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Over the last decade, there has been a movement in cancer treatment away from cytotoxic therapies toward strategies that enhance the immune system against cancer. Immune checkpoint inhibitors (ICIs) have been incorporated into the treatment regimens for patients with various solid tumors. Mesothelioma trials revealed encouraging efficacy; however, patients with peritoneal mesothelioma are usually excluded, slowing the progress of improving the treatment of this aggressive cancer and compelling oncologist to rely on retrospective studies despite their flaws and limitations. Currently, there is no consensus on the role of ICIs in the treatment of malignant peritoneal mesothelioma (MPeM). The present review discusses data from clinical studies that examined immunotherapy in MPeM and evaluates what is known about the relevance of the tumor microenvironment and clinically validated biomarkers for ICIs efficacy. Furthermore, a proposed strategy for utilizing immunotherapy in treating MPeM is discussed.

Standard chemotherapy agents, including carboplatin, have known immunogenic properties. We sought to determine how carboplatin may influence lymphocyte trafficking to tumor sites.Murine models of ovarian cancer were utilized to examine lymphocyte trafficking with common clinically used agents including carboplatin, anti-PD-1 antibody, or anti-VEGFR-2 antibody. Adhesion interactions of lymphocytes with tumor vasculature were measured using intravital microscopy, lymphocyte homing with immunohistochemistry, and treatment groups followed for overall survival.Carboplatin chemotherapy profoundly alters the tumor microenvironment to promote lymphocyte adhesive interactions with tumor vasculature and resultant improvement in lymphocyte trafficking. The measured results seen with carboplatin in the tumor microenvironment were superior to anti-PD-1 treatment or anti-VEGFR-2 which may have contributed to increased overall survival in carboplatin treated groups.These novel findings suggest a role for chemotherapeutic agents to broadly influence anti-tumor immune responses beyond the induction of immunogenic tumor cell death.

Hyperthermic intraperitoneal chemotherapy (HIPEC) can directly target microscopic peritoneal disease, has achieved regular consideration in the treatment of several adult cancer types, and is more recently being studied in pediatrics. This review paper provides an overview of the use of this modality in pediatrics in order to identify medication choice, discuss post-operative morbidity and mortality, and evaluate impact on overall survival. Four databases were searched including Scopus, PubMed, Embase, and CINAHL and ultimately 37 papers documenting the use of this modality comprising 264 pediatric patients were included. Malignancies treated include desmoplastic small round cell tumor, rhabdomyosarcoma, angiosarcoma, colorectal carcinoma, and mesothelioma, with several rarer tumor types. Cisplatin was the most commonly used drug for HIPEC at varying concentrations for 30–90 min in duration at temperatures of approximately 41–42 °C. Reported toxicities were generally self-limited and there was no post-operative mortality. The impact on overall survival versus systemic chemotherapy and debulking surgery is uncertain due to lack of clinical trials and very small sample size across tumor subsets and the overall pediatric population. The relationship between degree of tumor burden and extent of surgical debulking needs to be further clarified. Future directions include prospective clinical trials, establishment of patient databases to facilitate standardization of HIPEC in pediatric patients, and additional approaches to optimize HIPEC.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of desmoplastic small round cell tumor, breast, and gastrointestinal stromal tumor specifically related to peritoneal surface malignancy. These guidelines are developed with input from leading experts including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides multidisciplinary recommendations for palliative care specifically related to peritoneal surface malignancies. These guidelines are developed with input from leading experts including surgical oncologists, medical oncologists, gynecologic oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of neuroendocrine tumors specifically related to the management of peritoneal surface malignancy. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

Adjuvant systemic therapy for cutaneous melanoma has experienced practice-changing shifts over the last decade. The successful results of immunotherapies and targeted therapies in the metastatic setting have allowed for investigative trials of the same therapies in the adjuvant and now neoadjuvant setting, with the potential for improved clinical outcomes in patients with high risk resected Stage III and IV melanoma.

The NCCN Guidelines for Uveal Melanoma include recommendations for staging, treatment, and follow-up of patients diagnosed with uveal melanoma of the choroid or ciliary body. In addition, because distinguishing between uveal melanoma and benign uveal nevi is in some cases difficult, these guidelines also contain recommendations for workup of patients with suspicious pigmented uveal lesions, to clarify the tests needed to distinguish between those who should have further workup and treatment for uveal melanoma versus those with uncertain diagnosis and low risk who should to be followed and later reevaluated. These NCCN Guidelines Insights describe recommendations for treatment of newly diagnosed nonmetastatic uveal melanoma in patients who have already undergone a complete workup.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of peritoneal mesothelioma. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness of the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides the following multidisciplinary recommendations for the care of patients with peritoneal surface malignancies. This article focuses on the standards of a peritoneal surface malignancy center, standards of billing and coding, standards of operative reports for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, standards of cytoreductive surgery training, and standards of intraoperative chemotherapy preparation. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of ovarian neoplasms specifically related to the management of peritoneal surface malignancy. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, gynecologic oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

Primary cutaneous histiocytoid or signet-ring cell carcinoma represents an extremely rare adnexal neoplasm that most frequently presents on the eyelid but more rarely may present in the axilla. As this tumor can resemble metastatic carcinoma with signet-ring cells, especially lobular carcinoma of the breast, it can often present a diagnostic challenge. We present a case of cutaneous signet-ring cell carcinoma presenting in the axilla and outline the challenges of diagnosing this rare malignancy.

Pharmacological inhibition of the proteasome with bortezomib (BTZ) has translated into an improved clinical outcome in patients with multiple myeloma and mantle cell lymphoma. Despite the observed clinical activity, BTZ anti-tumor activity in B-cell lymphoma has been partially hindered by treatment-related toxicities (peripheral neuropathy) preventing further dose escalation and emergence of acquired resistance. To further develop therapeutic strategies targeting the proteasome system, we studied the anti-tumor activity and mechanisms-of-action of ixazomib (MLN2238), a reversible proteasome inhibitor, in pre-clinical lymphoma models. Previously we demonstrated that ixazomib is active in various lymphoma pre-clinical in vitro models and that is capable of inducing cancer cell death in a caspase-independent manner. To further explore the effects of ixazomib, we investigated its anti-tumor activity in murine lymphoma models and investigated the mechanisms responsible for cell death observed in our pre-clinical models. For in vivo studies, 6-8 week old severe combined immunodeficiency (SCID) mice were inoculated via tail vein injection (iv) with mantle cell lymphoma Granta cells (day 0) and assigned to observation, ixazomib (iv) (at 6mg/kg/dose on days +1, 4, 8, 11, 15 and 18) or BTZ (ip) (at 0.8mg/kg/dose on days +1, 4, 8, 11, 15, and 18). Differences in survival (measured as the time to limb paralysis development) were evaluated by log-rank test across treatment arms. In addition, we studied the role of p21 in the anti-tumor activity of ixazomib. A panel of rituximab-sensitive (RSCL) and -resistant cell lines (RRCL) was exposed to ixazomib. Changes in cell cycle distribution and expression levels of key cell cycle regulatory proteins were evaluated by Western blotting and flow cytometry respectively. To further define the role of p21 in ixazomib activity, transient p21 knock down was achieved using electroporation with a pooled p21 siRNA. Down regulation of p21 was confirmed by Western blotting. Following transient p21 knock down, RSCL or RRCL were exposed to ixazomib and changes in cell viability were determined using the cell titer glo assay. Finally, RSCL and RRCL were exposed to ixazomib (10nM) +/- the cell cycle inhibitor roscovitine (10nM) and viability was determined by measuring changes in ATP content. As single agent, ixazomib prolonged the survival of Granta-bearing SCID mice when compared to control or BTZ (median=24 vs. 27 vs. 35 days; P = 0.012). In addition, in vitro exposure of lymphoma cell lines to ixazomib resulted in p21 and cell cycle arrest in G1 (RSCL) or G2/M (RRCL). Transient knock down of p21 rescued both Raji RSCL and RRCL from the cytotoxic effects of ixazomib when compared to controls. Moreover, in vitro exposure of RSCL to ixazomib in the presence to roscovitine resulted in synergistic effects on cell viability. Together our data suggests that ixazomib is more effective than BTZ in controlling mantle cell lymphoma growth in vivo. In addition, MLN2238 anti-tumor activity appears to be mediated partially by the stabilization of p21. (Ixazomib was obtained from Millennium Pharmaceuticals, Inc. Research, in part, supported by a NIH grant R01 CA136907-01A1 awarded to Roswell Park Cancer Institute and The Eugene and Connie Corasanti Lymphoma Research Fund.) Disclosures: Czuczman: Genetech, Onyx, Celgene, Astellas, Millennium, Mundipharma: Advisory Committees Other.

Recent advances in the treatment of metastatic melanoma are designed to promote the cytotoxic CD8 T cell response (e.g., CTLA-4 blockade and adoptive cell transfer), but it remains poorly understood how T cells enter tumor tissues to contact tumor targets. Here, we investigated the hierarchy of chemokine receptor requirements during the trafficking of blood-borne T cells to melanoma tumors by studying three molecules associated with infiltration, i.e., CCR2, CCR5, and CXCR3. These studies used B16-F10 murine melanoma to discriminate the contributions of individual chemokine receptors to T cell trafficking as opposed to T cell retention, proliferation, and survival in situ. Tumor-reactive cytotoxic T cells expressed functional CCR2, CCR5, and CXCR3 in vitro, and their cognate chemokines (CCL2, CCL5, and CXCL10, respectively) were also detected in the tumor microenvironment. Unexpectedly, loss of CCR2 and CCR5 did not impact T cell delivery to melanoma tissues; only CXCR3 was required for extravasation of adoptively transferred T cells in tumors. Intravital microscopy further revealed that T cells require CXCR3 to transition from transient rolling to firm arrest during the stepwise migration cascade at the tumor vascular interface. Taken together, these studies establish the obligate role for CXCR3 in the migration of effector T cells into tumor tissue and support the development of chemokine-targeted strategies to improve T cell entry during cancer immunotherapy.

Trafficking of tumor-reactive T cells across vascular checkpoints is a critical juncture in the effector phase of cancer immunity although this step is largely unexplored. We recently showed that poor trafficking of blood-borne CD8 effector T cells across tumor microvascular checkpoints is a significant obstacle to antitumor immunity. This bottleneck can be overcome by preconditioning regimens using systemic thermal therapy (STT, 39.5 ± 0.5°C, 6 h) that promotes E/P-selectin and ICAM-1-dependent trafficking of adoptively transferred CD8 T cells and subsequent lysis of tumor targets. Here we investigated the chemokine receptor requirements for trafficking of tumor-specific OT-I CD8 T cells across microvascular barriers in B16-OVA murine melanoma. We identified a non-redundant role for CXCR3, but not CXCR4, in T cell trafficking to tumors under both homeostatic and STT conditions using CXCR3-deficient OT-I T cells. Parallel results were observed by intravital microscopy whereby CXCR3 was necessary for T cells to undergo chemokine-dependent transition from rolling to firm arrest in tumor vessels of STT-pretreated mice. Taken together, these studies provide the first evidence that CXCR3 is obligatory for T cell trafficking across tumor vascular gateways and support strategic use of therapies to augment chemokine-dependent delivery of immune cells for the treatment of cancer. Supported by the NIH (CA79765, CA085183), and the Jennifer Linscott Tietgen Family Foundation.