Single-cell tumor-immune microenvironment of BRCA1/2 mutated high-grade serous ovarian cancer.

The majority of high-grade serous ovarian cancers (HGSCs) are deficient in homologous recombination (HR) DNA repair, most commonly due to mutations or hypermethylation of the BRCA1/2 genes. We aimed to discover how BRCA1/2 mutations shape the cellular phenotypes and spatial interactions of the tumor microenvironment. Using a highly multiplex immunofluorescence and image analysis we generate spatial proteomic data for 21 markers in 124,623 single cells from 112 tumor cores originating from 31 tumors with BRCA1/2 mutation (BRCA1/2mut), and from 13 tumors without alterations in HR genes. We identify a phenotypically distinct tumor microenvironment in the BRCA1/2mut tumors with evidence of increased immunosurveillance. Importantly, we report a prognostic role of a proliferative tumor-cell subpopulation, which associates with enhanced spatial tumor-immune interactions by CD8+ and CD4 + T-cells in the BRCA1/2mut tumors. The single-cell spatial landscapes indicate distinct patterns of spatial immunosurveillance with the potential to improve immunotherapeutic strategies and patient stratification in HGSC.

Molecular pathogenesis of non muscle-invasive bladder cancer: implications for novel targeted therapies.

Approximately 70% to 80% of patients with urothelial carcinomas of the bladder are initially diagnosed with non-muscle invasive disease. Superficial, non-muscle invasive bladder cancers (NMIBCs) are managed with cystoscopic transurethral resection of all visible lesions followed by intravesical chemotherapy and/or immunotherapy. Despite this treatment, up to 70% of these tumors will recur within five years and 15% will ultimately progress to muscle-invasive disease, suggesting that novel therapeutic strategies are necessary. Recent studies have greatly advanced our understanding of urothelial carcinogenesis and have highlighted the distinct molecular pathogenesis of NMIBCs versus muscle-invasive bladder tumors. It is now clear that diverse genetic and epigenetic events are driving the oncogenesis of NMIBCs, thereby attesting to their potential as therapeutic targets for these tumors. This article reviews the molecular pathogenesis of NMIBCs, discusses recently completed and ongoing clinical trials and anticipates the future direction of molecular targeted agents in this disease.

Acquired immunodeficiency syndrome related Kaposi's sarcoma eroding the maxillary bone.

BACKGROUND: Oral involvement is a common manifestation of acquired immunodeficiency syndrome related Kaposi's sarcoma, and it occurs in approximately one-third of afflicted patients. METHODS: We report an unusual case of Kaposi's sarcoma of the hard palate which invaded the underlying maxillary bone. RESULTS: The patient underwent excisional biopsy and was subsequently treated with localised radiation and systemic chemotherapy including liposomal doxorubicin. CONCLUSIONS: The presentation, differential diagnosis, radiographic appearance and management of this serious complication are discussed. Our case highlights the need for a multidisciplinary approach, consisting of ENT, oncology and infectious disease consultation, to ensure appropriate management of maxillofacial, intraosseous, acquired immunodeficiency syndrome related Kaposi's sarcoma.

Androgen receptor (AR) expression is an independent unfavorable prognostic factor in gastric cancer.

PURPOSE: To investigate the expression of sex steroid receptors in gastric cancer and to correlate their tumor expression profile with the clinicopathological parameters and overall survival of the patients. METHODS: Immunohistochemical methodology was employed in formalin-fixed paraffin-embedded sections from 86 patients with gastric carcinoma. Monoclonal antibodies against androgen (AR), estrogen (ER), and progesterone (PR) receptors were used. Survival rates were estimated by the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis was performed by the Cox proportional hazards model. RESULTS: Fifteen (17.4%) cases of gastric adenocarcinomas were positive for AR, two (2.3%) were positive for PR and three (3.5%) were positive for ER. Significantly higher AR expression was found in tumors with metastases to lymph nodes (P = 0.03). Patients with AR-positive tumors (AR+) had worse prognosis than (AR-) patients (median survival 9 months vs 24 months, P = 0.03). Patients with AR- and heat shock protein 27 (HSP27)-positive tumors (AR+/HSP27+) had a median survival of 6 months, whereas (AR-/HSP27-) patients had a median survival of 42 months (P = 0.017). Multivariate analysis revealed that AR expression and UICC stage were independent factors of unfavorable prognosis (P = 0.037 and P = 0.0055, respectively). CONCLUSIONS: Identification of AR-positive gastric carcinomas in gastric biopsies may warrant a more aggressive therapeutic approach and anti-androgen or AR-targeted agents may represent a novel strategy in tackling this devastating malignancy.

Oestrogen receptor beta (ERbeta) is abundantly expressed in normal colonic mucosa, but declines in colon adenocarcinoma paralleling the tumour's dedifferentiation.

Oestrogen Receptor beta (ERbeta) may protect against prostate and mammary cell proliferation and malignant transformation. Epidemiological studies indicate that oestrogens may reduce colon cancer risk. Since ERalpha is minimally expressed in normal and malignant colon, the aim of this study was to investigate the expression of ERbeta in both normal colonic wall and colon cancer. ERbeta expression was evaluated by immunohistochemistry in 90 cases of colon adenocarcinoma and nearby (>30-cm away) normal colonic wall, using a monoclonal antibody. Moderate or strong nuclear immunostaining was detected in superficial and crypt epithelium, endothelial cells, vascular smooth muscle cells, lymphocytes, enteric neurons and smooth muscular cells of the normal colonic wall. Superficial epithelial cells in normal colon demonstrated a significantly higher ERbeta expression than colon adenocarcinoma cells in both genders. The decline in ERbeta expression paralleled the loss of differentiation of malignant colon cells, regardless of the tumour's localisation. These findings suggest a protective role for ERbeta against colon carcinogenesis.

Expression of the 27-kDa heat shock protein (HSP27) in gastric carcinomas and adjacent normal, metaplastic, and dysplastic gastric mucosa, and its prognostic significance.

PURPOSE: The investigation of heat shock protein 27 (HSP27) expression in gastric cancer and adjacent normal, metaplastic, and dysplastic gastric mucosa and its correlation with clinicopathological parameters and survival of patients. METHODS: Immunohistochemical methodology was performed on formalin-fixed paraffin-embedded sections by using a monoclonal anti-HSP27 antibody. HSP27 expression was screened and compared in 86 cases of gastric carcinoma and adjacent normal, metaplastic, and dysplastic gastric mucosa. RESULTS: In the normal mucosa, HSP27 was detected in 68 out of 86 cases (79%) and was more intense in the surface and upper two-thirds of gastric foveolae. In dysplastic gastric mucosa, HSP27 immunoreactivity was usually higher than that of the adjacent normal epithelium and was parallel to the severity of dysplasia. HSP27 expression was found in 54 out of 86 (62.7%) gastric carcinomas and was significantly related to more than six metastatic lymph nodes ( P =0.03). HSP27 expression was also higher in tumors of advanced stage and in those of female patients. HSP27 expression was associated with shorter overall survival in univariate analysis ( P =0.04), but this relationship was not retained in multivariate analysis. CONCLUSIONS: Our findings indicate that: i) HSP27 is commonly expressed in normal gastric epithelium where it seems to exert a protective role; and ii) HSP27 is involved in gastric carcinogenesis and its expression appears to be associated with parameters of unfavorable prognosis and shorter overall survival.