Upfront pembrolizumab as an effective treatment start in patients with PD-L1 ≥ 50% non-oncogene addicted non-small cell lung cancer and asymptomatic brain metastases: an exploratory analysis

Introduction The efficacy of immune checkpoint inhibitors in patients with brain metastases (BMs) from non-oncogene addicted non-small cell lung cancer (NSCLC) is under investigation. Here, we sought to determine the optimal management of NSCLCs with PD-L1 ≥ 50% and asymptomatic BMs who were treated with first-line pembrolizumab. Methods Thirty patients from 15 institutions with PD-L1 ≥ 50% NSCLC had asymptomatic BMs, and met inclusion criteria. Patients were classified based on whether they had undergone upfront local radiotherapy for BMs as well as on the type of brain radiotherapy received. Results Nine patients were treated with upfront pembrolizumab alone, 8 patients with whole-brain radiotherapy (WBRT) followed by pembrolizumab and 13 patients with stereotactic radiosurgery (SRS) followed by pembrolizumab. Patients’ characteristics were similar among the three groups of patients except for a higher number of BMs ≥ 3 in the WBRT group. One complete and 4 partial intracranial responses were observed with upfront pembrolizumab alone. The median survival was not reached for the pembrolizumab and WBRT (n = 8) groups, and it was 7.6 months for the SRS (n = 13) group (P = 0.09), with 12-month survival rates being 55.5%, 62.5%, and 23.0%, respectively. Salvage WBRT was delivered in 1 patient in the upfront pembrolizumab group and in 4 patients in the SRS group. Conclusions Upfront pembrolizumab showed efficacy in selected patients with PD-L1 ≥ 50% non-oncogene addicted NSCLC and asymptomatic BMs. Prospective studies should address whether pembrolizumab alone, and deferral of radiotherapy, could be pursued in this patient population (AU)

Upfront pembrolizumab as an effective treatment start in patients with PD-L1 ≥ 50% non-oncogene addicted non-small cell lung cancer and asymptomatic brain metastases: an exploratory analysis.

INTRODUCTION: The efficacy of immune checkpoint inhibitors in patients with brain metastases (BMs) from non-oncogene addicted non-small cell lung cancer (NSCLC) is under investigation. Here, we sought to determine the optimal management of NSCLCs with PD-L1 ≥ 50% and asymptomatic BMs who were treated with first-line pembrolizumab. METHODS: Thirty patients from 15 institutions with PD-L1 ≥ 50% NSCLC had asymptomatic BMs, and met inclusion criteria. Patients were classified based on whether they had undergone upfront local radiotherapy for BMs as well as on the type of brain radiotherapy received. RESULTS: Nine patients were treated with upfront pembrolizumab alone, 8 patients with whole-brain radiotherapy (WBRT) followed by pembrolizumab and 13 patients with stereotactic radiosurgery (SRS) followed by pembrolizumab. Patients' characteristics were similar among the three groups of patients except for a higher number of BMs ≥ 3 in the WBRT group. One complete and 4 partial intracranial responses were observed with upfront pembrolizumab alone. The median survival was not reached for the pembrolizumab and WBRT (n = 8) groups, and it was 7.6 months for the SRS (n = 13) group (P = 0.09), with 12-month survival rates being 55.5%, 62.5%, and 23.0%, respectively. Salvage WBRT was delivered in 1 patient in the upfront pembrolizumab group and in 4 patients in the SRS group. CONCLUSIONS: Upfront pembrolizumab showed efficacy in selected patients with PD-L1 ≥ 50% non-oncogene addicted NSCLC and asymptomatic BMs. Prospective studies should address whether pembrolizumab alone, and deferral of radiotherapy, could be pursued in this patient population.

Time trends, frequency, characteristics and prognosis of short-duration transient global amnesia.

BACKGROUND AND PURPOSE: Transient global amnesia (TGA) is characterized by a sudden onset of anterograde amnesia lasting up to 24 h. One major differential for TGA is transient epileptic amnesia, which typically lasts < 1 h. However, TGA can also be short in duration and little is known about the time trends, characteristics and prognosis of TGA cases lasting < 1 h. METHODS: We compared the clinical features of TGA ascertained in two independent cohort studies in Oxfordshire, UK [Oxford cohort 1977-1987 versus Oxford Vascular Study (OXVASC) 2002-2018] to determine the time trends of clinical features of TGA. Results were validated in another independent contemporary TGA cohort in Italy [Northern Umbria TGA registry (NU) 2002-2018]. We compared the risk factors, clinical features and long-term prognosis (major cardiovascular events, recurrent TGA and seizure/epilepsy) of patients presenting with episodes lasting < 1 h versus those lasting ≥ 1 h. RESULTS: Overall, 639 patients with TGA were included (114 Oxford cohort, 100 OXVASC, 425 NU). Compared with the original Oxford cohort, there were more cases with TGA lasting < 1 h in OXVASC [32 (32.0%) vs. 9 (8.8%)] and NU (11.8% vs. 8.8% in Oxford cohort). In both OXVASC and NU, patient age, vascular risk factors and clinical features were largely similar between those with TGA lasting < 1 h versus those lasting ≥ 1 h. Moreover, there was no difference in the long-term risk of seizure/epilepsy or major cardiovascular events between TGA lasting < 1 h versus TGA lasting ≥ 1 h. CONCLUSIONS: Short-duration TGA episodes (<1 h) were not uncommon and were more frequent than in earlier studies. The clinical features and long-term prognosis of short-duration TGA did not differ from more typical episodes lasting ≥ 1 h.

Regional indices of socio-economic and health inequalities: a tool for public health programming.

OBJECTIVES: The aim was to provide an affordable method of computing socio-economic (SE) deprivation indices at the regional level, in order to reveal the specific aspects of the relationship between SE inequalities and health outcomes. The Umbria Region Socio-Health Index (USHI) was computed and compared with the Italian National Deprivation Index at the Umbria regional level (NDI-U). METHODS: The USHI was computed by applying factor analysis to census tract SE variables correlated with general mortality and validated through comparison with the NDI-U. RESULTS: Overall mortality presented linear positive trends in USHI, while trends in NDI-U proved non-linear or non-significant. Similar results were obtained with regard to specific causes of death according to deprivation groups, gender and age. CONCLUSIONS: The USHI better describes a local population in terms of health-related SE status. Policy-makers could therefore adopt this method in order to obtain a better picture of SE-associated health conditions in regional populations and to target strategies for reducing health inequalities.

Changing the smoking habit: prevalence, knowledge and attitudes among Umbrian hospital healthcare professionals.

BACKGROUND: Health care professionals should work against smoking habit to promote a correct life style. This study aimed to evaluate smoking prevalence and attitudes towards tobacco among Umbrian hospital professionals in a period between 2006 and 2015, since the approbation of the law that ban smoking in hospitals and all public areas in 2003. METHODS: A cross-sectional study was carried out using a questionnaire administered in 2006, 2011 and 2015 to healthcare professionals. It consists of 53 multiple-choice questions. Potential predictors of current smoking habits were evaluated using univariate and multivariate logistic regression. RESULTS: The sample included 475 healthcare professionals. Current smokers constituted 34.53% of the sample and no significant difference (p = 0.257) emerged in prevalence over time (33.74% in 2006; 36.02% in 2011 and 33.77% in 2015). The risk of being a smoker increased by not considering the smoking habit as the main cause of preventable deaths (OR = 2.25; 95% CI: 1.47- 3.45). The strongest risk factor, which was significant in both models (p < 0.01), was being against the "No Smoking" law (OR = 18.90; 95% CI: 2.43-147.71; adjusted OR = 22.10; 95% CI: 1.85-264.78). CONCLUSIONS: The hospital staff has higher prevalence of smoking than the general population. The No Smoking law alone has been shown to be inadequate. Effective results can be achieved only by a common strategy and shared intervention programmes that are based on a workplace health promotion strategy. That for the moment has demonstrated to give interesting outcomes in modifying deep-rooted behaviour patterns.

Vacunación frente a la neumonía adquirida en la comunidad del adulto. Posicionamiento del Grupo de Neumoexpertos en Prevención / Vaccination against community acquired pneumonia in adult patients. A position paper by Neumoexpertos en Prevención

Introducción. La neumonía adquirida en la comunidad (NAC) es una causa importante de morbimortalidad en adultos. La incidencia anual de NAC en adultos en España varía entre 3 y 14 casos por 1.000 habitantes. Las guías clínicas actuales se centran básicamente en el abordaje terapéutico de la NAC más que en su prevención. El objetivo de este estudio es desarrollar y proponer una guía práctica de prevención de la NAC mediante vacunación en España en función de las vacunas y las evidencias disponibles. Métodos. Revisión bibliográfica y opinión de expertos. Resultados. Las vacunas contra el neumococo y la gripe son las principales herramientas preventivas disponibles frente a la NAC. La edad, las enfermedades crónicas y la inmunosupresión son factores de riesgo para la neumonía, por lo que estas poblaciones deben ser objetivo prioritario de vacunación. Además, se considera recomendable la vacunación antigripal y antineumocócica tanto en el adulto sano de menos de 60 años como en cualquier persona de cualquier edad con condición de riesgo para NAC. La vacuna de la gripe se administrará estacionalmente, mientras que la vacunación antineumocócica podrá administrarse en cualquier momento del año. Conclusiones. La vacunación frente a neumococo y gripe en el adulto puede contribuir a disminuir la carga de enfermedad por NAC y sus complicaciones asociadas. La evidencia disponible avala las indicaciones prioritarias establecidas en esta guía, y sería recomendable tratar de lograr una difusión e implementación amplia en la práctica de estas recomendaciones (AU)

Introduction. Community-acquired pneumonia (CAP) is a major cause of morbidity and mortality in adults. The annual incidence of CAP in adults in Spain ranges from 3 to 14 cases per 1,000 inhabitants. Current clinical guidelines primarily focus on the therapeutic approach to CAP rather than its prevention. The aim of this study is to develop and propose a practical guide for CAP prevention through vaccination in Spain according to available vaccines and evidence. Methods. A literature review and expert opinion. Results. Pneumococcal and influenza vaccines are the main preventive tools available against CAP. Age, chronic diseases, and immunosuppression are risk factors for pneumonia, so these populations should be a priority for vaccination. In addition, influenza and pneumococcal vaccination is considered advisable in healthy adults under 60 years of age, and anyone with risk condition for CAP, irrespective of age. The influenza vaccine will be administered seasonally, while pneumococcal vaccination can be administered at any time of the year. Conclusions. Vaccination against pneumococcus and influenza in adults can help to reduce the burden of CAP and its associated complications. The available evidence supports the priority indications set out in this guide, and it would be advisable to try to achieve a wide circulation and practical implementation of these recommendations (AU)

Comparison of in vitro cytotoxicity of N-acetyl and N-propionyl derivatives of phenolic thioether amines in melanoma and neuroblastoma cells and the relationship to tyrosinase and tyrosine hydroxylase enzyme activity.

Our laboratory has synthesized two new phenolic thioether amines, N-propionyl-4-S-cysteaminylphenol (N-Pr-4-S-CAP) and N[2-[(4-propionyloxyphenyl)thio]ethyl] propionamide (N,O-diPr-4-S-CAP). These compounds, along with the previously described phenolic thioether amine N-acetyl-4-S-cysteaminylphenol (N-Ac-4-S-CAP) and its acetyl form (N,O-diAc-4-S-CAP), are tyrosine-amine derivative analogues. The cytotoxicity of these compounds is thought to be tyrosinase dependent, which may make them suitable for targeted anti-melanoma therapy since only melanocytes and their malignant counterparts contain this active enzyme. To further investigate this hypothesis, we performed MTT [3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide] assays to determine the cytotoxicity of these compounds in 10 different cell lines. Specifically, we examined to what extent cytotoxicity is related to tyrosinase and tyrosine hydroxylase activity using melanoma and neuroblastoma cells, which have a common metabolic pathway using tyrosinase and tyrosine hydroxylase, respectively. The most sensitive cell line was the highly pigmented SK-MEL-23 melanoma cell line, which shows a very high tyrosinase activity with the highest melanin pigmentation. KAN and SK-NSH (two neuroblastoma cell lines), which have no tyrosinase activity but high tyrosine hydroxylase, were also sensitive. However, C32 (a non-pigmented melanoma with a lower tyrosinase activity) was also sensitive, and MeWo (a moderately pigmented melanoma with a high tyrosinase activity) was less sensitive. This in vitro study may indicate that there is a non-tyrosinase-mediated mechanism of cytotoxicity for phenolic thioether amines in addition to the tyrosinase-mediated one described previously.

[Abrikosoff's tumor of the soft palate. A case report]. / Tumor de Abrikossoff del paladar blando. Aportación de un caso.

Abrikossoff's tumor or granular cell tumor is an infrequent benign neoplasm, accurately described by Abrikossoff in 1926. We report the case of a young man, 19-year-old, affected with an Abrikossoff's tumor, sitting on the soft palate. After the timely perusal of the subject, we emphasize the peculiarity of the palatine localisation as well the importance of anatomical pathology in order to get a correct diagnosis of these neoformations of soft's parts.

[Malignant rhinosinusal inverted papilloma with orbital involvement]. / Papiloma invertido nasosinusal malignizado con invasión orbitaria.

Contribution with the case of a woman 55-year-old in whom was objectified the recurrence of an inverted rhinosinusal papilloma and, under the anatomopathological viewpoint, an epidermoid carcinoma on the inverted papilloma. Was treated with surgery and radiotherapy. Remarks on several clinical, pathological and therapeutic aspects about inverted rhinosinusal papillomata, underlying its uncertain course so characteristic of these neoformations.

Diagnostic criteria and management of subacute ventricular free wall rupture complicating acute myocardial infarction.

In this prospective study we evaluated the value of the main diagnostic criteria for postinfarction subacute rupture of the ventricular free wall. Two-dimensional echocardiograms and recordings of right atrial pressure and waveform were immediately obtained in every patient exhibiting rapid clinical and/or hemodynamic compromise in the acute infarction setting. The same protocol was applied to patients referred from other hospitals for suspected myocardial rupture. In 28 cases a subacute free wall rupture was identified. In most of the patients the diagnosis was based on the demonstration of hemopericardium and cardiac tamponade by echocardiography, cardiac catheterization and, occasionally, by pericardiocentesis. In 2 instances, the identification of intrapericardial echo densities suggesting clots, in the absence of cardiac tamponade, allowed a diagnosis of subacute rupture. Direct, but indistinct visualization of myocardial rupture was obtained in 4 cases. Among the 28 patients with this complication, 4 died while awaiting surgery and 24 underwent surgical repair (mortality rate 33%). Long-term outcome of survivors was favorable. Various myocardial lesions underlie postinfarction subacute free wall rupture. Clinical presentation varied widely. The diagnosis was based, usually but not always, on the association of hemopericardium and signs of cardiac tamponade. An organized approach to management of this complication of acute myocardial infarction was suggested.

[Kikuchi's necrotizing lymphadenitis. Clinical and pathological study of a new case]. / Linfadenitis necrotizante de Kikuchi. Estudio clínico-patológico de un nuevo caso.

Contribution to the topic with the case of a woman, 24, admitted in our ENT Department for exam and treatment of multiple right sided adenopathies of the neck. The histopathological study was consistent with diagnosis of Kikuchi's necrotizing lymphadenitis. This is a new clinicopathologic entity first described, 1972, by Kikuchi, of unknown etiology, an a picture characterized for painful cervical lymphadenitis presented in young women and healing spontaneously after 2-3 months course. We want to emphasize in this paper the scarcity of cases published and the difficulties arising when dealing with the differential diagnosis with lympho-proliferative malignancies as well.

[Cystic formations of the maxilla. Case report]. / Formaciones quísticas de los maxilares. A propósito de un caso.

The case of a man, 28, addressed to our ENT-Department complaining of pain and swelling of the left half of the face is presented. After X-Ray and tomographic study the diagnosis of an included tooth inside the maxillary sinus, accompanied by one cyst, is evidenced. In addition a canine tooth as well included on the floor of the nose and under the lower homonyme turbinate, is disclosed. Through sinusal approach, via Caldwell-Luc, are removed the lesions encountered. Then, the AA., attempt to classify the group of several cystic structures of maxillary sitting, aiming at unify the nomenclature of this pathology, and made a brief description of each type.

Selective in vivo accumulation of N-acetyl-4-S-cysteaminylphenol in B16F10 murine melanoma and enhancement of its in vitro and in vivo antimelanoma effect by combination of buthionine sulfoximine.

In order to develop a new chemotherapeutic agent based on exploitation of the specific metabolic pathway of malignant melanoma, a phenolic thioether, N-acetyl-4-S-cysteaminylphenol (NA-CAP), the substrate of melanin-forming enzyme, tyrosinase was developed. Our previous in vivo studies have clearly shown that this compound has a significant and selective melanocytotoxicity and antimelanoma effect. This study further examined the specificity of the antimelanoma effect of NA-CAP through the study of biodistribution and accumulation of NA-CAP in B16F10 melanoma-bearing mice. We also tested the antimelanoma effect of NA-CAP by combination treatment with buthionine sulfoximine on the growth of in vitro culture cells and in vivo B16F10 melanoma lung colonies. We found a selective accumulation of 14C-labeled NA-CAP into s.c. transplants and lung colonies of melanoma grown in C57BL mice. This accumulation was mediated by selective covalent binding of NA-CAP to the melanoma tissues. The combination of NA-CAP and buthionine sulfoximine significantly increased the chemosensitivity of B16F10 melanoma cells in vitro and reduced the number of in vivo melanoma lung colonies. We conclude that NA-CAP acts as an alkylating agent to melanoma tissue and that the combination of buthionine sulfoximine enhances the therapeutic index of this potent melanoma-specific drug through the depletion of tissue glutathione.

[Tumor of the mouth floor: submucosal schwannoma]. / Tumoración del suelo de la boca: schwannoma submucoso.

We report a 77 years old patient with a tumour of the floor of the mouth. The long clinical evolution and its big size--longest diameter: 7.5 cm.--, are the most stringling clinical characteristics of this case. The pathologic study showed a schwannoma, a very unusual neoplasm in this situation. We focus our discussion in pathological aspects and differential diagnosis.

[Microbiology of acute external otitis in our environment]. / Análisis microbiológico de las otitis externas agudas en nuestro medio.

The paper deals with the review done by the AA. about the microbiology of 135 acute diffuse external otitis cases, treated at their Department in one year term. In the series is emphasized the seasonal distribution, steadily uniform in the studied period, being the Pseudomonas aeruginosa and Candida albicans the paramount responsible for these otitis.

[Retropharyngeal abscess due to atypical mycobacteria. Case report]. / Absceso retrofaríngeo por micobacterias atípicas. Estudio de un caso.

It is a rare clinico-pathological infection located in the retropharyngeal space. Our contribution refer to a young man suffering this complaint caused by atypical mycobacteria, being the aim of the paper to underline the exceptional placement. The difficulties encountered in establishing the bacteriological diagnosis as well the excellent response to a combined treatment with tuberculostatics and surgery.

Breast cancer screening for women younger than 40.

The charts of 661 women aged 15 to 39 revealed that almost 50% of teenage patients had had breast screening examinations. Most of the physicians and residents involved began performing and teaching breast examination to patients in their teens. Concerned that it might do more harm than good, the Canadian guidelines do not advocate early screening.

PIP: In Canada, physicians reviewed the charts of 661 15-39 year old women who had attended the Toronto General Family Practice Unit in 1989 and, in February 1990, distributed a questionnaire to 38 physicians at the same clinic to examine the use of breast cancer screening by family physicians and at what age they begin screening. 2 women underwent a screening mammogram. 74.4% had undergone a breast examination during their visits. Physicians diagnosed an abnormality in 6 of these women, all older than 25 years old. The physicians ordered a diagnostic mammogram in all but 1 of these women. 3 women had a surgical consultation, 1 of whom had a breast biopsy. She was between 25 and 29 years old. The diagnosis is all 3 cases was benign breast problems. 6.5% of all women had a family history of breast cancer. They were not more likely to undergo a breast examination than were those with no such history, though. 41.6% of the women used oral contraceptives (OCs). They were more likely to undergo a breast examination than those who did not use OCs (p = .03). Just 1 of the physicians reported breast cancer in a sister or mother as the single most important risk factor for developing breast cancer besides age. All the physicians used screening mammography on women they considered to be at high risk of breast cancer and just 6 did for low risk women (p .000001). 84.2% were not familiar with the Canadian Task Force guidelines for clinical breast examination (i.e., it should be done annually on all women at least 40 years old). Most physicians taught women under 40 years old, and even teenagers, how to do a breast self-examination. Just 1 physician knew that the Task Force did not promote breast self-examination. It does not promote early screening, because it may do more harm than good. These findings indicated a need for a campaign to increase awareness about these guidelines and of the problems associated with screening younger women.

[Acute external otitis: retrospective study of 170 cases]. / Otitis externas agudas: estudio retrospectivo de 170 casos.

170 external otitis have been diagnosed and treated for one year (1989) in our ENT department. The etiology of the otitis was both bacterial and mycotic. The purpose of this paper is to study the clinical, therapeutic, epidemiologic and microbiologic aspects of this type of otitis.

Clinical and instrumental evaluation of the family of a patient with arrhythmogenic right ventricle dysplasia.

UNLABELLED: The aim of the present study is a clinical and instrumental evaluation of the family of a patient with arrhythmogenic right ventricle dysplasia (ARVD), initially complicated by recurrent ventricular tachycardia and later by congestive cardiac failure. Because the probability of familial involvement is very high in those cases described in the literature, the authors evaluated the patient's 3 children: 2 daughters, twenty-four and twenty years old, respectively, and a twenty-one-year-old son; his niece, thirty-one years old; and her sons three and eight years old. The authors did not evaluate his fifty-six-year-old sister, because she was affected by rheumatic mitral valve disease. All in the study were asymptomatic, and clinical examination did not show any pathologic findings. Rest ECG was normal in all cases, and the exercise stress test (Bruce protocol) showed normal functional capacity. Holter recordings were normal without arrhythmias; chest x rays showed normal cardiothoracic ratio and cardiac morphologic volume. Two-dimensional echocardiography and pulsed and continuous wave Doppler demonstrated normal sizes of cardiac chambers and normal function and morphology of cardiac valves. Nevertheless, in 4 cases (66.5%) the right ventricles showed an apical bulging with normal systolic thickness, without hypokinetic or akinetic areas or diverticular outpouchings. The authors did not find those abnormalities in 5 control subjects who were studied in the same way. CONCLUSIONS: In 4 family members (66.5%) of a patient with ARVD progressed to cardiac congestive failure, the authors found anomalies of right ventricle morphology: apical bulging, not revealed in a control group, and an absence of symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)