Artigos e Materiais de Revistas Científicas - LIM/24
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- Data-driven, cross-disciplinary collaboration: lessons learned at the largest academic health center in Latin America during the COVID-19 pandemic(2024) RITTO, Ana Paula; ARAUJO, Adriana Ladeira de; CARVALHO, Carlos Roberto Ribeiro de; SOUZA, Heraldo Possolo De; FAVARETTO, Patricia Manga e Silva; SABOYA, Vivian Renata Boldrim; GARCIA, Michelle Louvaes; KULIKOWSKI, Leslie Domenici; KALLAS, Esper Georges; PEREIRA, Antonio Jose Rodrigues; COBELLO JUNIOR, Vilson; SILVA, Katia Regina; ABDALLA, Eidi Raquel Franco; SEGURADO, Aluisio Augusto Cotrim; SABINO, Ester Cerdeira; RIBEIRO JUNIOR, Ulysses; FRANCISCO, Rossana Pulcineli Vieira; MIETHKE-MORAIS, Anna; LEVIN, Anna Sara Shafferman; SAWAMURA, Marcio Valente Yamada; FERREIRA, Juliana Carvalho; SILVA, Clovis Artur; MAUAD, Thais; GOUVEIA, Nelson da Cruz; LETAIF, Leila Suemi Harima; BEGO, Marco Antonio; BATTISTELLA, Linamara Rizzo; DUARTE, Alberto Jose da Silva; SEELAENDER, Marilia Cerqueira Leite; MARCHINI, Julio; FORLENZA, Orestes Vicente; ROCHA, Vanderson Geraldo; MENDES-CORREA, Maria Cassia; COSTA, Silvia Figueiredo; CERRI, Giovanni Guido; BONFA, Eloisa Silva Dutra de Oliveira; CHAMMAS, Roger; BARROS FILHO, Tarcisio Eloy Pessoa de; BUSATTO FILHO, GeraldoIntroduction The COVID-19 pandemic has prompted global research efforts to reduce infection impact, highlighting the potential of cross-disciplinary collaboration to enhance research quality and efficiency.Methods At the FMUSP-HC academic health system, we implemented innovative flow management routines for collecting, organizing and analyzing demographic data, COVID-related data and biological materials from over 4,500 patients with confirmed SARS-CoV-2 infection hospitalized from 2020 to 2022. This strategy was mainly planned in three areas: organizing a database with data from the hospitalizations; setting-up a multidisciplinary taskforce to conduct follow-up assessments after discharge; and organizing a biobank. Additionally, a COVID-19 curated collection was created within the institutional digital library of academic papers to map the research output.Results Over the course of the experience, the possible benefits and challenges of this type of research support approach were identified and discussed, leading to a set of recommended strategies to enhance collaboration within the research institution. Demographic and clinical data from COVID-19 hospitalizations were compiled in a database including adults and a minority of children and adolescents with laboratory confirmed COVID-19, covering 2020-2022, with approximately 350 fields per patient. To date, this database has been used in 16 published studies. Additionally, we assessed 700 adults 6 to 11 months after hospitalization through comprehensive, multidisciplinary in-person evaluations; this database, comprising around 2000 fields per subject, was used in 15 publications. Furthermore, thousands of blood samples collected during the acute phase and follow-up assessments remain stored for future investigations. To date, more than 3,700 aliquots have been used in ongoing research investigating various aspects of COVID-19. Lastly, the mapping of the overall research output revealed that between 2020 and 2022 our academic system produced 1,394 scientific articles on COVID-19.Discussion Research is a crucial component of an effective epidemic response, and the preparation process should include a well-defined plan for organizing and sharing resources. The initiatives described in the present paper were successful in our aim to foster large-scale research in our institution. Although a single model may not be appropriate for all contexts, cross-disciplinary collaboration and open data sharing should make health research systems more efficient to generate the best evidence.
- Frequency of Human Papillomavirus Detection in Chagasic Megaesophagus Associated or Not with Esophageal Squamous Cell Carcinoma(2022) MUNARI, F. F.; SICHERO, L.; CARLONI, A. C.; LACERDA, C. F.; NUNES, E. M.; OLIVEIRA, A. T. T. De; SCAPULATEMPO-NETO, C.; SILVA, S. R. M. Da; CREMA, E.; ADAD, S. J.; RODRIGUES, M. A. M.; HENRY, M. A. C. A.; GUIMARãES, D. P.; REIS, R. M.; VILLA, L. L.; LONGATTO-FILHO, A.Background: Chagasic megaesophagus (CM) as well as the presence of human papillomavirus (HPV) has been reported as etiological factors for esophageal squamous cell carcinoma (ESCC). Objective: We assessed the prevalence of HPV DNA in a series of ESCCs associated or not with CM. Data obtained were further correlated to the pathological and clinical data of affected individuals. Methods: A retrospective study was performed on 92 formalin-fixed and paraffin-embedded tissues collected from patients referred to 3 different hospitals in São Paulo, Brazil: Barretos Cancer Hospital, Barretos, São Paulo; Federal University of Triângulo Mineiro, Uberaba, Minas Gerais; and São Paulo State University, Botucatu, São Paulo. Cases were divided into 3 groups: (i) 24 patients with CM associated with ESCC (CM/ESCC); (ii) 37 patients with ESCC without CM (ESCC); and (iii) 31 patients with CM without ESCC (CM). Detection of HPV DNA was assessed in all samples by a genotyping assay combining multiplex polymerase chain reaction and bead-based Luminex technology. Results: We identified a high prevalence of high-risk HPV in patients in the CM group (12/31, 38.8%) and CM/ESCC (8/24, 33.3%), compared to individuals in the ESCC group (6/37, 16.3%). The individuals in the groups with cancer (ESCC and CM/ESCC) had a higher frequency of HPV-16 (4/9, 44.5% and 2/8, 25.0%). The other types of high-risk HPVs detected were HPV-31, 45, 51, 53, 56, 66, and 73. We also observed in some samples HPV coinfection by more than one viral type. Despite the high incidence of HPV, it did not show any association with the patient's clinical-pathological and molecular (TP53 mutation status) characteristics. Conclusion: This is the first report of the presence of HPV DNA in CM associated with ESCC. HPV infection was more presence in megaesophagus lesions. Further studies are needed to confirm and better understand the role of persistent HPV infection in patients with CM.
- Locking and Unlocking Thrombin Function Using Immunoquiescent Nucleic Acid Nanoparticles with Regulated Retention In Vivo(2022) KE, W.; CHANDLER, M.; CEDRONE, E.; SAITO, R. F.; RANGEL, M. C.; JUNQUEIRA, M. De Souza; WANG, J.; SHI, D.; TRUONG, N.; RICHARDSON, M.; ROLBAND, L. A.; DRéAU, D.; BEDOCS, P.; CHAMMAS, R.; DOKHOLYAN, N. V.; DOBROVOLSKAIA, M. A.; AFONIN, K. A.The unbalanced coagulation of blood is a life-threatening event that requires accurate and timely treatment. We introduce a user-friendly biomolecular platform based on modular RNA-DNA anticoagulant fibers programmed for reversible extracellular communication with thrombin and subsequent control of anticoagulation via a ""kill-switch""mechanism that restores hemostasis. To demonstrate the potential of this reconfigurable technology, we designed and tested a set of anticoagulant fibers that carry different thrombin-binding aptamers. All fibers are immunoquiescent, as confirmed in freshly collected human peripheral blood mononuclear cells. To assess interindividual variability, the anticoagulation is confirmed in the blood of human donors from the U.S. and Brazil. The anticoagulant fibers reveal superior anticoagulant activity and prolonged renal clearance in vivo in comparison to free aptamers. Finally, we confirm the efficacy of the ""kill-switch""mechanism in vivo in murine and porcine models.
- Complex Intrahepatic Lithiasis: A Case Report of Combined Treatment With Surgical Exploration of the Bilioenteric Anastomosis and Laser Lithotripsy by Cholangioscopy(2023) SANTOS, Marcos Eduardo Lera dos; SASSO, Joao Guilherme Ribeiro Jordao; FIGUEIRA, Estela R.; OLIVEIRA, Victor L. De; ARABI, Arthur Youssif Mota; MEIRA JUNIOR, Jose Donizeti; SILVA, Nathalia Camin Calixto Sarroche da; MOURA, Diogo Turiani De; JUKEMURA, Jose; MOURA, Eduardo Guimaraes DeIntrahepatic lithiasis, or hepatolithiasis, is an endemic disease in southeast Asia, although, with immigration from Eastern countries, the incidence of this pathology is rising worldwide. The Latin American experience demonstrates morbidity and mortality compatible with other Western countries, but minimally invasive procedures are lacking. We demonstrate a case of a combined surgical and endoscopic approach for stone clearance.We present a case of a 47-year-old female patient with biliary enteric anastomosis to treat recurrent pyogenic cholangitis resulting from intrahepatic lithiasis. The patient was admitted to the emergency room, presented with a new episode of cholangitis, and submitted to transcutaneous hepatobiliary drainage. The multidisciplinary approach, including the endoscopic and surgical teams, successfully performed the stone clearance with laser lithotripsy and stone removal by open access. The postoperative period was uneventful, and the patient did not present any sign of recurrence after one year. A combined surgical and endoscopic approach achieved short-term clinical and technical success in this novel case. Moreover, individualizing cases requiring open surgical access is feasible, which allows a combined endoscopic approach with safety.
- Increased sympathetic nervous system impairs prognosis in lung cancer patients: a scoping review of clinical studies(2023) GARRAMONA, Fabricio T.; CUNHA, Telma F.; VIEIRA, Janaina S.; BORGES, Gabriela; SANTOS, Gabriela; CASTRO, Gilberto de; UGRINOWITSCH, Carlos; BRUM, Patricia C.Aim: To summarize current knowledge, gaps, quality of the evidence and show main results related to the role of the autonomic nervous system in lung cancer. Methods: Studies were identified through electronic databases (PubMed, Scopus, Embase and Cochrane Library) in October 2023, and a descriptive analysis was performed. Twenty-four studies were included, and most were observational. Results: Our data indicated an increased expression of beta-2-adrenergic receptors in lung cancer, which was associated with poor prognosis. However, the use of beta-blockers as an add-on to standard treatment promoted enhanced overall survival, recurrence-free survival and reduced metastasis occurrence. Conclusion: Although the results herein seem promising, future research using high-quality prospective clinical trials is required to draw directions to guide clinical interventions. Lung cancer is one of the most common causes of cancer-related deaths in the world, which often goes undiagnosed until it is in an advanced stage. Recently, the autonomic nervous system (sympathetic and parasympathetic nervous systems) has been identified as a regulator of cancer growth and spread, including lung cancer. In fact, preclinical studies have demonstrated that autonomic innervation in lung cancer can trigger tumor progression, metastasis, and resistance to treatment, worsening the prognosis. In this sense, add-on strategies to standard cancer treatments have been investigating and one of them has stood out: the incidental use of beta-blockers (patients who used beta-blockers for the treatment of hypertension and/or cardiovascular diseases or anxiety) before surgeries or during chemotherapy, which has been associated with improved clinical outcomes. Thus, a scoping review was conducted to summarizing the current knowledge about the quality of evidence, gaps and main results related to the role of the autonomic nervous system in human lung cancer. Data from this review indicated an increase in sympathetic nervous system receptors associated with a worse prognosis in patients with lung cancer. Indeed, those patients who took beta-blockers along with lung cancer treatment showed an increase in survival and a reduction in the occurrence of metastases. Although the results herein seem promising, further prospective clinical studies are needed to investigate the effect of the intentional and controlled use of beta-blockers as an add-on strategy on the treatment of different types and stages of lung cancer. An increased expression of beta-2-adrenergic receptors is linked to a poor prognosis in lung cancer. Adding beta-blockers to treatment improved survival and reduced metastasis. See more in our study.
- Pregnancy After Breast Cancer in Young BRCA Carriers(2024) LAMBERTINI, Matteo; BLONDEAUX, Eva; AGOSTINETTO, Elisa; HAMY, Anne-Sophie; KIM, Hee Jeong; MEGLIO, Antonio Di; MOLHO, Rinat Bernstein; HILBERS, Florentine; POGODA, Katarzyna; CARRASCO, Estela; PUNIE, Kevin; BAJPAI, Jyoti; IGNATIADIS, Michail; MOORE, Halle C. F.; PHILLIPS, Kelly-Anne; TOSS, Angela; ROUSSET-JABLONSKI, Christine; PECCATORI, Fedro A.; RENAUD, Tiphaine; FERRARI, Alberta; PALUCH-SHIMON, Shani; FRUSCIO, Robert; CUI, Wanda; WONG, Stephanie M.; VERNIERI, Claudio; RUDDY, Kathryn J.; DIECI, Maria Vittoria; MATIKAS, Alexios; ROZENBLIT, Mariya; VILLARREAL-GARZA, Cynthia; MARCHIS, Laura De; MASTRO, Lucia Del; PUGLISI, Fabio; ESTEVEZ-DIZ, Maria Del Pilar; RODRIGUEZ-WALLBERG, Kenny A.; MRINAKOVA, Bela; MEISTER, Sarah; LIVRAGHI, Luca; CLATOT, Florian; YERUSHALMI, Rinat; ANGELIS, Carmine De; SANCHEZ-BAYONA, Rodrigo; MEATTINI, Icro; CICHOWSKA-CWALINSKA, Natalia; BERLIERE, Martine; SALAMA, Mahmoud; GIORGI, Ugo De; SONNENBLICK, Amir; CHIODI, Camila; LEE, Young-Jin; MARIA, Camille; AZIM JR., Hatem A.; BONI, Luca; PARTRIDGE, Ann H.Importance Young women with breast cancer who have germline pathogenic variants in BRCA1 or BRCA2 face unique challenges regarding fertility. Previous studies demonstrating the feasibility and safety of pregnancy in breast cancer survivors included limited data regarding BRCA carriers.Objective To investigate cumulative incidence of pregnancy and disease-free survival in young women who are BRCA carriers.Design, Setting, and Participants International, multicenter, hospital-based, retrospective cohort study conducted at 78 participating centers worldwide. The study included female participants diagnosed with invasive breast cancer at age 40 years or younger between January 2000 and December 2020 carrying germline pathogenic variants in BRCA1 and/or BRCA2. Last delivery was October 7, 2022; last follow-up was February 20, 2023.Exposure Pregnancy after breast cancer.Main Outcomes and Measures Primary end points were cumulative incidence of pregnancy after breast cancer and disease-free survival. Secondary end points were breast cancer-specific survival, overall survival, pregnancy, and fetal and obstetric outcomes.Results Of 4732 BRCA carriers included, 659 had at least 1 pregnancy after breast cancer and 4073 did not. Median age at diagnosis in the overall cohort was 35 years (IQR, 31-38 years). Cumulative incidence of pregnancy at 10 years was 22% (95% CI, 21%-24%), with a median time from breast cancer diagnosis to conception of 3.5 years (IQR, 2.2-5.3 years). Among the 659 patients who had a pregnancy, 45 (6.9%) and 63 (9.7%) had an induced abortion or a miscarriage, respectively. Of the 517 patients (79.7%) with a completed pregnancy, 406 (91.0%) delivered at term (>= 37 weeks) and 54 (10.4%) had twins. Among the 470 infants born with known information on pregnancy complications, 4 (0.9%) had documented congenital anomalies. Median follow-up was 7.8 years (IQR, 4.5-12.6 years). No significant difference in disease-free survival was observed between patients with or without a pregnancy after breast cancer (adjusted hazard ratio, 0.99; 95% CI, 0.81-1.20). Patients who had a pregnancy had significantly better breast cancer-specific survival and overall survival.Conclusions and RelevanceIn this global study, 1 in 5 young BRCA carriers conceived within 10 years after breast cancer diagnosis. Pregnancy following breast cancer in BRCA carriers was not associated with decreased disease-free survival.
- Durvalumab versus placebo with chemoradiotherapy for locally advanced cervical cancer (CALLA): a randomised, double-blind, phase 3 trial(2023) MONK, Bradley J.; TOITA, Takafumi; WU, Xiaohua; LIMON, Juan C. Vazquez; TARNAWSKI, Rafal; MANDAI, Masaki; SHAPIRA-FROMMER, Ronnie; MAHANTSHETTY, Umesh; ESTEVEZ-DIZ, Maria del Pilar; ZHOU, Qi; LIMAYE, Sewanti; GODINEZ, Francisco J. Ramirez; KUSSLER, Christina Oppermann; VARGA, Szilvia; VALDIVIEZO, Natalia; AOKI, Daisuke; LEIVA, Manuel; LEE, Jung-Yun; SULAY, Raymond; KREYNINA, Yulia; CHENG, Wen-Fang; REY, Felipe; RONG, Yi; KE, Guihao; WILDSMITH, Sophie; LLOYD, Andrew; DRY, Hannah; NUNES, Ana Tablante; MAYADEV, JyotiBackground Concurrent chemoradiotherapy has been the standard of care for locally advanced cervical cancer for over 20 years; however, 30-40% of treated patients have recurrence or progression within 5 years. Immune checkpoint inhibition has improved outcomes for patients with PD-L1 positive metastatic or recurrent cervical cancer. We assessed the benefit of adding durvalumab, a PD-L1 antibody, with and following chemoradiotherapy for locally advanced cervical cancer. Methods The CALLA randomised, double-blind, phase 3 trial included 105 hospitals across 15 countries. Patients aged at least 18 years with previously untreated locally advanced cervical cancer (adenocarcinoma, squamous, or adenosquamous; International Federation of Gynaecology and Obstetrics [FIGO] 2009 stage IB2-IIB lymph node positive, stage >= III any lymph node status) and WHO or Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) through an interactive web response system using a permuted block size of 4 to receive durvalumab (1500 mg intravenously once every 4 weeks) or placebo with and following chemoradiotherapy, for up to 24 cycles. Chemoradiotherapy included 45 Gy external beam radiotherapy at 5 fractions per week concurrent with intravenous cisplatin (40 mg/m2) or carboplatin (area under the concentration-time curve 2) once weekly for 5 weeks, followed by image-guided brachytherapy (high-dose rate, 27 center dot 5-30 Gy or low-dose/pulse-dose rate, 35-40 Gy). Randomisation was stratified by disease stage status (FIGO stage and node status) and geographical region. Chemoradiotherapy quality was continuously reviewed. The primary endpoint was progression-free survival, assessed by the investigator using Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03830866. Findings Between Feb 15, 2019, and Dec 10, 2020, 770 women were randomly assigned (385 to durvalumab and 385 to placebo; median age 49 years [IQR 41-57]). Median follow-up was 18 center dot 5 months (IQR 13 center dot 2-21 center dot 5) in the durvalumab group and 18 center dot 4 months (13 center dot 2-23 center dot 7) in the placebo group. At data cutoff, median progression-free survival had not been reached (95% CI not reached-not reached) for either group (HR 0 center dot 84; 95% CI 0 center dot 65-1 center dot 08; p=0 center dot 17); 12-month progression-free survival was 76 center dot 0% (71 center dot 3-80 center dot 0) with durvalumab and 73 center dot 3% (68 center dot 4-77 center dot 5) with placebo. The most frequently reported grade 3-4 adverse events in both groups were anaemia (76 [20%] of 385 in the durvalumab group vs 56 [15%] of 384 in the placebo group) and decreased white blood cells (39 [10%] vs 49 [13%]). Serious adverse events occurred for 106 (28%) patients who received durvalumab and 89 (23%) patients who received placebo. There were five treatment-related deaths in the durvalumab group (one case each of urinary tract infection, blood loss anaemia, and pulmonary embolism related to chemoradiotherapy only; one case of endocrine disorder related to durvalumab only; and one case of sepsis related to both durvalumab and chemoradiotherapy). There was one treatment-related death in the placebo group (pneumonia related to chemoradiotherapy). Interpretation Durvalumab concurrent with chemoradiotherapy was well tolerated in participants with locally advanced cervical cancer, however it did not significantly improve progression-free survival in a biomarker unselected, all-comers population. Concurrent durvalumab plus chemoradiotherapy warrants further exploration in patients with high tumoral PD-L1 expression. Rigorous monitoring ensured high chemoradiotherapy compliance with advanced technology and allowed patients to receive optimal care. Funding AstraZeneca.
- A novel program of infiltrative control in astrocytomas: ADAM23 depletion promotes cell invasion by activating γ-secretase complex(2023) JANDREY, Elisa Helena Farias; BARNABE, Gabriela Filoso; MALDAUN, Marcos; ASPRINO, Paula Fontes; SANTOS, Natalia Cristina dos; INOUE, Lilian Tiemi; ROZANSKI, Andrei; GALANTE, Pedro Alexandre Favoretto; MARIE, Suely Kazue Nagahashi; OBA-SHINJO, Sueli Mieko; SANTOS, Tiago Goss dos; CHAMMAS, Roger; LANCELLOTTI, Carmen Lucia Penteado; FURNARI, Frank B.; CAMARGO, Anamaria Aranha; COSTA, Erico TosoniBackground. Infiltration is a life-threatening growth pattern in malignant astrocytomas and a significant cause of therapy resistance. It results in the tumor cell spreading deeply into the surrounding brain tissue, fostering tumor recurrence and making complete surgical resection impossible. We need to thoroughly understand the mechanisms underlying diffuse infiltration to develop effective therapies.Methods We integrated in vitro and in vivo functional assays, RNA sequencing, clinical, and expression information from public data sets to investigate the role of ADAM23 expression coupling astrocytoma's growth and motility.Results. ADAM23 downregulation resulted in increased infiltration, reduced tumor growth, and improved overall survival in astrocytomas. Additionally, we show that ADAM23 deficiency induces gamma-secretase (GS) complex activity, contributing to the production and deposition of the Amyloid-beta and release of NICD. Finally, GS ablation in ADAM23-low astrocytomas induced a significant inhibitory effect on the invasive programs.Conclusions. Our findings reveal a role for ADAM23 in regulating the balance between cell proliferation and invasiveness in astrocytoma cells, proposing GS inhibition as a therapeutic option in ADAM23 low-expressing astrocytomas.
- ROBOTIC ASSISTED VERSUS LAPAROSCOPIC DISTAL PANCREATECTOMY: A RETROSPECTIVE STUDY(2023) JUREIDINI, Ricardo; NAMUR, Guilherme Naccache; RIBEIRO, Thiago Costa; BACCHELLA, Telesforo; STOLZEMBURG, Lucas; JUKEMURA, Jose; RIBEIRO JUNIOR, Ulysses; CECCONELLO, IvanBACKGROUND: Minimally invasive distal pancreatectomy (MIDP) is associated with less blood loss and faster functional recovery. However, the benefits of robotic assisted distal pancreatectomy (RDP) over laparoscopic distal pancreatectomy (LDP) are unknown. AIMS: To compare RDP versus LDP for surgical treatment of benign lesions, pre-malignant and borderline malignant pancreatic neoplasias. METHODS: This is a retrospective study comparing LDP with RDP. Main outcomes were overall morbidity and overall costs. Secondary outcomes were pancreatic fistula (PF), infectious complications, readmission, operative time (OT) and length of hospital stay (LOS). RESULTS: Thirty patients submitted to LDP and 29 submitted to RDP were included in the study. There was no difference regarding preoperative characteristics. There was no difference regarding overall complications (RDP - 72,4% versus LDP - 80%, p=0,49). Costs were superior for patients submitted to RDP (RDP=US$ 6,688 versus LDP=US$ 6,149, p=0,02), mostly due to higher costs of surgical materials (RDP=US$ 2,364 versus LDP=1,421, p=0,00005). Twenty-one patients submitted to RDP and 24 to LDP developed pancreatic fistula (PF), but only 4 RDP and 7 LDP experienced infectious complications associated with PF. OT (RDP=224 min. versus LDP=213 min., p=0.36) was similar, as well as conversion to open procedure (1 RDP and 2 LDP). CONCLUSIONS: The postoperative morbidity of robotic distal pancreatectomy is comparable to laparoscopic distal pancreatectomy. However, the costs of robotic distal pancreatectomy are slightly higher.
- Outcomes With Pembrolizumab Monotherapy in Patients With Programmed Death-Ligand 1-Positive NSCLC With Brain Metastases: Pooled Analysis of KEYNOTE-001, 010, 024, and 042(2021) MANS, Aaron S.; HERBST, Roy S.; JR, Gilberto de Castro; HUI, Rina; PELED, Nir; KIM, Dong-Wan; NOVELLO, Silvia; SATOUCHI, Miyako; WU, Yi-Long; GARON, Edward B.; RECK, Martin; ROBINSON, Andrew G.; SAMKARI, Ayman; PIPERDI, Bilal; EBIANA, Victoria; LIN, Jianxin; MOK, Tony S. K.Introduction: We retrospectively evaluated outcomes in patients with programmed death-ligand 1 (PD-L1)-positive non-small-cell lung cancer (NSCLC) to determine whether baseline (i.e., at study enrollment) brain metastases were associated with the efficacy of pembrolizumab versus chemotherapy.Methods: We pooled data for patients with previously treated or untreated PD-L1-positive (tumor proportion score [TPS], >= 1%) advanced or metastatic NSCLC in KEYNOTE-001 (NCT01295827), KEYNOTE-010 (NCT01905657), KEYNOTE 024 (NCT02142738), and KEYNOTE-042 (NCT02220894). Patients received pembrolizumab (2 mg/kg, 10 mg/kg, or 200 mg every 3 wk or 10 mg/kg every 2 wk); chemotherapy was a comparator in all studies except KEYNOTE-001. All studies included patients with previously treated, stable brain metastases.Results: A total of 3170 patients were included, 293 (9.2%) with and 2877 (90.8%) without baseline brain metastases; median (range) follow-up at data cutoff was 12.9 (0.1-43.7) months. Pembrolizumab improved overall survival versus chemotherapy in patients with or without baseline brain metastases: benefit was seen in patients with PD-L1 TPS >= 50% (0.67 [95% confidence intervals (CI): 0.44-1.02] and 0.66 [95% CI: 0.58-0.76], respectively) and PD-L1 TPS >= 1% (0.83 [95% CI: 0.62-1.10] and 0.78 [95% CI: 0.710.85], respectively). Progression-free survival was improved, objective response rates were higher, and duration of response was longer with pembrolizumab versus chemotherapy regardless of brain metastasis status. The incidence of treatment-related adverse events with pembrolizumab versus chemotherapy was 66.3% versus 84.4% in patients with brain metastases and 67.2% versus 88.3% in those without.Conclusions: Pembrolizumab monotherapy improved outcomes and was associated with fewer adverse events than chemotherapy in patients with treatment naive and previously treated PD-L1-positive advanced/metastatic NSCLC regardless of the presence of baseline treated, stable brain metastases.(c) 2021 The Authors.
- Aerobic exercise training mitigates tumor growth and cancer-induced splenomegaly through modulation of non-platelet platelet factor 4 expression(2023) TOBIAS, Gabriel C.; GOMES, Joao L. P.; FERNANDES, Larissa G.; VOLTARELLI, Vanessa A.; ALMEIDA, Ney R. de; JANNIG, Paulo R.; SOUZA, Rodrigo W. Alves de; NEGRAO, Carlos E.; OLIVEIRA, Edilamar M.; CHAMMAS, Roger; ALVES, Christiano R. R.; BRUM, Patricia C.Exercise training reduces the incidence of several cancers, but the mechanisms underlying these effects are not fully understood. Exercise training can affect the spleen function, which controls the hematopoiesis and immune response. Analyzing different cancer models, we identified that 4T1, LLC, and CT26 tumor-bearing mice displayed enlarged spleen (splenomegaly), and exercise training reduced spleen mass toward control levels in two of these models (LLC and CT26). Exercise training also slowed tumor growth in melanoma B16F10, colon tumor 26 (CT26), and Lewis lung carcinoma (LLC) tumor-bearing mice, with minor effects in mammary carcinoma 4T1, MDA-MB-231, and MMTV-PyMT mice. In silico analyses using transcriptome profiles derived from these models revealed that platelet factor 4 (Pf4) is one of the main upregulated genes associated with splenomegaly during cancer progression. To understand whether exercise training would modulate the expression of these genes in the tumor and spleen, we investigated particularly the CT26 model, which displayed splenomegaly and had a clear response to the exercise training effects. RT-qPCR analysis confirmed that trained CT26 tumor-bearing mice had decreased Pf4 mRNA levels in both the tumor and spleen when compared to untrained CT26 tumor-bearing mice. Furthermore, exercise training specifically decreased Pf4 mRNA levels in the CT26 tumor cells. Aspirin treatment did not change tumor growth, splenomegaly, and tumor Pf4 mRNA levels, confirming that exercise decreased non-platelet Pf4 mRNA levels. Finally, tumor Pf4 mRNA levels are deregulated in The Cancer Genome Atlas Program (TCGA) samples and predict survival in multiple cancer types. This highlights the potential therapeutic value of exercise as a complementary approach to cancer treatment and underscores the importance of understanding the exercise-induced transcriptional changes in the spleen for the development of novel cancer therapies.
article Oral squamous cell carcinoma cancer stem cells have different drug sensitive to pharmacological NFκB and histone deacetylation inhibition(2023) SILVA, Luan Cesar; LEITE, Amanda Almeida; BORGATO, Gabriell Bonifacio; WAGNER, Vivian Petersen; MARTINS, Manoela Domingues; LOUREIRO, Felippe Jose Almeida; LOPES, Marcio Ajudarte; SANTOS-SILVA, Alan Roger; SPERANDIO, Marcelo; JUNIOR, Gilberto de Castro; KOWALSKI, Luiz Paulo; SQUARIZE, Cristiane H.; CASTILHO, Rogerio Moraes; VARGAS, Pablo AgustinDespite many progresses in the development of new systemic therapies for oral squamous cell carcinoma (OSCC), the five-year survival rate of OSCC is low. The traditional chemotherapies approach (cisplatin - CDDP) shows some limitations like drug toxicity, limited efficacy, and drug resistance. Promising studies suggested OSCC cancer stem cells (CSC) presented resistance to CDDP. We have previously studied many targets, and we extensively showed the efficacy of the NF kappa B signaling and the role of histones acetylation, on different malignant tumors, including adenoid cystic carcinoma and mucoepidermoid carcinoma, but until then the effects of the NFkB inhibitor and histone deacetylase (HDAC) inhibitor on the biology of OSCC were not evaluated. Here we assessed the pharmacological inhibitor of NF kappa B emetine and HDAC inhibitor SAHA on the behavior of CSC derived from OSCC. Our data suggested that CDDP administration resulted in reduced viability of bulk OSCC cells and increased CSC. A single and isolated shot of emetine and SAHA were able to disrupt CSC by inhibiting the NF kappa B pathway and increasing the histone acetylation levels, respectively. Further, the combined administration of emetine and SAHA presented the same CSC disruption as seen in emetine alone.- Betapapillomavirus natural history and co-detection with alphapapillomavirus in cervical samples of adult women(2023) MALAGON, Talia; RIBEIRO, Aline Lopes; NUNES, Emily Montosa; GHEIT, Tarik; EL-ZEIN, Mariam; VILLA, Luisa L.; FRANCO, Eduardo L.; SICHERO, LauraHuman papillomaviruses (HPV) of the genus Betapapillomavirus can infect both cutaneous and mucosal sites, but research on their natural history at mucosal sites remains scarce. We examined the risk factors and co-detection patterns of HPVs of the Betapapillomavirus and Alphapapillomavirus genera in cervical samples of the Ludwig-McGill cohort study. We assessed a subset of 505 women from the Ludwig-McGill cohort study from Sao Paulo, Brazil. Cervical samples over the first year of follow-up were tested for DNA of over 40 alphapapillomavirus types and 43 betapapillomavirus types using a type-specific multiplex genotyping polymerase chain reaction assay. We assessed the risk factors for prevalent and incident betapapillomavirus type detection, and whether types were detected more frequently together than expected assuming independence using permutation tests, logistic regression, and Cox regression. We observed significant within-genus clustering but not cross-genus clustering. Multiple betapapillomavirus types were co-detected in the same sample 2.24 (95% confidence interval [CI]: 1.65-3.29) times more frequently than expected. Conversely, co-detections of alphapapillomavirus and betapapillomavirus types in the same sample occurred only 0.64 (95% CI: 0.51-0.83) times as often as expected under independence. In prospective analyses, positivity to one HPV genus was associated with a nonsignificant lower incidence of detection of types in the other genus. Lifetime number of sex partners and new sex partner acquisition were associated with lower risks of prevalent and incident betapapillomavirus detection. Betapapillomaviruses are commonly found in the cervicovaginal tract. Results suggest potentially different mechanisms of transmission for betapapillomavirus genital infections other than vaginal sex.
- Human Papillomavirus 16 Lineage A Variants Associated With Persistent Genital Infections in Men: The HPV Infection in Men (HIM) Study(2023) FERREIRA, Matthew Thomas; LOPEZ, Rossana Veronica Mendoza; GONCALVES, Milena Giulia; FERREIRA, Silvaneide; SIRAK, Bradley; BAGGIO, Maria Luizai; LAZCANO-PONCE, Eduardo; NYITRAY, Alan G.; GIULIANO, Anna R.; VILLA, Luisa L.; SICHERO, Laura; LIN, Huiyi; MESSINA, Jane; CAMPBELL, Christine Pierce; GAGE, Christine; INGLES, Donna J.; ISAACS, Kim; KENNEDY, Kayoko; BOBANIC, Andrea; RAHMAN, Shams; SCHABATH, Matthew; NYITRAY, Alan; RATHWELL, Julie; PAULA, Lenice Galan de; CINTRA, Ricardo; CERNICCHIARO, Filomena; RIBEIRO, Graca; OTERO, Rosaria; BOCALON, Roberta; ANTUNES, Juliana; SILVA, Fernanda; TERRERI, Rossana; VALDEZ, Aurelio Cruz; VASQUEZ, Rene de Jesus Alvear; JUAREZ, Oscar Rojas; SOSA, Rossana del Carmen Gonzalez; VENCES, Rosangel Rios; SEGURA, Martha Huerta; GALVAN, Alicia Rodriguez; RODRIGUEZ, Paula Roman; VELEZ, Ana Laura Landa; GARCIA, Griselda Diaz; ABARCA, Veronica Chavez; QUEVEDO, Gisela Flores; NEVAREZ, Maria del Pilar Hernandez; MARTINEZ, Guillermina Sanchez; ROJAS, Adriana Ortiz; FLORES, Carlos Omar Barrera; MANGONE, Flavia Rotea; PAVANELLI, Ana CarolinaWe show for the first time the influence of human papillomavirus (HPV) 16 nucleotide variability on the risk of persistent infection in the male genitalia. Our data suggest differences in the natural history of HPV-16 variants between men and women. Background Human papillomavirus (HPV) 16 non-A lineage variants have higher carcinogenic potential for cervical cancer. HPV-16 variants natural history among males is not established. We evaluated HPV-16 variants prevalence and persistence in the external genitalia of men enrolled in the prospective HPV Infection in Men (HIM) Study. Methods The HIM Study included men from the United States, Brazil, and Mexico. HPV-16 variants were distinguished using polymerase chain reaction sequencing. The prevalence of HPV-16 variants was assessed, and associations with infection persistence were estimated. Results We characterized the HPV-16 variants for 1700 genital swab samples from 753 men and 22 external genital lesions in 17 men. The prevalence of HPV-16 lineages differed by country and marital status (P < .001). Overall, 90.9% of participants harbored lineage A variants. The prevalence of non-A lineages was heterogenous among countries. HPV-16 lineage A variants were associated with a 2.69-fold increased risk of long-term persistent infections compared with non-A lineages. All high-grade penile intraepithelial neoplasia harbored lineage A variants and occurred in the context of long-term persistent infections with the same variants. Conclusions The prevalence and persistence of HPV-16 variants observed at the male external genitalia suggest differences in the natural history of these variants between men and women, which may be associated with intrinsic differences in the infected genital epithelia.
- A systematic review of clinical trials for gene therapies for ,B-hemoglobinopathy around the world(2023) ROS, Felipe Augusto; COUTO, Samuel Campanelli Freitas; MILHOMENS, Jonathan; OVIDER, Ian; MAIO, Karina Tozatto; JENNIFER, Viviane; RAMOS, Rodrigo Nalio; PICANCO-CASTRO, Virginia; KASHIMA, Simone; CALADO, Rodrigo T.; BARROS, Luciana Rodrigues Carvalho; ROCHA, VandersonBackground aims: Amidst the success of cell therapy for the treatment of onco-hematological diseases, the first recently Food and Drug Administration-approved gene therapy product for patients with transfusion-dependent ,B-thalassemia (TDT) indicates the feasibility of gene therapy as curative for genetic hematologic disorders. This work analyzed the current-world scenario of clinical trials involving gene therapy for ,B-hemoglobinopathies.Methods: Eighteen trials for patients with sickle cell disease (SCD) and 24 for patients with TDT were analyzed.Results: Most are phase 1 and 2 trials, funded by the industry and are currently recruiting volunteers. Treatment strategies for both diseases are fetal hemoglobin induction (52.4%); addition of wild-type or therapeutic ,B-globin gene (38.1%) and correction of mutations (9,5%). Gene editing (52.4%) and gene addition (40.5%) are the two most used techniques. The United States and France are the countries with the greatest number of clinical trials centers for SCD, with 83.1% and 4.2%, respectively. The United States (41.1%), China (26%) and Italy (6.8%) lead TDT trials centers.Conclusions: Geographic trial concentration indicates the high costs of this technology, logistical issues and social challenges that need to be overcome for gene therapy to reach low-and middle-income countries where SCD and TDT are prevalent and where they most impact the patient's health.(c) 2023 International Society for Cell & Gene Therapy.
- Does displacement of lower pole stones during retrograde intrarenal surgery improves stone-free status? A systematic review and meta-analysis(2023) SANTANA, Roberto Nogueira; PORTO, Breno Cordeiro; PASSEROTTI, Carlo Camargo; ARTIFON, Everson Luiz de Almeida; OTOCH, Jose Pinhata; CRUZ, Jose Arnaldo Shiomi daPurpose: Kidney stones are one of the most common urological diseases worldwide. The size and location of the stone are the most important factors in determining the most suitable treatment options. The aim of this review was to evaluate the displacement of lower pole stones. Methods: Three studies assessing the efficacy of translocating kidney stones from the lower pole of the kidney to other locations during retrograde intrarenal surgery published in the last 20 years were included. A systematic search was conducted in the PubMed, Embase, Latin American and Caribbean Health Sciences Literature (LILACS), and Web of Science databases using the following search terms: ""Lower pole,"" ""Lithotripsy."" Meta-analysis was performed using Review Manager version 5.4. Results: Stone-free rates were improved through displacement (odds ratio - OR = -0.15; 95% confidence interval-95%CI -0.24--0.05; p = 0.002; I2 = 21%), but at the cost of increased surgical duration (mean difference = -12.50; 95%CI -24.06--0.95; p = 0.03; I2 = 94%). Although this represents a potentially negative outcome, the improvement in clearance rates justifies the additional investment of time and effort. Conclusion: Displacement of lower pole kidney stones for subsequent lithotripsy brings significant benefits in terms of stone-free rate, with no difference in laser energy usage. However, it results in increased surgical time. Despite these factors, the benefits to patients undergoing the procedure are substantial.
- Comparing financing models for supplementary healthcare in appendectomy: activity-based costing (fee-for-service) vs. diagnosis related group remuneration (bundled payment) - a systematic review and meta-analysis(2023) LINO, Andre de Arimateia de Souza; CRUZ, Jose Arnaldo Shiomi da; PORTO, Breno Cordeiro; NOGUEIRA, Rhuan Pimentel; OTOCH, Jose Pinhata; ARTIFON, Everson Luiz de AlmeidaPurpose: In Brazil, healthcare services traditionally follow a fee-for-service (FFS) payment system, in which each medical procedure incurs a separate charge. An alternative reimbursement with the aim of reducing costs is diagnosis related group (DRG) remuneration, in which all patient care is covered by a fixed amount. This work aimed to perform a systematic review followed by meta-analysis to assess the effectiveness of the Budled Payment for Care Improvement (BPCI) versus FFS. Methods: Our work was performed following the items of the PRISMA report. We included only observational trials, and the primary outcome assessed was the effectiveness of FFS and DRG in appendectomy considering complications. We also assessed the costs and length of hospital stay. Meta-analysis was performed with Rev Man version 5.4. Results: Out of 735 initially identified articles, six met the eligibility criteria. We demonstrated a shorter hospital stay associated with the DRG model (mean difference = 0.39; 95% confidence interval - 95%CI - 0.38-0.40; p < 0.00001; I2 = 0%), however the hospital readmission rate was higher in this model (odds ratio = 1.57; 95%CI 1.02-2.44, p = 0.04; I2 = 90%). Conclusion: This study reveals a potential decrease in the length of stay for appendectomy patients using the DRG approach. However, no significant differences were observed in other outcomes analysis between the two approaches.
- Establishment of a 7-gene expression panel to improve the prognosis classification of gastric cancer patients(2023) SOTOMAYOR, Mariana Belen Velasquez; SEGURA, Anthony Vladimir Campos; MONTALVA, Ricardo Jose Asurza; MARIN-SANCHEZ, Obert; CARRASCO, Alexis German Murillo; ROJAS, Cesar Alexander OrtizGastric cancer (GC) ranks fifth in incidence and fourth in mortality worldwide. The high death rate in patients with GC requires new biomarkers for improving survival estimation. In this study, we performed a transcriptome-based analysis of five publicly available cohorts to identify genes consistently associated with prognosis in GC. Based on the ROC curve, patients were categorized into high and low-expression groups for each gene using the best cutoff point. Genes associated with survival (AUC > 0.5; univariate and multivariate Cox regressions, p < 0.05) were used to model gene expression-based scores by weighted sum using the pooled Cox beta regression coefficients. Cox regression (p < 0.05), AUC > 0.5, sensitivity > 0.5, and specificity > 0.5 were considered to identify the best scores. Gene set enrichment analysis (KEGG, REACTOME, and Gene Ontology databases), as well as microenvironment composition and stromal cell signatures prediction (CIBERSORT, EPIC, xCell, MCP-counter, and quanTIseq web tools) were performed. We found 11 genes related to GC survival in the five independent cohorts. Then, we modeled scores by calculating all possible combinations between these genes. Among the 2,047 scores, we identified a panel based on the expression of seven genes. It was named GES7 and is composed of CCDC91, DYNC1I1, FAM83D, LBH, SLITRK5, WTIP, and NAP1L3 genes. GES7 features were validated in two independent external cohorts. Next, GES7 was found to recategorize patients from AJCC TNM stages into a best-fitted prognostic group. The GES7 was associated with activation of the TGF-beta pathway and repression of anticancer immune cells. Finally, we compared the GES7 with 30 previous proposed scores, finding that GES7 is one of the most robust scores. As a result, the GES7 is a reliable gene-expression-based signature to improve the prognosis estimation in GC.
- Robotic Myotomy and Partial Fundoplication for Achalasia(2023) SALLUM, Rubens Antonio Aissar; FERNANDES, Felipe Alexandre; BRANCO, Leonardo Torres; PEREIRA, Luna Serena Arguelho; CAMARA, Camila Maria Arruda Vilanova de; SIMOES, italo Beltrao Pereira; MEIRA JUNIOR, Jose Donizeti de; MAZEPA, Melissa Mello; CORBI, Leonardo Ervolino; GARCIA, Rodrigo Nicida; TAKEDA, Flavio RobertoLaparoscopic Heller myotomy is currently considered the standard definitive treatment of achalasia. With the advancements in technology, robotic Heller myotomy has emerged as an alternative approach to traditional laparoscopy due to threedimensional (3D) visualization, fine motor control, and improved ergonomics provided by the robot. Although there is a lack of randomized controlled trials, robotic-assisted Heller myotomy seems to be associated with lower rates of intraoperative perforations compared to the laparoscopic approach. A robotic approach may also improve surgical outcomes by providing a more complete myotomy. Here, we describe the detailed steps of robotic myotomy and partial fundoplication for achalasia.