Diva R. Salomao

Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion.

B7-H1, a recently described member of the B7 family of costimulatory molecules, is thought to be involved in the regulation of cellular and humoral immune responses through the PD-1 receptor on activated T and B cells. We report here that, except for cells of the macrophage lineage, normal human tissues do not express B7-H1. In contrast, B7-H1 is abundant in human carcinomas of lung, ovary and colon and in melanomas. The pro-inflammatory cytokine interferon-γ upregulates B7-H1 on the surface of tumor cell lines. Cancer cell–associated B7-H1 increases apoptosis of antigen-specific human T-cell clones in vitro, and the apoptotic effect of B7-H1 is mediated largely by one or more receptors other than PD-1. In addition, expression of B7-H1 on mouse P815 tumor increases apoptosis of activated tumor-reactive T cells and promotes the growth of highly immunogenic B7-1+ tumors in vivo. These findings have implications for the design of T cell–based cancer immunotherapy.

Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5-IgG

Autoantibodies have defined two paraneoplastic visual disorders related to small‐cell lung carcinoma: retinopathy (“CAR”‐IgG [23kDa, recoverin]) and optic neuritis collapsin response‐mediated protein 5 (CRMP‐5‐IgG [62kDa]). Among 16 patients with CRMP‐5‐IgG and optic neuritis (aged 52–74 years; all smokers, 9 women), we documented coexisting retinitis in 5. None had CAR‐IgG. Fifteen had subacute vision loss, swollen optic discs, and field defects. Vascular leakage was evident at and remote from the disc; 5/5 tested had abnormal electroretinograms. Nine had striking vitreous cells. Vitrectomy showed reactive lymphocytosis (4/4), predominantly CD4+ (1/1). Most patients had multifocal neurological accompaniments. Cerebrospinal fluid contained lymphocytes (7‐32), elevated protein, multiple oligoclonal immunoglobulin bands, and CRMP‐5‐IgG. Three patients superficially resembled Devics disease at presentation. One autopsied patient had predominantly CD8+ T lymphocytes infiltrating optic nerve and spinal cord. Eleven patients had confirmed small‐cell carcinoma; 1 had imaging evidence of lung cancer; 3 had renal or thyroid carcinoma. Full‐length CRMP‐5 protein was identified in normal retina and optic nerve by Western blot analyses. Photoreceptor cells, retinal ganglion cells, and nerve fibers exhibited CRMP‐5–specific immunoreactivity. In summary, CRMP‐5‐IgG defines a paraneoplastic ophthalmological entity of combined optic neuritis and retinitis with vitreous inflammatory cells. Positive serology obviates the need for vitreous biopsy and expedites the search for cancer. Ann Neurol 2003

A prospective comparison of digital image analysis and routine cytology for the identification of malignancy in biliary tract strictures

BACKGROUND & AIMS Digital image analysis (DIA) allows quantification of nuclear DNA content and may help distinguish benign and malignant strictures of the biliary tract. METHODS One hundred ten consecutive patients undergoing endoscopic retrograde cholangiography for suspicious biliary tract strictures were enrolled in a prospective study comparing the accuracy of DIA and routine cytology (RC). Standard brush cytology sampling was performed twice by using 2 cytology brushes per patient. Both brushes were fixed in a single-specimen vial. Each specimen was formed into 1 pellet, and the sample was equally divided for evaluation by DIA and RC. DNA histograms were generated for ploidy analysis. The DIA criterion for malignancy was demonstration of aneuploidy. RESULTS Two patients had inadequate samples obtained for DIA analysis, 7 benign patients were excluded because of inadequate follow-up of less than 75 days, and 1 patient was lost to follow-up to clarify malignant versus benign disease. Of the remaining 100 patients, 56 strictures were malignant and 44 were benign. The sensitivities of DIA and RC were 39.3% and 17.9%, respectively (P = 0.014). The specificities of DIA and RC were 77.3% and 97.7%, respectively (P = 0.003). The accuracy of DIA (56.0%) was equivalent to RC (53.0%). CONCLUSIONS DIA is a valuable adjunct to RC for detecting malignant strictures of the biliary tract.

Orbital Inflammation With IgG4-Positive Plasma Cells: Manifestation of IgG4 Systemic Disease

OBJECTIVE To describe clinical, radiographic, and morphologic findings in patients with IgG4-positive cells present on orbital biopsy specimens. DESIGN Retrospective review (from January 1, 1993, through December 31, 2006) of patients with orbital biopsy specimens that excluded lymphoma; comparison of patients with and without IgG4-positive cells on immunostaining. RESULTS Of 21 patients, 11 had increased IgG4-positive cells (defined as >10 cells on biopsy). Symptoms included eyelid or periocular swelling (8 patients) or proptosis (3 patients), with bilateral involvement in 6 patients. Computed tomographic imaging displayed lacrimal gland mass in 10 patients; 6 patients had lesions in other organs. Two patients had increased serum IgG4 levels. In 10 patients without IgG4-positive cells (≤10 cells on biopsy), 6 had proptosis, 1 had eyelid swelling, 2 had eyelid mass, and 1 had diplopia, all unilateral. None had systemic symptoms. Patients with IgG4-positive cells had longer symptom duration, and their biopsy specimens showed more background fibrosis, lymphoid hyperplasia, plasma cells, and eosinophils. CONCLUSIONS The clinical appearance, high incidence of bilateral disease, association with lesions in other organs, and increased IgG4 serum levels in some patients-with an increased number of IgG4-positive cells in the biopsy specimen, which shows more background fibrosis, lymphoid hyperplasia, plasma cells, and eosinophils-indicate that these patients have an orbital manifestation of IgG4-associated systemic disease.

Malignant Melanoma in the 21st Century: The Emerging Molecular Landscape

Malignant melanoma presents a substantial clinical challenge. Current diagnostic methods are limited in their ability to diagnose early disease and accurately predict individual risk of disease progression and outcome. The lack of adequate approaches to properly define disease subgroups precludes rational treatment design and selection. Better tools are urgently needed to provide more accurate and personalized melanoma patient management. Recent progress in the understanding of the molecular aberrations that underlie melanoma oncogenesis will likely advance the diagnosis, prognosis, and treatment of melanoma. The emerging pattern of molecular complexity in melanoma tumors mirrors the clinical diversity of the disease and highlights the notion that melanoma, like other cancers, is not a single disease but a heterogeneous group of disorders that arise from complex molecular changes. Understanding of molecular aberrations involving important cellular processes, such as cellular signaling networks, cell cycle regulation, and cell death, will be essential for better diagnosis, accurate assessment of prognosis, and rational design of effective therapeutics. Defining an individual patients unique tumor characteristics may lead to personalized prediction of outcomes and selection of therapy. We review the emerging molecular landscape of melanoma and its implications for better management of patients with melanoma.

Small, nonfunctioning, asymptomatic pancreatic neuroendocrine tumors (PNETs): Role for nonoperative management

BACKGROUND Controversy exists regarding the optimal management of incidentally discovered, small pancreatic neuroendocrine tumors (PNETs). Our aim was to review the outcomes of patients who underwent nonoperative and operative management. METHODS We retrospectively reviewed patients with nonfunctioning PNETs at our institution from January 1, 2000 to June 30, 2011. Patients were included if the tumor was sporadic and <4 cm without radiographic evidence of local invasion or metastases. RESULTS Nonoperative patients (n = 77, median age, 67 years; range, 31-94) had a median tumor size of 1.0 cm (range, 0.3-3.2). Mean follow-up (F/U) was 45 months (max. 153 months). Median tumor size did not change throughout F/U; there was no disease progression or disease specific mortality. In the operative group (n = 56, median age, 60 years; range, 27-82), median neoplasm size was 1.8 cm (range, 0.5-3.6). Mean F/U was 52 months (max. 138 months). A total of 46% of the operative patients had some type of complication, more than half due to a clinically significant pancreatic leak. No recurrence or disease specific mortality was seen in the operative group, including 5 patients with positive lymph nodes. CONCLUSION Small nonfunctioning PNETs usually exhibit minimal or no growth over many years. Nonoperative management may be advocated when serial imaging demonstrates minimal or no growth without suspicious features.

INTRAOCULAR USE OF RITUXIMAB

PurposeTo evaluate the toxicity of 1 mg of intraocular rituximab and to present a small case-series of patients treated with intravitreal rituximab.MethodsRituximab (1 mg/0.1 ml) was injected in the vitreous of one eye of three Dutch-belted rabbits. Two animals were injected with balanced salt solution as controls. At 1 month the rabbits were killed and the eyes examined by light microscopy. Three patients (five eyes) with intraocular lymphoma were also treated with a 1 mg injection of rituximab.ResultsThe treated rabbit eyes and the control eyes showed no light microscopic evidence of ocular toxicity at 1 month following injection. The five human eyes of three patients have shown no evidence of intraocular toxicity with a median follow-up time of 3.6 months (range 2.0–6.4 months). One patient received a total of four injections in the right eye and three injections in the left eye.ConclusionIntravitreal rituximab at a dose of 1 mg does not appear to cause toxicity in rabbit eyes and in the five eyes of three patients.

Primary CNS lymphoma complicating treatment of myasthenia gravis with mycophenolate mofetil

Mycophenolate mofetil (MM), an immunosuppressant used after organ transplantation, is also used for treatment of autoimmune myasthenia gravis (MG). A patient with generalized MG was effectively managed with MM but developed CNS lymphoma after 3 years of treatment. Primary CNS lymphoma regressed on withdrawal of MM. Despite minimal short-term side effects and apparent efficacy, chronic treatment of MG with MM may be associated with increased risk of lymphoproliferative disorders.

Plexiform Fibrohistiocytic Tumor With Systemic Metastases: A Case Report

A case of plexiform fibrohistiocytic tumor with pulmonary metastases is presented. The tumor developed on the left wrist of a 4-year-old girl and metastasized to an axillary lymph node and lungs after an episode of local recurrence. This is the first report of systemic metastasis secondary to this neoplasm.

Paraneoplastic and Metastatic Neurologic Complications of Merkel Cell Carcinoma

Merkel cell carcinoma is a rare primary cutaneous neuroendocrine tumor that is locally aggressive and frequently accompanied by distant metastases. Neurologic complications of Merkel cell carcinoma are rare. We describe a 69-year-old man who presented with Lambert-Eaton myasthenic syndrome and was found to have Merkel cell carcinoma. The paraneoplastic syndrome improved with initial treatment of the malignancy. He subsequently developed a solitary brain metastasis and died of leptomeningeal carcinomatosis.