Combination therapies for cancer: challenges and opportunities.

BACKGROUND: Gastrointestinal cancers represent a major challenge to public health. Pancreatic cancer is the most lethal cancer among all gastrointestinal cancers. Most patients cannot meet the criteria of resection at diagnosis, indicating these patients will have dismal prognosis. MAIN TEXT: Neoadjuvant chemotherapy helps some patients regain the opportunity of radical resection. An optimal regimen of chemotherapy is one that maximizes the anti-tumor efficacy while maintaining a relatively manageable safety profile. The development of surgical procedures further improves the outcomes of these patients. CONCLUSIONS: Combination therapies in a multidisciplinary manner that involves modified chemotherapy regimen, radical resection, and intestine auto-transplantation may provide the currently best possible care to patients with locally advanced pancreatic cancer.

Innovative Imaging Techniques Used to Evaluate Borderline-Resectable Pancreatic Adenocarcinoma.

A diagnosis of pancreatic cancer carries a 5-y survival rate of less than 10%. Furthermore, the detection of pancreatic cancer occurs most often in later stages of the disease due to its location in the retroperitoneum and lack of symptoms (in most cases) until tumors become more advanced. Once diagnosed, cross-sectional imaging techniques are heavily utilized to determine the tumor stage and the potential for surgical resection. However, a major determinant of resectability is the extent of local vascular involvement of the mesenteric vessels and critical tributaries; current imaging techniques have limited capacity to accurately determine vascular involvement. Surrounding inflammation and fibrosis can be difficult to discriminate from viable tumor, making determination of the degree of vascular involvement unreliable. New innovations in fluorescence and optoacoustic imaging techniques may overcome these limitations and make determination of resectability more accurate. These imaging modalities are able to more clearly discern between viable tumor tissue and non-neoplastic inflammation or desmoplasia, allowing clinicians to more reliably characterize vascular involvement and develop individualized treatment plans for patients. This review will discuss the current imaging techniques used to diagnose pancreatic cancer, the barriers that current techniques raise to accurate staging, and novel fluorescence and optoacoustic imaging techniques that may provide more accurate clinical staging of pancreatic cancer.

ZIP4 Increases Expression of Transcription Factor ZEB1 to Promote Integrin α3ß1 Signaling and Inhibit Expression of the Gemcitabine Transporter ENT1 in Pancreatic Cancer Cells.

BACKGROUND & AIMS: Pancreatic tumors undergo rapid growth and progression, become resistant to chemotherapy, and recur after surgery. We studied the functions of the solute carrier family 39 member 4 (SLC39A4, also called ZIP4), which regulates concentrations of intracellular zinc and is increased in pancreatic cancer cells, in cell lines and mice. METHODS: We obtained 93 pancreatic cancer specimens (tumor and adjacent nontumor tissues) from patients who underwent surgery and gemcitabine chemotherapy and analyzed them by immunohistochemistry. ZIP4 and/or ITGA3 or ITGB1 were overexpressed or knocked down with short hairpin RNAs in AsPC-1 and MIA PaCa-2 pancreatic cancer cells lines, and in pancreatic cells from KPC and KPC-ZEB1-knockout mice, and pancreatic spheroids were established; cells and spheroids were analyzed by immunoblots, reverse transcription polymerase chain reaction, and liquid chromatography tandem mass spectrometry. We studied transcriptional regulation of ZEB1, ITGA3, ITGB1, JNK, and ENT1 by ZIP4 using chromatin precipitation and luciferase reporter assays. Nude mice were given injections of genetically manipulated AsPC-1 and MIA PaCa-2 cells, and growth of xenograft tumors and metastases was measured. RESULTS: In pancreatic cancer specimens from patients, increased levels of ZIP4 were associated with shorter survival times. MIA PaCa-2 cells that overexpressed ZIP4 had increased resistance to gemcitabine, 5-fluorouracil, and cisplatin, whereas AsPC-1 cells with ZIP4 knockdown had increased sensitivity to these drugs. In mice, xenograft tumors grown from AsPC-1 cells with ZIP4 knockdown were smaller and more sensitive to gemcitabine. ZIP4 overexpression significantly reduced accumulation of gemcitabine in pancreatic cancer cells, increased growth of xenograft tumors in mice, and increased expression of the integrin subunits ITGA3 and ITGB1; expression levels of ITGA3 and ITGB1 were reduced in cells with ZIP4 knockdown. Pancreatic cancer cells with ITGA3 or ITGB1 knockdown had reduced proliferation and formed smaller tumors in mice, despite overexpression of ZIP4; spheroids established from these cells had increased sensitivity to gemcitabine. We found ZIP4 to activate STAT3 to induce expression of ZEB1, which induced expression of ITGA3 and ITGB1 in KPC cells. Increased ITGA3 and ITGB1 expression and subsequent integrin α3ß1 signaling, via c-Jun-N-terminal kinase (JNK), inhibited expression of the gemcitabine transporter ENT1, which reduced gemcitabine uptake by pancreatic cancer cells. ZEB1-knockdown cells had increased sensitivity to gemcitabine. CONCLUSIONS: In studies of pancreatic cancer cell lines and mice, we found that ZIP4 increases expression of the transcription factor ZEB1, which activates expression of ITGA3 and ITGB1. The subsequent increase in integrin α3ß1 signaling, via JNK, inhibits expression of the gemcitabine transporter ENT1, so that cells take up smaller amounts of the drug. Activation of this pathway might help mediate resistance of pancreatic tumors to chemotherapeutic agents.

The Miami International Evidence-based Guidelines on Minimally Invasive Pancreas Resection.

OBJECTIVE: The aim of this study was to develop and externally validate the first evidence-based guidelines on minimally invasive pancreas resection (MIPR) before and during the International Evidence-based Guidelines on Minimally Invasive Pancreas Resection (IG-MIPR) meeting in Miami (March 2019). SUMMARY BACKGROUND DATA: MIPR has seen rapid development in the past decade. Promising outcomes have been reported by early adopters from high-volume centers. Subsequently, multicenter series as well as randomized controlled trials were reported; however, guidelines for clinical practice were lacking. METHODS: The Scottisch Intercollegiate Guidelines Network (SIGN) methodology was used, incorporating these 4 items: systematic reviews using PubMed, Embase, and Cochrane databases to answer clinical questions, whenever possible in PICO style, the GRADE approach for assessment of the quality of evidence, the Delphi method for establishing consensus on the developed recommendations, and the AGREE-II instrument for the assessment of guideline quality and external validation. The current guidelines are cosponsored by the International Hepato-Pancreato-Biliary Association, the Americas Hepato-Pancreato-Biliary Association, the Asian-Pacific Hepato-Pancreato-Biliary Association, the European-African Hepato-Pancreato-Biliary Association, the European Association for Endoscopic Surgery, Pancreas Club, the Society of American Gastrointestinal and Endoscopic Surgery, the Society for Surgery of the Alimentary Tract, and the Society of Surgical Oncology. RESULTS: After screening 16,069 titles, 694 studies were reviewed, and 291 were included. The final 28 recommendations covered 6 topics; laparoscopic and robotic distal pancreatectomy, central pancreatectomy, pancreatoduodenectomy, as well as patient selection, training, learning curve, and minimal annual center volume required to obtain optimal outcomes and patient safety. CONCLUSION: The IG-MIPR using SIGN methodology give guidance to surgeons, hospital administrators, patients, and medical societies on the use and outcome of MIPR as well as the approach to be taken regarding this challenging type of surgery.

ZIP4 Promotes Muscle Wasting and Cachexia in Mice With Orthotopic Pancreatic Tumors by Stimulating RAB27B-Regulated Release of Extracellular Vesicles From Cancer Cells.

BACKGROUND & AIMS: Cachexia, which includes muscle wasting, is a frequent complication of pancreatic cancer. There are no therapies that reduce cachexia and increase patient survival, so it is important to learn more about its mechanisms. The zinc transporter ZIP4 promotes growth and metastasis of pancreatic tumors. We investigated its effects on muscle catabolism via extracellular vesicle (EV)-mediated stimulation of mitogen-activated protein kinase 14 (p38 MAPK). METHODS: We studied nude mice with orthotopic tumors grown from human pancreatic cancer cell lines (AsPC-1 and BxPC-3); tumors were removed 8 days after cell injection and analyzed by histology. Mouse survival was analyzed by Kaplan-Meier curves. ZIP4 was knocked down in AsPC-1 and BxPC-3 cells with small hairpin RNAs; cells with empty vectors were used as controls. Muscle tissues were collected from mice and analyzed by histology and immunohistochemistry. Conditioned media from cell lines and 3-dimensional spheroid/organoid cultures of cancer cells were applied to C2C12 myotubes. The myotubes and the media were analyzed by immunoblots, enzyme-linked immunosorbent assays, and immunofluorescence microscopy. EVs were isolated from conditioned media and analyzed by immunoblots. RESULTS: Mice with orthotopic tumors grown from pancreatic cancer cells with knockdown of ZIP4 survived longer and lost less body weight and muscle mass than mice with control tumors. Conditioned media from cancer cells activated p38 MAPK, induced expression of F-box protein 32 and UBR2 in C2C12 myotubes, and also led to loss of myofibrillar protein myosin heavy chain and myotube thinning. Knockdown of ZIP4 in cancer cells reduced these effects. ZIP4 knockdown also reduced pancreatic cancer cell release of heat shock protein (HSP) 70 and HSP90, which are associated with EVs, by decreasing CREB-regulated expression of RAB27B. CONCLUSIONS: ZIP4 promotes growth of orthotopic pancreatic tumors in mice and loss of muscle mass by activating CREB-regulated expression of RAB27B, required for release of EVs from pancreatic cancer cells. These EVs activate p38 MAPK and induce expression of F-box protein 32 and UBR2 in myotubes, leading to loss of myofibrillar myosin heavy chain and myotube thinning. Strategies to disrupt these pathways might be developed to reduce pancreatic cancer progression and accompanying cachexia.

Safe implementation of minimally invasive pancreas resection: a systematic review.

BACKGROUND: Minimally invasive pancreas resection (MIPR) has been expanding in the past decade. Excellent outcomes have been reported, however, safety concerns exist. The aim of this study was to define prerequisites for performing MIPR with the objective to guide safe implementation of MIPR into clinical practice. METHODS: This systematic review was conducted as part of the 2019 Miami International Evidence-Based Guidelines on Minimally Invasive Pancreas Resection (IG-MIPR). PubMed, Embase and Cochrane databases were searched for literature concerning the implementation of MIPR between 1946 and November 2018. Quality assessment was according to The Scottish Intercollegiate Guidelines Network (SIGN). RESULTS: Overall, 1150 studies were screened, of which 32 studies with 8519 patients were included in this systematic review. Training programs for minimally invasive distal pancreatectomy, laparoscopic pancreatoduodenectomy and robotic pancreatoduodenectomy have been described with acceptable outcomes during the learning curve and improved outcomes after training. Learning curve studies have revealed an association between growing experience and improving perioperative outcomes. In addition, the association between higher center volume and lower mortality and morbidity has been reported by several studies. CONCLUSION: When embarking on MIPR, it is recommended to participate in a dedicated training program, to assure a sufficient volume, especially when implementing minimally invasive pancreatoduodenectomy, (20 procedures recommended annually), and prospectively collect and closely monitor outcomes for continuous quality assessment, this can be achieved through institutional databases and participation in national or international registries.

Comparing Short-term and Oncologic Outcomes of Minimally Invasive Versus Open Pancreaticoduodenectomy Across Low and High Volume Centers.

OBJECTIVE: To compare short-term and oncologic outcomes of patients with cancer who underwent open pancreaticoduodenectomy (OPD) versus minimally invasive pancreaticoduodenectomy (MIPD) using the National Cancer Database. SUMMARY BACKGROUND DATA: MIPD, including laparoscopic and robotic approaches, has continued to gain acceptance despite prior reports of increased short-term mortality when compared with OPD. METHODS: Patients with pancreatic cancer diagnosed from 2010 to 2015 undergoing curative intent resection were selected from the National Cancer Database. Patients submitted to OPD were compared with those submitted to MIPD. Laparoscopic and robotic approaches were included in the MIPD cohort. The primary outcome was 90-day mortality; secondary outcomes included 30-day mortality, hospital length of stay, unplanned 30-day readmission, surgical margins, number of lymph nodes harvested, and receipt of adjuvant chemotherapy. Propensity score-weighted random effects logistic regression models were used to examine the adjusted association between surgical approach and the specified outcomes. RESULTS: Between 2010 and 2015, 22,013 patients underwent OPD or MIPD for pancreatic cancer and 3754 (17.1%) were performed minimally invasively. On multivariable analysis, there was no difference in 90-day mortality between MIPD and OPD (OR, 0.92; 95% CI, 0.75-1.14). Patients undergoing MIPD were less likely to stay in the hospital for a prolonged time (OR, 0.75; 95% CI, 0.68-0.82). 30-day mortality, unplanned readmissions, margins, lymph nodes harvested, and receipt of adjuvant chemotherapy were equivalent between groups. Regardless of surgical approach, patients operated on at high volume centers had reduced 90-day mortality. CONCLUSION: Patients selected to receive MIPD for cancer have equivalent short-term and oncologic outcomes, when compared with patients who undergo OPD.

Quality of Life Following Major Laparoscopic or Open Pancreatic Resection.

PURPOSE: This study was designed to compare quality of life (QoL) among patients who underwent open versus laparoscopic pancreatic resection, including distal pancreatectomy and pancreaticoduodenectomy, and to identify clinical characteristics that are associated with changes in QoL. METHODS: Quality of life (QoL) was assessed in patients undergoing pancreatic resection with the Functional Assessment of Cancer Therapy-Hepatobiliary questionnaire preoperatively and 2 weeks, 1, 3, and 6 months postoperatively. Multilevel regression modeling was used to determine the variability in each QoL domain within the first 2 weeks (postoperative period) and thereafter (recovery period). RESULTS: Among 159 patients, 60.4% underwent open and 39.6% underwent laparoscopic surgery. Physical, functional, hepatobiliary, and total QoL scores decreased in the postoperative period but returned to baseline levels by 6 months postoperatively. Emotional QoL improved from baseline by 2 weeks after surgery (p < 0.001) and social QoL improved from baseline by 3 months after surgery (p < 0.001). Emotional QoL was the only domain where significant differences were observed in QoL in the postoperative and recovery periods between patients who underwent open and laparoscopic pancreatic resection. Controlling for surgical approach, patients who experienced a grade III or IV complication experienced greater declines in physical, functional, hepatobiliary, and total QoL in the postoperative period. The negative impact of complications on QoL resolved by 6 months postoperatively. CONCLUSIONS: The impact of pancreatic resection on QoL was comparable between patients who underwent laparoscopic versus open pancreatic resection. Complications were strongly associated with changes in postoperative QoL, suggesting that performing a safe operation is the best approach for optimizing patient reported QoL.

Cystic pancreatic neuroendocrine tumors: A distinctive subgroup with indolent biological behavior? A systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: The clinicopathological features and biological behaviors of cystic pancreatic neuroendocrine tumors (pNETs) are unclear and controversial. Here we performed a systematic review and meta-analysis to investigate the unique characteristics of cystic pNETs, to determine whether they represent a distinct clinical entity. METHODS: We selected comparative studies published since January 2000 that explore the differences between clinicopathological features of cystic and solid pNETs. Demographic information, pathological characteristics, and survival information were analyzed. RESULT: The 12 selected studies comprised 355 and 1530 patients diagnosed with cystic and solid pNETs, respectively. Compared with solid pNETs, cystic pNETs were less likely to be functional (odds ratio, OR = 0.31, 95% confidence interval (CI) 0.19-0.50, p < 0.00001), more likely to affect males (OR = 1.56, 95% CI 1.22-2.00, p = 0.0005), and significantly associated with multiple endocrine neoplasia type 1 (OR = 2.71). Cystic pNETs were more likely to present with G1 and G2 rather than G3 (OR = 1.66). Cystic pNETs were associated with less frequent distant organs and lymph node metastasis, microvascular invasion, perineural invasion, and a low Ki-67 index and mitotic count. There were no significant differences between 5- and 10-year overall survival. However, the 5-year disease-free survival (DFS) and 10-year DFS rate of patients with cystic pNETs was significantly higher compared with those with solid pNETs (94.6% vs 83.5%, OR = 3.00; 92.7% vs 63.6%, OR = 5.92, respectively). CONCLUSIONS: Cystic pNETs represent a distinct subgroup of pNETs that present with an indolent biological behavior, and patients experience better DFS. Observation and surveillance should be considered in some selected cases.

Perioperative outcomes and survival following neoadjuvant stereotactic body radiation therapy (SBRT) versus intensity-modulated radiation therapy (IMRT) in pancreatic adenocarcinoma.

BACKGROUND AND OBJECTIVES: To compare outcomes in patients receiving neoadjuvant stereotactic body radiation therapy (SBRT) with those receiving intensity-modulated radiation therapy (IMRT) for pancreatic adenocarcinoma. METHODS: We analyzed patients receiving neoadjuvant SBRT for borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC) (2012-2016). Differences in baseline characteristics, perioperative outcomes, progression-free survival (PFS), and overall survival (OS) were compared. RESULTS: Seventy-five (82.4%) patients received SBRT and 16 (17.6%) received IMRT. There were no differences in surgical resection rates in the SBRT (n = 38, 50.7%) and IMRT (n = 11, 68.8%) groups (P = 0.188). Among resected patients, there was no difference in postoperative outcomes or pathologic outcomes including lymph node status, margin status, lymphovascular and perineural invasion, or pathologic response to neoadjuvant treatment (P > 0.05). Among all patients, median PFS and OS were 9.9 and 23.5 months in the SBRT group, respectively, and 15.3 and 21.8 months in the IMRT group, respectively (P > 0.05). Similarly, there was no difference in PFS or OS between groups when stratified by BRPC, LAPC, and surgically resected patients (P > 0.05). CONCLUSIONS: In the neoadjuvant setting, SBRT and IMRT appear to have similar rates of resection, perioperative outcomes, and survival outcomes, but additional studies with increased sample size and longer follow up are needed.

Laparoscopic pancreaticoduodenectomy: changing the management of ampullary neoplasms.

BACKGROUND: The purpose of this study is to present the largest reported series comparing open pancreaticoduodenectomy (OPD) to total laparoscopic pancreaticoduodenectomy (TLPD) in patients with ampullary neoplasms. METHODS: Patients undergoing OPD or TLPD for ampullary neoplasms from June 2012 to August 2016 were retrospectively identified. Perioperative outcomes were compared using a Wilcoxon rank-sum test, Student's t test, and Chi square analysis where appropriate. Kaplan-Meier estimates for progression-free survival (PFS) and overall survival (OS) were compared between the groups using the log-rank test. RESULTS: We identified 47 patients with ampullary neoplasms (adenocarcinoma n = 36, neuroendocrine tumor n = 7, undifferentiated n = 1, adenoma n = 3) undergoing OPD (n = 25) and TLPD (n = 22). The proportion of patients being offered TLPD has progressively increased every year over 5 years: 0% (2012) to 50% (2015). There were no differences in baseline variables between the two groups. TLPD was associated with less blood loss (300 vs. 500 mL, p < 0.001) and shorter operative times (314 vs. 359 min, p = 0.024). No patient required conversion to an open procedure and there were no perioperative deaths in either group. TLPD was associated with lower rates of intra-abdominal abscess (0 vs. 16.0%, p = 0.049), but there were no differences in rates of pancreatic fistula, bile leak, delayed gastric emptying, wound infection, length of stay, and readmission (all p > 0.05). Among patients with adenocarcinoma, there was no difference in pathological features between the two groups (p > 0.05) and all patients had negative margins. At a median follow up of 25 months, there was no difference in PFS or OS between the two groups. CONCLUSIONS: TLPD in patients with ampullary neoplasms results in improved perioperative outcomes while having equivalent short and long-term oncologic outcomes compared to the traditional open approach.

Comparison of laparoscopic to open pancreaticoduodenectomy in elderly patients with pancreatic adenocarcinoma.

INTRODUCTION: The purpose of the study is to compare perioperative and survival outcomes in elderly patients undergoing laparoscopic pancreaticoduodenectomy (LPD) to those undergoing open pancreaticoduodenectomy (OPD). METHODS: Patients aged ≥ 75 years with pancreatic adenocarcinoma undergoing LPD or OPD were identified from the NCDB (2010-2013). Baseline characteristics and perioperative outcomes were compared using a χ 2 and Student's t test. The Kaplan-Meier method was used to generate survival curves, and differences were tested using a log-rank test. A multivariate cox proportional hazard model was applied to estimate the hazard ratio (HR) of LPD on overall survival (OS). RESULTS: We identified 1768 patients aged ≥ 75 years who underwent LPD (n = 248, 14.0%) or OPD (n = 1520, 86.0%). The majority of patients in the LPD group had their surgery at facilities performing less than 5 LPDs per year (n = 165, 66.5%). 90-day mortality was significantly lower in the LPD compared to the OPD (7.2 vs. 12.2%, p = 0.049). The laparoscopic conversion rate was 30% (n = 74) and was associated with higher readmission rates (13.5 vs. 8.1%), 30-day mortality (8.0 vs. 3.8%), and 90-day mortality (10.4 vs. 6.0%), but these did not reach statistical significance. Median OS was significantly longer in the LPD group (19.8 vs. 15.6 months, p = 0.022). After adjusting for patient and tumor-related characteristics, there was a trend towards improved survival in the LPD group (HR 0.85, 95% CI 0.69-1.03). CONCLUSION: The vast majority of the NCDB participating facilities perform less than 5 LPD cases per year, which was associated with an increased risk of perioperative mortality. Overall 90-day mortality was significantly lower in the LPD group and there was a trend towards improved OS in the LPD group compared to the OPD group after adjusting for patient and tumor-related characteristics. Studies with increased sample size and longer follow-up are needed before definitive conclusions can be made.

Perioperative and Survival Outcomes Following Neoadjuvant FOLFIRINOX versus Gemcitabine Abraxane in Patients with Pancreatic Adenocarcinoma.

CONTEXT: Neoadjuvant chemotherapy is increasingly used in borderline resectable and locally advanced pancreatic cancer to facilitate surgical resection. OBJECTIVE: To compare progression free survival and overall survival in patients receiving neoadjuvant FOLFIRINOX with those receiving gemcitabine/abraxane. DESIGN: Retrospective cohort study. SETTING: University of Colorado Hospital from 2012-2016. PARTICIPANTS: Patients with pancreatic adenocarcinoma. INTERVENTIONS: Neoadjuvant FOLFIRINOX or gemcitabine/abraxane. OUTCOME MEASURES: Perioperative outcomes, progression free survival, and overall survival were compared between groups. A multivariate Cox proportional hazard model was applied to evaluate survival outcomes. RESULTS: We identified 120 patients: 83 (69.2%) FOLFIRINOX and 37 (30.8%) gemcitabine/abraxane. The FOLIFRINOX group was younger and had a lower ECOG performance status (p<0.05). Patients in the FOLFIRINOX group were more likely to undergo surgical resection compared to gemcitabine/abraxane (66.3% vs. 32.4%, p=0.002). Among all patients, median follow up was 16.9 months and FOLFIRINOX was associated with improved PFS (15.3 vs. 8.2 months, p=0.006), but not overall survival (23.5 vs. 18.7 months, p=0.228). In these patients, insulin-dependent diabetes was associated with a worse progression free survival and overall survival and surgical resection was protective. Among surgically resected patients, median follow up was 21.1 months and there was no difference in progression free survival (19.5 vs. 15.1 months) or overall survival (27.4 vs. 19.8 months) between the FOLFIRINOX and gemcitabine/abraxane groups, respectively (p>0.05). Insulin-dependent diabetes and a poor-to-moderate pathologic response was associated with worse progression free survival and overall survival. CONCLUSION: Neoadjuvant FOLFIRINOX may improve progression free survival by increasing the proportion of patients undergoing surgical resection. Improved understanding of the role for selection bias and longer follow up are needed to better define the impact of neoadjuvant FOLFIRINOX on overall survival.

Blockade of CD112R and TIGIT signaling sensitizes human natural killer cell functions.

Trastuzumab is the first-line drug to treat breast cancer with high Her2 expression. However, many cancers failed to respond, largely due to their resistance to NK cell-triggered antibody-dependent cellular cytotoxicity (ADCC). Poliovirus receptor (PVR)-like molecules are known to be important for lymphocyte functions. We found that all PVR-like receptors are expressed on human NK cells, and only TIGIT is preferentially expressed on the CD16+ NK cell subset. Disrupting the interactions of PVR-like receptors with their ligands on cancer cells regulates NK cell activity. More importantly, TIGIT is upregulated upon NK cell activation via ADCC. Blockade of TIGIT or CD112R, separately or together, enhances trastuzumab-triggered antitumor response by human NK cells. Thus, our findings suggest that PVR-like receptors regulate NK cell functions and can be targeted for improving trastuzumab therapy for breast cancer.

Laparoscopic Spleen-Preserving Total Pancreatectomy for a Main-Duct Intraductal Papillary Mucinous Neoplasm.

INTRODUCTION: Main-duct intraductal papillary mucinous neoplasms of the pancreas (M-IPMN) are potentially malignant cystic neoplasms that can degenerate into invasive malignancy in 43 % of cases.1 Although laparoscopic pancreaticoduodenectomy and distal pancreatectomy have been previously described for the management of pancreatic neoplasms, laparoscopic total pancreatectomy is rarely described. We present a video demonstrating a laparoscopic spleen-preserving total pancreatectomy in a patient with M-IPMN. CASE PRESENTATION: A healthy 66-year-old male was diagnosed with recurrent pancreatitis. A computed tomography of the abdomen demonstrated a diffusely dilated pancreatic duct (10 mm) and a 5 mm mural nodule in the neck of the pancreas. Endoscopic retrograde cholangiopancreatography demonstrated a 'fish mouth' appearance at the major papilla, with a villous mass (15 mm) in the pancreatic head. Biopsy was consistent with M-IPMN, and tumor markers were normal. RESULTS: A spleen-preserving laparoscopic total pancreatectomy was performed over a period of 270 min, with 150 cc of blood loss without complications. The patient was admitted to the intensive care unit for continuous insulin infusion. On postoperative day (POD) 1, his nasogastric tube was discontinued, transitioned to subcutaneous insulin injections, and transferred to the floor. He tolerated a diabetic diet on POD 4. His surgical drain had minimal output with no evidence of a bile leak, and was discontinued on POD 5. The patient's hospital course was uncomplicated and he was discharged home on POD 7. Pathology demonstrated IPMN with moderate dysplasia. CONCLUSION: Laparoscopic total pancreatectomy can be safely performed in patients with M-IPMN. This video presentation describes the technique we used for this procedure.

Is Chemical Pyloroplasty Necessary for Minimally Invasive Esophagectomy?

BACKGROUND: Many centers use botulinum toxin for chemical pyloroplasty in minimally invasive esophagectomies as prophylaxis against delayed gastric emptying. No previous studies have compared botulinum toxin injection with no pyloric intervention for patients treated with a combined laparoscopic and thoracoscopic approach. The authors hypothesized that chemical pyloroplasty does not improve outcomes for these patients. METHODS: The study investigated patients undergoing minimally invasive esophagectomies from September 2009 to June 2015. Delayed gastric emptying was defined as inability to tolerate a soft diet by postoperative day 10, as corroborated by esophagram, upper endoscopy, or both. Data were compared using Student's t test, χ 2 analysis, and Mann-Whitney U test where appropriate. RESULTS: The study identified 71 patients treated with minimally invasive esophagectomy: 35 patients with chemical pyloroplasty treated from September 2009 to January 2014 and 36 patients without pyloric intervention from February 2014 to June 2015. The groups were statistically similar in age, gender distribution, T stage, percentage of patients receiving neoadjuvant therapy, body mass index, preoperative weight loss, preoperative serum albumin, and preoperative placement of feeding tubes (all p > 0.05). The overall incidence of delayed gastric emptying was low in both groups: 8.6% (3/35) of the patients with chemical pyloroplasty versus 5.6% (2/36) of the patients with no pyloric intervention (p = 0.62). The two groups also did not differ significantly in the development of aspiration pneumonia or the need for pyloric intervention. CONCLUSIONS: In a well-matched cohort study with a historical control group, use of botulinum toxin for chemical pyloroplasty in minimally invasive esophagectomies was not associated with improved outcomes related to the pylorus versus no pyloric intervention. Although preliminary, these data suggest that chemical pyloroplasty is not necessary in minimally invasive esophagectomy.

A combination of molecular markers and clinical features improve the classification of pancreatic cysts.

BACKGROUND & AIMS: The management of pancreatic cysts poses challenges to both patients and their physicians. We investigated whether a combination of molecular markers and clinical information could improve the classification of pancreatic cysts and management of patients. METHODS: We performed a multi-center, retrospective study of 130 patients with resected pancreatic cystic neoplasms (12 serous cystadenomas, 10 solid pseudopapillary neoplasms, 12 mucinous cystic neoplasms, and 96 intraductal papillary mucinous neoplasms). Cyst fluid was analyzed to identify subtle mutations in genes known to be mutated in pancreatic cysts (BRAF, CDKN2A, CTNNB1, GNAS, KRAS, NRAS, PIK3CA, RNF43, SMAD4, TP53, and VHL); to identify loss of heterozygozity at CDKN2A, RNF43, SMAD4, TP53, and VHL tumor suppressor loci; and to identify aneuploidy. The analyses were performed using specialized technologies for implementing and interpreting massively parallel sequencing data acquisition. An algorithm was used to select markers that could classify cyst type and grade. The accuracy of the molecular markers was compared with that of clinical markers and a combination of molecular and clinical markers. RESULTS: We identified molecular markers and clinical features that classified cyst type with 90%-100% sensitivity and 92%-98% specificity. The molecular marker panel correctly identified 67 of the 74 patients who did not require surgery and could, therefore, reduce the number of unnecessary operations by 91%. CONCLUSIONS: We identified a panel of molecular markers and clinical features that show promise for the accurate classification of cystic neoplasms of the pancreas and identification of cysts that require surgery.

Evolving Trends Towards Minimally Invasive Surgery for Solid-Pseudopapillary Neoplasms.

BACKGROUND: Solid-pseudopapillary neoplasms are rare pancreatic neoplasms with low malignant potential that predominantly arise in young women. We sought to characterize this population and the evolving trend at our institution towards laparoscopic management. METHODS: We identified all patients at our institution that were surgically treated for solid-pseudopapillary neoplasm from 2008-2015. Demographic and clinical information were queried from the medical record, and descriptive statistics were performed. Student's t test and chi-square analysis were used for comparison where appropriate. RESULTS: We identified 11 women and 1 man (average age 26 years; range 14-48 years) who were surgically treated for solid-pseudopapillary neoplasms; 5 with distal pancreatectomy (4 open, 1 laparoscopic), 6 with pancreaticoduodenectomy (3 open, 3 laparoscopic), and 1 open enucleation. From 2008 to 2013, seven of eight (87 %) procedures were performed open. Since 2014, three of four (75 %) procedures have successfully been completed laparoscopically (see video clips). Length of stay was similar for patients who had open versus laparoscopic procedures (8 vs. 9 days, p = 0.61). Two-thirds of patients (5/8) who had open procedures experienced postoperative complications compared with half (2/4) of patients who had laparoscopic procedures (p = 0.28). There have been no recurrences. CONCLUSIONS: Minimally invasive surgical management of solid-pseudopapillary neoplasms is becoming more popular, can be performed safely, and appears to have comparable outcomes to an open approach. Quality of life is an important metric for this relatively young population and may be improved with a laparoscopic approach, which warrants further investigation.

The Multidisciplinary Approach to GI Cancer Results in Change of Diagnosis and Management of Patients. Multidisciplinary Care Impacts Diagnosis and Management of Patients.

BACKGROUND: The multidisciplinary approach to GI cancer is becoming more widespread as a result of multimodality therapy. At the University of Colorado Hospital (UCH), we utilize a formal multidisciplinary approach through specialized clinics across a variety of settings, including pancreas and biliary cancer, esophageal and gastric cancer, liver cancer and neuroendocrine tumors (NET), and colorectal cancer. Patients with these suspected diagnoses are seen in a multidisciplinary clinic. We evaluated whether implementation of disease-specific multidisciplinary programs resulted in a change in diagnosis and/or change in management for these patients. METHODS: Data from 1747 patients were prospectively collected from inception of each multidisciplinary program through December 31, 2015. Change in diagnosis was defined as a change in radiographic or endoscopic findings that resulted in a change in cancer stage or clinical diagnosis and/or a change in pathologic diagnosis. Reports of incidental findings unrelated to primary diagnosis on radiographic evaluation were also assessed, but not included in overall change in diagnosis findings. We further evaluated if patients had a change in the management of their disease compared with outside recommendations. RESULTS: Of 1747 patients evaluated, change occurred in 38 % (pancreas and biliary), 13 % (esophageal and gastric); 22 % (liver and NET), and 16 % (colorectal). Change in management for each multidisciplinary program occurred in 35 % (pancreas and biliary), 20 % (esophageal and gastric), 27 % (liver and NET), and 13 % (colorectal). CONCLUSIONS: The use of a multidisciplinary clinic to manage GI cancer has a substantial impact in change in diagnosis and/or management in more than one-third of patients evaluated.