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Immune cells infiltrating the microenvironment of melanoma metastases may either limit or promote tumor progression, but the characteristics that distinguish these effects are obscure. In this study, we systematically evaluated the composition and organization of immune cells that infiltrated melanoma metastases in human patients. Three histologic patterns of immune cell infiltration were identified, designated immunotypes A, B, and C. Immunotype A was characterized by no immune cell infiltrate. Immunotype B was characterized by infiltration of immune cells limited only to regions proximal to intratumoral blood vessels. Immunotype C was characterized by a diffuse immune cell infiltrate throughout a metastatic tumor. These immunotypes represented 29%, 63%, and 8% of metastases with estimated median survival periods of 15, 23, and 130 months, respectively. Notably, from immunotypes A to C, there were increasing proportions of B cells and decreasing proportions of macrophages. Overall, the predominant immune cells were T cells (53%), B cell lineage cells (33%), and macrophages (13%), with natural killer and mature dendritic cells only rarely present. Whereas higher densities of CD8+ T cells correlated best with survival, a higher density of CD45+ leukocytes, T cells, and B cells also correlated with increased survival. Together, our findings reveal striking differences in the immune infiltrate in melanoma metastases in patients, suggesting microenvironmental differences in immune homing receptors and ligands that affect immune cell recruitment. These findings are important, not only by revealing how the immune microenvironment can affect outcomes but also because they reveal characteristics that may help improve individualized therapy for patients with metastatic melanoma. [ABSTRACT FROM AUTHOR]

Objective Most evidence describing outcomes of patients with brain metastases is based on number of brain metastases, rather than location or volume. We evaluated the impact of tumor location and relative volume on overall survival (OS) among a large cohort of patients treated with stereotactic radiosurgery. Methods Clinical, radiographic, and dosimetric data were collected on patients treated with first (if multiple) stereotactic radiosurgery for brain metastases. Multivariate analyses were performed to investigate the impact of brain metastasis relative location and volume on OS after stereotactic radiosurgery. Results Analysis included 300 patients with 817 tumors (116 patients with single brain metastasis). The most common tumor locations were supratentorial (75% of tumors), cerebellar (19%), and brainstem (5%). Median tumor volume was 0.4 mL (range, 0.003–65.0 mL). Tumor-specific factors associated with inferior OS included brainstem location versus both supratentorial and cerebellum locations for particular assumed values of cube root tumor volume ( P < 0.001 for each) and increasing total supratentorial tumor volume ( P = 0.004). Patients with supratentorial tumors and cerebellar tumors demonstrated similar OS, and cube root total tumor volume within the cerebellum and brainstem did not predict for OS. Conclusions The presence of brainstem metastases and cumulative supratentorial tumor volume are adverse features that result in inferior survival. These results can be used to inform patient prognosis and future clinical trial design. [ABSTRACT FROM AUTHOR]

Orbital metastases from breast cancer ( BC) are rare, but often debilitating. BC accounts for nearly half of metastases to the orbit. Orbital metastases may be discovered years after the initial diagnosis of BC, and are rare at initial presentation. A search of the institutional data base at an academic cancer center identified BC patients who developed or presented with orbital metastases from 2000 to 2013. Baseline characteristics, treatment modalities, survival and treatment responses were collected from the electronic medical record. There were 20 patients identified with orbital metastases (0.7% of all BC cases). The median age at diagnosis of BC was 49 years; 80% had estrogen positive disease. The interval between the initial diagnosis of BC and the presentation of orbital metastases was 8.5 years (0-19 years). Orbital disease was the initial presentation of BC in two cases. Three patients developed bilateral orbital metastases and seven had accompanying brain metastases. The most common presentation was decreased vision (55%), followed by diplopia (25%). The median survival after orbital metastases was 24 months. Thirteen patients (65%) received local radiation therapy. Of those radiated, 90% reported improvement of orbital symptoms. Other treatments included intraocular bevacizumab, surgery, and systemic therapy. Orbital metastases tend to occur in estrogen receptor positive disease and are often found years after BC onset. Orbital metastases may be associated with the development of brain metastases. Radiotherapy is the preferred local therapy and had high symptom control in this cohort. Oncologists should be aware of the signs of orbital metastases and the treatment options. [ABSTRACT FROM AUTHOR]

Approximately 50% of patients with muscle-invasive bladder cancer (MIBC) develop metastatic disease, which is almost invariably lethal. However, our understanding of pathways that drive aggressive behavior of MIBC is incomplete. Members of the FOXA subfamily of transcription factors are implicated in normal urogenital development and urologic malignancies. FOXA proteins are implicated in normal urothelial differentiation, but their role in bladder cancer is unknown. We examined FOXA expression in commonly used in vitro models of bladder cancer and in human bladder cancer specimens, and used a novel in vivo tissue recombination system to determine the functional significance of FOXA1 expression in bladder cancer. Logistic regression analysis showed decreased FOXA1 expression is associated with increasing tumor stage (p<0.001), and loss of FOXA1 is associated with high histologic grade (p<0.001). Also, we found that bladder urothelium that has undergone keratinizing squamous metaplasia, a precursor to the development of squamous cell carcinoma (SCC) exhibited loss of FOXA1 expression. Furthermore, 81% of cases of SCC of the bladder were negative for FOXA1 staining compared to only 40% of urothelial cell carcinomas. In addition, we showed that a subpopulation of FOXA1 negative urothelial tumor cells are highly proliferative. Knockdown of FOXA1 in RT4 bladder cancer cells resulted in increased expression of UPK1B, UPK2, UPK3A, and UPK3B, decreased E-cadherin expression and significantly increased cell proliferation, while overexpression of FOXA1 in T24 cells increased E-cadherin expression and significantly decreased cell growth and invasion. In vivo recombination of bladder cancer cells engineered to exhibit reduced FOXA1 expression with embryonic rat bladder mesenchyme and subsequent renal capsule engraftment resulted in enhanced tumor proliferation. These findings provide the first evidence linking loss of FOXA1 expression with histological subtypes of MIBC and urothelial cell proliferation, and suggest an important role for FOXA1 in the malignant phenotype of MIBC. [ABSTRACT FROM AUTHOR]

Abstract: Background: Differentiating melanoma metastasis from benign cutaneous lesions currently requires biopsy or costly imaging, such as positron emission tomography scans. Melanoma metastases have been observed to be subjectively warmer than similarly appearing benign lesions. We hypothesized that infrared (IR) thermography would be sensitive and specific in differentiating palpable melanoma metastases from benign lesions. Materials and methods: Seventy-four patients (36 females and 38 males) had 251 palpable lesions imaged for this pilot study. Diagnosis was determined using pathologic confirmation or clinical diagnosis. Lesions were divided into size strata for analysis: 0–5, >5–15, >15–30, and >30 mm. Images were scored on a scale from −1 (colder than the surrounding tissue) to +3 (significantly hotter than the surrounding tissue). Sensitivity and specificity were calculated for each stratum. Logistical challenges were scored. Results: IR imaging was able to determine the malignancy of small (0–5 mm) lesions with a sensitivity of 39% and specificity of 100%. For lesions >5–15 mm, sensitivity was 58% and specificity 98%. For lesions >15–30 mm, sensitivity was 95% and specificity 100%, and for lesions >30 mm, sensitivity was 78% and specificity 89%. The positive predictive value was 88%–100% across all strata, and the negative predictive value was 95% for >15–30 mm lesions and 80% for >30 mm lesions. Conclusions: Malignant lesions >15 mm were differentiated from benign lesions with excellent sensitivity and specificity. IR imaging was well tolerated and feasible in a clinic setting. This pilot study shows promise in the use of thermography for the diagnosis of malignant melanoma with further potential as a noninvasive tool to follow tumor responses to systemic therapies. [Copyright &y& Elsevier]