Primary melanoma of the bladder: a case report and review of the literature.

OBJECTIVE: Primary bladder melanomas are rare and aggressive neoplasms. We herein described a new case and performed a review of the literature. PATIENTS AND METHODS: We present the case of a 81-year-old woman with a primary mucosal melanoma of the bladder after a history of acral melanoma (KRAS mutated) and lentigo maligna of the forehead. Using PubMed, we found that in literature 38 cases were described. RESULTS: In our patients, during a transurethral resection (TURBT), two bladder lesions were detected. The histologic exam revealed a malignant melanoma, Mib1/ki67: 10-12%, PDL1 <1%. No BRAF, NRAS or KRAS mutations were detected. She subsequently underwent a transurethral revision of the trigone and a partial cystectomy of the dome with bilateral pelvic lymph node dissection. Microscopical findings showed a residual 5 mm non-muscle-invasive melanoma of the bladder, with negativity of the surgical margins and of the 17 pelvic lymph nodes. No adjuvant treatment was proposed. To date the patient is disease-free. CONCLUSIONS: Primary bladder melanoma carries a poor prognosis and poses a therapeutic challenge to clinicians who manage patients with this rare condition. In our experience the multidisciplinary approach for the diagnosis and management of this rare cancer is mandatory.

Viral clearance after early corticosteroid treatment in patients with moderate or severe covid-19.

The aim of this study was to evaluate the impact of early treatment with corticosteroids on SARS-CoV-2 clearance in hospitalized COVID-19 patients. Retrospective analysis on patients admitted to the San Raffaele Hospital (Milan, Italy) with moderate/severe COVID-19 and availability of at least two nasopharyngeal swabs. The primary outcome was the time to nasopharyngeal swab negativization. A multivariable Cox model was fitted to determine factors associated with nasopharyngeal swab negativization. Of 280 patients included, 59 (21.1%) patients were treated with steroids. Differences observed between steroid users and non-users included the proportion of patients with a baseline PaO2/FiO2 ≤ 200 mmHg (45.8% vs 34.4% in steroids and non-steroids users, respectively; p = 0.023) or ≤ 100 mmHg (16.9% vs 12.7%; p = 0.027), and length of hospitalization (20 vs 14 days; p < 0.001). Time to negativization of nasopharyngeal swabs was similar in steroid and non-steroid users (p = 0.985). According to multivariate analysis, SARS-CoV-2 clearance was associated with age ≤ 70 years, a shorter duration of symptoms at admission, a baseline PaO2/FiO2 > 200 mmHg, and a lymphocyte count at admission > 1.0 × 109/L. SARS-CoV-2 clearance was not associated with corticosteroid use. Our study shows that delayed SARS-CoV-2 clearance in moderate/severe COVID-19 is associated with older age and a more severe disease, but not with an early use of corticosteroids.

Cranial osteopathic treatment and stress-related effects on autonomic nervous system measured by salivary markers: A pilot study.

BACKGROUND: Variations in the concentration of salivary alpha amylase (sAA) may indicate a change in the autonomic nervous system functionality. In osteopathic medicine it has long been stated that the osteopathic manipulative treatment (OMT) can modulate the autonomic nervous system. Studies carried out on the compression of the fourth ventricle (CV4) have shown a positive effect in reducing the sympathetic tone. The goal of this pilot study is measuring the physiological response of the sAA levels after CV4 technique. METHODS: 90 subjects were randomly assigned to a sham, a control or a CV4 group. Randomization accounted for sex and score in the STAI-2 (form Y) questionnaire. Each subject completed the STAI-1 (form Y) questionnaire to evaluate the anxiety of the moment. sAA activity and saliva flow rate were measured. Saliva was collected before, immediately after and 30 min after treatment. RESULTS: Within group analysis revealed that sAA activity increased significantly immediately after the technique application only in the CV4 group (p = 0,05). Between groups analysis show a significant difference of the sAA activity in the CV4 group respect the control group (p < 0,05), but no significant difference between CV4 and sham group (p > 0,05). The effect in the CV4 group after the intervention is highly variable and appeared to be related to the level of stress measured with the STAI-Y1 questionnaire (p = 0,002). CONCLUSIONS: This study shows a positive effect of the CV4 procedure on sAA activity even if not significantly different from the sham procedure, probably due to the confounding effect of stress variability between groups.

IgG4-related disease in Italy: clinical features and outcomes of a large cohort of patients.

OBJECTIVES: To describe the clinical features, treatment response, and follow-up of a large cohort of Italian patients with immunoglobulin (Ig)G4-related disease (IgG4-RD) referred to a single tertiary care centre. METHOD: Clinical, laboratory, histological, and imaging features were retrospectively reviewed. IgG4-RD was classified as 'definite' or 'possible' according to international consensus guidelines and comprehensive diagnostic criteria for IgG4-RD. Disease activity was assessed by means of the IgG4-RD Responder Index (IgG4-RD RI). RESULTS: Forty-one patients (15 females, 26 males) were included in this study: 26 with 'definite' IgG4-RD and 15 with 'possible' IgG4-RD. The median age at diagnosis was 62 years. The median follow-up was 36 months (IQR 24-51). A history of atopy was present in 30% of patients. The pancreas, retroperitoneum, and major salivary glands were the most frequently involved organs. Serum IgG4 levels were elevated in 68% of cases. Thirty-six patients were initially treated with glucocorticoids (GCs) to induce remission. IgG4-RD RI decreased from a median of 7.8 at baseline to 2.9 after 1 month of therapy. Relapse occurred in 19/41 patients (46%) and required additional immunosuppressive drugs to maintain long-term remission. Multiple flares occurred in a minority of patients. A single case of orbital pseudotumour did not respond to medical therapy and underwent surgical debulking. CONCLUSIONS: IgG4-RD is an elusive inflammatory disease to be considered in the differential diagnosis of isolated or multiple tumefactive lesions. Long-term disease control can be achieved with corticosteroids and immunosuppressive drugs in the majority of cases.

Pancreatic involvement in Legionella pneumonia.

Legionella-associated pancreatitis has been rarely reported. Since this condition is very rarely suspected and investigated in patients with Legionella pneumonia, its incidence is probably underestimated. Here we report a case of Legionella pneumonia-associated pancreatitis and review the relevant related literature.

Meningeal involvement in Wegener's granulomatosis is associated with localized disease.

Meningeal involvement is a rare occurrence in Wegener's Granulomatosis (WG). A Medline search uncovered only 48 previously reported cases. Here we describe the clinical features of meningeal involvement in WG and to evaluate the association with systemic disease extension. Through a systematic literature review of papers concerning meningeal involvement in WG, we collected and analysed data about sex, age, disease extension, symptoms, cerebrospinal fluid examination, imaging, ANCA and histology about previously reported patients. Headache is almost always the first symptom of meningeal involvement in WG. Later in the course of the disease other abnormalities may develop. Among them cranial nerve palsy, seizures and encephalopathy are the most frequent. Diagnosis is obtained by neuroimaging, which may disclose two distinct patterns of meningeal thickening: diffuse or focal. 62.9% of patients tests positive for ANCA. Histology typically shows necrotizing granulomatosis. Meningeal involvement is by far more frequent in the setting of localized WG. Meningitis is a rare complication of WG. It usually develops in patients with localized disease who are more likely to have destructive lesions of the upper airways. It may be recognized by a constellation of clinical and radiological findings and by histological signs of necrotizing granulomatosis, with little or no vasculitis.

The prevalence and clinical implications of c-kit expression in plasma cell myeloma.

AIM: To evaluate the clinical implications of c-kit (CD117) expression in plasma cell myeloma (PCM). METHODS AND RESULTS: We first evaluated the reliability of immunohistochemistry in assessing c-kit expression by comparing the results with those obtained by flow cytometry and gene expression arrays in 22 PCM and in 10 PCM cell lines. Immunohistochemical results showed a perfect concordance with those of flow cytometry; likewise, immunohistochemical and gene expression data were also concordant in all but one PCM and cell lines analysed. Then, we investigated the clinical implications of c-kit immunoreactivity in bone marrow biopsies of 85 PCM patients with a mean follow-up of 41 months. C-kit immunoreactivity was detected in 24 (28.2%) of the 85 cases and it was significantly associated with a high microvessel density, but not with traditional clinicopathological characteristics or with survival. CONCLUSIONS: Our findings suggest that immunohistochemistry is a reliable indicator of c-kit gene expression and reinforce the notion that approximately one-third of PCM express high levels of c-kit. The lack of association with traditional clinicopathological parameters and patient survival suggests that c-kit expression may not be an adjunct in predicting the clinical course of the disease.

[Wegener's granulomatosis: an analysis of 50 patients]. / Granulomatosi di Wegener: descrizione di una casistica di 50 pazienti.

OBJECTIVES: To evaluate the rate of different organs involvement in 50 patients with Wegener's Granulomatosis (GW), and to describe their clinical manifestations and their response to treatment. METHODS: We evaluated 50 consecutive patients with GW, come to our attention from January 1987 to May 2003. 43 patients met the 1990 American College of Rheumatology (ACR) criteria for classification of GW; 7 patients the 1993 ELK criteria. RESULTS: 82% of patients presented Ear/Nose/Throat (ENT) involvement, which is the most common site of inflammation. 22% of our patients had ENT-restricted disease; in 78% of cases disease extended to other organs. Lungs were involved in 72% of cases; kidney in 36%; eye in 24%; nervous system (NS) in 14% (central NS in 10% and peripheral NS in 4%); skin in 10%; heart in 8%; testis in 4%. Arthritis was present in 10% of patients. We discuss treatment of all patients and response to therapy of those 28 whose follow-up is available. CONCLUSIONS: Involvement of airways and kidney is by far the most common in GW, though potentially any other organ or system may be affected. The total rate of other organs involvement is 70%.

Circular myotomy of the distal esophageal stump for long gap esophageal atresia.

PURPOSE: The aim of this work is to report the utility of the distal esophageal stump's circular myotomy in case of a long gap esophageal atresia repair. METHODS: Between 1972 and 1999 the authors treated 192 patients who had esophageal atresia (EA). Among them, 6 patients with EA long gap underwent both a distal and proximal stump circular myotomy. Five cases were Gross type C, and 1 case was Gross type A. The gap (average 4.5 cm) did not permit a simple and direct end-to-end anastomosis. RESULTS: One patient died 6 days after the operation because of a cardiac malformation. There was no mucosal tear during the myotomies or any anastomotic stricture later. Five patients survived. Three of them needed an antireflux procedure (60% of surviving patients). None of the 5 patients showed any mucosal outpouching, and their esophageal motility and swallowing were not different clinically compared with the patients who underwent an EA repair without a myotomy. CONCLUSIONS: Distal circular myotomy is a very useful, however, delicate, procedure that can help solve the problem given by long gap EA. It is mandatory not to tear the mucosa during the myotomy to avoid the shortening of the stump caused by its repair, which would lead to an increase in the size of the gap. J Pediatr Surg 36:855-857.

Primary granulocytic sarcoma presenting with bone pain and hypergammaglobulinemia.

Granulocytic sarcoma (GS), is an extramedullary tumorous aggregate of neoplastic myeloid precursor cells, most often associated with acute myeloid leukemia (AML). Primary GS occurs in patients with normal bone marrow and no history of hematological disorders. It is a rare disease, which can involve any organ and mimic other tumors. A correct initial diagnosis, which can be difficult, and early treatment with chemotherapy as for AML patients results in a higher rate of complete remission. We report a case of multifocal primary GS of the bone associated with oligoclonal hypergammaglobulinemia, successfully treated with AML-like induction chemotherapy followed by postinduction therapy with autologous peripheral stem cells transplantation. The possible significance of the associated hypergammaglobulinemia is discussed.

Prognostic factors for survival in metastatic renal cell carcinoma: retrospective analysis from 109 consecutive patients.

OBJECTIVE: Metastatic renal cell cancer (RCC) portends a bad prognosis, but survival is quite different among different patients. The objective of this study was to determine prognostic factors for survival with the aim to offer patients proper therapeutic options. METHODS: A consecutive series of 109 metastatic RCC patients admitted to our department since 1988 was reviewed, and survival from the time of diagnosis with metastases recognition was considered. The role of age, sex, disease-free interval (DFI), ECOG performance status (PS), stage at diagnosis, grading, number and type of metastatic sites, nephrectomy, blood levels of hemoglobin, creatinine, albumin, calcium, lactate dehydrogenase (LDH), ferritin, alkaline phosphatase, triglycerides was assessed in univariate and multivariate analysis. RESULTS: In our study, the following variables were found to be statistically significant at the univariate analysis (p < 0.01): DFI, ECOG PS, stage at diagnosis, grading, nephrectomy, sites of metastases, blood hemoglobin, serum albumin, calcium, LDH, alkaline phosphatase. Indeed, only an ECOG PS of 2-3 (relative risk 1.82; p = 0.003) and blood hemoglobin levels < or = 10 g/100 ml (relative risk 1.20; p = 0.017) retained their value as independent risk factors for poor survival at multivariate analysis. According to the number of independent risk factors, three groups of patients were identified, with significantly different median survival (21.7 vs. 8.6 vs. 3.5 months; log-rank test: p = 0.00004, p = 0.04126 and p = 0.00047, respectively). CONCLUSIONS: Poor performance status and anemia at diagnosis of metastatic RCC predict the worst outcome in our series. These factors could be taken into account to stratify patients in clinical trails and to select the proper treatment option in oncological practice.

Plasma nitrate plus nitrite changes during continuous intravenous infusion interleukin 2.

Nitric oxide (NO), a biologically active mediator generated in many cell types by the enzyme NO synthase, may play an important role in cardiovascular toxicity that is frequently observed in cancer patients during intravenous (i.v.) interleukin 2 (IL-2) therapy. The induction of NO synthase and the production of NO seem to be involved in the pathogenesis of the vascular leakage syndrome, as well as in the regulation of myocardial contractility. In the present study, we evaluated the pattern of plasmatic NO changes during multiple cycles of continuous i.v. infusion (CIVI) of IL-2 in ten advanced cancer patients (five males, five females, median age 59 years, range 33-67 years; eight affected by renal cell cancer and two affected by malignant melanoma). The patients received IL-2 at 18 MIU m-2 day-1 (14 cycles) or 9 MIU m-2 day-1 (seven cycles) for 96 h, repeated every 3 weeks. Interferon alpha (IFN alpha) was also administered subcutaneously (s.c) during the 3 week interval between IL-2 cycles. For each cycle, plasma samples were collected before treatment (t0), 24 h (t1), 48 h (t2), 72 h (t3) and 96 h (t4) after the start of IL-2 infusion, and 24 h after the end of the cycle. NO concentration was determined spectrophotometrically by measuring the accumulation of both nitrite and nitrate (after reduction to nitrite). The following observations may be drawn from data analysis: (1) plasma nitrate + nitrite significantly raised during treatment (P = 0.0226 for t0 vs t3), but statistical significance was retained only when cycles administered with IL-2 18 MIU m-2 day-1 are considered (P = 0.0329 for t0 vs t3; P = 0.0354 for t0 vs t2 vs t4) (dose-dependent pattern); (2) during subsequent cycles a significant trend toward a progressive increase of plasma nitrate + nitrite levels, with increasing cumulative dose of IL-2, was observed (linear regression coefficient r = 0.62, P = 0.0141 for t0; r = 0.80, P = 0.0003 for t1; r = 0.62, P = 0.013 for t2; r = 0.69, P = 0.045 for t3); (3) plasma nitrate + nitrite levels peaked earlier in subsequent cycles than in the first cycle; (4) all patients experienced hypotension. The mean of the systolic blood pressure values was significantly lower at the time of plasma nitrate + nitrite peak than at t0 (P = 0.0004); (5) the two cases of grade III hypotension occurred in patients with the higher mean and peak plasma nitrate + nitrite values. We conclude that determination of plasma nitrate + nitrite levels during CIVI IL-2 can usefully estimate, in a dose-dependent pattern, the degree of peripheral vascular relaxation and capillary leakage associated with cytokine action, clinically manifested as hypotension. However, isolated cardiac toxicity that continues to represent a relevant problem during IL-2 therapy, does not appear to correlate with plasma nitrate + nitrite levels; therefore, further studies are required to understand adequately the mechanisms underlying IL-2-induced cardiac toxicity.

Hyperacute pneumonitis in a patient with overwhelming Strongyloides stercoralis infection.

The case of a 64-year-old man who was admitted to hospital with fever, general deterioration and anorexia is reported. For the past 4 years, the patient had been receiving corticosteroid therapy for a chronic inflammatory demyelinating polyradiculoneuropathy. Soon after admission the patient developed respiratory insufficiency as a result of a massive pneumonitis, with severe hypoxia, acute anaemia, acute renal failure and a systemic inflammatory response syndrome (SIRS) requiring admission to the Intensive Care Unit (ICU). All faecal, bronchial, duodenal and urine samples showed Strongyloides stercoralis larvae. Despite antihelmintic therapy and cardiorespiratory support, the patient died from the consequences of irreversible shock. Strongyloidiasis is present worldwide and can be a chronic, essentially asymptomatic infection. This nematode can produce an overwhelming hyperinfection syndrome, especially in patients showing deficient cell-mediated immunity. Strongyloides hyperinfection syndrome is frequently fatal but is potentially a treatable clinical condition. Patients undergoing immunosuppressive therapy or with suspected immunity deficiency (HIV infection, malnutrition, lymphomas, leukaemias or other neoplasia treated with systemic radiotherapy or chemotherapy) must be also monitored for opportunistic Strongyloides stercoralis infection, because clinical manifestation of the systemic hyperinfection syndrome can be rather non-specific.

Isolated left ventricular filling abnormalities may predict interleukin-2-induced cardiovascular toxicity.

Interleukin-2 (IL-2) is a cytokine with proven activity against metastatic renal cell carcinoma (RCC) and malignant melanoma (MM). The intravenous administration of high-dose IL-2 is limited by important cardiovascular side effects such as hypotension, fluid retention, arrhythmias, and myocardial ischemia, which often cause dose reduction and/or treatment withdrawal. The occurrence of these toxic events is not predicted by routine pretreatment examinations. The aim of the present study was to test the reliability of serial echocardiography in predicting subsequent cardiac adverse effects in patients undergoing IL-2 administration. In 19 patients (15 men, 4 women; median age: 51 years, range 27-71 years; 10 affected by metastatic RCC and 9 affected by MM) we performed two-dimensional and Doppler echocardiography before and immediately after 28 continuous intravenous infusions (CIVI) of IL-2 at the dose of 18 MIU/m2/day for 4 days. Left ventricular systolic function and the diastolic transmitral flow pattern were assessed before and after IL-2 administration. Significant changes of two indexes of left ventricular filling were noted: a decrease of the ratio of maximal flow velocity in early diastole to that in late diastole (E/A) (basal: 1.12 +/- 0.46, mean +/- SD; posttreatment: 0.83 +/- 0.27; p < 0.01) and an increase of the percentage of the atrial contribution to left ventricular filling (basal: 37.75 +/- 11.58%; posttreatment: 49.43 +/- 16.48%; p < 0.01). Eight major cardiovascular events causing IL-2 infusion withdrawal were observed (two ischemic electrocardiographic modifications, three grade III-IV hypotension, one atrial fibrillation, one pericardial effusion, one acute heart failure). These major cardiovascular events were observed more often when an abnormal basal E/A ratio < 1.0 (p < 0.05) was found. We conclude that Doppler transmitral flow pattern analysis before and subsequent to IL-2 infusion is a useful and easily available procedure for the monitoring of cardiac modifications during CIVI IL-2 administration. It might also predict a major cardiovascular event during IL-2 administration. Patients with basal E/A ratio < 1.0 should be more carefully monitored during treatment and/or should be treated with lower IL-2 doses to avoid cardiovascular toxicity.

Unusual bleeding manifestations in a case of primary amyloidosis with factor X deficiency but elevations of in vivo markers of thrombin formation and activity.

We describe a case of primary amyloidosis (AL) with severe factor X (FX) deficiency in an amateur cyclist presenting with muscular pain at rest and ecchymoses in his legs. No circulating inhibitor of FX was found by mixing studies and there was no deficiency of other vitamin K-dependent coagulation factors and inhibitors or of alpha 2-antiplasmin. Thrombin-time and reptilase time were abnormally prolonged and were not corrected by mixing with normal plasma. Administration of plasma or prothrombin complex concentrate (PCC) were unsuccessful in controlling bleeding: the apparent half-life of transfused FX was 6 minutes. Resting resulted in cessation of muscular pain and bleeding. Renal and cardiac deterioration led the patient to death 3 years after presentation. No further bleeding manifestations did occur during this period. FX levels remained consistently below 3%, but prothrombin fragment 1.2 and thrombin-antithrombin complex--measured at distance from PCC administration and prior to deterioration of renal and cardiac function--were markedly elevated. At autopsy, disseminated amyloidosis was found with sparing of the skeletal muscles and of the skin. This is the first report of increased in vivo prothrombin activation and activity in AL-associated FX deficiency.