Faculty Bibliography

BACKGROUND:Traditional biopsies have numerous limitations in the developing era of precision medicine, with cancer treatment that relies on biomarkers to guide therapy. Tumor heterogeneity raises the potential for sampling error with the use of traditional biopsy of the primary tumor. Moreover, tumors continuously evolve as new clones arise in the natural course of the disease and under the pressure of treatment. Since traditional biopsy is invasive, it is neither feasible nor practical to perform serial biopsies to guide treatment in real time. PURPOSE/OBJECTIVE:The current manuscript will review the most commonly used types of liquid biopsy and how these apply to surgical patients in terms of diagnosis, prediction of outcome, and guiding therapy. CONCLUSIONS:Liquid biopsy has the potential to overcome many of the limitations of traditional biopsy as a highly tailored, minimally invasive, and cost-effective method to screen and monitor response to treatment. However, many challenges still need to be overcome before liquid biopsy becomes a reliable and widely available option.

Cancer-associated fibroblasts (CAF) are major players in the progression and drug resistance of pancreatic ductal adenocarcinoma (PDAC). CAFs constitute a diverse cell population consisting of several recently described subtypes, although the extent of CAF heterogeneity has remained undefined. Here we use single-cell RNA sequencing to thoroughly characterize the neoplastic and tumor microenvironment content of human and mouse PDAC tumors. We corroborate the presence of myofibroblastic CAFs and inflammatory CAFs and define their unique gene signatures in vivo. Moreover, we describe a new population of CAFs that express MHC class II and CD74, but do not express classic costimulatory molecules. We term this cell population "antigen-presenting CAFs" and find that they activate CD4⁺ T cells in an antigen-specific fashion in a model system, confirming their putative immune-modulatory capacity. Our cross-species analysis paves the way for investigating distinct functions of CAF subtypes in PDAC immunity and progression. SIGNIFICANCE: Appreciating the full spectrum of fibroblast heterogeneity in pancreatic ductal adenocarcinoma is crucial to developing therapies that specifically target tumor-promoting CAFs. This work identifies MHC class II-expressing CAFs with a capacity to present antigens to CD4⁺ T cells, and potentially to modulate the immune response in pancreatic tumors.See related commentary by Belle and DeNardo, p. 1001.This article is highlighted in the In This Issue feature, p. 983.

BACKGROUND:The literature suggests favorable survival for patients with isolated pulmonary recurrence after resection of pancreatic ductal adenocarcinoma (PDAC) as compared to other recurrence patterns. Within this cohort, it remains unclear what factors are associated with improved survival. METHODS:Patients who developed pulmonary recurrence after pancreatectomy were selected from a prospective database. Predictors for post-recurrence survival (PRS) were analyzed using a multivariable Cox regression model. RESULTS:Ninety-six patients were included. Median recurrence-free survival (RFS), PRS and overall survival (OS) were 16.3, 18.8 and 39.6 months, respectively. Further systemic treatment and/or metastasectomy (n = 64, 67%) was associated with significantly improved PRS and OS when compared to best supportive care (n = 35, 22%) (26.3 vs. 5.3 and 48.1 vs. 18.4, respectively; both P < 0.001). Patients who were able to undergo metastasectomy (n = 19) achieved a PRS and OS of 35.0 and 68.9 months, respectively. More than 5 pulmonary lesions, symptoms and CA 19-9 ≥100 U/mL at time of recurrence were predictive of decreased PRS. A recurrence-free interval of >16 months and treatment for recurrence were independently associated with improved PRS. CONCLUSIONS:Isolated pulmonary recurrence occurs in 13% of patients with recurrent PDAC and is associated with a median OS of 40 months. Aggressive treatment in highly selected patients was correlated with improved survival.

Pancreatic cysts are common and often pose a management dilemma, because some cysts are precancerous, whereas others have little risk of developing into invasive cancers. We used supervised machine learning techniques to develop a comprehensive test, CompCyst, to guide the management of patients with pancreatic cysts. The test is based on selected clinical features, imaging characteristics, and cyst fluid genetic and biochemical markers. Using data from 436 patients with pancreatic cysts, we trained CompCyst to classify patients as those who required surgery, those who should be routinely monitored, and those who did not require further surveillance. We then tested CompCyst in an independent cohort of 426 patients, with histopathology used as the gold standard. We found that clinical management informed by the CompCyst test was more accurate than the management dictated by conventional clinical and imaging criteria alone. Application of the CompCyst test would have spared surgery in more than half of the patients who underwent unnecessary resection of their cysts. CompCyst therefore has the potential to reduce the patient morbidity and economic costs associated with current standard-of-care pancreatic cyst management practices.

Locally advanced pancreatic cancer (LAPC) has several definitions but essentially is a nonmetastasized pancreatic cancer, in which upfront resection is considered not beneficial due to extensive vascular involvement and consequent high chance of a nonradical resection. The introduction of FOLFIRINOX chemotherapy and gemcitabine-nab-paclitaxel (gem-nab) has had major implications for the management and outcome of patients with LAPC. After 4-6 months induction chemotherapy, the majority of patients have stable disease or even tumor-regression. Of these, 12 to 35% are successfully downstaged to resectable disease. Several studies have reported a 30-35 months overall survival after resection; although it currently remains unclear if this is a result of the resection or the good response to chemotherapy. Following chemotherapy, selection of patients for resection is difficult, as contrast-enhanced computed-tomography (CT) scan is unreliable in differentiating between viable tumor and fibrosis. In case a resection is not considered possible but stable disease is observed, local ablative techniques are being studied, such as irreversible electroporation, radiofrequency ablation, and stereotactic body radiation therapy. Pragmatic, multicenter, randomized studies will ultimately have to confirm the exact role of both surgical exploration and ablation in these patients. Since evidence-based guidelines for the management of LAPC are lacking, this review proposes a standardized approach for the treatment of LAPC based on the best available evidence.

OBJECTIVE:To establish an international core set of patient-reported outcomes (PROs) selected by both patients and healthcare providers (HCPs) from the United States (US), Europe, and Asia. SUMMARY BACKGROUND DATA:PROs are increasingly recognized in pancreatic cancer studies. There is no consensus on which of the many available PROs are most important. METHODS:A multicenter Delphi study among patients with pancreatic cancer (curative- and palliative-setting) and HCPs in 6 pancreatic centers in the US (Baltimore, Boston), Europe (Amsterdam, Verona), and Asia (Mumbai, Seoul) was performed. In round 1, participants rated the importance of 56 PROs on a 1 to 9 Likert scale. PROs rated as very important (scores 7-9) by the majority (≥80%) of curative- and/or palliative-patients as well as HCPs were included in the core set. PROs not fulfilling these criteria were presented again in round 2, together with feedback on individual and group ratings. Remaining PROs were ranked based on the importance ratings. RESULTS:In total 731 patients and HCPs were invited, 501 completed round 1, and 420 completed both rounds. This included 204 patients in curative-setting, 74 patients in palliative-setting, and 142 HCPs. After 2 rounds, 8 PROs were included in the core set: general quality of life, general health, physical ability, ability to work/do usual activities, fear of recurrence, satisfaction with services/care organization, abdominal complaints, and relationship with partner/family. CONCLUSIONS:This international Delphi study among patients and HCPs established a core set of PROs in pancreatic cancer, which should facilitate the design of future pancreatic cancer trials and outcomes research.

INTRODUCTION:Investigation into right and left-sided primary colon liver metastasis (CLM) has revealed differences in the tumor biology and prognosis. This indicates that preoperative and operative factors may affect outcomes of right-sided primary CLM differently than left. This retrospective analysis investigated the effects of resection margin stratified by left and right-sided primary CLM on overall survival (OS) for patients undergoing hepatectomy. METHODS:A total of 732 patients undergoing hepatic resection for CLM at the Cleveland Clinic and Johns Hopkins were identified between 2002 and 2016. Clinically significant variables were analyzed using Cox proportional hazard regression. The cohort was then divided into patients with right and left-sided CLM and analyzed separately using Kaplan Meier analysis and Cox proportional hazard regression. RESULTS:Cox proportional hazard regression showed that left-sided CLM with an R0 margin was a statistically significant predictor of OS even after controlling for other important factors (HR = 0.629, P = 0.024) but right-sided CLM with R0 margin was not (HR = 0.788, P = 0.245). Kaplan-Meier analysis demonstrated that patients with a left-sided CLM and R0 margin had the best prognosis (P = 0.037). CONCLUSION:Surgical margin is an important prognostic factor for left-sided primary CLM but tumor biology may override surgical technique for right-sided CLM.

Background and Objectives: We previously proposed a nomogram predicting individual risks of malignancy and invasiveness of intraductal papillary mucinous neoplasms and validated it in an external cohort. However, it is difficult to apply if data on tumor marker are lacking. The aim of the current study was to develop a new nomogram based on radiologic findings using previous nomogram development and an external validation cohort.
Material(s) and Method(s): A total of 3049 patients who underwent surgical resection at 30 tertiary institutes in 7 countries were enrolled and clinicopathologic data were retrospectively analyzed. Based on fitted model, area under the receiver operating characteristics curve (AUC) was calculated using 10-fold cross validation by exhaustive search.
Result(s): The study consisted of 1914 (62.8%) patients for previous nomogram development and 1135 patients (37.2%) in the external validation cohort. Among patients, 1898 (62.3%) had low, 577 (18.9%) had high grade dysplasia, and 574 (18.8%) had invasive carcinoma. Patients were allocated randomly into model development and test sets to construct the nomogram, with fixed ratios according to malignancy and invasiveness. Exhaustive search resulted in three variables (cyst size, duct dilatation, and mural nodule) for malignancy and four variables (cyst size, duct dilatation, mural nodule, and location) for invasiveness being selected to construct the nomogram, and AUC was 0.742 and 0.741, respectively. AUC for test set was 0.727 and 0.704, respectively, and Hosmer-Lemeshow goodness of fit test showed good discrimination power (p = 0.066 and 0.067, respectively).
Conclusion(s): The new nomogram based on radiologic findings is accurate and helpful in identifying patients at risk of malignancy and invasiveness and selecting treatment options in clinical settings.
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OBJECTIVES:To establish an evidence-based cut-off to differentiate between early and late recurrence and to compare clinicopathologic risk factors between the two groups. SUMMARY BACKGROUND DATA:A clear definition of "early recurrence" after pancreatic ductal adenocarcinoma resection is currently lacking. METHODS:Patients undergoing pancreatectomy for pancreatic ductal adenocarcinoma between 2000 and 2013 were included. Exclusion criteria were neoadjuvant therapy and incomplete follow-up. A minimum P-value approach was used to evaluate the optimal cut-off value of recurrence-free survival to divide the patients into early and late recurrence cohorts based on subsequent prognosis. Potential risk factors for early recurrence were assessed with logistic regression models. RESULTS:Of 957 included patients, 204 (21.3%) were recurrence-free at last follow-up. The optimal length of recurrence-free survival to distinguish between early (n = 388, 51.5%) and late recurrence (n = 365, 48.5%) was 12 months (P < 0.001). Patients with early recurrence had 1-, and 2-year post-recurrence survival rates of 20 and 6% compared with 45 and 22% for the late recurrence group (both P < 0.001). Preoperative risk factors for early recurrence included a Charlson age-comorbidity index ≥4 (OR 1.65), tumor size > 3.0 cm on computed tomography (OR 1.53) and CA 19-9 > 210 U/mL (OR 2.30). Postoperative risk factors consisted of poor tumor differentiation grade (OR 1.66), microscopic lymphovascular invasion (OR 1.70), a lymph node ratio > 0.2 (OR 2.49), and CA 19-9 > 37 U/mL (OR 3.38). Adjuvant chemotherapy (OR 0.28) and chemoradiotherapy (OR 0.29) were associated with a reduced likelihood of early recurrence. CONCLUSION:A recurrence-free interval of 12 months is the optimal threshold for differentiating between early and late recurrence, based on subsequent prognosis.

OBJECTIVE:This study seeks to evaluate the efficacy of negative pressure wound therapy for surgical-site infection (SSI) after open pancreaticoduodenectomy. BACKGROUND:Despite improvement in infection control, SSIs remain a common cause of morbidity after abdominal surgery. SSI has been associated with an increased risk of reoperation, prolonged hospitalization, readmission, and higher costs. Recent retrospective studies have suggested that the use of negative pressure wound therapy can potentially prevent this complication. METHODS:We conducted a single-center randomized, controlled trial evaluating surgical incision closure during pancreaticoduodenectomy using negative pressure wound therapy in patients at high risk for SSI. We randomly assigned patients to receive negative pressure wound therapy or a standard wound closure. The primary end point of the study was the occurrence of a postoperative SSI. We evaluated the economic impact of the intervention. RESULTS:From January 2017 through February 2018, we randomized 123 patients at the time of closure of the surgical incision. SSI occurred in 9.7% (6/62) of patients in the negative pressure wound therapy group and in 31.1% (19/61) of patients in the standard closure group (relative risk = 0.31; 95% confidence interval, 0.13-0.73; P = 0.003). This corresponded to a relative risk reduction of 68.8%. SSIs were found to independently increase the cost of hospitalization by 23.8%. CONCLUSIONS:The use of negative pressure wound therapy resulted in a significantly lower risk of SSIs. Incorporating this intervention in surgical practice can help reduce a complication that significantly increases patient harm and healthcare costs.