability by using conjugation technologies. We will highlight some new technologies in prodrugs to enrich permeability properties, contributing to developing new effective and safe prodrugs.

Background: Biliary tract cancers (BTCs) have distinct tumor biology but share a poor prognosis, with a 5-year-survival-rate of 5-19%. Surgical resection is the only potential cure, but recurrences are common. The role of adjuvant radiotherapy (XRT) remains unclear. Methods: Using the National Cancer Database (2006-2018), we analyzed resected non-metastatic BTCs. Patients who survived beyond 90 days post-surgery were included, while those with R2 resections or neoadjuvant therapy were excluded. Propensity matching was performed based on predictors of adjuvant radiation, age, and sex. Survival outcomes were compared between no adjuvant therapy, chemotherapy alone, and XRT ± chemotherapy. Results: Among 21,275 patients, including 5308 intrahepatic cholangiocarcinoma (IHC), 2689 perihilar cholangiocarcinoma (PHC), 3092 distal cholangiocarcinoma (DCC), and 10,186 gallbladder cancer (GBC) cases, adjuvant XRT did not improve survival for IHC. For PHC and DCC, XRT improved survival over no adjuvant therapy (PHC: 31.2 vs. 26.3 months, p = 0.004; DCC: 33.7 vs. 27.0 months, p = 0.015) but not over chemotherapy alone. For GBC, XRT significantly improved survival compared to both no adjuvant therapy and chemotherapy (30.2 vs. 26.6 and 24.6 months; p = 0.05 and p = 0.001). Conclusions: XRT provides a survival benefit for GBC, especially in node-positive and R1-resected patients. For PHC and DCC, XRT improves outcomes compared to no therapy, but its benefit over chemotherapy is uncertain. No benefit was observed for IHC.

The only treatment with curative potential for distal cholangiocarcinoma (dCCA) is radical surgery which can be complemented with adjuvant chemotherapy. The aim of the present study was to perform an independent external validation of a prognostic model for 3-year overall survival based on routine clinicopathological variables for patients treated with pancreatoduodenectomy for dCCA.

All patients with a histopathological confirmed dCCA that underwent pancreatoduodenectomy in Sweden from 2009 through 2019 were identified in the Swedish National Registry for Pancreatic and Periampullary Cancer. Model performance was estimated using the C-index and calibration plots.

In total 220 patients were included in the study. The median survival was 33 months (IQR 26-40) and 3-year survival rate 47% (95% CI 40-53%). The prognostic model had a C-index of 0.69 (95% CI 0.62-0.72). Calibration plots revealed overestimated risk of death across risk groups in the full cohort. Calibration was good in the subgroup of patients that did not receive adjuvant treatment.

The prognostic model showed reasonable discriminative ability but some miscalibration likely since the effect of adjuvant treatment is not included in the model. Given that the model was developed in cohorts treated prior to the current adjuvant standard of care the model can be used to estimate baseline risk prior to risk/benefit decision for adjuvant treatment as well as stratification for clinical trials but with a risk to underestimate 3-year overall survival for patients that receive adjuvant treatment.

Biliary tract cancer (BTC) comprises a clinically diverse and genetically heterogeneous group of tumors along the intra- and extrahepatic biliary system (intrahepatic and extrahepatic cholangiocarcinoma) and gallbladder cancer with the common feature of a poor prognosis, despite increasing molecular knowledge of associated genetic aberrations and possible targeted therapies. Therefore, the search for even more precise and individualized therapies is ongoing and preclinical tumor models are central to the development of such new approaches.

The models described in the current review include simple and advanced in vitro and in vivo models, including cell lines, 2D monolayer, spheroid and organoid cultures, 3D bioprinting, patient-derived xenografts, and more recently, machine-perfusion platform-based models of resected liver specimens. All these models have individual advantages, disadvantages and limitations that need to be considered depending on the desired application.

In addition to potential cost limitations, availability of BTC cell types, time required for model establishment and growth success rate, the individual models differently reflect relevant characteristics such as tumor heterogeneity, spatial tumor-stroma microenvironment interactions, metabolic and nutritional gradients and immunological interactions. Therefore, a consequent combination of different models may be required to improve clinical study outcomes by strengthening the preclinical data basis.

Intrahepatic and peri-hilar cholangiocarcinoma are life threatening disease with poor outcomes despite optimal treatment currently available (5-year overall survival following resection 20-35%, and <10% cured at 10-years post resection). The insidious onset makes diagnosis difficult, the majority do not have a resection option and the high recurrence rate post-resection suggests that occult metastatic disease is frequently present. Advances in perioperative management, such as ipsilateral portal vein (and hepatic vein) embolisation methods to increase the future liver remnant volume, genomic profiling, and (neo)adjuvant therapies demonstrate great potential in improving outcomes. However multiple areas of controversy exist. Surgical resection rate and outcomes vary between centres with no global consensus on how 'resectable' disease is defined - molecular profiling and genomic analysis could potentially identify patients unlikely to benefit from resection or likely to benefit from targeted therapies. FDG-PET scanning has also improved the ability to detect metastatic disease preoperatively and avoid futile resection. However tumours frequently invade major vasculo-biliary structures, with resection and reconstruction associated with significant morbidity and mortality even in specialist centres. Liver transplantation has been investigated for very selected patients for the last decade and yet the selection algorithm, surgical approach and both value of both neoadjuvant and adjuvant therapies remain to be clarified. In this review, we discuss the contemporary management of intrahepatic and peri-hilar cholangiocarcinoma.

Cholangiocarcinoma (CCA) remains a devastating malignancy and a significant challenge to treat. The majority of CCA patients are diagnosed at an advanced stage, making the disease incurable in most cases. The advent of high-throughput genetic sequencing has significantly improved our understanding of the molecular biology underpinning cancer. The identification of 'druggable' genetic aberrations and the development of novel targeted therapies against them is opening up new treatment strategies. Currently, 3 targeted therapies are approved for use in CCA; Ivosidenib in patients with IDH1 mutations and Infigratinib/Pemigatinib in those with FGFR2 fusions. As our understanding of the biology underpinning CCA continues to improve it is highly likely that additional targeted therapies will become available in the near future. This is important, as it is thought up to 40 % of CCA patients harbour a potentially actionable mutation. In this review we provide an overview of the molecular pathogenesis of CCA and highlight currently available and potential future targeted treatments.

Hepatic artery infusion of chemotherapy has demonstrated disease control and suggested improvement in overall survival in intrahepatic cholangiocarcinoma. We report herein the long-term results and role of molecular alterations of a phase II clinical trial of hepatic artery infusion chemotherapy plus systemic chemotherapy, with a retrospective cohort of patients treated with hepatic artery infusion at Memorial Sloan Kettering Cancer Center.

This is a secondary analysis of a single-institution, phase II trial, and retrospective cohort of unresectable intrahepatic cholangiocarcinoma treated with hepatic artery infusion floxuridine plus systemic gemcitabine and oxaliplatin. The primary aim was to assess long-term oncologic outcomes. A subset underwent tissue-based genomic sequencing, and molecular alterations were correlated with progression-free survival (PFS) and overall survival.

A total of 38 patients were treated on trial with a median follow-up of 76.9 months. Median PFS was 11.8 months (95% confidence interval [CI] = 11 to 15.1 months). The median overall survival was 26.8 months (95% CI = 20.9 to 40.6 months). The 1-, 2-, and 5-year overall survival rate was 89.5%, 55%, and 21%, respectively. Nine (24%) patients received hepatic artery infusion with mitomycin C post-floxuridine progression with an objective response rate of 44% and a median PFS of 3.93 months (95% CI = 2.33 months to not reached). A total of 170 patients not treated on the clinical trial were included in a retrospective analysis. Median PFS and overall survival were 7.93 months (95% CI = 7.27 to 10.07 months) and 22.5 months (95% CI = 19.5 to 28.3 months), respectively. Alterations in the TP53 and cell-cycle pathway had a worse PFS to hepatic artery infusion-based therapy compared with wild-type disease.

In locally advanced intrahepatic cholangiocarcinoma, hepatic artery infusion with floxuridine in combination with systemic therapy can offer long-term durable disease control. Molecular alterations may predict for response.

We sought to characterize the benefit of lymphadenectomy among patients undergoing curative-intent surgery for perihilar cholangiocarcinoma (pCCA) utilizing the therapeutic index.

Data on patients who underwent curative-intent resection for pCCA were obtained from 8 high-volume international hepatobiliary centers. Multivariable Cox regression analysis was used to assess clinicopathological factors associated with overall survival (OS). The therapeutic index was determined to assess the therapeutic benefit of lymphadenectomy.

Among 341 patients, median number of lymph nodes (LNs) evaluated was 7 (IQR: 4-11). A total of 127 (37.2 %) patients underwent lymphadenectomy of station 12 only, while 146 (42.8 %) patients had LNs from stations 12 plus 8 ± 13 harvested. On multivariable analysis, lymphadenectomy of stations 12 plus 8 ± 13 was associated with improved OS (referent, station 12 only: HR 0.51, 95%CI 0.32-0.80). The therapeutic index was highest among patients who underwent LN evaluation of stations 12 plus 8 ± 13 (33.1) and had ≥6 LNs harvested (26.3).

At the time of surgery of pCCA, lymphadenectomy should include station 12, as well as stations 8 and 13, with the goal to evaluate ≥6 LNs to ensure optimal staging and maximize the therapeutic benefit for patients.