Reactive angioendotheliomatosis in association with a well-differentiated angiosarcoma

A 55-year-old white female with a complex medical history including mixed connective tissue disease and peripheral vascular disease developed a group of red-purple papules on her proximal medial thigh that was followed, five months later, by the development of a large violaceous patch. She reported a history of radiation to this site (for melanoma) during her childhood. She was admitted to the hospital with a presumptive diagnosis of cellulitis, but failed to respond to antibiotics. A biopsy was performed and demonstrated a well-differentiated angiosarcoma arising in conjunction with reactive angioendotheliomatosis. Excision of the lesion was performed, and fifteen months of follow-up have shown no recurrence or metastasis.     

Myxoinflammatory fibroblastic sarcoma of the neck

BACKGROUND: Myxoinflammatory fibroblastic sarcoma (MIFS), also named inflammatory myxohyaline tumor of distal extremities with virocyte or Reed-Sternberg cells, is a rare tumor typically presenting as a painless mass in the extremities. PATIENTS: We present an unusual case of MIFS presenting as a subcutaneous neck mass. This is the first reported case of MIFS presenting in the neck. RESULTS: Therefore, this lesion must be considered in the differential diagnosis for painless subcutaneous masses presenting not only in the distal extremities, but also in the neck. CONCLUSION: MIFS has only recently been recognized. The differential diagnosis for MIFS is broad, and it can often be mistaken for several different inflammatory and neoplastic processes, which may require different treatment.     

Gemcitabine, 5-fluorouracil, and leucovorin in advanced biliary tract and gallbladder carcinoma: a North Central Cancer Treatment Group phase II trial

BACKGROUND: Gemcitabine has broad activity in a variety of solid tumors including biliary tract carcinomas. The authors evaluated 6-month survival, response, and toxicity associated with a combination of gemcitabine, 5-fluorouracil (5-FU), and leucovorin (LV) in patients with unresectable or metastatic biliary tract or gallbladder adenocarcinoma (ACA). METHODS: A 4-week course included 1000 mg/m2 gemcitabine by intravenous infusion over 30 minutes on Days 1, 8, and 15, 25 mg/m2 LV by intravenous push, and 600 mg/m2 5-FU by intravenous push after LV. RESULTS: Forty-two patients were enrolled in 6 months, 35 of whom had metastatic disease. Patients with biliary tract ACA included 24 with hepatic disease (19 patients had intrahepatic disease and 5 patients had extrahepatic disease) and 4 with disease in the ampulla of Vater. All patients were evaluable and received a median of 4 courses of treatment (range, 1-21 courses). Commonly occurring severe toxicity (NCI CTC Grade 3 or worse) included: dyspnea (four patients), nausea (four patients), fatigue (seven patients), thrombocytopenia (six patients), emesis (four patients), and diarrhea (four patients). Five partial responses (9.5%) occurred, 3 of which were sustained for > or = 8 weeks. No treatment-related deaths occurred. Thirty-two patients had disease progression and 38 died after a median follow-up of 20 months (range, 1.4-24 months). The median time to disease progression was 4.6 months (95% confidence interval [95% CI], 2.4-6.6%). The median survival period was 9.7 months (95% CI, 7-12%). CONCLUSIONS: This combination regimen was manageable in patients with advanced biliary tract and gallbladder ACA. Of 42 patients, 24 (57%) survived > or = 6 months, satisfying the primary end point of the trial. The length of survival suggested that gemcitabine, 5-FU, and LV had benefit equivalent to gemcitabine alone.     

Clitoral therapy device for treatment of sexual dysfunction in irradiated cervical cancer patients

PURPOSE: The purpose of this pilot study was to evaluate the efficacy of the clitoral therapy device (Eros Therapy) in alleviating sexual dysfunction in irradiated cervical cancer patients. METHODS AND MATERIALS: Eligible patients had a history of cervical cancer treated with radiotherapy and self-reported sexual dysfunction of sexual arousal and/or orgasmic disorders. Patients used the noninvasive, nonpharmacologic clitoral therapy device using a hand-held, battery-powered vacuum to cause clitoral engorgement four times weekly for 3 months during foreplay and self-stimulation. Study instruments included the Female Sexual Function Index, Derogatis Interview for Sexual Functioning, and Dyadic Adjustment Scale. The outcome evaluation was performed at 3 months. RESULTS: Between 2001 and 2002, 15 women were enrolled and 13 completed the study. The median patient age and radiotherapy-enrollment interval was 43.5 years and 2 years, respectively. At baseline, all patients reported symptoms of sexual arousal and/or orgasmic disorders, and some also had sexual desire and pain disorders. At 3 months, statistically significant improvements were seen in all domains tested, including sexual desire, arousal, lubrication, orgasm, sexual satisfaction, and reduced pain. The median Female Sexual Function Index total score increased from 17 to 29.4 (maximal score, 36; p <0.001). The median Derogatis Interview for Sexual Functioning total raw score increased from 46 to 95 (maximal score, 118; p <0.001). At baseline, the Derogatis Interview for Sexual Functioning total T-score corresponded to the bottom 10th percentile of normal sexual functioning. At 3 months, the total T-score placed the patients at the normalcy cutoff. Gynecologic examinations revealed improved mucosal color and moisture and vaginal elasticity and decreased bleeding and ulceration. CONCLUSION: Our results from this pilot study suggest that the clitoral therapy device may alleviate sexual dysfunction in irradiated cervical cancer patients. A randomized, controlled trial is warranted to assess the full benefits of this approach.     

Immunocompetent mouse model of breast cancer for preclinical testing of EphA2-targeted therapy

EphA2, a receptor tyrosine kinase, is elevated in many invasive human breast cancers, and the majority of EphA2 remains unphosphorylated. The successful attachment of ligand EphrinA1 present on the surface of adjacent cells to EphA2 initiates EphA2 phosphorylation leading to its turnover. In vivo efficacy of various approaches targeting EphA2 for breast cancer therapy is usually evaluated in nude mice bearing human breast cancer xenografts. In order to establish an immunocompetent mouse model of breast cancer for EphA2-targeted therapies, we evaluated a mouse breast cancer cell line (MT1A2) for EphA2 expression and phosphorylation. Overexpression of EphA2 was observed in MT1A2 cells and the majority of it remained unphosphorylated signifying that EphA2 in MT1A2 cells behaved similar to that of human breast cancer cells. Human adenovirus subtype 5 (HAd5) vectors expressing secretory forms of EphrinA1 were used for in vitro and in vivo targeting of MT1A2-derived EphA2. MT1A2 cells infected with HAd-EphrinA1-Fc (HAd expressing extracellular domain of human EphrinA1 attached to Fc portion of human IgG1 heavy chain) induced EphA2 activation and its turnover. This led to inhibition in MT1A2 cell colony formation in soft agar and cell viability in monolayer culture. In addition, MT1A2 cells-infected with HAd-EphrinA1-Fc failed to form tumors in syngeneic FVB/n mice at least 32 days postinoculation. Moreover, intratumoral inoculation of FVB/n mice-bearing MT1A2-induced tumors with HAd-EphrinA1-Fc slowed the tumor growth and also resulted in the development of vector-specific immune response. These results indicate that FVB/n mice-bearing MT1A2-induced tumors could serve as an immunocompetent model of breast cancer for EphA2-targeted therapeutic strategies.     

Oxidative stress and stress signaling： menace of diabetic cardiomyopathy

Cardiovascular disease is the most common cause of death in the diabetic population and is currently one of the leading causes of death in the United States and other industrialized countries. The health care expenses associated with cardiovascular disease are staggering, reaching more than 350 billion dollars in 2003. The risk factors for cardiovascular disease include high fat/cholesterol levels, alcoholism, smoking, genetics, environmental factors and hypertension, which are commonly used to gauge an individual's risk of cardiovascular disease and to track their progress during therapy. Most recently, these factors have become important in the early prevention of cardiovascular diseases. Oxidative stress, the imbalance between reactive oxygen species production and breakdown by endogenous antioxidants, has been implicated in the onset and progression of cardiovascular diseases such as congestive heart failure and diabetes-associated heart dysfunction (diabetic cardiomyopathy). Antioxidant therapy has shown promise in preventing the development of diabetic heart complications. This review focuses on recent advances in oxidative stress theory and antioxidant therapy in diabetic cardiomyopathy, with an emphasis on the stress signaling pathways hypothesized to be involved. Many of these stress signaling pathways lead to activation of reactive oxygen species, major players in the development and progression of diabetic cardiomyopathy.     

The rise and fall of long-lived humoral immunity: terminal differentiation of plasma cells in health and disease

Summary: Long‐lived humoral immune responses are a hallmark of thymus‐dependent immunity. The cellular basis for enduring antibody‐mediated immunity is long‐lived memory B cells and plasma cells (PCs). Both of these cell populations acquire longevity as a result of antigen‐specific, CD40–dependent, cognate interactions with helper T cells within germinal centers (GCs). At the molecular level, defined functional domains of CD40 control the post‐GC fate of B cells. PC precursors that emerge from these GC reactions are highly proliferative and terminally differentiate to end‐stage cells within the bone marrow (BM). The striking phenotypic similarities between the PC precursors and the putative malignant cell in multiple myeloma (MM) suggests that MM may result from the transformation of PC precursors. Within the domain of autoimmune disease, recent studies have shown that dysregulated migration of PCs to the BM may impact immune homeostasis and the development of lupus. Understanding the processes of normal PC differentiation will provide strategic insights into identifying therapeutic targets for the treatment of differentiated B‐cell disorders.     

In Patients with Membranous Lupus Nephritis,Exostosin-Positivity and Exostosin-Negativity Represent Two Different Phenotypes

BackgroundIn patients with secondary (autoimmune) membranous nephropathy, two novel proteins, Exostosin 1 and Exostosin 2 (EXT1/EXT2), are potential disease antigens, biomarkers, or both. In this study, we validate the EXT1/EXT2 findings in a large cohort of membranous lupus nephritis.MethodsWe conducted a retrospective cohort study of patients with membranous lupus nephritis, and performed immunohistochemistry studies on the kidney biopsy specimens against EXT1 and EXT2. Clinicopathologic features and outcomes of EXT1/EXT2-positive versus EXT1/EXT2-negative patients were compared.ResultsOur study cohort included 374 biopsy-proven membranous lupus nephritis cases, of which 122 (32.6%) were EXT1/EXT2-positive and 252 (67.4%) were EXT1/EXT2-negative. EXT1/EXT2-positive patients were significantly younger (P=0.01), had significantly lower serum creatinine levels (P=0.02), were significantly more likely to present with proteinuria ≥3.5 g/24 h (P=0.009), and had significantly less chronicity features (glomerulosclerosis, P=0.001 or interstitial fibrosis and tubular atrophy, P<0.001) on kidney biopsy. Clinical follow-up data were available for 160 patients, of which 64 (40%) biopsy results were EXT1/EXT2-positive and 96 (60%) were EXT1/EXT2-negative. The proportion of patients with class 3/4 lupus nephritis coexisting with membranous lupus nephritis was not different between the EXT1/EXT2-positive and EXT1/EXT2-negative groups (25.0% versus 32.3%; P=0.32). The patients who were EXT1/EXT2-negative evolved to ESKD faster and more frequently compared with EXT1/EXT2-positive patients (18.8% versus 3.1%; P=0.003).ConclusionsThe prevalence of EXT1/EXT2 positivity was 32.6% in our cohort of membranous lupus nephritis. Compared with EXT1/EXT2-negative membranous lupus nephritis, EXT1/EXT2-positive disease appears to represent a subgroup with favorable kidney biopsy findings with respect to chronicity indices. Cases of membranous lupus nephritis that are EXT1/EXT2-negative are more likely to progress to ESKD compared with those that are EXT1/EXT2-positive.