Joel M. Baumgartner

Immunosuppressive dendritic and regulatory T cells are upregulated in melanoma patients.

BackgroundImmunologic therapies for melanoma rarely succeed, suggesting a persistent counter-regulatory immune modulation. Regulatory T cells (Tregs) and plasmacytoid subpopulations of dendritic cells (pDCs) inhibit the immune response. We hypothesize that melanoma upregulates Tregs and subpopulations of immunosuppressive dendritic cells (DCs).MethodsPeripheral blood mononuclear cells (PBMCs) were obtained from healthy controls, stage I and stage IV melanoma patients. Tregs were identified as CD4+ and CD25hi. Dendritic cells were identified using a DC cocktail of antibodies including CD11c+ myeloid dendritic cells (mDCs) and CD123+ pDCs. Serum transforming growth factor-β (TGF-β), interleukin-4 (IL-4) and interleukin-10 (IL-10) levels were determined by enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed using analysis of variance (ANOVA).ResultsStage IV melanoma patients had a doubling of regulatory T cells compared to both normal subjects and stage I melanoma patients. There was a significantly higher number of DCs in all melanoma patients compared to normal subjects. Stage I melanoma patients had a significantly higher number of pDCs than normal subjects, and all melanoma patients had a higher concentration of mDCs than controls. Serum IL-4 and IL-10 were not detectable but serum TGF-β levels were significantly higher in stage I and stage IV melanoma patients compared to normal controls.ConclusionAdvanced melanoma is associated with increased numbers of circulating dendritic cells and regulatory T cells. These data suggest that melanoma induces immunosuppressive DCs and regulatory T cells in the systemic circulation.

Stored Red Blood Cell Transfusion Induces Regulatory T Cells

BACKGROUND Allogeneic blood transfusion mediates immunosuppression in transfused recipients by an unknown mechanism. Regulatory T cells (T(regs)) are suppressive CD4(+)CD25(+)Foxp3(+) cells with a central role in immunosuppression in trauma victims, cancer patients, and transplant recipients. We hypothesized that transfusion-related immunosuppression is, in part, mediated by induction of T(regs), and this induction is attenuated with prestorage leukoreduction and accentuated with prolonged storage. STUDY DESIGN Packed red blood cell (PRBC) units were obtained and 50% of PRBCs were leukoreduced (LR) before routine storage for 1 day or 42 days and the supernatant was collected. Normal human peripheral blood mononuclear cells (PBMCs) were exposed to 1-day NLR, 42-day NLR, 1-day LR, or 42-day LR PRBC supernatants or to PRBC storage solution or washed PRBC supernatant +/- anti-CD3 stimulation, and analyzed by flow cytometry for Foxp3(+) T(regs) or CD25(+)-activated T cells. PRBC supernatants and cell culture supernatants were analyzed by immunoassay for interleukin (IL)-1beta, IL-2, IL-4, IL-10, interferon-gamma, tumor necrosis factor-alpha, and transforming growth factor-beta. T(reg) activity was evaluated by suppression assay. RESULTS All PRBC groups induced T(regs) compared with control media in anti-CD3-stimulated PBMCs, without alteration by LR or prolonged storage. PRBC supernatant did not alter nonspecific T-cell activation from control media. PRBC-induced T(regs) were suppressive, inhibiting proliferation of T-responder cells. All cytokines measured decreased with storage in LR PRBC units and no cytokines were substantially elevated in cell supernatants exposed to PRBC supernatant. PRBC storage solution did not reproduce the effects of PRBC supernatant, and washed PRBC supernatant attenuated T(reg) induction. CONCLUSIONS PRBC supernatant induces T(regs), but this induction is not altered by LR or prolonged storage. This induction appears to be independent of cytokines and is attenuated with washed PRBCs, implicating the plasma fraction.

Improved Perioperative Outcomes With Minimally Invasive Distal Pancreatectomy: Results From a Population-Based Analysis

IMPORTANCE Interest in minimally invasive distal pancreatectomy (MIDP) has grown in recent years, but currently available data are limited. Greater insight into application patterns and outcomes may be gained from a national database inquiry. OBJECTIVES To study trends in the use of MIDP and compare the short-term outcomes of MIDP with those of open distal pancreatectomy. DESIGN, SETTING, AND PARTICIPANTS Population-based retrospective cohort study evaluating perioperative outcomes and hospital charge measures for distal pancreatectomy, comparing the surgical approaches and adjusting for patient- and hospital-level factors, among patients undergoing elective distal pancreatectomy from 1998 to 2009 in the Nationwide Inpatient Sample in a 20% stratified sample of all US hospitals. MAIN OUTCOMES AND MEASURES In-hospital mortality, rates of perioperative complications and splenectomy, total charges, and length of stay. RESULTS A total of 8957 distal pancreatectomies were included in this analysis, of which 382 (4.3%) were MIDPs. On a national level, this projected to 42,320 open distal pancreatectomies and 1908 MIDPs. The proportion of distal pancreatectomies performed via minimally invasive approaches tripled between 1998 and 2009, from 2.4% to 7.3%. The groups were comparable for sex and comorbidity profiles, while patients who underwent MIDP were 1.5 years older. On multivariate analysis, MIDP was associated with lower rates of overall predischarge complications, including lower incidences of postoperative infections and bleeding complications, as well as a shorter length of stay by 1.22 days. There were no differences in rates of in-hospital mortality, concomitant splenectomy, or total charges. CONCLUSIONS AND RELEVANCE This population-based study of MIDP reveals that the application of this approach has tripled in practice and provides strong evidence that MIDP has evolved into a safe option in the treatment of benign and malignant pancreatic diseases.

The American Society of Peritoneal Surface Malignancies evaluation of HIPEC with Mitomycin C versus Oxaliplatin in 539 patients with colon cancer undergoing a complete cytoreductive surgery

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) are gaining acceptance as treatment for selected patients with colorectal cancer with peritoneal carcinomatosis (CRCPC). Tremendous variations exist in the HIPEC delivery.

Red Blood Cell Supernatant Potentiates LPS-Induced Proinflammatory Cytokine Response From Peripheral Blood Mononuclear Cells

Allogeneic blood transfusion has an immunomodulatory capacity on its recipients through accumulation of immunologically active substances with blood storage, and prestorage leukoreduction reduces many of these mediators. We investigated lipopolysaccharide (LPS)-induced cytokine response of peripheral blood mononuclear cells (PBMCs) exposed to packed red blood cell (PRBC) supernatants from leukoreduced (LR) or non-leukoreduced (NLR) units with variable duration of storage. PRBC units were collected with or without leukoreduction on Day 0 before routine storage. The plasma fraction (supernatant) was isolated from LR and NLR units after 1 day (D1) or 42 days (D42) of storage and exposed to PBMCs versus control media for 24 h, then with LPS for an additional 24 h. Cell supernatants were analyzed for IL-1beta, IL-6, IL-8, IL-10, and TNF-alpha by cytokine bead array. IL-1beta, TNF-alpha, and IL-6 were significantly elevated in PRBC groups versus control. D42 NLR PRBC supernatant significantly increased secretion of IL-1beta and IL-6 compared to D1 NLR PRBC supernatant. LR significantly attenuated the cytokine response of IL-1beta. Thus, PRBC supernatant potentiates proinflammatory LPS-induced cytokine secretion from PBMCs. This response is accentuated with storage duration and partially attenuated with leukoreduction. These findings may partially explain the immune activation seen clinically after blood transfusion.

Increased risk of additional cancers among patients with gastrointestinal stromal tumors: A population-based study

Most gastrointestinal stromal tumors (GISTs) are considered nonhereditary or sporadic. However, single‐institution studies suggest that GIST patients develop additional malignancies at increased frequencies. It was hypothesized that greater insight could be gained into possible associations between GISTs and other malignancies with a national cancer database inquiry.

Aggressive locoregional management of recurrent peritoneal sarcomatosis.

and Objectives Peritoneal sarcomatosis responds poorly to systemic chemotherapy and demonstrates high rates of recurrence after resection. We sought to determine perioperative and oncologic outcomes after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) for recurrent sarcomatosis.

Older adult oncology, version 2.2016: Featured updates to the NCCN guidelines

Cancer is the leading cause of death in older adults aged 60 to 79 years. Older patients with good performance status are able to tolerate commonly used treatment modalities as well as younger patients, particularly when adequate supportive care is provided. For older patients who are able to tolerate curative treatment, options include surgery, radiation therapy (RT), chemotherapy, and targeted therapies. RT can be highly effective and well tolerated in carefully selected patients, and advanced age alone should not preclude the use of RT in older patients with cancer. Judicious application of advanced RT techniques that facilitate normal tissue sparing and reduce RT doses to organs at risk are important for all patients, and may help to assuage concerns about the risks of RT in older adults. These NCCN Guidelines Insights focus on the recent updates to the 2016 NCCN Guidelines for Older Adult Oncology specific to the use of RT in the management of older adults with cancer.

DC Maturation and Function are Not Altered by Melanoma-Derived Immunosuppressive Soluble Factors

BACKGROUND Although melanoma can elicit robust tumor antigen-specific immune responses, advanced melanoma is associated with immune tolerance. We have previously described several mechanisms of melanoma-induced immunosuppression, including the skewing of the immune response towards a Th2 cytokine profile and the induction of regulatory T cells. Since dendritic cells (DCs) are potentially important players that can direct other cells of the immune system towards a cytotoxic, humoral, or regulatory phenotype, we hypothesized that melanoma-produced factors directly affect the maturation and function of DCs, influencing the nature and magnitude of the resulting immune response. MATERIALS AND METHODS To test this hypothesis, immature myeloid-derived DCs (mdDCs) were derived with cytokines from CD14+ peripheral blood mononuclear cells (PBMCs) and exposed to 20% melanoma-conditioned media (MCM). After 2 d, the expression of maturation markers and the function of these mdDCs, measured by cytokine production, the amount of endocytosis, expression of the inhibitory molecule indoleamine 2,3-dioxygenase (IDO), and the ability to stimulate T cells were determined. RESULTS We found that incubation with MCM did not inhibit the expression of maturation markers or IDO, the production of cytokines, the amount of antigen uptake, or the ability to induce T cell proliferation in mixed-lymphocyte reactions by mdDC. CONCLUSIONS These results suggest that the immunosuppressive effects of melanoma-produced factors are independent of directly measurable changes in mdDC function or maturation in vitro.

Suppressing the suppressor: Role of immunosuppressive regulatory T cells in cancer surgery.

THE POWER OF THE IMMUNE SYSTEM represents a tantalizing mechanism for potential tumor eradication in patients with cancer. Unfortunately, most immunologic strategies designed to treat malignancy ultimately fail. Regulatory T cells (Tregs) entail a suppressive population of CD4 Tcells with a central role in the prevention of autoimmunity and the promotion of tolerance via their suppressive function on a broad repertoire of cellular targets. These regulatory activities, particularly on tumor antigen-presenting cells and cytotoxic antitumor cells, highlight Tregs as a critical immune-suppressing cell capable of affecting tumor-induced immune suppression. The purpose of this review is to highlight the current understanding of Tregs and their role in cancer, and to discuss proposed therapies to mitigate Treg-mediated immune escape.