Search

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.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.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.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.

Immune checkpoint inhibitors (ICI) have not yielded significant efficacy in pancreatic ductal adenocarcinoma (PDA), despite the role of the innate and adaptive immune systems on progression and survival. However, recently identified pathways have identified new targets and generated promising clinical investigations into promoting an effective immune-mediated antitumor response in PDA.We review biological mechanisms associated with immunotherapy resistance and outline strategies for therapeutic combinations with established and novel therapies in PDA.Pancreatic cancers rarely benefit from treatment with ICI due to an immunosuppressive tumor microenvironment (TME). New understandings of factors associated with the suppressive TME include low- and poor-quality neoantigens, constrained effector T cells infiltration, and the presence of a dense, suppressive myeloid cell population. These findings have been translated into new clinical investigations evaluating novel therapies in combination with ICI and/or standard systemic chemotherapy and radiotherapy. The epithelial, immune, and stromal compartments are intricately related in PDA, and the framework for successful targeting of this disease requires a comprehensive and personalized approach.

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.

Immune cell infiltration into solid tumors, their movement within the tumor microenvironment (TME), and interaction with other immune cells are controlled by their directed migration towards gradients of chemokines. Dysregulated chemokine signaling in TME favors the growth of tumors, exclusion of effector immune cells, and abundance of immunosuppressive cells. Key chemokines directing the migration of immune cells into tumor tissue have been identified. In this review, we discuss well-studied chemokine receptors that regulate migration of effector and immunosuppressive immune cells in the context of cancer immunology. We discuss preclinical models that have described the role of respective chemokine receptors in immune cell migration into TME and review preclinical and clinical studies that target chemokine signaling as standalone or combination therapies.

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 β-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.

Purpose: This clinical trial combined pembrolizumab and vorinostat in recurrent/metastatic squamous cell carcinomas of the head and neck (HN), and salivary gland cancer (SGC). Patients and Methods: Patients with progressing incurable HN and SGC, Eastern Cooperative Oncology Group (ECOG) ≤1, no prior immunotherapy, RECIST1.1 measurable disease, and normal organ function were eligible. Pembrolizumab 200 mg was given intravenous every 21 days, and vorinostat 400 mg given orally 5 days on and 2 days off during each 21-day cycle. Primary endpoints were safety and objective response rates. Results: From November 2015 to August 2017, 25 patients with HN and 25 SGC were enrolled. Median age was 61 (range, 33–86) years, 39 (78%) were male, 21 (62%) were never smokers, and 27 (54%) had ECOG 0. In HN, 13 (52%) were p16+ oropharynx. Most common SGC histologies were adenoid cystic 12 (48%), acinic cell 3 (12%), and mucoepidermoid 3 (12%). Adverse events (AEs) in all patients were: 27 (54%) with grade ≥ 1 and 18 (36%) with grade ≥ 3. The most common AEs in all patients were renal insufficiency in seven, (14%), fatigue in six, (12%), and nausea in three (6%). There were three (12%) deaths on study. Responses in HN were complete response (CR) 0, partial response (PR) eight (32%), and stable disease (SD) five (20%). Efficacy in SGCs was CR 0, PR four (16%) in one lymphoepithelioma-like carcinoma, two acinic cell, one adenoid cystic, and SD 14 (56%). In the HN group, median follow-up (mFUP) was 12.6 months, median overall survival (mOS) was 12.6 months, and median progression-free survival (mPFS) was 4.5 months. In SGC, mFUP was 13.1 months, mOS was 14.0 months, and mPFS was 6.9 months. Conclusions: This combination demonstrated activity in HN, with fewer responses in SGC. Toxicities were higher than reported with pembrolizumab alone.

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.Lay SummaryEnhanced 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.

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.

Interferon-γ (IFNγ) has been studied as a cancer treatment with limited evidence of clinical benefit. However, it could play a role in cancer immunotherapy combination treatments. Despite high expression of immunogenic cancer–testis antigens, synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) have a cold tumor microenvironment (TME), with few infiltrating T cells and low expression of major histocompatibility complex class I (MHC-I). We hypothesized that IFNγ treatment could drive inflammation in a cold TME, facilitating further immunotherapy. We conducted a phase 0 clinical trial treating 8 SS or MRCL patients with weekly systemic IFNγ. We performed pre- and posttreatment biopsies. IFNγ changed the SS and MRCL TME, inducing tumor-surface MHC-I expression and significant T-cell infiltration (P < 0.05). Gene-expression analysis suggested increased tumor antigen presentation and less exhausted phenotypes of the tumor-infiltrating T cells. Newly emergent antigen-specific humoral and/or T-cell responses were found in 3 of 7 evaluable patients. However, increased expression of PD-L1 was observed on tumor-infiltrating myeloid cells and in some cases tumor cells. These findings suggest that systemic IFNγ used to convert SS and MRCL into “hot” tumors will work in concert with anti–PD-1 therapy to provide patient benefit.

BackgroundHuman immune cells, including monocyte-derived macrophages, can be engineered to deliver proinflammatory cytokines, bispecific antibodies, and chimeric antigen receptors to support immune responses in different disease settings. When gene expression is regulated by constitutively active promoters, lentiviral payload gene expression is unregulated, and can result in potentially toxic quantities of proteins. Regulated delivery of lentivirally encoded proteins may allow localized or conditional therapeutic protein expression to support safe delivery of adoptively transferred, genetically modified cells with reduced capacity for systemic toxicities.MethodsIn this study, we engineered human macrophages to express genes regulated by hypoxia responsive elements included in the lentiviral promoter region to drive conditional lentiviral gene expression only under hypoxic conditions. We tested transduced macrophages cultured in hypoxic conditions for the transient induced expression of reporter genes and the secreted cytokine, interleukin-12. Expression of hypoxia-regulated genes was investigated both transcriptionally and translationally, and in the presence of human tumor cells in a slice culture system. Finally, hypoxia-regulated gene expression was evaluated in a subcutaneous humanized-mouse cancer model.ResultsEngineered macrophages were shown to conditionally and tranisently express lentivirally encoded gene protein products, including IL-12 in hypoxic conditions in vitro. On return to normoxic conditions, lentiviral payload expression returned to basal levels. Reporter genes under the control of hypoxia response elements were upregulated under hypoxic conditions in the presence of human colorectal carcinoma cells and in the hypoxic xenograft model of glioblastoma, suggesting utility for systemic engineered cell delivery capable of localized gene delivery in cancer.ConclusionsMacrophages engineered to express hypoxia-regulated payloads have the potential to be administered systemically and conditionally express proteins in tissues with hypoxic conditions. In contrast to immune cells that function or survive poorly in hypoxic conditions, macrophages maintain a proinflammatory phenotype that may support continued gene and protein expression when regulated by conditional hypoxia responsive elements and naturally traffic to hypoxic microenvironments, making them ideal vehicles for therapeutic payloads to hypoxic tissues, such as solid tumors. With the ability to fine-tune delivery of potent proteins in response to endogenous microenvironments, macrophage-based cellular therapies may therefore be designed for different disease settings.

CD4(+) T cells that recognize tumor antigens are required for immune checkpoint inhibitor efficacy in murine models but their contributions in human cancer are unclear. We used single cell RNA sequencing and T cell receptor sequences to identify signatures and functional correlates of tumor specific CD4(+) T cells infiltrating human melanoma. Conventional CD4(+) T cells that recognize tumor neoantigens express CXCL13 and are subdivided into clusters expressing memory and T follicular helper markers, and those expressing cytolytic markers, inhibitory receptors, and IFN-γ. The frequency of CXCL13(+) CD4(+) T cells in the tumor correlated with the transcriptional states of CD8(+) T cells and macrophages, maturation of B cells, and patient survival. Similar correlations were observed in a breast cancer cohort. These results identify phenotypes and functional correlates of tumor specific CD4(+) T cells in melanoma and suggest the possibility of using such cells to modify the tumor microenvironment.

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.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.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%) (p0.001), 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 (p0.001). 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.

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.

BackgroundThough currently approved immunotherapies, including chimeric antigen receptor T cells and checkpoint blockade antibodies, have been successfully used to treat hematological and some solid tumor cancers, many solid tumors remain resistant to these modes of treatment. In solid tumors, the development of effective antitumor immune responses is hampered by restricted immune cell infiltration and an immunosuppressive tumor microenvironment (TME). An immunotherapy that infiltrates and persists in the solid TME, while providing local, stable levels of therapeutic to activate or reinvigorate antitumor immunity could overcome these challenges faced by current immunotherapies.MethodsUsing lentivirus-driven engineering, we programmed human and murine macrophages to express therapeutic payloads, including Interleukin (IL)-12. In vitro coculture studies were used to evaluate the effect of genetically engineered macrophages (GEMs) secreting IL-12 on T cells and on the GEMs themselves. The effects of IL-12 GEMs on gene expression profiles within the TME and tumor burden were evaluated in syngeneic mouse models of glioblastoma and melanoma and in human tumor slices isolated from patients with advanced gastrointestinal malignancies.ResultsHere, we present a cellular immunotherapy platform using lentivirus-driven genetic engineering of human and mouse macrophages to constitutively express proteins, including secreted cytokines and full-length checkpoint antibodies, as well as cytoplasmic and surface proteins that overcomes these barriers. GEMs traffic to, persist in, and express lentiviral payloads in xenograft mouse models of glioblastoma, and express a non-signaling truncated CD19 surface protein for elimination. IL-12-secreting GEMs activated T cells and induced interferon-gamma (IFNγ) in vitro and slowed tumor growth resulting in extended survival in vivo. In a syngeneic glioblastoma model, IFNγ signaling cascades were also observed in mice treated with mouse bone-marrow-derived GEMs secreting murine IL-12. These findings were reproduced in ex vivo tumor slices comprised of intact MEs. In this setting, IL-12 GEMs induced tumor cell death, chemokines and IFNγ-stimulated genes and proteins.ConclusionsOur data demonstrate that GEMs can precisely deliver titratable doses of therapeutic proteins to the TME to improve safety, tissue penetrance, targeted delivery and pharmacokinetics.

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.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.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.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.

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

Summary Metastatic colorectal cancer (CRC) is a major cause of cancer-related death, and incidence is rising in younger populations (younger than 50 years). Current chemotherapies can achieve response rates above 50%, but immunotherapies have limited value for patients with microsatellite-stable (MSS) cancers. The present study investigates the impact of chemotherapy on the tumor immune microenvironment. We treat human liver metastases slices with 5-fluorouracil (5-FU) plus either irinotecan or oxaliplatin, then perform single-cell transcriptome analyses. Results from eight cases reveal two cellular subtypes with divergent responses to chemotherapy. Susceptible tumors are characterized by a stemness signature, an activated interferon pathway, and suppression of PD-1 ligands in response to 5-FU+irinotecan. Conversely, immune checkpoint TIM-3 ligands are maintained or upregulated by chemotherapy in CRC with an enterocyte-like signature, and combining chemotherapy with TIM-3 blockade leads to synergistic tumor killing. Our analyses highlight chemomodulation of the immune microenvironment and provide a framework for combined chemo-immunotherapies., Graphical Abstract, Highlights CRLM slice culture can assess immune response to chemotherapy Single-cell analysis identifies cancer subtypes with differing response to chemotherapy 5-FU+irinotecan modulates interferon and PD-L1 pathways in stem-like CRLM Combining chemotherapy with TIM-3 blockade is synergistic in enterocyte-like CRLM, The response of colorectal liver metastases (CRLM) to chemotherapy is analyzed in 3D organotypic tumor slices by single-cell RNA-seq. Jabbari et al. find two subtypes (stem-like and enterocyte-like) of CRLM that express different immune checkpoint ligands and respond differently to chemotherapy. The study highlights the chemomodulation of the tumor immune microenvironment that can be targeted therapeutically.

Current clinical treatment regimens, including many emergent immune strategies (e.g., checkpoint inhibitors) have done little to affect the devastating course of pancreatic ductal adenocarcinoma (PDA). Clinical trials for PDA often employ multi-modal treatment, and have started to incorporate stromal-targeted therapies, which have shown promising results in early reports. Focused ultrasound (FUS) is one such therapy that is uniquely equipped to address local and systemic limitations of conventional cancer therapies as well as emergent immune therapies for PDA. FUS methods can non-invasively generate mechanical and/or thermal effects that capitalize on the unique oncogenomic/proteomic signature of a tumor. Potential benefits of FUS therapy for PDA include: (1) emulsification of targeted tumor into undenatured antigens in situ, increasing dendritic cell maturation, and increasing intra-tumoral CD8+/ T regulatory cell ratio and CD8+ T cell activity; (2) reduction in intra-tumoral hypoxic stress; (3) modulation of tumor cell membrane protein localization to enhance immunogenicity; (4) modulation of the local cytokine milieu toward a Th1-type inflammatory profile; (5) up-regulation of local chemoattractants; (6) remodeling the tumor stroma; (7) localized delivery of exogenously packaged immune-stimulating antigens, genes and therapeutic drugs. While not all of these results have been studied in experimental PDA models to date, the principles garnered from other solid tumor and disease models have direct relevance to the design of optimal FUS protocols for PDA. In this review, we address the pertinent limitations in current and emergent immune therapies that can be improved with FUS therapy for PDA.

Pancreatic cancer is a lethal disease with poor prognosis. Gemcitabine has been the first line systemic treatment for pancreatic cancer. However, the rapid development of drug resistance has been a major hurdle in gemcitabine therapy leading to unsatisfactory patient outcomes. With the recent renewed understanding of glutamine metabolism involvement in drug resistance and immuno-response, we investigated the anti-tumor effect of a glutamine analog (6-diazo-5-oxo-L-norleucine) as an adjuvant treatment to sensitize chemoresistant pancreatic cancer cells. We demonstrate that disruption of glutamine metabolic pathways improves the efficacy of gemcitabine treatment. Such a disruption induces a cascade of events which impacts glycan biosynthesis through Hexosamine Biosynthesis Pathway (HBP), as well as cellular redox homeostasis, resulting in global changes in protein glycosylation, expression and functional effects. The proteome alterations induced in the resistant cancer cells and the secreted exosomes are intricately associated with the reduction in cell proliferation and the enhancement of cancer cell chemosensitivity. Proteins associated with EGFR signaling, including downstream AKT-mTOR pathways, MAPK pathway, as well as redox enzymes were downregulated in response to disruption of glutamine metabolic pathways.

With the advent of immunotherapy as an integral component of multidisciplinary solid tumor treatment, we are confronted by an unfamiliar and novel pattern of radiographic responses to treatment. Enlargement of tumors or even new lesions may not represent progression, but rather reflect what will ultimately evolve into a clinically beneficial response. In addition, the kinetics of radiographic changes in response to immunotherapy treatments may be distinct from what has been observed with cytotoxic chemotherapy and radiation. The phenomenon of pseudoprogression has been documented in patients receiving immunotherapeutic agents, such as checkpoint inhibitors and cellular therapies. Currently, there are no clinical response guidelines that adequately account for pseudoprogression and solid tumor responses to immunotherapy in general. Even so, response criteria have evolved to account for the radiographic manifestations of novel therapies. The evolution of World Health Organization (WHO) criteria and Response Evaluation Criteria in Solid Tumors (RECIST), along with the emergence of immune-related response criteria (irRC) and the immune Response Evaluation Criteria in Solid Tumors (iRECIST) reflect the need for new frameworks. This review evaluates the relationship between pseudoprogression, clinical outcomes, and our current understanding of the biology of pseudoprogression. To achieve our goal, we discuss unusual response patterns in patients receiving immunotherapy. We seek to develop a deeper understanding of radiographic responses to immunotherapy such that clinical benefit is not underappreciated in individual patients and during clinical investigation.

Purpose: The role of surgery for first relapse locally recurrent retroperitoneal sarcoma (RPS-LR1) is uncertain. We report outcomes of the largest RPS-LR1 series and propose a new prognostic nomogram. Experimental Design: Patients with consecutive RPS-LR1 without distant metastases who underwent resection at 22 centers (2002–2011) were included. Endpoints were disease-free and overall survival (DFS, OS) and crude-cumulative-incidence (CCI) of local/distant recurrence from second surgery. Nomograms predicting DFS and OS from second surgery were developed and validated (calibration plots); discrimination was assessed (Harrell C index). Results: Of 684 patients identified, full prognostic variable data were available for 602. Initial surgery for primary RPS was performed at our institutions in 188 patients (31%) and elsewhere in 414 (69%). At a median follow-up of 119 months [Interquartile range (IQR), 80–169] from initial surgery and 75 months (IQR 50–105) from second surgery, 6-year DFS and OS were 19.2% [95% confidence interval (CI), 16.0–23.0%] and 54.1% (95% CI, 49.8–58.8%), respectively. Recurrence patterns and survival probability were histology-specific, with liposarcoma subtypes having the highest 6-year CCI of second local recurrence (LR, 60.2%–70.9%) and leiomyosarcoma (LMS) having higher 6-year CCI of distant metastasis (DM, 36.3%). Nomograms included age at second surgery, multifocality, grade, completeness of second surgery, histology, chemotherapy/radiotherapy at first surgery, and number of organs resected at first surgery. OS and DFS nomograms showed good calibration and discriminative ability (C index 0.70 and 0.67, respectively). Conclusions: We developed nomograms to predict DFS and OS for patients undergoing RPS-LR1 resection. Nomograms provide individualized, disease-relevant estimations of survival for RPS-LR1 patients and assist in clinical decisions.

Purpose: Pancreatic ductal adenocarcinoma (PDA) is rarely cured, and single-agent immune checkpoint inhibition has not demonstrated clinical benefit despite the presence of large numbers of CD8+ T cells. We hypothesized that tumor-infiltrating CD8+ T cells harbor latent antitumor activity that can be reactivated using combination immunotherapy. Experimental Design: Preserved human PDA specimens were analyzed using multiplex IHC (mIHC) and T-cell receptor (TCR) sequencing. Fresh tumor was treated in organotypic slice culture to test the effects of combination PD-1 and CXCR4 blockade. Slices were analyzed using IHC, flow cytometry, and live fluorescent microscopy to assess tumor kill, in addition to T-cell expansion and mobilization. Results: mIHC demonstrated fewer CD8+ T cells in juxtatumoral stroma containing carcinoma cells than in stroma devoid of them. Using TCR sequencing, we found clonal expansion in each tumor; high-frequency clones had multiple DNA rearrangements coding for the same amino acid binding sequence, which suggests response to common tumor antigens. Treatment of fresh human PDA slices with combination PD-1 and CXCR4 blockade led to increased tumor cell death concomitant with lymphocyte expansion. Live microscopy after combination therapy demonstrated CD8+ T-cell migration into the juxtatumoral compartment and rapid increase in tumor cell apoptosis. Conclusions: Endogenous tumor-reactive T cells are present within the human PDA tumor microenvironment and can be reactivated by combined blockade of PD-1 and CXCR4. This provides a new basis for the rational selection of combination immunotherapy for PDA. See related commentary by Medina and Miller, p. 3747

Author(s): Kohli, Karan; Yao, Lu; Nowicki, Theodore Scott; Zhang, Shihong; Black, Ralph Graeme; Schroeder, Brett A; Farrar, Erik A; Cao, Jianhong; Sloan, Heather; Stief, Dawn; Cranmer, Lee D; Wagner, Michael J; Hawkins, Douglas S; Pillarisetty, Venu G; Ribas, Antoni; Campbell, Jean; Pierce, Robert H; Kim, Edward Y; Jones, Robin L; Riddell, Stanley R; Yee, Cassian; Pollack, Seth M | Abstract: BackgroundSynovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are ideal solid tumors for the development of adoptive cellular therapy (ACT) targeting NY-ESO-1, as a high frequency of tumors homogeneously express this cancer-testes antigen. Data from early phase clinical trials have shown antitumor activity after the adoptive transfer of NY-ESO-1-specific T cells. In these studies, persistence of NY-ESO-1 specific T cells is highly correlated with response to ACT, but patients often continue to have detectable transferred cells in their peripheral blood following progression.MethodWe performed a phase I clinical trial evaluating the safety of NY-ESO-1-specific endogenous T cells (ETC) following cyclophosphamide conditioning. Peripheral blood mononuclear cells (PBMCs) from treated patients were evaluated by flow cytometry and gene expression analysis as well as through ex vivo culture assays with and without IL-15.ResultsFour patients were treated in a cohort using ETC targeting NY-ESO-1 following cyclophosphamide conditioning. Treatment was well tolerated without significant toxicity, but all patients ultimately had disease progression. In two of four patients, we obtained post-treatment tumor tissue and in both, NY-ESO-1 antigen was retained despite clear detectable persisting NY-ESO-1-specific T cells in the peripheral blood. Despite a memory phenotype, these persisting cells lacked markers of proliferation or activation. However, in ex vivo culture assays, they could be induced to proliferate and kill tumor using IL-15. These results were also seen in PBMCs from two patients who received gene-engineered T-cell receptor-based products at other centers.ConclusionsETC targeting NY-ESO-1 with single-agent cyclophosphamide alone conditioning was well tolerated in patients with SS and those with MRCL. IL-15 can induce proliferation and activity in persisting NY-ESO-1-specific T cells even in patients with disease progression following ACT. These results support future work evaluating whether IL-15 could be incorporated into ACT trials post-infusion or at the time of progression.

Robotic technology is being utilized in multiple hepatobiliary procedures, including hepatic resections. The benefits of minimally invasive surgical approaches have been well documented; however, there is some concern that robotic liver surgery may be prohibitively costly and therefore should be limited on this basis. A single-institution, retrospective cohort study was performed of robotic and open liver resections performed for benign and malignant pathologies. Clinical and cost outcomes were analyzed using adjusted generalized linear regression models. Clinical and cost data for 71 robotic (RH) and 88 open (OH) hepatectomies were analyzed. Operative time was significantly longer in the RH group (303 vs. 253 min; p = 0.004). Length of stay was more than 2 days shorter in the RH group (4.2 vs. 6.5 days; p

Although immunotherapy is currently being widely applied to treat a variety of cancers, there is great heterogeneity in the response to these treatments. Many in the field hypothesize that this may be attributable to the characteristics of each individual tumor immune microenvironment, in addition to systemic immune factors. Therefore, understanding the immune cell microenvironment in a variety of tumors is critically important. Specifically, the interactions among immune, stromal, and cancer cells, along with other factors in tumors, may hold the key to developing rational personalized combinations of immunotherapeutic drugs. We recently developed an organotypic slice culture technique, which enables precise study of the pancreatic ductal adenocarcinoma (PDA) tumor microenvironment. We used a Vibratome to cut fresh human tumor tissue into 250 μm thick slices, and cultured slices on cell culture inserts with 0.4 μm pore to produce our tumor slice culture (TSC) system. We showed that TSC maintained many elements of the original tumor microenvironment and architecture for approximately one week. Using this slice culture technique for PDA, we demonstrated that immune cells, including T cells and macrophages, cancer cells, and stromal myofibroblasts were present throughout the culture period. TSCs were functionally responsive to drug treatment. Live PDA slices could be stained for multicolor immunofluorescence imaging of each of the primary cellular constituents of the tumor. Finally, autologous CFSE-labeled splenocytes were observed to readily migrate into cocultured tumor slices.

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.

IntroductionPancreaticoduodenectomy is a complex surgical procedure associated with high morbidity and prolonged length of stay. Enhanced recovery after surgery principles have reduced complications rate and length of stay for multiple types of operations. We hypothesized that implementation of a standardized perioperative care pathway would facilitate safe discharge by five days after pancreaticoduodenectomy.MethodsWe performed a retrospective cohort study of patients undergoing pancreaticoduodenectomy 18 months prior to and 18 months following implementation of a perioperative care pathway at a quaternary center performing high volume pancreatic surgery.ResultsA total of 145 patients underwent pancreaticoduodenectomy (mean age 63 ± 10 years, 52% female), 81 before and 64 following pathway implementation, and the groups were similar in terms of preoperative comorbidities. The percentage of patients discharged within 5 days of surgery increased from 36% to 64% following pathway implementation (p = 0.001), with no observed differences in post-operative serious adverse events (p = 0.34), pancreatic fistula grade B or C (p = 0.28 and p = 0.27 respectively), or delayed gastric emptying (p = 0.46). Multivariate regression analysis showed length of stay ≤5 days three times more likely after pathway implementation. Rates of readmission within 30 days (20% pre- vs. 22% post-pathway (p = 0.75)) and 90 days (27% pre- vs. 36% post-pathway (p = 0.27)) were unchanged after pathway implementation, and were no different between patients discharged before or after day 5 at both 30 days (19% ≤5 days vs. 23% ≥ 6 days (p = 0.68)) and 90 days (32% ≤5 days vs. 30% ≥ 6 days (p = 0.81)).ConclusionsStandardizing perioperative care via enhanced recovery protocols for patients undergoing pancreaticoduodenectomy facilitates safe discharge by post-operative day five.

INTRODUCTION: Retroperitoneal sarcoma (RPS) is a rare disease accounting for 0.1%–0.2% of all malignancies. Management of RPS is complex and requires multidisciplinary, tailored treatment strategies at all stages, but especially in the context of metastatic or multifocal recurrent disease. Due to the rarity and heterogeneity of this family of diseases, the literature to guide management is limited. METHODS: The Trans-Atlantic Retroperitoneal Sarcoma Working Group (TARPSWG) is an international collaboration of sarcoma experts from all disciplines convened in an effort to overcome these limitations. The TARPSWG has compiled the available evidence surrounding metastatic and multifocally recurrent RPS along with expert opinion in an iterative process to generate a consensus document regarding the complex management of this disease. The objective of this document is to guide sarcoma specialists from all disciplines in the diagnosis and treatment of multifocal recurrent or metastatic RPS. RESULTS: All aspects of patient assessment, diagnostic processes, local and systemic treatments, and palliation are reviewed in this document, and consensus recommendations provided accordingly. Recommendations were guided by available evidence, in conjunction with expert opinion where evidence was lacking. CONCLUSIONS: This consensus document combines the available literature regarding the management of multifocally recurrent or metastastic RPS with the practical expertise of high-volume sarcoma centers from multiple countries. It is designed as a tool for decision making in the complex multidisciplinary management of this condition and is expected to standardize management across centers, thereby ensuring that patients receive the highest quality care.

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.

Choledochal cysts (CDCs) are believed to represent a risk factor for the development of neoplasia. However, the frequency and morphology of neoplastic changes have not been systematically studied, especially in North America. Our aims were to study the frequency and morphology of preneoplastic/neoplastic changes of CDCs. Thirty-six cysts were subjected to clinicopathological analyses. Metaplasia was found in 14 of 35, of which 9 had biliary intraepithelial neoplasia (BilIN). Of the 14 with metaplasia, 13 showed pyloric gland; 5, intestinal; and 2, squamous. BilINs included 6 BilIN-1, 2 BilIN-2, and 2 BilIN-3. Carcinoma was identified in 5 cases of which 3 were associated with metaplasia and BilIN. Only 1 of 18 cases without metaplasia had BilIN, and none had carcinoma (P = .0008). There was a trend toward more BilIN and carcinoma with intestinal rather than with pyloric gland metaplasia. All cases with metaplasia or/and BilIN were negative for MUC1. All cases with intestinal metaplasia were positive for CK20, CDX2, and MUC2, whereas cases with pyloric gland were positive for MUC6. MUC1, CEA, and B72.3 were positive only in carcinoma. There was a trend toward increasing p53 and Ki-67 from metaplasia to BilIN to carcinoma. Four of 5 patients with carcinoma died, and one was alive with disease. All others were free of disease except for one who developed new cysts. CDCs are associated with a high rate of BilIN (28.5%) and carcinoma (14.3%). CDCs show a sequence of tumor progression from metaplasia to BilIN and carcinoma.

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.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.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.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.

Pancreatic adenocarcinoma is the third most common cause of cancer death among men and women in the United States.To systematically review benefits and harms of screening for pancreatic adenocarcinoma to inform the US Preventive Services Task Force.MEDLINE, PubMed, and the Cochrane Collaboration Registry of Controlled Trials, from January 2002 through April 27, 2018; surveillance through March 22, 2019.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.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.Mortality, morbidity, or quality of life; diagnostic accuracy of screening tests; any harm of screening or treatment.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.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.

Summary Inflammation is paramount in pancreatic oncogenesis. We identified a uniquely activated γδT cell population, which constituted ∼40% of tumor-infiltrating T cells in human pancreatic ductal adenocarcinoma (PDA). Recruitment and activation of γδT cells was contingent on diverse chemokine signals. Deletion, depletion, or blockade of γδT cell recruitment was protective against PDA and resulted in increased infiltration, activation, and Th1 polarization of αβT cells. Although αβT cells were dispensable to outcome in PDA, they became indispensable mediators of tumor protection upon γδT cell ablation. PDA-infiltrating γδT cells expressed high levels of exhaustion ligands and thereby negated adaptive anti-tumor immunity. Blockade of PD-L1 in γδT cells enhanced CD4 + and CD8 + T cell infiltration and immunogenicity and induced tumor protection suggesting that γδT cells are critical sources of immune-suppressive checkpoint ligands in PDA. We describe γδT cells as central regulators of effector T cell activation in cancer via novel cross-talk.

Despite recent advancements in multimodal therapy, pancreatic ductal adenocarcinoma (PDA) continues to have a dismal prognosis. In the era of burgeoning immune therapies against previously difficult-to-treat malignancies, there has been growing interest in activating the immune system against PDA; however, unlike in other cancers such as melanoma and lymphoma, immunotherapy has not yielded many clinically significant results. To harness these mechanisms for therapeutic use, an in-depth understanding of T-cell programming in the immune microenvironment of PDA must be achieved. The outcome of T-cell programming against pathogens or cancer depends on the uptake and presentation of foreign antigens by dendritic cells and macrophages to T cells, and the expression of various co-stimulatory molecules and cytokines. Subsequent immune responses are kept in check via regulatory mechanisms such as immune checkpoints (for example, programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4)), as well as other immunosuppressive cell types such as regulatory T cells (Treg) and M2 macrophages. PDA presents a challenge from the perspective of immune therapy because of many immunosuppressive mechanisms at play in its microenvironment. The tumor itself produces IL-10 and transforming growth factor beta (TGF-β) that downregulate T-cell activation as well as the activity of antigen-presenting cells. At the same time, PDA also appears to recruit more regulatory elements into its milieu; higher infiltration of Treg, for instance, has been associated with poorer prognosis in PDA patients. M2 macrophages and myeloid-derived suppressive cells are also highly prevalent in the tumor microenvironment. T cells in PDA have high expression of PD-1, whereas the tumor has high expression of PD-L1, which likely inhibits activation of tumor antigen-specific T cells. Many of these immunosuppressive mechanisms have been targeted as potential immune therapies of PDA. Immune checkpoint inhibitors, which target PD-1 and CTLA-4, have been shown to be effective in other cancers such as melanoma; however, they have not demonstrated outcome benefits in PDA so far. Other novel investigational approaches under study currently include inhibiting the homing of immunosuppressive cell types to the tumor milieu, as well as vaccines designed to boost the adaptive response to PDA antigens. As our understanding of the nuanced and complex interactions of the immune microenvironment expands, more targeted approaches can be taken toward achieving therapeutic success in immune therapy against PDA.

BackgroundTumor-infiltrating lymphocyte (TIL) counts in colorectal cancer liver metastases (CRCLM) predict survival following resection. While CD4 and CD8 T cells have been correlated with outcome following CRCLM resection, the role of regulatory T cells (Treg) is not well defined.MethodsTIL in 188 patients who underwent CRCLM resection between 1998 and 2000 were analyzed by immunohistochemistry using tissue microarrays. Correlation between TIL composition and outcome was determined while controlling for established prognostic factors. Total T cells (CD3), helper T cells (CD4), cytotoxic T cells (CD8), and Treg (FoxP3) were analyzed.ResultsMedian follow-up time was 40 months for all patients and 95 months for survivors. Overall survival (OS) at 5 and 10 years was 40 and 25%, respectively. The CD4 T cell count correlated with OS (p = .02) and recurrence-free survival (p = .04). A high number of CD8 T cells relative to total T cells (CD8:CD3 ratio) predicted longer OS times (p = .05). Analysis of Treg revealed that high FoxP3:CD4 (p = .03) and FoxP3:CD8 (p = .05) ratios were independent predictors of shorter OS. Patients with a high clinical risk score (CRS) were more likely to have a high number of intratumoral Treg, and patients ≥65 years old had a less robust CRCLM T cell infiltration.ConclusionsA high number of Treg relative to CD4 or CD8 T cells predicted poor outcome, suggesting an immunosuppressive role for FoxP3 + TIL. The intratumoral immune response was an independent predictor of outcome in patients with colorectal liver metastases.

While tumor infiltrating lymphocytes (TIL) have been shown to independently predict survival in primary colorectal cancer, the prognostic implications of TIL in resectable colorectal cancer liver metastases (CRCLM) have not been previously defined. This study examines the correlation between TIL numbers and survival following hepatic resection. We studied patients who survived ≤2 or ≥10 years following CRCLM resection. Immunohistochemistry was performed on tissue microarrays (TMAs) to determine the number of T cells within CRCLM. Correlation between TIL frequency and ≤2 or ≥10 year survival was determined while controlling for established prognostic factors. Of 162 patients, 104 survived ≤2 years and 58 survived ≥10 years. Independent correlates of 10-year survival following CRCLM resection included a high number of CD8 T cells, a low number of CD4 T cells, and a clinical risk score of ≤2 (P

Intraductal papillary mucinous neoplasm (IPMN) is a mucin-producing epithelial neoplasm that carries a risk of progression to invasive pancreatic ductal adenocarcinoma. Lynch syndrome is an autosomal dominant condition caused by germline mutations in mismatch repair genes such as MSH2 that lead to microsatellite instability and increased risk of tumor formation. Although families with Lynch syndrome have an increased risk of pancreatic cancer, a clear connection between Lynch syndrome and IPMN has not been drawn. We present a report of a 58 year-old Caucasian woman with multiple cancers and a germline mutation of MSH2 consistent with Lynch syndrome. A screening abdominal computed tomography scan revealed a dilated main pancreatic duct and cystic ductular structure in the uncinate process that were consistent with IPMN of the main pancreatic duct on excision. Immunohistochemistry and polymerase chain reaction of the patient's pancreas specimen did not reveal microsatellite instability or mismatch repair gene loss of expression or function. Our findings may be explained by the fact that loss of mismatch repair function and microsatellite instability is a late event in neoplastic transformation. Given the relative rarity of main duct IPMN, its appearance in the setting of somatic MSH2 mutation suggests that IPMN may fit into the constellation of Lynch syndrome related malignancies.

Objective To determine if the density of FOXP3+ lymphocytes in primary tumors and lymph nodes in pancreatic cancer correlates with the presence of lymph node metastases. Methods FOXP3+ lymphocyte density in primary pancreatic cancer tissue and draining lymph nodes was measured using immunohistochemistry. We analyzed the clinical and pathological aspects associated with the accumulation of FOXP3+ lymphocytes in pancreatic cancer. We also analyzed the correlation of density of FOXP3+ lymphocytes in lymph nodes with the nodal status and distance from the primary tumor. Results FOXP3+ lymphocyte density in pancreatic cancer was significantly higher than in paratumoral pancreatic tissue. The density of FOXP3+ lymphocytes in local tumor tissue correlated significantly with the histological grade and overall lymph node status. Furthermore, FOXP3+ lymphocyte density was significantly higher in positive lymph nodes than in negative ones, while it had no correlation with the distance of the lymph node from the primary tumor. Conclusion FOXP3+ lymphocyte density in primary tumor tissue in patients with pancreatic cancer correlates with lymph node metastasis. Lymph nodes containing metastases having higher FOXP3+ lymphocyte densities than do negative lymph nodes.

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.

Objective The immune response to pancreatic ductal adenocarcinoma (PDA) may play a role in defining its uniquely aggressive biology; therefore, we sought to clearly define the adaptive immune infiltrate in PDA. Design We used immunohistochemistry and flow cytometry to characterize the immune infiltrate in human PDA and compared our findings to the patients’ peripheral blood. Results In contrast to the myeloid cell predominant infiltrate seen in murine models, T cells comprised the majority of the hematopoietic cell component of the tumor stroma in human PDA. Most intratumoral CD8+ T cells exhibited an antigen-experienced effector memory cell phenotype and were capable of producing IFN-γ. CD4+ regulatory T cells (Treg) and IL-17 producing T helper cells were significantly more prevalent in tumor than in blood. Consistent with the association with reduced survival in previous studies, we observed higher frequencies of both myeloid cells and Treg in poorly differentiated tumors. The majority of intratumoral T cells expressed the co-inhibitory receptor programmed death-1 (PD-1), suggesting one potential mechanism through which PDA may evade antitumor immunity. Successful multimodal neoadjuvant therapy altered the immunoregulatory balance and was associated with reduced infiltration of both myeloid cells and Treg. Conclusion Our data show that human PDA contains a complex mixture of inflammatory and regulatory immune cells, and that neoadjuvant therapy attenuates the infiltration of intratumoral cells associated with immunosuppression and worsened survival.

Background: Pancreatic cancer (PC) remains difficult to treat, despite the recent advances in various anticancer therapies. Immuno-inflammatory response is considered to be a major risk factor for the development of PC in addition to a combination of genetic background and environmental factors. Although patients with PC exhibit evidence of systemic immune dysfunction, the PC microenvironment is replete with immune cells. Methods: We searched PubMed for all relevant English language articles published up to March 2016. They included clinical trials, experimental studies, observational studies, and reviews. Trials enrolled at Clinical trial.gov were also searched. Results: PC induces an immunosuppressive microenvironment, and intratumoral activation of immunity in PC is attenuated by inhibitory signals that limit immune effector function. Multiple types of immune responses can promote an immunosuppressive microenvironment; key regulators of the host tumor immune response are dendritic cells, natural killer cells, macrophages, myeloid derived suppressor cells, and T cells. The function of these immune cells in PC is also influenced by chemotherapeutic agents and the components in tumor microenvironment such as pancreatic stellate cells. Immunotherapy of PC employs monoclonal antibodies/effector cells generated in vitro or vaccination to stimulate antitumor response. Immune therapy in PC has failed to improve overall survival; however, combination therapies comprising immune checkpoint inhibitors and vaccines have been attempted to increase the response. Conclusion: A number of studies have begun to elucidate the roles of immune cell subtypes and their capacity to function or dysfunction in the tumor microenvironment of PC. It will not be long before immune therapy for PC becomes a clinical reality.

Immunotherapy has evolved considerably in the last decade and is becoming an integral component of the armamentarium for the treatment of patients with advanced solid tumors. It is important for clinicians, especially surgeons, to understand the basic principles of novel immunotherapies and the immune system. This review summarizes the evolution of the most relevant immunotherapies, their mechanisms of action, the data supporting their clinical use, and integration of immunotherapy into multidisciplinary management of solid tumors. This review should serve as a primer for clinicians and surgeons to understand the rapidly evolving field of immunotherapy.

Editor: Yamanaka et al are to be congratulated on their study of radiofrequency (RF) ablation in a series of seven patients with gastrointestinal stromal tumor (GIST) with liver metastases (1). Two further important points can be drawn from their study and should be highlighted. The first point is that RF ablation does have a role in selected patients with metastatic GIST in the context of multimodality management. In their study, three patients did not resume imatinib after RF ablation. Importantly, each of these patients had three or fewer lesions. In patients with more widespread metastatic disease, RF ablation could potentially be performed in conjunction with systemic therapy. One advantage that RF ablation has over catheterbased intraarterial therapy (ie, chemoembolization, radioembolization) is that it allows for minimal interruption of systemic treatment. In contrast, intraarterial therapy may result in longer interruptions of systemic therapy because of potential procedure-related liver dysfunction and postembolization syndrome. RF ablation has a particular role in patients who have a solitary area of disease progression, in the context of metastatic disease that is otherwise effectively controlled by tyrosine kinase therapy. RF ablation can delay a change in systemic therapy by achieving local control at the site of solitary progression. In our previous study of 13 patients with GIST who were treated with RF ablation, 12 achieved a response at the RF ablation site, and 1 had stable disease after the first RF ablation procedure (2). The median time to progression from date of ablation to progression at the RF ablation site was 28 months (95% confidence interval undefined). The median time to progression at other sites from date of RF ablation was 26 months (95% confidence interval, 1–51). At the time of analysis, seven patients were on first-line imatinib, and a further five patients continued on first-line imatinib for a median of 11 months (range, 8–28 months) after RF ablation. We have also treated 2 GIST

Neuroendocrine tumors affect cells throughout the nervous and endocrine systems that produce and secrete regulatory hormones. Common sites of origin include the endocrine pancreas; parathyroid, adrenal, and pituitary glands; calcitonin-producing cells of the thyroid (causing medullary thyroid carcinoma); and argentaffin cells of the gut (causing carcinoid tumors). Neuroendocrine tumors are rare and can be broadly subdivided into those with and those without a clinical syndrome. Most neuroendocrine tumors are malignant and metastasize commonly to lymph nodes and the liver or less commonly to bone, lung, brain, and other organs. Despite the widespread metastasis, these tumors are typically slow-growing and often have an insidious presentation. These guidelines discuss the diagnosis and management of neuroendocrine tumors and special considerations relating to these tumors; important updates include expanded information on octreotide use and a new algorithm on neuroendocrine tumors of unknown primary.

BackgroundTumour-infiltrating lymphocytes (TILs) have been shown to predict survival in numerous malignancies. The importance of TILs in primary pancreatic neuroendocrine tumours (NETs) and NET liver metastases (NETLMs) has not been defined.MethodsWe identified 87 patients with NETs and 39 with NETLMs who had undergone resection. Immunohistochemistry was performed to determine TIL counts. Recurrence-free survival (RFS) and overall survival (OS) were determined using the log-rank test.ResultsThe median follow-up time was 62 months in NET patients and 48 months in NETLM patients. Vascular invasion and histologic grade were the only independent predictors of outcome for NETs and NETLMs, respectively. Analysis of intermediate-grade NETs indicated that a dense T cell (CD3+) infiltrate was associated with a median RFS of 128 months compared with 61 months for those with low levels of intratumoral T cells (P= 0.05, univariate analysis). Examination of NETLMs revealed that a low level of infiltrating regulatory T cells (Treg, FoxP3+) was a predictor of prolonged survival (P < 0.01, univariate analysis).ConclusionsA robust T cell infiltrate is associated with improved RFS following resection of intermediate-grade NETs, whereas the presence of more Treg correlated with shorter OS after treatment of NETLMs. Further study of the immune response to intermediate-grade NETs and NETLMs is warranted.

Electronic synoptic operative reports (E-SORs) have replaced dictated reports at many institutions, but whether E-SORs adequately document the components and findings of an operation has received limited study. This study assessed the reliability and completeness of E-SORs for pancreatic surgery developed at our institution.An attending surgeon and surgical fellow prospectively and independently completed an E-SOR after each of 112 major pancreatic resections (78 proximal, 29 distal, and 5 central) over a 10-month period (September 2008 to June 2009). Reliability was assessed by calculating the interobserver agreement between attending physician and fellow reports. Completeness was assessed by comparing E-SORs to a case-matched (surgeon and procedure) historical control of dictated reports, using a 39-item checklist developed through an internal and external query of 13 high-volume pancreatic surgeons.Interobserver agreement between attending and fellow was moderate to very good for individual categorical E-SOR items (kappa = 0.65 to 1.00, p0.001 for all items). Compared with dictated reports, E-SORs had significantly higher completeness checklist scores (mean 88.8 +/- 5.4 vs 59.6 +/- 9.2 [maximum possible score, 100], p0.01) and were available in patients' electronic records in a significantly shorter interval of time (median 0.5 vs 5.8 days from case end, p0.01). The mean time taken to complete E-SORs was 4.0 +/- 1.6 minutes per case.E-SORs for pancreatic surgery are reliable, complete in data collected, and rapidly available, all of which support their clinical implementation. The inherent strengths of E-SORs offer real promise of a new standard for operative reporting and health communication.

Minimally invasive resection has emerged as a surgical technique for gastric cancer, and there has been continued investigation to determine the appropriate extent of lymphadenectomy in gastric cancer patients. There has also been significant progress in evaluating the role of chemotherapeutic regimens used in the neoadjuvant and adjuvant settings for patients with resectable disease. We also summarize a selection of RCT trials focused on the perioperative care of the gastric cancer patient.

Purpose. Cytoreductive surgery (CS) and intraperitoneal hyperthermic chemotherapy (IPHC) in the treatment of peritoneal carcinomatosis (PC) in 15 patients are described. Summary. Fifteen patients with PC who were treated with CS and IPHC were retrospectively identified between January 2002 and December 2006. All patients underwent cytoreduction immediately followed by IPHC with mitomycin or cisplatin. The time between undergoing CS and IPHC and the date of the last follow-up appointment or the date of death was used to calculate survival data for each patient. Nine patients had complete cytoreduction, and all but one patient had evidence of invasive disease at the time of surgery. Eleven patients required concomitant bowel resection at the time of debulking. Thirteen patients required blood transfusions during the perioperative period. Nine patients were discharged home, and four were discharged to a rehabilitation facility. Two patients died during the perioperative hospital admission, both of whom had a preoperative Eastern Cooperative Oncology Group (ECOG) performance status score of 2. The median survival time was 8.4 months, similar to the findings of previously published studies. Further studies are needed to see if tumor type, ECOG performance status score, degree of cytoreduction, and the chemotherapy agent used in IPHC can be correlated to quality of life and survival in patients with heterogeneous primary sources of intraabdominal malignancies. Conclusion. Combination treatment with CS followed by IPHC in 15 patients with heterogeneous primary sources of intraabdominal malignancies resulted in a median survival time of 8.4 months.