GILBERTO DE CASTRO JUNIOR

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Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder

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  • article
    Repurposing NF kappa B and HDAC inhibitors to individually target cancer stem cells and non-cancer stem cells from mucoepidermoid carcinomas
    (2023) SILVA, Luan Cesar; BORGATO, Gabriell Bonifacio; WAGNER, Vivian Petersen; MARTINS, Manoela Domingues; SANTOS-SILVA, Alan Roger; JR, Gilberto de Castro; KOWALSKI, Luiz Paulo; SQUARIZE, Cristiane Helena; VARGAS, Pablo Agustin; CASTILHO, Rogerio Moraes
    Drug resistance remains a major obstacle in the treatment of mucoepidermoid carcinomas (MEC) lead-ing to tumor recurrence, disease progression, and metastasis. Emerging evidence suggests that drug resistance is mediated by the presence of a highly adaptative subpopulation of cancer cells known as cancer stem cells (CSC). We have previously reported that solid tumors use NFkB signaling as a chemotherapy-resistant mechanism. We have also shown that interfering with the epigenome of solid tumors is an effective strategy to control the popula-tion of CSC. Here, we sought to investigate the effects of the NFkB inhibitor emetine and the HDAC inhibitor SAHA on the biology of MEC CSC and assessed whether this combination therapy would favor the standard of care therapy comprised of the administration of Cisplatin (CDDP). Our findings suggested that the administration of low concen-trations of emetine and SAHA is more effective in disrupting CSC in MEC, while the administration of emetine in combination with CDDP constitutes an effective therapy to target non-CSC MEC tumor cells.
  • article 0 Citação(ões) na Scopus
    NEPTUNE China cohort: First-line durvalumab plus tremelimumab in Chinese patients with metastatic non-small-cell lung cancer
    (2023) CHENG, Ying; ZHOU, Qing; HAN, Baohui; FAN, Yun; SHAN, Li; CHANG, Jianhua; SUN, Si; FANG, Jian; CHEN, Yuan; SUN, Jianguo; WU, Gang; MANN, Helen; NAICKER, Kirsha; SHIRE, Norah; MOK, Tony; JR, Gilberto de Castro
    Objectives: The phase 3 NEPTUNE study (NCT02542293) evaluated first-line durvalumab plus tremelimumab (DT) versus chemotherapy for metastatic NSCLC. Prespecified exploratory analyses were conducted in an extended cohort enrolled in China. Materials and methods: Patients were randomized (1:1) to DT or standard chemotherapy, stratified by PD-L1 tumor cell (TC) expression (>= 25 % vs < 25 %), histology, and smoking history. The primary analysis for this cohort was overall survival (OS) in patients with PD-L1 TC < 1 %. Secondary analyses included OS and progression-free survival (PFS) in the ITT population and PD-L1 subgroups, and safety. No alpha was allocated to these cohort analyses (data cut-off, 21-September-2020). Results: 78 and 82 patients were randomized to DT and chemotherapy, respectively; 26 and 29 had PD-L1 TC < 1 % (median follow-up, 31.2 and 29.7 months [censored patients]). Among patients with PD-L1 TC < 1 %, OS favored DT versus chemotherapy (HR 0.60; 95 % CI, 0.32-1.11), with medians of 15.0 months (95 % CI, 10.5-27.4) and 11.7 months (95 % CI, 8.6-20.5), respectively; 24-month rates were 36.0 % (95 % CI, 18.2-54.2) and 17.9 % (95 % CI, 6.5-33.7). In the ITT population, OS was prolonged with DT versus chemotherapy (HR 0.70; 95 % CI, 0.48-1.02); medians were 20.0 and 14.1 months and 24-month rates were 44.2 % and 30.4 %. PFS was similar in the PD-L1 TC < 1 % (HR 1.13; 95 % CI, 0.59-2.14) and ITT (HR 0.95; 95 % CI, 0.66-1.36) populations; 12-month rates were 15.6 % versus 11.3 % and 23.9 % versus 16.6 %. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 31.2 % with DT and 52.6 % with chemotherapy; 3.9 % versus 10.3 % discontinued due to TRAEs. Conclusions: In exploratory analyses, first-line DT showed a trend towards improved OS versus chemotherapy among Chinese patients in the PD-L1 TC < 1 % population and ITT population, with 24-month OS and 12-month PFS rates indicating benefit in survival curve tails. DT was well tolerated with no new safety signals.
  • article 20 Citação(ões) na Scopus
    Exercise prescription for symptoms and quality of life improvements in lung cancer patients: a systematic review
    (2021) CODIMA, Alberto; SILVA, Willian das Neves; BORGES, Ana Paula de Souza; JR, Gilberto de Castro
    Purpose The purpose of this study was to conduct a systematic review to assess the effect of exercise on symptoms and quality of life in lung cancer patients. Methods We conducted a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Medline, Embase, Scopus, Web of Science, and SciELO were searched for studies published from January 1998 to January 2019. The review included all randomized controlled trials that evaluated the effect of exercise on symptoms and quality of life of lung cancer patients. Two reviewers independently assessed the quality of all the included studies using the Physiotherapy Evidence Database scale. Results In total, ten studies (835 participants) met all inclusion criteria. Three studies investigated the effect of exercise after lung resection, whereas four studies investigated it as a pre-surgery intervention. Two studies investigated the effect of exercise in patients under systemic treatment only, and one study included patients on diverse treatment plans. Exercise protocols consisted of different combinations of strength, aerobic, and inspiratory muscle training. Two trials, including 101 participants, found significant difference in quality of life between groups, favoring the intervention group; and five trials, including 549 participants, found significant inter-group differences in isolated symptoms, also favoring the intervention group. Conclusions Exercise can lead to improvements of symptoms and of quality of life in lung cancer survivors. Providing resistance training combined with high-intensity interval aerobic exercise after lung resection seems to be particularly effective. Further studies are warranted to investigate exercise for patients with poor performance status.
  • article 21 Citação(ões) na Scopus
    NEPTUNE: Phase 3 Study of First-Line Durvalumab Plus Tremelimumab in Patients With Metastatic NSCLC
    (2023) JR, Gilberto de Castro; RIZVI, Naiyer A.; SCHMID, Peter; SYRIGOS, Konstantinos; MARTIN, Claudio; YAMAMOTO, Nobuyuki; CHENG, Ying; MOISEYENKO, Vladimir; SUMMERS, Yvonne; VYNNYCHENKO, Ihor; LEE, Sung Yong; BRYL, Maciej; ZER, Alona; ERMAN, Mustafa; TIMCHEVA, Constanta; RAJA, Rajiv; NAICKER, Kirsha; SCHEURING, Urban; WALKER, Jill; MANN, Helen; CHAND, Vikram; MOK, Tony; NEPTUNE Investigators
    Introduction: NEPTUNE, a phase 3, open-label study, evaluated first-line durvalumab plus tremelimumab versus chemotherapy in metastatic NSCLC (mNSCLC).Methods: Eligible patients with EGFR and ALK wild-type mNSCLC were randomized (1:1) to first-line durvalumab (20 mg/kg every 4 weeks until progression) plus trem-elimumab (1 mg/kg every 4 weeks for up to four doses) or standard chemotherapy. Randomization was stratified by tumor programmed death-ligand 1 expression (>= 25% versus <25%), tumor histologic type, and smoking history. The amended primary end point was overall survival (OS) in patients with blood tumor mutational burden (bTMB) greater than or equal to 20 mutations per megabase (mut/ Mb). Secondary end points included progression-free sur-vival (PFS) in patients with bTMB greater than or equal to 20 mut/Mb and safety and tolerability in all treated patients. Results: As of June 24, 2019, 823 patients were randomized (intention-to-treat [ITT]); 512 (62%) were bTMB-evaluable, with 129 of 512 (25%) having bTMB greater than or equal to 20 mut/Mb (durvalumab plus tremelimumab [n = 69]; chemotherapy [n = 60]). Baseline characteristics were balanced in the intention-to-treat. Among patients with bTMB greater than or equal to 20 mut/Mb, OS improvement with durvalumab plus tremelimumab versus chemotherapy did not reach statistical significance (hazard ratio 0.71 [95% confidence interval: 0.49-1.05; p = 0.081]; median OS, 11.7 versus 9.1 months); the hazard ratio for PFS was 0.77 (95% confidence interval, 0.51-1.15; median PFS, 4.2 versus 5.1 months). In the overall safety population, incidence of grade 3 or 4 treatment-related adverse events was 20.7% (durva-lumab plus tremelimumab) and 33.6% (chemotherapy).Conclusions: NEPTUNE did not meet its primary end point of improved OS with durvalumab plus tremelimumab versus chemotherapy in patients with mNSCLC and bTMB greater than or equal to 20 mut/Mb. Despite the amended study design, with a resultant small primary analysis pop-ulation, therapeutic activity was aligned with expectations based on mechanistic biology and previous studies.(c) 2022 International Association for the Study of Lung Cancer.
  • article 2 Citação(ões) na Scopus
    Survival analysis of young adults from a Brazilian cohort of non-small cell lung cancer patients
    (2021) NICOLAU, Jessica Silva; LOPEZ, Rossana Veronica Mendoza; LUIZAGA, Carolina Terra de Moraes; RIBEIRO, Karina Braga; ROELA, Rosimeire Aparecida; MAISTRO, Simone; KATAYAMA, Maria Lucia Hirata; NATALINO, Renato Jose Mendonca; JR, Gilberto de Castro; NETO, Jose Eluf; FOLGUEIRA, Maria Aparecida Azevedo Koike
    Background: The influence of age at diagnosis in non-small cell lung cancer (NSCLC) prognosis is unclear. Objectives: To compare in a Brazilian cohort of NSCLC patients of different age groups: 1) The overall survival; 2) Clinical features and treatment options. Methods: This is a retrospective cohort study using a hospital-based registry, for NSCLC patients registered in years 2000-2009. Patients were grouped into three age groups: Young adults (YA: < 40 years), middle-aged (MA: 40-64 years) and elderly (E: >= 65 years). Kaplan-Meier was used to estimate overall survival and Cox regression for hazard ratios (HRs) and 95% confidence intervals. Results: 17,422 NSCLC patients were included: 370 YA (2.1%), 8,697 MA (49.9%) and 8,355 E (48.0%). Compared with older age groups, the YA group had a higher proportion of females, patients diagnosed with adenocarcinoma and metastatic disease (63.2%). Overall survival was longer in YA in the entire cohort and in all clinical stages (CSs) (p < 0.001). For YA, higher education level was a good prognosis factor (compared with illiterate and incomplete elementary); advanced or metastatic disease (compared with early-stage disease) and treatment based in radiotherapy or chemotherapy (CT) (without surgery), compared with treatment combinations with surgery, were poor prognostic factors. Young men (but not women) had lower HR of death compared with older groups; YA had lower HR of death in all CSs compared with patients from older groups. A higher percentage of YA were treated with surgery or CT in early-stage disease compared with older groups. Besides that, YA and MA patients treated with surgery or CT had a better prognosis than elderlies. Conclusions: In this Brazilian cohort of NSCLC patients, most young individuals were diagnosed with metastatic disease. YA presented longer survival than older age groups in all CSs, but mainly in CS I/II and III, where some patients may achieve long remissions or cure.
  • article 11 Citação(ões) na Scopus
    Oral leukoplakia and erythroplakia in young patients: a systematic review
    (2021) ROZA, Ana Luiza Oliveira Correa; KOWALSKI, Luiz Paulo; JR, William Nassib William; JR, Gilberto de Castro; CHAVES, Aline Lauda Freitas; ARAUJO, Anna Luiza Damaceno; RIBEIRO, Ana Carolina Prado; BRANDAO, Thais Bianca; LOPES, Marcio Ajudarte; VARGAS, Pablo Agustin; SANTOS-SILVA, Alan Roger
    Objective. The aim of this study was to estimate the frequency of oral leukoplakia and oral erythroplakia in young patients. Study Design. The systematic review was based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and performed in the following electronic databases: PubMed, Scopus, and Embase. The studies included were cross-sectional, cohort, and diagnostic, which provided with clinical and microscopic data of patients younger than 40 years. The Critical Appraisal Checklist for Prevalence Studies from the Joanna Briggs Institute and the Quality Assessment Tool for Diagnostic Accuracy Studies were used to assess the risk of bias. Results. Five studies met eligibility criteria and were included. The total number of patients from the studies was 1246, of which 115 were young patients (9.2%) with oral leukoplakia as the only oral potentially malignant disorder reported. Oral epithelial dysplasia was identified in 40 cases (34.7%), of which 8 (6.9%) presented malignant transformation. Conclusions. The frequency of oral leukoplakia is low in young patients. Observational studies are necessary for understanding oral leukoplakia and other oral potentially malignant disorders in younger patients.
  • article 14 Citação(ões) na Scopus
    Impact of the COVID-19 Pandemic on Oncology Clinical Research in Latin America (LACOG 0420)
    (2021) GONGORA, Aline B. Lara; WERUTSKY, Gustavo; JARDIM, Denis L.; NOGUEIRA-RODRIGUES, Angelica; BARRIOS, Carlos H.; MATHIAS, Clarissa; MALUF, Fernando; RIECHELMANN, Rachel; FRAGA, Mauricio; GOMES, Henry; WILLIAM, William N.; YAMADA, Camilla A. F.; JR, Gilberto de Castro; ROSA, Daniela D.; MELO, Andreia C. de; SALA, Raul; BUSTAMANTE, Eva; BRETEL, Denisse; ARRIETA, Oscar; CARDONA, Andres F.; BASTOS, Diogo A.
    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. (C) 2021 by American Society of Clinical Oncology
  • article 5 Citação(ões) na Scopus
    Non-Small-Cell Lung Cancer With CNS Metastasis: Disparities From a Real-World Analysis (GBOT-LACOG 0417)
    (2022) COELHO, Juliano Ce; CARVALHO, Giselle de Souza; CHAVES, Fabio; MARCHI, Pedro de; JR, Gilberto de Castro; BALDOTTO, Clarissa; MASCARENHAS, Eldsamira; PACHECO, Patricia; GOMES, Rafaela; WERUTSKY, Gustavo; ARAUJO, Luiz H.
    PURPOSE Despite the advances in the approach to non-small-cell lung cancer (NSCLC) with CNS metastasis, access to timely diagnosis and treatment may not be optimal in many instances. Our main objective was to describe a cohort of patients with NSCLC with brain metastases from public and private cancer centers, and the differences between patients' presentation, treatment, and outcomes. METHODS GBOT-LACOG 0417 is a multi-institutional retrospective cohort study of patients diagnosed with NSCLC and CNS metastasis in Brazil. All patients had confirmed diagnosis of NSCLC between January 2010 and December 2015. CNS metastases were identified by imaging. RESULTS A total of 273 patients were included. Patients treated at public institutions were more often Black or Brown (38.8% v 15.4%), current or former smoker (88.6% v 60.0%), of squamous cell histology (25.0% v 9.1%), EGFR- and ALK-negative (95.9% v 74.9%), and were less frequently assessed by using brain magnetic resonance imaging (38.8% v 83.6%). At public institutions, patients were more often symptomatic (78.1% v 44.6%) and had worse performance status (Eastern Cooperative Oncology Group 2 or higher 61.5% v 10.3%). CNS metastases were larger (median size 25 v 15 mm) and more often surrounded by edema (67.7% v 55.2%) at public institutions. Patients at public institutions were more frequently treated with whole-brain radiation therapy (72.9% v 45.4%) and less frequently with radiosurgery (6.3% v 24.1%). Among patients from private care, median overall survival was 24.2 months (95% CI, 20.0 to 30.6), significantly higher than in public care (median 12.1 months; 95% CI, 6.7 to 13.6; P < .001). CONCLUSION Our results demonstrate the discrepancy between public and private health care system in the critical setting of patients with CNS metastasis from NSCLC. (C) 2022 by American Society of Clinical Oncology
  • article 11 Citação(ões) na Scopus
    A phase 2 study of first-line nivolumab in patients with locally advanced or metastatic cutaneous squamous-cell carcinoma
    (2022) MUNHOZ, Rodrigo R.; NADER-MARTA, Guilherme; CAMARGO, Veridiana P. de; QUEIROZ, Marcello M.; CURY-MARTINS, Jade; RICCI, Herminia; MATTOS, Marcela R. de; MENEZES, Thiago A. F. de; MACHADO, Guilherme U. C.; BERTOLLI, Eduardo; BARROS, Milton; SOUZA, Carina E. de; FRANKE, Fabio; FERREIRA, Fabio O.; FEHER, Olavo; JR, Gilberto de Castro
    Background Cutaneous squamous-cell carcinoma (CSCC) is among the most frequent malignancies worldwide. For those not amenable to treatment with curative intent, immune checkpoint inhibition (ICI) with anti-programmed death receptor 1 (PD-1) antibodies has emerged as a novel therapeutic option. In this study, the authors sought to investigate the activity of the anti-PD-1 agent nivolumab in patients with advanced CSCC (aCSCC). Methods CA209-9JC was an open-label, single-arm, phase 2 study to evaluate the safety and/or efficacy of nivolumab in systemic treatment-naive patients with aCSCC. Nivolumab (3 mg/kg) was administered every 2 weeks until disease progression, unacceptable toxicity, or 12 months of treatment. The primary end point was the best objective response rate (BORR) as per RECIST 1.1 criteria. Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Results Twenty-four patients with aCSCC were enrolled with a median age of 74 years (range, 48-93). Among the 24 patients evaluable for response, the BORR was 58.3% (14/24); there were no complete responses. With a median follow-up of 17.6 months, median duration of response has not been reached, and the estimated median PFS and OS were 12.7 and 20.7 months, respectively. Prior exposure to radiotherapy was associated with worse outcomes (p = .035, univariate analysis). Treatment-related adverse events of any grade and grade >= 3 occurred in 21 (87.5%) and six (25%) patients, respectively, and one patient discontinued nivolumab due to toxicities. Conclusions Nivolumab resulted in robust antitumor activity, sustained responses, and good tolerability in systemic treatment-naive patients with aCSCC. These data provide further evidence to support the use of ICI as the standard treatment of aCSCC.
  • article 7 Citação(ões) na Scopus
    Valproic acid combined with cisplatin-based chemoradiation in locally advanced head and neck squamous cell carcinoma patients and associated biomarkers
    (2020) MAK, Milena Perez; PASINI, Fatima Solange; DIAO, Lixia; GARCIA, Fabyane O. Teixeira; TAKAHASHI, Tiago Kenji; NAKAZOTO, Denyei; MARTINS, Renata Eiras; ALMEIDA, Cristiane Maria; KULCSAR, Marco Aurelio Vamondes; LAMOUNIER, Valdelania Aparecida; NUNES, Emily Montosa; SOUZA, Isabela Cristina de; GARCIA, Marcio Ricardo Taveira; AMADIO, Alex Vieira; SIQUEIRA, Sheila Aparecida C.; SNITCOVSKY, Igor Moyses Longo; SICHERO, Laura; WANG, Jing; JR, Gilberto de Castro
    Background: Cisplatin-based chemoradiation (CCRT) offers locally advanced head and neck squamous cell carcinoma (LAHNSCC) patients high local control rate, however, relapses are frequent. Our goal was to evaluate if association of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, with CCRT improved response rate (RR) and associated biomarkers. Methods: This phase II trial included patients with unresectable locally advanced (LA) oropharynx (OP) squamous cell carcinoma. CCRT began after 2 weeks of VPA (P1). Primary goal was RR at 8 weeks after chemoradiation (CRT)+VPA (P2). Biomarkers included microRNA (miR) polymerase chain reaction (PCR)-array profiling in plasma compared to healthy controls by two-sample t-test. Distribution of p-values was analysed by beta-uniform mixture. Findings were validated by real-time PCR quantitative polymerase chain reaction (qPCR) for selected miRs in plasma and saliva. p16, HDAC2 and RAD23 Homolog B, Nucleotide Excision Repair Protein (HR23B) tumour immunohistochemistry were evaluated. Results: Given significant toxicities, accrual was interrupted after inclusion of ten LA p16 negative OP patients. All were male, smokers/ex-smokers, aged 41-65 and with previous moderate/high alcohol intake. Nine evaluable patients yielded a RR of 88%. At false discovery rate of 5%, 169 miRs were differentially expressed between patients and controls, including lower expression of tumour suppressors (TSs) such as miR-31, -222, -let-7a/b/e and -145. miR-let-7a/e expression was validated by qPCR using saliva. A HDAC2 H-score above 170 was 90% accurate in predicting 6-month disease-free survival. Conclusions: VPA and CRT offered high RR; however, with prohibitive toxicities, which led to early trial termination. Patients and controls had a distinct pattern of miR expression, mainly with low levels of TS miRs targeting Tumor protein P53 (TP53). miR-let-7a/e levels were lower in patients compared to controls, which reinforces the aggressive nature of such tumours (NCT01695122).