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Background Intraoperative ultrasound (IUS) localization for breast cancer is a noninvasive localization technique. In 2015, an IUS program for breast-conserving surgery (BCS) was initiated in a large, integrated health care system. This study evaluated the clinical results of IUS implementation. Methods The study identified breast cancer patients with BCS from 1 January to 31 October 2015 and from 1 January to 31 October 2019. Clinicopathologic characteristics were collected, and localization types were categorized. Clinical outcomes were analyzed, including localization use, surgeon adoption of IUS, day-of-surgery intervals, and re-excision rates. Multivariate logistic regression analysis was performed to evaluate predictors of re-excision. Results The number of BCS procedures increased 23%, from 1815 procedures in 2015 to 2226 procedures in 2019. The IUS rate increased from 4% of lumpectomies (n = 79) in 2015 to 28% of lumpectomies (n = 632) in 2019 (p p p = 0.006), and IUS predicted lower re-excision rates in a multivariable model (odds ratio [OR], 0.59). Conclusions In a high-volume integrated health system, IUS was adopted for BCS by a majority of surgeons. The use of IUS decreased the time from admission to incision compared with wire localization, and decreased re-excision rates compared with other localization techniques.

Pancreatic diseases have long been associated with impaired glucose control. This study sought to identify the incidence of new insulin-dependent diabetes mellitus (IDDM) after pancreatectomy and the predictive accuracy of hemoglobin A1c (HbA1c) or blood glucose. Patients who underwent partial pancreatectomy and had preoperative HbA1c available at two academic institutions were assessed for new IDDM on discharge in relation to complication rates and survival. Of the 267 patients analyzed, 67% had abnormal HbA1c levels prior to surgery (mean 6.8%, glucose 135 mg/dL). Two hundred eight (77.9%) were not insulin-dependent prior to surgery, and 35 (16.8%) developed new IDDM after resection. On multivariable regression, increasing HbA1c and preoperative glucose were the only significant predictors for new IDDM. Optimal predictive cutoffs (HbA1c of 6.25% and glucose of 121 mg/dL) were determined in a discovery group (n = 143) and confirmed in a validation group (n = 124) with a diagnostic sensitivity of 72.7% and specificity of 84.8%. Patients with new IDDM after resection had higher rates of severe complications (OR 3.39), increased TPN at discharge (OR 4.32), and increased rates of discharge to nursing facilities (OR 2.57) (all P < 0.05). New IDDM was also associated with a decreased cancer-specific survival. Preoperative HbA1c ≥ 6.25% and blood glucose ≥ 121 mg/dL can accurately identify patients at increased risk of IDDM. These diagnostics may help identify patients in a preoperative setting that may benefit from interventions such as diabetes education or enhanced glucose control preoperatively.

BACKGROUND: Advances in communication technology have enabled new methods of delivering test results to cancer survivors. We sought to determine patient preferences regarding the use of newer technology in delivering test results during cancer surveillance. METHODS: A single institutional, cross-sectional analysis of the preferences of adult cancer survivors regarding the means (secure digital communication versus phone call or office visit) to receive surveillance test results was undertaken. RESULTS: Among 257 respondents, the average age was 59.1 years (SD 13.5) and 61.8% were female. Common malignancies included melanoma/sarcoma (29.5%), thyroid (25.7%), breast (22.8%), and gastrointestinal (22.0%) cancer. Although patients expressed a relative preference to receive normal surveillance results via MyChart or secure e-mail, the majority preferred abnormal imaging (87.2%) or blood results (85.9%) to be communicated by in-office appointments or phone calls irrespective of age or cancer type. Patients with a college degree or higher were more likely to prefer electronic means of communication of abnormal blood results compared with a telephone call or in-person visit (odds ratio 2.18, 95% confidence interval: 1.01−4.73, P < .05). In contrast, patients >65 years were more likely to express a preference for telephone or in-person communication of normal imaging results (odds ratio: 2.03, 95% CI: 1.16−3.56, P < .05) versus patients ≤65 years. Preference also varied according to malignancy type. CONCLUSION: Although many cancer patients preferred to receive “normal” surveillance results electronically, the majority preferred receiving abnormal results via direct conversation with their provider. Shifting routine communication of normal surveillance results to technology-based applications may improve patient satisfaction and decrease health care system costs.

Pancreatic diseases have long been associated with impaired glucose control. This study sought to identify the incidence of new insulin-dependent diabetes mellitus (IDDM) after pancreatectomy and the predictive accuracy of hemoglobin A1c (HbA1c) or blood glucose.Patients who underwent partial pancreatectomy and had preoperative HbA1c available at two academic institutions were assessed for new IDDM on discharge in relation to complication rates and survival.Of the 267 patients analyzed, 67% had abnormal HbA1c levels prior to surgery (mean 6.8%, glucose 135 mg/dL). Two hundred eight (77.9%) were not insulin-dependent prior to surgery, and 35 (16.8%) developed new IDDM after resection. On multivariable regression, increasing HbA1c and preoperative glucose were the only significant predictors for new IDDM. Optimal predictive cutoffs (HbA1c of 6.25% and glucose of 121 mg/dL) were determined in a discovery group (n = 143) and confirmed in a validation group (n = 124) with a diagnostic sensitivity of 72.7% and specificity of 84.8%. Patients with new IDDM after resection had higher rates of severe complications (OR 3.39), increased TPN at discharge (OR 4.32), and increased rates of discharge to nursing facilities (OR 2.57) (all P0.05). New IDDM was also associated with a decreased cancer-specific survival.Preoperative HbA1c ≥ 6.25% and blood glucose ≥ 121 mg/dL can accurately identify patients at increased risk of IDDM. These diagnostics may help identify patients in a preoperative setting that may benefit from interventions such as diabetes education or enhanced glucose control preoperatively.

PURPOSE: Management of soft tissue and bone sarcoma presents many challenges, both diagnostically and therapeutically, and requires multidisciplinary collaboration; however, such collaboration is often challenging to establish, especially in the community setting. We share our experiences of a virtual multidisciplinary sarcoma case conference (VMSCC). METHODS: We conducted retrospective review of the VMSCC data—initially via Webex, now Microsoft Teams—and the surveys of referring physicians to understand the feasibility and value of the VMSCC. RESULTS: The VMSCC was established in March 2013 in Kaiser Permanente Northern California with consistent participation of the Departments of Musculoskeletal Oncology (orthopedic oncology), Musculoskeletal Radiology, Pathology, Medical Oncology, Radiation Oncology, Nuclear Medicine, Surgical Oncology, and Genetics. Pediatric Oncology participated ad hoc when pediatric sarcoma cases were presented. Referrals were from multiple specialties and regions, including the Kaiser Permanente Mid-Atlantic and Hawaii regions. From March 2013 to December 2019, 1,585 cases were reviewed encompassing 36 histologic types. More than 300 cases were reviewed per year from 2017 to 2019. Survey results of referring physicians demonstrate that the VMSCC enhanced the confidence of treating physicians, and its recommendations frequently led to treatment changes. CONCLUSION: Establishing a valuable community-based VMSCC is feasible. VMSCC recommendations frequently led to treatment changes and improved the confidence of treating physicians.

BackgroundCancer patients who lose weight have low treatment tolerance and poor outcomes compared to cancer patients without weight loss, termed cachexia. Despite the clear increased risk for patients, diagnosing cachexia still primarily relies on self-reported weight loss. A reliable biomarker to identify patients with cancer cachexia would be a valuable tool to improve clinical decision making and identification of patients at risk of adverse outcomes.MethodsTargeted metabolomics, including panels of amino acids, tricarboxylic acids, fatty acids, acylcarnitines, and sphingolipids, were conducted on plasma samples from patients with confirmed pancreatic ductal adenocarcinoma (PDAC) with and without cachexia and control patients without cancer. Receiver Operating Characteristic (ROC) analysis was undertaken to establish if any metabolite could effectively serve as a biomarker of cachexia.ResultsTargeted profiling revealed that cachectic patients had decreased circulating levels of three sphingolipids compared to either non-cachectic PDAC patients or patients without cancer. The ratio of C18-ceramide to C24-ceramide (C18:C24) outperformed a number of other previously proposed biomarkers of cachexia (area under ROC = 0.810). It was notable that some biomarkers, including C18:C24, were only elevated in cachectic males.ConclusionOur findings identify C18:C24 as a potentially new biomarker of PDAC-induced cachexia that also highlight a previously unappreciated sexual dimorphism in cancer cachexia.Trial registrationNone.FundingSupport was provided through a pilot grant from U24DK100469 from the National Institute of Diabetes and Digestive and Kidney Diseases (The Mayo Clinic), National Cancer Institute P30CA016058 (The Ohio State University), National Cancer Institute R01CA180057 (DCG), American Cancer Society PF-15-156-01-CSM (EET), and a Weiss Postdoctoral Fellowship (EET).

Introduction Hepatic arterial infusion pump (HAIP) therapy for colorectal liver metastases (CRLM) is beneficial in selected patients yet wide acceptance in the oncology community is lacking. Methods A surgeon-led team implemented a HAIP program in 2012. Pumps were placed by laparotomy for CRLM and fluorodeoxyuridine was infused via HAIP every 28 days without systemic chemotherapy supervised by the operating surgeon. Results Sixty patients were treated with HAIP, either in the adjuvant setting after liver resection or ablation of CRLM in 26 (43%) patients or with the unresectable disease in 34 (57%). Perioperative complications occurred in 19 (32%) and pump-specific complications in 14 (23%) that included intrahepatic biliary stricture in one (2%). Time to liver progression was a median 9.2 months (95% CI, 3.1-15.3 months) in unresectable patients and liver recurrence was a median 24.7 months (2.5-46.9 months) in the adjuvant group. Estimated 3-year overall survival from the time of HAIP placement was 64% in the adjuvant group and 37% in the unresectable group. Sarcopenia was prevalent (48%) and was associated with a worse survival (HR 2.4, 95% CI, 1.1-5.0). Conclusion A surgeon-led HAIP program may achieve outcomes on par with those of experienced centers and foster strong relationships between surgical and medical oncologists.

Background The patient-provider relationship (PPR) is an important element of health care delivery and may influence patient outcomes. The objective of the present study was to identify clinical predictors of PPR among patients with hepatopancreatobiliary (HPB) diseases and assess the association of PPR and health care utilization. Materials and Methods The Medical Expenditure Panel Survey database from 2008-2014 was used to identify adult patients with HPB diagnoses. A PPR score of “poor,” “average,” and “optimal” was calculated from the Consumer Assessment of Healthcare Providers and Systems Survey. Predictors of poor PPR and the association of PPR and health care utilization were assessed. Results Among 592 patients, PPR was optimal (210, 35.4%), average (270, 45.5%), or poor (114, 19.2%). Patients without insurance (36.3%) or with Medicaid (28.8%) were more likely to report poor PPR versus patients with private insurance (14.0%) or Medicare (15.4%) (P = 0.03). Poor (24.3%)- and low (21.5%)-income patients were more likely to report poor PPR versus middle (12.8%)- or high-income (14.0%) patients (P = 0.03). Poor mental health was also more common among patients with poor PPR (13.4%) versus average (5.4%) or optimal (3.7%) PPR (P = 0.02), and this association between poor PPR and poor mental health remained significant on multivariable analysis (odds ratio [OR] 2.43, 95% confidence interval [CI] 1.20-4.92). Poor PPR was associated with increased emergency room utilization on univariate (OR 2.50, 95% CI 1.21-5.14), but not multivariate (OR 2.18, 95% CI 0.92-5.15) analysis. Conclusions Among patients with HPB diseases, PPR was associated with insurance type, socioeconomic status, and mental health scores. Patients reporting poor PPR were more likely to be high utilizers of the emergency room. Efforts to improve the PPR are needed and should be focused on these high-risk populations.

BACKGROUND AND OBJECTIVES Reducing readmissions is an important quality improvement metric. We sought to investigate patterns of 90-day readmission after hepato-pancreatic (HP) procedures. METHODS The Nationwide Readmissions Database (NRD) was used to identify patients undergoing HP procedures between 2010 and 2014. Patients were stratified according to benign versus malignant HP diagnoses and as index (same hospital as operation) versus non-index (different hospital) readmissions. RESULTS Among the 41 059 patients who underwent HP procedures, 26 563 (65%) underwent a liver resection while 14 496 (35%) pancreatic resection. Among all patients, 11 902 (29%) had a benign diagnosis versus 29 157 (71%) who had a cancer diagnosis. Overall 90-day readmission was 22% (n = 8 998) with a slight increase in readmissions among patients with a malignant (n = 6 655;23%) versus benign (n = 2 343;20%) diagnosis (P

Biliary tract cancers (BTC) are aggressive malignancies that require complex surgical procedures. Patients with BTC can present with skeletal muscle depletion, yet the effects of muscle wasting (sarcopenia) on outcomes have not been well studied. The objective of the current study was to define the impact of sarcopenia on survival among patients undergoing resection of BTC. Patients who underwent exploration for BTC who had a pre-operative CT scan available for review were identified. Body composition variables including total and psoas muscle area (cm2), muscle density (Hounsfield units), visceral fat area, subcutaneous fat area, and waist-to-hip ratio were analyzed at the level of L3. Outcomes were assessed according to the presence or absence of sarcopenia defined using sex- and BMI-specific threshold values for Psoas Muscle Index (PMI, cm2/m2). Among 117 patients with BTC, 78 (67%) underwent curative-intent resection and 39 (33%) were explored but did not undergo resection due to metastatic/locally advanced disease. Tumor type included distal cholangiocarcinoma (n = 18, 15.4%), hilar cholangiocarcinoma (n = 27, 23.1%), gallbladder carcinoma (n = 52, 44.4%), and intrahepatic cholangiocarcinoma (n = 20, 17.1%). Median patient age was 65.6 years and 43.6% were male. Mean patient BMI was 26.1 kg/m2 among men and 27.5 kg/m2 among women. Overall, 41 (35.0%) patients had sarcopenia. Sarcopenia was associated with an increased risk of death among patients who underwent resection (HR 3.52, 95%CI 1.60–7.78, p = 0.002), which was comparable to patients with unresectable metastatic disease. Other factors such as low serum albumin (HR 3.17, 95% CI 1.30–7.74, p = 0.011) and low psoas density (HR 2.96, 95% CI 1.21–7.21, p = 0.017) were also associated with increased risk of death. Survival was stratified based on sarcopenia, psoas density, and serum albumin. The presence of each variable was associated with an incremental increased risk of death (0 variables ref.; 1 variable HR 3.8, 95% CI 1.0–14, p = 0.043; 2 variables HR 13.1, 95% CI 3.0–57.7, p = 0.001; 3 variables HR 14.6, 95% CI 2.5–87.1, p = 0.003). Patients who had no adverse prognostic factors had a 3-year OS of 67% versus no survival among patients with all 3 factors. Sarcopenia was common among patients undergoing resection of BTC, occurring in 1 of every 3 patients. Sarcopenia was associated with poor survival after resection, particularly among patients who experienced a recurrence. Body composition metrics such as sarcopenia and low psoas muscle density in addition to low albumin level were able to stratify patients into different prognostic categories.

Background The role of routine lymph node dissection (LND) in the surgical treatment of intrahepatic cholangiocarcinoma (ICC) remains controversial. The objective of this study was to investigate the trends of LND use in the surgical treatment of ICC. Methods Patients undergoing curative intent resection for ICC in 2000–2015 were identified from an international multi-institutional database. Use of lymphadenectomy was evaluated over time and by geographical region (West versus East); LND use and final nodal status were analysed relative to AJCC T categories. Results Among the 1084 patients identified, half (535, 49·4 per cent) underwent concomitant hepatic resection and LND. Between 2000 and 2015, the proportion of patients undergoing LND for ICC nearly doubled: 44·4 per cent in 2000 versus 81·5 per cent in 2015 (P < 0·001). Use of LND increased over time among both Eastern and Western centres. The odds of LND was associated with the time period of surgery and the extent of the tumour/T status (referent T1a: OR 2·43 for T2, P = 0·001; OR 2·13 for T3, P = 0·016). Among the 535 patients who had LND, lymph node metastasis (LNM) was noted in 209 (39·1 per cent). Specifically, the incidence of LNM was 24 per cent in T1a disease, 22 per cent in T1b, 42·9 per cent in T2, 48 per cent in T3 and 66 per cent in T4 (P < 0·001). AJCC T3 and T4 categories, harvesting of six or more lymph nodes, and presence of satellite lesions were independently associated with LNM. Conclusion The rate of LNM was high across all T categories, with one in five patients with T1 disease having nodal metastasis. The trend in increased use of LND suggests a growing adoption of AJCC recommendations in the treatment of ICC.

Surgical treatment of metastatic colorectal cancer offers a chance for cure or prolonged survival, particularly for those with more favorable prognostic factors and limited tumor burden. The treatment plan requires multidisciplinary evaluation because multiple therapy options exist. Advanced surgical techniques, adjuncts to resection, and modern chemotherapy all contribute to best outcomes for patients with hepatic metastases. Although cure is less common for patients with metastasis to lung or peritoneum, surgical resection for the former and cytoreduction and intraperitoneal chemotherapy for the latter may help to achieve cancer control in selected patients.

Time to tumor recurrence may be associated with outcomes following resection of hepatobiliary cancers. The objective of the current study was to investigate risk factors and prognosis among patients with early versus late recurrence of hilar cholangiocarcinoma (HCCA) after curative-intent resection. A total of 225 patients who underwent curative-intent resection for HCCA were identified from 10 academic centers in the USA. Data on clinicopathologic characteristics, pre-, intra-, and postoperative details and overall survival (OS) were analyzed. The slope of the curves identified by linear regression was used to categorize recurrences as early versus late. With a median follow-up of 18.0 months, 99 (44.0%) patients experienced a tumor recurrence. According to the slope of the curves identified by linear regression, the functions of the two straight lines were y = −0.465x + 16.99 and y = −0.12x + 7.16. The intercept value of the two lines was 28.5 months, and therefore, 30 months (2.5 years) was defined as the cutoff to differentiate early from late recurrence. Among 99 patients who experienced recurrence, the majority (n = 80, 80.8%) occurred within the first 2.5 years (early recurrence), while 19.2% of recurrences occurred beyond 2.5 years (late recurrence). Early recurrence was more likely present as distant disease (75.1% vs. 31.6%, p = 0.001) and was associated with a worse OS (Median OS, early 21.5 vs. late 50.4 months, p

Background Cancer-associated wasting, termed cancer cachexia, has a profound effect on the morbidity and mortality of cancer patients but remains difficult to recognize and diagnose. While increases in circulating levels of a number of inflammatory cytokines have been associated with cancer cachexia, these associations were generally made in patients with advanced disease and thus may be associated with disease progression rather than directly with the cachexia syndrome. Thus, we sought to assess potential biomarkers of cancer-induced cachexia in patients with earlier stages of disease. Methods A custom multiplex array was used to measure circulating levels of 25 soluble factors from 70 pancreatic cancer patients undergoing attempted tumour resections. A high-sensitivity multiplex was used for increased sensitivity for nine cytokines. Results Resectable pancreatic cancer patients with cachexia had low levels of canonical pro-inflammatory cytokines including interleukin-6 (IL-6), interleukin-1β (IL-1β), interferon-γ (IFN-γ), and tumour necrosis factor (TNF). Even in our more sensitive analysis, these cytokines were not associated with cancer cachexia. Of the 25 circulating factors tested, only monocyte chemoattractant protein-1 (MCP-1) was increased in treatment-naive cachectic patients compared with weight stable patients and identified as a potential biomarker for cancer cachexia. Although circulating levels of leptin and granulocyte-macrophage colony-stimulating factor (GM-CSF) were found to be decreased in the same cohort of treatment-naive cachectic patients, these factors were closely associated with body mass index, limiting their utility as cancer cachexia biomarkers. Conclusions Unlike in advanced disease, it is possible that cachexia in patients with resectable pancreatic cancer is not associated with high levels of classical markers of systemic inflammation. However, cachectic, treatment-naive patients have higher levels of MCP-1, suggesting that MCP-1 may be useful as a biomarker of cancer cachexia.

BACKGROUND Given the conflicting nature of reported risk factors for post-discharge venous thromboembolism (VTE) and unclear guidelines for post-discharge pharmacoprophylaxis, we sought to determine risk factors for 30-day post-discharge VTE after colectomy to predict which patients will benefit from post-discharge pharmacoprophylaxis. METHODS Patients who underwent colectomy in the American College of Surgeons National Surgical Quality Improvement Project Participant Use Files from 2011 to 2015 were identified. Logistic regression modeling was used. Receiver-operating characteristic curves were used and the best cut-points were determined using Youden's J index (sensitivity + specificity - 1). Hosmer-Lemeshow goodness-of-fit test was used to test model calibration. A random sample of 30% of the cohort was used as a validation set. RESULTS Among 77,823 cases, the overall incidence of VTE after colectomy was 1.9%, with 0.7% of VTE events occurring in the post-discharge setting. Factors associated with post-discharge VTE risk including body mass index, preoperative albumin, operation time, hospital length of stay, race, smoking status, inflammatory bowel disease, return to the operating room and postoperative ileus were included in logistic regression equation model. The model demonstrated good calibration (goodness of fit P = 0.7137) and good discrimination (area under the curve (AUC) = 0.68; validation set, AUC = 0.70). A score of ≥-5.00 had the maxim sensitivity and specificity, resulting in 36.63% of patients being treated with prophylaxis for an overall VTE risk of 0.67%. CONCLUSION Approximately one-third of post-colectomy VTE events occurred after discharge. Patients with predicted post-discharge VTE risk of ≥-5.00 should be recommended for extended post-discharge VTE prophylaxis.

BACKGROUND: We sought to investigate the prognosis of patients following curative-intent surgery for intrahepatic cholangiocarcinoma (ICC) stratified by hepatitis B (HBV-ICC), hepatolithiasis (Stone-ICC), and no identifiable cause (conventional ICC) etiologic subtype. METHODS: 986 patients with HBV-ICC (n = 201), stone-ICC (n = 103), and conventional ICC (n = 682) who underwent curative-intent resection were identified from a multi-institutional database. Propensity score matching (PSM) was used to mitigate residual bias. RESULTS: HBV-ICC patients more often had cirrhosis, earlier stage tumors, a mass-forming lesion, well-to-moderate tumor differentiation, and an R0 resection versus stone-ICC or conventional ICC patients. Five-year recurrence-free survival among HBV-ICC and conventional ICC patients was 23.9 and 17.8%, respectively, versus a recurrence-free of only 8.3% among patients with stone-ICC. Similarly, 5-year overall survival among patients with stone-ICC was only 18.3% compared with 48.9 and 38.0% for patients with HBV-ICC and conventional ICC, respectively. On PSM, patients with stone-ICC group had equivalent long-term outcomes as HBV-ICC patients. In contrast, on PSM, stone-ICC patients had a median overall survival of only 18.0 months versus 44.0 months for patients with conventional ICC. Median overall survival after intrahepatic-only recurrence among patients who had stone-ICC (6.0 months) was worse than OS among HBV-ICC (13.0 months) or conventional ICC (12.0 months) (p = 0.006 and p = 0.082, respectively). CONCLUSIONS: While HBV-ICC had a better prognosis on unadjusted analyses, these differences were mitigated on PSM suggesting no stage-for-stage differences in outcomes compared with stone-ICC or conventional ICC. In contrast, patients with stone-ICC had worse long-term outcomes. These data highlight the relative importance of ICC etiology relative to established clinicopathological factors in the prognosis of patients with ICC. info:eu-repo/semantics/publishedVersion

Hepatic malignancies are one of the leading causes of cancer death globally. Considering the limited efficacy of current standard treatments in management of patients with advanced liver cancers, there has been a growing interest in identifying novel therapies. Despite achieving promising results in initial clinical trials, the therapeutic benefit of immunotherapy is limited due to strong immune-tolerogenic characteristics of liver tumors. Therapeutic regimens that impede tumor immunosuppressive mechanisms or elaborate tumor-specific immunity may improve clinical outcomes of patients with liver malignancies. Programmed cell death 1 (PD-1), an inhibitory checkpoint molecule, and its ligands (PD-L1 and -L2) are the main mediators of immunosuppression within the tumor microenvironment. The expression level of PD-1/PD-L1 may act as a biomarker to predict disease progression, as well as long-term survival. Furthermore, early trials have demonstrated the efficacy and safety of targeting PD-1/PD-L1 as an emerging field in the management of patients with advanced hepatocellular carcinoma. We herein review the role of PD-1/PD-L1 in the pathogenesis of liver malignancies, as well as its potential diagnostic and therapeutic implications.

Ruptured hepatocellular (rHCC) is a rare but life-threatening presentation that often requires acute intervention. In this systematic review we identified 67 eligible studies reporting on 4941 patients with rHCC. Here we present the treatment approaches for the management of rHCC both in the acute setting with regards to management of hemorrhage, as well long-term with regards to oncological treatment.

Increasing incidence of lifelong obesity and associated nonalcoholic steatohepatitis in younger birth cohorts may have contributed to growing incidence of hepatocellular carcinoma (HCC) in the USA. Yet, the contribution of cohort effects to trends in HCC incidence is unclear. Using data from the Surveillance, Epidemiology, and End Results (SEER) program 1973–2013, race- and gender-specific trends in HCC incidence in the USA were decomposed using age-period-cohort (APC) modeling. Among SEER registry sites included in the analysis, there were 25,532 cases of HCC diagnosed including 15,867 (62%) White males, 3541 (14%) Black males, 5009 (20%) White females, and 1115 (4%) Black females. HCC incidence increases across periods, especially among men. Underlying this increase, APC models found significant cohort effects among White men, White women, and Black men, with rapid growth in HCC risk among cohorts born after 1940. A similar cohort trend among Black women did not reach statistical significance when compared to an age-period model. Cohort-specific trends have significantly contributed to increasing HCC incidence in recent decades. The rapid increase in HCC risk among younger cohorts suggests that the incidence of HCC will continue increasing in the near future.

Exosomes are nanovesicles that may play a role in intercellular communication by acting as carriers of functional contents such as proteins, lipids, RNA molecules and circulating DNA from donor to recipient cells. In addition, exosomes may play a potential role in immunosurveillance and tumor pathogenesis and progression. Recently, research has increasingly focused on the role of exosomes in hepatocellular carcinoma (HCC), the most common primary liver malignancy. We herein review data on emerging experimental and clinical studies focused on the role of exosomes in the pathogenesis, diagnosis, progression and chemotherapy response of patients with HCC. Beyond their diagnostic value in HCC, exosomes are involved in different mechanisms of HCC tumor pathogenesis and progression including angiogenesis and immune escape. Moreover, exosomes have been demonstrated to change the tumor microenvironment to a less tolerogenic state, favoring immune response and tumor suppression. These results underline a practical and potentially feasible role of exosomes in the treatment of patients with HCC, both as a target and a vehicle for drug design. Future studies will need to further elucidate the exact role and reliability of exosomes as screening, diagnostic and treatment targets in patients with HCC.

Current guidelines for the management of indeterminate nodules discovered on surveillance imaging recommend alternate imaging modality or biopsy. This study evaluates the use of short interval MRI rather than immediate CT or biopsy. This retrospective cohort study examines outcomes of 111 patients with indeterminate nodules reviewed by a single institution’s Liver Tumor Board 2011–2016. Analysis was focused on outcomes stratified by management decision. The tumor board recommended biopsy or immediate repeat CT imaging in 13 (12%), 3-month interval MRI in 64 (58%) and 6-month interval MRI for 34 (30%) patients. Twenty-eight (29%) patients in the interval MRI subgroups were diagnosed with hepatocellular carcinoma (HCC) during the period of follow-up, and 21 (75%) of these were located within the original indeterminate nodule. The median time to diagnosis was 6.5 months. Twenty-three (82%) were eligible for potentially curative therapy at the time of HCC diagnosis. Delay in HCC diagnosis was not the reason for inability to provide potentially curative therapy in any patient. This study supports the judicious use of interval MRI at 3 or 6 months in patients with liver cirrhosis and an indeterminate liver nodule rather than immediate CT scan or biopsy.

The use of liver transplantation (LT) for liver metastases attempted in the early 1990's was associated with poor perioperative outcomes and unacceptably low overall survival. Recently, there has been renewed interest in LT as a treatment option for colorectal liver metastases (CLM) in countries where organ supply is high. To date, no meticulous analysis about the efficacy, safety and outcomes of LT in CLM patients has been published. We present the first systematic review on the subject.

The MST1R (RON) kinase is overexpressed in >80% of human pancreatic cancers, but its role in pancreatic carcinogenesis is unknown. In this study, we examined the relevance of Mst1r kinase to Kras driven pancreatic carcinogenesis using genetically engineered mouse models. In the setting of mutant Kras, Mst1r overexpression increased acinar-ductal metaplasia (ADM), accelerated the progression of pancreatic intraepithelial neoplasia (PanIN), and resulted in the accumulation of (mannose receptor C type 1) MRC1+, (arginase 1) Arg+ macrophages in the tumor microenvironment. Conversely, absence of a functional Mst1r kinase slowed PanIN initiation, resulted in smaller tumors, prolonged survival and a reduced tumor-associated macrophage content. Mst1r expression was associated with increased production of its ligand Mst1, and in orthotopic models, suppression of Mst1 expression resulted in reduced tumor size, changes in macrophage polarization and enhanced T cell infiltration. This study demonstrates the functional significance of Mst1r during pancreatic cancer initiation and progression. Further, it provides proof of concept that targeting Mst1r can modulate pancreatic cancer growth and the microenvironment. This study provides further rationale for targeting Mst1r as a therapeutic strategy.

BACKGROUND: The objective of the current study was to investigate both short- and long-term outcomes of patients undergoing curative-intent resection for intrahepatic cholangiocarcinoma (ICC) stratified by extent of hepatic resection relative to overall final pathological margin status. METHODS: One thousand twenty-three patients with ICC who underwent curative-intent resection were identified from a multi-institutional database. Demographic, clinicopathological, and operative data, as well as overall (OS) and recurrence-free survival (RFS) were compared among patients undergoing major and minor resection before and after propensity score matching. RESULTS: Overall, 608 (59.4%) patients underwent major hepatectomy, while 415 (40.6%) had a minor resection. Major hepatectomy was more frequently performed among patients who had large, multiple, and bilobar tumors. Roughly half of patients (n = 294, 48.4%) developed a postoperative complication following major hepatectomy versus only one fourth of patients (n = 113, 27.2%) after minor resection (p < 0.001). In the propensity model, patients who underwent major hepatectomy had an equivalent OS and RFS versus patients who had a minor hepatectomy (median OS, 38 vs. 37 months, p = 0.556; and median RFS, 20 vs. 18 months, p = 0.635). Patients undergoing major resection had comparable OS and RFS with wide surgical margin (≥10 and 5-9 mm), but improved RFS when surgical margin was narrow (1-4 mm) versus minor resection in the propensity model. In the Cox regression model, tumor characteristics and surgical margin were independently associated with long-term outcome. CONCLUSIONS: Major hepatectomy for ICC was not associated with an overall survival benefit, yet was associated with increased perioperative morbidity. Margin width, rather than the extent of resection, affected long-term outcomes. Radical parenchymal-sparing resection should be advocated if a margin clearance of ≥5 mm can be achieved. info:eu-repo/semantics/publishedVersion

// Jeffery Chakedis 1 , Randall French 1 , Michele Babicky 1 , Dawn Jaquish 1 , Evangeline Mose 1 , Peter Cheng 1 , Patrick Holman 1 , Haleigh Howard 1 , Jaclyn Miyamoto 1 , Paula Porras 1 , Zakk Walterscheid 1 , Carsten Schultz-Fademrecht 2 , Christina Esdar 3 , Oliver Schadt 3 , Jan Eickhoff 2 , Andrew M. Lowy 1 1 Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA 2 Lead Discovery Center GmbH, Dortmund, Germany 3 Merck KGaA, Darmstadt, Germany Correspondence to: Andrew M. Lowy, email: alowy@ucsd.edu Keywords: RON, pancreatic cancer, isoform, alternative splicing, tyrosine kinase inhibitor Received: March 03, 2016 Accepted: May 23, 2016 Published: June 14, 2016 ABSTRACT The RON tyrosine kinase receptor is under investigation as a novel target in pancreatic cancer. While RON mutations are uncommon, RON isoforms are produced in cancer cells via a variety of mechanisms. In this study we sought to: 1) characterize RON isoform expression in pancreatic cancer, 2) investigate mechanisms that regulate isoform expression, and 3) determine how various isoforms effect gene expression, oncogenic phenotypes and responses to RON directed therapies. We quantified RON transcripts in human pancreatic cancer and found expression levels 2500 fold that of normal pancreas with RON isoform expression comprising nearly 50% of total transcript. RNA seq studies revealed that the short form (sfRON) and P5P6 isoforms which have ligand independent activity, induce markedly different patterns of gene expression than wild type RON. We found that transcription of RON isoforms is regulated by promoter hypermethylation as the DNA demethylating agent 5-aza-2’-deoxycytidine decreased all RON transcripts in a subset of pancreatic cancer cell lines. The viability of sfRON-expressing HPDE cells was reduced by a RON specific small molecule inhibitor, while a therapeutic monoclonal antibody had no demonstrable effects. In summary, RON isoforms may comprise half of total RON transcript in human pancreatic cancer and their expression is regulated at least in part by promoter hypermethylation. RON isoforms activate distinct patterns of gene expression, have transforming activity and differential responses to RON directed therapies. These findings further our understanding of RON biology in pancreatic cancer and have implications for therapeutic strategies to target RON activity.

INTRODUCTION: Patients with metastatic neuroendocrine tumor (NET) often have an indolent disease course yet the outcomes for patients with metastatic NET undergoing surgery for non-hormonal (NH) symptoms of GI obstruction, bleeding, or pain is not known. METHODS: We identified patients with metastatic gastroenteropancreatic NET who underwent resection from 2000 to 2016 at 8 academic institutions who participated in the US Neuroendocrine Tumor Study Group. RESULTS: Of 581 patients with metastatic NET to liver (61.3%), lymph nodes (24.1%), lung (2.1%), and bone (2.5%), 332 (57.1%) presented with NH symptoms of pain (n = 223, 67.4%), GI bleeding (n = 54, 16.3%), GI obstruction (n = 49, 14.8%), and biliary obstruction (n = 22, 6.7%). Most patients were undergoing their first operation (85.4%) within 4 weeks of diagnosis. The median overall survival was 110.4 months, and operative intent predicted survival (p < 0.001) with 66.3% undergoing curative resection. Removal of all metastatic disease was associated with the longest median survival (112.5 months) compared to debulking (89.2 months), or palliative resection (50.0 months; p < 0.001). The 1-, 3-, and 12-month mortality was 3.0%, 4.5%, and 9.0%, respectively. Factors associated with 1-year mortality included palliative operations (OR 6.54, p = 0.006), foregut NET (5.62, p = 0.042), major complication (4.91, p = 0.001), and high tumor grade (11.2, p < 0.001). The conditional survival for patients who lived past 1 year was 119 months. CONCLUSIONS: Patients with metastatic NET and NH symptoms that necessitate surgery have long-term survival, and goals of care should focus on both oncologic and quality of life impact. Surgical intervention remains a critical component of multidisciplinary care of symptomatic patients.

Background: The incidence and mortality of intrahepatic cholangiocarcinoma (ICC) are increasing worldwide. We used age-period-cohort (APC) modeling to evaluate the contribution of cohort effects to trends in ICC incidence and mortality in the US. Methods: Incidence data were acquired from the Surveillance, Epidemiology and End-Results (SEER) program. Mortality data were obtained from the Centers for Disease Control and Prevention WONDER Database. APC models using restricted cubic splines were fitted to estimate change in incidence and mortality risk over age, and modification of incidence and mortality risks according to birth cohort and period of diagnosis or death. Likelihood ratio tests were used to summarize improvement in model fit with APC modeling. Results: There were 4,053 cases of ICC at SEER registry sites between 1973–2012. ICC incidence increased with older age and across all birth cohorts examined. Inclusion of cohort effects tended to improve model fit relative to an age-period model (likelihood ratio test P=0.082). The national crude ICC-related mortality rate increased from 2.9 to 5.0 per 100,000 among males and 2.7 to 4.6 per 100,000 among females. Among males, ICC mortality risk varied across birth cohorts, and inclusion of cohort effects in a model predicting ICC mortality risk improved model fit (likelihood ratio test P=0.001), but cohort effects did not alter model fit among females (P=0.223). Conclusions: ICC incidence and mortality have increased over time in the United States. Birth cohort effects influenced increased ICC incidence and ICC mortality among males, but were not evident in the trend of ICC mortality among females.

Postoperative pancreatic fistula (POPF) remains a major cause of morbidity following pancreaticoduodenectomy (PD). We sought to develop and validate a risk score system that utilized preoperative computed tomography (CT) measurements, laboratory values, and intraoperative pancreatic texture to estimate risk of developing POPF after PD. Patients who underwent PD between 2014 and 2017 were identified. Pre- and intraoperative risk factors associated with POPF were identified. Three separate risk models were developed and assessed using multivariable analyses and receiver operating curves. Among the 150 patients who underwent a PD, mean age was 64 years and the majority of the patients were male (59.3%, n = 89). Overall, the incidence of BL/POPF following PD was 22%. On multivariable analysis, factors associated with POPF included preoperative total serum protein

BACKGROUND: Injury to the thoracic duct (TD) is the most common complication following a left lateral neck dissection and carries a high degree of morbidity. Currently no routine diagnostic imaging is used to assist with TD identification intra-operatively. Here we present the first clinical experience with lymphangiography using Indocyanine Green (ICG) during lateral neck dissections. METHODS: In six patients undergoing left lateral neck dissection (level II-IV) for either thyroid cancer or melanoma 2.5–5 mg of ICG was injected in the dorsum of the left foot 15 minutes before imaging. Intraoperative imaging was performed with a hand-held Near InfraRed (NIR) camera (Hamamatsu PDE-Neo). RESULTS: In five patients the TD was visualized using NIR fluorescence with time from injection to identification of 15 to 90 minutes. Imaging was optimized by positioning the camera at the angle of the mandible and pointing into the space below the clavicle. There were no adverse reactions from ICG injection; and the time required for imaging was 5–10 minutes. No intra-operative TD injury was identified and no chyle leak occurred post-operatively. In the one patient in whom the TD was not identified it is unclear if it was related to the timing of the injection or duct obliteration from prior dissection. CONCLUSION: This is the first described application of ICG lymphangiography for identification of the thoracic duct during left lateral neck dissection. TD identification with ICG is technically feasible simple to perform with NIR imaging and safe making it a potential important adjunct for the surgeon.

Hepatic arterial infusion pump (HAIP) therapy for colorectal liver metastases (CRLM) is beneficial in selected patients yet wide acceptance in the oncology community is lacking.A surgeon-led team implemented a HAIP program in 2012. Pumps were placed by laparotomy for CRLM and fluorodeoxyuridine was infused via HAIP every 28 days without systemic chemotherapy supervised by the operating surgeon.Sixty patients were treated with HAIP, either in the adjuvant setting after liver resection or ablation of CRLM in 26 (43%) patients or with the unresectable disease in 34 (57%). Perioperative complications occurred in 19 (32%) and pump-specific complications in 14 (23%) that included intrahepatic biliary stricture in one (2%). Time to liver progression was a median 9.2 months (95% CI, 3.1-15.3 months) in unresectable patients and liver recurrence was a median 24.7 months (2.5-46.9 months) in the adjuvant group. Estimated 3-year overall survival from the time of HAIP placement was 64% in the adjuvant group and 37% in the unresectable group. Sarcopenia was prevalent (48%) and was associated with a worse survival (HR 2.4, 95% CI, 1.1-5.0).A surgeon-led HAIP program may achieve outcomes on par with those of experienced centers and foster strong relationships between surgical and medical oncologists.

Background The objective of this study was to investigate the characteristics, treatment and prognosis of early versus late recurrence of intrahepatic cholangiocarcinoma (ICC) after hepatic resection. Methods Patients who underwent resection with curative intent for ICC were identified from a multi-institutional database. Data on clinicopathological characteristics, initial operative details, timing and sites of recurrence, recurrence management and long-term outcomes were analysed. Results A total of 933 patients were included. With a median follow-up of 22 months, 685 patients (73·4 per cent) experienced recurrence of ICC; 406 of these (59·3 per cent) developed only intrahepatic disease recurrence. The optimal cutoff value to differentiate early (540 patients, 78·8 per cent) versus late (145, 21·2 per cent) recurrence was defined as 24 months. Patients with early recurrence had extrahepatic disease more often (44·1 per cent versus 28·3 per cent in those with late recurrence; P < 0·001), whereas late recurrence was more often only intrahepatic (71·7 per cent versus 55·9 per cent for early recurrence; P < 0·001). From time of recurrence, overall survival was worse among patients who had early versus late recurrence (median 10 versus 18 months respectively; P = 0·029). In multivariable analysis, tumour characteristics including tumour size, number of lesions and satellite lesions were associated with an increased risk of early intrahepatic recurrence. In contrast, only the presence of liver cirrhosis was independently associated with an increased likelihood of late intrahepatic recurrence (hazard ratio 1·99, 95 per cent c.i. 1·11 to 3·56; P = 0·019). Conclusion Early and late recurrence after curative resection for ICC are associated with different risk factors and prognosis. Data on the timing of recurrence may inform decisions about the degree of postoperative surveillance, as well as help counsel patients with regard to their risk of recurrence.

Pancreatic cancer (PC) remains one of the most fatal forms of cancer worldwide with incidence nearly equal to mortality. This is often attributed to the fact that diagnosis is often not made until later disease stages when treatment proves difficult. Efforts have been made to reduce the mortality of PC through improvements in early screening techniques and treatments of late-stage disease. Exosomes, small extracellular vesicles involved in cellular communication, have shown promise in helping understand PC disease biology. In this review, we discuss current studies of the role of exosomes in PC physiology, and their potential use as diagnostic and treatment tools. Exosomes have a role in diagnosing pancreatic cancer and in understanding tumor biology including migration, proliferation, chemoresistance, immunosuppression, cachexia and diabetes, and have a potential role in therapy for pancreatic cancer. Exosomal analysis is beneficial in demonstrating mechanisms behind PC growth and metastasis, immunosuppression, drug resistance, and paraneoplastic conditions. Furthermore, the use of exosomes can be beneficial in detecting early-stage PC and exosomes have potential applications as therapeutic targets.

Surgical management of intrahepatic cholangiocarcinoma routinely includes resection of the hepatic parenchyma, yet the role of lymphadenectomy (LND) is more controversial. The objective of the current study was to define overall utilization, as well as temporal trends, in the utilization of LND among patients undergoing curative-intent hepatectomy for ICC using a nationwide database. One thousand four hundred ninety-six patients who underwent curative-intent resection for ICC were identified using the SEER database from 2000 to 2013. The utilization of LND was assessed over time and by geographic region. LND utilization and the incidence of lymph node metastasis (LNM) were evaluated relative to AJCC T categories. At the time of surgery, slightly over one-half of patients (n = 784, 52.4%) had at least one LN evaluated. Specifically, 613 (41.0%) patients had 1–5 LNs evaluated, whereas 171 (11.4%) patients had ≥ 6 LNs evaluated. The proportion of patients who had at least one LN evaluated at the time of surgery did not change with time (2000–2004: 50.5% vs. 2005–2009: 52.0% vs. 2010–2013: 53.7%) (p = 0.636). In contrast, the proportion of patients who had ≥ 6 LNs examined did increase (2000–2004: 6.9% vs. 2005–2009: 10.6% vs. 2009–2013: 14.3%) (p = 0.003). The risk of LNM was higher among patients with advanced T category tumors (Referent T1; T2a: OR 4.2, 95% CI 2.0–8.8, p

Background The objective of the current study was to define risk factors associated with the 30-day post-operative risk of VTE after HPB surgery and create a model to identify patients at highest risk of post-discharge VTE. Methods Patients who underwent hepatectomy or pancreatectomy in the ACS-NSQIP Participant Use Files 2011–2015 were identified. Logistic regression modeling was used; a model to predict post-discharge VTE was developed. Model discrimination was tested using area under the curve (AUC). Results Among 48,860 patients, the overall 30-day incidence of VTE after hepatectomy and pancreatectomy was 3.2% (n = 1580) with 1.1% (n = 543) of VTE events occurring after discharge. Patients who developed post-discharge VTE were more likely to be white, had a higher median BMI, have undergone pancreatic surgery, had longer median operative times, and to have had a transfusion. A weighted prediction model demonstrated good calibration and fair discrimination (AUC = 0.63). A score of ≥−4.50 had maximum sensitivity and specificity, resulting in 44% of patients being treating with prophylaxis for an overall VTE risk of 1.1%. Conclusions Utilizing independent factors associated with post-discharge VTE, a prediction model was able to stratify patients according to risk of VTE and may help identify patients who are most likely to benefit from pharmacoprophylaxis.

BACKGROUND: Early tumor recurrence after curative resection typically indicates a poor prognosis. The objective of the current study was to investigate the risk factors, treatment, and prognosis of early recurrence of neuroendocrine tumor (NET) liver metastasis (NELM) after hepatic resection. METHODS: A total of 481 patients who underwent curative-intent resection for NELM were identified from a multi-institutional database. Data on clinicopathological characteristics, intraoperative details, and outcomes were documented. The optimal cutoff value to differentiate early and late recurrence was determined to be 3 years based on linear regression. RESULTS: With a median follow-up of 60 months, 223 (46.4%) patients developed a recurrence, including 158 (70.9%) early and 65 (29.1%) late recurrences. On multivariable analysis, pancreatic NET, primary tumor lymph node metastasis, and a microscopic positive surgical margin were independent risk factors for early intrahepatic recurrence. While recurrence patterns and treatments were comparable among patients with early and late recurrences, early recurrence was associated with worse disease-specific survival than late recurrences (10-year NELM-specific survival, 44.5 vs 75.8%, p < 0.001). Among the 34 (21.5%) patients who underwent curative treatment for early recurrence, post-recurrence disease-specific survival was better than non-curatively treated patients (10-year NELM-specific survival, 54.2 vs 26.3%, p = 0.028), yet similar to patients with late recurrences treated with curative intent (10-year NELM-specific survival, 54.2 vs 37.4%, p = 0.519). CONCLUSIONS: Early recurrence after surgery for NELM was associated with the pancreatic type, primary lymph node metastasis, and extrahepatic disease. Re-treatment with curative intent prolonged survival after recurrence, and therefore, operative intervention even for early recurrences of NELM should be considered. info:eu-repo/semantics/publishedVersion

Postoperative adhesions remain one of the more challenging issues in surgical practice. Although peritoneal adhesions occur after every abdominal operation, the density, time interval to develop symptoms, and clinical presentation are highly variable with no predictable patterns. Numerous studies have investigated the pathophysiology of postoperative adhesions both in vitro and in vivo. Factors such as type and location of adhesions, as well as timing and recurrence of adhesive obstruction remain unpredictable and poorly understood. Although the majority of postoperative adhesions are clinically silent, the consequences of adhesion formation can represent a lifelong problem including chronic abdominal pain, recurrent intestinal obstruction requiring multiple hospitalizations, and infertility. Moreover, adhesive disease can become a chronic medical condition with significant morbidity and no effective therapy. Despite recent advances in surgical techniques, there is no reliable strategy to manage postoperative adhesions. We herein review the pathophysiology and clinical significance of postoperative adhesions while highlighting current techniques of prevention and treatment.

The MST1R gene is overexpressed in pancreatic cancer producing elevated levels of the RON tyrosine kinase receptor protein. While mutations in MST1R are rare, alternative splice variants have been previously reported in epithelial cancers. We report the discovery of a novel RON isoform discovered in human pancreatic cancer. Partial splicing of exons 5 and 6 (P5P6) produces a RON isoform that lacks the first extracellular immunoglobulin-plexin-transcription (IPT) domain. The splice variant is detected in 73% of pancreatic adenocarcinoma patient derived xenografts and 71% of pancreatic cancer cell lines. Peptides specific to RON P5P6 detected in human pancreatic cancer specimens by mass spectrometry confirms translation of the protein isoform. The P5P6 isoform is found to be constitutively phosphorylated, present in the cytoplasm, and it traffics to the plasma membrane. Expression of P5P6 in immortalized human pancreatic duct epithelial (HPDE) cells activates downstream AKT, and in human pancreatic epithelial nestin-expressing (HPNE) cells activates both the AKT and MAPK pathways. Inhibiting RON P5P6 in HPDE cells using a small molecule inhibitor BMS-777607 blocked constitutive activation and decreased AKT signaling. P5P6 transforms NIH3T3 cells and induces tumorigenicity in HPDE cells. Resultant HPDE-P5P6 tumors develop a dense stromal compartment similar to that seen in pancreatic cancer. In summary, we have identified a novel and constitutively active isoform of the RON tyrosine kinase receptor that has transforming activity and is expressed in human pancreatic cancer. These findings provide additional insight into the biology of the RON receptor in pancreatic cancer and are clinically relevant to the study of RON as a potential therapeutic target.

Re-operative neck surgery for hyperparathyroidism is a technically difficult operation that requires adjunctive studies to assist with finding the parathyroid tissues. Intraoperative tests help minimise exploration of the neck and decrease injuries to the surrounding structures. Indocyanine green is a near-infrared fluorescent dye that in pre-clinical models was found to be useful in locating the parathyroid glands of dogs. No study has yet reported its use as a tool for parathyroid localisation in humans. We investigated the use of indocyanine green to assist with localisation of a recurrent parathyroid adenoma using a near-infrared imaging system. After exposure of the neck tissues, the parathyroid gland fluoresced brightly and directed our dissection. Exploration of the neck was minimal, and allowed for fast localisation and excision of the adenoma. Overall, use of indocyanine green is a simple and safe technique of intraoperative parathyroid localisation that warrants further investigation.

RON is a cell-surface receptor for the macrophage-stimulating protein expressed in tissue-resident macrophages and overexpressed in multiple epithelial neoplasms including pancreatic cancer. Our laboratory recently found that RON serves to mediate pancreatic duct carcinogenesis initiated by KRAS. We demonstrated that RON overexpression in the pancreas results in more rapid local and metastatic progression ultimately associated with decreased survival. We also discovered profound changes in the immunophenotype within the tumor microenvironment associated with RON expression. We notably established that RON expression drives the polarization of tumor-associated macrophages into an alternative, pro-tumorigenic state. We hypothesize that these unique activities help to shape the immunosuppressive milieu of the pancreatic cancer microenvironment and that RON directed therapy has the potential to serve as a novel immunomodulatory strategy in this disease. The aim of this work is to define how RON signaling contributes to shaping the pancreatic cancer microenvironment. In order to further interrogate the role of RON during pancreatic carcinogenesis, we bred kinase-dead RON mice (KD) to Pdx1-cre/LSL-KRASG12D mice. We observed a significant delay in the onset of pancreatic neoplasia and a significant decrease in tumor weight. The absence of functional RON kinase markedly reduced trafficking of CD11b+ cells to the pancreas and immunophenotyping in tumors showed a clear reduction of alternatively polarized macrophages when compared to RON overexpression or KRAS mutation alone. Because RON is expressed in both epithelial and stromal cell populations, we further sought to dissect the relevance of RON function to tumor growth within these cellular compartments. We performed orthotopic injections of organoïd-3D cells derived from tumors of KPC mice (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre). These cells were injected in wild type (WT) or RON KD mice. Preliminary results show that tumor growth is impaired in KD mice, suggesting that RON activity in the host microenvironment influence tumor growth. In order to identify all immune populations regulated by RON, we will conduct an exhaustive immunophenotyping of murine pancreatic tumors. A transcriptomic analysis will then be conducted on selected cell populations to better define the molecular mechanisms associated with the RON regulation. Finally, given the effect of RON signaling on macrophage polarization, we will also dissect the effects of RON signaling from bone marrow derived myeloid cells versus resident tissue macrophages. Preliminary results and future experiments will significantly narrow the gap in our understanding of how RON signaling contributes to shaping the pancreatic cancer chimera and therefore how RON-directed therapies could be most successfully utilized to the benefit of those afflicted with this most deadly disease Citation Format: Alex Cazes, Michele L. Babicky, Jeffery Chakedis, Divya Sood, Dawn Jaquish, Andrew M. Lowy. Role of the RON kinase in the regulation of the antitumor immune response in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2676. doi:10.1158/1538-7445.AM2017-2676

RESULTS: A total of 81 patients underwent distal pancreatectomy during the study period (41 open and 40 laparoscopic). Median age was 62 years. Two-thirds of patients were female, with similar American Society of Anesthesiologists (ASA) distribution among both groups. The LDP had significantly shorter mean operative time (150 vs 183 minutes; p

Introduction:The RON tyrosine kinase receptor is increasingly overexpressed during progression to Pancreatic Intraepithelial Neoplasia (PanIN) and pancreatic duct adenocarcinoma (PDAC). RON expression in these neoplastic cells is associated with a highly invasive phenotype and resistance to gemcitabine. Mutations in the gene for RON, MST1R, are rare but alternative splicing produces a wide variety of protein isoforms. Exon skipping is the most common and a skipping of exon 11 produces RONΔ165. Alternative transcription start in intron 10 produces short-form RON (sfRON) which promotes metastasis in breast cancer. Eight RON isoforms have previously been reported in different epithelial cancer types (Colon, Breast, Stomach) and we initially sought to characterize their expression in PDAC. Using low passage patient derived xenografts (PDXs), we found that the known RON isoforms Δ165 and sfRON were expressed in the majority of PDX’s. Results: This study revealed a novel RON isoform resulting from partial splicing of exons 5 and 6 (P5P6) to produce a protein that lacks the first extracellular immunoglobulin-plexin-transcription (IPT) domain. Peptides specific to RON P5P6 were detected in pancreatic cancer specimens by mass spectrometry which confirms translation of the protein. Using end point PCR we determined that RON is overexpressed in 90% of PDX and P5P6 expressed in 73%. In PDXs absolute quantification PCR determined RON isoforms P5P6, sfRON, and RONΔ165 make up 15 – 50% of total RON transcripts. This puts total isoform expression at up to 500 times more than the full length protein in normal pancreas. To determine function of these isoforms we overexpressed sfRON, RON P5P6, and RONΔ165 in a Human Pancreatic Ductal Epithelial (HPDE) cell line using a lentiviral vector. We found that all isoforms are constitutively phosphorylated, present in the cytoplasm in a reticular pattern, and RON P5P6 traffics to the plasma membrane. RON P5P6 is spliced into α and β subunits and can bind its ligand Macrophage Stimulating Protein similar to full length RON. Expression of P5P6 in HPDE cells activates downstream AKT and MAPK signaling pathways and increases cell motility, VEGF secretion, and markers of EMT. HPDE cells expressing P5P6 and short form RON were injected orthotopically into NOD SCID Gamma mouse pancreata and are tumorigenic while the parental cell line is not. P5P6 and short form RON tumors induce a denser stroma not characteristically observed in cell line derived xenografts. In HPDE sfRON tumors, host mouse acini adjacent to the tumor undergo acinar to ductal metaplasia. As the tumor invades into the mouse pancreas these newly formed ducts become increasingly dysplastic and begin to express mesenchymal markers. Conclusion: We have identified protein isoforms of the RON tyrosine kinase receptor which are expressed in human pancreatic cancer. A novel isoform RON P5P6 and short form RON transform human pancreatic ductal epithelial cells to become tumorigenic. Expression of short form RON in these tumors causes host mouse pancreas to undergo acinar to ductal metaplasia. Ultimately these findings demonstrate that RON isoform expression by pancreatic cancer cells has significant biologic consequences and promotes interaction with the adjacent normal pancreas. Further work to characterize the soluble factors responsible for RON paracrine signaling is currently underway. Citation Format: Jeffery M. Chakedis, Randall French, Michele Babicky, Dawn Jaquish, Haleigh Howard, Evangeline Mose, Jaclyn Miyamoto, Zakk Walterscheid, Patrick Holman, Andrew M. Lowy. Protein isoforms of the RON tyrosine kinase receptor transform human pancreatic ductal epithelial cells and induce acinar to ductal metaplasia. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A72.

Introduction - The RON tyrosine kinase receptor is overexpressed in 80% of Pancreatic Ductal Adenocarcinomas (PDAC) and mediates invasiveness, resistance to apoptosis, and VEGF secretion. Though point mutations are rare a wide variety of RON protein isoforms have been identified, some of which are constitutively active and oncogenic. Previous studies of the DNA methylation patterns of pancreatic cancer specimens identified the gene for RON, MST1R, to be controlled by epigenetic modification. Methylation is one mechanism to regulate expression of RON, and we seek to investigate the effects of hypomethylating therapy on isoform expression and alteration of PDAC biology. Methods - Established pancreatic cancer cell lines (MiaPaca2, BxPC3, AsPC1, HPDE, Panc1) and 2 novel cell lines derived from patient tumor specimens (34E, 79E) were treated with 5-Aza-2′-deoxycytidine (Decitabine, DAC) for 96 hours. Genomic DNA was analyzed using the Methylflash (Epigentek) assay to determine genomic methylation percentage. Reverse Transcriptase PCR and western blot analysis was used to determine treatment effects on RON transcription and expression. Results - Genomic methylation analysis of pancreatic cancer cell lines revealed that compared to the control HPDE line (1.2% methylation) some lines were hypomethylated (ASPC1-1.13%, 34E-1.17%, Panc1-1.17%) while others were hypermethylated (BxPC3-1.6%, MiaPaca2-1.98%, 79E-2.06%). Hypomethylating therapy was effective in decreasing genomic methylation to below normal levels (0.4%-0.9%) in all cell lines and depleted DNA MethylTransferase 1 (DNMT1) protein levels. The effects of demethylating therapy on RON expression were differential. The amount of RON transcripts and protein expression in the RON expressing lines (79E and 34E) was decreased but increased in MiaPaca2 and Panc1. MiaPaca2 does not normally express RON, but demethylation induced RON expression. Transcripts specific for the Δ55 isoform of RON decreased in 34E, 79E, and HPDE cell lines but did not change in the others. Transcription and expression of other RON isoforms which are constitutively active decreased in 34E, 79E, ASPC1, and BxPC3 lines, with less exon 11 skipping and partial splicing of exon 5 and 6. Though RON protein expression was decreased overall in the expressing lines, phosphorylation was still detectable following DAC treatment. Conclusions - Genomic methylation of pancreatic cancer cell lines is variable and RON expression is modulated by the methylation status of its promoter. Demethylating therapy has variable effects on RON expression and is context specific. RON isoform expression was decreased in response to treatment, linking DNA methylation to alternative splicing events. These findings suggest that the consequences of demethylating therapy on PDAC biology are complex and additional studies are required to further elucidate definitive mechanisms. Citation Format: Jeffery Chakedis, Randall French, Dawn Jaquish, Evangeline Mose, Andrew Lowy. Demethylating therapy modulates expression of the RON tyrosine kinase receptor in pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2315. doi:10.1158/1538-7445.AM2014-2315