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Background The management of patients with liver and biliary malignancies is rapidly changing. Over the past year, important new studies have been published that offer new treatment options for patients with hepatobiliary cancers. Methods This article summarizes the top studies published in hepatobiliary cancer over the past year and describes how this latest evidence will impact clinical practice. Results Advances in systemic therapy with immune checkpoint inhibition and precision oncology approaches for primary liver cancers were reported. For colorectal liver metastases, long-term results from one large randomized trial report limited effects of chemotherapy on overall survival following liver metastasectomy. Conclusions Key new evidence informs that treatment strategies for hepatobiliary cancer are now available and should be incorporated into practice to improve outcomes for patients with liver and biliary malignancies.

BackgroundThe added value of radiotherapy following neoadjuvant FOLFIRINOX chemotherapy in patients with resectable or borderline resectable pancreatic cancer ((B)RPC) is unclear. The objective of this meta-analysis was to compare outcomes of patients who received neoadjuvant FOLFIRINOX alone or combined with radiotherapy.MethodsA systematic literature search was performed in Embase, Medline (ovidSP), Web of Science, Scopus, Cochrane, and Google Scholar. The primary endpoint was pooled median overall survival (OS). Secondary endpoints included resection rate, R0 resection rate, and other pathologic outcomes.ResultsWe included 512 patients with (B)RPC from 15 studies, of which 7 were prospective nonrandomized studies. In total, 351 patients (68.6%) were treated with FOLFIRINOX alone (8 studies) and 161 patients (31.4%) were treated with FOLFIRINOX and radiotherapy (7 studies). The pooled estimated median OS was 21.6 months (range 18.4–34.0 months) for FOLFIRINOX alone and 22.4 months (range 11.0–37.7 months) for FOLFIRINOX with radiotherapy. The pooled resection rate was similar (71.9% vs. 63.1%, p = 0.43) and the pooled R0 resection rate was higher for FOLFIRINOX with radiotherapy (88.0% vs. 97.6%, p = 0.045). Other pathological outcomes (ypN0, pathologic complete response, perineural invasion) were comparable.ConclusionsIn this meta-analysis, radiotherapy following neoadjuvant FOLFIRINOX was associated with an improved R0 resection rate as compared with neoadjuvant FOLFIRINOX alone, but a difference in survival could not be demonstrated. Randomized trials are needed to determine the added value of radiotherapy following neoadjuvant FOLFIRINOX in patients with (B)PRC.

Background For some patients with colorectal liver metastases (CRLMs), surgical resection of all visible disease can lead to long-term survival and even cure. When complete resection is not feasible, microwave ablation (MWA) can help achieve hepatic disease control. As modern 2.45-GHz MWA generators gain popularity, the characteristics of tumors most likely to benefit from this method remain unclear. This study aimed to evaluate local recurrence (LR) rates, patterns of recurrence, and factors contributing to treatment failure after 2.45-GHz MWA of CRLM. Methods Patients with CRLM who underwent operative 2.45-GHz MWA between 2011 and 2019 were identified in a prospectively maintained single-institution database. Recurrence outcomes were ascertained for each lesion by imaging review. Factors associated with LR were analyzed. Results The study enrolled 184 patients bearing 416 ablated tumors. Most of the patients (65.8%) had high clinical risk scores (3–5), and 165 (90%) underwent concurrent liver resection. The median tumor size was 10 mm. After a median follow-up period of 28.8 months, LR was observed in 45 tumors, and the cumulative incidence of LR at 24 months was 10.9% (95% confidence interval [CI], 8.0–14.3%]. In 7%, LR was the first recurrence site, often combined with recurrence elsewhere. The cumulative incidence of LR at 24 months was 6.8% (95% CI 3.8–11.0%) for tumors 10 mm in size or smaller, 12.4% (95% CI 7.8–18.1%) for tumors 11 to 20 mm in size, and 30.2% (95% CI 14.2–48.0%) for tumors larger than 20 mm. In the multivariable analysis, tumors larger than 20 mm with a subcapsular location were significantly associated with increased LR risk. Conclusions Treatment of CRLM with 2.45-GHz MWA offers excellent local control at 2 years and is most successful for small tumors deep within the parenchyma.

Background Performance of pancreaticoduodenectomy (PD) in high-volume centers has been posited to improve postoperative morbidity and mortality, consistent with the volume-outcomes hypothesis. We sought to evaluate the impact of hospital volume on 90-day PD outcomes at hepatopancreatobiliary (HPB) centers within a regionalized system. Methods A retrospective population-based observational cohort study was performed, using administrative records of patients undergoing PD between 2005 and 2013 in Ontario, Canada. Postoperative administrative codes were used to define complications. Patients’ 90-day postoperative outcomes were compared between center-volume categories using chi-square tests and multivariable regression. Volume cutoffs were defined using minimal regional standards (20PD/year), with assessment of the impact of further volume increases. Results Of 2660 patients, 2563 underwent PD at HPB centers. Of these, 38.9% underwent surgery at higher-volume centers ( > 40 PD/year), 36.9% at medium-volume centers (20–39 PD/year), and 24.1% at lower-volume centers (10–19 PD/year). Mortality (30- and 90-day) was lowest at higher-volume hospitals (1.5%, 2.7%, respectively) compared to medium-volume (3.9%, 6.3%) and lower-volume hospitals (2.9%, 5.2%) ( p  < 0.01). Patients treated at higher- and medium-volume centers had lower reoperation rates (10.3%, 10.7% vs. 16.7%, p  = 0.0002) and less prolonged length of stay (23.2%, 22.0% vs. 31.6%, p  < 0.0001) compared to lower-volume centers. Conclusion Progressive increases in hospital volume correspond to improved 90-day outcomes following PD.

Background Pancreatic acinar cell carcinoma (ACC) is a rare primary neoplasm of acinar cell origin. Histologically, it can present as pure ACC or mixed with neuroendocrine or ductal differentiation. We studied whether ACC shared genomic similarities with pancreatic ductal adenocarcinoma (PDAC) or well-differentiated pancreatic neuroendocrine tumors (PNET) using the hidden genome classifier methodology. Methods The hidden genome classifier was trained using next-generation sequencing of KRAS wild-type ( KRAS- WT) PDAC ( n  = 251), KRAS -mutated ( KRAS- mut) PDAC ( n  = 1872) and PNET ( n  = 127). We applied the classifier to 62 primary and metastatic ACC samples from two institutions to identify the genomic class and its relationship to histologic differentiation and clinical outcomes. Results According to the classifier, KRAS mutations and tumor mutation burden contributed to the KRAS- mut PDAC class, while ATRX , VHL and SETD2 mutations contributed to the PNET class. Copy number alterations (CNA) in chromosomes 1q and 11q were key factors in the genomic classification of KRAS -WT PDAC. Most ACC (49/62) aligned genomically with KRAS -WT PDAC. Fifteen ACCs had mixed histology, and the majority of those (11/15) also classified as KRAS -WT PDAC. CNA were present in most ACC tumors, even those without mutations in DNA damage repair or chromatin modification pathways. The predicted genomic class was not associated with survival outcomes. Conclusions The hidden genome classifier found most ACC shares genomic similarities with KRAS -WT PDAC, independent of ductal or neuroendocrine differentiation. This may reflect a common cell of origin in ACC tumorigenesis and explain the improved clinical outcome compared to KRAS- mut PDAC.

Metastatic colorectal cancer is a major cause of cancer death in North America. Hepatic resection offers the potential for cure in selected patients. We report the long-term outcomes of patients who underwent hepatic resection for colorectal metastases over a 10-year period at a single hepatobiliary surgical oncology center. All patients who underwent liver resection for metastatic colorectal cancer between 1992 and 2002 were identified. Data were retrospectively obtained through chart review. Major outcome variables were disease-free survival and overall survival. Risk factors for disease recurrence and mortality were identified by multivariate analysis by using the Cox proportional hazard method. A total of 423 hepatectomies were performed for metastatic colorectal cancer. Most operations (n = 276; 65%) were major (four or more segments) hepatectomies. Perioperative morbidity occurred in 74 (17%) patients. There were seven (1.6%) perioperative deaths. The disease-free survival at 1, 5, and 10 years was 64%, 27%, and 22%, respectively. The overall survival at 1, 5, and 10 years was 93%, 47%, and 28%, respectively. Multivariate analysis identified four negative predictive factors for overall survival (hazard ratio; 95% confidence interval): a positive surgical margin (2.9; 1.5-5.3), large metastases (>5 cm; 1.5; 1.1-2.0), multiple metastases (1.4; 1.1-1.9), and age >60 years (1.4; 1.1-1.9). Hepatic resection for metastatic colorectal cancer is safe and provides good long-term overall survival rates of 47% at 5 years and 28% at 10 years. An aggressive approach is justified by the low operative mortality rate and good long-term survival, even in individuals with multiple bilobar metastases.

Background Despite reduced perioperative mortality and routine use of adjuvant therapy following pancreatectomy for pancreatic ductal adenocarcinoma (PDAC), improvement in long-term outcome has been difficult to ascertain. This study compares outcomes in patients undergoing resection for PDAC within a single, high-volume academic institution over two sequential time periods. Methods Retrospective review of patients with resected PDAC, in two cohorts: period 1 (P1), 1991–2000; and period 2 (P2), 2001–2010. Univariate and multivariate analyses using the Cox proportional hazards model were performed to determine prognostic factors associated with long-term survival. Survival was evaluated using Kaplan–Meier analyses. Results A total of 179 pancreatectomies were performed during P1 and 310 during P2. Perioperative mortality was 6.7 % (12/179) in P1 and 1.6 % (5/310) in P2 ( p  = 0.003). P2 had a greater number of lymph nodes resected (17 [0–50] vs. 7 [0–31]; p  < 0.001), and a higher lymph node positivity rate (69 % [215/310] vs. 58 % [104/179]; p  = 0.021) compared with P1. The adjuvant therapy rate was 30 % (53/179) in P1 and 63 % (195/310) in P2 ( p  < 0.001). By multivariate analysis, node and margin status, tumor grade, adjuvant therapy, and time period of resection were independently associated with overall survival (OS) for both time periods. Median OS was 16 months (95 % confidence interval [CI] 14–20) in P1 and 27 months (95 % CI 24–30) in P2 ( p  < 0.001). Conclusions Factors associated with improved long-term survival remain comparable over time. Short- and long-term survival for patients with resected PDAC has improved over time due to decreased perioperative mortality and increased use of adjuvant therapy, although the proportion of 5-year survivors remains small.

PurposePreoperative radiographic differentiation of mucinous cystic neoplasms (MCN) and simple cysts (SLC) of the liver is challenging. Previous data have demonstrated that the finding of septations arising from the cyst wall without indentation on cross-sectional imaging is associated with MCN. We aim to assess whether this radiographic feature is diagnostic of MCN.MethodsA prospectively maintained database was queried for patients with a preoperative diagnosis of a cystic liver lesion who subsequently underwent operative intervention. The feature of septations without indentation of the cyst wall was evaluated on cross-sectional imaging obtained within 3 months of operation. Imaging was independently evaluated by three radiologists blinded to pathology and interobserver agreement was compared to assess the diagnostic accuracy of this feature as well as the overall likelihood of the lesion representing a MCN.ResultsThere were 95 patients who met inclusion criteria; 80 (84%) had SLC on pathology, while 15 (16%) had MCN. Presence of septa without indentation of cyst wall had high sensitivity (range 80–87%), but low specificity (range 48–66%). Interobserver percent agreement (PA) was 51% [κ = 0.35 (95% CI 0.22–0.47)]. Sensitivity among the three radiologists ranged between 20 and 80% and specificity between 71 and 91% for the likelihood of the lesion representing MCN versus SLC, with an area under the curve (AUC) of 0.67–0.79; however, interobserver agreement was fair [κ = 0.40 (95% CI 0.25–0.55), PA = 67%].ConclusionThe presence of septations without indentation of cyst wall demonstrates adequate sensitivity to differentiate MCN and SLC. However, there is variability for detection of this feature and therefore, it alone is of limited clinical value.

Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients 1 , yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2 , 3 . Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA–lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8 + T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P  = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence. A phase I clinical trial of an adjuvant personalized mRNA neoantigen vaccine, autogene cevumeran, in patients with pancreatic ductal carcinoma demonstrates that the vaccine can induce T cell activity that may correlate with delayed recurrence of disease.