Contemporary trends and outcomes after liver transplantation and resection for intrahepatic cholangiocarcinoma.

BACKGROUND: Liver transplantation (LT) has been shown to be superior to resection in highly selected patients with perihilar cholangiocarcinoma (CCA), yet has traditionally been contraindicated for intrahepatic CCA (iCCA). Herein, we aimed to examine contemporary trends and outcomes for surgical resection and LT for iCCA. METHODS: The National Cancer Database was queried for patients presenting with stage I-III iCCA between 2010 and 2018 who underwent resection or LT. Overall survival (OS) was compared with Kaplan-Meier and multivariable Cox proportional hazards methods stratified by management. Secondary analysis of patients undergoing transplant for CCA was performed with the United Network for Organ Sharing database. RESULTS: Of 2565 patients, 2412 (94.0%) underwent resection and 153 (5.96%) LT of whom 84 (54.9%) received neoadjuvant therapy. Utilization of LT remained between 3.9% and 7.8% annually. Unadjusted 5-year OS was higher for LT than resection (59.8% vs 39.9%, P = .0067), yet adjusted analysis revealed no significant difference in mortality (hazard ratio, 0.91; 95% CI, 0.66-1.27; P = .58). On secondary analysis including 437 patients with all subtypes of CCA, unadjusted 5-year OS was higher for non-CCA indications (79% vs 52%-54%, P < .001). CONCLUSION: Utilization of LT for iCCA remains low and many cases are likely incidental. Although partial hepatectomy remains the standard of care for patients with resectable disease, our findings suggest that highly selected patients with unresectable iCCA may achieve favorable outcomes after LT. Granular, prospective data are needed to identify patients most likely to benefit from transplant and allocate scarce liver grafts.

Initial Report: Personalized Circulating Tumor DNA and Survival in Patients with Resectable Pancreatic Cancer.

ABSTRACT: BACKGROUND: Pancreatic adenocarcinoma (PDAC) is highly lethal with up to 80% of resected patients experiencing disease recurrence within 2 years (Watanabe, Nakamura, Kimura et al in Int J Mol Sci 23(19):11521, 2022). Cross-sectional imaging and serum tumor markers are used for monitoring post-operative recurrence; however, both have significant limitations (Edland, Tjensvoll, Oltedal et al in Mol Oncol 17:1857-1870, 2023). Circulating tumor DNA (ctDNA) has emerged as a valuable prognostic tool to measure molecular residual disease (MRD) and predict recurrence in solid tumors (Watanabe, Nakamura, Kimura et al in Int J Mol Sci 23(19):11521, 2022). In this study, we evaluated the feasibility of a personalized, tumor-informed ctDNA assay to detect recurrence prior to standard surveillance tools in patients with PDAC. PATIENTS AND METHODS: After Institutional Review Board (IRB) approval (Pro00106870), we assessed serial ctDNA measurements (n = 177) from 35 patients with resectable PDAC treated by either upfront resection or neoadjuvant chemotherapy. Plasma samples (median 4 ml, interquartile range 0.6-5.9 ml) were isolated from blood collected in EDTA tubes and banked at diagnosis, during neoadjuvant therapy if applicable, on the day of surgery, and every 2-3 months postoperatively. A tumor-informed assay (Signatera™, Natera, Inc.) that tracks up to 16 individual-specific, somatic single nucleotide variants in the corresponding patient's plasma samples were used for ctDNA detection. Survival was calculated using Kaplan-Meier curves, and significance was determined with the log-rank test. RESULTS: Personalized ctDNA assays were successfully designed for all patients (with 32/35 patients having 16-plex assays). Median follow-up from initial treatment was 13 months (range 1-26 months; Table 1). ctDNA-positivity at any time point was observed in 40% (14/35) of patients. During the follow-up period, 18 patients (51%) developed radiographic evidence of recurrence after a median of 9 months of follow-up (range 1-26 months). At the time of radiographic recurrence, 50% (9/18) of patients were ctDNA-positive. During the immediate postoperative period (up to 9 weeks post-surgery), RFS and OS were significantly inferior in patients who were ctDNA-positive versus ctDNA-negative (RFS 97 versus 297 days, p < 0.001; OS 110 versus 381 days, p < 0.001; Fig. 1). Table 1 Cohort demographics (N = 35); patient demographics, tumor characteristics, and survival Gender (%) Female 17 (49%) Male 18 (51%) Median age (IQR) 70 years (65-75 years) Neoadjuvant treatment (%) 11 (31%) Median sample plasma volume (IQR) 4.0 mL (0.6-5.9 mL) Median follow-up (range) 13 months (1-26 months) Median initial CA 19-9 in U/mL (IQR) 56 (18-160) Median tumor size in cm (IQR) 2.5 (1.8-3.3) Median number of positive lymph nodes (IQR) 1 (0-3) Median recurrence-free survival 9.4 months Median overall survival N/A (not reached) Fig. 1 a Overview plot showing longitudinal ctDNA status, treatment regimen, and clinical outcomes for each patient (N = 35); median follow-up from the start of the neoadjuvant therapy/surgery was 13 months (range 1-26 months); ctDNA at any time point was 40% (14/35); out of the 35 patients, 18 (51%) developed radiographic evidence of recurrence (median RFS: 9 months), and of these 18 patients with clinical recurrence, 9 (50%) were ctDNA-positive and the remaining ctDNA-negative; notably, all ctDNA-negative patients with recurrence had suboptimal plasma volume available for ctDNA analysis; b, c Kaplan-Meier estimates representing the association of ctDNA status with (b) RFS and (c) OS, at MRD time point (9 weeks post-surgery) DISCUSSION: Our study demonstrates the feasibility of tumor-informed ctDNA-based MRD testing in resectable PDAC and shows that MRD detected by ctDNA within the immediate postoperative period portends a dismal prognosis. This information is valuable for both patients and clinicians in setting prognostic expectations.

Tumor size and survival in intrahepatic cholangiocarcinoma treated with surgical resection or ablation.

OBJECTIVES: We performed a retrospective analysis within a national cancer registry on outcomes following resection or ablation for intrahepatic cholangiocarcinoma (iCCA). METHODS: The National Cancer Database was queried for patients with clinical stage I-III iCCA diagnosed during 2010-2018, who underwent resection or ablation. Overall survival (OS) was compared with Kaplan-Meier and multivariable Cox proportional hazards methods. RESULTS: Of 2140 patients, 1877 (87.7%) underwent resection and 263 (12.3%) underwent ablation, with median tumor sizes of 5.5 and 3 cm, respectively. Overall, resection was associated with greater median OS (41.2 months (95% confidence interval [95% CI]: 37.6-46.2) vs. 28 months (95% CI: 15.9-28.6) on univariable analysis (p < 0.0001). There was no significant difference on multivariable analysis (p = 0.42); however, there was a significant interaction between tumor size and management. On subgroup analysis of patients with tumors <3 cm, there was no difference in OS between resection versus ablation. However, ablation was associated with increased mortality for tumors ≥3 cm. CONCLUSION: Although resection is associated with improved OS for tumors ≥3 cm, we observed no difference in survival between management strategies for tumors < 3 cm. Ablation may be an alternative therapeutic strategy for small iCCA, particularly in patients at risk for high surgical morbidity.

Impact of Tumor Size and Management on Survival in Small Gastric Gastrointestinal Stromal Tumors.

BACKGROUND: Society guidelines remain inconsistent on the role of endoscopic and radiographic surveillance as an alternative to surgical resection of small gastric gastrointestinal stromal tumors (GISTs). Herein, we aimed to assess survival among patients with gastric GISTs undergoing observation versus surgical resection, stratified by tumor size. METHODS: The National Cancer Database (NCDB) was queried for gastric GISTs < 2 cm diagnosed from 2010-2017. Patients were stratified by management strategy-observation vs surgical resection. The primary outcome, overall survival (OS), was examined with Kaplan-Meier and multivariable Cox proportional hazard methods. Subgroup analyses were conducted on tumors < 1 cm and 1-2 cm in size. RESULTS: Altogether, 1208 patients were identified: 439 (36.3%) undergoing observation and 769 (63.7%) receiving surgical resection. In the overall cohort, patients undergoing surgical resection demonstrated improved survival (93.6 vs. 88.8% 5-year OS, p=0.02). In multivariable analysis, upfront surgical resection was not associated with a reduction in mortality; however, there was a significant interaction with tumor size. For patients with tumors < 1 cm, there was no difference in survival based on management strategy. However, resection of tumors 1-2 cm was associated with improved survival relative to surveillance. CONCLUSIONS: While surgical resection and surveillance were associated with similar survival for patients with gastric GISTs < 1 cm, this NCDB analysis suggests that patients with tumor size ≥ 1 cm may benefit from upfront surgical resection. Prospective studies comparing these two approaches and their impact on recurrence-free and disease-specific survival are needed to better align consensus guidelines and recommendations.

Comparing Survival After Resection, Ablation, and Radiation in Small Intrahepatic Cholangiocarcinoma.

BACKGROUND: Hepatectomy is the cornerstone of curative-intent treatment for intrahepatic cholangiocarcinoma (ICC). However, in patients unable to be resected, data comparing efficacy of alternatives including thermal ablation and radiation therapy (RT) remain limited. Herein, we compared survival between resection and other liver-directed therapies for small ICC within a national cancer registry. PATIENTS AND METHODS: Patients with clinical stage I-III ICC < 3 cm diagnosed 2010-2018 who underwent resection, ablation, or RT were identified in the National Cancer Database. Overall survival (OS) was compared using Kaplan-Meier and multivariable Cox proportional hazards methods. RESULTS: Of 545 patients, 297 (54.5%) underwent resection, 114 (20.9%) ablation, and 134 (24.6%) RT. Median OS was similar between resection and ablation [50.5 months, 95% confidence interval (CI) 37.5-73.9; 39.5 months, 95% CI 28.7-58.4, p = 0.14], both exceeding that of RT (20.9 months, 95% CI 14.1-28.3). RT patients had high rates of stage III disease (10.4% RT vs. 1.8% ablation vs. 11.8% resection, p < 0.001), but the lowest rates of chemotherapy utilization (9.0% RT vs. 15.8% ablation vs. 38.7% resection, p < 0.001). In multivariable analysis, resection and ablation were associated with reduced mortality compared with RT [hazard ratio (HR) 0.44, 95% CI 0.33-0.58 and HR 0.53, 95% CI 0.38-0.75, p < 0.001, respectively]. CONCLUSION: Resection and ablation were associated with improved survival in patients with ICC < 3 cm compared with RT. Acknowledging confounders, anatomic constraints of ablation, limitations of available data, and need for prospective study, these results favor ablation in small ICC where resection is not feasible.

Impact of surgical approach on short- and long-term outcomes in gastroenteropancreatic neuroendocrine carcinomas.

BACKGROUND: Literature is lacking on the impact of advancements in minimally invasive surgery (MIS) on outcomes for patients with gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs). Herein, we compared perioperative and oncologic outcomes among patients with GEP-NECs undergoing open, laparoscopic, and robotic resection. METHODS: Patients with GEP-NECs diagnosed 2010-2019 were identified from the National Cancer Database (NCDB). We used the inverse probability of treatment weighting method to account for selection bias. Patients were stratified by surgical approach; and pairwise comparisons were conducted by analyzing short- and long-term outcomes. RESULTS: Receipt of MIS increased from 34.2% in 2010 to 67.5 % in 2019. Altogether, 6560 patients met study criteria: 3444 (52.5%) underwent open resection, 2783 (42.4%) underwent laparoscopic resection and 333 (5.1%) underwent robotic resection. Compared with open resection, laparoscopic or robotic resection were associated with shorter post-operative length of stay, reduced 30-day and 90-day post-operative mortality, and prolonged overall survival (OS). Compared with laparoscopic resection, robotic resection was associated with reduced 90-day post-operative mortality, however, there was no significant difference in OS. CONCLUSION: This NCDB analysis demonstrates that MIS approaches for treating GEP-NECs have become more common, with improved perioperative mortality, shorter post-operative length of stay and favorable OS, compared with open resection.

Tyrosine Kinase Inhibitors in Leukemia and Cardiovascular Events: From Mechanism to Patient Care.

Targeted oncology therapies have revolutionized cancer treatment over the last decade and have resulted in improved prognosis for many patients. This advance has emanated from elucidation of pathways responsible for tumorigenesis followed by targeting of these pathways by specific molecules. Cardiovascular care has become an increasingly critical aspect of patient care in part because patients live longer, but also due to potential associated toxicities from these therapies. Because of the targeted nature of cancer therapies, cardiac and vascular side effects may additionally provide insights into the basic biology of vascular disease. We herein provide the example of tyrosine kinase inhibitors utilized in chronic myelogenous leukemia to illustrate this medical transformation. We describe the vascular considerations for the clinical care of chronic myelogenous leukemia patients as well as the emerging literature on mechanisms of toxicities of the individual tyrosine kinase inhibitors. We additionally postulate that basic insights into toxicities of novel cancer therapies may serve as a new platform for investigation in vascular biology and a new translational research opportunity in vascular medicine.