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Pancreatic neuroendocrine tumors (PNETs) comprise a heterogeneous group of neoplasms arising from pancreatic islet cells that remain relatively rare but are increasing in incidence worldwide. While significant advances have been made in recent years with regard to systemic therapies for patients with advanced disease, surgical resection remains the standard of care for most patients with localized tumors. Although formal pancreatectomy with regional lymphadenectomy is the standard approach for most PNETs, pancreas-preserving approaches without formal lymphadenectomy are acceptable for smaller tumors at low risk for lymph node metastases. Furthermore, observation of small, asymptomatic, low-grade PNETs is a safe, initial strategy and is generally recommended for tumors < 1 cm in size. In this Landmark Series review, we highlight the critical studies that have defined the surgical management of PNETs.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and third leading cause of cancer-related mortality worldwide. While surgical resection and transplantation are the standard first-line treatments for early-stage HCC, most patients do not fulfill criteria for surgery. Fortunately, catheter-directed and percutaneous locoregional approaches have evolved as major treatment modalities for unresectable HCC. Improved outcomes have been achieved with novel techniques which can be employed for diverse applications ranging from curative-intent for small localized tumors, to downstaging or bridging to resection and transplantation for early and intermediate disease, and locoregional control and palliation for advanced disease. This review explores recent advances in liver-directed techniques for HCC including bland transarterial embolization, chemoembolization, radioembolization, and ablative therapies, with a focus on patient selection, procedural technique, periprocedural management, and outcomes.

IntroductionIntrahepatic cholangiocarcinoma (ICC) is an aggressive biliary tract cancer (BTC) with distinct anatomic, molecular, and clinical characteristics that distinguishes it from other BTCs.MethodsIn this landmark series review, we highlight the critical studies that have defined the surgical management of ICC, as well as several randomized controlled trials that have investigated adjuvant therapy strategies.ResultsSurgical resection is the mainstay of treatment and should involve margin-negative resection with regional lymphadenectomy. Several recently completed and ongoing randomized controlled trials are defining the indications for adjuvant therapy among patients with resected ICC.ConclusionsIn the near future, improved understanding of the molecular features of ICC should lead to newer targeted therapies as well as a more personalized approach to systemic therapy.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease due to its late presentation and tendency to recur early even after optimal surgical resection. Currently, there are limited options for effective systemic therapy. In addition, PDAC typically generates an immune-suppressive tumor microenvironment; trials of immunotherapy in metastatic PDAC have yielded disappointing results. There is considerable interest in using immunotherapy approaches in the neoadjuvant setting in order to prime the immune system to detect and prevent micrometastatic disease and recurrence. A scoping review was conducted to identify published and ongoing trials utilizing preoperative immunotherapy. In total, 9 published trials and 27 ongoing trials were identified. The published trials included neoadjuvant immune checkpoint inhibitors, cancer vaccines, and other immune-modulating agents that target mechanisms distinct from that of immune checkpoint inhibition. Most of these are early phase trials which suggest improvements in disease-free and overall survival when combined with standard neoadjuvant therapy. Ongoing trials are exploring various combinations of these agents with each other and with chemotherapy and/or radiation. Rational combination immunotherapy in addition to standard neoadjuvant therapy has the potential to improve outcomes in PDAC, but further clinical trials are needed, particularly those which utilize an adaptive trial design.

The efficacy of neoadjuvant therapy (NT) versus surgery first (SF) for pancreatic ductal adenocarcinoma (PDAC) remains controversial. A random-effects meta-analysis of only prospective randomized controlled trials (RCTs) comparing NT versus SF for potentially resectable (PR) or borderline resectable (BR) PDAC was performed. Among six RCTs including 850 patients, 411 (48.3%) received NT and 439 (51.6%) SF. In all included trials, NT was gemcitabine-based: four using chemoradiation and two chemotherapy alone. Based on an intention-to-treat analysis, NT resulted in improved overall survival (OS) compared to SF (HR 0.73, 95% CI 0.61–0.86). This effect was independent of anatomic classification (PR: hazard ratio (HR) 0.73, 95% CI 0.59–0.91; BR: HR 0.51 95% CI 0.28–0.93) or NT type (chemoradiation: HR 0.77, 95% CI 0.61–0.98; chemotherapy alone: HR 0.68, 95% CI 0.54–0.87). Overall resection rate was similar (risk ratio (RR) 0.93, 95% CI 0.82–1.04, I2 = 39.0%) but NT increased the likelihood of a margin-negative (R0) resection (RR 1.51, 95% CI 1.18–1.93, I2 = 0%) and having negative lymph nodes (RR 2.07, 95% CI 1.47–2.91, I2 = 12.3%). In this meta-analysis of prospective RCTs, NT significantly improved OS in an intention-to-treat fashion, compared with SF for localized PDAC. Randomized controlled trials using contemporary multi-agent chemotherapy will be needed to confirm these findings and to define the optimal NT regimen.

Purpose This review aimed to assess the measurement and reporting of time toxicity (i.e., time spent receiving care) within prospective oncologic studies. Methods On July 23, 2023, PubMed, Scopus, and Embase were queried for prospective or randomized controlled trials (RCT) from 1984 to 2023 that reported time toxicity as a primary or secondary outcome for oncologic treatments or interventions. Secondary analyses of RCTs were included if they reported time toxicity. The included studies were then evaluated for how they reported and defined time toxicity. Results The initial query identified 883 records, with 10 studies (3 RCTs, 2 prospective cohort studies, and 5 secondary analyses of RCTs) meeting the final inclusion criteria. Treatment interventions included surgery ( n  = 5), systemic therapies ( n  = 4), and specialized palliative care ( n  = 1). The metric “days alive and out of the hospital” was used by 80% ( n  = 4) of the surgical studies. Three of the surgical studies did not include time spent receiving ambulatory care within the calculation of time toxicity. “Time spent at home” was assessed by three studies (30%), each using different definitions. The five secondary analyses from RCTs used more comprehensive metrics that included time spent receiving both inpatient and ambulatory care. Conclusions Time toxicity is infrequently reported within oncologic clinical trials, with no standardized definition, metric, or methodology. Further research is needed to identify best practices in the measurement and reporting of time toxicity to develop strategies that can be implemented to reduce its burden on patients seeking cancer care.

Background Because duodenal adenocarcinoma (DA) is relatively rare, few studies have investigated the impact of resection type on long-term outcomes. Methods The Surveillance, Epidemiology, and End Results database was used to identify all patients between 1988 and 2010 with DA. Patients were divided into two groups based on the type of surgery received: simple resection (SR), defined as a simple removal of the primary site, and radical resection (RR), defined as removal of the primary site with a resection in continuity with other organs. Differences in disease-specific survival (DSS) and overall survival (OS) were compared. Results Of the 1,611 patients included, 746 (46.3 %) underwent SR and 865 (53.7 %) underwent RR. As expected, patients undergoing RR were more likely to present with poorly differentiated and large tumors, as well as advanced stage disease. Despite greater lymph node (LN) retrieval (11.0 vs. 6.8; p  < 0.0001), RR was not associated with improved survival (5-year DSS and OS rates of 52.8 and 41.3 % for SR vs. 48.8 and 37.6 % for RR; p  > 0.05). On univariate Cox proportional hazards regression analysis, the type of surgery was not associated with OS (odds ratio [OR] 0.98; 95 % confidence interval [CI] 0.87–1.11). Increasing TNM stages, tumor grade, fewer LNs removed, LN ratio, and absence of radiation were associated with worse survival. After controlling for confounding factors, type of surgery still did not influence OS (OR 1.11; 95 % CI 0.97–1.27). Conclusions Radical resection (e.g., in the form of pancreaticoduodenectomy) does not appear to impact survival compared with simple segmental resection for DA.

Although a significant proportion of patients are readmitted to non-index hospitals after surgery, risk factors for non-index hospital readmission are not well defined. Using the California Office of State Health Planning and Development database from 2008 to 2012, patients readmitted to index versus non-index hospitals after colorectal surgery were directly compared. Risk factors for non-index hospital readmission were assessed through logistic regression. Among the 14,401 patients requiring readmission, 10,890 (75.6%) were readmitted to index hospitals, whereas 3,511 (24.4%) were readmitted to non-index hospitals. Patients readmitted to non-index hospitals were more likely to be men and have a greater Charlson comorbidity index, non-private insurance, longer initial length of stay, longer travel distance, and non-home discharge disposition. On multivariable logistic regression analysis, living ≥10 miles from the index hospital was strongly predictive of non-index hospital readmission (odds ratio, 1.8; 95% confidence interval, 1.63 to 2.00). Approximately 25% of readmissions after colorectal surgery will be to non-index hospitals. Risks factors include greater comorbidities, non-private health insurance, occurrence of an inpatient complication, longer length of stay, greater travel distance, and non-home discharge disposition. •Up to one fourth of readmissions after colorectal surgery will be to non-index hospitals.•Substantial variability in non-index hospital readmission rates exists.•Multiple factors are associated with non-index hospital readmission.•Greater travel distance is one of the strongest predictors.

Thermal ablation, including microwave ablation, has become increasingly important in the management of many solid tumors, including primary and metastatic tumors of the liver, kidney, and lung. However, its adoption to treat pancreatic lesions has been slowed due to concerns about potential adverse events. The success of radiofrequency ablation (RFA) in inoperable pancreatic cancers paved the way for its use in pancreatic neuroendocrine tumors and pancreatic cystic neoplasms (PCLs). In the last decade, other thermal ablation techniques, like microwave ablation, have emerged as alternatives to RFA. Microwaves, with frequencies ranging from 900 to 2450 MHz, generate heat by rapidly oscillating water molecules. Microwave ablation’s advantage lies in its ability to achieve higher intra-lesion temperatures and uniform heating compared with RFA. Microwave ablation’s application in pancreatic cancer and pancreatic neuroendocrine tumors has demonstrated promise with similar technical success to RFA. Yet, concern for peri-procedure complications, as well as a dearth of studies comparing RFA and microwave ablation, emphasize the need for further research. No studies have evaluated microwave ablation in PCLs. We herein review thermal ablation’s potential to treat pancreatic lesions.