Assessment of pain and quality of life in patients undergoing cardiac surgery: a cohort study

SUMMARY OBJECTIVE: This study aimed to evaluate postoperative pain and quality of life in patients undergoing median sternotomy. METHODS: A cohort study was carried out on a sample of 30 patients who underwent elective cardiac surgery by longitudinal median sternotomy. Patients were interviewed at Intensive Care Unit discharge and hospital discharge, when the Visual Numeric Scale and the Brief Pain Inventory were applied, and 2 weeks after hospital discharge, when the World Health Organization Quality of Life-Bref questionnaire was administered. The normality of the results was analyzed by the Shapiro-Wilk test, and Wilcoxon Rank Sum and McNemar tests were utilized for the analysis of numerical and categorical variables. For correlation between numerical variables, Spearman's linear correlation test was applied. To compare numerical variables, Mann-Whitney U and Kruskal-Wallis tests were applied. Differences between groups were considered significant when the p-value was <0.05. RESULTS: Between Intensive Care Unit and hospital discharge, there was a reduction in median pain intensity assessed by the Visual Numeric Scale from 5.0 to 2.0 (p<0.001), as well as in eight Brief Pain Inventory parameters: worst pain intensity in the last 24 h (p=0.001), analgesic relief (p=0.035), and pain felt right now (p=0.009); and in interference in daily activities (p<0.001), mood (p=0.017), ability to walk (p<0.001), relationship with other people (p=0.005), and sleep (p=0.006). Higher pain intensity at Intensive Care Unit discharge was associated with worse performance in the psychological domain of quality of life at out-of-hospital follow-up. CONCLUSION: Proper management of post-sternotomy pain in the Intensive Care Unit may imply better quality of life at out-of-hospital follow-up.

Assessment of pain and quality of life in patients undergoing cardiac surgery: a cohort study.

OBJECTIVE: This study aimed to evaluate postoperative pain and quality of life in patients undergoing median sternotomy. METHODS: A cohort study was carried out on a sample of 30 patients who underwent elective cardiac surgery by longitudinal median sternotomy. Patients were interviewed at Intensive Care Unit discharge and hospital discharge, when the Visual Numeric Scale and the Brief Pain Inventory were applied, and 2 weeks after hospital discharge, when the World Health Organization Quality of Life-Bref questionnaire was administered. The normality of the results was analyzed by the Shapiro-Wilk test, and Wilcoxon Rank Sum and McNemar tests were utilized for the analysis of numerical and categorical variables. For correlation between numerical variables, Spearman's linear correlation test was applied. To compare numerical variables, Mann-Whitney U and Kruskal-Wallis tests were applied. Differences between groups were considered significant when the p-value was <0.05. RESULTS: Between Intensive Care Unit and hospital discharge, there was a reduction in median pain intensity assessed by the Visual Numeric Scale from 5.0 to 2.0 (p<0.001), as well as in eight Brief Pain Inventory parameters: worst pain intensity in the last 24 h (p=0.001), analgesic relief (p=0.035), and pain felt right now (p=0.009); and in interference in daily activities (p<0.001), mood (p=0.017), ability to walk (p<0.001), relationship with other people (p=0.005), and sleep (p=0.006). Higher pain intensity at Intensive Care Unit discharge was associated with worse performance in the psychological domain of quality of life at out-of-hospital follow-up. CONCLUSION: Proper management of post-sternotomy pain in the Intensive Care Unit may imply better quality of life at out-of-hospital follow-up.

Sex and age differences in sensory threshold for transcutaneous electrical stimulation / Diferenças de sexo e idade no limiar sensitivo para estimulação elétrica transcutânea

Abstract Introduction Pain is one of the main symptoms prevalent in most pathologies. Transcutaneous Electrical Nerve Stimulation (TENS) represents not only a therapeutic measure, but also a mean to quantify the neurosensory and pain perception in patients with chronic pain. Objective To evaluate the relationship between sex and age with neurosensory thresholds (sensory threshold and tolerance threshold) in the application of therapeutic current in patients with chronic pain. Methods Forty-five patients with chronic pain (30 women and 15 men) aged between 24 and 87 years were selected. Each patient answered the Individual Questionnaire, McGill Pain Questionnaire (MPQ) and Beck Depression Inventory (BDI). Subsequently, the electric current was applied, through which the sensory and pain thresholds were analyzed, as well as the perception of activation of the neurosensory pathways for each individual. Data were analyzed using the SPSS 24.0 for Windows. Results There was no significant correlation (p > 0.05) between a possible depressive diagnosis and the perception of current by the sensory and pain thresholds. Regarding sex, there was a significant difference in sensory thresholds (p = 0.003) between men and women, while no statistical differences were observed between sexes for pain complaint and pain threshold (p > 0.05). For the correlational analysis, a significant correlation (p = 0.05) was identified between the variables BMI and pain tolerance threshold (r = 0.68) for females and age and sensory threshold (r = 0.65) for males. Conclusion The sex and age variables are important in the measurement of TENS parameters because they lead to significant differences in sensory and pain thresholds.

Resumo Introdução A dor é um dos principais sintomas preva-lentes na maioria das patologias. A estimulação elétrica ervosa transcutânea (TENS) se apresenta não apenas como medida terapêutica, como também um meio de quantificar a percepção neurossensitiva e dolorosa em pacientes com dores crônicas. Objetivo Avaliar a relação entre sexo e idade com os limiares neurossensitivos (limiar sensitivo e limiar de tolerância) na aplicação da corrente terapêutica TENS, em pacientes com dores crônicas. Métodos Foram selecionados 45 pacientes com dores crônicas (30 mulheres), com idade entre 24 e 87 anos. Cada paciente respondeu ao Questionário Individual, ao Questionário McGill de Dor (MPQ) e ao Inventário de Depressão de Beck (BDI). Posteriormente, aplicou-se a corrente elétrica TENS, pela qual foram analisados o limiar sensitivo e doloroso, bem como a percepção de acionamento das vias neurossensitivas para cada indivíduo. Os dados foram analisados pelo pacote SPSS 24.0 for Windows. Resultados Não houve correlação significativa (p > 0,05) entre possível diagnós-tico depressivo e a percepção da corrente pelos limiares de sensibilidade e dor. Em relação ao sexo, houve diferença significativa nos limiares sensitivos (p = 0,003) entre homens e mulheres. Já para a queixa de dor e limiar de dor, não foram observadas diferenças estatísticas entre os sexos (p > 0,05). Para as análises correlacionais, identificou-se correlação significativa (p = 0,05) entre as variáveis de índice de massa corporal e limiar de tolerância à dor (r = 0,68) para o sexo feminino e idade e limiar sensitivo (r = 0,65) paro o sexo masculino. Conclusão As diferenças identificadas entre os limiares de sensibilidade entre os sexos, onde as mulheres identificaram o estímulo elétrico significativamente primeiro que os homens, podem auxiliar nas doses de intensidade ou tipo de corrente terapêutica dos pacientes.

The role of single-nucleotide polymorphism (SNPs) in toxicity of induction chemotherapy based on cisplatin and paclitaxel in patients with advanced head and neck cancer.

BACKGROUND: Induction chemotherapy in locally-advanced head and neck squamous cell carcinoma (LAHNSCC) patients is potentially associated to serious adverse events. Biomarkers associated with toxicity could tailor its indication. This study evaluated the association between single-nucleotide polymorphisms (SNPs) in metabolic genes and toxicity to induction chemotherapy. METHODS: 59 LAHNSCC phase II clinical trial patients (NCT00959387) were assessed regarding 47 metabolic genes (366 SNPs). Toxicities were graded (CTCAE 3.0) and statistical analysis was performed. RESULTS: The SNPs rs8187710 (ABCC2) and rs1801131 (MTHFR) were associated to increased risk of gastrointestinal toxicity, whereas the SNPs rs3788007 (ABCG1) and rs4148943 (CHST3) were associated to decreased risk. Two other SNPs, rs2301159 (SLC10A2) and rs2470890 (CYP1A2), were associated with increased risk of hematological toxicity. Nevertheless, these SNPs did not remain significant after adjusting for multiple comparisons. CONCLUSIONS: This study could not demonstrate relationship between SNPs and toxicity to induction chemotherapy in LAHNSCC patients. The small number of patients may have affected the results.

Afatinib as second-line treatment in patients with recurrent/metastatic squamous cell carcinoma of the head and neck: Subgroup analyses of treatment adherence, safety and mode of afatinib administration in the LUX-Head and Neck 1 trial.

OBJECTIVES: Patients with head and neck squamous cell carcinoma (HNSCC) can experience severe symptom burden and/or difficulty swallowing, leading to problems with treatment adherence/administration. In LUX-Head and Neck 1 (LH&N1; NCT01345682), second-line afatinib improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic HNSCC. We report adherence and safety across pre-specified and additional subgroups potentially linked to afatinib PFS benefit in LH&N1 (p16 status, smoking history), and afatinib adherence, safety and efficacy by administration (oral versus feeding tube; post-hoc analysis). METHODS: Patients were randomized (2:1) to afatinib (40 mg/day) or intravenous methotrexate (40 mg/m2/week). RESULTS: Among 320 afatinib-treated and 160 methotrexate-treated patients, 83-92% and 76-92% (of patients with data available) across all subgroups took ≥80% of treatment. Across p16 status and smoking history subgroups, the most common treatment-related adverse events (AEs) were diarrhea (70-91%), rash/acne (72-84%), stomatitis (34-73%) with afatinib; and included stomatitis (39-100%), fatigue (22-50%), nausea (19-36%) with methotrexate. Dose reduction decreased AE incidence/severity. Baseline characteristics were generally similar between oral/feeding tube (n = 276/n = 46) groups. 89%/89% (of patients with data available) took ≥80% of assigned afatinib. Median PFS was 2.6 versus 2.7 months (hazard ratio: 0.997; 95% confidence interval: 0.72-1.38). The most common afatinib-related AEs were: rash/acne (74% versus 74%), diarrhea (73% versus 65%), stomatitis (40% versus 30%). CONCLUSION: Subgroup analyses of LH&N1 demonstrate that afatinib has predictable and manageable safety across patient subgroups, with high treatment adherence, and is effective via oral and feeding tube administration.

Circulating extracellular vesicle-associated TGFß3 modulates response to cytotoxic therapy in head and neck squamous cell carcinoma.

Management of locally advanced head and neck squamous cell carcinoma (HNSCC) requires a multi-prong approach comprising surgery, radiation and/or chemotherapy, yet outcomes are limited. This is largely due to a paucity of biomarkers that can predict response to specific treatment modalities. Here, we evaluated TGFß3 protein levels in extracellular vesicles (EVs) released by HNSCC cells as a predictor for response to chemoradiation therapy (CRT). To this end, specific EV-fractions were isolated from cell lines or HNSCC patient plasma, and TGFß3 protein was quantified. In patients treated with CRT, TGFß3 levels were found to be significantly higher in plasma EV-fractions or non-responders compared with responders. High levels of TGFß3 levels in Annexin V-EVs were associated with the worst progression-free survival. In vitro experiments demonstrated that TGFß3 silencing sensitized HNSCC cells to cytotoxic therapies, and this phenotype could be rescued by treatment with exogenous. In addition, specific EV-fractions shed by cisplatin-resistant cells were sufficient to transfer the resistant phenotype to sensitive cells through activation of TGFß-signaling pathway. Therefore, our data show that TGFß3 transmitted through EV plays a significant role in response to cytotoxic therapy, which can be exploited as a potential biomarker for CRT response in HNSCC patients treated with curative intent.

Afatinib vs Placebo as Adjuvant Therapy After Chemoradiotherapy in Squamous Cell Carcinoma of the Head and Neck: A Randomized Clinical Trial.

IMPORTANCE: Locoregionally advanced head and neck squamous cell cancer (HNSCC) is treated curatively; however, risk of recurrence remains high among some patients. The ERBB family blocker afatinib has shown efficacy in recurrent or metastatic HNSCC. OBJECTIVE: To assess whether afatinib therapy after definitive chemoradiotherapy (CRT) improves disease-free survival (DFS) in patients with HNSCC. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, phase 3, double-blind randomized clinical trial (LUX-Head & Neck 2) studied 617 patients from November 2, 2011, to July 4, 2016. Patients who had complete response after CRT, comprising radiotherapy with cisplatin or carboplatin, with or without resection of residual disease, for locoregionally advanced high- or intermediate-risk HNSCC of the oral cavity, hypopharynx, larynx, or oropharynx were included in the study. Data analysis was of the intention-to-treat population. INTERVENTIONS: Patients were randomized (2:1) to treatment with afatinib (40 mg/d) or placebo, stratified by nodal status (N0-2a or N2b-3) and Eastern Cooperative Oncology Group performance status (0 or 1). Treatment continued for 18 months or until disease recurrence, unacceptable adverse events, or patient withdrawal. MAIN OUTCOMES AND MEASURES: The primary end point was DFS, defined as time from the date of randomization to the date of tumor recurrence or secondary primary tumor or death from any cause. Secondary end points were DFS at 2 years, overall survival (defined as time from the date of randomization to death), and health-related quality of life. RESULTS: A total of 617 patients were studied (mean [SD] age, 58 [8.4] years; 528 male [85.6%]). Recruitment was stopped after a preplanned interim futility analysis on July 4, 2016, on recommendation from an independent data monitoring committee. Treatment was discontinued. Median DFS was 43.4 months (95% CI, 37.4 months to not estimable) in the afatinib group and not estimable (95% CI, 40.1 months to not estimable) in the placebo group (hazard ratio, 1.13; 95% CI, 0.81-1.57; stratified log-rank test P = .48). The most common grade 3 and 4 drug-related adverse effects were acneiform rash (61 [14.8%] of 411 patients in the afatinib group vs 1 [0.5%] of 206 patients in the placebo group), stomatitis (55 [13.4%] in the afatinib group vs 1 [0.5%] in the placebo group), and diarrhea (32 [7.8%] in the afatinib group vs 1 [0.5%] in the placebo group). CONCLUSIONS AND RELEVANCE: This study's findings indicate that treatment with afatinib after CRT did not improve DFS and was associated with more adverse events than placebo in patients with primary, unresected, clinically high- to intermediate-risk HNSCC. The use of adjuvant afatinib after CRT is not recommended. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01345669.

A preliminary investigation of circulating extracellular vesicles and biomarker discovery associated with treatment response in head and neck squamous cell carcinoma.

BACKGROUND: There is a paucity of plasma-based biomarkers that prospectively segregate the outcome of patients with head and neck squamous-cell carcinoma (HNSCC) treated with chemoradiation therapy (CRT). Plasma extracellular vesicles (EVs) might be an alternative source for discovery of new specific markers present in patients with HNSCC, which could help to re-direct patients to appropriate curative therapies without delay. METHODS: In order to identify new markers in plasma compartments, Cholerae toxin B chain (CTB) and Annexin V (AV) were used to isolate EVs from pooled plasma samples from patients with locally advanced HNSCC who responded (CR, n = 6) or presented incomplete response (NR, n = 6) to CRT. The crude plasma and EVs cargo were screened by antibody array. RESULTS: Of the 370 polypeptides detected, 119 proteins were specific to NR patients while 38 were exclusive of the CR subjects. The Gene Set Enrichment Analysis (GSEA) and Search Tool for the Retrieval of Interacting Genes (STRING) database analysis indicated that the content of circulating plasma EVs might have a relevant function for the tumor intercellular communication in the HNSCC patients. CONCLUSION: This study provides a list of potential markers present in plasma compartments that might contribute to the development of tools for prediction and assessment of CRT response and potentially guide therapeutic decisions in this context.

Mutational profile of Brazilian lung adenocarcinoma unveils association of EGFR mutations with high Asian ancestry and independent prognostic role of KRAS mutations.

Lung cancer is the deadliest cancer worldwide. The mutational frequency of EGFR and KRAS genes in lung adenocarcinoma varies worldwide per ethnicity and smoking. The impact of EGFR and KRAS mutations in Brazilian lung cancer remains poorly explored. Thus, we investigated the frequency of EGFR and KRAS mutations in a large Brazilian series of lung adenocarcinoma together with patients' genetic ancestry, clinicopathological and sociodemographic characteristics. The mutational frequency of EGFR was 22.7% and KRAS was 20.4%. The average ancestry proportions were 73.1% for EUR, 13.1% for AFR, 6.5% for AME and 7.3% for ASN. EGFR mutations were independently associated with never-smokers, high-Asian ancestry, and better performance status. KRAS mutations were independently associated with tobacco exposure and non-Asian ancestry. EGFR-exon 20 mutations were associated with worse outcome. The Cox regression model indicated a worse outcome for patients whose were older at diagnosis (>61 y), solid histological subtype, loss of weight (>10%), worse performance status (≥2), and presence of KRAS mutations and EGFR mutational status in TKi non-treated patients. In conclusion, we assessed the clinicopathological and ethnic impact of EGFR and KRAS mutations in the largest series reported of Brazilian lung adenocarcinomas. These findings can support future clinical strategies for Brazilian lung cancer patients.

High expression of MLANA in the plasma of patients with head and neck squamous cell carcinoma as a predictor of tumor progression.

BACKGROUND: There is a paucity of plasma-based biomarkers that predict outcome in patients with head and neck squamous cell carcinoma (HNSCC) treated with chemoradiation therapy (CRT). Here, we evaluate the prognostic potential of plasma Melanoma-Antigen Recognized by T-cells 1 (MLANA) in this setting. METHODS: MLANA expression in HNSCC lines were evaluated by reverse transcription polymerase chain reaction, whereas plasma levels were quantified using ELISA in 48 patients with locally advanced HNSCC undergoing a phase 2 trial with CRT. RESULTS: MLANA is expressed at variable levels in a panel of HNSCC lines. In plasma, levels were elevated in patients with tumor relapse compared to those without (P < .004); 73.9% of the patients expressing high plasma MLANA levels progressed with recurrent disease (P = .020). Multivariate analysis showed that plasma MLANA levels and tumor resectability were independent prognostic factors for progression free survival. CONCLUSION: Plasma MLANA expression appears to be an effective noninvasive biomarker for outcomes in patients treated with CRT, and could potentially guide therapeutic decisions in this context.

EGF+61 A>G polymorphism is not associated with lung cancer risk in the Brazilian population.

Epidermal growth factor (EGF) and its receptor (EGFR) play an important role in lung carcinogenesis. A functional single nucleotide polymorphism (SNP) in EGF promoter region (EGF+61 A>G-rs4444903) has been associated with cancer susceptibility. Yet, in lung cancer, the EGF+61 A>G role is unclear. The aim of this study was to evaluate the risk of lung cancer associated with EGF+61 A>G SNP in the Brazilian population. For that, 669 lung cancer patients and 1104 controls were analyzed. EGF+61 A>G genotype was assessed by PCR-RFLP and TaqMan genotyping assay. Both patients and controls were in Hardy-Weinberg equilibrium. As expected, uni- and multivariate analyses showed that tobacco consumption and age were significant risk factors for lung cancer. The genotype frequencies in lung cancer patients were 27.3% of AA, 47.4% of AG and 25.3% of GG, and for controls were 25.3% of AA, 51.6% of AG and 23.1% of GG. The allele frequencies were 51.1% of A and 48.9% of G for both cases and controls. No significant differences for the three genotypes (AA, AG and GG-codominant model) were observed between cases and controls. We then grouped AG and GG (recessive model) genotypes, as well as AA and AG (dominant model), and again, no significant differences were also found. This is the largest study to explore EGF+61 A>G polymorphism association with lung cancer risk and suggests that this SNP is not a risk factor for lung cancer in the Brazilian population.

Effect of Induction Chemotherapy on Swallowing in Head and Neck Cancer Patients

Objective: To evaluate the effect of induction chemotherapy on swallowing and swallowing-related quality of life of patients with oropharyngeal, laryngeal and hypopharyngeal cancer. Study design: Prospective study of 33 patients with locally advanced tumors who were eligible for treatment with neoadjuvant chemotherapy followed by radiotherapy and concurrent chemotherapy. A multidimensional assessment of swallowing was performed using the following tools: (1) Clinical analysis, numerical scale for general pain and painful swallowing, American Speech and Hearing Association (ASHA) Functional Communication Measures (FCM) swallowing assessment scales, (2) assessment of Swallowing-Related Quality of Life (The MD Anderson Dysphagia Inventory - MDADI), and (3) swallowing videofluoroscopy. Results: There was a reduction in general pain scale (p=0.021), and quality of life (emotional, functional and physical) improved from average limitation (score of 61-80) to minimal limitation (81-100) after induction chemotherapy. According to the swallowing videofluoroscopy results, 26 (78.7%) of the patients had some degree of dysphagia pre-treatment, which decreased to 21 (63.6%) after induction. Conclusion: Our results suggest that induction chemotherapy improves numerous aspects of swallowing and has a positive impact on the quality of life of pre-chemoradiotherapy patients.

Spatial analysis and temporal trends of suicide mortality in Sergipe, Brazil, 2000-2015 / Análise espacial e tendência temporal da mortalidade por suicídio em Sergipe, Brasil, 2000-2015

Abstract Background The World Health Organization defines suicide as the act of deliberately killing oneself. It is the second leading cause of death among 15-29 year olds globally. Objective To analyze the epidemiological profile and the spatial distribution of suicide deaths in the state of Sergipe. Methods We performed an ecological time-series study with data from the Brazilian Mortality Information System (Sistema de Informações sobre Mortalidade - SIM) about deaths by suicide occurring between 2000 and 2015. We considered as suicide deaths cases recorded as voluntary self-inflicted injuries. Suicide rates were estimated and age-adjusted in the population above 9 years. We analyzed temporal trends by sex and age groups using the simple linear regression model. For the spatial analysis, we performed Kernel density estimation with the software TerraView version 4.2.2. Results We identified 1,560 suicide cases in the state of Sergipe between 2000 and 2015, with a mean of 97.5 cases per year. We also observed that suicide rates in the state increased 102.3% (from 2.69/100,000 population in 2000 to 5.44 in 2015). Suicides occurred predominantly among males (1,160 cases; 74.35%), single people (1,010 cases; 64.7%), and brown-skinned people (1,039 cases; 66.6%). We observed significantly growing temporal trends in the general population, especially among male adults. Spatial analysis allowed us to draw a map that showed the regions with the highest occurrence of suicide. Conclusion We observed growing suicide trends in the state of Sergipe and the spatial analysis was an important tool that showed the areas with higher incidences of suicide.

Resumo Introduçao A Organização Mundial da Saúde define o suicídio como o ato de se matar deliberadamente. É a segunda principal causa de morte entre jovens de 15 a 29 anos no mundo. Objetivo Analisar o perfil epidemiológico e a distribuição espacial dos óbitos por suicídio no estado de Sergipe. Métodos Foi realizado estudo ecológico e de série temporal com dados do Sistema de Informações sobre Mortalidade (SIM) dos óbitos por suicídio ocorridos entre 2000 e 2015. Foram considerados suicídio os casos de mortes registrados como lesões voluntárias autoinfligidas. As taxas de suicídio foram estimadas e ajustadas por idade na população acima de 9 anos. Foram analisadas as tendências temporais por sexo e grupos etários usando o modelo de regressão linear simples. Para a análise espacial, foi realizada a estimativa de Kernel com o software TerraView 4.2.2. Resultados Foram identificados 1.560 casos de suicídio no estado de Sergipe entre 2000 e 2015, com média de 97,5 casos por ano. Observou-se um aumento de 102,3% das taxas de suicídio no estado (de 2,69/100.000 habitantes em 2000 para 5,44 em 2015). Os suicídios ocorreram predominantemente no sexo masculino (1.160 casos; 74,35%), em solteiros (1.010 casos; 64,7%) e pardos (1.039 casos; 66,6%). Foram observadas tendências temporais crescentes na população geral, especialmente entre adultos do sexo masculino. A análise espacial permitiu a construção de mapas exibindo as regiões com maiores concentrações de suicídio. Conclusão Observaram-se tendências crescentes de suicídio no estado de Sergipe e a análise espacial foi uma importante ferramenta ao mostrar áreas com maiores incidências de suicídio.

Feasibility of concomitant cisplatin with hypofractionated radiotherapy for locally advanced head and neck squamous cell carcinoma.

BACKGROUND: The evolution of radiotherapy over recent decades has reintroduced the hypofractionation for many tumor sites with similar outcomes to those of conventional fractionated radiotherapy. The use of hypofractionation in locally advanced head and neck cancer (LAHNC) has been already used, however, its use has been restricted to only a few countries. The aim of this trial was to evaluate the safety and feasibility of moderate hypofractionated radiotherapy (HYP-RT) with concomitant cisplatin (CDDP). METHODS: This single-arm trial was designed to evaluate the safety and feasibility of HYP-RT with concomitant CDDP in LAHNC. Stage III and IV patients withnonmetastatic disease were enrolled. Patients were submitted to intensity modulatedradiation therapy, which comprised 55 Gy/20 fractions to the gross tumor and44-48 Gy/20 fractions to the areas of subclinical disease. Concomitant CDDPconsisted of 4 weekly cycles of 35 mg/m2. The primary endpoints were the treatment completion rate and acute toxicity. RESULTS: Twenty patients were enrolled from January 2015 to September 2016, and 12 (60%) were classified as unresectable. All patients completed the total dose of radiotherapy, and 19 patients (95%) received at least 3 of 4 cycles of chemotherapy. The median overall treatment time was 29 days (27-34). Grade 4 toxicity was reported twice (1 fatigue and 1 lymphopenia). The rates of grade 3 dermatitis and mucositis were 30% and 40%, respectively, with spontaneous resolution. Nasogastric tubes were offered to 15 patients (75%) during treatment; 4 patients (20%) needed feeding tubes after 2 months, and only 1 patient needed a feeding tube after 12 months. CONCLUSION: HYP-RT with concomitant CDDP was considered feasible for LAHNC, and the rate of acute toxicity was comparable to that of standard concomitant chemoradiation. A feeding tube was necessary for most patients during treatment. Further investigation of this strategy is warranted. TRIAL REGISTRATION: ClinicalTrials, NCT03194061 . Registered 21 Jun 2017 - Retrospectively registered.

Spatial analysis and temporal trends of suicide mortality in Sergipe, Brazil, 2000-2015.

BACKGROUND: The World Health Organization defines suicide as the act of deliberately killing oneself. It is the second leading cause of death among 15-29 year olds globally. OBJECTIVE: To analyze the epidemiological profile and the spatial distribution of suicide deaths in the state of Sergipe. METHODS: We performed an ecological time-series study with data from the Brazilian Mortality Information System (Sistema de Informações sobre Mortalidade - SIM) about deaths by suicide occurring between 2000 and 2015. We considered as suicide deaths cases recorded as voluntary self-inflicted injuries. Suicide rates were estimated and age-adjusted in the population above 9 years. We analyzed temporal trends by sex and age groups using the simple linear regression model. For the spatial analysis, we performed Kernel density estimation with the software TerraView version 4.2.2. RESULTS: We identified 1,560 suicide cases in the state of Sergipe between 2000 and 2015, with a mean of 97.5 cases per year. We also observed that suicide rates in the state increased 102.3% (from 2.69/100,000 population in 2000 to 5.44 in 2015). Suicides occurred predominantly among males (1,160 cases; 74.35%), single people (1,010 cases; 64.7%), and brown-skinned people (1,039 cases; 66.6%). We observed significantly growing temporal trends in the general population, especially among male adults. Spatial analysis allowed us to draw a map that showed the regions with the highest occurrence of suicide. CONCLUSION: We observed growing suicide trends in the state of Sergipe and the spatial analysis was an important tool that showed the areas with higher incidences of suicide.

Lung cancer in Brazil.

Lung cancer is one of the most incident types of cancer and a leading cause of cancer mortality in Brazil. We reviewed the current status of lung cancer by searching relevant data on prevention, diagnosis, and treatment in the country. This review highlights several issues that need to be addressed, including smoking control, patient lack of awareness, late diagnosis, and disparities in the access to cancer health care facilities in Brazil. We propose strategies to help overcome these limitations and challenge health care providers, as well as the society and governmental representatives, to work together and to take a step forward in fighting lung cancer.

Lung cancer in Brazil / Câncer de pulmão no Brasil

ABSTRACT Lung cancer is one of the most incident types of cancer and a leading cause of cancer mortality in Brazil. We reviewed the current status of lung cancer by searching relevant data on prevention, diagnosis, and treatment in the country. This review highlights several issues that need to be addressed, including smoking control, patient lack of awareness, late diagnosis, and disparities in the access to cancer health care facilities in Brazil. We propose strategies to help overcome these limitations and challenge health care providers, as well as the society and governmental representatives, to work together and to take a step forward in fighting lung cancer.

RESUMO O câncer de pulmão é um dos tipos de câncer com maior incidência e uma das principais causas de mortalidade por câncer no Brasil. Revisamos a situação atual do câncer de pulmão por meio de pesquisa de dados relevantes a respeito de prevenção, diagnóstico e tratamento no país. Esta revisão mostra várias questões que precisam de atenção, tais como controle do tabagismo, educação dos pacientes, desconhecimento por parte dos pacientes, diagnóstico tardio e desigualdade de acesso ao tratamento de câncer no Brasil. Propomos estratégias para ajudar a superar essas limitações e desafiamos os profissionais de saúde, a sociedade e os representantes do governo a trabalhar em conjunto e dar um passo à frente na luta contra o câncer de pulmão.

Is Lipidomic the Answer to the Search of a Biomarker for Organ Preservation Protocol in Head and Neck Squamous Cell Carcinoma?

In the last decade organ preservation protocols based on chemoradiotherapy (CRT) has been showing the possibility of preserving function without jeopardizing survival for locally advanced head and neck squamous cell carcinoma (HNSCC). Still, only a percentage of the patients will benefit from this approach and, to date, no biomarkers are known to correctly predict these patients. More recently, modern mass spectrometry method has been used to determine metabolic profiles, and lipidomics, in particular, emerged as a new field of study in oncology and other diseases. This study aimed to analyze the lipid profile on saliva from patients undergoing to a prospective, single center, open-label, non-randomized phase II trial for organ preservation on HNSCC. The lipid analysis was performed using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS). Multivariate statistical analyses based on principal component analysis and orthogonal partial least square-discriminant analysis were applied to MALDI-TOF-MS data to visualize differences between the lipid profiles and identify potential biomarkers. The results assisted on distinguishing complete responders from non-responders to the treatment protocol. In conclusion, we demonstrated that a group of lipids is differentially abundant in saliva from HNSCC patients submitted to an organ preservation protocol, being able to differentiate responders from non-responders. These results suggest the potential use of lipid biomarkers to identify patients who may benefit from this treatment. Also, we showed that saliva testing might be routinely used in clinical practice, for being a non-invasive alternative to blood testing, besides inexpensive and easy to obtain.

AKT can modulate the in vitro response of HNSCC cells to irreversible EGFR inhibitors.

Epidermal growth factor receptor (EGFR) is overexpressed in up to 90% of head and neck squamous cell carcinoma (HNSCC) tumors. Cetuximab is the first targeted (anti-EGFR) therapy approved for the treatment of HNSCC patients. However, its efficacy is limited due to primary and secondary resistance, and there is no predict biomarkers of response. New generation of EGFR inhibitors with pan HER targeting and irreversible action, such as afatinib and allitinib, represents a significant therapeutic promise. In this study, we intend to compare the potential cytotoxicity of two anti-EGFR inhibitors (afatinib and allitinib) with cetuximab and to identify potential predictive biomarkers of response in a panel of HNSCC cell lines. The mutational analysis in the eight HNSCC cell lines revealed an EGFR mutation (p.H773Y) and gene amplification in the HN13 cells. According to the growth inhibition score (GI), allitinib was the most cytotoxic drug, followed by afatinib and finally cetuximab. The higher AKT phosphorylation level was associated with resistance to anti-EGFR agents. Therefore, we further performed drug combinations with anti-AKT agent (MK2206) and AKT1 gene editing, which demonstrated afatinib and allitinib sensitivity restored. Additionally, in silico analysis of TCGA database showed that AKT1 overexpression was present in 14.7% (41/279) of HNSCC cases, and was associated with perineural invasion in advanced stage. In conclusion, allitinib presented a greater cytotoxic profile when compared to afatinib and cetuximab. AKT pathway constitutes a predictive marker of allitinib response and combination with AKT inhibitors could restore response and increase treatment success.

MiR-21 as prognostic biomarker in head and neck squamous cell carcinoma patients undergoing an organ preservation protocol.

Despite progress in the treatment of head and neck squamous cell carcinoma (HNSCC) in recent decades, including new surgical techniques, radiotherapy advances and chemotherapy schedules, the prognosis for the affected patients has not improved at the same pace, and still, most HNSCC patients are diagnosed in advanced stages. To increase their survival, the development of better screening methods for early detection is required and appropriate tailored therapeutic interventions are desired. The aim of the present study was to evaluate miRNAs as prognostic biomarkers in patients undergoing organ preservation protocol for locally advanced HNSCC. For this purpose, we assessed the global miRNA expression profile of 15 HNSCC patients ('screening set') to identify miRNAs differentially expressed in responders and non-responders to therapy. Four miRNAs differentially expressed in HNSCC samples from the 'screening set' were validated in a different cohort of patients (47 samples - 'validation set'). The results from the 'validation set' showed that the higher expression of one of these miRNAs, miR-21, was negatively associated with the treatment response to the organ preservation protocol (p=0.029). A multivariate analysis showed that, in a model adjusted for age, tumor site, p16 immunoexpression and tumor resectability, high expression of miR-21 remained an independent predictor of poor response to the organ preservation protocol (OR=5.69; 95%CI 1.27-25.58; p=0.023), together with clinical stage IV (OR=5.05; 95%CI 1.22-20.88; p=0.025). Furthermore, considering the entire cohort, patients with high expression of miR-21 had worse survival. A multivariate Cox regression analysis also showed miR-21 (HR=2.05; 95%CI 1.05-4.02; p=0.036) and clinical stage IV (HR=3.17; 95%CI 1.49-6.77; p=0.003) as independent prognostic factors (model adjusted for age, tumor site, tumor resectability, and sets 'screening' or 'validation').In conclusion, the results of this study suggest that the evaluation of miR-21 expression could be an important tool for treatment planning and a prognosis predictior for HNSCC patients undergoing organ preservation protocols.