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Background: Endometrial cancer is of increasing concern in several countries, including Brazil, in part because of an ageing population, declines in fertility, and the increasing prevalence of obesity. Although endometrial tumors had lagged behind other cancer types in terms of treatment improvements, molecular characterization of these tumors is paving the way for novel therapies and an expansion of the therapeutic arsenal. We aimed to help medical oncologists who manage patients with recurrent or metastatic endometrial cancer in the Brazilian healthcare setting., Methods: The panel, composed of 20 medical oncologists, convened in November 2021 to address 50 multiple-choice questions on molecular testing and treatment choices. We classified the level of agreement among panelists as (1) consensus (≥75% choosing the same answer), (2) majority vote (50% to <75%), or (3) less than majority vote (<50%)., Results: Consensus was present for 25 of the 50 questions, whereas majority vote was present for an additional 23 questions. Key recommendations include molecular testing for every patient with recurrent/metastatic endometrial cancer; choice of first-line treatment according to microsatellite instability and HER2, with the addition of programmed death ligand 1 (PD-L1) and hormone receptors (HRs) for second-line therapy; carboplatin and paclitaxel as the preferred option in first-line treatment of HER2-negative disease, with the addition of trastuzumab in HER2-positive disease; pembrolizumab plus lenvatinib as a key option in second line, regardless of HER2, PD-L1 or HRs; and various recommendations regarding treatment choice for patients with distinct comorbidities., Conclusion: Despite the existing gaps in the current literature, the vast majority of issues addressed by the panel provided a level of agreement sufficient to inform clinical practice in Brazil and in other countries with similar healthcare environments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 de Andrade, Guimarães, de Melo, Nogueira-Rodrigues, Gomes, Scaranti, Maia, Morelle, Santos, Souza, de Freitas, Callegaro Filho, Paulino, Júnior, Pimenta, Santos, de Almeida, Souza, Cabral and Maluf.)

Cervical cancer (CC) is a worldwide problem, especially in low- and middle-income countries, where patients are often diagnosed with locally advanced disease. Until recently, all chemotherapy drugs achieved low ORR and 12-month overall survival (12- month OS) for advanced CC after failure for platinum compounds. Advances in systemic therapy with immunotherapy, targeted therapy, and antibody-drug conjugates (ADC) have leveraged the 12-month OS limit. Recently, immunotherapy (pembrolizumab) has become the standard of care in first-line advanced CC combined with platinum and taxane and in second-line after platinum doublet failure., Competing Interests: Conflict of interest The authors declare no potential., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: To analyze the epidemiological profile and the specific survival of patients diagnosed with tongue squamous cell carcinoma at the National Cancer Institute (INCA)., Materials and Methods: Hospital Cancer Registry System Data and Mortality Information from 2007 to 2009 were retrieved in a retrospective cohort study of patients diagnosed with tongue squamous cell carcinoma. Specific survival was estimated using the Kaplan-Meier method. The association between independent variables and the risk of death was explored in a Cox proportional hazards regression model., Results: A total of 346 patients were eligible, mostly male (77.5%), smokers (87.6%), with alcohol consumption (80.9%), with low education (65.6%), advanced staging at the time of diagnosis (71.1%), and presenting a high mortality rate (72.5%). In total, 44.5% of patients underwent a surgical approach alone or associated with another treatment modality, of which 85.1% of patients underwent neck dissection and 90.1% had free surgical margins. Specific survival was 40.6% in two years and 31.2% in five years., Conclusion: The 5-year specific survival was considered worse in individuals over 60 years, and who did not undergo surgical treatment or had surgery associated with another treatment, compared to patients undergoing isolated surgery., (© 2021 Wiley Periodicals LLC.)

Acute and chronic lung injuries are among the leading causes of mortality worldwide. Lung injury can affect several components of the respiratory system, including the airways, parenchyma, and pulmonary vasculature. Although acute and chronic lung injuries represent an enormous economic and clinical burden, currently available therapies primarily focus on alleviating disease symptoms rather than reversing and/or preventing lung pathology. Moreover, some supportive interventions, such as oxygen and mechanical ventilation, can lead to (further) deterioration of lung function and even the development of permanent injuries. Lastly, sepsis, which can originate extrapulmonary or in the respiratory system itself, contributes to many cases of lung-associated deaths. Considering these challenges, we aim to summarize molecular and cellular mechanisms, with a particular focus on airway inflammation and oxidative stress that lead to the characteristic pathophysiology of acute and chronic lung injuries. In addition, we will highlight the limitations of current therapeutic strategies and explore new antioxidant-based drug options that could potentially be effective in managing acute and chronic lung injuries.

Due to immunosuppressive cancer therapies, cancer patients diagnosed with COVID-19 have a higher chance of developing severe symptoms and present a higher mortality rate in comparison to the general population. Here we show a comparative analysis of the microbiome from naso-oropharyngeal samples of breast cancer patients with respect to SARS-CoV-2 status and identified bacteria associated with symptom severity. Total DNA of naso-oropharyngeal swabs from 74 women with or without breast cancer, positive or negative for SARS-CoV-2 were PCR-amplified for 16S-rDNA V3 and V4 regions and submitted to massive parallel sequencing. Sequencing data were analyzed with QIIME2 and taxonomic identification was performed using the q2-feature-classifier QIIME2 plugin, the Greengenes Database, and amplicon sequence variants (ASV) analysis. A total of 486 different bacteria were identified. No difference was found in taxa diversity between sample groups. Cluster analysis did not group the samples concerning SARS-CoV-2 status, breast cancer diagnosis, or symptom severity. Three taxa ( Pseudomonas , Moraxella , and Klebsiella ,) showed to be overrepresented in women with breast cancer and positive for SARS-CoV-2 when compared to the other women groups, and five bacterial groups were associated with COVID-19 severity among breast cancer patients: Staphylococcus , Staphylococcus epidermidis , Scardovia , Parasegitibacter luogiensis , and Thermomonas . The presence of Staphylococcus in COVID-19 breast cancer patients may possibly be a consequence of nosocomial infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Viana, Curty, Furtado, Singh, Bendall, Viola, de Melo, Soares and Moreira.)

Glyphosate excessive use is reported in Brazilian citrus orchards, whereas there is speculation about its consequences and the published studies are contradictory and inconclusive. This study aimed to describe the possible harmful effects by simulating glyphosate drift directly to the leaves of ∼4-yr-old citrus plants. As major results, glyphosate doses >360 g ae ha -1 increased the shikimate accumulation in leaves (up to 2.3-times above control), which was increased after a second glyphosate application (up to 3.5-times above control), even after a 240-d interval. Interestingly, shikimate accumulation was occasionally related to a dose-response of the herbicide at specific times; however, the doses had their accumulation peak on determined dates. These accumulations were directly correlated to reduced net photosynthesis even months after the glyphosate sprays. Quantum productivity based on electron transport through the photosystem II and apparent electron transport reductions up to 17% were also observed during the entire experiment course. Similarly, quantum productivity based on CO 2 assimilation of glyphosate sprayed leaves decreased up to four times compared to the control after the second application. Glyphosate doses >360 g ae ha -1 increased stomatal conductance and transpiration as the carboxylation efficiency decreased, evidencing a carbon drainage in the Calvin-Benson cycle. These metabolic and physiological disturbances suggest possible photooxidative damage and an increase in photorespiration, which may be a mitigation strategy by the citrus plants to glyphosate effects, by the cost of reducing the citrus fruit yield (up to 57%). It is concluded that glyphosate phytotoxicity damages citrus plants over time due to chronic disturbances in the shikimate pathway and photosynthesis, even when there are no symptoms. This study is the first report to demonstrate how glyphosate damages citrus trees beyond the shikimate pathway., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rodrigo Martinelli reports financial support was provided by Coordination of Higher Education Personnel Improvement. Fernando Alves de Azevedo reports financial support was provided by State of Sao Paulo Research Foundation. Dirceu de Mattos Jr reports financial support was provided by State of Sao Paulo Research Foundation. Fernando Alves de Azevedo reports financial support was provided by National Council for Scientific and Technological Development., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

To investigate similarities in the gene profile of Oral Lichen Planus and Oral Squamous Cell Carcinoma that may justify a carcinogenic potential, we analyzed the gene expression signatures of Oral Lichen Planus and Oral Squamous Cell Carcinoma in early and advanced stages. Based on gene expression data from public databases, we used a bioinformatics approach to compare expression profiles, estimate immune infiltrate composition, identify differentially and co-expressed genes, and propose putative therapeutic targets and associated drugs. Our results revealed gene expression patterns related to processes of keratinization, keratinocyte differentiation, cell proliferation and immune response in common between Oral Lichen Planus and early and advanced Oral Squamous Cell Carcinoma, with the cornified envelope formation and antigen processing cross-presentation pathways in common between Oral Lichen Planus and early Oral Squamous Cell Carcinoma. Together, these results reveal that key tumor suppressors and oncogenes such as PI3, SPRR1B and KRT17, as well as genes associated with different immune processes such as CXCL13, HIF1A and IL1B are dysregulated in OLP., (© 2022. The Author(s).)

Muscadine grape supplements (MGS) with high polyphenol content are a potential therapeutic option to combat oxidative stress; however, the precise identity and concentration of individual phenolics in commercially processed MGSs is not well defined. We probed for 17 phenolic compounds by ultra-high pressure liquid chromatography and mass spectroscopy from distinct lots of four commercially processed MGSs composed of MG seed and/or skin waste products. The total phenolic content (TPC) and antioxidant capacity were highest in a dried water-extract MGS as compared to three ground seed and/or skin products. The TPC was not different between MGS lots from individual companies and remained stable for 3 years without microbial contamination. The extract MGS had the highest concentration of epicatechin, ellagic acid, gallic acid, procyanidin B2, catechin and catechin gallate compared to the other supplements. Only ellagic acid and gallic acid were detected in all four MGSs, while catechin and catechin gallate were below detection in two supplements. Based on gram weight, only the extract MGS prevented the angiotensin II-induced increase in malondialdehyde and 4-hydroxynonenol in rat H9c2 cardiomyocytes as well as upregulated superoxide dismutase and catalase. This study demonstrates that commercial MGSs differ in phenolic composition and concentration, resulting in disparate antioxidant activity.

Muscadine grapes are abundant in dietary polyphenols, but their effect on hypertension-induced cardiac damage is limited. This study assessed whether a muscadine grape skin/seed extract supplement (MGES) prevents hypertension-induced cardiac damage and oxidative stress. Male Sprague Dawley rats were treated for four weeks with drinking water, angiotensin II (Ang II) to induce hypertension, MGES, or both Ang II and MGES. Cardiac function assessed by echocardiography showed that Ang II increased systolic blood pressure while MGES alone or in combination with Ang II had no effect. Ang II increased E/e', an indicator of left ventricular filling pressure and diastolic dysfunction, by 41% compared to Control and co-treatment with MGES prevented the Ang II-mediated increase, suggesting that the extract attenuated hypertension-induced diastolic function. Ang II infusion increased urinary 8-hydroxy-2'-deoxyguanosine and cardiac 4-hydroxynonenal and malondialdehyde, which were prevented by the extract. The antioxidant enzymes catalase and superoxide dismutase 1 activity and mRNA were increased significantly in animals treated with MGES alone or in combination with Ang II, suggesting that the extract upregulates oxidative stress defense mechanisms in cardiac tissue. Thus, MGES may serve as a medical food to protect the heart from hypertension-induced diastolic dysfunction caused in part by excessive reactive oxygen species production.

Introduction: Due to scant literature and the absence of high-level evidence, the treatment of vulvar cancer is even more challenging in countries facing limited resources, where direct application of international guidelines is difficult. Recommendations from a panel of experts convened to address some of these challenges were developed., Methods: The panel met in Rio de Janeiro in September 2019 during the International Gynecological Cancer Society congress and was composed of specialists from countries in Africa, Asia, Eastern Europe, Latin America, and the Middle East. The panel addressed 62 questions and provided recommendations for the management of early, locally advanced, recurrent, and/or metastatic vulvar cancer. Consensus was defined as at least 75% of the voting members selecting a particular recommendation, whereas a majority vote was considered when one option garnered between 50.0% and 74.9% of votes. Resource limitation was defined as any issues limiting access to qualified surgeons, contemporary imaging or radiation-oncology techniques, antineoplastic drugs, or funding for the provision of contemporary medical care., Results: Consensus was reached for nine of 62 (14.5%) questions presented to the panel, whereas a majority vote was reached for 29 (46.7%) additional questions. For the remaining questions, there was considerable heterogeneity in the recommendations., Conclusion: The development of guidelines focusing on areas of the world facing more severe resource limitations may improve medical practice and patient care., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Maluf, Zibetti, Paulino, de Melo, Racy, Ferrigno, Uson Junior, Ribeiro, Moretti, Sadalla, Nogueira Rodrigues, Carvalho, Baiocchi, Callegaro-Filho and Angioli.)

INDUCTION: chemotherapy (IC) followed by chemoradiation (CRT) is an attractive approach in high-risk locally advanced rectal cancer. Additionally, ASA has shown potential to improve outcomes alongside CRT in rectal cancer. The ICAR trial aimed to evaluate the safety and efficacy of IC followed by CRT with or without ASA on MRI tumor response., Methods: Single-center, double-blind, randomized phase II trial to evaluate induction treatment with CAPOX, followed by capecitabine-based chemoradiotherapy with ASA (arm 1) or placebo (arm 2) in high-risk stage II-III rectal adenocarcinoma staged by MRI. The primary endpoint was MRI tumor regression grade (mrTRG). Secondary endpoints were pathological response, surgical outcomes, postoperative complications, treatment tolerance, DFS, and OS., Results: Between January 2018 and August 2019, 27 patients were eligible, 25 (92.5%) completed IC, and 23 patients were randomly assigned (12 to ASA group; 11 to placebo group). In the ASA arm, 3 pts (25%) presented distant disease progression at restaging. Seven patients (30.4%) had cCR after neoadjuvant treatment. All 13 patients submitted to surgery after neoadjuvant treatment underwent R0 resections except for 1 patient with positive CRM, and 12 patients (92.3%) had sphincter preservation. After a median follow-up of 34.9 months, the 2-year DFS was 83.1% and 3-year OS was 81.5%., Conclusion: There was good compliance in both treatment arms and encouraging cCR rate. ASA during CRT was safe but failed to improve on MRI tumor response. The study was closed due to the absence of benefits., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: Nearly 85% of cervical cancer new cases are diagnosed in limited resources countries. Although several strategies have been proposed to reduce the disease burden, challenges remain to provide the best possible care. We report recommendations from an expert consensus meeting convened to address from prevention to management of cervical cancer in limited resources countries., Methods: The expert panel, composed by invited specialists from 38 developing countries in Africa, Asia, Eastern Europe, Latin America, and the Middle East, convened in Rio de Janeiro in September 2019, during the Global Meeting of the International Gynecological Cancer Society (IGCS). Panel members considered the published scientific evidence and their practical experience on the topics, as well as the perceived cost-effectiveness of, and access to, the available interventions. The focus of the recommendations was on geographic regions rather than entire countries because medical practice varies considerably in the countries represented. Resource limitation was qualified as limited access to qualified surgeons, contemporary imaging or radiation-oncology techniques, antineoplastic drugs, or overall funding for provision of state-of-the-art care. Consensus was defined as at least 75% of the voting members selecting a particular answer of the multiple-choice questionnaire, whereas the majority vote was considered as 50% to 74.9%., Results: Consensus was reached for 25 of the 121 (20.7%) questions, whereas for 54 (44.6%) questions there was one option garnering between 50% to 74.9% of votes (majority votes). For the remaining questions, considerable heterogeneity in responses was observed., Discussion: The implementation of international guidelines is challenging in countries with resource limitations or unique health-care landscapes. The development of guidelines by the health care providers in those regions is more reflective of the reality on the ground and may improve medical practice and patient care. However, challenges remain toward achieving that goal at political, economic, social, and medical levels., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Maluf, Dal Molin, de Melo, Paulino, Racy, Ferrigno, Uson Junior, Ribeiro, Moretti, Sadalla, Nogueira-Rodrigues, Carvalho, Baiocchi, Callegaro-Filho and Abu-Rustum.)

Grumixama ( Eugenia brasiliensis Lam.) is a native fruit of the Brazilian Atlantic Forest, belonging to the Myrtaceae family, which designatesthe most significant number of species with food potential. It stands out due to its phytochemical characteristics because of the presence of polyphenols and volatile organic compounds. Volatile compounds are substances released by foods that give off an aroma and influence flavor. Solid-phase microextraction is a technique that allows for low-cost, fast, and solvent-free extraction, has an affinity for numerous analytes, and is easily coupled to gas chromatography. The objectives of this work were to evaluate the efficiency of different fibers of SPME (solid-phase microextraction) in the extraction of volatile organic compounds from grumixama pulp; optimize a method for extraction time, temperature, and sample weight; and to determine the characteristic volatile profile of this fruit. For the extraction of volatile compounds, three fibers of different polarities were used: polar polyacrylate (PA) fibers, divinylbenzene/carboxyne/polydimethylsiloxane (DVB/CAR/PDMS) semipolar fibers, and polydimethylsiloxane/divinylbenzene (PDMS/DVB). Fourteen volatile organic compounds (VOCs) were identified by DVB/CAR/PDMS, six by PA, and seven by PDMS/DVB through solid-phase microextraction in the headspace mode (SPME-HS). Considering the total number of compounds identified, regardless of the fiber used, and the optimization of the method, Eugenia brasiliensis presented sesquiterpene fractions (85.7%, 83.3%, and 85.7% of total VOCs) higher than the monoterpene fractions (14.3%, 16.7%, and 14.3%) for DVB/CAR/PDMS, PA, and PDMS/DVB, respectively in its composition. In addition, it was possible to verify that the fiber DVB/CAR/PDMS presented a better efficiency due to the larger chromatographic area observed when the grumixama pulp was subjected to conditions of 75 °C, 2.0 g, and an adsorption time of 20 min.

Doxorubicin (Dox), an effective chemotherapeutic, can cause cumulative dose-dependent cardiovascular toxicity, which may manifest as vascular dysfunction leading to long-term end-organ damage. Currently, there are no effective treatments to mitigate Dox-induced vascular damage in cancer patients, particularly pediatric patients. We showed that angiotensin-(1-7) [Ang-(1-7)], an endogenous peptide hormone, mitigated cardiac damage in Dox-treated juvenile rats. In this study assessing aortic stiffness, juvenile male and female rats were administered a clinically equivalent dose of Dox (21-24 mg/kg) over 6 weeks, in the presence and absence of Ang-(1-7) [24 µg/kg/h]. Aortic function was measured using echocardiography. Ang-(1-7) reduced the Dox-mediated increase in pulse wave velocity, a measure of arterial stiffness (males: p < 0.05; females: p < 0.001) as compared in control animals. Dox decreased aortic lumen diameter (p < 0.0001) and increased wall thickness (p < 0.01) in males, which was attenuated by Ang-(1-7). In male but not female aortic arches, Dox increased media hypertrophy (p < 0.05) and reduced elastin content (p < 0.001), which were prevented by Ang-(1-7). Conversely, Dox increased fibrosis (p < 0.0001) in juvenile female rats, which was reduced by Ang-(1-7). Adjunct Ang-(1-7) prevented the Dox-induced increase in total cell and nuclear pERK1/2 in the aortic intima and media of male rats and nuclear pSMAD2 in the intimal and medial regions of the aortic arches of both sexes. These results demonstrate that Ang-(1-7) attenuated Dox-induced aortic dysfunction in both sexes of juvenile rats, albeit through different mechanisms, suggesting that Ang-(1-7) may serve as an effective adjuvant to ameliorate cardiovascular and long-term end-organ damage in pediatric patients produced by anthracyclines., (Copyright © 2022. Published by Elsevier Inc.)

Background: Few prospective studies have compared poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors to chemotherapy for the treatment of BRCA1-mutated or BRCA2-mutated ovarian carcinoma. We aimed to assess rucaparib versus platinum-based and non-platinum-based chemotherapy in this setting., Methods: In this open-label, randomised, controlled, phase 3 study (ARIEL4), conducted in 64 hospitals and cancer centres across 12 countries (Brazil, Canada, Czech Republic, Hungary, Israel, Italy, Poland, Russia, Spain, Ukraine, the UK, and the USA), we recruited patients aged 18 years and older with BRCA1-mutated or BRCA2-mutated ovarian carcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had received two or more previous chemotherapy regimens. Eligible patients were randomly assigned (2:1), using an interactive response technology and block randomisation (block size of six) and stratified by progression-free interval after the most recent platinum-containing therapy, to oral rucaparib (600 mg twice daily) or chemotherapy (administered per institutional guidelines). Patients assigned to the chemotherapy group with platinum-resistant or partially platinum-sensitive disease were given paclitaxel (starting dose 60-80 mg/m 2 on days 1, 8, and 15); those with fully platinum-sensitive disease received platinum-based chemotherapy (single-agent cisplatin or carboplatin, or platinum-doublet chemotherapy). Patients were treated in 21-day or 28-day cycles. The primary endpoint was investigator-assessed progression-free survival, assessed in the efficacy population (all randomly assigned patients with deleterious BRCA1 or BRCA2 mutations without reversion mutations), and then in the intention-to-treat population (all randomly assigned patients). Safety was assessed in all patients who received at least one dose of assigned study treatment. This study is registered with ClinicalTrials.gov, NCT02855944; enrolment is complete, and the study is ongoing., Findings: Between March 1, 2017, and Sept 24, 2020, 930 patients were screened, of whom 349 eligible patients were randomly assigned to rucaparib (n=233) or chemotherapy (n=116). Median age was 58 years (IQR 52-64) and 332 (95%) patients were White. As of data cutoff (Sept 30, 2020), median follow-up was 25·0 months (IQR 13·8-32·5). In the efficacy population (220 patients in the rucaparib group; 105 in the chemotherapy group), median progression-free survival was 7·4 months (95% CI 7·3-9·1) in the rucaparib group versus 5·7 months (5·5-7·3) in the chemotherapy group (hazard ratio [HR] 0·64 [95% CI 0·49-0·84]; p=0·0010). In the intention-to-treat population (233 in the rucaparib group; 116 in the chemotherapy group), median progression-free survival was 7·4 months (95% CI 6·7-7·9) in the rucaparib group versus 5·7 months (5·5-6·7) in the chemotherapy group (HR 0·67 [95% CI 0·52-0·86]; p=0·0017). Most treatment-emergent adverse events were grade 1 or 2. The most common grade 3 or worse treatment-emergent adverse event was anaemia or decreased haemoglobin (in 52 [22%] of 232 patients in the rucaparib group vs six [5%] of 113 in the chemotherapy group). Serious treatment-emergent adverse events occurred in 62 (27%) patients in the rucaparib group versus 13 (12%) in the chemotherapy group; serious adverse events considered related to treatment by the investigator occurred in 32 (14%) patients in the rucaparib group and six (5%) in the chemotherapy group. Three deaths were considered to be potentially related to rucaparib (one due to cardiac disorder, one due to myelodysplastic syndrome, and one with an unconfirmed cause)., Interpretation: Results from the ARIEL4 study support rucaparib as an alternative treatment option to chemotherapy for patients with relapsed, BRCA1-mutated or BRCA2-mutated ovarian carcinoma., Funding: Clovis Oncology., Competing Interests: Declaration of interests RK has received institutional funding from Clovis Oncology for this clinical trial; reports clinical trial grants from Merck Sharp & Dohme; has served as a consultant for Basilea Pharmaceutica and Shattuck Pharma; has received honoraria from Clovis Oncology, AstraZeneca, GlaxoSmithKline, and Incyte; received travelling support from AstraZeneca, GlaxoSmithKline, and Sierra Oncology; has served on data safety monitoring boards or advisory boards for Clovis Oncology, AstraZeneca, BeiGene, Eisai, GlaxoSmithKline, Incyte, iTeos Therapeutics, PharmaMar, and Roche. AF is currently at P A Herzen Cancer Research Institute, Moscow, Russia and delcares no competing interests. ACdM has received institutional funding from Clovis Oncology for this cl.inical trial; reports institutional clinical trial grants from Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Regeneron, and Roche; has received honoraria for lectures from AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Roche, and Sanofi; has served on advisory boards for AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, and Roche. YS has received honoraria from AstraZeneca, Merck Sharp & Dohme, and Roche. NC reports grants from AstraZeneca and Roche; has served as a consultant for Clovis Oncology, AstraZeneca, BIOCAD, Eisai, GlaxoSmithKline, Immunogen, Merck Sharp & Dohme/Merck, Mersana, Oncxerna, Pfizer, Pharmamar, Roche, Takeda, and Tesaro; has received honoraria from Clovis Oncology, AstraZeneca, Eisai, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, and Tesaro; received traveling support from Tesaro; and has served on data safety monitoring boards or advisory boards for Clovis Oncology, AstraZeneca, BIOCAD, Eisai, GlaxoSmithKline, Immunogen, Merck Sharp & Dohme/Merck, Mersana Therapeutics, OncXerna, Pfizer, PharmaMar, Roche, Takeda, and Tesaro. DL has received institutional funding from Clovis Oncology for this clinical trial; reports institutional research grants from Clovis Oncology, GlaxoSmithKline, and Merck Sharp & Dohme; has served as a consultant for Merck Serono and ParmaMar; has served on advisory boards for Amgen, AstraZeneca, GlaxoSmithKline, Merck Sharp & Dohme, and PharmaMar; has received travelling support from AstraZeneca, GlaxoSmithKline, PharmaMar, and Roche; has served on data safety monitoring committee for Novartis; and has served on the board of directors for the Gynecological Cancer Academy, the Gynecological Cancer InterGroup, and Multicenter Italian Trials in Ovarian Cancer and Gynecologic Malignancies. GS reports grants and research support from Merck Sharp & Dohme Italia SRL; has served as a consultant for Tesaro Bio Italy SRL and Johnson & Johnson; and has received honoraria and served on a speakers' bureau for Clovis Oncology Italy SRL. DC has served as a consultant for Akeso Biopharma, AstraZeneca, GlaxoSmithKline, Merck Sharp & Dohme, Novocure, Roche, Seagen, and SOTIO. DT, KKL, KM, and SG are employees of Clovis Oncology, and have stock and stock options. AMO reports institutional research grants from AstraZeneca; has served on an advisory board (uncompensated) for GlaxoSmithKline; has served on advisory boards and steering committees (uncompensated) for Clovis Oncology and AstraZeneca; and has served as a principal investigator on investigator-initiated trials for Clovis Oncology, AstraZeneca, and GlaxoSmithKline. All other authors declare no competing interests. Authors received writing support from Clovis Oncology during the conduct of the study. RK is currently at the Department of Oncology, Guy's and St Thomas' NHS Foundation Trust, Great Maze Pond, London, UK. AL is currently at the Department of Oncology, Almazov National Medical Research Center, Saint Petersburg, Russia. DL is currently at Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS and Catholic University of Sacred Heart, Rome, Italy., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Despite technological advances in the production processes of the materials for ceramic façade coatings, the problems of detachments are still frequent. Therefore, this work aims to investigate, through a literature review, the existing gaps related to the adhesion ability of adhesive mortars, identifying new research needs that can better explain the behavior of the material. In addition, an experimental procedure was developed to evaluate the mechanical capacity of adhesive mortars when subjected to cyclic stresses. Dynamic stress measurements are presented for several blocks of mortar and on similar blocks but with a slot drilled prior to measurements (intended to represent failure). From these data we calculated values of stress energy, elastic energy, and dissipated energy. The experimental results showed that the energy involved in the test process accompanied the load values and current stress values. The mortar samples with the previous failure absorbed and dissipated less energy than mortars without failure, showing that materials that have less energy to dissipate, are materials that have developed less capacity to adhere, that is, to keep their parts together.

Purpose: Sarcomas are a heterogeneous group of cancers classified as rare cancers and are often poorly characterized. In Brazil, little is known about the adult sarcoma burden and patients' clinical pathways., Materials and Methods: We analyzed data from the Brazilian Hospital-Based Cancer Registries System, which encompasses the entire country. The histologic criteria included sarcomas according to the International Classification of Diseases for Oncology, 3rd edition. All cases were histology-based . No central pathology review was performed. Patients < 18 years old were excluded. The variables were analyzed according to the center type, hospital patient volume (> 70 patients/year for 3 consecutive years), and geographical region. The results were based on valid data, and the missing values were reported., Results: From 2000 to 2017, a total of 312 units and 49,878 cases were identified. Missing data proportion was stable. Soft tissue sarcomas were predominant, followed by bone sarcomas and gastrointestinal stromal tumors. The Southeast concentrated on the largest number of patients (51%), of high-complexity centers (CACONs; 52%), and of patients treated at CACONs (56.9%). In all regions, the majority of patients had localized disease at diagnosis. The proportion of patients starting their treatment within 60 days from diagnosis at CACON was 59.3% and 62.3% at others. Ten hospitals achieved the established threshold for high-volume center, of which seven were CACON., Conclusion: This article highlights the need for further research on the profile of patients with sarcoma in Brazil and the importance of providing them a more effective diagnostic and therapeutic approach. This initiative is critical not just for planning treatment strategies but also to allocate medical resources and to improve quality of care and sarcoma patients outcomes., Competing Interests: Celso Abdon MelloConsulting or Advisory Role: Daichii Sankyo Andreia Cristina de MeloHonoraria: MSD Oncology, Novartis, BMS BrazilSpeakers' Bureau: BMS Brazil, MSD OncologyResearch Funding: Roche (Inst), MSD Oncology (Inst), BMS Brazil (Inst), Novartis (Inst), Clovis Oncology (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: MSD OncologyNo other potential conflicts of interest were reported.

Copaiba oleoresin has been related to properties including healing and anti-inflammatory effects, making it a potential candidate to treat oral lesions. We aimed to define the benefits related to the anti-inflammatory and healing capacity of Copaiba-based formulations on the oral cavity. This is a systematic review, conducted in PubMed, Web of Science, Scopus, Embase, Scielo, Cochrane Library, BVS, and Google Scholar databases selecting full articles in English, Portuguese, or Spanish, until March 3 rd , 2021. Pre-clinical, clinical, or randomized clinical trials, cohort and case-control in vivo studies were included; studies with other designs, in vitro, and those that did not match the PICO question were excluded (PROSPERO: CRD42021244938). Data was collected and synthesized descriptively through a specific form. The risk of bias was evaluated by SYRCLE's RoB Tool. So, five studies were included. Two reported beneficial wound healing effects, such as early reduction in the wound area and greater immature bone formation in the rats' mandibles; and two related benefic anti-inflammatory effects, like reduced acute inflammatory reaction and more advanced tissue repair stage, early formation of collagen fibrils, with greater quantity, thickness and better organization, and more expressive anti-inflammatory activity, reduction of the edema intensity and the CD68 + macrophages concentration. Based on the articles, benefits related to the wound healing and anti-inflammatory effects in the oral cavity of rats treated with Copaiba oleoresin were suggested. However, due to the limited data, future studies are necessary, especially clinical ones., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

Background: Patients with recurrent cervical cancer have a poor prognosis. Cemiplimab, the fully human programmed cell death 1 (PD-1)-blocking antibody approved to treat lung and skin cancers, has been shown to have preliminary clinical activity in this population., Methods: In this phase 3 trial, we enrolled patients who had disease progression after first-line platinum-containing chemotherapy, regardless of their programmed cell death ligand 1 (PD-L1) status. Women were randomly assigned (1:1) to receive cemiplimab (350 mg every 3 weeks) or the investigator's choice of single-agent chemotherapy. The primary end point was overall survival. Progression-free survival and safety were also assessed., Results: A total of 608 women were enrolled (304 in each group). In the overall trial population, median overall survival was longer in the cemiplimab group than in the chemotherapy group (12.0 months vs. 8.5 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.84; two-sided P<0.001). The overall survival benefit was consistent in both histologic subgroups (squamous-cell carcinoma and adenocarcinoma [including adenosquamous carcinoma]). Progression-free survival was also longer in the cemiplimab group than in the chemotherapy group in the overall population (hazard ratio for disease progression or death, 0.75; 95% CI, 0.63 to 0.89; two-sided P<0.001). In the overall population, an objective response occurred in 16.4% (95% CI, 12.5 to 21.1) of the patients in the cemiplimab group, as compared with 6.3% (95% CI, 3.8 to 9.6) in the chemotherapy group. An objective response occurred in 18% (95% CI, 11 to 28) of the cemiplimab-treated patients with PD-L1 expression greater than or equal to 1% and in 11% (95% CI, 4 to 25) of those with PD-L1 expression of less than 1%. Overall, grade 3 or higher adverse events occurred in 45.0% of the patients who received cemiplimab and in 53.4% of those who received chemotherapy., Conclusions: Survival was significantly longer with cemiplimab than with single-agent chemotherapy among patients with recurrent cervical cancer after first-line platinum-containing chemotherapy. (Funded by Regeneron Pharmaceuticals and Sanofi; EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 ClinicalTrials.gov number, NCT03257267.)., (Copyright © 2022 Massachusetts Medical Society.)

Objectives: Cervical cancer is the fourth most common cancer in women worldwide. Epidemiological and quality of life (QoL) data in patients with cervical cancer from low- and middle-income countries are scarce. We aimed to describe sociodemographic and clinicopathological characteristics and quality of life of patients with cervical cancer at diagnosis in Brazil., Methods: EVITA is a prospective cohort study of newly diagnosed patients with cervical cancer from May 2016 to December 2017, stages I-IVB, from 16 Brazilian sites representing the five Brazilian regions. At baseline, medical evaluation was performed and European Organization for Research and Treatment of Cancer (EORTC) QLQ-CX24/C30 questionnaires were administered., Results: A total of 631 patients were included. Mean±SD age was 49.3±13.9 years; skin color was non-white in 65.3%, and 68.0% had ≤8 years of formal education. In total, 85.1% of patients had a Pap smear. The main reasons reported by patients for not having a Pap smear were: lack of interest (46.9%), shame or embarrassment (19.7%), lack of knowledge (19.7%), and difficulty with access (9.1%). Most patients were diagnosed with locally advanced or metastatic disease (FIGO clinical stage II-IV in 81.8%- stage II in 35.2%, stage III in 36.1%, and stage IV in 10.5%). Patients with clinical stage III-IV had worse physical functioning and role functioning., Conclusions: Cervical cancer in Brazil is usually diagnosed at an advanced stage. Most patients have low formal education and are unemployed. Lack of interest was identified as a main reason for not having a screening test, and limited access was reported as a reason by <10% of the patients. Awareness campaigns must be a governmental priority, specially focused on the needy population, along with wide access to treatment., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To examine the prevalence and prognostic role of tumor microenvironment (TME) markers in uterine carcinosarcoma (UCS) through immunohistochemical characterization., Methods: The internal database of our institution was queried out for women with UCS who underwent surgery and thereafter postoperative chemotherapy with carboplatin and paclitaxel between January 2012 and December 2017. Tissue microarrays containing surgical samples of UCS from 57 women were assessed by immunohistochemistry for CD3, CD4, CD8, FOXP3, PD-1, PD-L1, and PD-L2., Results: The mean age was 65.3 years (range, 49 to 79 years). For the epithelial component (E), CD3&#95;E and CD4&#95;E were highly expressed in 38 (66.7%) and in 40 (70.1%) patients, respectively, and were significantly associated with more advanced stages (p = 0.038 and p = 0.025, respectively). CD8&#95;E was highly expressed in 42 (73.7%) patients, FOXP3&#95;E 16 (28.1%), PD-1&#95;E 35 (61.4%), PD-L1&#95;E 27 (47.4%) and PD-L2&#95;E 39 (68.4%). For the sarcomatous component (S), the prevalence of high expression was: CD3&#95;S 6 (10.5%), CD4&#95;S 20 (35.1%), CD8&#95;S 44 (77.2%), FOXP3&#95;S 8 (14%), PD-1&#95;S 14 (24.6%), PD-L1&#95;S 14 (24.6%) and PD-L2&#95;S 8 (14%). By multivariate analysis, the CD8/FOXP3&#95;S ratio (p = 0.026), CD4&#95;E (p = 0.010), PD-L1&#95;E (p = 0.013) and PD-L1&#95;S (p = 0.008) markers significantly influenced progression-free survival. CD4/FOXP3&#95;S ratio (p = 0.043), PD-1&#95;E (p = 0.011), PD-L1&#95;E (p = 0.036) and PD-L1&#95;S (p = 0.028) had a significant association with overall survival., Conclusion: Some differences in UCS clinical outcomes may be due to the subtype of TILs and PD-1/PD-L1 axis immune checkpoint signaling., (© 2021. The Author(s).)

Myrciaria floribunda , also known as rumberry, is a tree native to the Brazilian Atlantic Forest, where its fruits have the potential for commercial use. This study evaluates the antioxidant potential, determines the phytochemical profile, and chemically characterizes the rumberry fruit. Accessions were sampled from the Rumberry Active Germplasm Bank of the Federal University of Alagoas, Brazil. Physical characteristics, chemical characteristics, and phenolic compound content were analyzed. Chemical profile characterization was carried out using PSMS. Accessions had an average weight of 0.86 g. Accession AC137 presented a higher pulp yield (1.12 g). AC132 and AC156 had larger fruits, AC137 showed greater firmness (5.93 N), and AC160 had a higher and total phenolic content ratio (279.01 ± 11.11). Orange-colored accessions scored higher in evaluated parameters, except for AC160 for phenolic content. Thirty-two compounds were identified on positive ionization mode and 42 compounds on negative ionization mode using PSMS. Flavonoids, followed by the derivatives of benzoic acid, sugars, and phenylpropanoids, were the most prominent. Myricitrin, quercitrin, and catechin stand out as flavonoids that have been reported in previous studies with antioxidant and antimicrobial properties, in addition to health and therapeutical benefits, demonstrating the potential of the rumberry fruit.

Objective: This study aimed to examine the prevalence and prognostic role of tumor microenvironment (TME) in triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NACT) through immunohistochemical characterization., Methods: The internal database of the Brazilian National Cancer Institute for women diagnosed with TNBC who underwent NACT and thereafter curative surgery between January 2010 and December 2014 was queried out. Core biopsy specimens and tissue microarrays containing surgical samples of TNBC from 171 and 134 women, respectively, were assessed by immunohistochemistry for CD3, CD4, CD8, CD14, CD56, CD68, CD117, FOXP3, PD-1, PD-L1, and PD-L2. Immune cell profiles were analyzed and correlated with response and survival., Results: Mean age was 50.5 years, and most cases were clinical stage III [143 cases (83.6%)]. According to the multivariate analysis, only Ki67 and clinical stage significantly influenced the pattern of response to systemic treatment ( p = 0.019 and p = 0.033, respectively). None of the pre-NACT IHC markers showed a significant association with event-free survival (EFS) or overall survival (OS). As for post-NACT markers, patients with high CD14 had significantly shorter EFS ( p = 0.015), while patients with high CD3 ( p = 0.025), CD4 ( p = 0.025), CD8 ( p = 0.030), CD14 ( p = 0.015), FOXP3 ( p = 0.005), high CD4/FOXP3 ( p = 0.034), and CD8/FOXP3 ( p = 0.008) showed longer EFS. Only high post-NACT CD4 showed significantly influenced OS ( p = 0.038)., Conclusion: The present study demonstrated that the post-NACT TIL subtype can be a determining factor in the prognosis of patients with TNBC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The sponsor approved the study design and the final manuscript., (Copyright © 2021 da Silva, de Albuquerque, Rodrigues, de Mesquita, Fernandes, Thuler and de Melo.)

Construction and demolition waste (CDW) substantially contributes to environmental degradation because of its intrinsic characteristics of fast and high generation volume, low recycling rate, and low revenue margins. A systemic problem is that recycling facilities are not usually a part of a reverse supply chain (RSC) specific for CDW. This makes the recovery process costs prohibitive, especially where companies are unable to receive and process large volumes of waste continuously. This paper presents a systematic analysis of the extant literature and utilizes the results accrued to develop a conceptual RSC model for CDW. In so doing, the research seeks to provide clarity on this phenomenon, while simultaneously stimulating wider academic discourse and further research endeavours. A mixed philosophies epistemological design was adopted using both interpretavism and constructivism to undertake a qualitative systematic analysis of the literature. A process diagram was produced to represent the conceptual model (CM) and thematically group the nodes into three key swim lanes that delineate the boundaries between distribution, manufacturing, and sourcing and warehousing processes. Within each swim lane, stakeholders were incorporated as key actors. A further layer of nuanced complexity was added to illustrate the key actors involved in the process, government strategies, and activity flow paths. This novel CM offers both practical and theoretical contributions to existing knowledge and signposts a future research direction. Such work will demystify reverse logistics for managing CDW, and assist government policy-makers to develop informed policies that reduce the negative environmental impact of construction activities.

Objective: The aim of this systematic review was to describe the epidemiology, diagnostic criteria, differential diagnosis, treatment, prognostic factors, and treatment outcomes of secretory carcinoma., Study Design: A comprehensive search of Lilacs, PubMed, Science Direct, and Web of Science databases was conducted to identify all case reports, letter to the editor, and histopathologic reclassifications regarding salivary gland secretory carcinoma published in English, Spanish, French, and Portuguese., Results: The final analysis included 119 studies, which totaled 642 secretory carcinoma diagnoses, with 239 case reports and 403 diagnostic reclassifications, mostly in the United States. The age range was 5 to 87 years, and cases were predominantly in males (58.7%) and mostly affecting the parotid glands (73.7%). The disease usually presents as a slow-growing, painless mass. The main differential diagnosis is acinic cell carcinoma, and the tumor is usually treated with surgery. The prognosis is considered favorable, although there have been reports of local recurrences, distant metastases, and deaths., Conclusions: It is important that clinicians become aware of this salivary gland neoplasm and report clinical data, clinical course, management and long-term follow-up. There is an urgent need to conduct more clinical trials, especially on tropomyosin receptor kinase (TRK) inhibitors and other potential target therapy modalities., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Inflammation plays a crucial role in the initiation and progression of many cancers. This study aimed to investigate the utility of pretreatmentneutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), derived neutrophil-lymphocyte ratio (dNLR), and a combination of PLR and NLR in predicting the risk of death according to clinical staging in cervical cancer (CC) patients., Methods: A cohort study of women with CC, diagnosed and treated at a single cancer referral center in Brazil, from 2006 to 2009. A multivariate Cox regression analysis and ROC curve analysis accessed the predictive value of inflammatory response biomarkers in overall survival (OS). The median values of the biomarkers were used as cut-off points., Results: A total of 1,266 patients were included in the study, 76.0% with locally advanced disease. After adjusting for clinical variables, NLR > 2.57, PLR ≥ 146.70, dNLR ≥ 1.778 and PLR + NLR in combination had equivalent performance in predicting worse OS, but only among patients with locally advanced disease (adjusted Hazard Ratio [aHR] = 1.453, 95% Confidence Interval [CI] = 1.227-1.722; p < 0.001; aHR = 1.429; 95% CI = 1.209-1.688; p < 0.001; aHR = 1.486, 95% CI = 1.257-1.756, p < 0.001, aHR = 1.731; 95% CI = 1.411-2.123; p < 0.001, respectively)., Conclusion: In conclusion, PLR, NLR, dNLR and PLR + NLR in combination presented equivalent performance in predicting OS in locally advanced CC patients. They are simple and readily available from routine blood tests, not entailing additional costs. PLR, NLR, dNLR and PLR + NLR in combination are strong prognostic biomarkers candidates in locally advanced CC and should be further explored in prospective trials., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Anti-programmed death-1 agents are an established option for advanced melanoma, but the anti-programmed death-ligand 1 (anti-PD-L1) antibody atezolizumab, an agent approved for the treatment of multiple solid tumors, was not previously evaluated. This phase 1b study cohort (NCT03178851; cohort C) evaluated first-line atezolizumab 1,200 mg every 3 weeks in adults with BRAF V600 wild-type, histologically confirmed, advanced or metastatic melanoma. The co-primary end points were confirmed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors v1.1 and disease control rate (DCR = complete response [CR] +partial response [PR] +stable disease [SD] at 16 weeks). Of 52 enrolled patients, most had lactate dehydrogenase levels lower than the upper limit of normal (77%) and PD-L1-positive tumors (55%). Investigator-assessed confirmed ORR was 35% (95% CI, 22%-49%) and included three CRs (6%) and 15 PRs (29%); DCR was 46%. Median investigator-assessed progression-free survival was 3.7 months (95% CI, 2.1-7.3). The most common any-grade adverse events were anemia (27%), headache (19%), hypertension (19%), constipation (17%), diarrhea (17%), hypothyroidism (17%), asthenia (15%), and pain in extremity (15%). First-line atezolizumab monotherapy is safe and tolerable and has antitumor activity in patients with BRAF V600 wild-type advanced or metastatic melanoma., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Brazil is a country of continental dimensions with great potential for the development of clinical studies across the whole territory to tackle the needs of the population. It is therefore important to obtain the national profile of clinical trials in order to identify local strengths and weaknesses in terms of productivity and study application. Thus, this paper aims to highlight the profiles of clinical studies on cancer developed and sponsored by hospitals, institutes, universities and international institutions in Brazil between 1997 and 2015., Methods: This is a retrospective and analytical study in which the content analysis method of Laurence Bardin was used. Data were collected from the clinicaltrials.govdatabase, where 783 clinical studies on cancer prevention, diagnosis and treatment were found; 188 (24 %) of these corresponded to national initiatives and 595 (76 %) to international initiatives., Results: The results show an increase in the number of national clinical studies, in particular phase III studies. There is a clear absence of national clinical studies focusing on the development of new chemical and biotechnological products in oncology., Conclusion: The results indicate a regional imbalance in the distribution of national and international clinical trials., Policy Summary: The present study aims to improve understanding of the profile of clinical studies registered in Brazil and to draw attention to the improvements needed in the health sector's productivity to address the national demand., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

There has been high interest in the use of traditional medicines for COVID-19 from early in the course of the pandemic. Significant advances in the science of ethnopharmacology have helped to introduce chemical entities identified from natural sources into modern medicine. However, the wider integration of natural products into the modern drug discovery process will require enhanced collaboration amongst the pharmaceutical industry, academic research units, regulatory bodies, ethics review committees and local, regional, continental and international organizations. Revisiting this topic holds promise of benefit for both the current and future pandemics., (© 2021 British Pharmacological Society.)

General and local anaesthetics alter tumour behaviour in experimental models. Objectives: To investigate the relationship between general anaesthesia and recurrence or survival in patients who received surgery for malignant melanoma. A meta-analysis was performed based on a comprehensive literature search. Controlled and observational studies of patients undergoing surgery for melanoma under general anaesthesia, compared with other types of anaesthesia, were included. The primary outcomes were overall survival and disease-free survival. The secondary outcomes included cancer-specific survival, cost analysis, and adverse events. Risk of bias was assessed. Individual study information was summarized. The meta-analysis was performed using a random-effects model. The GRADE approach was used to summarise the certainty of evidence. Eight studies were included (n = 5,832). The use of general anaesthesia was not associated with any statistical difference in overall survival (p = 0.087; 1 NRS; n= 104; very low certainty of evidence) or disease-free survival (HR: 1.266; 95% CI: 0.904-1.773; p = 0.169; 1 NRS; n = 281; very low certainty of evidence). However, general anaesthesia was associated with worse melanoma-specific survival (HR: 1.46; 95% CI: 1.22-1.68: p < 0.00001; 3 NRS; n = 4654; low certainty of evidence). Three studies reported increased intraoperative costs associated with the use of general anaesthesia (3 NRT; n = 513; very low certainty of evidence). No study adequately reported other primary or secondary outcomes. General anaesthesia may reduce melanoma-specific survival in patients undergoing surgery for treatment of cutaneous melanoma. We are uncertain whether general anaesthesia impacts the other reported outcomes.

Melanoma is considered the most lethal skin cancer and its incidence has increased during the past decades. About 10 % of cases are classified as hereditary melanoma. Genetic predisposition usually manifests itself clinically as early onset and multiple cutaneous melanomas. Several genes have been identified as involved to melanoma susceptibility, some of them still with unknown clinical relevance. Beyond melanoma, the affected families are also more prone to develop other malignancies, such as pancreatic cancer. The identification of risk families and involved genes is of great importance, since different forms of oncological surveillance are recommended. However, well established guidelines to standardize both the selection of individuals and the genetic panel to be requested are still lacking. Given the importance of the genetic counseling and testing in the context of clinical suspicion of hereditary melanoma, this paper aims to review the literature regarding genetic panel indications worldwide., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aims: The current study aims to present epidemiologic changes and clinical aspects of Merkel cell carcinoma (MCC) in Brazil. Methods: Data were collected from the Brazilian Population-Based Cancer Registries (2000-2015) and Hospital-Based Cancer Registries (2000-2017). Results: The average age-standardized incidence rates significantly increased in men between the years 2000 (0.31/1,000,000) and 2015 (1.21/1,000,000), with an annual percentage change of 9.4 (95% CI: 4.7-14.4; p < 0.001). In women, the incidence rates rose insignificantly in the period with an annual percentage change of 3.1 (95% CI: 0.0-6.2; p < 0.10). From the hospital-based database, 881 MCC patients were identified. Most of the patients were females (51.2%), aged >60 years (82.2%), White (67.6%) and diagnosed at stages III or IV (50.5%). Conclusions: A key aspect of public health promotion is to understand the incidence and morbidity of MCC.

Purpose: To evaluate hemostasis of the ovarian arteriovenous complex (OAVC) in relation to surgical time, practicality and feasibility in three ovariohysterectomy (OH) techniques for queens., Methods: The experiment was performed on 21 female cats aged between six months and seven years, randomly arranged into three groups in a completely randomized design. Group one was spayed using the conventional three-clamp technique, group two using the OAVC knotting technique, and group three using the ovarian pedicle rotation technique. The student's t-test and Tukey's test were used to compare the mean surgical times., Results: The conventional technique, which uses thread wires, was more laborious and required longer execution time compared to the other two techniques. The OAVC knotting technique was the fastest and had the least blood loss., Conclusions: The use of techniques that do not use synthetic materials for OAVC hemostasis was proven to be appropriate in castration projects, provided that the surgical team has sufficient training.

Epidermal growth factor receptor (EGFR) signaling and components of the fibrinolytic system, including urokinase-type plasminogen activator (uPA) and thrombomodulin (TM), have been implicated in tumor progression. In the present study, we employed cBioPortal platform (http://www.cbioportal.org/), cancer cell lines, and an in vivo model of immunocompromised mice to evaluate a possible cooperation between EGFR signaling, uPA, and TM expression/function in the context of cervical cancer. cBioPortal analysis revealed that EGFR, uPA, and TM are positively correlated in tumor samples of cervical cancer patients, showing a negative prognostic impact. Aggressive human cervical cancer cells (CASKI) presented higher gene expression levels of EGFR, uPA, and TM compared to its less aggressive counterpart (C-33A cells). EGFR induces uPA expression in CASKI cells through both PI3K-Akt and MEK1/2-ERK1/2 downstream effectors, whereas TM expression induced by EGFR was dependent on PI3K/Akt signaling alone. uPA induced cell-morphology modifications and cell migration in an EGFR-dependent and -independent manner, respectively. Finally, treatment with cetuximab reduced in vivo CASKI xenografted-tumor growth in nude mice, and decreased intratumoral uPA expression, while TM expression was unaltered. In conclusion, we showed that EGFR signaling regulated expression of the fibrinolytic system component uPA in both in vitro and in vivo settings, while uPA also participated in cell-morphology modifications and migration in a human cervical cancer model.

The Brazilian National Health System (BR-NHS) is one of the largest public health systems in the world. In 2019 Brazil had 114,352 community pharmacies (76.8% private owned), that represent the first point of access to healthcare in Brazil due to their wide distribution. Unfortunately, from the government's point of view, the main expected activity of private and public community pharmacies is related to dispensing medicines and other health products. Public community pharmacies can be part of a healthcare center or be in a separate location, sometimes without the presence of a pharmacist. Pharmacists working in these separated locations do not have access to patients' medical records, and they have difficulty in accessing other members of the patient care team. Pharmacists working in public pharmacies located in healthcare centers may have access to patients' medical records, but pharmacy activities are frequently under other professional's supervision (e.g., nurses). Private pharmacies are usually open 24/7 with the presence of a pharmacist for 8 hours on business days. Private community pharmacies have a very limited integration in the BR-NHS and pharmacists are the third largest healthcare workforce in Brazil with more than 221,000 registered in the Brazilian Federal Pharmacist Association [CFF - Conselho Federal de Farmácia]. A University degree in pharmacy is the only requirement to entry into the profession, without any proficiency exam for maintenance or career progression. The Brazilian pharmacist's annual income is ranked as the 2 nd better-paid profession with an annual average income of EUR 5,502.37 (in 2020). Description of clinical activities for pharmacies by the CFF increased in the recent years, however there is still a long way to effectively implement them into practice., Competing Interests: CONFLICT OF INTEREST All authors declare no conflicts of interest in this paper., (Copyright: © The Authors.)

Purpose: COVID-19 has affected cancer care worldwide. Clinical trials are an important alternative for the treatment of oncologic patients, especially in Latin America, where trials can be the only opportunity for some of them to access novel and, sometimes, standard treatments., Methods: This was a cross-sectional study, in which a 22-question survey regarding the impact of the COVID-19 pandemic on oncology clinical trials was sent to 350 representatives of research programs in selected Latin American institutions, members of the Latin American Cooperative Oncology Group., Results: There were 90 research centers participating in the survey, with 70 of them from Brazil. The majority were partly private or fully private (n = 77; 85.6%) and had confirmed COVID-19 cases at the institution (n = 57; 63.3%). Accruals were suspended at least for some studies in 80% (n = 72) of the responses, mostly because of sponsors' decision. Clinical trials' routine was affected by medical visits cancelation, reduction of patients' attendance, reduction of other specialties' availability, and/or alterations on follow-up processes. Formal COVID-19 mitigation policies were adopted in 96.7% of the centers, including remote monitoring and remote site initiation visits, telemedicine visits, reduction of research team workdays or home office, special consent procedures, shipment of oral drugs directly to patients' home, and increase in outpatient diagnostic studies. Importantly, some of these changes were suggested to be part of future oncology clinical trials' routine, particularly the ones regarding remote methods, such as telemedicine., Conclusion: To our knowledge, this was the first survey to evaluate the impact of COVID-19 on Latin American oncology clinical trials. The results are consistent with surveys from other world regions. These findings may endorse improvements in clinical trials' processes and management in the postpandemic period., Competing Interests: Aline B. Lara GongoraHonoraria: MSD Oncology, Amgen Denis L. JardimHonoraria: Janssen-Cilag, Roche/Genentech, Astellas Pharma, MSD Oncology, BMS Brazil, Pfizer, Libbs, MerckConsulting or Advisory Role: Janssen-Cilag, Pfizer, MSDTravel, Accommodations, Expenses: MSD, BMS Brazil, Janssen-Cilag Angelica Nogueira-RodriguesHonoraria: Roche, MSD, AstraZenecaConsulting or Advisory Role: Roche, AstraZeneca, MSD, Eisai Carlos H. BarriosStock and Other Ownership Interests: Biomarker, MedSIR, TummiHonoraria: Novartis, Roche/Genentech, Pfizer, GlaxoSmithKline, Sanofi, Boehringer Ingelheim, Eisai, MSD, Lilly, Bayer, AstraZeneca, Zodiac PharmaConsulting or Advisory Role: Boehringer Ingelheim, Roche/Genentech, Novartis, GlaxoSmithKline, Eisai, Pfizer, AstraZeneca, Libbs, MSD Oncology, United Medical, LillyResearch Funding: Pfizer, Novartis, Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Roche/Genentech, Lilly, Sanofi, Taiho Pharmaceutical, Mylan, Merrimack, Merck, AbbVie, Astellas Pharma, Biomarin, Bristol Myers Squibb, Daiichi Sankyo, Abraxis BioScience, AB Science, Asana Biosciences, Medivation, Exelixis, ImClone Systems, LEO Pharma, Millennium, Janssen, Clinica Atlantis, INC Research, Halozyme, Covance, Celgene, inVentiv Health, Merck KGaA, Shanghai Henlius Biotech, Polyphor, PharmaMarTravel, Accommodations, Expenses: Roche/Genentech, Novartis, Pfizer, BMS Brazil, AstraZeneca, MSD Oncology, Lilly Fernando MalufHonoraria: Janssen Oncology, Astellas Pharma, Bayer Schering Pharma, Merck Sharp & Dohme, Roche/Genentech, BMS Brazil, Ipsen, Sanofi/Aventis, Merck Serono, AstraZenecaConsulting or Advisory Role: Janssen Oncology, Astellas Pharma, Bayer Schering Pharma, Merck Sharp & Dohme, Roche/Genentech, BMS Brazil, Ipsen, Merck Serono, AstraZenecaResearch Funding: Janssen-Cilag, Merck Sharp & DohmeTravel, Accommodations, Expenses: Merck Sharp & Dohme, Bayer Schering Pharma Rachel RiechelmannHonoraria: Novartis, Amgen, MSD Oncology, Servier, Roche/GenentechConsulting or Advisory Role: Bayer, Roche/Genentech, Ipsen, Astellas PharmaResearch Funding: Bayer, Roche/Foundation Medicine, Amgen Henry GomesConsulting or Advisory Role: AstraZenecaSpeakers' Bureau: Roche, Novartis, AstraZeneca, Bristol Myers Squibb, LillyResearch Funding: MSD Oncology William N. WilliamHonoraria: Roche/Genentech, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Merck, Lilly, PfizerConsulting or Advisory Role: AstraZeneca, Merck, Pfizer, Bristol Myers Squibb, Bayer, RocheSpeakers' Bureau: Boehringer IngelheimResearch Funding: OSI Pharmaceuticals, Boehringer Ingelheim, Merck, Lilly, Bristol Myers SquibbTravel, Accommodations, Expenses: AstraZeneca, Merck, Bristol Myers Squibb, Roche/Genentech Camilla A. F. YamadaSpeakers' Bureau: Janssen OncologyTravel, Accommodations, Expenses: Bayer, Janssen Gilberto de Castro JuniorHonoraria: AstraZeneca, Pfizer, Merck Sharp & Dohme, Bristol Myers Squibb, Novartis, RocheConsulting or Advisory Role: Boehringer Ingelheim, Pfizer, Bayer, Roche, Merck Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, Yuhan, Merck SeronoSpeakers' Bureau: AstraZeneca, Bayer, Novartis, Roche, Merck Serono, Bristol Myers Squibb, Merck Sharp & Dohme, Boehringer Ingelheim, PfizerTravel, Accommodations, Expenses: Merck Sharp & Dohme, Novartis, Pfizer, Roche, AstraZeneca, Boehringer Ingelheim, Bayer, Bristol Myers Squibb Daniela D. RosaConsulting or Advisory Role: Roche, Novartis, AstraZeneca, Lilly, GlaxoSmithKline, Sanofi, Libbs, Pfizer, Amgen, Zodiac PharmaSpeakers' Bureau: Novartis, Lilly, PfizerTravel, Accommodations, Expenses: Roche Andreia C. de MeloHonoraria: MSD Oncology, Novartis, BMS BrazilSpeakers' Bureau: BMS Brazil, MSD OncologyResearch Funding: Roche, MSD Oncology, BMS Brazil, Novartis, Clovis Oncology, AstraZenecaTravel, Accommodations, Expenses: MSD Oncology Denisse BretelConsulting or Advisory Role: Merck Oscar ArrietaHonoraria: AstraZeneca, Merck Sharp & Dohme, RocheConsulting or Advisory Role: Boehringer Ingelheim, Bristol Myers Squibb, Lilly, PfizerResearch Funding: AstraZeneca, Roche, Merck Sharp & Dohme Andrés F. CardonaHonoraria: Bristol Myers Squibb, Roche, Boehringer Ingelheim, AbbVie, Merck Sharp & Dohme, CelldexConsulting or Advisory Role: Roche, Merck Sharp & Dohme, Novartis, AstraZeneca, Bristol Myers Squibb, Foundation Medicine, Boehringer Ingelheim, Foundation for Clinical and Applied Cancer Research (FICMAC)Speakers' Bureau: Merck Sharp & Dohme, Roche, Bristol Myers Squibb, Novartis, Foundation for Clinical and Applied Cancer Research (FICMAC), Foundation MedicineTravel, Accommodations, Expenses: Merck Sharp & Dohme, Bristol Myers Squibb, Roche, Boehringer Ingelheim, Foundation Medicine Diogo A. BastosHonoraria: MSD, Roche, Bristol Myers Squibb, Janssen-Cilag, Astellas Pharma, AstraZeneca, BayerConsulting or Advisory Role: Roche, Bayer, Janssen-Cilag, MSD OncologyResearch Funding: Janssen-Cilag, Pfizer, Astellas PharmaTravel, Accommodations, Expenses: Janssen-Cilag, BayerNo other potential conflicts of interest were reported.

Background: The landscape of cutaneous melanoma (CM) diagnosis, staging, prognosis, and treatment has undergone fundamental changes in the past decade. While the benefits of new health resources are recognized, there is a distinct lack of accurate cost-of-illness information to aid healthcare decision makers., Methods: The cost-of-illness study for CM was conducted from the perspective of two health systems in Brazil: the public health system (Unified Health System, SUS) and the private health system (Health Management Organization, HMO). The study considered the direct medical cost in a bottom-up analysis, using melanoma incidence, knowledge of the disease's progression, and the overall survival rates. The executional costs for the complete healthcare delivery cycle were investigated considering different disease stages and possible clinical course variations. The structural cost was assessed qualitatively considering the health value chain in Brazil., Results: CM represents a critical financial burden in Brazil, and the cost of illness varied according to the health system and by stage at diagnosis. HMO patient costs are approximately 10-fold and 90-fold more than a SUS patient in the early-stage and advanced disease, respectively. Overall, spending on advanced disease patients can be up to 34-fold (SUS) or 270-fold (HMO) higher than that required for the early-stage disease. Given the massive amount of resources spent by the SUS and HMO, significant efforts must be made to improve the health value chain to deliver the right mix of medical care goods and services using available resources., Conclusion: The cost-of-illness study for CM has the potential to inform policymakers and decision-makers regarding the economic burden that melanoma impose on a society in terms of the use of health care services, assisting them in making projections of future health care costs and resource allocation decisions. We believe that cost-of-illness analysis from a strategic perspective could be of help in assessing executional costs and be used to support the change in structural costs required for long-term strategies related to the health value chain.

BACKGROUND Gastrointestinal stromal tumors (GISTs) are rare mesenchymal cancers that affect the gastrointestinal tract and are most often located in the stomach and proximal small intestine. The most common molecular genetic abnormalities underlying GIST carcinogenesis are mutations in the tyrosine kinase gene (KIT) and in the platelet-derived growth factor receptor alpha (PDGFRA) gene. To the best of our knowledge, no cases have been reported so far of synchronous diagnosis of GIST in 2 monozygotic twins presenting with clinical and morphological features of sporadic disease. CASE REPORT This report presents the cases of 2 monozygotic twin sisters who were diagnosed with GIST at the same age and who had different KIT exon 11 tumor mutational statuses. In the current report, the screening examination that led to early detection of GIST in one of the sisters was not motivated by any symptom, but by a GIST diagnosis in her twin a few days before. The literature was reviewed for pathological and molecular features associated with prognosis and treatment response. Furthermore, we identified identical genotypes of KIT and PDGFRA polymorphisms in the DNA of both tumors that might be present in the germline DNA. The present case supports the implementation of specific cancer screening in the context of monozygotic twins, regardless of identification of the genetic components involved. CONCLUSIONS Our report suggests that monozygotic twins with GIST can have different mutational statuses for KIT and PDGFRA. Referral for special screening should be considered for individuals who have a monozygotic twin diagnosed with cancer.

The standard treatment for locally advanced cervical cancer (CC) is chemo-radiotherapy. Once the bladder receives part of the radiation, a typical inflammatory condition that configures radiation-induced cystitis may develop. Chronic radiation-induced cystitis is commonly characterized by the bladder new submucosal vascularization, which is typically fragile and favors hematuria. The current study aims to investigate if Hypoxia-Induced Factor (HIF-1α) and its transcriptional target Vascular Endothelial Growth Factor A (VEGF-A) could be a primary pathway leading to increased submucosal vascularization. HIF-1α and VEGF-A mRNA levels in bladder core biopsies from CC patients treated with radiotherapy versus untreated (non-irradiated) patients were analyzed using a droplet digital polymerase chain reaction technology. Gene expression results showed that HIF-1α and VEGF-A had no significant differences between bladder samples from patients previously irradiated and untreated patient samples. However, a direct relationship between the degree of late morbidity and the expression of HIF-1α and VEGF-A has been demonstrated. Despite the lack of statistical significance precludes a definitive conclusion, the data presented herein suggests that further studies investigating the role of HIF-1α in bladder neovascularization in radiation-induced cystitis are highly recommended., Competing Interests: None declared., (Copyright® by the International Brazilian Journal of Urology.)

Competing Interests: The authors have no conflict of interests to declare.

Objective: To identify the determinants of tuberculosis-related variables in the various regions of Brazil and evaluate trends in those variables over the ten-year period preceding the end of the timeframe defined for the United Nations Millennium Development Goals (MDGs)., Methods: This was an ecological analytical study in which we utilized eight national public databases to investigate the 716,971 new tuberculosis cases reported between 2006 and 2015., Results: Over the study period, there were slight reductions in the prevalence, incidence, and mortality associated with tuberculosis. Brazil did not reach the MDG for tuberculosis-related mortality. Among the performance indicators of tuberculosis control, there were improvements only in those related to treatment and treatment abandonment. In terms of the magnitude of tuberculosis, substantial regional differences were observed. The tuberculosis incidence rate was highest in the northern region, as were the annual mean temperature and relative air humidity. That region also had the second lowest human development index, primary health care (PHC) coverage, and number of hospitalizations for tuberculosis. The northeastern region had the highest PHC coverage, number of hospitalizations for primary care-sensitive conditions, and tuberculosis-related mortality rate. The southern region showed the smallest reductions in epidemiological indicators, together with the greatest increases in the frequency of treatment abandonment and retreatment. The central-west region showed the lowest overall magnitude of tuberculosis and better monitoring indicators., Conclusions: The situation related to tuberculosis differs among the five regions of Brazil. Those differences can make it difficult to control the disease in the country and could explain the fact that Brazil failed to reach the MDG for tuberculosis-related mortality. Tuberculosis control measures should be adapted to account for regional differences.

Numerous factors have been identified to influence susceptibility to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and disease severity. Cancer patients are more prone to clinically evolve to more severe COVID-19 conditions, but the determinants of such a more severe outcome remain largely unknown. We have determined the full-length SARS-CoV-2 genomic sequences of cancer patients and healthcare workers (non-cancer controls) by deep sequencing and investigated the within-host viral population of each infection, quantifying intrahost genetic diversity. Naso- and oropharyngeal SARS-CoV-2 + swabs from 57 cancer patients and 14 healthcare workers from the Brazilian National Cancer Institute were collected in April to May 2020. Complete genome amplification using ARTIC network V3 multiplex primers was performed followed by next-generation sequencing. Assemblies were conducted in Geneious R11, where consensus sequences were extracted and intrahost single nucleotide variants were identified. Maximum likelihood phylogenetic analysis was performed using PhyMLv.3.0 and lineages were classified using Pangolin and CoV-GLUE. Phylogenetic analysis showed that all but one strain belonged to clade B1.1. Four genetically linked mutations known as the globally dominant SARS-CoV-2 haplotype (C241T, C3037T, C14408T and A23403G) were found in the majority of consensus sequences. SNV signatures of previously characterized Brazilian genomes were also observed in most samples. Another 85 SNVs were found at a lower frequency (1.4%-19.7%) among the consensus sequences. Cancer patients displayed a significantly higher intrahost viral genetic diversity compared to healthcare workers. This difference was independent of SARS-CoV-2 Ct values obtained at the diagnostic tests, which did not differ between the two groups. The most common nucleotide changes of intrahost SNVs in both groups were consistent with APOBEC and ADAR activities. Intrahost genetic diversity in cancer patients was not associated with disease severity, use of corticosteroids, or use of antivirals, characteristics that could influence viral diversity. Moreover, the presence of metastasis, either in general or specifically in the lung, was not associated with intrahost diversity among cancer patients. Cancer patients carried significantly higher numbers of minor variants compared to non-cancer counterparts. Further studies on SARS-CoV-2 diversity in especially vulnerable patients will shed light onto the understanding of the basis of COVID-19 different outcomes in humans., (© The Author(s) 2021. Published by Oxford University Press.)

Background: Cancer patients suffer from worse coronavirus disease-2019 (COVID-19) outcomes. Whether active oncologic treatment is an additional risk factor in this population remains unclear. Therefore, here we have conducted a systematic review and meta-analysis to summarize the existing evidence for the effect of active oncologic treatment on COVID-19 outcomes., Methods: Systematic search of databases (PubMed, Embase) was conducted for studies published from inception to July 1, 2020, with a subsequent search update conducted on 10 October 2020. In addition, abstracts and presentations from major conference proceedings (ASCO, ESMO, AACR) as well as pre-print databases (medxriv, bioxriv) were searched. Retrospective and prospective studies reporting clinical outcomes in cancer patients with laboratory confirmation or clinical diagnosis of COVID-19 and details of active or recent oncologic treatment were selected. Random-effects model was applied throughout meta-analyses. Summary outcome measure was the pooled odds ratio (OR) of death for active cancer therapy versus no active cancer therapy for each of the following modalities: recent surgery, chemotherapy, targeted therapy, immunotherapy, or chemoimmunotherapy., Results: Sixteen retrospective and prospective studies (3558 patients) were included in the meta-analysis. Active chemotherapy was associated with higher risk of death compared to no active chemotherapy (OR, 1.60, 95% CI, 1.14-2.23). No significant association with risk of death was identified for active targeted therapy, immunotherapy, chemoimmunotherapy, or recent surgery. Meta-analysis of multivariate adjusted OR of death for active chemotherapy was consistently associated with higher risk of death compared to no active chemotherapy (OR, 1.42, 95% CI, 1.01-2.01)., Conclusions: Active chemotherapy appears to be associated with higher risk of death in cancer patients with COVID-19. Further research is necessary to characterize the complex interactions between active cancer treatment and COVID-19.