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Objective The RhoA/Rho kinase pathway plays a pivotal role in cold-induced vasoconstriction, vascular smooth muscle cells function, and vascular homeostasis. This study evaluates the efficacy of fasudil, a RhoA/Rho kinase inhibitor, to reverse cold-induced vasospasm in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (SSc; scleroderma). Methods This is a single-center, double-blind, placebo-controlled, randomized, 3-period crossover study of oral fasudil (40 mg or 80 mg) or placebo administered 2 hours before a standardized cold challenge. The fall in skin temperature after the cold challenge and time to recover 50% and 70% of prechallenge digital skin temperature were used as primary outcomes. Digital blood flow assessed by laser Doppler, time to minimum skin temperature, and rate of skin cooling were also measured. Results A total of 17 patients with SSc and RP completed the study. After the cold challenge, skin temperatures and the average time (minutes) to recover 50% (7.9 minutes for placebo, 7.5 minutes for fasudil 40 mg, and 8.2 minutes for fasudil 80 mg; P = 0.791) and 70% (18.2 minutes for placebo, 15.0 minutes for fasudil 40 mg, and 17.1 minutes for fasudil 80 mg; P = 0.654) of prechallenge skin temperature were not significantly different across the 3 groups. The digital blood flow measurements were higher in fasudil-treated groups than placebo, but differences were not significant (P = 0.693). Conclusion Fasudil administered at a single oral dose of 40 mg or 80 mg was not associated with significant benefit in terms of the skin temperature recovery time and the digital blood flow after the cold challenge.

RESENTATION previously healthy 45-year-old African-American man resented to the hospital with a 1-week history of malaise, atigue, anorexia, fever, and rigors. He reported temperaures exceeding 104° F (40° C); intermittent chills and renching sweats that occurred mainly at night; and lowerxtremity myalgias and paresthesias that made it uncomortable for him to walk. He also had a 2-day history of mild yspnea at rest, accompanied by a nonproductive cough. On he day prior to admission, the patient noticed that he was roducing only very small amounts of urine, and that this as dark brown. His wife stated that he had been mildly onfused for the last day. A review of systems was negative or abdominal pain, diarrhea, dysuria, headaches, hemoptyis, focal neurological symptoms, nasal congestion, nausea, leuritic pain, precordial discomfort, or vomiting. He deied sick contacts. His past medical history was unremarkable, and the paient was not taking any medications, supplements, or herbal emedies. He had no known drug allergies. His family istory was positive only for a brother with adult polycystic idney disease. He was an active smoker with a 15-packear smoking history, but he did not drink alcohol or use llicit drugs. He denied foreign travel and had no risk factors or HIV.

The treatment of Wegener's granulomatosis, one of the most common forms of systemic vasculitis, has changed substantially over the past two decades. The principal aims of therapy are to control the disease swiftly, to limit the extent and severity of permanent organ damage, and to minimize the short-term and long-term morbidities that often result from therapy. This review provides an overview of the treatment regimens that are currently available for inducing and maintaining remission in patients with Wegener's granulomatosis, and also discusses newer agents that might have a role in the management of this disease in the future. Severe toxicity associated with the available agents and, therefore, there is keen interest in the development of alternative treatment strategies for this disease.

A 27-year-old Filipino man with no known past medical history presented with a 2-week history of progressive symmetric facial and neck swelling. On physical examination, the neck and anterior chest wall veins were engorged and distended. The examination was otherwise unremarkable, including a lack of lymphadenopathy in the cervical, axillary, or inguinal regions. Computed tomography (CT) of the chest showed a large mediastinal mass (10 × 6.5 × 8 cm) that had almost completely compressed the superior vena cava (Fig 1A). Additionally, several enlarged mediastinal lymph nodes were identified. A transthoracic biopsy of the mediastinal mass was performed, and the histology and immunostains were consistent with seminoma. Testicular ultrasound did not reveal a gonadal mass. Alpha fetal protein and beta-human chorionic gonadotropin levels were within normal limits. Lactate dehydrogenase was slightly elevated at 266 IU/L (0 to 200 U/L). A diagnosis of extragonadal seminoma presenting as superior vena cava syndrome was made. Interestingly, an abdominal CT showed three ill-defined hypodensities in the liver, with the largest measuring 1.5 cm in diameter. These lesions (Fig 1C; arrows), in addition to the mediastinal mass and one right hilar node, all demonstrated intense 2-[18F]fluorodeoxyglucose ([18F]FDG) uptake (Figs 1Aand 1C). The patient underwent standard chemotherapy with three cycles of bleomycin, etoposide, and cisplatin, and one cycle of etoposide and cisplatin. He had a dramatic clinical response to the chemotherapy, with complete resolution of symptoms and physical examination findings. After completing four cycles of chemotherapy, whole-body positron emission tomography (PET)/CT showed almost complete resolution of the mediastinal mass, with insignificant standard uptake value levels. However, the previously described liver lesions and the one right hilar node (Fig 1B, arrow) did not change in size or number and continued to show intense [18F]FDG uptake. Six weeks later, a repeat PET/CT remained unchanged. Fig. 1 Germ cell tumors account for approximately1%of all malignancies, but are the most common tumors in men between the ages of 15 to 35 years.1 Small subsets of these tumors (2% to 5%) are of extragonadal origin.2 Liver has been a rarely described site for metastatic extragonadal seminoma. In the largest case series of patients with extragonadal germ cell tumors, liver metastasis was only described in one of 51 patients.3 Residual masses found in patients with bulky seminoma after chemotherapy are commonly reported in approximately 56% to 78%4; however only a small fraction of these lesions were found to actually harbor viable tumor cells. There is a disagreement on whether the size of residual masses after chemotherapy predicts for the presence of active disease. Although not proven, there is postulation that the size of the residual mass may be a predictor for residual disease as a large residual mass may have a higher potential to contain tumor cells. One study5 determined that there was a higher likelihood of finding viable tumor tissue within residual lesions that were 3 cm or larger, whereas another study6 did not see such a correlation. Based on the experience from Memorial Sloan-Kettering Cancer Center (New York, NY), patients with residual masses of 3 cm or larger are recommended to undergo surgical excision of the lesion.5 In contrast, the experience of the Indiana University group (Indianapolis, IN) suggests that an initial period of observation is a plausible option, regardless of the size of the residual mass, and further therapy is reserved for patients with progressive disease.6 PET imaging has been assessed for its validity in predicting persistent disease in patients with residual mass after apparent successful chemotherapy for testicular cancer. The largest prospective study showed that this imaging modality was highly sensitive and specific in predicting residual disease, particularly in patients with residual mass larger than 3 cm. From the 56 scans performed in 51 patients, the sensitivity, specificity, positive predictive value, and negative predictive value were determined to be 80%, 100%, 100%, and 96%, respectively. In this series of patients, PET imaging was more accurate in predicting residual disease than size determination of the residual mass (>3 cm v ≤ 3 cm) by CT.4 In a retrospective analysis looking at 24 scans from 19 patients, PET imaging demonstrated a high negative predictive value (100%), but a significantly lower positive predictive value (67%).7 Given the unusual location of the residual lesions, we felt compelled to pursue additional work-up, especially with the discrepancy in the response to chemotherapy between the mediastinal mass and the residual lesions. We were concerned for the potential of a mixed tumor with nonseminomatous component in the residual lesions. A CT-guided biopsy of one of the hepatic lesions showed rare noncaseating granulomata in benign liver parenchyma without evidence of tumor. A second CT-guided liver biopsy showed benign appearing hepatocytes with portal fibrosis and chronic inflammation. The liver biopsy was stained for acid fast Bacillus and sent for viral, fungal, mycobacterial, and bacterial cultures, all of which were negative. Current data on management of postchemotherapy residual mass in seminoma is still quite limited. This case demonstrates the complexity in interpreting positive PET images in a patient with apparent response to chemotherapy, and it highlights the necessity to tailor the medical management to each individual whose disease does not follow the expected course. Fortunately, this patient continues to have stable findings on serial follow-up CT imagings and remains in remission 2 years after successful chemotherapy.

Raynaud’s phenomenon (RP) is seen in over 95% of patients with SSc and is often the first symptom of the disease. Scleroderma vascular disease is secondary to an obliterative vasculopathy causing not only vasospasm but also structural disease of the involved vessels. Digital ulcers are representative of vascular involvement in scleroderma and occur in about 30–50% of patients with scleroderma. The primary goal in the management of RP is the prevention of digital ischemia through the use of non-pharmacological and pharmacological measures. In the setting of acute digital ischemia, rapid intervention using both treatment modalities is required. This case illustrates the problem of RP and digital ischemia and the approach to management.

Objective Weight gain is a side effect of glucocorticoid (GC) use, but the natural history and health implications of changes in weight that occur during the treatment of inflammatory disease are not understood. Methods We evaluated data from the Wegener's Granulomatosis Etanercept Trial. Patients were categorized according to clinical outcome at 1 year: remission (no disease flares), single flare, or multiple flares. Risk factors for gaining ≥10 kg were examined in multivariate models. Results Weights at baseline and 1 year were available for 157 (93%) of the 168 patients analyzed. During year 1, the mean cumulative prednisone dosage in the multiple flares subgroup was 7.9 gm, compared with 6.0 gm and 3.9 gm in the single flare and remission subgroups, respectively (P < 0.001). Patients in these subgroups gained an average of 2.6 kg, 4.1 kg, and 5.8 kg, respectively (P = 0.005). Weight gain did not correlate with cumulative GC dose (R = 0.10, P = 0.25). Thirty-five patients (22.3%) gained and maintained ≥10 kg in the first year. New diagnosis of Wegener's granulomatosis at baseline was an independent predictor of gaining ≥10 kg at 1 year (odds ratio 19.7, 95% confidence interval 2.4–162.6, P = 0.006). Among the 78 patients in the remission subgroup, 40 sustained remissions through the 2-year time point. For these 40 patients, the mean weight gained at year 1 did not regress by the end of year 2, despite the absence of continued GC use. Conclusion Disease control was associated with lower cumulative GC doses but greater weight gain. More than one-fifth of patients gained >10 kg in the first year of treatment. The quantity of weight gained by patients during treatment has potential future health implications.

Purpose To evaluate the risk factors for herpes zoster as well as the incidence and timing of this complication in patients who were treated with immunosuppression because of active Wegener's granulomatosis. Subjects and methods We studied the 180 Wegener's granulomatosis patients in the Wegener's Granulomatosis Etanercept Trial (WGET). Herpes zoster events during WGET were documented prospectively. Follow-up questionnaires were employed to describe the location, treatment, and complication(s) of herpes zoster and its therapy. Univariate and multivariate analyses were performed to evaluate risk factors, including history of herpes zoster, for the occurrence of herpes zoster during the trial. All analyses were based on the time to first occurrence of herpes zoster. Results Eighteen patients (10% of the WGET cohort) suffered a total of 19 herpes zoster episodes over a mean follow-up period of 27 months. The annual incidence of herpes zoster in the WGET cohort was 45 cases/1000 patient-years (95% confidence interval [CI]: 27, 70). The median time from enrollment to the occurrence of herpes zoster in the subgroup of patients with that complication was 16.5 months (± 9.4). Fifteen of the 19 herpes zoster events (79%) occurred between months 6 and 36, many months after the period of most intensive immunosuppression. In univariate analyses, history of serum creatinine ≥1.5 mg/dL before enrollment was associated with a relative risk (RR) of 3.0 (95% CI: 1.1, 7.8) for herpes zoster during WGET (P=.03). In multivariate analyses, serum creatinine ≥1.5 mg/dL was associated with an RR of 6.3 (95% CI: 2.0, 19.8; P=.002), and female sex with an RR of 4.6 (95% CI: 1.6, 13.2; P=.004). Conclusion Renal dysfunction and female sex were consistently strong risk factors for herpes zoster events in this population. Contrary to expectation, most herpes zoster events did not occur during periods of most intensive immunosuppression. These data may inform studies of interventions designed to prevent herpes zoster in patients on treatment for immune-mediated diseases.