Purpose To assess the safety and tolerability of pre-operative cryoablation-mediated tumor antigen presentation and/or ipilimumab-mediated immune modulation in women with operable breast cancer. Experimental design In this pilot study, 19 women with breast cancer for whom mastectomy was planned were treated with pre-operative tumor cryoablation (n=7), single-dose ipilimumab at 10mg/kg (n=6), or both (n=6). The primary outcome for this pilot study was safety/tolerability as defined as freedom from delays in pre-planned, curative-intent mastectomy. Exploratory studies of immune activation were performed on peripheral blood and tumor. Results Pre-operative cryoablation and/or ipilimumab were safe and tolerable, with no delays in pre-planned surgery. Grade III toxicity was seen in 1/19 (unrelated rash after ipilimumab). Combination therapy was associated with sustained peripheral elevations in: Th1-type cytokines, activated (ICOS+) and proliferating (Ki67+) CD4+ and CD8+ T cells, and post-treatment proliferative T-effector cells relative to T-regulatory cells within tumor. Conclusions Pre-operative cryoablation and single-dose ipilimumab are safe alone or in combination with no surgical delays incurred. Potentially favorable intra-tumoral and systemic immunologic effects were observed with the combination, suggesting the possibility for induced and synergistic anti-tumor immunity with this strategy.

Background:Malignant transformation requires the interaction of cancer cells with their microenvironment, including infiltrating leukocytes. However, somatic mutational studies have focused on alterations in cancer cells, assuming that the microenvironment is genetically normal. Because we hypothesized that this might not be a valid assumption, we performed exome sequencing and targeted sequencing to investigate for the presence of pathogenic mutations in tumor-associated leukocytes in breast cancers.Methods:We used targeted sequencing and exome sequencing to evaluate the presence of mutations in sorted tumor-infiltrating CD45-positive cells from primary untreated breast cancers. We used high-depth sequencing to determine the presence/absence of the mutations we identified in breast cancer-infiltrating leukocytes in purified tumor cells and in circulating blood cells.Results:Capture-based sequencing of 15 paired tumor-infiltrating leukocytes and matched germline DNA identified variants in known cancer genes in all 15 primary breast cancer patients in our cohort. We validated the presence of mutations identified by targeted sequencing in infiltrating leukocytes through orthogonal exome sequencing. Ten patients harbored alterations previously reported as somatically acquired variants, including in known leukemia genes (DNTM3A, TET2, and BCOR). One of the mutations observed in the tumor-infiltrating leukocytes was also detected in the circulating leukocytes of the same patients at a lower allele frequency than observed in the tumor-infiltrating cells.Conclusions:Here we show that somatic mutations, including mutations in known cancer genes, are present in the leukocytes infiltrating a subset of primary breast cancers. This observation allows for the possibility that the cancer cells interact with mutant infiltrating leukocytes, which has many potential clinical implications.

Traumatic brain injury (TBI) is a leading cause of long-term disability and mortality in young adults. The devastating effects of TBI on emotion regulation, executive functioning, and cognition have been wellestablished, and recent research links TBI as a risk factor for neurodegenerative diseases such as Alzheimer's disease. Despite an increased focus on the long-term cognitive dysfunction associated with TBI, research into potential treatments has not yet generated consistent successful results in human subjects. Many foundational studies have analyzed the cellular and molecular events involved in the inflammatory and healing processes following TBI, enhancing our understanding of the mechanisms that may contribute to the progression of dementia and cognitive decline in these patients. In this review, we will discuss the emergent research on melatonin within the framework of neuroinflammation and oxidative stress resulting from TBI and possibly preventing further sequelae such as Alzheimer's disease.A literature review was conducted using standard search strategies to query the PubMed database. The following search terms were used with qualifiers of various combinations: TBI, traumatic brain injury, melatonin, treatment, dementia, Alzheimer's, cognition, and neurodegeneration. Selected studies included meta-analyses, literature reviews, and randomized controlled trials (RCT) that evaluated melatonin's role as a potential therapy to prevent post-TBI neurodegeneration, specifically the development of dementia and deficits in memory and cognition. Three independent reviewers assessed all articles for eligibility. After assessment for eligibility, 11 total studies were included.Much of the available data on melatonin in TBI has highlighted its significant neuroprotective and antiinflammatory effects, which can be significant in fighting against the neuroinflammatory processes indicated in neurodegeneration. In animal models, immunohistochemistry and histopathology have allowed researchers to study measures of cell injury such as inflammatory cytokines, edema, and markers of oxidative stress. Though the effects of melatonin in TBI appear to be mediated through mostly indirect mechanisms on inflammatory processes, some research has explored potential mechanisms that could be specific to melatonin.Animal model studies support that melatonin treatment after TBI significantly improves cognition and behavioral outcomes. However, clinical studies with human subjects are scarce. Beyond the apparent general antiinflammatory and antioxidant actions of melatonin, a review of the evidence identified some preliminary research that has suggested the significance of melatonin receptors specifically in TBI. While there is some evidence to suggest that melatonin is able to reduce post-TBI cognitive decline as measured by subject performance on memory tasks, there is a lack of longitudinal data on whether melatonin decreases the risk of developing dementia after TBI. Considering melatonin therapy's promising preclinical data, favora...

67 Background: Intratumoral cryo combined with immune modulation generates a potent systemic anti-tumor immune response that might improve recurrence free survival in ESBC. In this study, we evaluate the safety of pre-op cryo and/or ipi (10mg/kg) in pts with ESBC. Radiographic correlates and intratumoral/serologic immune responses are also explored. Methods: Eligible pts are ≥18y of age with operable ≥1.5 cm invasive ESBC, no history of autoimmune disease and planned mastectomy. Pts are sequentially assigned to receive pre-op: cryo alone (Group-A), ipi alone (B), or ipi with cryo (C). Cryo is administered 7-10d prior to surgery. Ipi is administered 8-15d prior to surgery (1-5d prior to cryo). If at least 5/6 pts in each group proceed with surgery without delay, the regimen will be considered safe/tolerable. Toxicity evaluation continues for 12 wks after ipi administration for Groups B and C. Results: As of May 1, 2013, 7/7 pts were enrolled to Group-A (expanded after a possible technical failure in 1 pt) and 6/6 pts were enrolled to Group-B. The median age was 45y (range 39-69y). All 13 pts in Groups A and B underwent mastectomy without delay. Group C is now accruing with 1/6 patients enrolled and awaiting surgery. 6/7 pts in Group-A and none in Group-B had ischemic tumor necrosis/infarction in the mastectomy tissue. Overall, pre-op cryo or ipi alone have been well tolerated with no study related grade 3/4 adverse events (AE) reported (Table). Conclusions: To date, pre-op cryo or ipi is safe and tolerable in pts with ESBC. A Phase II study of pre-op ipi and cryo in ESBC is planned. Clinical trial information: NCT01502592. [Table: see text]

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