Laparoscopic Common Bile Duct Exploration.

This article describes advances that are leading to a resurgence in surgeon interest and adoption of laparoscopic common bile duct exploration, making an innovation out of an old technique.

Radiologic-pathologic correlation of lesions in resected liver specimens with an ex vivo MRI-compatible localization device.

OBJECTIVE: Liver lesion characterization is limited by the lack of an established gold standard for precise correlation of radiologic characteristics with their histologic features. The objective of this study was to demonstrate the feasibility of using an ex vivo MRI-compatible sectioning device for radiologic-pathologic co-localization of lesions in resected liver specimens. METHODS: In this prospective feasibility study, adults undergoing curative partial hepatectomy from February 2018 to January 2019 were enrolled. Gadoxetic acid was administered intraoperatively prior to hepatic vascular inflow ligation. Liver specimens were stabilized in an MRI-compatible acrylic lesion localization device (27 × 14 × 14 cm3) featuring slicing channels and a silicone gel 3D matrix. High-resolution 3D T1-weighted fast spoiled gradient echo and 3D T2-weighted fast-spin-echo images were acquired using a single channel quadrature head coil. Radiologic lesion coordinates guided pathologic sectioning. A final histopathologic diagnosis was prepared for all lesions. The proportion of successfully co-localized lesions was determined. RESULTS: A total of 57 lesions were identified radiologically and sectioned in liver specimens from 10 participants with liver metastases (n = 8), primary biliary mucinous cystic neoplasm (n = 1), and hepatic adenomatosis (n = 1). Of these, 38 lesions (67%) were < 1 cm. Overall, 52/57 (91%) of radiologically identified lesions were identified pathologically using the device. Of these, 5 lesions (10%) were not initially identified on gross examination but were confirmed histologically using MRI-guided localization. One lesion was identified grossly but not on MRI. CONCLUSIONS: We successfully demonstrated the feasibility of a clinical method for image-guided co-localization and histological characterization of liver lesions using an ex vivo MRI-compatible sectioning device. KEY POINTS: • The ex vivo MRI-compatible sectioning device provides a reliable method for radiologic-pathologic correlation of small (< 1 cm) liver lesions in human liver specimens. • The sectioning method can be feasibly implemented within a clinical practice setting and used in future efforts to study liver lesion characterization. • Intraoperative administration of gadoxetic acid results in enhancement in ex vivo MRI images of liver specimens hours later with excellent image quality.

Machine learning principles applied to CT radiomics to predict mucinous pancreatic cysts.

PURPOSE: Current diagnostic and treatment modalities for pancreatic cysts (PCs) are invasive and are associated with patient morbidity. The purpose of this study is to develop and evaluate machine learning algorithms to delineate mucinous from non-mucinous PCs using non-invasive CT-based radiomics. METHODS: A retrospective, single-institution analysis of patients with non-pseudocystic PCs, contrast-enhanced computed tomography scans within 1 year of resection, and available surgical pathology were included. A quantitative imaging software platform was used to extract radiomics. An extreme gradient boosting (XGBoost) machine learning algorithm was used to create mucinous classifiers using texture features only, or radiomic/radiologic and clinical combined models. Classifiers were compared using performance scoring metrics. Shapely additive explanation (SHAP) analyses were conducted to identify variables most important in model construction. RESULTS: Overall, 99 patients and 103 PCs were included in the analyses. Eighty (78%) patients had mucinous PCs on surgical pathology. Using multiple fivefold cross validations, the texture features only and combined XGBoost mucinous classifiers demonstrated an area under the curve of 0.72 ± 0.14 and 0.73 ± 0.14, respectively. By SHAP analysis, root mean square, mean attenuation, and kurtosis were the most predictive features in the texture features only model. Root mean square, cyst location, and mean attenuation were the most predictive features in the combined model. CONCLUSION: Machine learning principles can be applied to PC texture features to create a mucinous phenotype classifier. Model performance did not improve with the combined model. However, specific radiomic, radiologic, and clinical features most predictive in our models can be identified using SHAP analysis.

Pancreatic cyst characterization: maximum axial diameter does not measure up.

BACKGROUND: Unidimensional size is commonly used to risk stratify pancreatic cysts (PCs) despite inconsistent performance. The current study aimed to determine if unidimensional size, demonstrated by maximum axial diameter (MAD), is an appropriate surrogate measurement for volume and surface area. METHODS: Patients with cross-sectional imaging of PCs from 2012 to 2013 were identified. Cyst MAD, volume, and surface area were measured using quantitative imaging software. Non-pseudocystic PCs >1 cm were selected for inclusion to assess MAD correlation with volume and surface area. Cysts imaged twice >1 year apart were selected to evaluate volumetric growth rate. RESULTS: In total, 195 cysts were included. Overall, MAD was strongly correlated with volume (r = 0.83) and surface area (r = 0.93). However, cysts 1-2 cm and 2-3 cm were weakly correlated with volume and surface area: r = 0.78, 0.57 and 0.82, 0.61, respectively. Cyst volumes and surface areas varied widely within unidimensional size groups with 51% and 40% of volumes and surface areas overlapping unidimensional size groups, respectively. Estimated changes in volume poorly predicted measured changes in volume with 42% of cysts having >100% absolute percent difference. CONCLUSIONS: Pancreatic cyst volume and surface area may be useful adjunct measurements to risk stratify patients and surveil cyst changes and deserves further study.

Specific Growth Rate as a Predictor of Survival in Pancreatic Neuroendocrine Tumors: A Multi-institutional Study from the United States Neuroendocrine Study Group.

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) are often indolent; however, identifying patients at risk for rapidly progressing variants is critical, particularly for those with small tumors who may be candidates for expectant management. Specific growth rate (SGR) has been predictive of survival in other malignancies but has not been examined in PNETs. METHODS: A retrospective cohort study of adult patients who underwent PNET resection from 2000 to 2016 was performed utilizing the multi-institutional United States Neuroendocrine Study Group database. Patients with ≥ 2 preoperative cross-sectional imaging studies at least 30 days apart were included in our analysis (N = 288). Patients were grouped as "high SGR" or "low SGR." Demographic and clinical factors were compared between the groups. Kaplan-Meier and log-rank analysis were used for survival analysis. Cox proportional hazard analysis was used to assess the impact of various clinical factors on overall survival (OS). RESULTS: High SGR was associated with higher T stage at resection, shorter doubling time, and elevated HbA1c (all P ≤ 0.01). Patients with high SGR had significantly decreased 5-year OS (63 vs 80%, P = 0.01) and disease-specific survival (72 vs 91%, P = 0.03) compared to those with low SGR. In patients with small (≤ 2 cm) tumors (N = 106), high SGR predicted lower 5-year OS (79 vs 96%, P = 0.01). On multivariate analysis, high SGR was independently associated with worse OS (hazard ratio 2.67, 95% confidence interval 1.05-6.84, P = 0.04). CONCLUSION: High SGR is associated with worse survival in PNET patients. Evaluating PNET SGR may enhance clinical decision-making, particularly when weighing expectant management versus surgery in patients with small tumors.

Texture Analysis: An Emerging Clinical Tool for Pancreatic Lesions.

Radiologic characterization of pancreatic lesions is currently limited. Computed tomography is insensitive in detecting and characterizing small pancreatic lesions. Moreover, heterogeneity of many pancreatic lesions makes determination of malignancy challenging. As a result, invasive diagnostic testing is frequently used to characterize pancreatic lesions but often yields indeterminate results. Computed tomography texture analysis (CTTA) is an emerging noninvasive computational tool that quantifies gray-scale pixels/voxels and their spatial relationships within a region of interest. In nonpancreatic lesions, CTTA has shown promise in diagnosis, lesion characterization, and risk stratification, and more recently, pancreatic applications of CTTA have been explored. This review outlines the emerging role of CTTA in identifying, characterizing, and risk stratifying pancreatic lesions. Although recent studies show the clinical potential of CTTA of the pancreas, a clear understanding of which specific texture features correlate with high-grade dysplasia and predict survival has not yet been achieved. Further multidisciplinary investigations using strong radiologic-pathologic correlation are needed to establish a role for this noninvasive diagnostic tool.

Impact of Insurance Status on Survival in Gastroenteropancreatic Neuroendocrine Tumors.

BACKGROUND: Insurance status predicts access to medical care in the USA. Previous studies have shown uninsured patients with some malignancies have worse outcomes than insured patients. The impact of insurance status on patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is unclear. PATIENTS AND METHODS: A retrospective cohort study of adult patients with resected GEP-NETs was performed using the US Neuroendocrine Tumor Study Group (USNETSG) database (2000-2016). Demographic and clinical factors were compared by insurance status. Patients ≥ 65 years were excluded, as these patients are almost universally covered by Medicare. Kaplan-Meier and log-rank analyses were used for survival analysis. Logistic regression was used to assess factors associated with overall survival (OS). RESULTS: The USNETSG database included 2022 patients. Of those, 1425 were aged 18-64 years at index operation and were included in our analysis. Uninsured patients were more likely to have an emergent operation (7.9% versus 2.5%, p = 0.01) and less likely to receive postoperative somatostatin analog therapy (1.6% versus 9.9%, p = 0.03). OS at 1, 5, and 10 years was significantly higher for insured patients (96.3%, 88.2%, and 73.8%, respectively) than uninsured patients (87.7%, 71.9%, and 44.0%, respectively) (p < 0.01). On Cox multivariate regression analysis controlling for T/M stage, tumor grade, ASA class, and income level, being uninsured was independently associated with worse OS [hazard ratio (HR) 2.69, 95% confidence interval (CI) 1.32-5.48, p = 0.006]. CONCLUSIONS: Insurance status is an independent predictor of survival in patients with GEP-NETs. Our study highlights the importance of access to medical care, disparities related to insurance status, and the need to mitigate these disparities.

Severity of Postoperative Complications From the Perspective of the Patient.

BACKGROUND: Although provider-derived surgical complication severity grading systems exist, little is known about the patient perspective. OBJECTIVE: To assess patient-rated complication severity and determine concordance with existing grading systems. METHODS: A survey asked general surgery patients to rate the severity of 21 hypothetical postoperative events representing grades 1 to 5 complications from the Accordion Severity Grading System. Concordance with the Accordion scale was examined. Separately, descriptive ratings of 18 brief postoperative events were ranked. RESULTS: One hundred sixty-eight patients returned a mailed survey following their discharge from a general surgery service. Patients rated grade 4 complications highest. Grade 1 complications were rated similarly to grade 5 and higher than grades 2 and 3 (P ≤ .01). Patients rated one event not considered an Accordion scale complication higher than all but grade 4 complications (P < .001). The brief events also did not follow the Accordion scale, other than the grade 6 complication ranking highest. CONCLUSION: Patient-rated complication severity is discordant with provider-derived grading systems, suggesting the need to explore important differences between patient and provider perspectives.

Impact of perioperative blood transfusion on survival in pancreatic neuroendocrine tumor patients: analysis from the US Neuroendocrine Study Group.

BACKGROUND: Packed red blood cell (PRBC) transfusion has been associated with worse survival in multiple malignancies but its impact on pancreatic neuroendocrine tumors (PNETs) is unknown. The aim of this study was to determine the impact of PRBC transfusion on survival following PNET resection. METHODS: A retrospective cohort study of PNET patients was performed using the US Neuroendocrine Tumor Study Group database. Demographic and clinical factors were compared. Kaplan-Meier and log-rank analyses were performed. Factors associated with transfusion, overall (OS), recurrence-free (RFS) and progression-free survival (PFS) were assessed by logistic regression. RESULTS: Of 1129 patients with surgically resected PNETs, 156 (13.8%) received perioperative PRBC transfusion. Transfused patients had higher ASA Class, lower preoperative hemoglobin, larger tumors, more nodal involvement, and increased major complications (all p < 0.010). Transfused patients had worse median OS (116 vs 150 months, p < 0.001), worse RFS (83 vs 128 months, p < 0.01) in curatively resected (n = 1047), and worse PFS (11 vs 24 months, p = 0.110) in non-curatively resected (n = 82) patients. On multivariable analysis, transfusion was associated with worse OS (HR 1.80, p = 0.011) when controlling for TNM stage, tumor grade, final resection status, and pre-operative anemia. CONCLUSION: PRBC transfusion is associated with worse survival for patients undergoing PNET resection.

Evaluating the ACS NSQIP Risk Calculator in Primary Pancreatic Neuroendocrine Tumor: Results from the US Neuroendocrine Tumor Study Group.

BACKGROUND: In a changing health care environment where patient outcomes will be more closely scrutinized, the ability to predict surgical complications is becoming increasingly important. The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) online risk calculator is a popular tool to predict surgical risk. This paper aims to assess the applicability of the ACS NSQIP calculator to patients undergoing surgery for pancreatic neuroendocrine tumors (PNETs). METHODS: Using the US Neuroendocrine Tumor Study Group (USNET-SG), 890 patients who underwent pancreatic procedures between 1/1/2000-12/31/2016 were evaluated. Predicted and actual outcomes were compared using C-statistics and Brier scores. RESULTS: The most commonly performed procedure was distal pancreatectomy, followed by standard and pylorus-preserving pancreaticoduodenectomy. For the entire group of patients studied, C-statistics were highest for discharge destination (0.79) and cardiac complications (0.71), and less than 0.7 for all other complications. The Brier scores for surgical site infection (0.1441) and discharge to nursing/rehabilitation facility (0.0279) were below the Brier score cut-off, while the rest were equal to or above and therefore not useful for interpretation. CONCLUSION: This work indicates that the ACS NSQIP risk calculator is a valuable tool that should be used with caution and in coordination with clinical assessment for PNET clinical decision-making.

Analysis of National Presentations of Surgical Case Series Discussions: What Matters to Surgeons?

BACKGROUND: Although the surgical case series is a useful study design for surgical disciplines, elements of its presentation have not been standardized with a widely accepted reporting guideline. Hence, case series may not include all components necessary for surgeons to best interpret their results. We aimed to determine core elements of case series through qualitative analysis of discussions after presentations at national meetings. METHODS: Case series with accompanying discussions in three high-impact journals from 2010 to 2015 were analyzed with conventional content analysis. All interrogative sentences were selected for analysis and were classified by a redundant iterative process into descriptive categories and subcategories. RESULTS: Two hundred twenty-one case series were identified, 56 of which included discussion transcripts. Four hundred seventy six unique interrogatives were classified into 4 categories and 13 subcategories. The main categories identified were "Application of Results to Patient Care," "Clarification of Study Methodology," "Facilitation of Author Insight," and "Request for Additional Study-Specific Data." The most frequent subcategories of inquiry pertained to the changes to current standard of care, clarification of study variables, and subgroup data and outcomes. CONCLUSIONS: We determined major themes of inquiry that reflected core elements surgeons use to evaluate case series for relevance and applicability to their own practice. Discussants frequently questioned how the study's results changed the author's standard of care. Specifically encouraging surgical case series authors to comment on changes they made to their practice as a result of their findings would allow the surgical audience to quickly assess potential clinical applicability.

Predictive Value of Chromogranin A and a Pre-Operative Risk Score to Predict Recurrence After Resection of Pancreatic Neuroendocrine Tumors.

INTRO: Chromogranin A (CgA) may be prognostic for patients with neuroendocrine tumors; however, the clinical utility of this test is unclear. METHODS: Patients undergoing resection for pancreatic neuroendocrine tumors (pNET) were selected from the eight institutions of the US Neuroendocrine Tumor Study Group database. Cox regression was used to identify pre-operative variables that predicted recurrence-free survival (RFS), and those with p < 0.1 were included in a risk score. The risk score was tested in a unique subset of the overall cohort. RESULTS: In the entire cohort of 287 patients, median follow-up time was 37 months, and 5-year RFS was 73%. Cox regression analysis identified four variables for inclusion in the risk score: CgA > 5x ULN (HR 4.3, p = 0.01), tumor grade 2/3 (HR 3.7, p = 0.01), resection for recurrent disease (HR 6.2, p < 0.01), and tumor size > 4 cm (HR 4.5, p = 0.1). Each variable was assigned 1 point. Risk-score testing in the unique validation cohort of 63 patients revealed a 95% negative predictive value for recurrence in patients with zero points. DISCUSSION: This simple pre-operative risk scoring system resulted in a high degree of specificity for identifying patients at low-risk for tumor recurrence. This test can be utilized pre-operatively to aid informed decision-making.

Heparan sulfate mimetic PG545-mediated antilymphoma effects require TLR9-dependent NK cell activation.

Heparan sulfate (HS) is an essential component of the extracellular matrix (ECM), which serves as a barrier to tumor invasion and metastasis. Heparanase promotes tumor growth by cleaving HS chains of proteoglycan and releasing HS-bound angiogenic growth factors and facilitates tumor invasion and metastasis by degrading the ECM. HS mimetics, such as PG545, have been developed as antitumor agents and are designed to suppress angiogenesis and metastasis by inhibiting heparanase and competing for the HS-binding domain of angiogenic growth factors. However, how PG545 exerts its antitumor effect remains incompletely defined. Here, using murine models of lymphoma, we determined that the antitumor effects of PG545 are critically dependent on NK cell activation and that NK cell activation by PG545 requires TLR9. We demonstrate that PG545 does not activate TLR9 directly but instead enhances TLR9 activation through the elevation of the TLR9 ligand CpG in DCs. Specifically, PG545 treatment resulted in CpG accumulation in the lysosomal compartment of DCs, leading to enhanced production of IL-12, which is essential for PG545-mediated NK cell activation. Overall, these results reveal that PG545 activates NK cells and that this activation is critical for the antitumor effect of PG545. Moreover, our findings may have important implications for improving NK cell-based antitumor therapies.

Innate immune activation by tissue injury and cell death in the setting of hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) with donor lymphocyte infusion is the mainstay of treatment for many types of hematological malignancies, but the therapeutic effect and prevention of relapse is complicated by donor T-cell recognition and attack of host tissue in a process known as graft-versus-host disease (GvHD). Cytotoxic myeloablative conditioning regimens used prior to Allo-HSCT result in the release of endogenous innate immune activators that are increasingly recognized for their role in creating a pro-inflammatory milieu. This increased inflammatory state promotes allogeneic T-cell activation and the induction and perpetuation of GvHD. Here, we review the processes of cellular response to injury and cell death that are relevant following Allo-HSCT and present the current evidence for a causative role of a variety of endogenous innate immune activators in the mediation of sterile inflammation following Allo-HSCT. Finally, we discuss the potential therapeutic strategies that target the endogenous pathways of innate immune activation to decrease the incidence and severity of GvHD following Allo-HSCT.

Outcomes following splenectomy in patients with myeloid neoplasms.

BACKGROUND AND OBJECTIVES: Myeloid neoplasms are classified into five major categories. These patients may develop splenomegaly and require splenectomy to alleviate mechanical symptoms, to ameliorate transfusion-dependent cytopenias, or to enhance stem cell transplantation. The objective of this study was to determine which clinical variables significantly impacted morbidity, mortality, and survival in patients with myeloid neoplasms undergoing splenectomy, and to determine if operative outcomes have improved over time. METHODS: The records of all patients with myeloid neoplasms undergoing splenectomy from 1993 to 2010 were retrospectively reviewed. RESULTS: Eighty-nine patients (n = 89) underwent splenectomy for myeloid neoplasms. Over half of patients who had symptoms preoperatively had resolution of their symptoms post-splenectomy. The morbidity rate was 38%, with the most common complications being bleeding (14%) or infection (20%). Thirty-day mortality rate was 18% and median survival after splenectomy was 278 days. Decreased survival was associated with a diagnosis of myelodysplastic syndrome/myeloproliferative neoplasm, anemia, abnormal white blood cell count, and hypoalbuminemia. Patients who underwent stem cell transplantation did not show an increased risk for morbidity or mortality. CONCLUSIONS: Patients with myeloid neoplasms have a poor prognosis after splenectomy and the decision to operate is a difficult one, associated with high morbidity and mortality.

Morphine modulation of thrombospondin levels in astrocytes and its implications for neurite outgrowth and synapse formation.

Opioid receptor signaling via EGF receptor (EGFR) transactivation and ERK/MAPK phosphorylation initiates diverse cellular responses that are cell type-dependent. In astrocytes, multiple µ opioid receptor-mediated mechanisms of ERK activation exist that are temporally distinctive and feature different outcomes. Upon discovering that chronic opiate treatment of rats down-regulates thrombospondin 1 (TSP1) expression in the nucleus accumbens and cortex, we investigated the mechanism of action of this modulation in astrocytes. TSP1 is synthesized in astrocytes and is released into the extracellular matrix where it is known to play a role in synapse formation and neurite outgrowth. Acute morphine (hours) reduced TSP1 levels in astrocytes. Chronic (days) opioids repressed TSP1 gene expression and reduced its protein levels by µ opioid receptor and ERK-dependent mechanisms in astrocytes. Morphine also depleted TSP1 levels stimulated by TGFß1 and abolished ERK activation induced by this factor. Chronic morphine treatment of astrocyte-neuron co-cultures reduced neurite outgrowth and synapse formation. Therefore, inhibitory actions of morphine were detected after both acute and chronic treatments. An acute mechanism of morphine signaling to ERK that entails depletion of TSP1 levels was suggested by inhibition of morphine activation of ERK by a function-blocking TSP1 antibody. This raises the novel possibility that acute morphine uses TSP1 as a source of EGF-like ligands to activate EGFR. Chronic morphine inhibition of TSP1 is reminiscent of the negative effect of µ opioids on EGFR-induced astrocyte proliferation via a phospho-ERK feedback inhibition mechanism. Both of these variations of classical EGFR transactivation may enable opiates to diminish neurite outgrowth and synapse formation.

Mu and kappa opioids modulate mouse embryonic stem cell-derived neural progenitor differentiation via MAP kinases.

As embryonic stem cell-derived neural progenitors (NPs) have the potential to be used in cell replacement therapy, an understanding of the signaling mechanisms that regulate their terminal differentiation is imperative. In previous studies, we discovered the presence of functional mu opioid receptors (MOR) and kappa opioid receptors (KOR) in mouse embryonic stem cells and NPs. Here, MOR and KOR immunoreactivity was detected in NP-derived oligodendrocytes during three stages of their maturation in vitro. Moreover, we examined the modulation of retinoic acid-induced NP differentiation to astrocytes and neurons by mu, [D-ala(2), mephe(4), gly-ol(5)] enkephalin, or kappa, U69, 593, opioids. Both opioid agonists inhibited NP-derived neurogenesis and astrogenesis via their corresponding receptors as determined by immunocytochemistry. By administering selective inhibitors, we found that opioid inhibition of NP-derived astrogenesis was driven via extracellular-signal regulated kinase (ERK), while the p38 mitogen-activated protein kinase pathway was implicated in opioid attenuation of neurogenesis. In addition, mu and kappa opioids stimulated oligodendrogenesis from NP-derived NG2(+) oligodendrocyte progenitors via both ERK and p38 signaling pathways. Accordingly, both opioids induced ERK phosphorylation in NG2(+) cells. These results indicate that small molecules, such as MOR and KOR agonists may play a modulatory role in NP terminal differentiation.