Immune-related adverse events predict the therapeutic efficacy of anti-PD-1 antibodies in cancer patients.

BACKGROUND: Cancer immune therapy has shown remarkable benefit in the treatment of a range of cancer types, although it may initiate autoimmune-related disorders in some patients. We have attempted to establish whether the incidence of irAEs after the use of anti-PD-1 antibodies nivolumab or pembrolizumab in advanced malignancies is associated with anti-PD-1 treatment efficacy. PATIENTS AND METHODS: We studied patients treated with single-agent nivolumab or pembrolizumab for advanced cancer. irAEs (immune-related adverse events) were identified clinically and graded as per the Common Terminology Criteria for Adverse Events version 4.0. Efficacy was evaluated with objective response rate (ORR, immune-Response Evaluation Criteria in Solid Tumours [RECIST] criteria) progression-free survival (PFS) and overall survival (OS). Tests were performed to determine the association between irAEs and ORR, PFS or OS. RESULTS: We identified 106 patients. Primary diagnoses were lung cancer (n = 77), melanoma (n = 8), head and neck carcinoma (n = 7), renal carcinoma (n = 5), Hodgkin's lymphoma (n = 3), urothelial carcinoma (n = 3) and gallbladder adenocarcinoma, hepatocellular carcinoma and Merkel cell carcinoma (n = 1 each). IrAEs were observed in 40 patients (37.7%). The most frequent irAEs were hypothyroidism (n = 15), nephritis (n = 5) and hyperthyroidism (n = 4). Objective response was observed in 44 patients (41.5%), and median PFS was 5.5 months (0.5-31 months). Thirty-three of the 40 patients with irAEs had objective response (82.5%) in contrast with 11 of the 66 cases without irAEs (16.6%) (OR 23.5, P < 0.000001). PFS in patients with irAEs was 10 months and 3 months in those without irAEs (HR 2.2, P = 0.016). OS in patients with irAEs was 32 months and 22 in those without irAEs, without statistically significant differences. CONCLUSION: In advanced cancer treated with single-agent anti-PD-1 antibodies, patients with irAEs showed a markedly improved efficacy over patients without irAEs (ORR of 82.5% and PFS of 10 months vs ORR of 16.6% and PFS of 3 months). Future studies of anti-PD-1 immune-therapy should address this association to explore the underlying biological mechanisms of efficacy.

Escalas de gravedad y neumonía adquirida en la comunidad. ¿Por qué no las uso si son tan excelentes? / No disponible

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Initial management of pneumonia and sepsis: factors associated with improved outcome.

Processes of care and adherence to guidelines have been associated with improved survival in community-acquired pneumonia (CAP). In sepsis, bundles of processes of care have also increased survival. We aimed to audit compliance with guideline-recommended processes of care and its impact on outcome in hospitalised CAP patients with sepsis. We prospectively studied 4,137 patients hospitalised with CAP in 13 hospitals. The processes of care evaluated were adherence to antibiotic prescription guidelines, first dose within 6 h and oxygen assessment. Outcome measures were mortality and length of stay (LOS). Oxygen assessment was measured in 3,745 (90.5%) patients; 3,024 (73.1%) patients received antibiotics according to guidelines and 3,053 (73.8%) received antibiotics within 6 h. In CAP patients with sepsis, the strongest independent factor for survival was antibiotic adherence (OR 0.4). In severe sepsis, only compliance to antibiotic adherence plus first dose within 6 h was associated with lower mortality (OR 0.60), adjusted for fine prognostic scale and hospital. Antibiotic adherence was related to shorter hospital stay. In sepsis, antibiotic adherence is the strongest protective factor of care associated with survival and LOS. In severe sepsis, combined antibiotic adherence and first dose within 6 h may reduce mortality.

Todos nuestros productos son de primera calidad / All our products are of high quality

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Impact of initial antibiotic choice on mortality from pneumococcal pneumonia.

To determine the impact of initial antimicrobial choice on 30-day mortality rate in patients with community-acquired pneumonia due to Streptococcus pneumoniae (CAP-SP), a prospective, observational study was conducted in 35 Spanish hospitals. A total of 638 patients with CAP-SP were identified. Antimicrobials were chosen by the attending physician. Patients were grouped into the following categories: beta-lactam monotherapy (n = 251), macrolide monotherapy (n = 37), beta-lactam plus macrolide (n = 198), levofloxacin alone/combination (n = 48), and other combinations (n = 104). The reference category was beta-lactam+macrolide. The 30-day survival probability was 84.9%. Using multivariate survival analysis, factors related to mortality in the entire population were: bilateral disease, suspected aspiration, shock, HIV infection, renal failure and pneumonia severity index (PSI) score Class IV versus I-III and categories V versus I-III. The association of beta-lactams+macrolides was not better than the use of beta-lactams alone. The current authors analysed the different groups of patients with significant mortality/morbidity: intensive care unit, PSI Class >III, renal failure, chronic lung disease and bacteraemia. Only in patients with PSI Class >III, who had undergone initial antimicrobial choice classified as other combinations, were associated with higher mortality. In conclusion, the current authors have not demonstrated an independent association between initial antimicrobial regimen and 30-day mortality in community-acquired pneumococcal pneumonia patients, except for those with a higher pneumonia severity index score.

Risk factors of treatment failure in community acquired pneumonia: implications for disease outcome.

BACKGROUND: An inadequate response to initial empirical treatment of community acquired pneumonia (CAP) represents a challenge for clinicians and requires early identification and intervention. A study was undertaken to quantify the incidence of failure of empirical treatment in CAP, to identify risk factors for treatment failure, and to determine the implications of treatment failure on the outcome. METHODS: A prospective multicentre cohort study was performed in 1424 hospitalised patients from 15 hospitals. Early treatment failure (<72 hours), late treatment failure, and in-hospital mortality were recorded. RESULTS: Treatment failure occurred in 215 patients (15.1%): 134 early failure (62.3%) and 81 late failure (37.7%). The causes were infectious in 86 patients (40%), non-infectious in 34 (15.8%), and undetermined in 95. The independent risk factors associated with treatment failure in a stepwise logistic regression analysis were liver disease, pneumonia risk class, leucopenia, multilobar CAP, pleural effusion, and radiological signs of cavitation. Independent factors associated with a lower risk of treatment failure were influenza vaccination, initial treatment with fluoroquinolones, and chronic obstructive pulmonary disease (COPD). Mortality was significantly higher in patients with treatment failure (25% v 2%). Failure of empirical treatment increased the mortality of CAP 11-fold after adjustment for risk class. CONCLUSIONS: Although these findings need to be confirmed by randomised studies, they suggest possible interventions to decrease mortality due to CAP.

Community-acquired pneumonia in the elderly: Spanish multicentre study.

Community-acquired pneumonia (CAP) in the elderly has increased as a consequence of an overall increase of the elderly population. A controversy about the aetiology and outcome of CAP in this population still exists and more epidemiological studies are needed. A prospective, 12-month, multicentre study was carried out to assess the clinical characteristics, aetiology, evolution and prognostic factors of elderly patients (> or = 65 yrs) admitted to hospital for CAP. The study included 503 patients (age 76 +/- 7 yrs). The clinical picture lasted < or = 5 days in 318 (63%) and the main clinical features were cough (n = 407, 81%) and fever (n = 380, 76%). Aetiological diagnosis was achieved in 199 (40%) cases, with a definite diagnosis obtained in 164 (33%). Of the 223 microorganisms isolated the main agents found were Streptococcus pneumoniae in 98 (49%) and Haemophilus influenzae in 27 (14%). A total of 53 patients died (11%) and the multivariate analysis showed the following factors of bad prognosis: previous bed confinement, alteration in mental status, absence of chills, plasma creatinine > or = 1.4 mg x dL(-1), oxygen tension in arterial blood/inspiratorv oxygen fraction ratio < 200 at the time of admission, and shock and renal failure during the evolution. The results of this study may aid in the management of empiric antibiotic treatment in elderly patients with community-acquired pneumonia and the patients who have a greater probability of bad evolution may be identified based on the risk factors.

Characterization of a possible nosocomial aspergillosis outbreak.

OBJECTIVE: To study the epidemiologic aspects of a suspected outbreak of nosocomial invasive aspergillosis. METHODS: Sixteen Aspergillus fumigatus strains were isolated from bronchoalveolar washings or sputa of 10 patients during a 9-month period. Furthermore, two environmental samples, isolated in a microbiological screening of the hospital, were also available for analysis. Random amplified polymorphic DNA analysis (RAPD) was carried out. RESULTS: The analysis performed by RAPD clearly demonstrated substantial genetic variation among the isolates. Both of the two different primers selected for RAPD analysis (R-108 and AP12h) were able to demonstrate that the strains isolated from all patients infected with the same fungal species and the environmental samples were genotypically distinct. The results by RAPD typing demonstrated that this technique could detect variability among isolates of Aspergillus fumigatus from different patients and even from the same patient. CONCLUSIONS: RAPD genotyping proved that the outbreak of invasive aspergillosis consisted of a series of events, non-related, and probably not coming from the same source within the hospital. This type of analysis is an easy, quick and highly discriminatory technique that may help in planning epidemiologic studies of aspergillosis.

Bronchoalveolar lavage cell composition in allogeneic bone marrow transplant patients without symptomatic lung complications.

The purpose of this study was to assess the cytological composition of bronchoalveolar lavage (BAL) fluid in allogeneic BMT patients without lung complications and compare it with that obtained from healthy volunteers. During the first 6 months post-BMT we studied the differential cell counts of 98 BALs from 56 patients as well as the total cell count of 44 BALs from 27 patients. The BAL cellular composition in BMT patients was clearly different from that of healthy subjects: there was a marked increase in alveolar neutrophils (in 82% of the patients when sequential BALs were performed) and an increase in lymphocytes, with a lower percentage of macrophages and similar numbers of eosinophils. A greater variation in cellular populations was found without an evident cause. The total number of cells per ml of fluid recovered appeared similar to that of healthy volunteers. A high frequency of neutrophilic alveolitis was found in patients with asymptomatic CMV on BAL. Owing to the variability of BAL cellular composition in asymptomatic BMT patients and its difference from that in healthy volunteers, great caution should be taken when interpreting the BAL composition data from patients with lung complications. In order to avoid drawing wrong conclusions these data should be compared with those obtained from a control group of BMT patients without lung complications and not from healthy volunteers.

Expression of lymphocyte activation surface antigens in bronchoalveolar lavage and peripheral blood cells from young healthy subjects.

Cell surface phenotypes of bronchoalveolar lavage (BAL) and peripheral blood lymphocytes (PBL) obtained from a group of young healthy volunteers, including smokers and nonsmokers were studied. Results indicate that the proportions of T (CD3+) and B (CD19+) lymphocytes were comparable in PBL and BAL lymphocytes, whereas the numbers of cells bearing natural killer cell-associated markers (CD16, CD11b, CD56, and CD57) were significantly higher in PBL; in BAL lymphocytes of smokers, the CD4+/CD8+ ratio was < 1. The surface density of CD3 in every case was lower in BAL T cells. The expression of different surface antigens considered to reflect lymphocyte activation was variable; the human lymphocyte antigen (HLA)-DR, CD25 (alpha chain of the interleukin-2 receptor), and CD71 (transferrin receptor) were displayed at low levels in both types of samples. In contrast, the expression of 4F2, CD49a, and particularly, the early activation antigen CD69 were significantly higher in BAL cells compared with PBL; BAL samples from smokers included significantly lower proportions of lymphocytes bearing the CD69, HLA-DR, and 4F2 activation antigens.

Fiberoptic bronchoscopic diagnosis of pulmonary disease in 151 HIV-infected patients with pneumonitis.

In a prospective study the efficacy of fiberoptic bronchoscopy was evaluated in the diagnosis of infections with opportunistic pathogens, Kaposi's sarcoma and nonspecific interstitial pneumonitis in 171 episodes of pneumonitis in 151 HIV-infected patients. Samples were collected by suction through the inner aspiration channel of the bronchoscope (n = 164), telescoping plugged catheter (n = 117) and transbronchial lung biopsy (n = 82). A high incidence of infections with pyogenic bacteria (12%), Legionella spp. (5 %) and Mycobacterium tuberculosis were diagnosed (9%). Bronchoalveolar lavage demonstrated a high diagnostic rate in bacterial pneumonia (significance level greater than 10(5) cfu/ml) and a low degree (10%) of contamination (less than 1% squamous epithelial cells). Bronchoalveolar lavage was more effective than the telescoping plugged catheter in yielding a significant number of colonies in patients with bacterial pneumonia previously treated with antibiotics. Nondiagnosed pneumonitis was more frequent in intravenous drug abusers than in homosexual men (p less than 0.001).

[Carcinoma arising in thyroglossal duct cyst: presentation of a new case and review of the literature]. / Carcinoma sobre quiste del conducto tirogloso: aportación de un nuevo caso y revisión de la literatura.

Carcinoma arising in thyroglossal duct remnants is a rare even that appears in about 1% of all surgically treated cases. A survey of the literature reveals more than 100 reported cases. We present a new case of malignant transformation of thyroid remnants in thyroglossal duct cyst wall: a non invasive papillary carcinoma. Local resection by the Sistrunk method, without any other treatment, was considered curative. We also review the available literature regarding this entity.