The diagnostic accuracy of increased late night salivary cortisol for Cushing's syndrome: a real-life prospective study.

INTRODUCTION AND AIM: A prompt diagnosis of Cushing's Syndrome (CS) in high-risk populations is mandatory: 1-mg dexamethasone suppression test (1-mg DST), late night salivary cortisol (LNSC), and urinary-free cortisol (UFC) are recommended, despite thresholds calculated in retrospective studies. Our aim was to study the diagnostic accuracy of LNSC measured with chemiluminescence assay in a prospective study, confirming discrepancies with mass spectrometry (MS). MATERIALS AND METHODS: We enrolled 117 controls and 164 suspected CS (CS = 47, non-CS = 117). In case of increased LNSC, high clinical suspicion of CS or adrenal incidentaloma, patients were hospitalized to exclude/confirm CS. RESULTS: LNSC levels were higher in patients with suspected CS, CS, and non-CS than controls. Considering 16 nmol/L as threshold for CS, overall LNSC revealed SE 97% and SP 84% in the whole group of subjects considered, achieving positive/negative likelihood ratio of 5.56/0.045, respectively. 35 out of 81 subjects with increased LNSC were non-CS (15 diabetic and 20 obese): considering only those patients with increased likelihood to have a CS (the non-CS patients) SP decreased to 70%, and further reduced to 60% if we discharged subjects with adrenal incidentaloma. MS analyses reduced partially the number of false-positive LNSC. CONCLUSIONS: LNSC measured in automated chemiluminescence is reliable in clinical practice: it present a high diagnostic accuracy to exclude hypercortisolism in patients with normal cortisol levels. MS could be used to reduce the number of false-positive results; nevertheless, some non-CS subjects with functional hypercortisolism could have a mild impairment of cortisol rhythm.

A Single-Center 10-Year Experience with Pasireotide in Cushing's Disease: Patients' Characteristics and Outcome.

Pasireotide is the first pituitary-directed drug approved for treating patients with Cushing's disease (CD). Our 10-year experience with pasireotide in CD is reported here. Twenty patients with de novo, persistent, or recurrent CD after pituitary surgery were treated with pasireotide from December 2003 to December 2014. Twelve patients were treated with pasireotide in randomized trials and 8 patients with pasireotide sc (Signifor(®); Novartis AG, Basel, Switzerland) in clinical practice. The mean treatment duration was 20.5 months (median 9 months; range, 3-72 months). Urinary free cortisol (UFC) levels mean percentage change (± SD) at last follow-up was-40.4% (± 35.1; range, 2-92%; median reduction 33.3%) with a normalization rate of 50% (10/20). Ten patients achieved sustained normalized late night salivary cortisol (LNSC) levels during treatment. LNSC normalization was associated with UFC normalization in 7/10 patients. Serum cortisol and plasma ACTH significantly decreased from baseline to last follow-up. Body weight decrease and blood pressure improvement during pasireotide treatment were independent from UFC response. Glucose profile worsening was observed in all patients except one. The frequency of diabetes mellitus increased from 40% (8/20) at baseline to 85% (17/20) at last follow-up requiring initiation of medical treatment only in 44% of patients. Pasireotide treatment was associated with sustained biochemical and clinical benefit in about 60% of CD patients. Glucose profile alteration is a frequent complication of pasireotide treatment; however, it seems to be easy to manage with diet and lifestyle intervention in almost half of the patients.

The role of an acute pasireotide suppression test in predicting response to treatment in patients with Cushing's disease: findings from a pilot study.

Pasireotide is a multireceptor-targeted somatostatin analog effective in the treatment of Cushing's disease (CD). We evaluate the value of an acute pasireotide suppression test (PST) in predicting response to medium/long-term treatment in CD. Nineteen patients with active CD were prospectively investigated at two referral centers from May 2013 to August 2014. Follow-up data (median 6 months; range 1-9 months) were available for sixteen patients. All patients received at 09:00 h a single subcutaneous (sc) injection of 600 µg pasireotide. Serum cortisol and plasma ACTH were assessed before, and every 2 h for 8 h after, drug administration. Late-night salivary cortisol (LNSC) was assessed before and after pasireotide administration. After acute PST, all patients were continued on pasireotide 600 µg sc twice a day. During PST, cortisol and ACTH levels quickly decreased in all patients except one with a mean percentage fall, respectively, of 48.9 ± 24.3 and 48.1 ± 25.4 % compared to baseline. LNSC decreased in about 82 % of patients (14/17) achieving a normalization in five of them. Pasireotide treatment was associated with a normalization of 24-h urinary-free cortisol at last follow-up in about 68 % of patients. A fall >27 % of LNSC during PST calculated by ROC curve was the best parameter in predicting a positive response to treatment with pasireotide (sensitivity 91 %; specificity 100 %; positive predictive value 100 %; negative predictive value 75 %). Acute PST may be useful to identify CD patients who will benefit from pasireotide treatment. A LNSC fall >27 % as well as a LNSC normalization during PST is associated with a probability of 100 % of achieving a favorable response to pasireotide treatment in the medium/long term.

Second-line chemotherapy in malignant pleural mesothelioma: results of a retrospective multicenter survey.

The pemetrexed-cisplatin chemotherapy is standard of care in first-line (FL) treatment of malignant pleural mesothelioma (MPM). The second-line (SL) chemotherapy is considered, but the optimal treatment has not been defined yet. The aim of this study was to evaluate the clinical outcomes of SL-therapy in a series of MPM-patients included in a retrospective multicenter database. Clinical records of MPM-patients who received SL-treatment from 1996 to 2008 were reviewed. Study endpoints were response, overall-survival (OS), and progression-free-survival (PFS) for SL, stratified for patient characteristics, FL-outcomes, and type of SL. Out of 423 patients, 181 with full clinical data were identified. Patients' characteristics: median-age 64 years (range: 36-85); male gender 115 (63.5%); good EORTC-score 109 (60.2%); epithelial histology 135 (74.6%). After FL, 147 (81.2%) patients achieved disease-control (DC) and 45 had a time-to-progression≥12 months (TTP≥12). After SL, 95 patients (52.6%) achieved DC (21 response; 74 stable-disease); median PFS and OS were 4.3 and 8.7 months, respectively. According to multivariate analysis, DC after SL-therapy was significantly related to pemetrexed-based treatment (OR: 2.46; p=0.017) and FL-TTP≥12 (OR: 3.50; p=0.006). PFS was related to younger age (<65 years) (HR: 0.70; p=0.045), ECOG-PS0 (HR: 0.67; p=0.022), and FL-TTP≥12 (HR: 0.45; p<0.001). OS was significantly related to ECOG-PS0 (HR: 0.43; p<0.001) and to FL-TTP≥12 (HR: 0.54; p=0.005). In pemetrexed pre-treated patients, re-treatment with a pemetrexed/platinum combination significantly reduced the risk-of-death than pemetrexed alone (HR: 0.11; p<0.001). In conclusion, SL-chemotherapy seems to be active in MPM-patients, particularly in younger patients with ECOG-PS0 and prolonged TTP after FL-pemetrexed-based chemotherapy. In selected patients, re-challenge with pemetrexed-based regimens, preferentially associated with platinum-compound, appears to be an option for SL-setting. Considering the important limitations of this study, due to retrospective nature and the possible selection bias, prospective clinical trials are warranted to clarify these issues.

Phase III study in stage IV non-small-cell lung cancer patients treated with two courses of cisplatin/gemcitabine followed by a randomization to three additional courses of the same combination or gemcitabine alone.

BACKGROUND: This randomised phase III study investigated if in responsive and stable disease (SD) stage IV patients after two courses of cisplatin and gemcitabine, single-agent gemcitabine (experimental arm) was not inferior in terms of overall survival (OS) to cisplatin-gemcitabine (standard arm). PATIENTS AND METHODS: Noninferiority was defined as an increase in the hazard of death (HR) < or = 1.33 in the experimental arm. From January 2001 to February 2004, 340 patients were registered and 250 were randomised. Cisplatin was administered on day 1 at 75 mg/m2 and Gemcitabine on days 1 and 8 at 1250 mg/m2 every 3 weeks. RESULTS: Response rate after two courses was 29%. The 1-year progression-free survival was 13% in both arms. One-year survival was 52% in the standard and 42% in the experimental arm for an HR of 1.21 [90% confidence interval (CI) 0.97-1.51]. Postprogression survival was in favour of the standard arm (HR 1.30, 95% CI 0.99-1.70, P = 0.051). Grades 3-4 toxicity favoured in the experimental arm. CONCLUSION: In responsive and SD patients with stage IV non-small-cell lung cancer it was not possible to demonstrate that three courses of gemcitabine alone are not inferior, in terms of OS, to the standard approach of three courses of cisplatin-gemcitabine.

Induced sputum cellularity. Reference values and distribution in normal volunteers.

Sputum induction has recently been proposed as the only direct noninvasive method for measuring airway inflammatory indices. The reference values and the distribution of cells in induced sputum in a control population have not yet been well defined. We therefore evaluated data from a large number of healthy volunteers. One hundred fourteen healthy, nonatopic, nonsmoking volunteers without airway hyperreactivity were enrolled (age: 38 +/- 13 yr [mean +/- SD]; FEV(1): 105 +/- 10% predicted; provocative dose of methacholine inducing a 20% decrease FEV(1) > 3,200 microgram). Ninety-six subjects (84%) produced adequate analysis samples. The subjects had a normal age distribution. Their induced sputum was rich in macrophages (69.2 +/- 13%) and neutrophils (27.3 +/- 13%), and poor in eosinophils (0.6 +/- 0.8%), lymphocytes (1.0 +/- 1.2%), and epithelial cells (1.5 +/- 1.8%). Only macrophages and neutrophils showed a normal distribution; total and differential counts of other cells did not. We propose that these data be used in comparison of the induced sputum cells of normal subjects and those of patients with airway inflammation.

Gemcitabine plus vinorelbine in elderly or unfit patients with non-small cell lung cancer.

Cisplatin-based combinations are efficacious in increasing the overall survival of patients with non-small cell lung cancer (NSCLC), but their toxicity makes them unsuitable for elderly and unfit patients. The primary objective of this non-randomized phase II study was to evaluate the feasibility and activity of the gemcitabine plus vinorelbine combination in previously untreated elderly and/or unfit patients with measurable stage III or IV NSCLC. Forty-three patients aged >/= 65 years or with contraindications against cisplatin treatment (36 males and seven females: median age 66 years; range 48-75: PS 0 = 11, PS 1 = 19, PS 2 = 13) received intravenous (i.v.) gemcitabine 1000 mg m(-2), followed by vinorelbine 25 mg m(-2)i.v. on day 1 and 8 every 21 days. Fifteen patients (34.9%) achieved partial remission (confidence interval: 27. 6-42.2%) for a median duration of 6 months; the median survival of these patients has not yet been reached. A further 15 had stable disease for a median of 4 months and a median survival of 7 months. The 10 patients (23.2%) who experienced disease progression had a median survival of 4 months. Three patients are not evaluable. The 1-year actuarial survival rate is 31.1%. The treatment was well tolerated: only 35% of the patients had grade 3 or 4 granulocytopenia on day 14, none experienced episodes of neutropenic fever, and there was no evidence of severe haematological toxicity upon recycling. Only 9% of the patients suffered from gastrointestinal toxicity (grade 3); increased but reversible transaminase levels were observed in 11.6%. In conclusion, the results of this phase II study show that the combination of gemcitabine and vinorelbine is active and well tolerated in NSCLC, and thus encourage its use in elderly or unfit patients.

Imported and autochthonous histoplasmosis in Bergamo province, Northern Italy.

This paper reviews the Italian literature and illustrates the results of a survey on Histoplasma capsulatum var. capsulatum infection carried out in the Bergamo area of Italy over the last 10 y. During the period January 1989-July 1999, 7 patients were diagnosed as being affected by the H. capsulatum var. capsulatum infection. Until 1999 41 cases have been described in the Italian literature (9 before the 1980s, 6 in the 1980s and 26 in the 1990s). The epidemiological profile of histoplasmosis is well-defined: risk factors are activities such as visiting caves or building sites, travelling and immigration, and it affects both immunocompetent and patients with AIDS. However, in the past, the Italian soil was considered as a low-endemic pabulum for H. capsulatum var. capsulatum and only a few autochthonous cases of histoplasmosis have been reported in Italy, specifically in the Po valley. In the present series, the identification of new cases in the Po valley in Lombardy suggests the possible autochthonous presence of histoplasmosis in Italy.

Pneumonia due to Leptospira spp.: results of an epidemiological and clinical study.

OBJECTIVE: To evaluate the prevalence of Leptospira spp. infections in a population of in- and out-patients with community acquired pneumonia (CAP) and the incidence of leptospiral pneumonia. DESIGN AND RESULTS: Of 176 patients infected with CAP who were evaluated for the presence of Leptospira spp. as causative agent, 10 were found positive for leptospiral antibodies (prevalence rate: 5.7%), but seroconversion was observed in only one case (incidence rate: 0.6%). The patient had had recent contact with possibly contaminated water. She had pulmonary involvement and signs of mild hepatic damage, but recovered fully. CONCLUSION: The authors highlight the importance of testing for leptospirosis in case of pneumonia in endemic areas where the more common causative pathogens for CAP can not be documented and when initial empiric therapy is ineffective.

Bronchial carcinoid tumours: a study on clinicopathological features and role of octreotide scintigraphy.

Several authors proposed the stage at diagnosis and some histopathological features as prognostic factors of bronchial carcinoids. However, since large tumour diameters or nodal metastases are frequently associated to aggressive histology, their prognostic role is unclear. To investigate the relationships between the clinicopathological parameters at diagnosis and outcome, 21 patients were analysed. Overall 26% of the radically resected patients recurred. Recurrences and disease-specific mortality were related to atypical histology and, only in cases with typical histology, to the presence of hilar or mediastinal lymph node metastases. These prognostic factors were valuable independently of the size of the primary tumour, that was remarkably homogeneous, always less than 3 cm, thus not predictive of recurrence. Moreover we evaluated the role of somatostatin receptor scintigraphy, a diagnostic tool only preliminary studied in this field. Scintigraphy with 111In-octreotide revealed the primary tumours at diagnosis (8/8), the increase in tumour size in two unresected patients, and all the cases of recurrent or metastatic disease (5/11), sometimes before the appearance of symptoms. These results suggest the usefulness of histology and nodal status as prognostic factors in clinical practice. Somatostatin receptor scintigraphy turns out to be a powerful diagnostic tool, for an accurate staging and an early diagnosis of recurrence in bronchial carcinoids.

Cefepime versus ceftazidime in the treatment of lower respiratory tract infections.

The objective of the study was to compare the safety and efficacy of cefepime and ceftazidime in the treatment of community acquired lower respiratory tract infections of moderate intensity. Eighty-six patients were randomized at a 2:1 ratio to receive respectively cefepime 1 g b.i.d. or ceftazidime 1 g t.i.d. The drugs were well tolerated and the occurrence of adverse events in each group was comparable. The rates of satisfactory clinical response were 96% (49/51) for cefepime and 89% (24/27) for ceftazidime. A total of 73 pathogens were isolated and pathogen eradication rates were 98% and 96% respectively for the cefepime and ceftazidime treatment groups. In conclusion, the data confirmed that cefepime could be a good alternative to ceftazidime.

Unusual case of pulmonary rickettsiosis in non-Hodgkin's lymphoma.

A case report of boutonneuse fever with pulmonary complications in a patient with non-Hodgkin's lymphoma (NHL) is described. The patient was hospitalized for persistent hypertermia and marked dyspnea, with radiographic findings of bilateral involvement of the lungs. The confirmation of the diagnosis was obtained by means of serum analyses (Weil-Felix serodiagnosis and IFA); the patient responded to doxycycline with progressive improvement of her general health condition. In this case the occurrence of a NHL could justify the lower reactivity and the facilitated diffusion of rickettsiosis in the patient.

Langerhans' cell granulomatosis and Hodgkin's lymphoma. Report of a case.

A 48-year-old female with a history of accentuated dyspnea, pleural thickening in anteromedial portion with left patchy parenchymal shadowing invading adjoining parasternal structure of the rib cage, presented 13 months later marked superclavicular, anterior mediastinic and parahilar left lymphadenopathy. Open surgical biopsies on the pleural lesion invading the hypodermic tissues of parasternal region showed morphological and immunocytochemical patterns of Langerhans' cell histiocytosis (LCH). 13 months later the superclavicular lymph node biopsy diagnosed Hodgkin's lymphoma (HD), mixed cellularity type II, stage AE. On a total of 29 cases with association of LCH and HD, the described case in the second case that shows morphologically demonstrated LCh with subsequent development of HD. It is postulated that the development of HD in a patient with LCH, might represent malignant evolution of this hyperplastic process.

Community-acquired pneumonia: is there difference in etiology between hospitalized and out-patients?

Since March 1991 a prospective 1-year study of patients with community-acquired, radiologically verified, pneumonia (CAP) was performed at the Divisione Pneumologica, Ospedali Riuniti Bergamo, and at the Centro Pneumo-Allergologico, Bergamo, Italy. The study included 119 out-patients and 60 in-patients, with a median age of 37.4 and 49.8 years respectively. There were not statistically significant differences between the patients included with respect to the various months. The most common underlying illnesses were: chronic obstructive pulmonary disease (20.7%), diabetes (7.3%) and malignancy (3.4%). We found a quite different etiology of CAP between out- and in-patients. By far the most common etiologic agent in out-patients was Mycoplasma pneumoniae (32.8%), while in in-patients was Legionella pneumophila (11.7%). 5 patients had a double infection. There were no distinctive clinical and radiological features found to be diagnostic for any etiologic agent. Hospital stay averaged 12.1 days. 35% of the patients included in the study were been treated by beta-lactam, often parenterally, nevertheless 88 pathogens of the 100 identified were resistant to this antimicrobial therapy. We believe that there should always be a macrolide, erythromycin or the latest ones such as azythromycin, in the treatment of CAP, owing to their efficiency, ease of use and lower cost.

Primary mediastinal seminoma.

We describe three cases of primary mediastinal seminoma, a rare neoplasm histologically similar to the testicular form, which mainly affects men between 30-60 yrs of age. Case No. 1--a 45 year old patient was treated with a combination of radiotherapy and chemotherapy. Twenty six months after the diagnosis, the patient shows a limited residual lesion, a good general health status and was asymptomatic. Case No. 2--a 56 year old patient was admitted for suspected epithelial lung cancer, with subsequent histological diagnosis of seminoma on surgical sample. The exeresis of the lesion was followed by radiotherapy and chemotherapy, the latter interrupted owing to the onset of thrombotic complications resulting in the patient's death. Case No. 3--a 35 year old patient was subjected to diagnostic and therapeutic thoracotomy, with diagnosis of primary mediastinal seminoma. The surgical therapy was followed by a cycle of radiotherapy. Five years later, the general health of the patient is good and he is still asymptomatic. In the discussion we consider the embryogenesis, clinical picture, radiological and anatomicopathological aspects, typical biomarkers of cancer, diagnostic procedures and therapeutic protocols currently followed.

Bronchoalveolar lavage and its role in diagnosing cobalt lung disease.

The bronchoalveolar lavage (BAL) of two groups of hard metal workers (11 subjects) were examined and compared with BALs of 14 unexposed individuals as controls. The first group of workers included five asymptomatic subjects (2 females and 3 males) with normal lung function tests and chest X-rays. All the workers had been exposed daily to hard metal dust for 5 years before fiberoptic bronchoscopy. The second group of workers included six individuals (1 female and 5 males) with cobalt lung disease at biopsy. The BAL's cytology at the deep lung level is in agreement with a possible immunologic pathogenesis of the lung disease, similar to hypersensitivity pneumonitis (lymphocytosis with helper-suppressor ratio reduction). In order to identify diagnostic key-parameters, the data presented here are compared with data reported in literature for workers with a history of hard metal or cobalt (alone) exposure. Although the BAL can be useful, for a better definition of the reaction at the deep lung level, it seems insufficient per se for the diagnosis of hard metal lung disease.

Hard metal disease: eight workers with interstitial lung fibrosis due to cobalt exposure.

Eight hard metal workers exposed to cobalt containing dust (four producers of stone-cutting cobalt-diamond wheels and four grinders of hard metal tools) and affected by interstitial lung fibrosis have been examined. A close relationship between cobalt exposure and clinical findings was observed in six patients who were still working. The clinical picture ranged from minor symptoms to manifestations resembling those of hypersensitivity pneumonitis, with fever, weight-loss, non-productive cough and dyspnea. A restrictive impairment of the ventilatory function was prevalent. The chest roentgenogram of one patient showed a diffuse reticular nodular pattern, while the others presented a mild reticular accentuation of the interstitium. In five patients, bioptic specimens of the lung parenchyma showed interstitial collagenic fibrosis with inflammatory cells infiltrating the alveolar septa. An increased number of lymphocytes and polymorphs was reported in the bronchoalveolar lavage (BAL) fluid from seven patients. Giant multinucleated cells were present in the BAL of four subjects while an inversion of the helper-suppressor ratio was evident in those patients who were still exposed to cobalt when BAL was performed. In this study, the causal role of metallic cobalt inhalation in the etiology of the lung disease is examined and discussed.

Uncommon evolution of fibrosing alveolitis in a hard metal grinder exposed to cobalt dusts.

This study reports a case of fibrosing alveolitis with uncommon evolution in a 27-year-old male non-smoker, working as a hard metal grinder for 10 years. Personal and occupational history, routine clinical and laboratory check-up, chest X-rays, lung function tests, fiberoptic bronchoscopy with bronchoalveolar lavage and open lung biopsy returned a diagnosis of hard metal lung fibrosis. The patient felt greatly improved after removal from the workplace, without any therapy. At present, he is complaining of only mild exertional dyspnea and shows an attenuation of his ventilatory defect. The radiological picture has clearly improved and the cellular pattern of bronchoalveolar lavage was normal.

[The importance of measuring plasma carcinoembryonic antigen in small-cell anaplastic carcinoma]. / Il significato del dosaggio dell'antigene carcinoembrionario plasmatico nel carcinoma anaplastico a piccole cellule.

The clinical value of the serum biomarker carcinoembryonic antigen (CEA) was evaluated prospectively in 118 patients with small cell lung cancer (SCLC) entered chemotherapy protocol between 1986 and 1992. Five quantitative categories were determined: less than 2.5 ng/ml and 2.6-5.0 ng/ml (the standard normal), 5.1-20.0 ng/ml, 20.1-100 ng/ml and greater than 100 ng/ml. 70% of patients had levels less than 5 ng/ml and only 19% had levels greater than 20 ng/ml. There was no clearcut relationship of plasma CEA level to stage of disease, in which 61% of patients with extensive disease (59 patients) had levels less than 5 ng/ml and 22% of patients with limited disease (59 patients) had levels greater than 5 ng/ml. There was a modest relationship of CEA levels to presence of metastases, in that 50% of patients with metastases had levels greater than 20 ng/ml. The average survival for the pathologic and normal category was almost similar, ranging from 13.27 to 16.81 months. The correlation between disease extent and survival was more sensitive for lactate dehydrogenase (LDH) than for CEA. So CEA as a tumor marker for SCLC must be applied in conjunction with other biomarkers, particularly LDH and neuron specific enolase (NSE) and is meaningful in only a small proportion of patients.