Real-world data from the Portuguese Nivolumab Expanded Access Program (EAP) in previously treated Non Small Cell Lung Cancer (NSCLC).

OBJECTIVE: The main aim of the study was to evaluate the efficacy and safety profile of Nivolumab, an immune-checkpoint-inhibitor antibody, in advanced, previously treated, Non-Small Cell Lung Cancer (NSCLC) patients, in a real world setting. METHODS: We performed a retrospective, multicentre data analysis of patients who were included in the Portuguese Nivolumab Expanded Access Program (EAP). Eligibility criteria included histologically or citologically confirmed NSCLC, stage IIIB and IV, evaluable disease, sufficient organ function and at least one prior line of chemotherapy. The endpoints included Overall Response Rate (ORR), Disease Control Rate (DCR), Progression Free Survival (PFS) and Overall Survival (OS). Safety analysis was performed with the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, and immune-related Adverse Events (irAEs) were treated according to protocol treatment guidelines. Tumour response was assessed using the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Data was analysed using SPSS, version 21.0 (IBM Statistics). RESULTS: From June 2015 to December 2016, a total of 229 patients with advanced NSCLC were enrolled at 30 Portuguese centres. Clinical data were collected up to the end of July 2018. The baseline median age was 64 years (range 37-83) and the majority of patients were males (70.3%) and former/current smokers (69.4%). Patients with non-squamous histology predominated (88.1%), and 67.6% of the patients had received 2 or more prior lines of chemotherapy. Out of 229 patients, data was available for 219 patients (3 patients did not start treatment, while data was unavailable in 7 patients); of the 219 patients, 15.5% were not evaluated for radiological tumour assessment, 1.4% had complete response (CR), 21% partial response (PR), 31% stable disease (SD) and 31.1% progressive disease (PD). Thus, the ORR was 22.4% and DCR was 53.4% in this population. At the time of survival analysis the median PFS was 4.91 months (95% CI, 3.89-6.11) and median OS was 13.21 months (95% CI, 9.89-16.53). The safety profile was in line with clinical trial data. CONCLUSIONS: Efficacy and safety results observed in this retrospective analysis were consistent with observations reported in clinical trials and from other centres.

Detection of rare and novel EGFR mutations in NSCLC patients: Implications for treatment-decision.

OBJECTIVES: Mutations in the gene that encodes epidermal growth factor receptor (EGFR) are biomarkers that predict how non-small cell lung cancer (NSCLC) patients respond to EGFR-targeted therapies collectively known as tyrosine kinase inhibitors (TKIs). Thus, EGFR genotyping provides crucial information for treatment decision. Both Sanger sequencing and real-time PCR methodologies are used for EGFR genotyping. However, methods based on real-time PCR have limitations, as they may not detect rare or novel mutations. The aim of this study was to determine the prevalence of rare mutations in the tyrosine kinase domain (exons 18-21) of the EGFR gene not targeted by the most frequently used real-time PCR approaches, i.e., the cobas® EGFR Mutation Test, and the Idylla™ EGFR Mutation Assay. METHODS: A total of 1228 NSCLC patients were screened for mutations in exons 18-21 of the EGFR gene using Sanger sequencing. RESULTS: We observed that 252 patients (∼20%) had at least one mutation in the EGFR gene, and 38 (∼3%) carried uncommon genetic alterations that would not be identified by the cobas® or the Idylla™ tests. We further found six new single mutations and seven previously unreported compound mutations. Clinical information and patient outcome are presented for these cases. CONCLUSIONS: This study highlights the value of sequencing-based approaches to identify rare mutations. Our results add to the inventory of known EGFR mutations, thus contributing to improved lung cancer precision treatment.

APPLICATION OF DROPLET DETECTORS TO ALPHA RADIATION DETECTION.

Superheated droplet detectors (SDDs) are traditionally employed in the detection of neutrons. In this work the focus is on the detection of alpha particles using C2ClF5 as the target liquid. The alpha-droplet interaction is examined via computational studies, and a geometric model developed to describe the expected detector response. Experiments with alpha-emitting uranium- and samarium-doped SDDs at temperatures of 5-12°C confirm that the event rate is related to the size of the droplets, and are in model agreement for temperatures below 8°C; above this temperature, the acoustic sensitivity is reduced by signal attenuation as a result of the increasing bubble population, for which the addition of an attenuation coefficient restores the agreement with experiment. The results suggest the viability of a SDD-based alpha spectrometer using mono-sized droplets.

Final analysis and results of the Phase II SIMPLE dark matter search.

We report the final results of the Phase II SIMPLE measurements, comprising two run stages of 15 superheated droplet detectors each, with the second stage including an improved neutron shielding. The analyses include a refined signal analysis, and revised nucleation efficiency based on a reanalysis of previously reported monochromatic neutron irradiations. The combined results yield a contour minimum of σp=5.7×10(-3) pb at 35 GeV/c2 in the spin-dependent sector of weakly interacting massive particle (WIMP) proton interactions, the most restrictive to date for MW}≤60 GeV/c2 from a direct search experiment and overlapping, for the first time, with results previously obtained only indirectly. In the spin-independent sector, a minimum of 4.7×10(-6) pb at 35 GeV/c2 is achieved, with the exclusion contour challenging a significant part of the light mass WIMP region of current interest.

Virulence and molecular aspects of Bordetella avium isolated from cockatiel chicks (Nymphicus hollandicus) in Brazil.

Bordetella avium is an opportunistic pathogen that presents tropism for ciliated epithelia, leading to upper respiratory tract disease in turkeys. This agent has also been associated with Lockjaw Syndrome in psittacine birds, but literatures describing the importance of this agent in such species are rare. The purpose of the present study was to report the first outbreak of B. avium infection in juvenile cockatiels demonstrating the Lockjaw Syndrome in Brazil and to investigate the antimicrobial resistance profile and phenotypic and genotypic characteristics of these strains. Surprising, the strains obtained from five infected cockatiel chicks from three different breeders from different Brazilian states showed a clonal relationship using the Pulsed Field Gel Electrophoresis and Single Enzyme Amplified Fragment Length Polymorphism techniques. The virulence potentials of the B. avium strains were assessed using tracheal adherence and cytotoxic effects on a VERO cell monolayer.

Organising pneumonia - the experience of an outpatient clinic of a central hospital.

AIM: to characterise outpatients of a Portuguese central hospital diagnosed with organising pneumonia (OP) and compare results with current literature. METHODS: medical processes with diagnosis of OP were retrospectively studied as to demographics, aetiology, clinical and radiological features, average time until and date of diagnosis, laboratory and histological changes, treatment and relapse. Results - thirteen patients with a mean follow -up of 171.6 weeks (max 334 and min 28 weeks) were evaluated. Nine of these patients (70%) had cryptogenic OP (COP) while 30% had secondary OP (SOP), two with rheumatoid arthritis, one with dermatomyositis and another undergoing radiotherapy for breast cancer. Mean age was 55.6 (+ -15.3 years), 92% female, 77% were non -smokers. Average time until diagnosis was 77.2 weeks (min 3 and max 432 weeks). Symptoms at presentation were tiredness (92%), cough (85%), fever (65%), shortness of breath (54%), thoracic pain (23%) and weight loss (23%). At the time of diagnosis, the mean erythrocyte sedimentation rate was 70mm (max 170mm and min 16mm). C -reactive protein level was increased in eight patients. Significant leucocytosis was absent. Chest X -ray and chest CT scan showed bilateral distribution in 12 patients (92%). Consolidation with an air bronchogram was present in 12 patients and in four (31%), consolidation was migratory. Four patients (30%) underwent transbronchial pulmonary biopsy, all uncharacteristic and eight patients surgical pulmonary biopsy, four showed histological confirmation of SOP. Corticosteroids were started in 11 patients and average treatment was 61.6 weeks (16-288 weeks). 15% (2/13) had spontaneous resolution. Four patients (31%) relapsed, one of them five times. Two patients are dependent on a low dose of corticosteroids, one due to underlying disease and another due to multiple relapses. Therapy of relapse was corticosteroids alone in minimum effective dosage or associated to azathioprine or ciclosporin. DISCUSSION AND CONCLUSION: such a high incidence in females (92%) may be explained by the limited sample of patients. In 70% of the patients diagnosis were established by clinical and radiology criteria. Mean time to diagnosis was very variable which suggests that in some cases the disease was not diagnosed and treated as another interstitial lung disease or as recurrent pneumonia. Most patients (53.8%) had a favourable clinical course after treatment with corticosteroids with a very low number of relapses (30.8%), much lower than described by other authors (60%). Only in experienced centres should the diagnosis of OP established by clinical and radiological criteria.

First results of the Phase II SIMPLE dark matter search.

We report results of a 14.1 kg d measurement with 15 superheated droplet detectors of total active mass 0.208 kg, comprising the first stage of a 30 kg d Phase II experiment. In combination with the results of the neutron-spin sensitive XENON10 experiment, these results yield a limit of |a(p)|<0.32 for M(W)=50 GeV/c² on the spin-dependent sector of weakly interacting massive particle-nucleus interactions with a 50% reduction in the previously allowed region of the phase space, formerly defined by XENON, KIMS, and PICASSO. In the spin-independent sector, a limit of 2.3×10⁻5 pb at M(W)=45 GeV/c² is obtained.

Obstructive sleep apnoea syndrome as a cause of road traffic accidents.

UNLABELLED: Several studies have demonstrated that obstructive sleep apnoea syndrome (OSAS) patients have a higher rate of road traffic accidents. Our study aimed to analyse any differences in OSAS patients between those who reported having had road traffic accidents and/or near misses and those who did not. METHODS: We studied 163 patients with OSAS (apnoea- hypopnoea index (AHI)>10/h) diagnosed using nocturnal polysomnography (NPSG), all drivers, 18.4% of whom drove for a living. Patients were asked at their first clinical interview to self-report road traffic accidents and/or near misses over the past 3 years which had been caused by abnormal daytime drowsiness. This allowed patients to be divided into two groups, those who had had road traffic accidents and/or near misses and those who had not. Both were compared as to age, body mass index (BMI), Epworth Sleepiness Scale (ESS), daytime PaO2 and PaCO2, Functional Outcomes of Sleep Questionnaire (FOSQ) test and NPSG data. This latter was total sleep time (TTS), sleep efficiency, sleep stages, arousal index (ARI), AHI, minimal and average SaO2, % of time with SaO2 < 90% (T90), desaturation index (ODI), total duration of apnoea-hypopnoea (TDAH) (T test). RESULTS: Group I (no road traffic accidents) No=89 patients; group II (road traffic accidents) No=74 patients. Age (years) was 57.6+/-11.8 vs. 54.7+/-10.9 (ns); male gender, 75% vs. 78.4%; ESS, 12.3+/-5.4 vs. 17.6+/-4.3 (p<0.001); BMI, (Kg/m2) 36.2+/-8.1 vs. 35.6+/-6.3 (ns); PaO2 (mmHg), 76.1+/-11.4 vs. 78.5+/-12.6 (ns); PaCO2 (mmHg), 42.6+/-5.1 vs. 42.2+/-4.7 (ns); FOSQ, 15.1+/-3.1 vs. 12.9+/-3.4 (p<0.001). NPSG data revealed differences only in AHI: 45.0+/-21.6 vs. 56.2+/-29.7 (p=0.01) and in TDAH (minutes), 98.5+/-63.7 vs. 133.3+/-83.2 (p=0,005). CONCLUSIONS: In our experience patients who had road traffic accidents and/or near misses had a more severe OSAS, with higher AHI, excessive daytime sleepiness and lower quality of life.

Four years' follow up at a smoking cessation clinic.

UNLABELLED: Smoking is an important cause of pulmonary pathology and this addiction can be regarded as a chronic, recurrent disease. The benefits of smoking cessation are unquestionable and all physicians should become more active and assertive in recommending it. AIM: To characterise the population seeking medical support for smoking cessation and understand why some successfully stop smoking and others do not. MATERIAL AND METHODS: Retrospective analysis of medical records of outpatients in follow-up between January 2003 and June 2006. Age, gender, age at smoking initiation, smoking burden (number of pack-years), associated diseases, degree of dependence (Fagerström test for nicotine addiction), prior attempts at and motivation for smoking cessation, need for cognitive/behavioural support and success and abandonment rates were evaluated. RESULTS: Five hundred and twenty six patients were studied, 50% male with an average age of 45.5+/-11.4 years. Almost half (43.1 %; n=227) of the patients started smoking before the age of 15. Average smoking burden was 35.8+/-20 pack-years although 21.4% (n=113) smoked more than 50 pack-years. Respiratory disease was present in 52.1% (COPD, 39.9% and others, 12.2%) and cardiovascular disease in 14.6% of the patients. In 46% of patients (n=242) a relevant psychiatric disorder was identified; depression (21.4%), anxiety disorder (19.4%), other dependencies (2.1%) bipolar disorder (1.5%) and schizophrenia (0.6%). The evaluation of degree of addiction revealed maximum level in 69.7% of the patients (n=380). Many patients (72.2%; n=380) reported prior attempts to quit smoking. The strongest reasons for giving up smoking were concern over health (83.5%), financial issues (8.2%) and search for better quality of life (5.7%). Most patients (81.7%; n=430) had undergone nicotine replacement therapy; skin patches (53.3%), chewing gum (1.1%) or both (45.6%). Psychopharmacological treatment included administration of sedative-hypnotics (86.5%), bupropion hydrochloride (2.3%) and antidepressants (0.6%). Seventy six patients (14%) benefited from cognitive/ behavioural support. Two hundred and twenty three patients (42.4%) were successful in giving up smoking while 219 (41.6%) abandoned follow up, the majority after the first appointment. Most patients that abandoned follow up reported lack of motivation and the price of therapy. CONCLUSIONS: The population under study had a high rate of psychiatric disorders and a high level of dependence and lack of motivation that might justify the drop-out rate. Successful treatment was associated with close follow up, behavioural support and pharmacological therapy.

Intravascular pulmonary lymphoma with good response to treatment. A case report.

Intravascular lymphoma is a very rare form of large B cell non-Hodgkin's lymphoma, characterised by the presence of lymphoma cells in the lumina of small vessels only, particularly in the capillaries. We report a 54 year-old female non-smoker, admitted to hospital for further examination of a four month long clinical condition involving high fever, night sweats, unqualified weight loss and progressive dyspnea. Patient's temperature was 38.5 degrees C, pulse 100/min and respiratory 22 cycles/min. Patient's haemoglobin was 9.4 g/dL, she had leukocytosis, elevated LDH and arterial blood gas analysis with moderate hypoxaemia (FiO2 1l/m: PaO2-63.6 mm Hg). Chest X-ray revealed diffuse interstitial changes. All the possible causes of unknown origin fever were excluded. Diagnosis was made through lung biopsy and treatment with combined chemotherapy and rituximab was prescribed leading to a 48 hours clinical remission. We present this case to show how difficult this diagnosis can be and how a good response to therapy is possible.

[Surgery of pulmonary metastasis]. / Cirurgia das metáses pulmonares.

UNLABELLED: Between April 1993 and December 2007, 92 patients underwent the complete resection of pulmonary metastases, 47 mens (51.1%) and 45 womens (49.9%). 26 patients (27.2%) had solitary pulmonary metastasis, 25 (26.1%) multiple pulmonary metastasis and 41 (44.5%) patients presented bilateral pulmonary metastasis. 42 patients (45.6%) presented pulmonary metastasis recurrence, 14 patients (15.2%) a second recurrence and 6 patients (6.5%) a third pulmonary metastasis recurrence. 49 patients (53.2%) were reoperated. The mean cumulative survival after complete resection was 78.4 months (+/- 52.5 months). There were no operative mortality. CONCLUSION: Thys work demonstrated that every attempt should be made to completely ressect all clinically detected metastases. Complete resection of pulmonary metastasis, even in recurrent disease is compatible with long-term survival.

Aberrant expression of cytoskeleton proteins in hippocampus from patients with mesial temporal lobe epilepsy.

Mesial temporal lobe epilepsy (MTLE), the most common form of epilepsy, is characterised by cytoarchitectural abnormalities including neuronal cell loss and reactive gliosis in hippocampus. Determination of aberrant cytoskeleton protein expression by proteomics techniques may help to understand pathomechanism that is still elusive. We searched for differential expression of hippocampal proteins by an analytical method based on two-dimensional gel electrophoresis (2-DE) coupled with mass spectrometry unambiguously identifying 77 proteins analysed in eight control and eight MTLE hippocampi. Proteins were quantified and we observed 18 proteins that were altered in MTLE. Cytoskeleton proteins tubulin alpha-1 chain, beta-tubulin, profilin II, neuronal tropomodulin were significantly reduced and one actin spot was missing, whereas ezrin and vinculin were significantly increased in MTLE. Proteins of several classes as e.g. antioxidant proteins (peroxiredoxins 3 and 6), chaperons (T-complex protein 1-alpha, stress-induced-phosphoprotein 1), signaling protein MAP kinase kinase 1, synaptosomal proteins (synaptotagmin I, alpha-synuclein), NAD-dependent deacetylase sirtuin-2 and 26S protease regulatory subunit 7 protein, neuronal-specific septin 3 were altered in MTLE. Taken together, the findings may represent or lead to cytoskeletal impairment; aberrant antioxidant proteins, chaperons, MAP kinase kinase 1 and NAD-dependent deacetylase sirtuin-2 may have been involved in pathogenetic mechanisms and altered synaptosomal protein expression possibly reflects synaptic impairment in MTLE.

The simple SDD.

We describe the fabrication and characterisation of the SIMPLE superheated droplet detector, a 10 g active mass device of C(2)ClF(5) in 1-3% weight concentrations currently employed in a direct search for spin-dependent astroparticle dark matter candidates.

Neutron spectrometry with large volume, heavy-loaded superheated droplet detectors: a simple spin-off.

SIMPLE is a superheated droplet detector (SDD) experiment designed to search for the evidence of spin-dependent weakly interacting neutralino dark matter (WIMPs). SDDs, a type of emulsion detector, consist of a uniform suspension of superheated liquid droplets in a compliant material such as a polymeric or aqueous gel. We report on the first neutron spectrometry experiments with SIMPLE SDDs, a spin-off of the neutron detector calibrations performed at the Portuguese Research Reactor. SIMPLE SDDs differ from most SDDs available commercially as they have a 10 times higher loading factor, containing 10(3) times more freon than their commercial counterparts and a 100 times larger volume. We have analysed the response of SIMPLE SDDs to two quasi-monochromatic neutron beams of energies 54 and 144 keV obtained with passive filters. Results show that the characteristic peaks in the fluence distribution of both filters could be determined and their energy position obtained using a simple thermodynamic relation.

Expression of proteasomal proteins in ten different tumor cell lines.

Controlled intracellular protein degradation is crucial for the maintenance of normal cell functions. An evolving concept claims that alterations in the exact timely degradation of proteins involved in growth control, apoptosis, signaling and differentiation contribute to carcinogenesis. This tightly regulated process is facilitated by the ubiquitin-26S proteasome system, a multi-enzyme complex, and inhibitors of this pathway have already been developed as potential anticancer agents. In order to generate proteasomal protein expression patterns of tumor cells and to provide an analytical tool we applied two-dimensional electrophoresis (2-DE) followed by mass spectrometry (MALDI-TOF-TOF with LIFT technology) in ten individual tumor cell lines (Saos-2; SK-N-SH; HCT-116; Caov3; A-549; HL60; A-673; A-375; MCF-7; HeLa) widely used in tumor research. A series of 39 proteasomal/proteolytic proteins was unambiguously identified by this proteomic approach, comprising proteins of the 20S core complex, the 19S regulatory complex, the 11S regulator, components of the ubiquitin pathway and proteases. Construction of individual protein maps by 2-DE and mass spectrometry provides an analytical tool and reference base for studying the pivotal importance of the proteasome and other proteolytic enzymes in tumor cells, independent of antibody availability and specificity. This preliminary database enables for designing studies in this area of research and reveals proteins that can be used as targets for new therapeutic strategies.

Leishmaniose visceral e sindrome da imunodeficiencia adquirida (SIDA): relato de um caso / Visceral leishmaniais and acquired immunodeficiency syndrome (AIDS) : case report

Os autores descrevem um caso de associacao de leishmaniose visceral, SIDA e provavel tuberculose disseminada. Discutem a possibilidade de associacao desta protozoonose e infeccao pelo virus da Imunodeficiencia Adquirida (VIH) principalmente pelo aumento de prevalencia de infeccao pelo VIH em areas endemicas para o calazar. A presenca de imunodepressao pelo VIH possibilita manifestacoes de agentes oportunistas muitas vezes associados e relacionados com as endemias prevalentes nestas regioes de subdesenvolvimento.

[Visceral leishmaniasis and acquired immunodeficiency syndrome (AIDS). Report of a case]. / Leishmaniose visceral e síndrome da imunodeficiência adquirida (SIDA). Relato de um caso.

This is a case report that describe an association of AIDS, visceral leishmaniasis and probable disseminated tuberculosis. Due to the spread of AIDS in developing areas worldwide this association would be more frequently, seen on subjects from endemic areas where this protozoonosis is prevalent. More than one opportunistic infection related with the endemic diseases of the developing regions can be associated with those immunocompromised patients.