Anti-fibrotic effects of pirfenidone and rapamycin in primary IPF fibroblasts and human alveolar epithelial cells.

BACKGROUND: Pirfenidone, a pleiotropic anti-fibrotic treatment, has been shown to slow down disease progression of idiopathic pulmonary fibrosis (IPF), a fatal and devastating lung disease. Rapamycin, an inhibitor of fibroblast proliferation could be a potential anti-fibrotic drug to improve the effects of pirfenidone. METHODS: Primary lung fibroblasts from IPF patients and human alveolar epithelial cells (A549) were treated in vitro with pirfenidone and rapamycin in the presence or absence of transforming growth factor ß1 (TGF-ß). Extracellular matrix protein and gene expression of markers involved in lung fibrosis (tenascin-c, fibronectin, collagen I [COL1A1], collagen III [COL3A1] and α-smooth muscle actin [α-SMA]) were analyzed. A cell migration assay in pirfenidone, rapamycin and TGF-ß-containing media was performed. RESULTS: Gene and protein expression of tenascin-c and fibronectin of fibrotic fibroblasts were reduced by pirfenidone or rapamycin treatment. Pirfenidone-rapamycin treatment did not revert the epithelial to mesenchymal transition pathway activated by TGF-ß. However, the drug combination significantly abrogated fibroblast to myofibroblast transition. The inhibitory effect of pirfenidone on fibroblast migration in the scratch-wound assay was potentiated by rapamycin combination. CONCLUSIONS: These findings indicate that the combination of pirfenidone and rapamycin widen the inhibition range of fibrogenic markers and prevents fibroblast migration. These results would open a new line of research for an anti-fibrotic combination therapeutic approach.

Increasing isolation of rapidly growing mycobacteria in a low-incidence setting of environmental mycobacteria, 1994-2015.

To determine trends in incidence and clinical relevance of rapidly growing mycobacteria (RGM) in a low-prevalence region of non-tuberculous mycobacteria. We retrospectively identified all patients with RGM-positive cultures between January 1994 and December 2015. Trends in incidence, clinical significance, and outcomes were assessed. One hundred and forty patients had RGM-positive cultures (116 respiratory and 24 extra-respiratory sources). The incidence of RGM isolates increased steadily from 2003 (0.34 per 100,000) to 2015 (1.73 per 100,000), with an average annual increase of 8.3%. Thirty-two patients (22.9%) had clinical disease, which trended to cluster in the second half of the study period. A positive acid-fast bacilli smear (odds ratio [OR] 97.7, 95 % CI 13.8-689.4), the presence of extra-respiratory isolates (OR 19.4, 95 % CI 5.2-72.7), and female gender (OR 5.9, 95 % CI 1.9-19.1) were independently associated with clinical disease. Cure rates were 73.3 and 87.5% for pulmonary and extra-pulmonary disease respectively. Although the burden of disease remains low, the presence of RGM isolates is increasing in our geographical setting. Whether this rise will be sustained over time and will coincide with an increase in clinical disease, or whether it is merely a cycle in the poorly understood epidemiological behaviour of environmental mycobacteria, will be seen in the near future.

Prognostic factors for relapse in stage I seminoma: a new nomogram derived from three consecutive, risk-adapted studies from the Spanish Germ Cell Cancer Group (SGCCG).

BACKGROUND: We aimed to analyze prognostic factors for relapse in stage I seminoma managed by either active surveillance or adjuvant chemotherapy, and to describe the long-term patterns of recurrence in both groups. PATIENTS AND METHODS: From 1994 to 2008, 744 patients were included in three consecutive, prospective risk-adapted studies by the Spanish Germ Cell Cancer Group. Low-risk patients were managed by surveillance and high-risk patients were given two courses of adjuvant carboplatin. Relapses were treated mainly with chemotherapy. Patient age, tumor size, histological variant, pT staging, rete testis invasion, and preoperative serum BHCG levels were assessed for prediction of disease-free survival (DFS). RESULTS: After a median follow-up of 80 months, 63 patients (11.1%) have relapsed: 51/396 (14.8%) on surveillance and 12/348 (3.2%) following adjuvant carboplatin. Actuarial overall 5-year DFS was 92.3% (88.3% for surveillance versus 96.8% for chemotherapy, P = 0.0001). Median time to relapse was 14 months. Most recurrences were located at retroperitoneum (86%), with a median tumor size of 26 mm. All patients were rendered disease-free with chemotherapy (92%), radiotherapy (5%), or surgery followed by chemotherapy (3%). A nomogram was developed from surveillance patients that includes two independent, predictive factors for relapse: rete testis invasion and tumor size (as a continuous variable). CONCLUSION: Long-term follow-up confirms the risk-adapted approach as an effective option for patients with stage I seminoma. The pattern of relapses after adjuvant chemotherapy is similar to that observed following surveillance. A new nomogram for prediction of DFS among patients on surveillance is proposed. Rete testis invasion and tumor size should be taken into account when considering the administration of adjuvant carboplatin. Prospective validation is warranted.

Obstructive sleep apnoea and metabolic impairment in severe obesity.

Obstructive sleep apnoea (OSA) seems to worsen metabolism. This effect has not been evaluated in morbid obesity (MO). We hypothesised that the metabolic profile is more impaired in MO patients with OSA than in those without, and investigated whether any specific metabolic dysfunction is related to OSA in MO. A prospective multicentre cross-sectional study was conducted in consecutive subjects before bariatric surgery. OSA was defined as apnoea/hypopnoea index (AHI) ≥15 by overnight polysomnography. Anthropometrical, blood pressure (BP) and fasting blood measurements were obtained the morning after. Metabolic syndrome (MetS) was defined according to National Cholesterol Education Program Adult Treatment Panel III modified criteria. 159 patients were studied: 72% were female and 72% had OSA. MetS prevalence was 70% in OSA versus 36% in non-OSA (p<0.001). As AHI severity increased, metabolic parameters progressively worsened, even in those without type 2 diabetes (DM2). AHI was independently associated with systolic and diastolic BP, triglycerides and the percentage of glycosylated haemoglobin (HbA1c) in the total sample, and with systolic BP, high-density lipoprotein cholesterol and HbA1c in those samples without DM2. OSA increased the adjusted odds ratio of having MetS by 2.8 (95% CI 1.3-6.2; p=0.009). In MO, OSA is associated with major metabolic impairment caused by higher BP and poorer lipid and glucose control, independent of central obesity or DM2.

Pneumococcal pneumonia presenting with septic shock: host- and pathogen-related factors and outcomes.

BACKGROUND: Host- and pathogen-related factors associated with septic shock in pneumococcal pneumonia are not well defined. The aim of this study was to identify risk factors for septic shock and to ascertain patient outcomes. Serotypes, genotypes and antibiotic resistance of isolated strains were also analysed. METHODS: Observational analysis of a prospective cohort of non-severely immunosuppressed hospitalised adults with pneumococcal pneumonia. Septic shock was defined as a systolic blood pressure of <90 mm Hg and peripheral hypoperfusion with the need for vasopressors for >4 h after fluid replacement. RESULTS: 1041 patients with pneumococcal pneumonia diagnosed by Gram stain and culture of appropriate samples and/or urine antigen test were documented, of whom 114 (10.9%) had septic shock at admission. After adjustment, independent risk factors for shock were current tobacco smoking (OR, 2.11; 95% CI, 1.02 to 4.34; p = 0.044), chronic corticosteroid treatment (OR, 4.45; 95% CI, 1.75 to 11.32; p = 0.002) and serotype 3 (OR, 2.24; 95% CI, 1.12 to 4.475; p = 0.022). No significant differences were found in genotypes and rates of antibiotic resistance. Compared with the remaining patients, patients with septic shock required mechanical ventilation more frequently (37% vs 4%; p<0.001) and had longer length of stay (11 vs 8 days; p<0.001). The early (10% vs 1%; p<0.001) and overall case fatality rates (25% vs 5%; p<0.001) were higher in patients with shock. CONCLUSIONS: Septic shock is a frequent complication of pneumococcal pneumonia and causes high morbidity and mortality. Current tobacco smoking, chronic corticosteroid treatment and infection caused by serotype 3 are independent risk factors for this complication.

Impact of antibiotic therapy on systemic cytokine expression in pneumococcal pneumonia.

The aim of this study was to compare the evolution of systemic cytokine levels over time in patients with pneumococal pneumonia treated either with ß-lactam monotherapy or with combination therapy (ß-lactam plus fluoroquinolone). Prospective observational study of hospitalized non-immunocompromised adults with PP. Concentrations of IL-6, IL-8, IL-10, and TNF-α were determined on days 0, 1, 2, 3, 5, and 7. Patients on ß-lactam monotherapy were compared with those receiving combination therapy. Fifty-two patients were enrolled in the study. Concentrations of IL-6, IL-8, and IL-10 decreased rapidly in the first days after admission, in accordance with the mean time to defervescence. High levels of IL-6 were found in patients with the worst outcomes, measured by the need for intensive care unit admission and mortality. No major differences in demographic or clinical characteristics or severity of disease were found between patients treated with ß-lactam monotherapy and those treated with combination therapy. IL-6 levels fell more rapidly in patients with combination therapy in the first 48 h (p = 0.016). Our data suggest that systemic expression of IL-6 production in patients with PP correlates with prognosis. Initial combination antibiotic therapy produces a faster decrease in this cytokine in the first 48 h.

A prospective study of lung disease in a cohort of early rheumatoid arthritis patients.

Lung disease is common in patients with rheumatoid arthritis (RA). The onset of lung involvement in RA is not well known. The objective is to describe the features and evolution of lung involvement in early RA, its relationship with disease activity parameters, smoking and treatments. Consecutive patients with early RA without respiratory symptoms were included and tracked for 5 years. Lung assessment included clinical, radiological and pulmonary function tests at diagnosis and during follow-up. Peripheral blood parameters (erythrocyte sedimentation rate, C reactive protein, rheumatoid factor and anti-citrullinated peptide autoantibodies) and scales of articular involvement, such as DAS28-CRP, were evaluated. 40 patients were included and 32 completed the 5-year follow up. 13 patients presented lung involvement in the initial 5 years after RA diagnosis, 3 of them interstitial lung disease. Significant decrease of diffusion lung transfer capacity of carbon monoxide over time was observed in six patients, 2 of them developed interstitial lung disease. DLCO decrease was correlated with higher values of CRP and ESR at diagnosis. Methotrexate was not associated with DLCO deterioration or lung disease development. Subclinical progressive lung disease correlates with RA activity parameters. Smoking status and methotrexate were not associated with development or progression of lung disease.

Long-term relapses after 12-month treatment for Mycobacterium kansasii lung disease.

Long-lasting therapy for Mycobacterium kansasii lung disease with rifampin-containing multidrug regimens is needed to avoid relapses. The aim of the present study is to evaluate a short multidrug treatment regimen for M. kansasii lung disease. A retrospective observational study of 75 patients with M. kansasii lung disease was conducted in a teaching hospital from January 1990 to December 2005. In total, 75 (67.6%) out of 111 patients diagnosed with M. kansasii lung disease completed a 12-month multidrug treatment regimen, including rifampin, isoniazid and ethambutol, supplemented with streptomycin during the first 2-3 months. After a 41.5-month median follow-up, five (6.6%) patients relapsed. The relapse rate was 2.19 (95% confidence interval 0.71-5.12) per 100 person.yrs. Treatment compliance was considered to be appropriate in all five patients and no drug resistance developed in any case. In conclusion, a 12-month fixed-course treatment is effective in most cases of Mycobacterium kansasii lung disease, but may not be long enough for all patients.

Early mortality in patients with community-acquired pneumonia: causes and risk factors.

The first 48 h of evolution of patients with community-acquired pneumonia (CAP) are critical. The aim of the present study was to determine the frequency, causes and factors associated with early mortality in CAP. Nonimmunocompromised adults hospitalised with CAP were prospectively observed from 1995 to 2005. Early deaths, defined as death due to any cause < or = 48 h after admission, were compared with all patients who survived > 48 h. Furthermore, early deaths were compared with late deaths (patients who died > 48 h) and with survivors. Of 2,457 patients, 57 (2.3%) died < or = 48 h after admission. Overall mortality was 7.7%. The main causes of early mortality were respiratory failure and septic shock/multiorgan failure. Independent factors associated with early deaths were increased age, altered mental status at presentation, multilobar pneumonia, shock at admission, pneumococcal bacteraemia and discordant empiric antibiotic therapy. Currently, early mortality is relatively low and is caused by pneumonia-related factors. It occurs mainly among the elderly and in patients presenting with altered mental status, multilobar pneumonia and septic shock. Pneumococcal bacteraemia and discordant antibiotic therapy, mainly due to lack of coverage against Pseudomonas aeruginosa are also significant risk factors.

Prevention and treatment of tuberculosis infection in candidates for biologic therapy: A multidisciplinary consensus statement adapted to the dermatology patient. / Consenso multidisciplinar sobre prevención y tratamiento de la tuberculosis en pacientes candidatos a tratamiento biológico. Adaptación al paciente dermatológico.

Patients with chronic inflammatory diseases being treated with immunosuppressive drugs, and with tumor necrosis factor inhibitors in particular, have an increased risk of infection by Mycobacterium tuberculosis. Screening for latent tuberculosis infection and preventive therapy to reduce the risk of progression to active tuberculosis are mandatory in this group of patients. This updated multidisciplinary consensus document presents the latest expert opinions on the treatment and prevention of tuberculosis in candidates for biologic therapy and establishes recommendations based on current knowledge relating to the use of biologic agents.

Declining mortality among hospitalized patients with community-acquired pneumonia.

Little information is available on the changes over time in community-acquired pneumonia (CAP) management and their impact on 30-day mortality in hospitalized patients. We performed a prospective, observational study of non-severely immunosuppressed hospitalized adults with CAP from 1995 to 2014. A total of 4558 patients were included. Thirty-day mortality decreased from 9.6% in the first study period (1995-99) to 4.1% in the last period (2010-14); with a progressive downward trend (-0.2% death/year; p for trend = 0.003). Over time, patients were older (p 0.02), had more co-morbidities (p 0.037), more frequently presented severe illness according to the Pneumonia Severity Index (p <0.001) and septic shock (p <0.001), and more often required intensive care unit admission (p <0.001). Combination antibiotic therapy (p <0.001) and fluoroquinolone use (p <0.001) increased. Factors independently associated with 30-day mortality were increasing age (OR 1.04; 95% CI 1.03-1.05), co-morbidities (OR 1.48; 95% CI 1.04-2.11), shock at admission (OR 4.95; 95% CI 3.49-7.00), respiratory failure (OR 1.89; 95% CI 1.42-2.52), bacteraemia (OR 2.16; 95% CI 1.58-2.96), Gram-negative bacilli aetiology (OR 4.79; 95% CI 2.52-9.10) and fluoroquinolone use (OR 0.45; 95% CI 0.29-0.71). When we adjusted for a propensity score to receive fluoroquinolones, the protective effect of fluoroquinolone use was not confirmed. In conclusion, 30-day mortality decreased significantly over time in hospitalized patients with CAP in spite of an upward trend in patient age and other factors associated with poor outcomes. Several changes in the management of CAP and a general improvement in global care over time may have caused the observed outcomes.

Aberrant gene methylation and bronchial dysplasia in high risk lung cancer patients.

INTRODUCTION: The risk for lung cancer is incremented in high degree dysplasia (HGD) and in subjects with hypermethylation of multiple genes. We sought to establish the association between them, as well as to analyze the DNA aberrant methylation in sputum and in bronchial washings (BW). METHODS: Cross sectional study of high risk patients for lung cancer in whom induced sputum and autofluorescence bronchoscopy were performed. The molecular analysis was determined on DAPK1, RASSF1A and p16 genes using Methylation-specific PCR. RESULTS: A total of 128 patients were enrolled in the study. Dysplasia lesions were found in 79 patients (61.7%) and high grade dysplasia in 20 (15.6%). Ninety eight patients out of 128 underwent molecular analysis. Methylation was observed in bronchial secretions (sputum or BW) in 60 patients (61.2%), 51 of them (52%) for DAPK1, in 20 (20.4%) for p16 and in three (3.1%) for RASSF1A. Methylated genes only found in sputum accounted for 38.3% and only in BW in 41.7%, and in both 20.0%. In the 11.2% of the patients studied, HGD and a hypermethylated gene were present, while for the 55.1% of the sample only one of both was detected and for the rest of the subjects (33.6%), none of the risk factors were observed. CONCLUSIONS: Our data determines DNA aberrant methylation panel in bronchial secretions is present in a 61.2% and HGD is found in 15.6%. Although both parameters have previously been identified as risk factors for lung cancer, the current study does not find a significative association between them. The study also highlights the importance of BW as a complementary sample to induced sputum when analyzing gene aberrant methylation.

Clindamycin vs penicillin for anaerobic lung infections. High rate of penicillin failures associated with penicillin-resistant Bacteroides melaninogenicus.

Thirty-seven adult patients with anaerobic lung infections (27 lung abscesses and 10 necrotizing pneumonias) were submitted to transthoracic needle-aspiration and/or bronchoscopic specimen brush cultures before therapy and thereafter in all cases considered to be failures. Patients were randomly assigned to receive either clindamycin, 600 mg intravenously every 6 hours, or penicillin G, 2 million U every 4 hours for no less than 8 days, until clinical and radiological improvement became apparent. Treatment was continued orally with clindamycin, 300 mg every 6 hours, or penicillin V, 750 mg every 6 hours, until completing a minimum of 4 weeks. Ten of the 47 anaerobes initially isolated from the lung (nine Bacteroides melaninogenicus and one Bacteroides capillosus) were resistant to penicillin, but none were resistant to clindamycin. Five of the nine patients harboring these penicillin-resistant Bacteroides received penicillin, and all failed to respond to therapy. Overall, eight of the 18 patients in the penicillin group and one of 19 in the clindamycin group failed to respond to therapy. These drugs were equally well tolerated in both groups. The presence of penicillin-resistant Bacteroides is a frequent cause of penicillin failure in patients with anaerobic lung infections. In this setting, clindamycin appears to be the current therapy of choice for initial treatment.

[Small cell lung cancer and cancer-associated retinopathy]. / Carcinoma broncogénico microcítico y retinopatía asociada a cáncer.

We report the case of a patient who presented with cancer-associated retinopathy and small cell carcinoma of the lung, which was treated surgically because the initial diagnostic biopsy finding was squamous cell carcinoma. The patient then underwent chemotherapy and radiation therapy. We discuss the characteristics and pathogenesis of this paraneoplastic syndrome as well as its association with the lung tumor's aberrant production of a protein that competes with retinal recoverin at the photoreceptors of the retinal cone.

Phase II trial of carboplatin in combination with etoposide in locally advanced large cell carcinoma and adenocarcinoma of the lung.

A total of 18 patients with locally advanced (Stage III) adenocarcinoma and large cell undifferentiated carcinoma of the lung, previously untreated, were enrolled in a Phase II trial. Treatment consisted of carboplatin 325 mg/m2, day 1 and etoposide 100 mg/m2 on days 2 and 3. All patients were evaluable for response. Of these, one patient had a partial response (5.5%; confidence interval 0-24%). Toxicity comprised mainly leukopenia and anaemia. Other toxicities were mild. This Phase II study evidenced a poor response rate for these regimes on adenocarcinoma and large cell undifferentiated carcinoma of the lung.

Usefulness of betalactam therapy for community-acquired pneumonia in the era of drug-resistant Streptococcus pneumoniae: a randomized study of amoxicillin-clavulanate and ceftriaxone.

Empirical antibiotic therapy of community-acquired pneumonia (CAP) has been complicated by the worldwide emergence of penicillin resistance among Streptococcus pneumoniae. The impact of this resistance on the outcome of patients hospitalized for CAP, empirically treated with betalactams, has not been evaluated in a randomized study. We conducted a prospective, randomized trial to assess the efficacy of amoxicillin-clavulanate (2 g/200 mg/8 hr) and ceftriaxone (1 g/24 hr) in a cohort of patients hospitalized for moderate-to-severe CAP. Three-hundred seventy-eight patients were randomized to receive amoxicillin-clavulanate (184 patients) or ceftriaxone (194 patients). Efficacy was assessed on Day 2, after completion of therapy and at long term follow-up. There were no significant differences in outcomes between treatment groups, both in intention-to-treat and per-protocol analysis. Overall mortality was 10.3% for amoxicillin-clavulanate and 8.8% for ceftriaxone (NS). There were 116 evaluable patients with proven pneumococcal pneumonia. Rates of high-level penicillin resistance (MIC of penicillin > or = 2 microg/mL) were similar in the two groups (8.2 and 10.2%). Clinical efficacy at the end of therapy was 90.6% for amoxicillin-clavulanate and 88.9% for ceftriaxone (95% C.I. of the difference: -9.3 to +12.7%). No differences in outcomes were attributable to differences in penicillin susceptibility of pneumococcal strains. Sequential i.v./oral amoxicillin-clavulanate and parenteral ceftriaxone were equally safe and effective for the empirical treatment of acute bacterial pneumonia, including penicillin and cephalosporin-resistant pneumococcal pneumonia. The use of appropriate betalactams in patients with penumococcal pneumonia and in the overall CAP population, is reliable at the current level of resistance.

Neurological assessment of high grade astrocytomas following high dose radiotherapy as sole treatment.

Between January 1985 and June 1991, 19 patients, in whom the site and extension of the tumour prevented surgical excision, were treated with high dose radiotherapy as sole treatment for high grade astrocytomas. Quality of life, according to functional capacity, was measured prospectively before treatment and 4 weeks later. High dose radiation improved the functional capacity in only four of the patients (21%). The mean duration of improvement was 12 weeks and median survival 22 weeks (range 4-80). We conclude that high dose radiotherapy is not very useful and is probably not justified in this group of patients.

Vertebral and rib sarcoidosis: long-term clinical remission with methotrexate.

We describe a patient with bilateral hilar lymphadenopathy shown on a chest radiograph and supraclavicular lymphadenopathy. Biopsy of a supraclavicular lymph node showed non-caseating granulomas. A diagnosis of sarcoidosis was made and no treatment was given. One year later she complained of cervical and lumbar pain and decreasing strength of the right hand. Magnetic resonance imaging of the spine showed multiple lesions within the vertebral bodies of six vertebrae, and thoracic computed tomography showed partial destruction of the first right rib. A biopsy of the second lumbar vertebra demonstrated non-caseating granulomas. Corticosteroid treatment was unsuccessful and long-term remission of the symptoms was achieved with a weekly low dose of methotrexate.

[The risk of breast cancer in Catalonia]. / El riesgo del cáncer de mama en Cataluña.

BACKGROUND: To evaluate the risk of developing breast cancer among Catalan women and to estimate the number of new cases of this tumor that appear annually in Catalonia (north-east of Spain). MATERIAL AND METHODS: The incidence rates of breast cancer were used in the period 1985-1989 proceeding from the population-based cancer registries of Tarragona and Girona. The age-specific rates (ASR) in Catalonia were estimated by an ASR average of Girona and Tarragona, that were adjusted by the standardized mortality ratio (SMR) of these health regions in relation to Catalonia. The cumulative rate and the risk of developing breast cancer were calculated, considering the probability of death by other causes. The temporal trend of breast cancer incidence was analysed by the Poisson's regression model. RESULTS: The cumulative risk (0-74 years) for breast cancer among Catalan women was 5.17% (1 out of 19 women). The highest risk of developing breast cancer is in the group of age between 60 and 79 years old. Tarragona and Girona had both a moderate increase that was not statistically significant. About 2,550 new cases of breast cancer have been estimated in 1994 and 2,600 in 1996. CONCLUSION: The risk of developing breast cancer in Catalonia after adjusting for the probability of dying by other causes, is lower than in other countries of Northern Europe and the United States.