Clear Cell Papillary Renal Cell Carcinoma and Renal Angiomyoadenomatous Tumor: Two Variants of a Morphologic, Immunohistochemical, and Genetic Distinct Entity of Renal Cell Carcinoma.

Clear cell papillary renal cell carcinoma (ccpRCC) and renal angiomyoadenomatous tumor (RAT) share morphologic similarities with clear cell (ccRCC) and papillary RCC (pRCC). It is a matter of controversy whether their morphologic, immunophenotypic, and molecular features allow the definition of a separate renal carcinoma entity. The aim of our project was to investigate specific renal immunohistochemical biomarkers involved in the hypoxia-inducible factor pathway and mutations in the VHL gene to clarify the relationship between ccpRCC and RAT. We investigated 28 ccpRCC and 9 RAT samples by immunohistochemistry using 25 markers. VHL gene mutations and allele losses were investigated by Sanger sequencing and fluorescence in situ hybridization. Clinical follow-up data were obtained for a subset of the patients. No tumor recurrence or tumor-related death was observed in any of the patients. Immunohistochemistry and molecular analyses led to the reclassification of 3 tumors as ccRCC and TFE3 translocation carcinomas. The immunohistochemical profile of ccpRCC and RAT samples was very similar but not identical, differing from both ccRCC and pRCC. Especially, the parafibromin and hKIM-1 expression exhibited differences in ccpRCC/RAT compared with ccRCC and pRCC. Genetic analysis revealed VHL mutations in 2/27 (7%) and 1/7 (14%) ccpRCC and RAT samples, respectively. Fluorescence in situ hybridization analysis disclosed a 3p loss in 2/20 (10%) ccpRCC samples. ccpRCC and RAT have a specific morphologic and immunohistochemical profile, but they share similarities with the more aggressive renal tumors. On the basis of our results, we regard ccpRCC/RAT as a distinct entity of RCCs.

Single stage transforaminal retrojugular tumor resection: The spinal keyhole for dumbbell tumors in the cervical spine.

BACKGROUND: Dumbbell tumors are defined as having an intradural and extradural component with an intermediate component within an expanded neural foramen. Complete resection of these lesions in the subaxial cervical spine is a challenge, and it has been achieved through a combined posterior/anterior or anterolateral approach. This study describes a single stage transforaminal retrojugular (TFR) approach for dumbbell tumors resection in the cervical spine. METHODS: This is a retrospective review of a series of 17 patients treated for cervical benign tumors, 4 of which were "true" cervical dumbbell tumors operated by a simplified retrojugular approach. The TFR approach allows a single stage gross total resection of both the extraspinal and intraspinal/intradural components of the tumor, taking advantage of the expanded neural foramen. All patients were followed clinically and radiologically with magnetic resonance imaging (MRI). RESULTS: Gross total resection was confirmed in all four patients by postoperative MRI. Minimal to no bone resection was performed. No fusion procedure was performed and no delayed instability was seen. At follow up, one patient had a persistent mild hand weakness and Horners syndrome following resection of a hemangioblastoma of the C8 nerve root. The other three patients were neurologically normal. CONCLUSIONS: The TFR approach appears to be a feasible surgical option for single stage resection in selective cases of dumbbell tumors of the cervical spine.

Local Salmonella immunostimulation recruits vaccine-specific CD8 T cells and increases regression of bladder tumor.

NlmCategory="UNASSIGNED">The efficacy of antitumoral responses can be increased using combinatorial vaccine strategies. We recently showed that vaccination could be optimized by local administration of diverse molecular or bacterial agents to target and augment antitumoral CD8 T cells in the genital mucosa (GM) and increase regression of cervical cancer in an animal model. Non muscle-invasive bladder cancer is another disease that is easily amenable to local therapies. In contrast to data obtained in the GM, in this study we show that intravesical (IVES) instillation of synthetic toll-like receptor (TLR) agonists only modestly induced recruitment of CD8 T cells to the bladder. However, IVES administration of Ty21a, a live bacterial vaccine against typhoid fever, was much more effective and increased the number of total and vaccine-specific CD8 T cells in the bladder approximately 10 fold. Comparison of chemokines induced in the bladder by either CpG (a TLR-9 agonist) or Ty21a highlighted the preferential increase in complement component 5a, CXCL5, CXCL2, CCL8, and CCL5 by Ty21a, suggesting their involvement in the attraction of T cells to the bladder. IVES treatment with Ty21a after vaccination also significantly increased tumor regression compared to vaccination alone, resulting in 90% survival in an orthotopic murine model of bladder cancer expressing a prototype tumor antigen. Our data demonstrate that combining vaccination with local immunostimulation may be an effective treatment strategy for different types of cancer and also highlight the great potential of the Ty21a vaccine, which is routinely used worldwide, in such combinatorial therapies.

Identification of Rare High-Avidity, Tumor-Reactive CD8+ T Cells by Monomeric TCR-Ligand Off-Rates Measurements on Living Cells.

The avidity of the T-cell receptor (TCR) for antigenic peptides presented by the peptide-MHC (pMHC) on cells is a key parameter for cell-mediated immunity. Yet a fundamental feature of most tumor antigen-specific CD8(+) T cells is that this avidity is low. In this study, we addressed the need to identify and select tumor-specific CD8(+) T cells of highest avidity, which are of the greatest interest for adoptive cell therapy in patients with cancer. To identify these rare cells, we developed a peptide-MHC multimer technology, which uses reversible Ni(2+)-nitrilotriacetic acid histidine tags (NTAmers). NTAmers are highly stable but upon imidazole addition, they decay rapidly to pMHC monomers, allowing flow-cytometric-based measurements of monomeric TCR-pMHC dissociation rates of living CD8(+) T cells on a wide avidity spectrum. We documented strong correlations between NTAmer kinetic results and those obtained by surface plasmon resonance. Using NTAmers that were deficient for CD8 binding to pMHC, we found that CD8 itself stabilized the TCR-pMHC complex, prolonging the dissociation half-life several fold. Notably, our NTAmer technology accurately predicted the function of large panels of tumor-specific T cells that were isolated prospectively from patients with cancer. Overall, our results demonstrated that NTAmers are effective tools to isolate rare high-avidity cytotoxic T cells from patients for use in adoptive therapies for cancer treatment.

Ocular adnexal (orbital) solitary fibrous tumor: nuclear STAT6 expression and literature review.

PURPOSE: To report the clinico-pathological features of solitary fibrous tumor occurring in the ocular adnexa (OA) in a single center. To assess the presence of NAB2-STAT6 genes fusion in OA solitary fibrous tumor detected by nuclear overexpression of STAT6. METHODS: Retrospective study including orbital and OA solitary fibrous tumors treated between 2006 and 2014 in our center. The clinical, radiological, and histopathological findings were evaluated. STAT6 expression was assessed by immunohistochemistry. RESULTS: Five patients were identified and presented with a chronic OA mass. The tumors were radiologically well delimited, highly vascularized and without bone erosion. All the patients underwent complete surgical excision. Pathological examination confirmed solitary fibrous tumor in all cases. All tumors demonstrated a nuclear expression of STAT6. There were no recurrences, with a mean follow-up of 5 years after surgery. Our review demonstrated that proptosis was the most common presentation occurring in 60 % of the cases. In the ocular adnexa, adverse histological criteria were found in 19.7 % of the tumors, and recurrences were observed in 48 % of these cases. Thirty-six percent of patients presented at least one local recurrence, and metastastic spread was found in 2.4 % of the cases. Tumor-related death was described in two cases. CONCLUSION: Ocular adnexal SFT are rare and usually present as a chronic orbital mass with proptosis. In the OA, solitary fibrous tumor demonstrates STAT6 nuclear expression, as documented in other locations. Recurrences are unusual and metastasis exceptional. Initial surgical resection should be complete in order to avoid recurrence.

Efficacy of tumor necrosis factor inhibitors in patients with ankylosing spondylitis

Objectives: This study aims to investigate the efficacy of tumor necrosis factor-alpha blockers such as infliximab, etanercept, and adalimumab in the treatment of ankylosing spondylitis. Patients and methods: The outcome of tumor necrosis factor-alpha blocker treatment was analyzed retrospectively in 59 patients with ankylosing spondylitis who were being treated in our clinic during last nine years. The patients' Assessment of SpondyloArthritis International Society (ASAS) 20 and ASAS 40 response rates, adverse drugs effects, and treatment compliance were evaluated. Results: ASAS 20 response was achieved by 89.8% of the patients in the third month, and by 93.2% in the sixth month. ASAS 40 response was achieved by 61% of the patients in the third and sixth month. No statistically significant difference was detected between the three tumor necrosis factor-alpha blockers with regards to the ASAS 40 response rates. Mild infections, observed in 31 of the patients, were the most common side effects. Serious side effect was observed in only one patient. The number of patients who withdrew from the treatment for various reasons was six.

Acute pulmonary hypertension caused by tumor embolism: a report of two cases.

Acute pulmonary hypertension leading to right ventricular failure and circulatory collapse is usually caused by thromboembolic obstruction of the pulmonary circulation. However, in rare instances, other causes can be associated with a similar clinical presentation. We present and discuss the clinical histories of two patients with acute right ventricular failure due to an atypical cause of pulmonary hypertension, disseminated pulmonary tumor embolism.

Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma.

BACKGROUND: Immune checkpoint inhibitors targeting programmed cell death 1 (PD1) or its ligand (PD-L1) showed activity in several cancer types. METHODS: We performed immunohistochemistry for CD3, CD8, CD20, HLA-DR, phosphatase and tensin homolog (PTEN), PD-1, and PD-L1 and pyrosequencing for assessment of the O6-methylguanine-methyltransferase (MGMT) promoter methylation status in 135 glioblastoma specimens (117 initial resection, 18 first local recurrence). PD-L1 gene expression was analyzed in 446 cases from The Cancer Genome Atlas. RESULTS: Diffuse/fibrillary PD-L1 expression of variable extent, with or without interspersed epithelioid tumor cells with membranous PD-L1 expression, was observed in 103 of 117 (88.0%) newly diagnosed and 13 of 18 (72.2%) recurrent glioblastoma specimens. Sparse-to-moderate density of tumor-infiltrating lymphocytes (TILs) was found in 85 of 117 (72.6%) specimens (CD3+ 78/117, 66.7%; CD8+ 52/117, 44.4%; CD20+ 27/117, 23.1%; PD1+ 34/117, 29.1%). PD1+ TIL density correlated positively with CD3+ (P < .001), CD8+ (P < .001), CD20+ TIL density (P < .001), and PTEN expression (P = .035). Enrichment of specimens with low PD-L1 gene expression levels was observed in the proneural and G-CIMP glioblastoma subtypes and in specimens with high PD-L1 gene expression in the mesenchymal subtype (P = 5.966e-10). No significant differences in PD-L1 expression or TIL density between initial and recurrent glioblastoma specimens or correlation of PD-L1 expression or TIL density with patient age or outcome were evident. CONCLUSION: TILs and PD-L1 expression are detectable in the majority of glioblastoma samples but are not related to outcome. Because the target is present, a clinical study with specific immune checkpoint inhibitors seems to be warranted in glioblastoma.

Perivascular epithelioid cell tumor (PEComa) of the uterus: A case report

Background. Perivascular epithelioid cell tumors (PEComas) are a rare family of mesenchymal tumors arising in a wide array of anatomic locations and characterized by coexpression of melanocytic and muscle markers. The uterus accounts for around one-fourth of the overall PEComa cases reported in the literature. Methods. We report a case of PEComa of the uterus with multiple malignancy features. Results. A uterine mass suspect for leiomyosarcoma was found in a 53-year-old woman with post-menopausal bleeding. Total hysterectomy and bilateral adnexectomy was performed. The tumor measured 7 cm in diameter, was unique, well-circumscribed, nodular, and whiteyellow without haemorrhage or necrosis. Microscopically, two populations of cells could be seen: small fusiform cells growing in fascicles resembling a smooth muscle tumor, and large epithelioid cells with abundant pale vacuolated cytoplasm growing in a diffuse pattern. Cytologic atypias were marked and mitoses numerous and often atypical in the second component. The tumor infiltrated into the myometrium with lymphovascular invasion. Immunostains showed positivity for MelanA, HMB45, smooth muscle actin, CD10, TFE3 and cathepsin K. Conclusions. This PEComa case presents several of the recently precised criteria for malignancy (Schoolmeester JK et al. Perivascular epithelioid cell neoplasm (PEComa) of the gynecologic tract: Clinicopathologic and immunohistochemical characterization of 16 cases. Am J Surg Pathol 2014; 38:176-188).