Immunotherapy in Non-small Cell Lung Cancer: a Review.

Immunotherapy has revolutionized the field of oncology by utilizing the body's immune system to target and eliminate cancer cells. In non-small cell lung cancer (NSCLC), immunotherapeutic agents such as immune checkpoint inhibitors (ICIs) have shown promising results. ICIs target receptors like PD-1, PD-L1, and CTLA-4 to enhance the immune response against tumors. However, resistance mechanisms to immunotherapy are not fully understood, and ongoing research aims to overcome these challenges. In the early-stage setting, neoadjuvant and adjuvant trials are investigating the efficacy of ICIs in combination with chemotherapy, with interesting results. Additionally, in the metastatic landscape of NSCLC the therapeutic options multiplied in recent years. The use of immunotherapy in NSCLC holds great promise, and future studies may provide more effective therapies and biomarkers for personalized treatment approaches.

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.

[Modification of specialised care prescriptions by Primary Healthcare physicians]. / Modificación de la prescripción procedente del segundo nivel de asistencia por parte del médico de Atención Primaria.

OBJECTIVE: To determine the percentage of new Specialist Healthcare prescriptions received and modified by Primary Healthcare physicians. DESIGN: Descriptive, cross-sectional and multi-centre study with the participation of Primary Healthcare physicians from one Madrid Health Area during 2 months. A method was established for registering the origin of the new prescriptions in the Computerised Medical Record System. In order to register new prescriptions without any change from Specialist Healthcare, the «second level¼ option was marked when the prescription was issued. A protocol was prepared and was available on the Computerized Medical Record System, so for those cases where there was a new Specialist Healthcare prescription, the Primary Healthcare physician would not issue any prescription or issue a prescription with changes as regards the original one. RESULTS: A total of 69 Primary Healthcare physicians from 15 Primary Healthcare centres registered 46,512 new prescriptions, 3,893 (8.4%) from Specialist Healthcare. From this number, 3,544 prescriptions (91.0% 95% CI: 90.1-91.9) were issued without changes, and 298 prescriptions were modified (7.7% 95% CI: 7.0-8.7). In 46 cases (1.2% 95% CI: 0.8-1.5) no prescription was issued. Some prescriptions were changed by 51% of Primary Healthcare physicians, and the median of prescriptions changed or not issued was 3. The main reason for the modification was replacement with generics. CONCLUSIONS: A high percentage of new Specialist Healthcare prescriptions are issued without any changes being made by Primary Healthcare physicians. Modifications are concentrated in half of the participating physicians. Therefore, these data suggest that this practice is not generally adopted by the professionals.

Modulation of transcription by PARP-1: consequences in carcinogenesis and inflammation.

Post-translational modification of proteins by poly(ADP-ribosyl)ation is involved in the regulation of a number of biological functions. While an 18 member superfamily of poly(ADP-ribose) polymerases (PARP)s has been described PARP-1 accounts for more than 90% of the poly(ADP-ribosyl)ating capacity of the cells. PARP-1 act as a DNA nick sensor and is activated by DNA breaks to cleave NAD(+) into nicotinamide and ADP-ribose to synthesize long branching poly(ADP-ribose) polymers (PAR) covalently attached to nuclear acceptor proteins. Whereas activation of PARP-1 by mild genotoxic stimuli facilitate DNA repair and cell survival, severe DNA damage triggers different pathways of cell death including PARP-mediated cell death through the translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus. PAR and PARP-1 have also been described as having a function in transcriptional regulation through their ability to modify chromatin-associated proteins and as a cofactor of different transcription factors, most notably NF-kappaB and AP-1. Pharmacological inhibition or genetic ablation of PARP-1 not only provided remarkable protection from tissue injury in various oxidative stress-related disease models but it result in a clear benefit in the treatment of cancer by different mechanisms including selective killing of homologous recombination-deficient tumor cells, down regulation of tumor-related gene expression and decrease in the apoptotic threshold in the co-treatment with chemo and radiotherapy. We will summarize in this review the current findings and concepts for the role of PARP-1 and poly(ADP-ribosyl)ation in the regulation of transcription, oxidative stress and carcinogenesis.

Surgery for coarctation of the aorta in infants weighing less than 2 kg.

BACKGROUND: Low- and very low-birth weight infants are now candidates for reparative cardiac surgery. Outcomes after coarctation repair have not been characterized in this patient population. METHODS: We performed a retrospective review of 18 consecutive neonates less than 2 kg who underwent repair of aortic coarctation between August 1990 and December 1999. RESULTS: Median weight was 1,330 g, and median gestational age was 31 weeks. A ventricular septal defect was present in 5 patients, and Shone's complex in 4. Sixteen patients had resection and end-to-end anastomosis, and 2 had resection and subclavian flap. Median clamp time was 15.5 minutes. One patient died during hospitalization. Two patients died late postoperatively (5-year estimated survival 80%). Mean follow-up was 28.5 months. Eight patients (44%) had a residual or recurrent coarctation, 5 underwent balloon dilation, and 3 underwent reoperation. Freedom from reintervention for recoarctation was 60% at 5 years. Shone's complex or a hypoplastic arch was an independent risk factor for decreased survival (p < 0.001). Very low birth weight was a multivariate predictor for increased risk of recoarctation (p = 0.01). CONCLUSIONS: Coarctation repair in less than 2-kg premature non-Shone's infants can be performed with a low mortality. The rate of recoarctation is higher in the very low-birth weight infants, but can be managed with low risk.

Synchronized independent lung ventilation in palliated congenital heart disease with variable sources of pulmonary blood flow.

OBJECTIVE: Presentation of two patient studies demonstrating the use of synchronized independent lung ventilation in the management of acute respiratory failure in patients with complex palliated congenital heart disease and variable sources of pulmonary blood flow. DESIGN: Clinical course of two patients. SETTING: Cardiac intensive care unit in a tertiary care, university-affiliated pediatric teaching hospital. PATIENTS: Patient 1 was a 22-yr-old woman with a single ventricle and right lung blood flow supplied by a classic Glenn shunt and left lung blood flow through a systemic-to-pulmonary artery shunt. Patient 2 was a 12-yr-old boy with tetralogy of Fallot and complete common atrioventricular canal defect with right lung blood flow supplied by a classic Glenn shunt and left lung blood flow supplied by the right ventricle. Both patients presented with acute, left-sided lung disease and hypoxemia. INTERVENTIONS: We used selective bronchial intubation via a double-lumen tracheal tube with a bronchial extension for synchronized independent lung ventilation to permit high-pressure ventilation of the abnormal left lung low-pressure ventilation of the normal right lung supplied by a Glenn shunt. Inhaled nitric oxide was administered to both patients and continued in one when improved oxygenation was observed. MEASUREMENTS AND MAIN RESULTS: Serial arterial blood gas measurements, mechanical indices of pulmonary function, and chest radiographs were closely followed. Synchronized independent lung ventilation contributed to improvements in systemic arterial blood oxygenation and alveolar ventilation allowing resumption of conventional ventilation in both patients. No adverse effects related to bronchial tube placement or maintenance occurred. CONCLUSION: Independent lung ventilation is an effective means of isolating the two lungs for differential ventilation, as well as the selective delivery of inhaled medications. In patients with unilateral lung disease and a Glenn shunt supplying the unaffected lung, selective lung ventilation allows aggressive treatment of the abnormal lung while optimizing flow through the Glenn shunt to maximize effective pulmonary blood flow, systemic oxygenation, and hemodynamics.

Interaction between ionizing radiation, estrogens and antiestrogens in the modification of tumor microenvironment in estrogen dependent multicellular spheroids.

MCF7 human breast cancer cells growing as multicellular spheroids were examined as a model of three-dimensional cellular organization. Estrogen-free medium inhibited spheroid formation. In medium containing estrogens, the antiestrogen hydroxytamoxifen decreased the spheroid growth rate. Analyses with the recursion formula after Gompertz fitting showed that the rate of exponential decrease in growth rate (alpha) was alpha 0.099 +/- 0.013 d-1, and the decrease in alpha' was 0.061 +/- 0.015 d-1 for 0.1 microM hydroxytamoxifen and control spheroids respectively. MCF7 cells which had been growth arrested in an estrogen-free medium showed a significant decrease in radiosensitivity (surviving fraction at 2 Gy, SF2 = 63%) when compared with 0.1 nM 17 beta-estradiol-treated cells (SF2 = 38%). No differences in radiosensitivity were seen in MCF7 spheroids in estrogen-supplemented medium (radiation dose necessary to control 50% of spheroids (SCD50) was 5.51 Gy; derived alpha, beta and SF2 were 0.301 +/- 0.110 Gy-1, 0.018 +/- 0.005 Gy-2, and 51% respectively) when compared with monolayer cultures in the same medium (alpha = 0.316 +/- 0.059 Gy-1, beta = 0.023 +/- 0.006 Gy-2 and SF2 = 50%). In the spheroid model, manipulating the cellular environment, i.e., with estrogen treatment, modulates sensitivity to ionizing radiation.

[Long-term evolution of immunologic and thyroid function in Graves disease according different therapeutic options]. / Evolución inmunológica y de la función tiroidea a largo plazo en la enfermedad de Graves según distintas opciones terapéuticas.

BACKGROUND: A prospective study was carried out to compare the evolution of thyroid hormones, thyroglobulin (Tg) and immunoglobulins inhibiting the binding of thyrotropin to its receptor (TBII) in patients with Graves disease treated with antithyroid drugs, radioactive iodine and subtotal thyroidectomy. METHODS: Ninety-five patients with Graves disease were studied, being distributed according to clinical criteria: Group I (n = 35) patients treated with antithyroid drugs; Group II (n = 30) patients who received 131I; and Group III (n = 30) patients treated with subtotal thyroidectomy. The thyroid hormones, Tg, antithyroglobulin antibodies and TBII were determined by radioimmunoassay (RIA), prior to treatment, and at 1, 3, 6, 12, 24, and 36 months of follow up, except in those patients from Group III who were followed up to 24 months. RESULTS: The rate of reactivation at 12 months did not significantly differ among the three groups. At 24 months a higher percentage of reactivations was observed in Group I (42%), versus Group II (16%, p < 0.001) and Group III (13%, p < 0.005). At 36 months reactivation was 30% in Group I, versus 5% in Group II (p < 0.01). Upon comparison of the TBII values among the three groups, the highest basal values corresponded to Group III with significant differences being found versus Group I (p < 0.05) and Group II (p < 0.001). TBII concentrations in the three groups studied remained high at 6 and 12 months with no significant differences being observed. Negativization was shown in the TBII at 24 months in Group II with a significant difference being seen versus Group I and III. At 36 months negativization was seen in the TBII in Group I with significant differences with respect to Group II. CONCLUSIONS: The rate of reactivation following antithyroid treatment is greater to that obtained in groups treated with iodine or surgery. The earliest negativization of TBII was obtained with radioiodine.

[Catheter management in parenteral nutrition]. / Estudio sobre manejo de catéteres en nutrición parenteral.

Following the appearance of Staphylococcus epidermidis positive hemocultures in four patients undergoing parenteral nutrition in different services, and after microbiological controls of the mixtures prepared by the Pharmacy Service in order to discard contamination during preparation, it was decided to assess the handling o catheters and central pathways by the Hospital Nursing Staff. A survey was carried out of 34 nurses, 17 each from the morning and evening shifts, from the floors with patients undergoing parenteral nutrition, representing 13.3% of all the nurses of those floors. There were five sections in the survey, with fifty-two questions referring to the introduction of catheters, change of dressing, care of the point of insertion, uses of the administrative pathway, change and handling of the parenteral nutrition bag, intravenous administration of medicines and parenteral nutrition, and withdrawal of the catheter. According to the results, 76% of central catheters are introduced in the operating theatre: once in place, the catheter is checked by X-ray to ensure that it is in the correct position, in all cases. There were major differences in the changing of dressings. The pathway for administration of the parenteral nutrition is used for a variety of functions. Medicines are administered in "Y" with the nutrient mixture, although their stability is not known. In changing the parenteral nutrition bag and the handling of the catheter, adequate sterilization measures were not taken.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone mass in females with different thyroid disorders: influence of menopausal status.

The aim of this study was to evaluate the effect of thyroid functional state on cortical and trabecular bone mineral density (BMD) (g/cm2) in premenopausal and postmenopausal women. Control subjects were used as a reference population to calculate Z-scores from patient data. In patients with active hyperthyroidism, BMD was reduced in lumbar spine (LS; P < 0.01), femoral neck (FN; P < 0.01) and Ward triangle (WT; P < 0.0001) in comparison with reference standards. In premenopausal women treated in the past for hyperthyroidism or treated at the time of study with L-thyroxine in non-TSH-suppressive doses, there was no significant decrease in BMD. In postmenopausal women with hyperthyroidism in remission, we found a significant decrease in BMD in LS (P < 0.01), FN (P < 0.05) and WT (P < 0.0001). In postmenopausal women treated with L-thyroxine (L-T4), there was a significant decrease in BMD in LS (P < 0.01) and WT (P < 0.01). There was a significant negative correlation between the cumulative dose of L-T4 and BMD in FN (r = -0.688, P < 0.05) and WT (r = -0.657, P < 0.05) in postmenopausal women. Our findings suggest that the deleterious effects of thyroid hormones on BMD are accentuated in areas consisting predominantly of trabecular bone, e.g., the LS and WT. Postmenopausal women subjected to excess thyroid hormone represent a population at greater risk for osteoporosis.

[Epidemiology of parenteral nutrition during 5 years of follow-up by a nutrition team]. / Epidemiología de la nutrición parenteral a lo largo de cinco años de seguimiento por parte de un equipo de nutrición.

The purpose of this retrospective study is to ascertain the physiopathological characteristics of patients on parenteral nutrition (PN), the types of diet used and duration of treatment. Presentation of epidemiological results and evolution of 637 adults receiving PN after a five-year period of nutritional follow-up, conducted by a Nutrition Team (NT) in hospital. For the purpose of this study, we used the Follow-Up charts of all the patients treated with PN from 1986-1990. The results obtained lead us to affirm that most patients suffered a malignant gastrointestinal process, that the duration of the PN was reduced significantly during the five-year term, mainly using dietary protocols, and that there was a gradual increase in preparations of nutrient units subjected to controls compared to the total prepared by the Pharmacy Department.

[Stability of folic acid and vitamin B12 in TPN]. / Estabilidad del ácido fólico y vitamina B12 en NPT.

The stability of folic acid (FA) in mixtures of Total Parenteral Nutrition has been and is a controversial subject, with discussion concerning the influence of factors such as temperature, light and storage time. As regards the stability of the vitamin B12, there are few studies in scientific literature. For all those reasons, we consider it necessary to make a proper study to evaluate the influence of different factors in the stability of both vitamins. The study was made on 3 liter TPN bags of the EVA type, the composition of which was as follows: AA (85g), glucosa (225g), fat (50g), Na (86mEq), K (60 mEq), Ca (15 mEq), Cl (90 mEq), P (17 mmol) acetate (149 mEq) and 10 ml of MVI-12 which contain 400 micrograms of PA and 5 micrograms of Vitamin B 12. Consideration was also given to the stability of these two vitamins in the same diet, to which were added 10 ml of a commercial preparation of oligo-elements. Six TPN bags were prepared (without oligo-elements); two of them were kept in a fridge and protected from the light, two were kept at room temperature and protected from the light and the other two at room temperature without protection from the light. Samples were taken from all the bags immediately after their preparation and after 24, 48, 72 and 96 hours. The same process was carried with other TPN bags which did contain oligo-elements. The method for determining FA and Vitamin B12 was by radioassay.(ABSTRACT TRUNCATED AT 250 WORDS)

[Diuretic isotopic urography. A method for its diagnostic use in nephro-urologic pathology in children]. / Urografía isotópico diurética (UID). Un método de aplicación diagnóstica en patología nefrourológica infantil.

In clinical pediatric urology distinction between obstructive and non obstructive dilatation of the upper urinary tract represents a difficult task for which usual procedures, both radioisotopes and conventional radiologic methods, have not discriminatory value. The aim of this investigation in to suggest a method of study that contributes to establish, in children, true diagnosis in clinical situations of hydronephrosis and to study evolution of renal function in surgical patients. Suggested technique, known an isotopic diuretic urography (UID), consists in intravenous administration of a diuretic (Furosemide, 0.4 mg/kg body weight) thirty minutes after injection of a radiotracer (I-123 Hippuran and or Tc-99-DTPA) into the vascular space and recording and analysis of variations of activity in parenchyma and renal pelvis during, at least, the following 60 m. Method described has been used in a series of 24 patients suffering from uni or bilateral hydronephrosis, with ages ranging from 2 months to 12 years. Results obtained, have shown that UID is notably superior to actually existing non-invasive methods of study of obstructive uropathy.