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.

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.

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.

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.

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.

[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%.

Treatment of advanced renal cell cancer with sequential intravenous recombinant interleukin-2 and subcutaneous alpha-interferon.

Starting from in vitro studies suggesting synergistic antitumour activity against renal cell cancer (RCC) of recombinant interleukin-2 (rIL-2) and alpha-interferon (IFN), a phase II trial was initiated to test the clinical activity of this combination. The two cytokines were administered sequentially, with the aim of reducing the risk of additive toxicity and enhancing the immunological reaction against the tumour. The original treatment schedule consisted of rIL-2 18 x 10(6) U/m2/day by continuous intravenous infusion for 120 h days 1-5, and alpha-IFN 2b, at a flat dose of 9 x 10(6) U by subcutaneous or intramuscular injection thrice in a week, from day 8 to 28. Treatment was planned to be continued for six or more 28-day cycles, depending on clinical response. 12 patients were treated according to this schedule; as some cardiovascular toxicity was experienced in this set of patients, 11 further patients were treated with half-dose rIL-2 (i.e. 9 x 10(6) U/m2/day). 17 out of 23 enrolled patients completed at least one cycle of treatment and were evaluated for response. We observed six major responses [one complete response (CR) + five partial responses (PR)] for an objective response rate of 35% [95% confidence interval (CI) 17-59%]. 5 additional patients achieved stabilisation of disease; one of them reached CR after surgical extirpation of a lung mass. Sites of response included lung, nodes and bone. Duration of response is 12+ months for CR; 17, 16, 12+, 9 and 9 months for PRs. Median survival is 16 months. Response was not significantly different between full-dose and half-dose rIL-2. Considering stable disease (SD) as responses, there seemed to be a higher chance of response for patients with smaller tumour burden (P = 0.032). The toxicity of rIL-2 treatment, mainly cardiovascular, was substantial; 9 patients experienced severe cardiotoxicity, consisting of major arrhythmias, myocardial ischaemia, reduction of ejection fraction measured with heart radionuclide scan, and were excluded from continuing treatment. Other rIL-2-related toxicities forcing exclusion from the study were severe thrombocytopenia (1 case), and generalised exfoliative dermatitis requiring steroids (1 case). Otherwise, treatment was well tolerated; rIL-2-related toxicities promptly recovered after rIL-2 discontinuation in the majority of cases, and no treatment-related deaths were reported. The half-dose rIL-2 regimen was significantly less toxic in terms of hypotension (P = 0.014), fever (P = 0.014), oliguria (P = 0.042), serum creatinine elevation (P = 0.009) and prothrombin time elongation (P = 0.038).(ABSTRACT TRUNCATED AT 400 WORDS)

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.

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.

Solitary plasmacytoma of the sphenoid sinus involving the pituitary fossa: a case report and review of the literature.

A rare case of solitary plasmacytoma of the sphenoid sinus involving the pituitary fossa is reported. A 50-year-old woman with a history of diplopia and a mass in the sphenoid sinus and the sellar region, documented by computed tomography, was referred to our department with a presumed diagnosis of nonfunctioning pituitary adenoma. The clinical and biochemical characteristics were unrevealing, but magnetic resonance imaging examination demonstrated the extrapituitary origin of the lesion. The patient was operated on by the transsphenoidal approach, and the lesion was histologically diagnosed as a plasmacytoma. Review of the literature disclosed 11 previously described cases of myelomatous disease presenting clinically as a pituitary adenoma. Our case demonstrates that magnetic resonance imaging investigation may help in distinguishing the extrapituitary origin of a mass involving the pituitary fossa.

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.

Intrapleural administration of interleukin-2 and LAK cells in locally advanced non-small-cell lung cancer. A case report.

AIMS AND BACKGROUND: The systemic administration of recombinant interleukin-2 (rIL-2) and lymphokine-activated killer (LAK) cells is ineffective in non-small-cell lung cancer (NSCLC). However, there is some evidence that their intrapleural administration could be effective, since it increases the concentrations of the cytokine and the effector cells in the tumor area, thereby obtaining greater antitumor activity. STUDY DESIGN: We report the case of a patient affected by a locally advanced lung adenocarcinoma with pleural effusion (T4 N0 M0-stage IIIb) treated with repetitive courses consisting of a priming continuous i.v. infusion (48 h) of rIL-2 (18 MIU/m2/day) intraplural administration of LAK cells (3-9 x 10(9)/day), in a single daily bolus, for 3 consecutive days and concomitant administration of rIL-2 (1.8-7.2 x 10(6) IU/day), for 5 days. RESULTS: We observed early disappearance of neoplastic cells in the pleural effusion, progressive decrease until disappearance of the pleural effusion, cavitation of the primary lesion during the treatment, and its stabilization for 9 months until progression. Radiologic changes were accompanied by a marked eosinophilia (up to 50 x 10(9)/L), and the intrapleural route of administration of rIL-2 induced a relevant increase in eosinophil count in peripheral blood. Immunologic changes in lymphocyte subpopulation phenotypes were also observed. The performance status of the patient improved, and she was still alive and eupnoic 25 months from the diagnosis and 23 months from the start of treatment. CONCLUSIONS: This case suggests a therapeutic role for intrapleural rIL-2, and we believe that the relationship among intrapleural administration of rIL-2 and LAK cells, the development of peripheral eosinophilia, and clinical response should be further investigated.

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.

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.

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.