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Abstract Background In the general population, a higher omega‐3 polyunsaturated fatty acids intake is associated with lower levels of several psychological symptoms, especially depression. However, the existing evidence in cancer is equivocal. Methods This phase IIB double‐blind, placebo‐controlled trial was aimed at comparing the effects of eicosapentaenoic acid monoacylglyceride (MAG‐EPA) supplementation and high oleic acid sunflower oil (HOSO; placebo) on depression levels (primary outcome) and other symptoms (anxiety, fear of cancer recurrence, fatigue, insomnia, perceived cognitive impairments; secondary outcomes). Participants, recruited in a prostate cancer clinic, were randomized to MAG‐EPA (3.75 g daily; n = 65) or HOSO (3.75 g daily; n = 65) for 1 year post‐radical prostatectomy (RP), starting 4–10 weeks before surgery. Patients completed self‐report scales at baseline (before RP) and 3, 6, 9, and 12 months after: Hospital Anxiety and Depression Scale (HADS), Fear of Cancer Recurrence Inventory (FCRI), Insomnia Severity Index (ISI), Fatigue Symptom Inventory (FSI), and Functional Assessment of Cancer Therapy—Cognitive Function (FACT‐Cog). Results Analyses showed significant reductions in HADS‐depression, HADS‐anxiety, FCRI, ISI, FSI‐number of days, and FACT‐Cog‐impact scores over time. A significant group‐by‐time interaction was obtained on FACT‐Cog‐Impact scores only; yet, the temporal change was significant in HOSO patients only. Conclusions Several symptoms significantly decreased over time, mainly within the first months of the study. However, MAG‐EPA did not produce greater reductions than HOSO. Omega‐3 supplementation does not seem to improve psychological symptoms of men treated with RP.

Background: Men are three to four times more likely to be diagnosed with bladder cancer (BCa) than women, who often have more aggressive tumors. Intravesical bacillus Calmette-Guerin (BCG) for non–muscle-invasive bladder cancer (NMIBC) is one of the first immunotherapies, with use of immune checkpoint inhibitors for BCa immunotherapy expanding. Sex hormones, and notably androgens, might impact the outcome of these therapies. Objective: To understand immunological sex differences in BCa and investigate androgen receptor (AR) inhibition as a novel strategy to improve the response to BCa immunotherapy. Design, setting, and participants: Human NMIBC tumors were freshly collected following transurethral resection. In vivo studies used the subcutaneous MBT-2 BCa model in male and female C3H mice. The AR antagonist enzalutamide was given alone or in combination with anti–programmed cell death protein-1 (anti–PD-1) or intratumoral BCG + poly(I:C) treatments. Outcome measurements and statistical analysis: Tumor growth and survival were evaluated in vivo. Flow cytometry and RNA sequencing characterized the immune cells present in murine and human tumors. Descriptive comparisons were performed for MBT-2 tumors between sexes and with human NMIBC tumors. Results and limitations: The MBT-2 model shows multiple similarities to the immune composition of human NMIBC tumors and recapitulates previously observed human tumor immune cell sex differences. Enzalutamide in combination with either anti–PD-1 or BCG + poly(I:C) treatment in male mice synergized to improve response rates. Notably, the proportion of complete responses in male mice treated with the combination treatment resembles that observed in female mice with either immunotherapy alone. Limitations include the sample size for murine experiments. Conclusions: Our results suggest that combining AR antagonism with immunotherapy in male BCa patients may potentiate the antitumor immune response and increase response rates. The MBT-2 model appears relevant to investigate immunological BCa sex differences. Patient summary: Our studies suggest that combining antiandrogen treatments with BCa immunotherapy may improve response rates in men. We also demonstrate the utility of the MBT-2 mouse model to study sex differences in BCa.

Abstract Aim Deregulated signaling pathways are a hallmark feature of oncogenesis and driver of tumor progression. Dual specificity protein phosphatase 4 (DUSP4) is a critical negative regulator of the mitogen-activated protein kinase (MAPK) pathway and is often deleted or epigenetically silenced in tumors. DUSP4 alterations lead to hyperactivation of MAPK signaling in many cancers, including breast cancer, which often harbor mutations in cell cycle checkpoint genes, particularly in TP53. Methods Using a genetically engineered mouse model, we generated mammary-specific Dusp4-deleted primary epithelial cells to investigate the necessary conditions in which DUSP4 loss may drive breast cancer oncogenesis. Results We found that Dusp4 loss alone is insufficient in mediating tumorigenesis, but alternatively converges with loss in Trp53 and MYC amplification to induce tumorigenesis primarily through chromosome 5 amplification, which specifically upregulates Dbf4, a cell cycle gene that promotes cellular replication by mediating cell cycle checkpoint escape. Conclusions This study identifies a novel mechanism for breast tumorigenesis implicating Dusp4 loss and p53 mutations in cellular acquisition of Dbf4 upregulation as a driver of cellular replication and cell cycle checkpoint escape.

Abstract BACKGROUND There is limited data on the longitudinal trajectories of psychiatric disorders in children with cancer and risk factors for their persistence. The current study aimed to longitudinally assess the trajectories and risk factors for anxiety and depressive symptoms and disorders in children and adolescents with cancer. METHODS Children and adolescents with cancer and their parents completed the Patient‐Reported Outcomes Measurement Information System (PROMIS) Depression and Anxiety Module and were interviewed by the semi‐structured Affective and Anxiety Modules of the Kiddie Schedule for Affective Disorders and Schizophrenia for School‐Age Children (K‐SADS), at 4 time points, 1, 4, 7, and 12 months following the diagnosis of cancer. RESULTS Of the 99 patients enrolled, 48% met criteria for anxiety and/or depressive disorders at least once during the follow‐up period. There was a significant decrease in PROMIS pediatric and parent anxiety and depression scores (all p's

We found that pediatric glioblastoma (PED-GBM) cell lines from diffuse intrinsic pontine glioma (DIPG) carrying the H3K27M mutation or from diffuse hemispheric glioma expressing the H3G34R mutation are sensitive to the combination of vorinostat (a histone deacetylase inhibitor) and PARP-1 inhibitors. The combined treatment increased the phosphorylation of eIF2α (P-eIF2α) relative to each drug alone and enhanced the decrease in cell survival. To explore the role played by increased P-eIF2α in modulating PED-GBM survival and response to treatments, we employed brain-penetrating inhibitors of P-eIF2α dephosphorylation: salubrinal and raphin-1. These drugs increased P-eIF2α, DNA damage, and cell death, similarly affecting the sensitivity of DIPG cells and derived neurospheres to PARP-1 inhibitors. Interestingly, these drugs also decreased the level of eIF2Bϵ (the catalytic subunit of eIF2B) and increased its phosphorylation, thereby enhancing the effect of increased P-eIF2α. Transient transfection with the S51D phosphomimetic eIF2α variant recapitulated the effect of salubrinal and raphin-1 on PED-GBM survival and sensitivity to PARP-1 inhibitors. Importantly, either salubrinal or raphin-1 dramatically increased the sensitivity of DIPG cells to radiation, the main treatment modality of PED-GBM. Finally, PED-GBM was more sensitive than normal human astrocytes to salubrinal, raphin-1, and the treatment combinations described herein. Our results indicate that combinations of histone deacetylase inhibitors and PARP-1 inhibitors should be evaluated for their toxicity and efficacy in PED-GBM patients and point to drugs that increase P-eIF2α or modulate its downstream effectors as a novel means of treating PED-GBM.

Background CD19 chimeric antigen receptor T (CAR-T) cells demonstrate remarkable remission rates in pediatric and adult patients with refractory or relapsed (r/r) acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL). In 2016, we initiated a clinical trial with in-house produced CD19 CAR-T cells with a CD28 co-stimulatory domain. We analyzed, for the first time, differences in production features and phenotype between ALL and NHL patients.Methods Non-cryopreserved CAR-T cells were produced from patients’ peripheral blood mononuclear cells within 9 to 10 days. 93 patients with r/r ALL and NHL were enrolled under the same study. CAR-T cells of ALL and NHL patients were produced simultaneously, allowing the head-to-head comparison.Results All patients were heavily pretreated. Three patients dropped out from the study due to clinical deterioration (n=2) or production failure (n=1). Cells of ALL patients (n=37) expanded significantly better and contained more CAR-T cells than of NHL patients (n=53). Young age had a positive impact on the proliferation capacity. The infusion products from ALL patients contained significantly more naïve CAR-T cells and a significantly higher expression of the chemokine receptor CXCR3. PD-1, LAG-3, TIM-3, and CD28 were equally expressed. 100% of ALL patients and 94% of NHL patients received the target dose of 1×10e6 CAR-T/kg. The overall response rate was 84% (30/36) in ALL and 62% (32/52) in NHL. We further compared CAR-T cell infusion products to tumor infiltrating lymphocytes (TIL), another common type of T cell therapy, mainly clinically effective in solid tumors. CAR-T cells contained significantly more naïve T cells and central memory T cells and significantly less CCR5 compared to TIL infusion products.Conclusions The in-house production of CAR-T cells is highly efficient and fast. Clinical response rate is high. CAR-T cells can be successfully produced for 99% of patients in just 9 to 10 days. Cells derived from ALL patients demonstrate a higher proliferation rate and contain higher frequencies of CAR-T cells and naïve T cells than of NHL patients. In addition, understanding the differences between CAR-T and TIL infusion products, may provide an angle to develop CAR-T cells for the treatment of solid tumors in the future.Trial registration number ClinicalTrials.gov; CAR-T: NCT02772198, First posted: May 13, 2016; TIL: NCT00287131, First posted: February 6, 2006.

Tuberculosis: Defining the proteins that drive immune responses Specific bacterial proteins have been found that drive effective immune responses to tuberculosis, with use in making more effective vaccines. Immunity to tuberculosis (TB) is facilitated by two types of white blood cell; however, most research has focused on one: the CD4+ T cell. Deborah A. Lewinsohn and David Lewinsohn, of the Oregon Health & Science University, USA, and collaborators lay out the essential functions of the oft-neglected CD8+ T cell, and undertook a broad approach to catalogue and define the bacterial proteins that activate the CD8+ T cell response. The team found that TB-infected humans reacted strongly to their protein library, and described several characteristics of CD8+ T cell ‘antigens’ (activators of immune cells) that will likely prove highly useful in the design of more protective TB vaccines.

Pediatric brain tumors are the most common solid tumor type and the leading cause of cancer-related death in children. The immune system plays an important role in cancer pathogenesis and in the response to immunotherapy treatments. T lymphocytes are key elements for the response of the immune system to cancer cells and have been associated with prognosis of different cancers. Neutrophils on the other hand, which secrete pro-angiogenic and anti-apoptotic factors, enhance the ability of tumor cells to grow and develop into metastases. We conducted a retrospective study of 120 pediatric brain cancer patients and 171 elective pediatric patients hospitalized in Dana Children's Hospital and Sheba Medical Center. Data on age, sex, treatment, lymphocyte, neutrophil, and monocyte count were collected from routinely performed preoperative blood tests. Neutrophil-to-lymphocyte ratio (NLR), and the lymphocyte-to-monocyte ratio (LMR) were calculated and significance was determined by paired T test. p < 0.05 was considered as statistically significant. NLR was significantly higher in the pediatric brain cancer patients. The high NLR in pediatric brain cancer patients is the result of a combination of low lymphocytes and high neutrophils. Both of these factors can have a role in cancer development and propagation and also in response to therapy.

Purpose An encounter between Palestinian parents of children with cancer and Israeli medical staff is a very special situation where “potential enemies” interact in a caring, trusting and intimate relationship for long periods of time. Our aim was to study the psychological and cultural encounter in order to understand the dynamics involved. Method The study is a qualitative one. Data was collected by way of structured in-depth interviews. Participants were physicians and nurses employed in the department, and Palestinian parents accompanying their children who were hospitalized during the research period. Results Six main themes emerged from the analysis of the interviews: (1) The decision to come to Israel for treatment. (2) The “meeting points” of the two peoples: the Israeli check points and the Palestinian Authority permits. (3) Encounter with the Israeli hospital. (4) Relationship between medical staff and parents. (5) Language and cultural barriers. (6) Emotions, thoughts and behaviors during high security tension. Conclusion The interviews depict a poignant picture of the unique encounter between Israeli Doctors and nurses and Palestinian parents. The psychological mechanism used by parents and doctors is “splitting”-having a dichotomized, simple emotional-perceptual picture of a situation with no conflicts. Nurses use another psychological mechanism in addition which enables them to contain the paradox and the conflict.