Citations

PurposeAdvanced systemic mastocytosis (SM), a fatal hematopoietic malignancy characterized by drug resistance, has no standard therapy. The effectiveness of allogeneic hematopoietic stem-cell transplantation (alloHCT) in SM remains unknown.Patients and MethodsIn a global effort to define the value of HCT in SM, 57 patients with the following subtypes of SM were evaluated: SM associated with clonal hematologic non–mast cell disorders (SM-AHNMD; n = 38), mast cell leukemia (MCL; n = 12), and aggressive SM (ASM; n = 7). Median age of patients was 46 years (range, 11 to 67 years). Donors were HLA-identical (n = 34), unrelated (n = 17), umbilical cord blood (n = 2), HLA-haploidentical (n = 1), or unknown (n = 3). Thirty-six patients received myeloablative conditioning (MAC), and 21 patients received reduced-intensity conditioning (RIC).ResultsResponses in SM were observed in 40 patients (70%), with complete remission in 16 patients (28%). Twelve patients (21%) had stable disease, and five patients (9%) had primary refractory disease. Overall survival (OS) at 3 years was 57% for all patients, 74% for patients with SM-AHNMD, 43% for those with ASM, and 17% for those with MCL. The strongest risk factor for poor OS was MCL. Survival was also lower in patients receiving RIC compared with MAC and in patients having progression compared with patients having stable disease or response.ConclusionAlloHCT was associated with long-term survival in patients with advanced SM. Although alloHCT may be considered as a viable and potentially curative therapeutic option for advanced SM in the meantime, given that this is a retrospective analysis with no control group, the definitive role of alloHCT will need to be determined by a prospective trial.

AbstractObjective The high level of stress associated with caring for others with medical conditions has been recognized for some time. Reducing caregiver stress can improve caregiver quality of life as well as improve the care they provide to loved ones. This systematic review assesses the effectiveness of internet-based interventions to decrease caregiver stress.Materials and methods A comprehensive literature search of Ovid MEDLINE (1946–2013), Embase (1988–2013), PsycINFO (1987–2013), and CINAHL was conducted using terms related to caregiver and internet-based interventions. Internet-based interventions involving informal caregivers in an open-label or randomized controlled trial setting were included. A pair of raters independently reviewed all published abstracts. Data regarding participants, interventions, and outcomes were extracted and, for randomized trials, methodology quality was also reviewed.Results Eight open-label trials met the review criteria: three showed positive benefit in reducing caregiver stress, four were partially positive (some outcomes positive, others negative), and one was a negative study. Sixteen randomized trials met the review criteria: six showed positive benefit, five were partially positive, and five were negative. There were no clear patterns as to the variables (such as study duration and complexity of intervention) associated with better outcomes, although earlier studies typically had more negative outcomes.Discussion Internet-based interventions were mostly effective in reducing aspects of caregiver stress and improving their well-being. Further studies to assess outcomes for caregivers and their recipients’ health, different technology delivery methods, and the cost of such interventions are needed.

Abstract Background: Women with benign breast disease (BBD) have increased breast cancer risk, and histologic features of the lesion stratify individual risk. We hypothesized that the concentration and type of terminal duct lobular units in BBD tissue is associated with future breast cancer risk. Methods: A nested case-control series of 770 breast cancer cases and 1273 age- and year of biopsy-matched controls was identified within a cohort of 13,647 women with BBD from 1967-2001 (median follow-up 15.3 years). One representative H&E slide from each biopsy was reviewed by a single pathologist, who recorded total # of lobules present, and # of fibrocystic lobules (total and # with epithelial proliferation). Samples were also evaluated for lobular involution and primary BBD histology. Lobule density (LD) was calculated as # of lobules/cm2 in each tissue section. Breast cancer associations with LD's (total, fibrocystic, proliferative) were examined with conditional logistic regression. Odds ratios are reported per 1 SD increase in LD. Results: Each LD measure was significantly associated with involution and primary BBD histology (p<0.0001 for each). Fibrocystic (OR 1.17, 95% CI 1.06-1.28) and proliferative (OR 1.37, 95% CI 1.16-1.61) LD were each associated with case status (p≤0.001) but total LD did not reach significance (OR 1.09, 95% CI 1.0-1.20; p=0.06). LD associations were somewhat attenuated after adjusting for involution (total OR 1.04 p=0.41; fibrocystic OR 1.13 p=0.02; proliferative OR 1.28 p=0.002) and primary BBD histology (total OR 1.04 p=0.49; fibrocystic OR 1.08 p=0.15; proliferative OR 1.18 p=0.07). Conclusions: The density of proliferative lobules in benign breast biopsy tissue is related to other BBD histologic features but may provide additional breast cancer risk stratification among women with proliferative BBD. Additional research will more fully evaluate the ability of this promising novel measure to predict breast cancer risk. Lobule Density Measures (lobules per square cm) All values are Medians Total Lobule Density Fibrocystic Lobule Density Proliferative Lobule Density Overall 17.5 4.5 0.7 Cases 18.1 4.9 1.3 Controls 17.0 4.2 0.4 Primary BBD Histology Nonproliferative disease 16 3.3 0 Proliferative disease 18.6 5.8 2.7 Atypical hyperplasia 20.9 6.2 3.3 Involution Category None 28.7 5.3 1.0 Partial 19.0 5 1.2 Complete 8.5 2.1 0 Citation Format: Amy C. Degnim, Lynn C. Hartmann, Tanya L. Hoskin, Marlene H. Frost, V Shane Pankratz, Derek C. Radisky, Lorelle L. Benetti, Celine M. Vachon, Teresa M. Allers, Robert A. Vierkant, Daniel W. Visscher. Density of breast lobules in benign breast tissue and association with future breast cancer risk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 155. doi:10.1158/1538-7445.AM2013-155

Abstract Multiple myeloma (MM) is a neoplastic plasma cell (PC) disorder of the oldster, and it is characterized by clonal proliferation of PC in the bone marrow (BM), monoclonal protein in biological fluids and organ dysfunction. While monoclonal gammopathy of undetermined significance (MGUS) often anticipates MM, the role of the cellular components of the BM microenvironment in the shift from MGUS to MM is unknown. Our aim was to define if the immune system has a role in this process. Thus, clinical signs of disease development and progression were investigated in the peripheral blood, bone marrow, kidney and bone of aging Vk*MYC mice to pinpoint the shift from MGUS to MM. We have also defined by immunohistochemistry and multiparametric flow-cytometry the phenotypic and functional characteristics of tumor infiltrating immune cells in the different phases of disease. We have found that the BM of Vk*MYC mice is the primary organ of PC accumulation, and accrual of PC in the BM associates with the presence of a measurable M-spike. Based on the frequency of PC in the BM and the quantification of M-spike in serum we were able to segregate MGUS from MM. The transition from MGUS to MM in Vk*MYC mice was characterized by increased vascularization of the BM that associated with local enrichment of proangiogenic molecules such as VEGF-A and IL18. The BM was also enriched in molecules that favor survival and proliferation of myeloma cells, and signs of osteoporosis accompanied these alterations. A comparison between Vk*MYC mice affected by MGUS and age matched wild type C57BL/6 mice revealed precocious alteration of the CD4/CD8 T cell ratio, increased percentage of IL2 and IL4 producing CD4+ T cells, and CD8+ T cells more prone to produce IFNγ in the BM of the former. In summary, our data suggest that early in disease development, yet unknown factors elicit an inflammatory reaction that significantly modifies the cellular composition of the BM and associates with neoangiogenesis and PC accumulation. Being the pathology in the Vk*MYC mouse similar to the human disease, our data might be relevant to understand the mechanisms of progression from MGUS to MM in humans. Citation Format: Arianna Calcinotto, Matteo Grioni, Maria Teresa Sabrina Bertilaccio, Marta Chesi, Leif Bergsagel, Giulia Casorati, Paolo Dellabona, Matteo Bellone. Modifications of the bone marrow microenvironment in the transition from monoclonal gammopathy of undetermined significance to multiple myeloma in Vk*MYC mice. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A83.

Abstract Bag3, a nucleotide exchange factor of the heat shock protein Hsp70, has been implicated in cell signaling. Here, we report that Bag3 interacts with the SH3 domain of Src, thereby mediating the effects of Hsp70 on Src signaling. Using several complementary approaches, we established that the Hsp70–Bag3 module is a broad-acting regulator of cancer cell signaling by modulating the activity of the transcription factors NF-κB, FoxM1, Hif1α, the translation regulator HuR, and the cell-cycle regulators p21 and survivin. We also identified a small-molecule inhibitor, YM-1, that disrupts the Hsp70–Bag3 interaction. YM-1 mirrored the effects of Hsp70 depletion on these signaling pathways, and in vivo administration of this drug was sufficient to suppress tumor growth in mice. Overall, our results defined Bag3 as a critical factor in Hsp70-modulated signaling and offered a preclinical proof-of-concept that the Hsp70–Bag3 complex may offer an appealing anticancer target. Cancer Res; 74(17); 4731–40. ©2014 AACR.

Abstract We report that administration of celecoxib, a specific cyclooxygenase-2 (COX-2) inhibitor, in combination with a dendritic cell-based cancer vaccine significantly augments vaccine efficacy in reducing primary tumor burden, preventing metastasis, and increasing survival. This combination treatment was tested in MMTV-PyV MT mice that develop spontaneous mammary gland tumors with metastasis to the lungs and bone marrow. Improved vaccine potency was associated with an increase in tumor-specific CTLs. Enhanced CTL activity was attributed to a significant decrease in levels of tumor-associated IDO, a negative regulator of T cell activity. We present data suggesting that inhibiting COX-2 activity in vivo regulates IDO expression within the tumor microenvironment; this is further corroborated in the MDA-MB-231 human breast cancer cell line. Thus, a novel mechanism of COX-2-induced immunosuppression via regulation of IDO has emerged that may have implications in designing future cancer vaccines.