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Targeted therapy with a tyrosine kinase inhibitor (TKI) such as imatinib is effective in treating gastrointestinal stromal tumor (GIST), but it is rarely curative. Despite the presence of a robust immune CD8+ T-cell infiltrate, combining a TKI with immune-checkpoint blockade (ICB) in advanced GIST has achieved only modest effects. To identify limitations imposed by imatinib on the antitumor immune response, we performed bulk RNA sequencing (RNA-seq), single-cell RNA-seq, and flow cytometry to phenotype CD8+ T-cell subsets in a genetically engineered mouse model of GIST. Imatinib reduced the frequency of effector CD8+ T cells and increased the frequency of naïve CD8+ T cells within mouse GIST, which coincided with altered tumor chemokine production, CD8+ T-cell recruitment, and reduced CD8+ T-cell intracellular PI3K signaling. Imatinib also failed to induce intratumoral T-cell receptor (TCR) clonal expansion. Consistent with these findings, human GISTs sensitive to imatinib harbored fewer effector CD8+ T cells but more naïve CD8+ T cells. Combining an IL15 superagonist (IL15SA) with imatinib restored intratumoral effector CD8+ T-cell function and CD8+ T-cell intracellular PI3K signaling, resulting in greater tumor destruction. Combination therapy with IL15SA and ICB resulted in the greatest tumor killing and maintained an effector CD8+ T-cell population in the presence of imatinib. Our findings highlight the impact of oncogene inhibition on intratumoral CD8+ T cells and support the use of agonistic T-cell therapy during TKI and/or ICB administration.

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Group 2 innate lymphoid cells (ILC2s) regulate inflammation and immunity in mammalian tissues1,2. Although ILC2s are found in cancers of these tissues3, their roles in cancer immunity and immunotherapy are unclear. Here we show that ILC2s infiltrate pancreatic ductal adenocarcinomas (PDACs) to activate tissue-specific tumour immunity. Interleukin-33 (IL33) activates tumour ILC2s (TILC2s) and CD8+ T cells in orthotopic pancreatic tumours but not heterotopic skin tumours in mice to restrict pancreas-specific tumour growth. Resting and activated TILC2s express the inhibitory checkpoint receptor PD-1. Antibody-mediated PD-1 blockade relieves ILC2 cell-intrinsic PD-1 inhibition to expand TILC2s, augment anti-tumour immunity, and enhance tumour control, identifying activated TILC2s as targets of anti-PD-1 immunotherapy. Finally, both PD-1+ TILC2s and PD-1+ T cells are present in most human PDACs. Our results identify ILC2s as anti-cancer immune cells for PDAC immunotherapy. More broadly, ILC2s emerge as tissue-specific enhancers of cancer immunity that amplify the efficacy of anti-PD-1 immunotherapy. As ILC2s and T cells co-exist in human cancers and share stimulatory and inhibitory pathways, immunotherapeutic strategies to collectively target anti-cancer ILC2s and T cells may be broadly applicable.

Type I IFNs are implicated in tumor immunogenicity and response to systemic therapy, but their interaction with oncogene signaling is not well understood. Here, we studied oncogenic KIT, which drives gastrointestinal stromal tumor (GIST), the most common sarcoma. Using mouse models of GIST, we found that KIT inhibition reduced type I IFN production and signaling, which downregulated tumor MHC class I expression. Absence of type I IFN signaling increased tumor size, in part due to CD8+ T-cell impairment. Oncogenic KIT was required for GIST type I IFN signal transduction via STAT1. In human GIST cell lines and surgical specimens, type I IFN signaling contributed to human lymphocyte antigen class I expression and correlated with tumor immunogenicity. Augmenting the type I IFN response partially compensated for the immunosuppressive effects of KIT inhibition. Thus, KIT signaling contributes to type I IFN signaling, whereas KIT inhibition attenuates tumor immunogenicity and is partly rescued by innate immune stimulation. See related Spotlight on p. 489

Management of gastrointestinal stromal tumors (GISTs) has been revolutionized by the identification of activating mutations in KIT and PDGFRA and clinical application of RTK inhibitors in advanced disease. Stratification of GISTs into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in most GISTs, resistance remains a significant clinical problem. Development of effective treatment strategies for refractory GISTs requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases essential in GISTs. Using multiplexed inhibitor beads and mass spectrometry, we explored the majority of the kinome in GIST specimens from the 3 most common molecular subtypes (KIT mutant, PDGFRA mutant, and succinate dehydrogenase deficient) to identify kinase targets. Kinome profiling with loss-of-function assays identified an important role for G2/M tyrosine kinase, Wee1, in GIST cell survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in KIT mutant and PDGFRA mutant GIST cell lines as well as notable efficacy of MK-1775 as a monotherapy in the engineered PDGFRA mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.

Background Pancreatic metastases (PM) from renal cell carcinoma (RCC) are uncommon. We herein describe the long-term outcomes associated with pancreatectomy at two academic institutions, with a specific focus on 10-year survival. Methods This investigation was limited to patients undergoing pancreatectomy for PM between 2000 and 2008 at the University of Verona and Memorial Sloan Kettering Cancer Center, allowing a potential for 10 years of surveillance. The probabilities of further RCC recurrence and RCC-related death were estimated using a competing risk analysis (method of Fine and Gray) to account for patients who died of other causes during follow-up. Results The study population consisted of 69 patients, mostly with isolated metachronous PM (77%). The median interval from nephrectomy to pancreatic metastasectomy was 109 months, whereas the median post-pancreatectomy follow-up was 141 months. The 10-year cumulative incidence of new RCC recurrence was 62.7%. In the adjusted analysis, the relative risk of repeated recurrence was significantly higher in PM synchronous to the primary RCC (sHR = 1.27) and in patients receiving extended pancreatectomy (sHR = 3.05). The 10-year cumulative incidence of disease-specific death was 25.5%. The only variable with an influence on disease-specific death was the recurrence-free interval following metastasectomy (sHR = 0.98). In patients with repeated recurrence, the 10-year cumulative incidence of RCC-related death was 35.4%. Conclusion In a selected group of patients followed for a median of 141 months and mostly with isolated metachronous PM, resection was associated with a high possibility of long-term disease control in surgically fit patients with metastases confined to the pancreas.

Background The COVID-19 outbreak has spread worldwide and has resulted in hospital restrictions. The perceived impact of these practices on patients undergoing essential surgeries is less understood. Methods Adult (≥18 years) patients who underwent medically-necessary surgical procedures spanning multiple surgical specialties from March 23, 2020 to April 24, 2020 during the COVID-19 pandemic were identified as eligible for a phone survey. Survey responses were analyzed using a mixed-methods approach involving descriptive statistics and thematic analysis of coded and annotated survey results. Results Of the 212 patients who underwent medically-necessary surgical procedures during the COVID-19 pandemic, the majority of these patients were male (61.3%), White (83.5%), married or with a domestic partner (68.9%), and underwent oncologic procedures (69.3%). Of the 46 (21.7%) patients who completed the survey, the majority of these patients indicated that COVID-19 pandemic restrictions had no impact on their inpatient hospital stay and were satisfied with their decision to proceed with surgery. Severity of patient condition (44.4%), the risk/benefit discussion with the surgeon (24.4%), and COVID-19 education and testing (19.5%) were the most important factors in proceeding with surgery during the pandemic; 34.4% of patients felt their inpatient postoperative course was negatively impacted by the lack of visitors. Conclusion Medically-necessary, time-sensitive surgical procedures, as determined by the surgeon, can be performed during a pandemic with good patient satisfaction provided there is an appropriate discussion between the surgeon and patient about the risks and benefits., The COVID-19 outbreak has resulted in hospital restrictions that have decreased operative censuses and altered the surgical experience, but the perceived impact of these practices on patients undergoing medically-necessary surgeries is less understood. The importance of this study was to portray patients’ perceptions of their perioperative experience given the pandemic restrictions by administering a phone survey to those patients undergoing medically-necessary surgical procedures during the pandemic

Objective To test the degree of agreement in selecting therapeutic options for patients suffering from colorectal liver metastasis (CRLM) among surgical experts around the globe. Summary/background Only few areas in medicine have seen so many novel therapeutic options over the past decades as for liver tumors. Significant variations may therefore exist regarding the choices of treatment, even among experts, which may confuse both the medical community and patients. Methods Ten cases of CRLM with different levels of complexity were presented to 43 expert liver surgeons from 23 countries and 4 continents. Experts were defined as experienced surgeons with academic contributions to the field of liver tumors. Experts provided information on their medical education and current practice in liver surgery and transplantation. Using an online platform, they chose their strategy in treating each case from defined multiple choices with added comments. Inter-rater agreement among experts and cases was calculated using free-marginal multirater kappa methodology. A similar, but adjusted survey was presented to 60 general surgeons from Asia, Europe, and North America to test their attitude in treating or referring complex patients to expert centers. Results Thirty-eight (88%) experts completed the evaluation. Most of them are in leading positions (92%) with a median clinical experience of 25 years. Agreement on therapeutic strategies among them was none to minimal in more than half of the cases with kappa varying from 0.00 to 0.39. Many general surgeons may not refer the complex cases to expert centers, including in Europe, where they also engage in complex liver surgeries. Conclusions Considerable inconsistencies of decision-making exist among expert surgeons when choosing a therapeutic strategy for CRLM. This might confuse both patients and referring physicians and indicate that an international high-level consensus statements and widely accepted guidelines are needed.

Rectal cancer (RC) is a challenging disease to treat that requires chemotherapy, radiation, and surgery to optimize outcomes for individual patients. No accurate model of RC exists to answer fundamental research questions relevant to patients. We established a biorepository of 65 patient-derived RC organoid cultures (tumoroids) from patients with primary, metastatic, or recurrent disease. RC tumoroids retained molecular features of the tumors from which they were derived, and their ex vivo responses to clinically relevant chemotherapy and radiation treatment correlated with the clinical responses noted in individual patients’ tumors. Upon engraftment into murine rectal mucosa, human RC tumoroids gave rise to invasive RC followed by metastasis to lung and liver. Importantly, engrafted tumors displayed the heterogenous sensitivity to chemotherapy observed clinically. Thus, the biology and drug sensitivity of RC clinical isolates can be efficiently interrogated using an organoid-based, ex vivo platform coupled with in vivo endoluminal propagation in animals.

BACKGROUND: Organ-specific complications (OSC) remain serious potential sequela of gastrointestinal surgery. Hypophosphatemia correlates with poor outcomes and may be a harbinger of OSC after gastrointestinal surgery. Our goal was to describe and evaluate the relationship between postoperative phosphate levels and OSC. METHODS: Consecutive patients who underwent pancreatic, colorectal, or gastric resections were analyzed. OSC were defined as those resulting from failure of at least one anastomosis performed during the primary resection, manifesting as an anastomotic leak, fistula, and/or intra-abdominal abscess. Postoperative serum phosphate levels and other recognized OSC risk factors were compared among patients who did and did not develop OSC. RESULTS: A total of 8034 patients who underwent pancreatic (n=397), colorectal (n=5808), or gastric (n=1829) resections were included in the study. In each resection group, the majority of patients experienced hypophosphatemia post-resection with the nadir on postoperative day (POD) 2, and the subgroups that developed OSC exhibited lower phosphate levels on POD3–7. On multivariate analysis, lower phosphate level on POD3 remained significantly associated with OSC following pancreatic resection (median [interquartile range] mmol/L, 0.65 [0.53–0.76] vs. 0.71 [0.61–0.84], p=0.045) and colorectal resection (0.71 [0.61–0.87] vs 0.77 [0.65–0.94], p=0.006), and lower phosphate level on POD4 remained associated with OSC following gastric resection (0.87 [0.74–1.03] vs 0.96 [0.81–1.13], p=0.049). CONCLUSION: This study identified a consistent trajectory of serum phosphate levels following 3 different gastrointestinal operations and association between early postoperative phosphate levels and OSC. Persistent lower phosphate levels should raise level of concern for evolving postoperative leak and may lead to earlier radiographic evaluation and treatment.

Liver resection can be curative for well-selected metastatic colorectal cancer (CRC) patients. Circulating tumor DNA (ctDNA) has shown promise as a biomarker for tumor dynamics and recurrence following CRC resection. This prospective pilot study investigated the use of ctDNA to predict disease outcome in resected CRC patients. Between November 2014 and November 2015, 60 patients with CRC were identified and prospectively enrolled. During liver resection, blood was drawn from peripheral (PERIPH), portal (PV), and hepatic (HV) veins, and 3–4 weeks postoperatively from a peripheral vein (POSTOP). Kappa statistics were used to compare mutated (mt) genes in tissue and ctDNA. Disease-specific and disease-free survival (DSS and DFS) were assessed from surgery with Kaplan–Meier and Cox methods. For the 59 eligible patients, the most commonly mutated genes were TP53 (mtTP53: 47.5%) and APC (mtAPC: 50.8%). Substantial to almost-perfect agreement was seen between ctDNA from PERIPH and PV (mtTP53: 89.8%, κ = 0.73, 95% confidence interval [CI] 0.53–0.93; mtAPC: 94.9%, κ = 0.83, 95% CI 0.64–1.00), as well as HV (mtTP53: 91.5%, κ = 0.78, 95% CI 0.60–0.96; mtAPC: 91.5%, κ = 0.73, 95% CI 0.51–0.95). Tumor mutations and PERIPH ctDNA had fair-to-moderate agreement (mtTP53: 72.9%, κ = 0.44, 95% CI 0.23–0.66; mtAPC: 61.0%, κ = 0.23, 95% CI 0.04–0.42). Detection of PERIPH mtTP53 was associated with worse 2-year DSS (mt+ 79% vs. mt− 90%, P = 0.024). Peripheral blood reflects the perihepatic ctDNA signature. Disagreement between tissue and ctDNA mutations may reflect the true natural history of tumor genes or an assay limitation. Peripheral ctDNA detection before liver resection is associated with worse DSS.

BACKGROUND: Colorectal liver metastases that demonstrate a complete radiographic response during chemotherapy are increasingly common with advances in chemotherapy regimens and are described as disappearing liver metastases (DLMs). However, these DLMs often continue to harbor residual viable tumor. If these tumors are found in the operating room with ultrasound (US), they should be treated. The intraoperative sonographic visualization of these lesions, however, can be hindered by chemotherapy-associated liver parenchyma changes. The objective of this study was to evaluate the use of an intraoperative image guidance system, Explorer (Analogic Corporation, Peabody, MA), to aid surgeons in the identification of DLMs initially undetected by US alone. STUDY DESIGN: In a single-arm prospective trial, patients with colorectal liver metastases undergoing liver resection and/or ablation with one or more DLMs during neoadjuvant chemotherapy were enrolled. Intraoperatively, DLMs were localized with conventional US. Any DLM not found by conventional US was re-evaluated with the image guidance system. The primary outcome was the proportion of sonographically occult DLMs subsequently located by image-guided US. RESULTS: Between April 2016 and November 2017, 25 patients with 61 DLMs were enrolled. Thirty-eight DLMs (62%) in 14 patients (56%) were not identified with US alone. Six (16%) DLMs in five patients (36%) were subsequently located with assistance of the image guidance system. The image guidance changed the intraoperative surgical plan in four of these patients. CONCLUSIONS: Image guidance can aid surgeons in the identification of initially sonographically occult DLMs and facilitate the complete surgical clearance of all sites of liver disease.

OBJECTIVE: Preliminary work by our group suggested that proteins within the pancreatic cyst fluid (CF) may discriminate degree of IPMN dysplasia. We sought to externally validate these markers, and determine if their inclusion in a pre-operative clinical nomogram could increase diagnostic accuracy. SUMMARY BACKGROUND DATA: IPMN is the most common radiographically identifiable precursor to pancreatic cancer, however, the timing and frequency of its malignant progression is unknown, and there are currently no reliable pre-operative tests that can determine the grade of dysplasia in IPMN. METHODS: Clinical and radiographic data, as well as CF samples, were obtained from 149 patients who underwent resection for IPMN at one of three institutions. High-risk disease was defined as the presence of high-grade dysplasia or invasive carcinoma. Multianalyte bead array analysis (Luminex) of CF was performed for four protein markers that were previously associated with high-risk disease. Logistic regression models were fit on training data, with and without adjustment for a previously developed clinical nomogram, and validated with an external testing set. The models incorporating clinical risk score were presented graphically as nomograms. RESULTS: Within the group of 149 resected patients, 89 (60%) had low-risk disease, and 60 (40%) had high-risk disease. All four CF markers (MMP9, CA72-4, sFASL and IL-4) were over-expressed in patients with high-risk IPMN (p

BACKGROUND. Pancreatic cancer is a highly lethal cancer with no established a priori markers of survival. Existing nomograms rely mainly on post-resection data and are of limited utility in directing surgical management. This study investigated the use of quantitative computed tomography (CT) features to preoperatively assess survival for pancreatic ductal adenocarcinoma (PDAC) patients. METHODS. A prospectively maintained database identified consecutive chemotherapy-naive patients with CT angiography and resected PDAC between 2009 and 2012. Variation in CT enhancement patterns was extracted from the tumor region using texture analysis, a quantitative image analysis tool previously described in the literature. Two continuous survival models were constructed, with 70% of the data (training set) using Cox regression, first based only on preoperative serum cancer antigen (CA) 19–9 levels and image features (model A), and then on CA19–9, image features, and the Brennan score (composite pathology score; model B). The remaining 30% of the data (test set) were reserved for independent validation. RESULTS. A total of 161 patients were included in the analysis. Training and test sets contained 113 and 48 patients, respectively. Quantitative image features combined with CA19–9 achieved a c-index of 0.69 [integrated Brier score (IBS) 0.224] on the test data, while combining CA19–9, imaging, and the Brennan score achieved a c-index of 0.74 (IBS 0.200) on the test data. CONCLUSION. We present two continuous survival prediction models for resected PDAC patients. Quantitative analysis of CT texture features is associated with overall survival. Further work includes applying the model to an external dataset to increase the sample size for training and to determine its applicability.

Background Exosomes are nanovesicles that have been shown to mediate carcinogenesis in pancreatic ductal adenocarcinoma (PDAC). Given the direct communication of pancreatic duct fluid with the tumor and its relative accessibility, we aimed to determine the feasibility of isolating and characterizing exosomes from pancreatic duct fluid. Methods Pancreatic duct fluid was collected from 26 patients with PDAC (n = 13), intraductal papillary mucinous neoplasm (IPMN) (n = 8) and other benign pancreatic diseases (n = 5) at resection. Exosomes were isolated by serial ultracentrifugation, proteins were identified by mass spectrometry, and their expression was evaluated by immunohistochemistry. Results Exosomes were isolated from all specimens with a mean concentration of 5.9 ± 1 × 108 particles/mL and most frequent size of 138 ± 9 nm. Among the top 35 proteins that were significantly associated with PDAC, multiple carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) and extracellular matrix (ECM) proteins were identified. Interestingly, CEACAM 1/5 expression by immunohistochemistry was seen only on tumor epithelia whereas tenascin C positivity was restricted to stroma, suggesting that both tumor and stromal cells contributed to exosomes. Conclusion This is the first study showing that exosome isolation is feasible from pancreatic duct fluid, and that exosomal proteins may be utilized to diagnose patients with PDAC.

BACKGROUND: Many patients with resectable perihilar cholangiocarcinoma (PHC) on imaging are intra-operatively diagnosed with occult metastatic or locally advanced disease precluding a curative-intent resection. This study aimed to develop and validate a preoperative risk score. STUDY DESIGN: Patients with resectable PHC on imaging who underwent surgery in two high-volume centers (USA and Europe) between 2000 and 2015 were included. Multivariable logistic regression analysis was used to develop the risk score. Cross-validation was used to validate the score, alternating the two centers as ‘training’ and ‘testing’ dataset. RESULTS: Of 566 patients who underwent surgery 309 patients (55%) underwent a resection, while in 257 patients (45%) a curative-intent resection was precluded due to distant metastasis (n=151; 27%) or locally advanced disease (n=106; 19%). Preoperative predictors included bilirubin above 2 mg/dL, bile duct involvement on imaging, portal vein involvement on imaging (≥ 180 degrees), hepatic artery involvement on imaging (≥ 180 degrees), and suspicious lymph nodes on imaging. The new risk score (c-index 0.75 after cross-validation) provided significantly more accurate predictions than the Bismuth classification (c-index 0.62), Blumgart T-staging (c-index 0.67), and cTNM staging (c-index 0.68). The new risk score identified four risk groups for occult metastatic or locally advanced disease: low (14.7%), intermediate (29.5%), high (47.3%), and very high risk (81.3%). The preoperative score groups also predicted survival after surgery, irrespective of intra-operative findings (P

Background Hepatocellular adenomas (HCA) are benign liver tumors that may transform into hepatocellular carcinoma (HCC), but the molecular drivers of this transformation remain ill-defined. This study evaluates the molecular changes in HCA and HCC and in comparison to their adjacent non-neoplastic liver. Methods 11 patients with HCA and 10 patients with HCC without underlying hepatitis or cirrhosis were included in this pilot study. Tumor and non-tumor liver tissues were selected for immunohistochemical staining, small RNA sequencing, and targeted gene sequencing. We compared microRNA expressions and mutations between HCA and HCC and non-neoplastic liver. Results HCA were classified as inflammatory (n = 6), steatotic (n = 4), or β-catenin activated (n = 1) subtypes. MicroRNA profile of all 3 HCA subtypes clustered between that of normal liver and HCC in principal component analysis. In both HCA and HCC, miR-200a, miR-429, and miR-490-3p were significantly downregulated compared to normal liver, whereas miR-452, miR-766, and miR-1180 were significantly upregulated. In addition, compared to HCA, HCC had significantly higher expression of members of the chromosome 19 miRNA cluster (C19MC), including miR-515-5p, miR-517a, miR-518b, and miR-520c-3p. Conclusions This study indicates that while there are significant differences in the molecular profile between HCA and HCC, several miRNAs are similarly deregulated in HCA and HCC compared to adjacent normal liver. These results may provide insights into the drivers of hepatocarcinogenesis and warrant further investigations.

Purpose: Imatinib dramatically reduces gastrointestinal stromal tumor (GIST) 18F-FDG uptake, providing an early indicator of treatment response. Despite decreased glucose internalization, many GIST cells persist, suggesting that alternative metabolic pathways are used for survival. The role of mitochondria in imatinib-treated GIST is largely unknown. Experimental Design: We quantified the metabolic activity of several human GIST cell lines. We treated human GIST xenografts and genetically engineered KitV558del/+ mice with the mitochondrial oxidative phosphorylation inhibitor VLX600 in combination with imatinib and analyzed tumor volume, weight, histology, molecular signaling, and cell cycle activity. In vitro assays on human GIST cell lines were also performed. Results: Imatinib therapy decreased glucose uptake and downstream glycolytic activity in GIST-T1 and HG129 cells by approximately half and upregulated mitochondrial enzymes and improved mitochondrial respiratory capacity. Mitochondrial inhibition with VLX600 had a direct antitumor effect in vitro while appearing to promote glycolysis through increased AKT signaling and glucose transporter expression. When combined with imatinib, VLX600 prevented imatinib-induced cell cycle escape and reduced p27 expression, leading to increased apoptosis when compared to imatinib alone. In KitV558del/+ mice, VLX600 alone did not induce tumor cell death, but had a profound antitumor effect when combined with imatinib. Conclusions: Our findings show that imatinib alters the metabolic phenotype of GIST, and this may contribute to imatinib resistance. Our work offers preclinical proof of concept of metabolic targeting as an effective strategy for the treatment of GIST. Clin Cancer Res; 24(4); 972–84. ©2017 AACR.

BACKGROUND/OBJECTIVES: Combination hepatic artery infusion (HAI) and systemic (SYS) chemotherapy for unresectable CRLM results in high tumor-response rates. This study represents an update of long-term survival and conversion to resectability in patients with unresectable CRLM treated with HAI and SYS chemotherapy in a phase II study. METHOD: The primary endpoint was complete resection. Multivariate and landmark analysis assessed the effect of complete resection on progression-free (PFS) and overall survival (OS). RESULTS: From 2007 to 2012, 64 patients with median of 13 tumors were enrolled; 67% had prior chemotherapy. 33 patients (52%) were converted to resection. Median follow-up among survivors was 81 months. Median PFS and OS were 13 and 38 months, respectively, with 5-year-OS of 36%. Chemotherapy-naïve patients had 5-year-OS of 51%. Conversion to resection was the only independent factor prognostic of improved PFS and OS. Nine of 64 patients (14%) are NED (5 since initial resection, 3 after resection of recurrent disease, 1 from chemotherapy alone) at median follow-up of 86 months from treatment initiation, and 72 months from last operative intervention. CONCLUSION: Combination HAI and SYS is an effective therapy for high-volume unresectable CRLM, resulting in a high rate of resection, long-term survival and the potential for cure. TRIAL REGISTRATION: #NCT00492999, https://clinicaltrials.gov/ct2/show/NCT00492999

The aim of this study was to evaluate the outcome of patients presumed to have mucinous cysts of the pancreas who were initially selected for radiographic surveillance. Patients with a pancreatic cyst and a measured cyst fluid carcinoembryonic antigen (CEA) ≥192 ng/mL were included. Patients were stratified by those who underwent initial resection and those who were recommended for radiographic surveillance. The natural history of these two groups was examined. From 1999 to 2014, 227 patients were identified who had a cyst fluid CEA ≥192 ng/mL (median 961, range 192–300,000 ng/mL). Immediate resection was performed on 63 patients (28%). Initial radiographic surveillance was recommended for 164 patients; 87% did not have main pancreatic duct dilation, and 87% met consensus criteria for radiographic surveillance. After a median follow-up of 56 months, 48 of the 164 patients (29%) had undergone resection. Ultimately, there were three cases (2%) of high-grade dysplasia and two cases of invasive carcinoma (1%) within these 164 patients selected for observation. Three of the five cases of either high-grade dysplasia or invasive carcinoma were among the 22 patients followed outside of consensus guidelines. Appropriately selected patients with mucinous pancreatic cysts can be safely followed with serial surveillance with a low risk of malignant progression.

We aimed to identify key principles of targeted therapy of protein kinases and their application to the management of solid tumors.Concurrent advances in tumor genomic analysis and molecular inhibitor development have dramatically impacted the diagnosis and treatment of solid tumors, and common themes regarding the use of kinase inhibitors are developing.The list of kinase inhibitors that have been approved by the US Food and Drug Administration was reviewed and articles related to the agents were searched in the PubMed database up until December 2015. We included pivotal, randomized controlled phase 2 and 3 trials, and also pertinent preclinical studies.Small molecule inhibitors targeted against driver kinases, overactive in selected subsets of solid tumors, elicit improved response rates and survival compared with standard chemotherapy. Disease control has been proven in the metastatic and, to a limited extent, the adjuvant setting. However, tumor eradication is rare, and duration of treatment response is limited by the development of drug resistance.Kinase inhibitors induce response in diverse types of solid tumors. Although the agents are often effective in defined molecular subsets, cure is rare and resistance is common. This broad review provides rationale for further investigation of multimodality therapy combining kinase inhibitors with additional systemic and local therapies, including surgery.

WOS: 000412130500018 PubMed ID: 28923937 Gastrointestinal stromal tumors (GISTs) predominantly harbor activating mutations in the receptor tyrosine kinase KIT. To genetically dissect in vivo the requirement of different signal transduction pathways emanating from KIT for tumorigenesis, the oncogenic Kit(V558 Delta) mutation was combined with point mutations abrogating specific phosphorylation sites on KIT. Compared with single-mutant Kit(V558 Delta/+) mice, double-mutant Kit(V558 Delta; Y567F/Y567F) knock-in mice lacking the SRC family kinase-binding site on KIT (pY567) exhibited attenuated MAPK signaling and tumor growth. Surprisingly, abrogation of the PI3K-binding site (pY719) in Kit(V558 Delta;Y719F/Y719F) mice prevented GIST development, although the interstitial cells of Cajal (ICC), the cells of origin of GIST, were normal. Pharmacologic inhibition of the PI3K pathway in tumor-bearing Kit(V558 Delta/+) mice with the dual PI3K/mTOR inhibitor voxtalisib, the pan-PI3K inhibitor pilaralisib, and the PI3K-alpha-restricted inhibitor alpelisib each diminished tumor proliferation. The addition of the MEK inhibitor PD-325901 or binimetinib further decreased downstream KIT signaling. Moreover, combining PI3K and MEK inhibition was effective against imatinibresistant Kit(V558 Delta;T669I/+) tumors. National Institutes of Health [R01 HL55748, CA102774, P50 CA140146, R01 CA102613, P30 CA008748]; Starr Cancer Consortium We thank Willie Mark and Antoinette Rookard from the Mouse Genetics Core facility for help with gene targeting experiments; Mesru Turkekul, Asfar Barlas, and Ning Fan from the Molecular Cytology core facility at Memorial Sloan Kettering Cancer Center for help with histological analysis; Peterson Chao and Adriana Guevara for assistance with experiments; and Russell Holmes and John Burrowes for logistical and administrative support. This study was supported by the National Institutes of Health (Grants R01 HL55748, to P.B.; CA102774, to P.B.; P50 CA140146, to P.B. and C.R.A.; R01 CA102613, to R.P.D.; and P30 CA008748) and the Starr Cancer Consortium (P.B. and C.R.A.).

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies.

Twenty-five percent of patients with colorectal cancer present with simultaneous liver metastasis. Complete resection is the only potential curative treatment. Due to improvements in operative and perioperative management, simultaneous liver and colon resections are an accepted procedure at specialized centers for selected patients. Nevertheless, little is known about the long-term, oncologic results of simultaneous operative procedures compared with those of staged operations.Patients with colorectal cancer and simultaneous liver metastases presenting for complete resection at a tertiary cancer center were identified. Patients who received the primary colon resection at an outside institution were excluded from analysis.Between 1984 and 2008, 429 patients underwent operative treatment for colorectal cancer with simultaneous liver metastasis. Of these, 320 (75%) had simultaneous resection and 109 had staged resection. There was no difference in the distribution of primary tumor locations between the 2 groups. Mean size of the hepatic metastases was significantly greater in the staged group (median 4 cm vs 2.5 cm; P .01). Neither disease-free nor overall survival differed significantly between the 2 treatment strategies. The extent of the liver procedure (more than 3 segments) was identified as a risk factor for decreased disease-free and overall survival (both P .01).Simultaneous liver and colorectal resections for metastatic colorectal cancer are associated with similar long-term cancer outcome compared with staged procedures.

Imatinib mesylate targets mutated KIT oncoproteins in gastrointestinal stromal tumor (GIST) and produces a clinical response in 80% of patients. The mechanism is believed to depend predominantly on the inhibition of KIT-driven signals for tumor-cell survival and proliferation. Using a mouse model of spontaneous GIST, we found that the immune system contributes substantially to the antitumor effects of imatinib. Imatinib therapy activated CD8(+) T cells and induced regulatory T cell (T(reg) cell) apoptosis within the tumor by reducing tumor-cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Ido). Concurrent immunotherapy augmented the efficacy of imatinib in mouse GIST. In freshly obtained human GIST specimens, the T cell profile correlated with imatinib sensitivity and IDO expression. Thus, T cells are crucial to the antitumor effects of imatinib in GIST, and concomitant immunotherapy may further improve outcomes in human cancers treated with targeted agents.

OBJECTIVE:The aim of the present study is to determine if CEACAM6 can be detected in the bile of patients with biliary cancer and can serve as a diagnostic biomarker for cholangiocarcinoma. SUMMARY BACKGROUND DATA:Distinguishing bile duct carcinoma from other diagnoses is often difficult using endoscopic or percutaneous techniques. The cell surface protein CEACAM6 is over-expressed in many gastrointestinal cancers and may be selectively elevated in biliary adenocarcinoma. METHODS:Bile from patients with benign biliary disease and cholangiocarcinoma (hilar, intrahepatic and distal) was collected at the time of index operation. The concentration of CEACAM6 was quantified by sandwich enzyme-linked immunosorbent assay (ELISA) and correlated to pathologic diagnosis. Diagnostic capability of CEACAM6 was evaluated by Wilcoxon rank-sum, linear regression, multiple regression, and receiver operating characteristic (ROC) curve analysis. RESULTS:Bile from 83 patients was analyzed: 42 with benign disease and 41 with cholangiocarcinoma. Patients in the benign cohort were younger, predominantly female, and had lower median biliary CEACAM6 levels than patients in the malignant cohort (7.5 ng/ml vs. 40 ng/ml; p = 14 ng/ml associated with 87.5% sensitivity, 69.1% specificity, and a likelihood ratio of 2.8 (AUC 0.74). Multiple regression analysis suggested elevated alkaline phosphatase and the presence of biliary endoprostheses may influence CEACAM6 levels. CONCLUSION:Biliary CEACAM6 can identify patients with extrahepatic cholangiocarcinoma with a high degree of sensitivity and should be investigated further as a potential screening tool.

Purpose Transarterial chemoembolization is accepted therapy for hepatocellular carcinoma (HCC). No randomized trial has demonstrated superiority of chemoembolization compared with embolization, and the role of chemotherapy remains unclear. This randomized trial compares the outcome of embolization using microspheres alone with chemoembolization using doxorubicin-eluting microspheres. Materials and Methods At a single tertiary referral center, patients with HCC were randomly assigned to embolization with microspheres alone (Bead Block [BB]) or loaded with doxorubicin 150 mg (LC Bead [LCB]). Random assignment was stratified by number of embolizations to complete treatment, and assignments were generated by permuted blocks in the institutional database. The primary end point was response according to RECIST 1.0 (Response Evaluation Criteria in Solid Tumors) using multiphase computed tomography 2 to 3 weeks post-treatment and then at quarterly intervals, with the reviewer blinded to treatment allocation. Secondary objectives included safety and tolerability, time to progression, progression-free survival, and overall survival. This trial is currently closed to accrual. Results Between December 2007 and April 2012, 101 patients were randomly assigned: 51 to BB and 50 to LCB. Demographics were comparable: median age, 67 years; 77% male; and 22% Barcelona Clinic Liver Cancer stage A and 78% stage B or C. Adverse events occurred with similar frequency in both groups: BB, 19 of 51 patients (38%); LCB, 20 of 50 patients (40%; P = .48), with no difference in RECIST response: BB, 5.9% versus LCB, 6.0% (difference, −0.1%; 95% CI, −9% to 9%). Median PFS was 6.2 versus 2.8 months (hazard ratio, 1.36; 95% CI, 0.91 to 2.05; P = .11), and overall survival, 19.6 versus 20.8 months (hazard ratio, 1.11; 95% CI, 0.71 to 1.76; P = .64) for BB and LCB, respectively. Conclusion There was no apparent difference between the treatment arms. These results challenge the use of doxorubicin-eluting beads for chemoembolization of HCC.

A recent prospective randomized trial demonstrated that prophylactic pasireotide reduces the incidence of pancreatic complications (PC) after resection. This secondary analysis aimed to describe quality of life (QoL) before and after resection, to characterize the impact of PC on QoL, and to assess whether pasireotide improves QoL. A randomized, double-blind, placebo-controlled trial of preoperative pasireotide in patients undergoing pancreatectomy was conducted. Participants completed the European Organization for Research and Treatment of Cancer (EORTC) C30 and PAN26 modules preoperatively and on postoperative days 14 and 60. Scores were compared using t tests. The percentage of patients with clinically important worsening (a decline ≥0.5 times the baseline standard deviation) was reported. All questionnaires were completed by 87 % (260/300) of the patients. No major differences were observed between the pasireotide and placebo groups. Therefore, the data were pooled for further analyses. A significant worsening of function at 14 days was detected on all the PAN26 and C30 function scales except hepatic and emotional functioning (EF), and on all the C30 symptom scales. More than 75 % of the patients experienced clinically important worsening of fatigue, pain, and role functioning. Most effects persisted at 60 days, with the 60-day EF significantly better than at baseline (p = 0.03). PC were associated with worse outcomes on most function scales. During the 14 days after resection, patients can be expected to have a significant decline in QoL. Many symptoms abate by 60 days, and EF improves. PC were associated with impaired QoL in several domains. Although pasireotide effectively reduced PC, its effect did not appear to translate to improved QoL in this sample of 300 patients.

The aim of this study is to determine the prevalence of diabetes mellitus (DM) in patients with intraductal papillary mucinous neoplasm of the pancreas (IPMN) and compare rates of new/progressive DM between IPMN patients undergoing pancreatectomy versus observation. Patients diagnosed with IPMN were identified from institutional databases, divided into two groups based on treatment type, pancreatectomy versus clinical observation, and subsequently evaluated. Standard demographic and clinicopathologic variables, fasting glucose, diabetic status, and pancreatic volume data, were obtained and compared between groups. One hundred thirty-four IPMN patients were identified; 103 (77 %) underwent pancreatectomy and 31 (23 %) were observed. Baseline DM rate was 18 % (24/134). This was not different between groups [17 % (17/103) resected vs. 23 % (7/31) observed, p = 0.51]. Median follow-up was 53 months and new/progressive DM occurred in 37 (28 %) patients with no difference between groups [29 (28 %) resected vs. 8 (26 %) observed, p = 0.74]. Among resected patients, degree of dysplasia was associated with increase risk of new/progressive DM [moderate dysplasia OR 5.76 (1.24–26.79) and severe dysplasia OR 9.43 (1.54–57.74), p = 0.04], while procedure type and remnant volume were not. The incidence and prevalence of DM among patients with IPMN was high and did not differ between resected and observed groups. Degree of dysplasia, not the amount of resected pancreas, was associated with increased risk of DM, suggesting that the presence or development of DM may be a marker of malignant progression. Confirmatory studies are required.

Background Published prognostic models for overall survival after liver resection for intrahepatic cholangiocarcinoma require external validation before use in clinical practice. Study Design From January 1993 to May 2013, consecutive patients who underwent resection of intrahepatic cholangiocarcinoma were identified from a prospective database. The Wang nomogram was derived in an Asian cohort (n = 367) and included clinicopathologic variables and preoperative CEA and cancer antigen 19-9 levels. The Hyder nomogram was derived in an Eastern and Western multicenter cohort (n = 514) using clinicopathologic variables only. The AJCC Cancer Staging System (7th ed) and the preoperative Fudan risk score were also evaluated. Prognostic performance was assessed in terms of discrimination, calibration, and stratification. Results One hundred and eighty-eight patients were included, with a median follow-up of 41 months. Median overall survival was 48.7 months and estimated 3-year and 5-year overall survival rates were 59% and 45%, respectively. Overall survival prediction accuracy, according to concordance-index calculation, was 0.72 with the Wang nomogram, 0.66 with the Hyder nomogram, 0.63 with the AJCC system, and 0.55 using the Fudan score. Both nomograms provided effective patient stratification in distinct survival groups. Conclusions Both the Wang and Hyder nomograms provided accurate patient prognosis estimation after liver resection for intrahepatic cholangiocarcinoma and can be useful for decision making about adjuvant therapy. The Wang nomogram appears to be more appropriate in patients undergoing formal portal lymphadenectomy and requires preoperative CEA and cancer antigen 19-9 levels for optimal performance.

Gastrointestinal stromal tumors (GIST) are the most common adult sarcomas and the oncogenic driver is usually a KIT or PDGFRA mutation. Although GISTs are often initially sensitive to imatinib or other tyrosine kinase inhibitors, resistance generally develops, necessitating backup strategies for therapy. In this study, we determined that a subset of human GIST specimens that acquired imatinib resistance acquired expression of activated forms of the MET oncogene. MET activation also developed after imatinib therapy in a mouse model of GIST (KitV558del/+ mice), where it was associated with increased tumor hypoxia. MET activation also occurred in imatinib-sensitive human GIST cell lines after imatinib treatment in vitro. MET inhibition by crizotinib or RNA interference was cytotoxic to an imatinib-resistant human GIST cell population. Moreover, combining crizotinib and imatinib was more effective than imatinib alone in imatinib-sensitive GIST models. Finally, cabozantinib, a dual MET and KIT small-molecule inhibitor, was markedly more effective than imatinib in multiple preclinical models of imatinib-sensitive and imatinib-resistant GIST. Collectively, our findings showed that activation of compensatory MET signaling by KIT inhibition may contribute to tumor resistance. Furthermore, our work offered a preclinical proof of concept for MET inhibition by cabozantinib as an effective strategy for GIST treatment. Cancer Res; 75(10); 2061–70. ©2015 AACR.

Though immune responses correlate with prognosis in primary colorectal cancer, the role of tumor immunity in metastatic disease is less clear. We hypothesized that patient survival and tumor recurrence correlate with transcriptional evidence of lymphocyte proliferation/activation in resected colorectal cancer liver metastases (CRLM). Microarray gene analysis was performed on liver tumor specimens from 96 patients who underwent resection for CRLM. A Cox proportional hazards model identified genes associated with overall survival (OS) and recurrence-free survival (RFS). Conventional gene ontology (GO) enrichment analysis ranked biologically relevant processes. Survival probabilities of prioritized processes were assessed. Protein expression was validated with immunohistochemistry in an independent set of patients. GO analysis identified and ranked unique biologic processes that correlated with survival. Genes that specifically functioned in the biologic process of “T-cell proliferation” were significant predictors of OS (P = 0.01), and both “T-cell proliferation” and “activation” were highly associated with RFS (P ≤ 0.01). Analysis of genes in these GO categories identified increased TNFSF14/LIGHT expression to be most associated with improved OS and RFS (P ≤ 0.0006). Immunohistochemistry of an independent validation set of CRLM confirmed that both increased tumor-infiltrating lymphocytes (TIL) and higher LIGHT expression on TILs were associated with improved OS and RFS. Differential expression of genes involved in T-cell proliferation/activation was associated with survival outcomes in a large number of surgical patients who underwent resection of CRLM. These biologic functions determined by GO analysis of the tumor microenvironment have identified specific immune-related genes that may be involved in an antitumor immune response. Cancer Immunol Res; 3(4); 380–8. ©2015 AACR.

Purpose To investigate associations between imaging features of cholangiocarcinoma by visual assessment and texture analysis, which quantifies heterogeneity in tumor enhancement patterns, with molecular profiles based on hypoxia markers. Methods The institutional review board approved this HIPAA-compliant retrospective study of CT images of intrahepatic cholangiocarcinoma, obtained before surgery. Immunostaining for hypoxia markers (EGFR, VEGF, CD24, P53, MDM2, MRP-1, HIF-1α, CA-IX, and GLUT1) was performed on pre-treatment liver biopsies. Quantitative imaging phenotypes were determined by texture analysis with gray level co-occurrence matrixes. The correlations between quantitative imaging phenotypes, qualitative imaging features (measured by radiographic inspection alone), and expression levels of the hypoxia markers from the 25 tumors were assessed. Results Twenty-five patients were included with a median age of 62 years (range: 54–84). The median tumor size was 10.2 cm (range: 4–14), 10 (40%) were single tumors, and 90% were moderately differentiated. Positive immunostaining was recorded for VEGF in 67% of the cases, EGFR in 75%, and CD24 in 55%. On multiple linear regression analysis, quantitative imaging phenotypes correlated significantly with EGFR and VEGF expression levels (R2 = 0.4, p

Texture analysis is a promising method of analyzing imaging data to potentially enhance diagnostic capability. This approach involves automated measurement of pixel intensity variation that may offer further insight into disease progression than do standard imaging techniques alone. We postulated that postoperative liver insufficiency, a major source of morbidity and mortality, correlates with preoperative heterogeneous parenchymal enhancement that can be quantified with texture analysis of cross-sectional imaging.A retrospective case-matched study (waiver of informed consent and HIPAA authorization, approved by the Institutional Review Board) was performed comparing patients who underwent major hepatic resection and developed liver insufficiency (n = 12) with a matched group of patients with no postoperative liver insufficiency (n = 24) by procedure, remnant volume, and year of procedure. Texture analysis (with gray-level co-occurrence matrices) was used to quantify the heterogeneity of liver parenchyma on preoperative CT scans. Statistical significance was evaluated using Wilcoxon's signed rank and Pearson's chi-square tests.No statistically significant differences were found between study groups for preoperative patient demographics and clinical characteristics, with the exception of sex (p0.05). Two texture features differed significantly between the groups: correlation (linear dependency of gray levels on neighboring pixels) and entropy (randomness of brightness variation) (p0.05).In this preliminary study, the texture of liver parenchyma on preoperative CT was significantly more varied, less symmetric, and less homogeneous in patients with postoperative liver insufficiency. Therefore, texture analysis has the potential to provide an additional means of preoperative risk stratification.

Background After portal vein embolization (PVE), the future liver remnant (FLR) hypertrophies for several weeks. An early marker that predicts a low risk of post-hepatectomy liver failure can reduce the delay to surgery. Study Design Liver volumes of 153 patients who underwent a major hepatectomy (>3 segments) after PVE for primary or secondary liver malignancy between September 1999 and November 2012 were retrospectively evaluated with computerized volumetry. Pre- and post-PVE FLR volume and functional liver volume were measured. Degree of hypertrophy (DH = post-FLR/post-functional liver volume − pre-FLR/pre-functional liver volume) and growth rate (GR = DH/weeks since PVE) were calculated. Postoperative complications and liver failure were correlated with DH, measured GR, and estimated GR derived from a formula based on body surface area. Results Eligible patients underwent 93 right hepatectomies, 51 extended right hepatectomies, 4 left hepatectomies, and 5 extended left hepatectomies. Major complications occurred in 44 patients (28.7%) and liver failure in 6 patients (3.9%). Nonparametric regression showed that post-embolization FLR percent correlated poorly with liver failure. Receiver operating characteristic curves showed that DH and GR were good predictors of liver failure (area under the curve [AUC] = 0.80; p = 0.011 and AUC = 0.79; p = 0.015) and modest predictors of major complications (AUC = 0.66; p = 0.002 and AUC = 0.61; p = 0.032). No patient with GR >2.66% per week had liver failure develop. The predictive value of measured GR was superior to estimated GR for liver failure (AUC = 0.79 vs 0.58; p = 0.046). Conclusions Both DH and GR after PVE are strong predictors of post-hepatectomy liver failure. Growth rate might be a better guide for the optimum timing of liver resection than static volumetric measurements. Measured volumetrics correlated with outcomes better than estimated volumetrics.

Tumor-infiltrating lymphocytes (TIL) in colorectal cancer liver metastases (CLM) have been associated with more favorable patient outcomes, but whether MHC class I (MHC-I) expression on cancer cells affects prognosis is uncertain. Immunohistochemistry was performed on a tissue microarray of 158 patients with CLM, who underwent partial hepatectomy with curative intent. Using the antibody HC-10, which detects HLA-B and HLA-C antigens and a minority of HLA-A antigens, MHC-I expression was correlated with β-2 microglobulin (β2m; r = 0.7; P < 0.001), but not with T-cell density (r < 0.32). The median follow-up for survivors was 9.7 years. High levels of MHC-I expression in tumors concomitant with high T-cell infiltration (CD3, CD4, or CD8) best identified patients with favorable outcomes, compared with patients with one or none of these immune features. The median overall survival (OS) of patients with MHC-IhiCD3hi tumors (n = 31) was 116 months compared with 40 months for the others (P = 0.001), and the median time to recurrence (TTR) was not reached compared with 17 months (P = 0.008). By multivariate analysis, MHChiCD3hi was associated with OS and TTR independent of the standard clinicopathologic variables. An immune score that combines MHC-I expression and TIL density may be a valuable prognostic tool in the treatment of patients with CLM. Cancer Immunol Res; 2(6); 530–7. ©2014 AACR.

Risk of high-grade dysplasia and invasive carcinoma in intraductal papillary mucinous neoplasms (IPMN) of the pancreas is increased in main duct compared to branch duct lesions. We hypothesized that isolated uncinate duct dilation may also be a radiographic indicator of high-risk disease, as the primary drainage of this portion of the gland originates from a distinct embryologic precursor.All patients with available preoperative imaging who underwent resection for IPMN between 1994 and 2010 were included (n = 184). Imaging studies were reviewed by an experienced radiologist who was blinded to the pathologic results, and studies were categorized as main duct, branch duct, or combined-duct. The presence of uncinate duct dilation was assessed as a risk factor for tumors which proved to have high-grade dysplasia (HGD) or invasive carcinoma (IC) on pathologic assessment.IPMN with HGD or IC were identified in 82 of 184 cases (45%). Without considering uncinate duct dilation, IPMN with HGD or IC were present in 84% of patients with main duct IPMN (n = 31/37), 58% with combined-duct IPMN (n = 23/40), and 26% with branch \duct IPMN (n = 28/107). Dilation of the uncinate duct was observed in 47 patients, with or without main duct dilation, and 30 of these (64%) contained HGD or IC on pathology. Isolated uncinate duct dilation without main duct dilation was observed in 17 patients, and 11 (65%) had HGD. On multivariate analysis of IPMN without associated main duct dilation, uncinate duct dilation was independently associated with IPMN with HGD or IC (p = 0.002).Uncinate duct dilation on preoperative radiologic imaging appears to be an additional risk factor for IPMN-associated high-grade dysplasia or adenocarcinoma.

We report a case of safe and successful yttrium-90 resin microsphere radioembolization in a patient with a long history of multiple recurrent colon cancer hepatic metastases progressing after hepatic resections, hepatic arterial chemotherapy, and multiple regimens of systemic chemotherapy. One month prior to radioembolization, a biliary stent was placed above the level of the ampulla to relieve tumor-related biliary obstruction and normalize bilirubin levels.

Background The significance of a positive margin in resected non‐invasive pancreatic intraductal papillary mucinous neoplasms (IPMN) remains controversial. The aim of this study was to determine recurrence rates when dysplasia was present at the final surgical margin. Methods A prospectively maintained database identified 192 patients undergoing resection of non‐invasive IPMN. Pathological, peri‐operative and recurrence data were analysed. Results Ductal dysplasia was identified at the final surgical margin in 86 patients (45%) and defined as IPMN or Pancreatic Intraepithelial Neoplasia PanIN in 38 (20%) and 54 (28%) patients, respectively. At a median follow‐up of 46 months, 40 (21%) patients recurred with 31 developing radiographical evidence of new cysts, 6 re‐resected for IPMN and 3 diagnosed with pancreatic cancer within the remnant. Of those with margin dysplasia, 31% developed recurrent disease compared with 13% in those without dysplasia ( P = 0.002). On multivariate analysis, margin dysplasia was associated with a three‐fold increased risk of recurrence ( P = 0.02). No relationship between dysplasia and development of pancreatic cancer was found. Discussion In this study, dysplasia at the margin after a pancreatectomy for non‐invasive IPMN was associated with recurrence in the remnant gland, but not at the resection margin. While this finding may warrant closer follow‐up, it does not identify a gland at higher risk for the subsequent development of invasive disease.

Gastrointestinal stromal tumors (GISTs) are rare but treatable soft tissue sarcomas. Nearly all GISTs have somatic mutations in either the KIT or PDGFRA gene, but there are no known inherited genetic risk factors. We assessed the relationship between KIT/PDGFRA mutations and select deletions or single nucleotide polymorphisms (SNPs) in 279 participants from a clinical trial of adjuvant imatinib mesylate. Given previous evidence that certain susceptibility loci and carcinogens are associated with characteristic mutations, or "signatures" in other cancers, we hypothesized that the characteristic somatic mutations in the KIT and PDGFRA genes in GIST tumors may similarly be mutational signatures that are causally linked to specific mutagens or susceptibility loci. As previous epidemiologic studies suggest environmental risk factors such as dioxin and radiation exposure may be linked to sarcomas, we chose 208 variants in 39 candidate genes related to DNA repair and dioxin metabolism or response. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association between each variant and 7 categories of tumor mutation using logistic regression. We also evaluated gene-level effects using the sequence kernel association test (SKAT). Although none of the association p-values were statistically significant after adjustment for multiple comparisons, SNPs in CYP1B1 were strongly associated with KIT exon 11 codon 557-8 deletions (OR = 1.9, 95% CI: 1.3-2.9 for rs2855658 and OR = 1.8, 95% CI: 1.2-2.7 for rs1056836) and wild type GISTs (OR = 2.7, 95% CI: 1.5-4.8 for rs1800440 and OR = 0.5, 95% CI: 0.3-0.9 for rs1056836). CYP1B1 was also associated with these mutations categories in the SKAT analysis (p = 0.002 and p = 0.003, respectively). Other potential risk variants included GSTM1, RAD23B and ERCC2. This preliminary analysis of inherited genetic risk factors for GIST offers some clues about the disease's genetic origins and provides a starting point for future candidate gene or gene-environment research.

Background Neoadjuvant chemoradiation therapy for locally unresectable and borderline resectable pancreatic cancer may allow some patients to a undergo a resection, but whether or not this increases post‐operative morbidity remains unclear. Methods The post‐operative morbidity of 29 patients with initially locally unresectable/borderline pancreatic cancer who underwent a resection were compared with 29 patients with initially resectable tumours matched for age, gender, the presence of comorbidities (yes/no), American Society of Anesthesiology (ASA) score, tumour location (head/body‐tail), procedure (pancreaticoduodenectomy/distal pancreatectomy) and vascular resection (yes /no). Wilcoxon's signed ranks test was used for continuous variables and McNemar's chi‐square test for categorical variables. Results Compared with patients with initially resectable tumours, patients who underwent a resection after pre‐operative chemoradiation therapy had similar rates of overall post‐operative complications (55% versus 41%, P = 0.42), major complications (21% versus 21%, P = 1), pancreatic leaks and fistulae (7% versus 10%, P = 1) and mortality (0% versus 1.7%, P = 1). Conclusion Although some previous studies have suggested differences in post‐operative morbidity after chemoradiation, our case‐matched analysis did not find statistical differences in surgical morbidity and mortality associated with pre‐operative chemoradiation therapy.

Despite being the most common sarcoma of the gastrointestinal tract, gastrointestinal stromal tumor (GIST) has only been widely recognized as a unique entity for just over a decade. The advent of tyrosine kinase inhibitors (TKIs) has revolutionized the diagnosis and treatment of GIST. While surgery remains the only chance for cure, multimodal treatment that includes molecular therapy continues to develop. Optimal management of GIST requires careful radiographic, pathologic, medical and surgical care, emphasizing the need for a multidisciplinary approach. In this review we highlight recent developments in the management of GIST.