Emerging interleukin targets in the tumour microenvironment: implications for the treatment of gastrointestinal tumours.

The effectiveness of antitumour immunity is dependent on intricate cytokine networks. Interleukins (ILs) are important mediators of complex interactions within the tumour microenvironment, including regulation of tumour-infiltrating lymphocyte proliferation, differentiation, migration and activation. Our evolving and increasingly nuanced understanding of the cell type-specific and heterogeneous effects of IL signalling has presented unique opportunities to fine-tune elaborate IL networks and engineer new targeted immunotherapeutics. In this review, we provide a primer for clinicians on the challenges and potential of IL-based treatment. We specifically detail the roles of IL-2, IL-10, IL-12 and IL-15 in shaping the tumour-immune landscape of gastrointestinal malignancies, paying particular attention to promising preclinical findings, early-stage clinical research and innovative therapeutic approaches that may properly place ILs to the forefront of immunotherapy regimens.

Blockade of interleukin 10 potentiates antitumour immune function in human colorectal cancer liver metastases.

OBJECTIVE: Programmed cell death protein 1 (PD-1) checkpoint inhibition and adoptive cellular therapy have had limited success in patients with microsatellite stable colorectal cancer liver metastases (CRLM). We sought to evaluate the effect of interleukin 10 (IL-10) blockade on endogenous T cell and chimeric antigen receptor T (CAR-T) cell antitumour function in CRLM slice cultures. DESIGN: We created organotypic slice cultures from human CRLM (n=38 patients' tumours) and tested the antitumour effects of a neutralising antibody against IL-10 (αIL-10) both alone as treatment and in combination with exogenously administered carcinoembryonic antigen (CEA)-specific CAR-T cells. We evaluated slice cultures with single and multiplex immunohistochemistry, in situ hybridisation, single-cell RNA sequencing, reverse-phase protein arrays and time-lapse fluorescent microscopy. RESULTS: αIL-10 generated a 1.8-fold increase in T cell-mediated carcinoma cell death in human CRLM slice cultures. αIL-10 significantly increased proportions of CD8+ T cells without exhaustion transcription changes, and increased human leukocyte antigen - DR isotype (HLA-DR) expression of macrophages. The antitumour effects of αIL-10 were reversed by major histocompatibility complex class I or II (MHC-I or MHC-II) blockade, confirming the essential role of antigen presenting cells. Interrupting IL-10 signalling also rescued murine CAR-T cell proliferation and cytotoxicity from myeloid cell-mediated immunosuppression. In human CRLM slices, αIL-10 increased CEA-specific CAR-T cell activation and CAR-T cell-mediated cytotoxicity, with nearly 70% carcinoma cell apoptosis across multiple human tumours. Pretreatment with an IL-10 receptor blocking antibody also potentiated CAR-T function. CONCLUSION: Neutralising the effects of IL-10 in human CRLM has therapeutic potential as a stand-alone treatment and to augment the function of adoptively transferred CAR-T cells.

KRAS Mutation Variants and Co-occurring PI3K Pathway Alterations Impact Survival for Patients with Pancreatic Ductal Adenocarcinomas.

BACKGROUND: KRAS variant alleles may have differential biological properties which impact prognosis and therapeutic options in pancreatic ductal adenocarcinomas (PDA). MATERIALS AND METHODS: We retrospectively identified patients with advanced PDA who received first-line therapy and underwent blood and/or tumor genomic sequencing at the University of Washington between 2013 and 2020. We examined the incidence of KRAS mutation variants with and without co-occurring PI3K or other genomic alterations and evaluated the association of these mutations with clinicopathological characteristics and survival using a Cox proportional hazards model. RESULTS: One hundred twenty-six patients had genomic sequencing data; KRAS mutations were identified in 111 PDA and included the following variants: G12D (43)/G12V (35)/G12R (23)/other (10). PI3K pathway mutations (26% vs. 8%) and homologous recombination DNA repair (HRR) defects (35% vs. 12.5%) were more common among KRAS G12R vs. non-G12R mutated cancers. Patients with KRAS G12R vs. non-G12R cancers had significantly longer overall survival (OS) (HR 0.55) and progression-free survival (PFS) (HR 0.58), adjusted for HRR pathway co-mutations among other covariates. Within the KRAS G12R group, co-occurring PI3K pathway mutations were associated with numerically shorter OS (HR 1.58), while no effect was observed on PFS. CONCLUSIONS: Patients with PDA harboring KRAS G12R vs. non-G12R mutations have longer survival, but this advantage was offset by co-occurring PI3K alterations. The KRAS/PI3K genomic profile could inform therapeutic vulnerabilities in patients with PDA.

Impact of enhanced recovery protocols after pancreatoduodenectomy: meta-analysis.

BACKGROUND: This individual-patient data meta-analysis investigated the effects of enhanced recovery after surgery (ERAS) protocols compared with conventional care on postoperative outcomes in patients undergoing pancreatoduodenectomy. METHODS: The Cochrane Library, MEDLINE, Embase, Scopus, and Web of Science were searched systematically for articles reporting outcomes of ERAS after pancreatoduodenectomy published up to August 2020. Comparative studies were included. Main outcomes were postoperative functional recovery elements, postoperative morbidity, duration of hospital stay, and readmission. RESULTS: Individual-patient data were obtained from 17 of 31 eligible studies comprising 3108 patients. Time to liquid (mean difference (MD) -3.23 (95 per cent c.i. -4.62 to -1.85) days; P < 0.001) and solid (-3.84 (-5.09 to -2.60) days; P < 0.001) intake, time to passage of first stool (MD -1.38 (-1.82 to -0.94) days; P < 0.001) and time to removal of the nasogastric tube (3.03 (-4.87 to -1.18) days; P = 0.001) were reduced with ERAS. ERAS was associated with lower overall morbidity (risk difference (RD) -0.04, 95 per cent c.i. -0.08 to -0.01; P = 0.015), less delayed gastric emptying (RD -0.11, -0.22 to -0.01; P = 0.039) and a shorter duration of hospital stay (MD -2.33 (-2.98 to -1.69) days; P < 0.001) without a higher readmission rate. CONCLUSION: ERAS improved postoperative outcome after pancreatoduodenectomy. Implementation should be encouraged.

Enhanced recovery protocols consist of interdisciplinary interventions aimed at standardizing care and reducing the impact of surgical stress. They often include a short period of preoperative fasting during the night before surgery, early removal of lines and surgical drains, early food intake and mobilization out of bed on the day of surgery. This study gives a summary of reports assessing such care protocols in patients undergoing pancreatic head surgery, and assesses the impact of these protocols on functional recovery in an analysis of individual-patient data. The study revealed the true benefits of enhanced recovery protocols, including shorter time to food intake, earlier bowel activity, fewer complications after surgery, and a shorter hospital stay compared with conventional care.

IWATE criteria are associated with perioperative outcomes in robotic hepatectomy: a retrospective review of 225 resections.

BACKGROUND: Robotic hepatectomy (RH) is increasingly utilized for minor and major liver resections. The IWATE criteria were developed to classify minimally invasive liver resections by difficulty. The objective of this study was to apply the IWATE criteria in RH and to describe perioperative and oncologic outcomes of RH over the last decade at our institution. METHODS: Perioperative and oncologic outcomes of patients who underwent RH between 2011 and 2019 were retrospectively collected. The difficulty level of each operation was assessed using the IWATE criteria, and outcomes were compared at each level. Univariate linear regression was performed to characterize the relationship between IWATE criteria and perioperative outcomes (OR time, EBL, and LOS), and a multivariable model was also developed to address potential confounding by patient characteristics (age, sex, BMI, prior abdominal surgery, ASA class, and simultaneous non-hepatectomy operation). RESULTS: Two hundred and twenty-five RH were performed. Median IWATE criteria for RH were 6 (IQR 5-9), with low, intermediate, advanced, and expert resections accounting for 23% (n = 51), 34% (n = 77), 32% (n = 72), and 11% (n = 25) of resections, respectively. The majority of resections were parenchymal-sparing approaches, including anatomic segmentectomies and non-anatomic partial resections. 30-day complication rate was 14%, conversion to open surgery occurred in 9 patients (4%), and there were no deaths within 30 days postoperatively. In the univariate linear regression analysis, IWATE criteria were positively associated with OR time, EBL, and LOS. In the multivariable model, IWATE criteria were independently associated with greater OR time, EBL, and LOS. Two-year overall survival for hepatocellular carcinoma and intrahepatic cholangiocarcinoma was 94% and 50%, respectively. CONCLUSION: In conclusion, the IWATE criteria are associated with surgical outcomes after RH. This series highlights the utility of RH for difficult hepatic resections, particularly parenchymal-sparing resections in the posterosuperior sector, extending the indication of minimally invasive hepatectomy in experienced hands and potentially offering select patients an alternative to open hepatectomy or other less definitive liver-directed treatment options.

A phase II trial of lanreotide for the prevention of postoperative pancreatic fistula.

BACKGROUND: Clinically relevant postoperative pancreatic fistula (CR-POPF) is a significant contributor to morbidity after pancreatectomy. Somatostatin analogues have shown variable efficacy in the prevention of CR-POPF. Lanreotide is a somatostatin analogue ideally suited for perioperative use due to its long half-life and favorable side effect profile. METHODS: We conducted a phase II single-arm trial of a single dose of preoperative lanreotide (120 mg) in patients undergoing either pancreaticoduodenectomy (PD) or distal pancreatectomy (DP). The primary outcome was development of CR-POPF or intra-abdominal abscess. Secondary outcomes included biochemical leak and overall morbidity. RESULTS: A total of 98 patients completed the study. Sixty-two underwent PD (63.3%) and 36 underwent DP (36.7%). The primary outcome was observed in eight (8%) patients in the overall cohort, one from the DP group and seven from the PD group. Biochemical leak was detected in 12 (12.2%) patients in the overall cohort. Twenty-seven (27.5%) patients developed complications, of which 14 (14.2%) were major complications. Drug-related adverse events were limited to mild skin reactions in two (2%) patients. CONCLUSION: Patients who received preoperative lanreotide developed CR-POPF at rates significantly lower than historical controls or published literature. This provides strong justification for a randomized controlled trial.

The CXCL12-CXCR4/CXCR7 axis as a mechanism of immune resistance in gastrointestinal malignancies.

Single agent checkpoint inhibitor therapy has not been effective for most gastrointestinal solid tumors, but combination therapy with drugs targeting additional immunosuppressive pathways is being attempted. One such pathway, the CXCL12-CXCR4/CXCR7 chemokine axis, has attracted attention due to its effects on tumor cell survival and metastasis as well as immune cell migration. CXCL12 is a small protein that functions in normal hematopoietic stem cell homing in addition to repair of damaged tissue. Binding of CXCL12 to CXCR4 leads to activation of G protein signaling kinases such as P13K/mTOR and MEK/ERK while binding to CXCR7 leads to ß-arrestin mediated signaling. While some gastric and colorectal carcinoma cells have been shown to make CXCL12, the primary source in pancreatic cancer and peritoneal metastases is cancer-associated fibroblasts. Binding of CXCL12 to CXCR4 and CXCR7 on tumor cells leads to anti-apoptotic signaling through Bcl-2 and survivin upregulation, as well as promotion of the epithelial-to-mesechymal transition through the Rho-ROCK pathway and alterations in cell adhesion molecules. High levels of CXCL12 seen in the bone marrow, liver, and spleen could partially explain why these are popular sites of metastases for many tumors. CXCL12 is a chemoattractant for lymphocytes at lower levels, but becomes chemorepellant at higher levels; it is unclear exactly what gradient exists in the tumor microenvironment and how this influences tumor-infiltrating lymphocytes. AMD3100 (Plerixafor or Mozobil) is a small molecule CXCR4 antagonist and is the most frequently used drug targeting the CXCL12-CXCR4/CXCR7 axis in clinical trials for gastrointestinal solid tumors currently. Other small molecules and monoclonal antibodies against CXCR4 are being trialed. Further understanding of the CXCL12- CXCR4/CXCR7 chemokine axis in the tumor microenvironment will allow more effective targeting of this pathway in combination immunotherapy.

Postoperative Morbidity After Resection of Recurrent Retroperitoneal Sarcoma: A Report from the Transatlantic Australasian RPS Working Group (TARPSWG).

BACKGROUND: This study aimed to evaluate perioperative morbidity after surgery for first locally recurrent (LR1) retroperitoneal sarcoma (RPS). Data concerning the safety of resecting recurrent RPS are lacking. METHODS: Data were collected on all patients undergoing resection of RPS-LR1 at 22 Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) centers from 2002 to 2011. Uni- and multivariable logistic models were fitted to study the association between major (Clavien-Dindo grade ≥ 3) complications and patient/surgery characteristics as well as outcome. The resected organ score, a method of standardizing the number of organs resected, as previously described by the TARPSWG, was used. RESULTS: The 681 patients in this study had a median age of 59 years, and 51.8% were female. The most common histologic subtype was de-differentiated liposarcoma (43%), the median resected organ score was 1, and 83.3% of the patients achieved an R0 or R1 resection. Major complications occurred for 16% of the patients, and the 90-day mortality rate was 0.4%. In the multivariable analysis, a transfusion requirement was found to be a significant predictor of major complications (p < 0.001) and worse overall survival (OS) (p = 0.010). However, having a major complication was not associated with a worse OS or a higher incidence of local recurrence or distant metastasis. CONCLUSIONS: A surgical approach to recurrent RPS is relatively safe and comparable with primary RPS in terms of complications and postoperative mortality when performed at specialized sarcoma centers. Because alternative effective therapies still are lacking, when indicated, resection of a recurrent RPS is a reasonable option. Every effort should be made to minimize the need for blood transfusions.

Analysis of Differentiation Changes and Outcomes at Time of First Recurrence of Retroperitoneal Liposarcoma by Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG).

BACKGROUND: Local recurrence following resection of retroperitoneal liposarcoma (RLPS) is common. Well-differentiated (WD) and dedifferentiated (DD) RLPS are distinct entities with differing outcomes. A few reports suggest that WDLPS can recur as DDLPS and that DDLPS can recur as WDLPS. This study evaluates whether this change in differentiation from the primary tumor to the first local recurrence impacts long-term outcomes. METHODS: Retrospective review from 22 sarcoma centers identified consecutive patients who underwent resection for a first locally recurrent RLPS from January 2002 to December 2011. Outcomes measured included overall survival, local recurrence, and distant metastasis. RESULTS: A total of 421 RPLS patients were identified. Of the 230 patients with primary DDLPS, 34 (15%) presented WDLPS upon recurrence (DD → WD); and of the 191 patients with primary WDLPS, 54 (28%) presented DDLPS upon recurrence (WD → DD). The 6-year overall survival probabilities (95% CI) for DD → DD, DD → WD, WD → WD, and WD → DD were 40% (32-48%), 73% (58-92%), 76% (68-85%), and 56% (43-73%) (p < 0.001), respectively. The 6-year second local recurrence incidence was 66% (59-73%), 63% (48-82%), 66% (57-76%), and 77% (66-90%), respectively. The 6-year distant metastasis incidence was 13% (9-19%), 3% (0.4-22%), 5% (2-11%), and 4% (1-16%), respectively. On multivariable analysis, DD → WD was associated with improved overall survival when compared with DD → DD (p < 0.001). Moreover, WD → DD was associated with a higher risk of LR (p = 0.025) CONCLUSION: A change in RLPS differentiation from primary tumor to first local recurrence appears to impact survival. These findings may be useful in counseling patients on their prognosis and subsequent management.

Neuroendocrine and Adrenal Tumors, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroendocrine and Adrenal Gland Tumors focus on the diagnosis, treatment, and management of patients with neuroendocrine tumors (NETs), adrenal tumors, pheochromocytomas, paragangliomas, and multiple endocrine neoplasia. NETs are generally subclassified by site of origin, stage, and histologic characteristics. Appropriate diagnosis and treatment of NETs often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Specialists include pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists. These guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine and adrenal tumors and are intended to assist with clinical decision-making. This article is focused on the 2021 NCCN Guidelines principles of genetic risk assessment and counseling and recommendations for well-differentiated grade 3 NETs, poorly differentiated neuroendocrine carcinomas, adrenal tumors, pheochromocytomas, and paragangliomas.

Patterns of recurrence and survival probability after second recurrence of retroperitoneal sarcoma: A study from TARPSWG.

BACKGROUND: In this series from the Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG), the authors examined longitudinal outcomes of patients with a second recurrence of retroperitoneal sarcoma (RPS) after complete resection of a first local recurrence (LR). METHODS: Data from patients undergoing resection of a first LR from January 2002 to December 2011were collected from 22 sarcoma centers. The primary outcome was overall survival (OS) after second recurrence. RESULTS: Second recurrences occurred in 400 of 567 patients (70.5%) after an R0/R1 resection of a first locally recurrent RPS. Patterns of disease recurrence were LR in 323 patients (80.75%), distant metastases (DM) in 55 patients (13.75%), and both LR and DM in 22 patients (5.5%). The main subtype among the LR group was liposarcoma (77%), whereas DM mainly were leiomyosarcomas (43.6%). In patients with a second LR only, a total of 200 patients underwent re-resection (61.9%). The 5-year OS rate varied significantly based on the pattern of failure (P < .001): 45.6% for the LR group, 25.5% for the DM group, and 0% for the group with LR and DM. The only factors found to be associated with improved OS on multivariable analysis were both time between second surgery and the development of the second recurrence (32 months vs 8 months: hazard ratio, 0.44 [P < .001]) and surgery for second recurrence (yes vs no: hazard ratio, 3.25 [P < .001]). The 5-year OS rate for patients undergoing surgery for a second LR was 59% versus 18% in the patients not deemed suitable for surgical resection. CONCLUSIONS: Survival rates after second recurrence of RPS varied based on patterns of disease recurrence and treatment. Durable disease-free survivors were identified after surgery for second LR in patients selected for this intervention.

Dendritic Cells in the Tumor Microenvironment.

Dendritic cells (DCs) are professional antigen-presenting cells (APCs) of the immune system. They capture foreign antigens and can present them to lymphocytes, that is, T cells and B cells, to activate them. DCs are the most potent of all immune cells at inducing the adaptive immune system. Thus, the presence of DCs at the anatomical site of the immune challenge is imperative for the immune system to mount an effective immune response. From the anatomical site of the immune challenge, DCs cargo antigens to the draining lymph nodes, specialized immune organs where adaptive immunity is generated. DCs are heterogeneous as a type of immune cell, and various subsets of DCs have been reported and their functions described. In this chapter, we discuss various aspects of DC development and function. We further discuss how various tumor microenvironments can affect DC development, function, and migration, thus evading a strong adaptive immune response.

Screening for Pancreatic Cancer: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Pancreatic adenocarcinoma is the third most common cause of cancer death among men and women in the United States. Objective: To systematically review benefits and harms of screening for pancreatic adenocarcinoma to inform the US Preventive Services Task Force. Data Sources: MEDLINE, PubMed, and the Cochrane Collaboration Registry of Controlled Trials, from January 2002 through April 27, 2018; surveillance through March 22, 2019. Study Selection: Studies of adults with or without risk factors for pancreatic adenocarcinoma (eg, family history of pancreatic cancer, personal history of new-onset diabetes) undergoing imaging-based screening; studies of treatment for adults with screen-detected or asymptomatic pancreatic adenocarcinoma. Included study designs were randomized clinical trials, nonrandomized controlled intervention studies, diagnostic accuracy studies with a reference standard, cohort studies, and case-control studies (for evaluation of harms only). Studies consisting entirely of populations with known genetic syndromes associated with pancreatic cancer were excluded. Data Extraction and Synthesis: Two investigators independently reviewed abstracts and full-text articles and rated included studies for quality; data were quantitatively analyzed to calculate a pooled diagnostic yield and narratively synthesized. Main Outcomes and Measures: Mortality, morbidity, or quality of life; diagnostic accuracy of screening tests; any harm of screening or treatment. Results: Thirteen fair-quality prospective cohort screening studies (N = 1317) conducted predominantly in populations at high familial risk for pancreatic adenocarcinoma were included. No studies reported on the effect of screening on morbidity or mortality or on the effectiveness of treatment for screen-detected pancreatic adenocarcinoma. Although no studies evaluated the diagnostic accuracy of screening tests, all 13 studies reported the diagnostic yield. Yields ranged from 0 to 75 cases per 1000 persons in studies using endoscopic ultrasound, magnetic resonance imaging, and/or computed tomography-based screening. In total, 18 cases of pancreatic adenocarcinoma were detected in 1156 adults at increased familial risk and 0 cases were detected in 161 average-risk adults. In 8 studies (n = 675) assessing procedural harms of screening, no serious harms from initial screening were reported. Two studies (n = 271) found no evidence of psychosocial harms related to screening. Evidence of surgical harms was limited. Conclusions and Relevance: Imaging-based screening in groups at high familial risk can detect pancreatic adenocarcinoma with limited evidence of minimal harms. However, the effect of screening on morbidity and mortality in groups at high familial risk has not been studied, and no data are available in average-risk populations. There is limited evidence to assess benefits or harms of surgical intervention for screen-detected pancreatic adenocarcinoma.

NCCN Guidelines Insights: Neuroendocrine and Adrenal Tumors, Version 2.2018.

The NCCN Guidelines for Neuroendocrine and Adrenal Tumors provide recommendations for the management of adult patients with neuroendocrine tumors (NETs), adrenal gland tumors, pheochromocytomas, and paragangliomas. Management of NETs relies heavily on the site of the primary NET. These NCCN Guidelines Insights summarize the management options and the 2018 updates to the guidelines for locoregional advanced disease, and/or distant metastasis originating from gastrointestinal tract, bronchopulmonary, and thymus primary NETs.

T-cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death-ligand 1 expression in patients with soft tissue sarcomas.

BACKGROUND: Patients with metastatic sarcomas have poor outcomes and although the disease may be amenable to immunotherapies, information regarding the immunologic profiles of soft tissue sarcoma (STS) subtypes is limited. METHODS: The authors identified patients with the common STS subtypes: leiomyosarcoma, undifferentiated pleomorphic sarcoma (UPS), synovial sarcoma (SS), well-differentiated/dedifferentiated liposarcoma, and myxoid/round cell liposarcoma. Gene expression, immunohistochemistry for programmed cell death protein (PD-1) and programmed death-ligand 1 (PD-L1), and T-cell receptor Vß gene sequencing were performed on formalin-fixed, paraffin-embedded tumors from 81 patients. Differences in liposarcoma subsets also were evaluated. RESULTS: UPS and leiomyosarcoma had high expression levels of genes related to antigen presentation and T-cell infiltration. UPS were found to have higher levels of PD-L1 (P≤.001) and PD-1 (P≤.05) on immunohistochemistry and had the highest T-cell infiltration based on T-cell receptor sequencing, significantly more than SS, which had the lowest (P≤.05). T-cell infiltrates in UPS also were more oligoclonal compared with SS and liposarcoma (P≤.05). A model adjusted for STS histologic subtype found that for all sarcomas, T-cell infiltration and clonality were highly correlated with PD-1 and PD-L1 expression levels (P≤.01). CONCLUSIONS: In the current study, the authors provide the most detailed overview of the immune microenvironment in sarcoma subtypes to date. UPS, which is a more highly mutated STS subtype, provokes a substantial immune response, suggesting that it may be well suited to treatment with immune checkpoint inhibitors. The SS and liposarcoma subsets are less mutated but do express immunogenic self-antigens, and therefore strategies to improve antigen presentation and T-cell infiltration may allow for successful immunotherapy in patients with these diagnoses. Cancer 2017;123:3291-304. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Neuroendocrine tumors, version 1.2015.

Neuroendocrine tumors (NETs) comprise a broad family of tumors that may or may not be associated with symptoms attributable to hormonal hypersecretion. The NCCN Clinical Practice Guidelines in Oncology for Neuroendocrine Tumors discuss the diagnosis and management of both sporadic and hereditary NETs. This selection from the guidelines focuses on sporadic NETs of the pancreas, gastrointestinal tract, lung, and thymus.

A contemporary large single-institution evaluation of resected retroperitoneal sarcoma.

PURPOSE: Retroperitoneal sarcomas (RPS) are rare malignancies, comprising just 10-15 % of all soft-tissue sarcomas. These are challenging tumors to treat, with surgical resection being the only modality capable of providing a cure. This study analyzed the management and survival of patients resected at a large academic institution. METHODS: A retrospective study of all patients with primary localized RPS referred to the University of Washington between January 2000 and January 2013 was performed. Univariate and multivariate Cox regression models were used to analyze progression-free survival (PFS) and overall survival (OS) by patient, tumor, and treatment variables. RESULTS: The study identified 132 patients. Median follow-up was 31.8 months. Median PFS was 33 months, and median OS was 111 months. Sixty patients (45.5 %) underwent a margin-negative resection (R0), 59 (44.7 %) had a microscopic margin-positive resection (R1), and 7 (5.3 %) had a macroscopic margin-positive resection (R2). Forty (30.3 %) patients received preoperative radiation, 28 (21.2 %) received neoadjuvant chemotherapy, and 7 (5.3 %) received both. Tumor grade and microscopic margin status emerged as statistically significant predictors for both PFS and OS. Tumor size was also found to correlate with PFS. No significant difference in OS or PFS was observed for histologic subtype, neoadjuvant chemotherapy, or neoadjuvant radiation. CONCLUSIONS: Complete surgical resection should remain the mainstay of management for RPS, with emphasis on achieving negative microscopic margins. Neither neoadjuvant chemotherapy nor radiation was shown to significantly improve survival, and their unclear role in the management of RPS requires evaluation in a prospective setting.

The prognostic value of liver tumor T cell infiltrates.

Tumor infiltrating lymphocytes (TIL) have been demonstrated to predict oncologic outcomes following resection of primary intrahepatic neoplasms and metastatic liver tumors. Despite strong immunosuppressive factors within the intrahepatic space, TIL are frequently demonstrated in liver tumors. The presence of TIL within liver tumors provides evidence of a host immune response that may be protective, but often is rendered ineffective by tumor induced immune dysfunction. In this review, we discuss techniques involved in studying TIL and subsets of TIL commonly identified. We emphasize the unique nature of the intrahepatic milieu that promotes immunosuppression, and how liver TIL and TIL ratios can be used as indicators of prognosis. Several types of primary and metastatic liver tumors are considered to highlight the similarities and important differences in TIL responses, which likely reflect how intrahepatic immunity is influenced by tumor biology. The studies we discuss indicate that tumor infiltration by suppressor cells and expression of immunoinhibitory molecules by TIL limits the anti-tumor immune function of effector T cells. Most patients fail to mount an adequate immune response to liver tumors, which provides compelling rationale for clinical study of immunotherapy for intrahepatic neoplasms.