Cisplatin fails to induce puma mediated apoptosis in mucosal melanomas

Objectives

Mucosal melanomas (MM) are aggressive subtypes of common melanomas. It remains unclear whether limitations in their resectability or their distinctive molecular mechanisms are responsible for the aggressive phenotype.

Methods

In total, 112 patients with cutaneous melanomas (CM) and 27 patients with MM were included. Clinical parameters were analysed using Chi square, Fisher exact and student''s t-test. Survival rates were calculated by Kaplan–Meier. Analysis of p53, p21, Mdm2, Hipk2, Gadd45, Puma, Bax, Casp9 and Cdk1 via quantitative PCR and immunohistochemistry (IHC) was performed. TP53 induction after cisplatin treatment was analysed in 10 cell lines (melanocytes, four MM and five CM) using western blot (WB) and qPCR.

Results

The overall/recurrence-free survival differed significantly between MM (40 months and 30 months) and CM (90 months and 107 months; p < 0.001). IHC and WB confirmed high p53 expression in all melanomas. Hipk2 and Gadd45 showed significantly higher expressions in CM (p < 0.005; p = 0.004). QPCR and WB of wild-type cell lines demonstrated no differences for p53, p21, Mdm2, Bax and Casp9. WB failed to detect Puma in MM, while Cdk1 regulation occurred exclusively in MM.

Conclusions

The aggressive phenotype of MM did not appear to be due to differential expressions of p53, p21, Mdm2, Bax or Casp9. A non-functional apoptosis in MM may have further clinical implications.     

Eliminating roles for T-bet and IL-2 but revealing superior activation and proliferation as mechanisms underpinning dominance of regulatory T cells in tumors

Foxp3⁺ regulatory T cells (Tregs) are often highly enriched within the tumor-infiltrating T cell pool. Using a well-characterised model of carcinogen-induced fibrosarcomas we show that the enriched tumor-infiltrating Treg population comprises largely of CXCR3⁺ T-bet⁺ ‘T_H1-like’ Tregs which are thymus-derived Helios⁺ cells. Whilst IL-2 maintains homeostatic ratios of Tregs in lymphoid organs, we found that the perturbation in Treg frequencies in tumors is IL-2 independent. Moreover, we show that the T_H1 phenotype of tumor-infiltrating Tregs is dispensable for their ability to influence tumor progression. We did however find that unlike Tconvs, the majority of intra-tumoral Tregs express the activation markers CD69, CD25, ICOS, CD103 and CTLA4 and are significantly more proliferative than Tconvs. Moreover, we have found that CD69⁺ Tregs are more suppressive than their CD69⁻ counterparts. Collectively, these data indicate superior activation of Tregs in the tumor microenvironment, promoting their suppressive ability and selective proliferation at this site.     

The prognostic impact of age in different molecular subtypes of breast cancer

Breast cancer is a heterogeneous entity composed of distinct molecular subgroups with different molecular and clinical features. We analyzed the association between molecular breast cancer subgroups, age at diagnosis, and prognosis in a compilation of publicly available gene expression datasets. Affymetrix gene expression data (U133A or U133Plus2.0 arrays) of 4467 breast cancers from 40 datasets were compiled and homogenized. Breast cancer subgroups were defined based on expression of ESR1, PR, HER2, and Ki67. Event-free survival was calculated as recurrence-free survival or distant metastasis-free survival if recurrence-free survival was not available. Young age at diagnosis is associated with higher frequency of triple negative and HER2 subtypes and lower frequency of luminal A breast cancers. The 5-year event-free survival rates of patients aged less than 40, between 40 and 50, and >50 years were 54.3 ± 3.5, 68.5 ± 1.9, and 70.4 ± 1.3 %, respectively. When controlling for breast cancer subtype, we found that age <40 years remained significantly associated with poor prognosis in triple negative breast cancer. The effect was modest in luminal tumors and not found in HER2 subtype. Both subtypes and age retained their significances in multivariate analysis. Association of age at diagnosis with molecular breast cancer subtype contributes to its important role as prognostic factor among patients with breast cancer. Still, within the group of triple negative breast cancer, young age <40 years has a significant prognostic value which was retained in multivariate analysis.     

Reprioritization of research for combat casualty care

Since the beginning of the conflicts in Iraq and Afghanistan more than a decade ago, much has been learned with regard to combat casualty care. Although progress has been significant, knowledge gaps still exist. The seventh Extremity War Injuries symposium, held in January 2012, reviewed the current state of knowledge and defined knowledge gaps in acute care, reconstructive care, and rehabilitative care in order to provide policymakers information on the areas in which research funding would be the most beneficial.     

Predictors of Nipple–Areolar Complex Involvement by Breast Carcinoma: Histopathologic Analysis of 787 Consecutive Therapeutic Mastectomy Specimens

Background  

Breast-conserving therapy (BCT) is an accepted therapeutic option for most breast cancer patients. However, mastectomy is still performed in 30–50% of patients undergoing surgeries. There is increasing interest in preservation of the nipple and/or areola in hopes of achieving improved cosmetic and functional outcomes; however, the oncologic safety of nipple–areolar complex (NAC) preservation is a major concern. We sought to identify the predictive factors for NAC involvement in breast cancer patients.     

New Technologies in Breast Cancer Surgery

Since breast-conserving surgery has become the gold standard for early breast cancer, the development of less radical or less burdensome technologies has been pressed for in order to preserve the patient from unnecessary harm through the operative procedure. Different technical approaches are under evaluation, and some of them are already being used in the clinical setting. The aim of this article is to present a perspective on future breast cancer surgery by shedding light on the current innovative and new techniques.