Reports of spontaneous regressions of metastases and the demonstration of tumor-reactive cytotoxic T lymphocytes indicate the importance of the host's immune system in controlling the devastating course of metastatic renal cell carcinoma1,2,3. Recent research indicates that immunization with hybrids of tumor and antigen presenting cells results in protective immunity and rejection of established tumors in various rodent models4,5,6,7,8. Here, we present a hybrid cell vaccination study of 17 patients. Using electrofusion techniques5, we generated hybrids of autologous tumor and allogeneic dendritic cells that presented antigens expressed by the tumor in concert with the co-stimulating capabilities of dendritic cells. After vaccination, and with a mean follow-up time of 13 months, four patients completely rejected all metastatic tumor lesions, one presented a ‘mixed response’, and two had a tumor mass reduction of greater 50%. We also demonstrate induction of HLA-A2-restricted cytotoxic T cells reactive with the Muc1 tumor-associated antigen and recruitment of CD8+ lymphocytes into tumor challenge sites. Our data indicate that hybrid cell vaccination is a safe and effective therapy for renal cell carcinoma and may provide a broadly applicable strategy for other malignancies with unknown antigens.

Regression of human metastatic renal cell carcinoma after vaccination with tumor cell-dendritic cell hybrids.

Context: Adrenocortical carcinoma (ACC) is a rare and heterogeneous malignancy with incompletely understood pathogenesis and poor prognosis Patients present with hormone excess (eg virilization, Cushing’s syndrome) or a local mass effect (median tumor size at diagnosis > 10 cm) This paper reviews current diagnostic and therapeutic strategies in ACC Evidence Acquisition: Original articles and reviews were identified using a PubMed search strategy (http://wwwncbinlmnihgov/entrez/queryfcgi) covering the time period up until November 2005 The following search terms were used in varying combinations: adrenal, adrenocortical, cancer, carcinoma, tumor, diagnosis, imaging, treatment, radiotherapy, mitotane, cytotoxic, surgery Evidence synthesis: Tumors typically appear inhomogeneous in both computerized tomography and magnetic resonance imaging with necroses and irregular borders and differ from benign adenomas by their low fat content Hormonal analysis reveals evidence of steroid hormone secretion b

Clinical review: Adrenocortical carcinoma: clinical update.

Thiazolidinediones (TZDs) are widely used to treat type 2 diabetes mellitus; however, their use is complicated by systemic fluid retention. Along the nephron, the pharmacological target of TZDs, peroxisome proliferator-activated receptor-gamma (PPARgamma, encoded by Pparg), is most abundant in the collecting duct. Here we show that mice treated with TZDs experience early weight gain from increased total body water. Weight gain was blocked by the collecting duct-specific diuretic amiloride and was also prevented by deletion of Pparg from the collecting duct, using Pparg (flox/flox) mice. Deletion of collecting duct Pparg decreased renal Na(+) avidity and increased plasma aldosterone. Treating cultured collecting ducts with TZDs increased amiloride-sensitive Na(+) absorption and Scnn1g mRNA (encoding the epithelial Na(+) channel ENaCgamma) expression through a PPARgamma-dependent pathway. These studies identify Scnn1g as a PPARgamma target gene in the collecting duct. Activation of this pathway mediates fluid retention associated with TZDs, and suggests amiloride might provide a specific therapy.

Thiazolidinediones expand body fluid volume through PPARγ stimulation of ENaC-mediated renal salt absorption

THE MANAGEMENT OF chordomas and chondrosarcomas involving the cranial base remains controversial. The options for therapy include biopsy, partial resection, radical resection, and various forms of radiotherapy. In this article, we analyze the outcome of 60 patients with cranial base chordoma

Chordomas and chondrosarcomas of the cranial base: results and follow-up of 60 patients.

Background
Fungal (rhino-) sinusitis encompasses a wide spectrum of immune and pathological responses, including invasive, chronic, granulomatous, and allergic disease. However, consensus on terminology, pathogenesis, and optimal management is lacking. The International Society for Human and Animal Mycology convened a working group to attempt consensus on terminology and disease classification.

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Fungal rhinosinusitis: A categorization and definitional schema addressing current controversies

A case of the chondroid variant of chordoma is presented. The differentiating features of this entity are discussed on a clinical and histopathologic basis. A review of the topic of chordoma is also provided.

Case Report and Literature Review

Bone resorption is an important aspect of chronic otitis media contributing to many complications of this disease. It is postulated that the mechanism of this localized destructive process is chemical in origin. Collagenase, lysosomal enzymes, prostaglandins, and other cell mediators are thought to induce bone resorption, but the site of action and cellular origin of these substances remains unclear. In this report, we demonstrate the location and attempt to delineate the cellular origin of two enzymes, collagenase and the lysosomal enzyme acid phosphatase in guinea pig temporal bones and human ossicles from ears containing chronic otitis media. Tissue localization of these enzymes identifies sites of active bone resorption and demonstrates the cells initiating this process. Using immunohistochemical and immunocytochemical techniques, collagenase was seen surrounding mononuclear inflammatory cells of granulation tissue at bone resorbing margins and at the periphery of osteocyte lacunae adjacent to resorbing areas. Electron microscopic data suggests that collagenase is an extracellular enzyme foun at the periphery of osteocytes. In addition, abundant acid phosphatase activity was seen in the same cells that exhibited collagenase staining, lending credence to the destructive function of these cells. The chronic inflammatory reaction found in chronic otitis media appears to activate bone destruction through the dynamic activity of mononuclear inflammatory cells and stimulates bone cells to increase their destructive biochemical functions.

Bone Resorption in Chronic Otitis Media

Four ears are presented with extensive destruction of the bony and membranous labyrinth with the loss of caloric function but with retention of hearing. Fourteen similar cases described previously in the literature are reviewed. Our cases are unique in that hearing was preserved after surgical removal of the disease in the inner ear itself. We are unaware of any previous well-documented reports showing such extensive destruction of the pars superior portion of the labyrinth with the preservation of hearing. Possible explanations and theoretical implications are discussed.

Preservation of cochlear function after extensive labyrinthine destruction.

By questionnaire, parents of 28 children with CPI were asked about pregnancy and delivery; speech, developmental, and health history; and the circumstances of the CPI diagnosis. A normal control group was used for comparison. CPI children had lower birth weights and, during early childhood, were more poorly understood by parents and more frequently had nasalized speech. In 50%, CPI diagnosis was made following adenoidectomy. Data and clinical findings indicate that possible predictors of CPI are unusually defective speech production, particularly characterized by nasalization, as a young child; a short or poorly mobile palate; anterior dimpling of the soft palate during elevation; radiographic abnormalities of the cervical vertebrae; neurologic abnormalities (developmental milestones or clinical examination); and nasal leakage of liquids as a very young infant. Temporary velopharyngeal incompetence and nasalized speech may occur in the normal patient following adenoidectomy but the disorder resolves in a day or two. Persistent nasalized speech following adenoidectomy indicates the likelihood of CPI; such a patient requires evaluation by a speech pathologist and possible surgical correction.

Robert M. Bumsted

Papers

Case Report and Literature Review

Bone Resorption in Chronic Otitis Media

Preservation of cochlear function after extensive labyrinthine destruction.

Indications of Congenital Palatal Incompetence before Diagnosis