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1.
Adv Exp Med Biol ; 1280: 219-230, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33791985

RESUMO

Head and neck squamous cell carcinoma (HNSCC) glycolysis is an important factor for the advancement of the disease and metastasis. Upregulation of glycolysis leads to decreased sensitivity to chemotherapy and radiation. HNSCC cells maintain constitutive glycolytic flux generating metabolic intermediates for the synthesis of amino acids, nucleotides, and fats for cell survival and disease progression. There are several pathways such as PI3K/Akt, EGFR, and JAK-STAT that contribute a major role in metabolic alteration in HNSCC. Recent studies have demonstrated that cancer-associated fibroblasts abundant in the HNSCC tumor microenvironment play a major role in HNSCC metabolic alteration via hepatocyte growth factor (HGF)/c-Met cross signaling. Despite therapeutic advancement, HNSCC lacks broad range of therapeutic interventions for the treatment of the disease. Thus, understanding the different key players involved in glucose metabolism and targeting them would lead to the development of novel drugs for the treatment of HNSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Glicólise , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Fosfatidilinositol 3-Quinases/genética , Microambiente Tumoral
3.
Gan To Kagaku Ryoho ; 48(2): 207-210, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33597360

RESUMO

OBJECTIVE: Cisplatin(CDDP)is a key drug for head and neck cancer therapy, but frequently induces severe adverse events including renal dysfunction. Nedaplatin(CDGP)was developed and is used in Japan; it has certain benefits over CDDP. Unlike CDDP, CDGP treatment does not require hydration. However, CDGP is not used globally and thus safety information is lacking. Therefore, we surveyed safety profiles for CDGP-based chemotherapy. METHODS: A survey was conducted at Showa University Hospital. Thirty-eight patients treated for head and neck cancer combined with radiotherapy(RTx)and tegafur- gimeracil-oteracil(S-1)between April 2012 and March 2015 were included. Laboratory-based adverse events(WBC, Hb, platelet[Plt], SCr, Alb)and oral mucositis were assessed according to CTCAE v5.0. Time-onset profiles for adverse events were evaluated after starting chemoradiotherapy. RESULTS: In 38 patients, Plt nadir was observed following 40(30-70)Gy and sustained for 14(7-35)days. WBC patterns followed similar profiles, but for Hb, nadir was observed following 60(40- 70)Gy and was less frequently sustained throughout the RTx. Alb and SCr levels were not correlated with therapy. Oral mucositis was observed following 50(10-70)Gy. CONCLUSION: In conclusion, at approximately 40 Gy, we observed decreases in WBC and Plt, with an increase in oral mucositis. Based on these results, medical staffs must closely monitor patients, especially at doses within range of 40 Gy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de Cabeça e Pescoço , Cisplatino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Japão , Compostos Organoplatínicos
4.
Artigo em Inglês | MEDLINE | ID: mdl-33535507

RESUMO

BACKGROUND: Cisplatin administration may induce muscle atrophy, thereby reducing the fitness level of patients with head and neck cancer (HNC). To date, only animal studies have been conducted to test the effectiveness of exercise interventions in diminishing side effects of cisplatin. AIM: To determine whether exercise training improves physical fitness and health-related quality of life (HRQoL) in patients receiving chemotherapy for Head & Neck (H&N). MATERIAL AND METHODS: This pilot-randomized controlled trial was conducted on 57 participants receiving chemotherapy for HNC. The participants were randomized into an exercise group and a control group. The exercise group received moderate-intensity combined aerobic, resistance and flexibility exercises three times a week for eight weeks during chemotherapy. The control group received no specific information regarding exercise. The outcome measures including body composition, muscle strength, balance, flexibility, cardiovascular fitness and health-related quality of life (HRQoL) were assessed at baseline and eight weeks following baseline. RESULTS: The body composition (body fat percentage, p = 0.002; skeletal muscle percentage, p = 0.008), dynamic balance (p = 0.01), muscle strength (upper extremity, p = 0.037; lower extremity, p = 0.025) and HRQoL (p = 0.001) showed a significant difference between the exercise group and the control group eight weeks following baseline. Significant deteriorations were noted in flexibility, muscle strength, cardiovascular fitness and several domains of HRQoL scale in the control group at eight weeks following baseline. CONCLUSIONS: This study found that a combined aerobic, resistance and flexibility exercise program during chemotherapy may improve physical fitness (i.e., muscle strength, balance, flexibility and body composition) and HRQoL and alleviate the deterioration of cardiovascular fitness in patients with HNC. Further research studies with large sample sizes are warranted to investigate the long-term effects of exercise in this population.


Assuntos
Neoplasias de Cabeça e Pescoço , Treinamento de Resistência , Exercício Físico , Terapia por Exercício , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Força Muscular , Aptidão Física , Projetos Piloto , Qualidade de Vida
5.
Medicine (Baltimore) ; 100(4): e24339, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33530227

RESUMO

BACKGROUND: In recent years, a number of clinical trials for antibody drugs targeting programmed cell death protein 1 (PD1)/programmed cell death 1 ligand 1 (PD-L1) have been carried out on recurrent or metastatic head and neck squamous cell carcinoma (R/M SCCHN) and reported promising prospects. To further evaluate and understand the effects and risk of anti-PD1/PD-L1 monotherapy vs standard of care (SoC) in R/M SCCHN, we conducted this meta-analysis of published randomized controlled trials. METHOD: The potential eligible trials were searched from Cochrane library and Pubmed and Embase databases. Randomized controlled trials evaluating the effects and risk of anti-PD1/PD-L1 monotherapy vs SoC in platinum refractory R/M SCCHN were selected. The outcomes, including objective response rate, disease control rate, progression-free survival, overall survival, and treatment-related adverse events, were extracted and pooled. RESULTS: 1345 patients with R/M SCCHN from three randomized controlled trials were enrolled in this analysis. Compared with SoC, anti-PD1/PD-L1 monotherapy could provide statistically significant overall survival benefit, hazard ratio (95% confidence interval ) = 0.79 [0.70-0.90]. However, we observed no significant difference between 2 treatments in progression-free survival (hazard ratio [95% confidence interval] = 0.96 [0.85-1.09]). Furthermore, anti-PD1/PD-L1 monotherapy caused less treatment-related adverse events than standard of care. CONCLUSION: Anti-PD1/PD-L1 monotherapy could indeed reduce the risk of death in R/M SCCHN patients, and provide higher safety vs SoC. Expression level of PD-L1 may be a useful biomarker for selecting patients with better response to anti-PD1/PD-L1 monotherapy.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Padrão de Cuidado/estatística & dados numéricos , Adulto , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/imunologia , Feminino , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/mortalidade , Seleção de Pacientes , Receptor de Morte Celular Programada 1/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Resultado do Tratamento
6.
BMJ Case Rep ; 14(1)2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436358

RESUMO

Desmoid tumours are rare locally aggressive mesenchymal tumours with a high local recurrence rate, particularly in the head and neck locations. We present the case of a 5-year-old child with a locally invasive inoperable desmoid tumour of the masticator space who underwent a low-dose chemotherapy regimen for 17 months, obtaining a long-term complete response. Definitive evidenced-based treatment guidelines are lacking. Therefore, paediatric patients should be managed by specialised multidisciplinary teams to try to achieve the best tumour control while minimising treatment associated morbidity and mortality. Available treatment options include surgery, radiotherapy and different systemic medical therapies. Whereas traditionally, surgery was the mainstay of treatment, more conservative options have increasingly shown adequate tumour control with little associated morbidity. In this decision making it is mandatory to take into account the patient's age, tumour location and extension, and potential short-term and long-term treatment-related sequelae to minimise functional and cosmetic compromise.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Pré-Escolar , Humanos
7.
Anal Chem ; 93(5): 2767-2775, 2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33474935

RESUMO

Clinical tissue specimens are often unscreened, and preparation of tissue sections for analysis by mass spectrometry imaging (MSI) can cause aerosolization of particles potentially carrying an infectious load. We here present a decontamination approach based on ultraviolet-C (UV-C) light to inactivate clinically relevant pathogens such as herpesviridae, papovaviridae human immunodeficiency virus, or SARS-CoV-2, which may be present in human tissue samples while preserving the biodistributions of analytes within the tissue. High doses of UV-C required for high-level disinfection were found to cause oxidation and photodegradation of endogenous species. Lower UV-C doses maintaining inactivation of clinically relevant pathogens to a level of increased operator safety were found to be less destructive to the tissue metabolome and xenobiotics. These doses caused less alterations of the tissue metabolome and allowed elucidation of the biodistribution of the endogenous metabolites. Additionally, we were able to determine the spatially integrated abundances of the ATR inhibitor ceralasertib from decontaminated human biopsies using desorption electrospray ionization-MSI (DESI-MSI).


Assuntos
Descontaminação/métodos , Raios Ultravioleta , Animais , Azetidinas/análise , Azetidinas/uso terapêutico , /virologia , Neoplasias de Cabeça e Pescoço/química , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Metaboloma , Naftalenos/análise , Naftalenos/uso terapêutico , Fotólise/efeitos da radiação , Ratos , Ratos Wistar , /efeitos da radiação , Espectrometria de Massas por Ionização por Electrospray/métodos , Terfenadina/química , Inativação de Vírus/efeitos da radiação
8.
J Med Chem ; 64(1): 741-767, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33400524

RESUMO

Erlotinib was covalently linked to 3-(1'-hexyloxy)ethyl-3-devinylpyropheophorbide-a (HPPH) and structurally related chlorins and bacteriochlorins at different positions of the tetrapyrrole ring. The functional consequence of each modification was determined by quantifying the uptake and subcellular deposition of the erlotinib conjugates, cellular response to therapeutic light treatment in tissue cultures, and in eliminating of corresponding tumors grown as a xenograft in SCID mice. The experimental human cancer models the established cell lines UMUC3 (bladder), FaDu (hypopharynx), and primary cultures of head and neck tumor cells. The effectiveness of the compounds was compared to that of HPPH. Furthermore, specific functional contribution of the carboxylic acid side group at position 172 and the chiral methyl group at 3(1') to the overall activity of the chimeric compounds was assessed. Among the conjugates investigated, the PS 10 was identified as the most effective candidate for achieving tumor cell-specific accumulation and yielding improved long-term tumor control.


Assuntos
Cloridrato de Erlotinib/química , Fármacos Fotossensibilizantes/síntese química , Porfirinas/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Camundongos , Camundongos SCID , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Estereoisomerismo , Relação Estrutura-Atividade , Taxa de Sobrevida
12.
Nat Commun ; 11(1): 5667, 2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-33168818

RESUMO

Poor tissue penetration remains a major challenge for antibody-based therapeutics of solid tumors, but proper dosing can improve the tissue penetration and thus therapeutic efficacy of these biologics. Due to dose-limiting toxicity of the small molecule payload, antibody-drug conjugates (ADCs) are administered at a much lower dose than their parent antibodies, which further reduces tissue penetration. We conducted an early-phase clinical trial (NCT02415881) and previously reported the safety of an antibody-dye conjugate (panitumumab-IRDye800CW) as primary outcome. Here, we report a retrospective exploratory analysis of the trial to evaluate whether co-administration of an unconjugated antibody could improve the intratumoral distribution of the antibody-dye conjugate in patients. By measuring the multiscale distribution of the antibody-dye conjugate, this study demonstrates improved microscopic antibody distribution without increasing uptake (toxicity) in healthy tissue when co-administered with the parent antibody, supporting further clinical investigation of the co-administration dosing strategy to improve the tumor penetration of ADCs.


Assuntos
Anticorpos/administração & dosagem , Anticorpos/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Imunoconjugados/administração & dosagem , Imunoconjugados/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Indóis/administração & dosagem , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados não Aleatórios como Assunto , Panitumumabe/administração & dosagem , Estudos Prospectivos , Estudos Retrospectivos
13.
Mol Carcinog ; 59(10): 1147-1158, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32805066

RESUMO

Acquired resistance is a barrier to cetuximab efficacy in patients with head and neck squamous cell carcinoma (HNSCC). Secreted phosphoprotein 1 (SPP1) is involved in various biological processes, including immune responses, cancer progression, and prognosis in many cancers, while little is known in HNSCC. Bioinformatics methods were used to identify candidate genes and further in vivo and in vitro experiments were performed to examine and validate the function of SPP1. We found that SPP1 was upregulated and has been found to have an oncogenic role in HNSCC. We further confirmed that overexpression of SPP1 affected proliferation, migration, invasion, and survival, and inhibited apoptosis, whereas silencing of SPP1 yielded opposite results to those of SPP1 overexpression. In addition, activation of the KRAS/MEK pathway contributed to the SPP1-induced malignant progression of HNSCC and resistance to cetuximab. Furthermore, SPP1 knockdown or an MEK inhibitor overcame this cetuximab-resistance pattern. Taken together, our findings for the first time identify the role of SPP1 in tumor promotion, prognostic prediction, and potential therapeutic targeting, as well as resistance to cetuximab in HNSCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Cetuximab/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias de Cabeça e Pescoço/patologia , MAP Quinase Quinase 1/metabolismo , Osteopontina/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Animais , Antineoplásicos Imunológicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , MAP Quinase Quinase 1/genética , Camundongos , Camundongos Nus , Invasividade Neoplásica , Osteopontina/genética , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Lancet Glob Health ; 8(9): e1213-e1222, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32827483

RESUMO

BACKGROUND: Regimens for palliation in patients with head and neck cancer recommended by the US National Comprehensive Cancer Network (NCCN) have low applicability (less than 1-3%) in low-income and middle-income countries (LMICs) because of their cost. In a previous phase 2 study, patients with head and neck cancer who received metronomic chemotherapy had better outcomes when compared with those who received intravenous cisplatin, which is commonly used as the standard of care in LMICs. We aimed to do a phase 3 study to substantiate these findings. METHODS: We did an open-label, parallel-group, non-inferiority, randomised, phase 3 trial at the Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India. We enrolled adult patients (aged 18-70 years) who planned to receive palliative systemic treatment for relapsed, recurrent, or newly diagnosed squamous cell carcinoma of the head and neck, and who had an Eastern Cooperative Oncology Group performance status score of 0-1 and measurable disease, as defined by the Response Evaluation Criteria In Solid Tumors. We randomly assigned (1:1) participants to receive either oral metronomic chemotherapy, consisting of 15 mg/m2 methotrexate once per week plus 200 mg celecoxib twice per day until disease progression or until the development of intolerable side-effects, or 75 mg/m2 intravenous cisplatin once every 3 weeks for six cycles. Randomisation was done by use of a computer-generated randomisation sequence, with a block size of four, and patients were stratified by primary tumour site and previous cancer-directed treatment. The primary endpoint was median overall survival. Assuming that 6-month overall survival in the intravenous cisplatin group would be 40%, a non-inferiority margin of 13% was defined. Both intention-to-treat and per-protocol analyses were done. All patients who completed at least one cycle of the assigned treatment were included in the safety analysis. This trial is registered with the Clinical Trials Registry-India, CTRI/2015/11/006388, and is completed. FINDINGS: Between May 16, 2016, and Jan 17, 2020, 422 patients were randomly assigned: 213 to the oral metronomic chemotherapy group and 209 to the intravenous cisplatin group. All 422 patients were included in the intention-to-treat analysis, and 418 patients (211 in the oral metronomic chemotherapy group and 207 in the intravenous cisplatin group) were included in the per-protocol analysis. At a median follow-up of 15·73 months, median overall survival in the intention-to-treat analysis population was 7·5 months (IQR 4·6-12·6) in the oral metronomic chemotherapy group compared with 6·1 months (3·2-9·6) in the intravenous cisplatin group (unadjusted HR for death 0·773 [95% CI 0·615-0·97, p=0·026]). In the per-protocol analysis population, median overall survival was 7·5 months (4·7-12·8) in the oral metronomic chemotherapy group and 6·1 months (3·4-9·6) in the intravenous cisplatin group (unadjusted HR for death 0·775 [95% CI 0·616-0·974, p=0·029]). Grade 3 or higher adverse events were observed in 37 (19%) of 196 patients in the oral metronomic chemotherapy group versus 61 (30%) of 202 patients in the intravenous cisplatin group (p=0·01). INTERPRETATION: Oral metronomic chemotherapy is non-inferior to intravenous cisplatin with respect to overall survival in head and neck cancer in the palliative setting, and is associated with fewer adverse events. It therefore represents a new alternative standard of care if current NCCN-approved options for palliative therapy are not feasible. FUNDING: Tata Memorial Center Research Administration Council. TRANSLATIONS: For the Hindi, Marathi, Gujarati, Kannada, Malayalam, Telugu, Oriya, Bengali, and Punjabi translations of the abstract see Supplementary Materials section.


Assuntos
Cisplatino/administração & dosagem , Cisplatino/economia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Metástase Neoplásica/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Administração Intravenosa , Administração Metronômica , Administração Oral , Adolescente , Adulto , Idoso , Custos e Análise de Custo , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
15.
J Cancer Res Ther ; 16(3): 539-545, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719264

RESUMO

Aim: The purpose of this study was to assess and compare the incidence and severity of sensorineural hearing loss (SNHL) in head-and-neck patients undergoing radiotherapy (RT) and concurrent cisplatin-based chemoradiotherapy (CRT). Materials and Methods: Pure tone audiometry (PTA) was performed at 0.25-12 kHz on 35 RT and 25 CRT patients after 12-month followed up. The hearing loss was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) criteria. Results: SNHL increased to 84% in patients who had received CRT, compared with 26% increasing in patients who had treated with RT. There was an increased risk of SNHL at all frequencies for ears received a cochlear mean dose >50 Gy in RT group, compared to those receiving cochlear mean dose >30 Gy in CRT group. SNHL was more severe at higher frequencies in both patient groups. Conclusion: Characteristic of radiation-induced SNHL is different from CRT-induced SNHL, especially in threshold radiation dose and PTA frequency.


Assuntos
Quimiorradioterapia/efeitos adversos , Cisplatino/efeitos adversos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/etiologia , Radioterapia Conformacional/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Audiometria de Tons Puros/métodos , Criança , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/terapia , Perda Auditiva Neurossensorial/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Dosagem Radioterapêutica , Adulto Jovem
16.
J Cancer Res Ther ; 16(3): 559-564, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719267

RESUMO

Background: Head-and-neck cancer is the most common cancer in developing countries of Southeast Asia. Most of the patients present to the hospital in advanced stage and have a poor prognosis. This study aims to evaluate the efficacy and toxicity profile of oral metronomic chemotherapy (MCT) in the form of methotrexate and celecoxib in locally advanced, recurrent and metastatic head-and-neck cancers. Materials and Methods: This was a single-arm retrospective observational study that included posttreatment patients with locally advanced, recurrent and metastatic disease in the year 2016 (January 1, to December 31, 2016). A total of 84 patients warranting palliative chemotherapy but not willing to take intravenous chemotherapy were included in the study. The oral MCT schedule consisted of oral celecoxib (200 mg twice daily) and oral methotrexate (15 mg/m2/week). Response evaluation was done using the Response Evaluation Criteria in Solid Tumors criteria version 1.1, and toxicity profile was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Descriptive statistics and Kaplan-Meier analysis were performed. Results: Eighty-four patients, 68 males and 16 females, with a median age of 62 years (range: 35-80 years), were enrolled in the study to receive oral MCT. The Eastern Cooperative Oncology Group performance status was 0-1 in 62 patients and 2-3 in 22 patients. The primary sites of disease were buccal mucosa (18), tongue (22), tonsil (24), lower alveolus (7), hypopharynx (10), and soft palate (3). The best clinical response rate in post oral MCT was seen in the first 4 months (120 days). Objective response was observed in 67% of patients in the form of stable disease (56%) and partial response (11%). Disease progression was observed in 27% of patients. The median follow-up was 192 (6.4 months) days. The median estimated overall survival was 195 (6.5 months) days. The median estimated progression-free survival was 110 (3.6 months) days. Symptomatic relief with respect to pain was reported in about 75% of patients. Eighteen (21%) patients had Grade I-II mucosal reactions. Grade III-IV mucosal reactions were observed in five (6%) patients. Seventy-eight (93%) patients died at the end of the study at 1 year. Dose reduction was required in 15 (18%) patients. Conclusion: Oral MCT using celecoxib and methotrexate is an effective, economical, and well-tolerated regimen with good pain control and low toxicity profile in patients with locally advanced, recurrent and metastatic head-and-neck cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Cuidados Paliativos/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Administração Metronômica , Adulto , Idoso , Idoso de 80 Anos ou mais , Celecoxib/administração & dosagem , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Índia , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Taxa de Sobrevida
17.
J Cancer Res Ther ; 16(3): 565-568, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719268

RESUMO

Context: Head-and-neck cancer patients undergoing chemoradiation. Aims: The aim of the study was to see if there is any correlation between the planning target volume (PTV) and mucositis. Settings and Design: This was a single-arm prospective study. Subjects and Methods: A total of forty head-and-neck cancer patients undergoing chemoradiation were assessed for mucositis at the 5th week. The grades of mucositis were correlated with PTVs of low risk (54 Gy) and high risk (60-66 Gy). Statistical Analysis Used: The data were analyzed using the statistical software, SPSS Inc. Release 2009, predictive analytics software statistics for windows version 20.0, Chicago. Log transformation was done as the data were skewed. Independent t-test was used to compare between the two grades of toxicity. P <0.01 was considered for statistical significance. Results: The mean PTVlow risk was 522cc (228-771) and PTVhigh risk was 254cc (20-780). Grade II mucositis was seen in 27 (67%) patients and Grade III in 11 (28%) patients. The mean PTVlow risk was higher for patients, who had Grade III compared to Grade II mucositis (571 vs. 517 cc, P = 0.052). Conclusions: The same was seen for PTVhigh risk(367 vs. 222 cc, P = 0.017). PTV is a better predictor of mucositis, and those patients with larger PTV require close monitoring and early intervention of mucositis.


Assuntos
Neoplasias de Cabeça e Pescoço/radioterapia , Mucosite/etiologia , Lesões por Radiação/etiologia , Planejamento da Radioterapia Assistida por Computador/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mucosite/diagnóstico , Mucosite/patologia , Gradação de Tumores , Estadiamento de Neoplasias , Estudos Prospectivos , Lesões por Radiação/patologia , Dosagem Radioterapêutica , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Estomatite/diagnóstico , Estomatite/etiologia , Estomatite/patologia
18.
Oncology ; 98(11): 763-770, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32629446

RESUMO

OBJECTIVES: Induction chemotherapy followed by cetuximab and RT (IBRT) (Arm A) was compared to cisplatin/RT (CRT) (Arm B) in a randomized phase III study. PATIENTS AND METHODS: Naïve patients with stage III-IVa, histologically proven locally advanced head and neck cancer (LASCCHN) were eligible. Arm A (IBRT): 3 TPF induction followed by cetuximab-RT (equivalent daily dose 2 Gy up to 70 Gy); Arm B: 3 cisplatin concurrent with the same RT scheduling. Due to slow accrual and incomplete data collection a futility analysis was performed. RESULTS: 236/282 patients were evaluable. Therefore, no formal analyses can be made between the two arms. OS was 45.2/53.6 months in Arm A/B. Complete responses were achieved in 64% of patients in both arms. Neutropenia and skin toxicity were significantly worse in Arm A and body weight loss was significantly worse in Arm B. Compliance with the planned drug administration was higher in Arm B (p = 0.0008). CONCLUSION: The study suggests that IBRT and CRT have similar efficacy, activity and toxicity.


Assuntos
Cetuximab/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Cetuximab/efeitos adversos , Quimiorradioterapia , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Quimioterapia de Indução , Masculino , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
19.
Medicine (Baltimore) ; 99(28): e21273, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664183

RESUMO

BACKGROUND: The combination of durvalumab and tremelimumab results in clinical benefit, with a tolerable safety profile in patients with solid tumors. OBJECTIVE: To evaluate the efficacy and safety of durvalumab in combination with tremelimumab compared with either drug alone. METHODS: The online databases (PubMed, Web of Science, EMBASE, and Cochrane Library) were searched for potential clinical studies up to Nov 26, 2019. Eligible studies were prospective and registered clinical trials. Pooled odds ratios for objective response rate and disease control rate and pooled risk ratios for treatment-related adverse events were meta-analyzed. A random-effect model was used due to the synthesis of different cancer types. RESULTS: Overall, 5 studies were eligible for systematic review, 3 of which were further meta-analyzed. Durvalumab plus tremelimumab was superior to tremelimumab monotherapy in improving disease control rate in head and neck squamous cell carcinoma. However, there were no significant differences between dual immunotherapy and mono-immunotherapy in pancreatic ductal adenocarcinoma and gastric and gastroesophageal junction adenocarcinoma. Additionally, pooled analyses illustrated that no significant differences in treatment-related adverse events were displayed between the 2 groups. CONCLUSION: Durvalumab and tremelimumab combination therapy had a good safety profile and resulted in clinical benefit in head and neck squamous cell carcinoma. Future explorations are needed to further confirm the application of durvalumab plus tremelimumab.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Idoso , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento
20.
Mol Cell ; 79(3): 425-442.e7, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32615088

RESUMO

Double-strand breaks (DSBs) are the most deleterious DNA lesions, which, if left unrepaired, may lead to genome instability or cell death. Here, we report that, in response to DSBs, the RNA methyltransferase METTL3 is activated by ATM-mediated phosphorylation at S43. Phosphorylated METTL3 is then localized to DNA damage sites, where it methylates the N6 position of adenosine (m6A) in DNA damage-associated RNAs, which recruits the m6A reader protein YTHDC1 for protection. In this way, the METTL3-m6A-YTHDC1 axis modulates accumulation of DNA-RNA hybrids at DSBs sites, which then recruit RAD51 and BRCA1 for homologous recombination (HR)-mediated repair. METTL3-deficient cells display defective HR, accumulation of unrepaired DSBs, and genome instability. Accordingly, depletion of METTL3 significantly enhances the sensitivity of cancer cells and murine xenografts to DNA damage-based therapy. These findings uncover the function of METTL3 and YTHDC1 in HR-mediated DSB repair, which may have implications for cancer therapy.


Assuntos
Adenosina/análogos & derivados , Neoplasias de Cabeça e Pescoço/genética , Metiltransferases/genética , Proteínas do Tecido Nervoso/genética , Fatores de Processamento de RNA/genética , Reparo de DNA por Recombinação/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Adenosina/metabolismo , Animais , Antibióticos Antineoplásicos/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Bleomicina/farmacologia , Linhagem Celular Tumoral , DNA/genética , DNA/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Células HEK293 , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Metiltransferases/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas do Tecido Nervoso/metabolismo , Hibridização de Ácido Nucleico , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoblastos/patologia , Fosforilação , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Fatores de Processamento de RNA/metabolismo , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismo , Ribonuclease H/genética , Ribonuclease H/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
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