RESUMO
Human pharyngeal squamous cell carcinoma (HPSCC) is the most common malignancy in the head and neck region, characterized by high mortality and a propensity for metastasis. Fucoxanthin, a carotenoid isolated from brown algae, exhibits pharmacological properties associated with the suppression of tumor proliferation and metastasis. Nevertheless, its potential to inhibit HPSCC proliferation and metastasis has not been fully elucidated. This study represents the first exploration of the inhibitory effects of fucoxanthin on two human pharyngeal squamous carcinoma cell lines (FaDu and Detroit 562), as well as the mechanisms underlying those effects. The results showed dose-dependent decreases in the proliferation, migration, and invasion of HPSCC cells after fucoxanthin treatment. Further studies indicated that fucoxanthin caused a significant reduction in the expression levels of proteins in the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway, as well as the downstream proteins matrix metalloproteinase (MMP)-2 and MMP-9. Specific activators of PI3K/AKT reversed the effects of fucoxanthin on these proteins, as well as on cell proliferation and metastasis, in FaDu and Detroit 562 cells. Molecular docking assays confirmed that fucoxanthin strongly interacted with PI3K, AKT, mTOR, MMP-2, and MMP-9. Overall, fucoxanthin, a functional food component, is a potential therapeutic agent for HPSCC.
Assuntos
Movimento Celular , Proliferação de Células , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Serina-Treonina Quinases TOR , Xantofilas , Humanos , Serina-Treonina Quinases TOR/metabolismo , Xantofilas/farmacologia , Xantofilas/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proliferação de Células/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Neoplasias Faríngeas/tratamento farmacológico , Neoplasias Faríngeas/patologia , Neoplasias Faríngeas/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Metástase Neoplásica , Simulação de Acoplamento MolecularRESUMO
BACKGROUND: Concurrent chemo-radiotherapy (CCRT) is an ideal treatment for advanced head and neck squamous cell carcinoma (HNSCC). The performance of CCRT induces severe toxicities in HNSCC patients and decreases the quality of life (QOL). Maitake D-Fraction is proteoglycan which has anti-tumor function associated with its immunomodulatory capacity. The polysaccharides of Maitake also have anti-radiation effect in radiation therapy during cancer treatment. This research aimed to illustrate Maitake D-Fraction effects on CCRT-associated adverse events and QOL. METHODS: During CCRT, Maitake capsules were taken orally 3 times a day, each time 4 capsules, one hour before meals. QOL were analyzed by EORTC QLQ-C30-Chinese version and EORTC QLQ-HandN-35-Chinese version. 141 patients were recruited and divided into an intervention group and a placebo group. RESULTS: Frequencies of severe CCRT-associated adverse events in intervention group were less than in placebo group. Global QOL score in intervention group was higher than in placebo group 5 weeks post treatment. The proportion of patients returning to baseline global QOL score at 6-month was increased by Maitake D-Fraction administration. CONCLUSION: In conclusion, this randomized clinical trial demonstrated that in advanced laryngeal and pharyngeal cancer patients, the oral administration of Maitake D-Fraction alleviated CCRT-related adverse events and deterioration in QOL.
Assuntos
Quimiorradioterapia , Grifola , Neoplasias de Cabeça e Pescoço , Neoplasias Faríngeas , Proteoglicanas , Quimiorradioterapia/efeitos adversos , Grifola/química , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Neoplasias Faríngeas/tratamento farmacológico , Neoplasias Faríngeas/radioterapia , Polissacarídeos , Proteoglicanas/uso terapêutico , Qualidade de Vida , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapiaRESUMO
Squamous cell carcinoma is the major form of malignancy that arises in head and neck cancer. The modest improvement in the 5year survival rate underpins its complex etiology and provides the impetus for the discovery of new therapeutics. The present study describes the discovery of an indolebased small molecule (24a) that was a potent cytotoxic agent with antiproliferative and proapoptotic properties against a pharyngeal carcinoma cell line, Detroit 562, effectively killing the cells at a halfmaximal inhibitory concentration of 0.03 µM, as demonstrated using cell proliferation studies. The antiproliferative property of 24a was demonstrated by its ability to promote G2/M blockade, as assessed by cell cycle analysis using flow cytometry and the monitoring of realtime cell cycle progression by the fluorescence ubiquitinationbased cell cycle indicator. This proapoptotic property is supported by the promotion of TUNELstaining and increase in the activities of caspases3/7 and 6, in addition to the expression of death receptors and the cleavage of poly (ADPribose) polymerase 1 protein as demonstrated by western blotting. Given that Detroit 562 lacks functional p53, it is suggested that 24a acts independently of the tumor suppressor.
Assuntos
Apoptose/efeitos dos fármacos , Citotoxinas/farmacologia , Neoplasias Faríngeas/tratamento farmacológico , Apoptose/genética , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/metabolismo , Citotoxinas/metabolismo , Inibidores do Crescimento/metabolismo , Inibidores do Crescimento/farmacologia , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Neoplasias Faríngeas/metabolismoRESUMO
RATIONALE: Synovial sarcoma is a rare malignant tumor that typically originates from the soft tissue of the extremities. The occurrence of primary pharyngeal synovial sarcoma is even rarer, and few studies have reported its radiological features. Here, we report a case of pediatric primary pharyngeal synovial sarcoma and describe the conventional and advanced magnetic resonance imaging (MRI) findings with pathologic correlation. PATIENT CONCERNS: An 11-year-old girl presented to the otolaryngologic clinic with dysphagia. DIAGNOSIS: Laryngoscopy revealed a large mass in the oropharynx. MRI revealed a well-defined soft tissue mass with a maximal diameter of approximately 5âcm originating from the submucosal space of the oropharynx. The mass was primarily solid and showed homogeneous contrast-enhancement. The mass was hypointense on T1-weighted images and hyperintense on T2-weighted images. The mass showed a homogeneously low apparent diffusion coefficient value on diffusion-weighted imaging, which indicated high tumor cellularity. Dynamic contrast-enhanced MRI revealed a hypovascular tumor with low values of the volume transfer constant between the extracellular extravascular space and blood plasma and blood plasma volume per unit tissue volume. Amide proton transfer-weighted MRI revealed a relatively high amide proton transfer signal in the tumor, indicating a high protein/peptide component. The patient underwent partial surgical resection of the tumor, and the diagnosis of biphasic synovial sarcoma was confirmed on postoperative pathological examination. INTERVENTION: The patient was started on chemotherapy with vincristine, ifosfamide, doxorubicin, and etoposide. OUTCOMES: The tumor did not respond to the 3 cycles of the chemotherapy. Thus, the patient underwent second surgery and subsequent radiation therapy. The patient is now under ifosfamide/carboplatin/etoposide chemotherapy. LESSON: Synovial sarcoma should be considered in the differential diagnosis of pediatric oropharyngeal submucosal tumors. Multimodal MRI may aid diagnosis, although the final diagnosis should be based on the postoperative pathological examination findings.
Assuntos
Neoplasias Faríngeas , Sarcoma Sinovial , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Transtornos de Deglutição/etiologia , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Imageamento por Ressonância Magnética/métodos , Imagem Multimodal/métodos , Neoplasias Faríngeas/diagnóstico por imagem , Neoplasias Faríngeas/tratamento farmacológico , Neoplasias Faríngeas/radioterapia , Neoplasias Faríngeas/cirurgia , Reoperação , Sarcoma Sinovial/diagnóstico por imagem , Sarcoma Sinovial/tratamento farmacológico , Sarcoma Sinovial/radioterapia , Sarcoma Sinovial/cirurgia , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
AIMS: To analyze changes in oropharynx microbiota composition after receiving induced chemotherapy followed by surgery for hypopharyngeal squamous cell carcinoma (HPSCC) patients. METHODS: Clinical data and swab samples of 38 HPSCC patients (HPSCC group) and 30 patients with benign disease (control group, CG) were enrolled in the study. HPSCC group was stratified into two groups: induced chemotherapy group (IC) of 10 patients and non-induced chemotherapy group (nIC) of 28 patients. The microbiota from oropharyngeal membrane was analyzed through 16S rRNA sequencing. RESULTS: Alpha-diversity (Shannon and Ace indexes) and weighted UniFrac based beta-diversity severely decreased in the HPSCC group when compared with CG. In pre-operative comparisons, PCoA and NMDS analyses showed microbial structures in the IC group were more similar to CG than nIC. Both IC group and nIC group yielded significantly diverse post-operative communities in contrast to their pre-operative counterparts, evident by the decrease in genera Veillonella and Fusobacterium and increase in genera Streptococcus and Gemella. Given that post-operative oropharynx microbiota showed no difference between IC and nIC groups, the IC group showed less accumulation in anaerobic communities. The abundance of genera Fusobacterium, Parvimonas, Actinomyces were enhanced in the advanced stages (III/IV). CONCLUSIONS: Oropharynx microbiota in the HPSCC group presents dysbiosis with low diversity and abundance. Induced chemotherapy is beneficial in adjusting the oropharynx microbial environment leading to fewer amounts of anaerobe accumulation after operation. Higher amounts of Fusobacterium in advanced stages (III/IV) may influence the progression of HPSCC.
Assuntos
Bactérias/isolamento & purificação , Carcinoma/microbiologia , Microbiota , Orofaringe/microbiologia , Neoplasias Faríngeas/microbiologia , Adulto , Idoso , Antineoplásicos/administração & dosagem , Bactérias/classificação , Bactérias/genética , Carcinoma/tratamento farmacológico , Carcinoma/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Faríngeas/tratamento farmacológico , Neoplasias Faríngeas/cirurgia , FilogeniaRESUMO
INTRODUCTION: Standardized systemic treatment options are lacking for carcinoma ex pleomorphic adenoma, which is a rare and aggressive tumor primarily found in salivary glands.Here we report the case of a 63-year-old male with carcinoma ex pleomorphic adenoma of the left parotid and parapharyngeal space harboring a neurotrophic receptor tyrosine kinase (NTRK) 2 fusion who was treated with a small molecule inhibitor that targets the tropomyosin receptor kinase (TRK) proteins. To the best of our knowledge, no similar case has been described in the literature so far. PATIENT CONCERNS: After multiple surgical resections and radiotherapy for localized cancer disease over several years, our patient again developed an increasing swelling and pain around the left ear and numbness of the left half of the face. DIAGNOSIS: Magnetic resonance imaging and positron emission tomography/computed tomography scans showed tumor recurrence in the left parotid, below the left ear, and in the parapharyngeal space, as well as metastases of the lungs and cervical lymph nodes. As data on the efficacy of systemic therapies for inoperable carcinoma ex pleomorphic adenoma are scarce, we performed a next-generation sequencing that revealed the presence of a hitherto unknown NTRK2 fusion. INTERVENTIONS: Treatment with the TRK inhibitor larotrectinib was initiated, which induced rapid symptom improvement. However, part of the tumor had to be removed shortly afterwards due to local progression. Molecular testing did not demonstrate any alterations accounting for resistance to larotrectinib, with maintenance of the NTRK2 fusion. OUTCOMES: Three months later, imaging confirmed mixed response. While the reason for this remains unknown, the patient is in good condition and continues to receive larotrectinib. CONCLUSION: It remains unclear why our patient showed mixed response to larotrectinib and further studies are needed to explore other possible mechanisms of resistance.
Assuntos
Adenoma Pleomorfo/tratamento farmacológico , Neoplasias Parotídeas/tratamento farmacológico , Neoplasias Faríngeas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenoma Pleomorfo/genética , Adenoma Pleomorfo/cirurgia , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Glicoproteínas de Membrana , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Proteínas de Fusão Oncogênica/genética , Neoplasias Parotídeas/genética , Neoplasias Parotídeas/cirurgia , Neoplasias Faríngeas/genética , Neoplasias Faríngeas/patologia , Receptor trkBRESUMO
OBJECTIVES: To examine the impact of treatment sequences of Immune checkpoint inhibitor (ICI) and cetuximab on clinical outcomes in patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Clinicopathologic data were retrospectively collected on patients with R/M HNSCC who received ICI treatment. Association between treatment sequence and clinical outcomes were assessed. RESULTS: A total of 113 patients with R/M HNSCC were analyzed. Patients who had cetuximab prior to ICI had worse overall (HR, 1.83) and progression-free survival (HR, 1.76) compare to those without prior cetuximab. Among patients who had subsequent therapy after ICI, cetuximab-based therapy was associated with a trend toward higher response rate and longer survival than non-cetuximab regimen. CONCLUSION: Our single institution analysis showed that treatment sequence of cetuximab and ICI in R/M HNSCC may affect clinical outcomes. Cetuximab prior to ICI was associated with worse outcomes while the efficacy of cetuximab may be enhanced after ICI therapy.
Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Cetuximab/administração & dosagem , Inibidores de Checkpoint Imunológico/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Feminino , Humanos , Neoplasias Laríngeas/tratamento farmacológico , Neoplasias Laríngeas/mortalidade , Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/virologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/mortalidade , Neoplasias Bucais/patologia , Neoplasias Bucais/virologia , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Papillomaviridae , Neoplasias dos Seios Paranasais/tratamento farmacológico , Neoplasias dos Seios Paranasais/mortalidade , Neoplasias dos Seios Paranasais/patologia , Neoplasias dos Seios Paranasais/virologia , Neoplasias Faríngeas/tratamento farmacológico , Neoplasias Faríngeas/mortalidade , Neoplasias Faríngeas/patologia , Neoplasias Faríngeas/virologia , Intervalo Livre de Progressão , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologiaRESUMO
OBJECTIVES: Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs) that occur as a consequence of enhanced immune response due to T-cell activation. The objective of this retrospective study was to investigate the association between irAEs and disease outcome in patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: This study included 89 patients with R/M HNSCC who were treated with nivolumab in our center from October 2015 to January 2020. Overall survival (OS) and post-progression survival (PPS) were calculated from the date of nivolumab initiation or from the date of progression on nivolumab respectively to the date of death or censored at the last date of follow up. RESULTS: Twenty-four patients (27%) developed irAEs, with more common thyroiditis (N = 13, 14.6%). ORR did not differ between patients with irAEs (29.2%) and patients without irAEs (21.9%, p = 0.576). Median PFS was similar between the two groups (3.1 months for patients with irAEs vs. 2.6 months for patients without irAEs, p = 0.412). Median OS was significantly longer in patients with irAEs (17.9 vs. 6.3 months in patients without irAEs, log-rank p = 0.004). Additionally, median PPS was significantly improved in patients who developed irAEs (10.2 months vs. 2.8 months for patients without irAEs, log-rank p = 0.001). In multivariate analysis, the development of irAEs and response to nivolumab were shown to be independent prognostic factors for favorable OS and PPS. CONCLUSIONS: The development of irAEs is a strong predictor of improved survival in patients with advanced HNSCC treated with nivolumab.
Assuntos
Autoimunidade , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Bucais , Recidiva Local de Neoplasia , Nivolumabe/efeitos adversos , Neoplasias Faríngeas , Carcinoma de Células Escamosas de Cabeça e Pescoço , Idoso , Progressão da Doença , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/imunologia , Neoplasias Bucais/mortalidade , Neoplasias Bucais/patologia , Nivolumabe/uso terapêutico , Neoplasias Faríngeas/tratamento farmacológico , Neoplasias Faríngeas/imunologia , Neoplasias Faríngeas/mortalidade , Neoplasias Faríngeas/patologia , Intervalo Livre de Progressão , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/secundário , Tireoidite/etiologia , Resultado do TratamentoRESUMO
Aim: Photodynamic therapy utilizes a light-sensitive molecule that produces reactive oxygen species following irradiation. Photodynamic activities of free Zn phthalocyanine (ZnPc) and its liposomal formulations on human oral squamous cell carcinoma and pharyngeal carcinoma cells were assessed. Materials & methods: ZnPc was incorporated in extruded and nonextruded liposomes composed of palmitoyloleoylphosphatidylglycerol (POPG):palmitoyloleoylphosphatidylcholine (POPC) or POPG:dioleoylphosphatidylethanolamine liposomes and incubated with CAL 27 or FaDu cells. Cell viability was assessed following illumination and further incubation. Results: ZnPc incorporated in extruded POPG:POPC liposomes caused extensive cytotoxicity, while ZnPc in extruded or nonextruded POPG:dioleoylphosphatidylethanolamine liposomes or in multilamellar POPG:POPC liposomes were not effective. Conclusion: Extruded POPG:POPC liposomes are a useful delivery vehicle for ZnPc in photodynamic therapy of oral and pharyngeal cancers.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Neoplasias Faríngeas , Fotoquimioterapia , Carcinoma de Células Escamosas/tratamento farmacológico , Humanos , Indóis , Isoindóis , Lipossomos , Neoplasias Bucais/tratamento farmacológico , Compostos Organometálicos , Neoplasias Faríngeas/tratamento farmacológico , Fármacos Fotossensibilizantes , Carcinoma de Células Escamosas de Cabeça e Pescoço , Compostos de ZincoRESUMO
The dominant paradigm for HPV carcinogenesis includes integration into the host genome followed by expression of E6 and E7 (E6/E7). We explored an alternative carcinogenic pathway characterized by episomal E2, E4, and E5 (E2/E4/E5) expression. Half of HPV positive cervical and pharyngeal cancers comprised a subtype with increase in expression of E2/E4/E5, as well as association with lack of integration into the host genome. Models of the E2/E4/E5 carcinogenesis show p53 dependent enhanced proliferation in vitro, as well as increased susceptibility to induction of cancer in vivo. Whole genomic expression analysis of the E2/E4/E5 pharyngeal cancer subtype is defined by activation of the fibroblast growth factor receptor (FGFR) pathway and this subtype is susceptible to combination FGFR and mTOR inhibition, with implications for targeted therapy.
Assuntos
Carcinogênese/genética , Proteínas Oncogênicas Virais/genética , Infecções por Papillomavirus/genética , Neoplasias Faríngeas/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Neoplasias do Colo do Útero/genética , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/genética , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/patogenicidade , Humanos , Camundongos , Camundongos Transgênicos , Infecções por Papillomavirus/tratamento farmacológico , Infecções por Papillomavirus/mortalidade , Infecções por Papillomavirus/virologia , Neoplasias Faríngeas/tratamento farmacológico , Neoplasias Faríngeas/mortalidade , Neoplasias Faríngeas/virologia , Cultura Primária de Células , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/virologiaRESUMO
The CDC estimates that 70% of these cancers are caused by HPV. And yet, in 2018, only about two-thirds of adolescents had received 1 or more doses of HPV vaccine.
Assuntos
Neoplasias Bucais/virologia , Neoplasias Faríngeas/virologia , Criança , Feminino , Humanos , Masculino , Programas de Rastreamento/métodos , Programas de Rastreamento/estatística & dados numéricos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/epidemiologia , Infecções por Papillomavirus/tratamento farmacológico , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/uso terapêutico , Neoplasias Faríngeas/tratamento farmacológico , Neoplasias Faríngeas/epidemiologia , Grupos Raciais/estatística & dados numéricos , Estados Unidos/epidemiologia , Estados Unidos/etnologia , Vacinação/métodos , Vacinação/estatística & dados numéricosRESUMO
BACKGROUND: Several programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) antibodies have been approved for cancer treatment worldwide. Their pharmacokinetic and pharmacodynamic characteristics have been reported mainly in western countries, but related data in Chinese patients are limited. This study was conducted to investigate the safety, efficacy, pharmacokinetics, and pharmacodynamics of an anti-PD-1 antibody, toripalimab, in Chinese patients. METHODS: A single-center phase I study was conducted in Sun Yat-sen University Cancer Center. Eligible patients were adults with histologically confirmed, treatment-refractory, advanced, solitary malignant tumors. Toripalimab was intravenously infused every 2 weeks in dose-escalating cohorts at 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg, and 240 mg. The study followed standard 3 + 3 design. RESULTS: Between 15th March 2016 and 27th September 2016, 25 patients were enrolled, of whom 3 (12.0%), 7 (28.0%), 6 (24.0%), 6 (24.0%), 3 (12.0%) received 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg, and 240 mg toripalimab, respectively. After a median follow-up time of 5.0 months (range: 1.5-19.8 months), we observed that the commonest treatment-related adverse events (TRAEs) were fatigue (64.0%) and rash (24.0%). No grade 3 or higher TRAEs were observed. No dose-limiting toxicity, treatment-related serious adverse events (SAEs), or treatment-related death occurred. Objective response rate was 12.5%. The half-life of toripalimab was 150-222 h after a single dose infusion. Most patients, including those from the 0.3 mg/kg group, maintained complete PD-1 receptor occupancy (> 80%) on activated T cells since receiving the first dose of toripalimab. CONCLUSIONS: Toripalimab is a promising anti-PD-1 antibody, which was well tolerated and demonstrated anti-tumor activity in treatment-refractory advanced solitary malignant tumors. Further exploration in various tumors and combination therapies is warranted.
Assuntos
Adenocarcinoma , Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Melanoma , Adenocarcinoma/tratamento farmacológico , Adulto , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Feminino , Humanos , Masculino , Melanoma/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Faríngeas/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Neoplasias da Língua/tratamento farmacológicoRESUMO
Nivolumab, an antibody against human programmed cell death 1 (PD-1), enhances pre-existing immune responses and has antitumor activity. However, it may also cause undesirable immune-related adverse events (irAEs), such as anti-PD-1-related colitis. In addition, Nivolumab can worsen pre-existing autoimmune diseases. Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. Its exact cause is unknown, but it may involve the dysregulation of the mucosal immune response. Thus, it is of great interest whether nivolumab can affect UC activity. This is the first report of a patient with epipharyngeal carcinoma and ulcerative colitis who was confirmed to have been safely treated with nivolumab based on autopsy findings.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Colite Ulcerativa/complicações , Nivolumabe/uso terapêutico , Neoplasias Faríngeas/complicações , Neoplasias Faríngeas/tratamento farmacológico , Colite Ulcerativa/patologia , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Immune checkpoint inhibitors are indicated for non-small cell lung cancer (NSCLC) and head and neck cancer, and combined treatment of immune checkpoint inhibitor and chemotherapy has recently been carried out in patients with NSCLC. However, there is no established standard therapy for synchronous locally advanced or metastatic cancers of lung and nasopharynx. CASE REPORT: We report a case of a metastatic lung adenocarcinoma and locally advanced epipharyngeal carcinoma successfully treated with chemotherapy and immune checkpoint inhibitor, paclitaxel, carboplatin, bevacizumab and atezolizumab. The tumor proportion score of programmed death ligand 1 was 5-10% and 70-80% for metastatic lung adenocarcinoma and locally advanced epipharyngeal carcinoma, respectively. Shrinkage of both carcinomas was confirmed, and the treatment effect was judged to be a partial response. CONCLUSION: This was the first patient who was treated with this combination treatment. Our clinical experience suggests that this treatment could be one of the options for patients with these advanced cancers and an overall good clinical condition.
Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Faríngeas/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Antígeno B7-H1/antagonistas & inibidores , Bevacizumab/administração & dosagem , Neoplasias Ósseas/secundário , Carboplatina/administração & dosagem , Humanos , Neoplasias Pulmonares/patologia , Masculino , Paclitaxel/administração & dosagem , Neoplasias Faríngeas/patologia , PrognósticoRESUMO
PURPOSE: Concurrent chemoradiotherapy (CCRT) is one of the standard treatments for patients with advanced head and neck squamous cell carcinoma (HNSCC). However, CCRT may lead to decreased quality of life (QoL) and treatment compliance. This study aimed to determine the effects of PG2 (Astragalus polysaccharides) injection on CCRT-associated adverse events (AEs) and patients' compliance with the CCRT course. METHODS: In this phase II double-blind randomized placebo-controlled trial, PG2 injection (sterile powder form) or placebo was administrated three times per week in parallel with CCRT to patients with HNSCC. The chemotherapy regimen included 50 mg/m2 cisplatin every 2 weeks with daily tegafur-uracil (300 mg/m2) and leucovorin (60 mg/day). RESULTS: The study was terminated prematurely due to the successful launch of a newly formulated PG2 injection (lyophilized form). A total of 17 patients were enrolled. The baseline demographics and therapeutic compliance were comparable between the CCRT/PG2 and CCRT/placebo groups. During CCRT, severe treatment-associated AEs were less frequent in the CCRT/PG2 group than in the CCRT/placebo group. Furthermore, less QoL fluctuations from the baseline during CCRT were noted in the CCRT/PG2 group than in the CCRT/placebo group, with a significant difference in the pain, appetite loss, and social eating behavior. The tumor response, disease-specific survival and overall survival did not differ between the two groups. CONCLUSION: This preliminary study demonstrated PG2 injection exhibited an excellent safety profile, and has potential in ameliorating the deterioration in QoL and the AEs associated with active anticancer treatment among patients with advanced pharyngeal or laryngeal HNSCC under CCRT. Further research in patients with other cancer types or treatment modalities may widen PG2's application in clinical settings.
Assuntos
Neoplasias Laríngeas/tratamento farmacológico , Neoplasias Laríngeas/radioterapia , Neoplasias Faríngeas/tratamento farmacológico , Neoplasias Faríngeas/radioterapia , Polissacarídeos/administração & dosagem , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Astrágalo , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Cisplatino/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Tegafur/administração & dosagem , Uracila/administração & dosagemRESUMO
Acute neurological events are a common cause of ECG abnormalities and transient elevations in cardiac biomarkers. This case describes an uncommon presentation of cryptococcal meningitis in a non-immunosuppressed patient, presenting with altered sensorium and derangements in cardiac profile. Delay in diagnosing meningitis was avoided by paying close attention to the patient's presenting symptoms and by pursuing non-cardiac causes of ECG changes and elevations in cardiac troponin. Expeditious treatment and involvement of the infectious disease consultant resulted in excellent clinical response without permanent neurological sequelae.
Assuntos
Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Flucitosina/uso terapêutico , Meningite Criptocócica/diagnóstico , Transtornos Mentais/microbiologia , Infarto do Miocárdio com Supradesnível do Segmento ST/microbiologia , Biomarcadores/metabolismo , Cryptococcus neoformans/isolamento & purificação , Diagnóstico Tardio , Tratamento Farmacológico , Humanos , Masculino , Meningite Criptocócica/tratamento farmacológico , Meningite Criptocócica/fisiopatologia , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/fisiopatologia , Pessoa de Meia-Idade , Neoplasias Faríngeas/tratamento farmacológico , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Punção Espinal , Resultado do TratamentoRESUMO
A 63-year-old man with pharyngeal cancer had been prescribed pilocarpine hydrochloride for xerostomia after concomitant chemoradiotherapy. After 6 months of taking pilocarpine hydrochloride, he was referred to our hospital due to gradually developing renal insufficiency. The patient underwent detailed urinalysis, blood chemistry analysis, immune-serology testing. A renal biopsy was also performed. He was diagnosed with chronic tubulointerstitial nephritis (TIN) caused by lymphocytic infiltration of the interstitium, tubular atrophy, and interstitial fibrotic changes. Infections, autoimmune diseases, and genetic factors were ruled out as causes of TIN; a drug-induced lymphocyte stimulation test confirmed that he had high stimulation index scores for pilocarpine hydrochloride and a normal range stimulation score for other supplements. These results indicated that the TIN could have been induced by pilocarpine hydrochloride. Drug discontinuation partly improved his renal function and tubule marker levels. To our knowledge, this is the first report of TIN following administration of pilocarpine hydrochloride. This finding could contribute to future treatment decisions for patients with TIN and those using pilocarpine hydrochloride.
Assuntos
Agonistas Muscarínicos/efeitos adversos , Nefrite Intersticial/induzido quimicamente , Pilocarpina/efeitos adversos , Insuficiência Renal/etiologia , Quimiorradioterapia/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Nefrite Intersticial/sangue , Nefrite Intersticial/patologia , Nefrite Intersticial/urina , Neoplasias Faríngeas/complicações , Neoplasias Faríngeas/tratamento farmacológico , Neoplasias Faríngeas/radioterapia , Suspensão de Tratamento , Xerostomia/tratamento farmacológico , Xerostomia/etiologiaRESUMO
BACKGROUND/AIM: The aim of this retrospective cohort study was to investigate the association between renal dysfunction (RD) and the development of oral mucositis (OM) in patients undergoing concurrent chemoradiotherapy (CCRT) for pharyngeal cancer including radiation to the oral cavity. PATIENTS AND METHODS: Of 130 patients diagnosed as having pharyngeal cancer who received CCRT at the Okayama University Hospital Head and Neck Cancer Center, 44 were finally selected. RESULTS: During the observation period, 24 (54.5%) patients experienced severe OM (grade 3). The Cox proportional hazards regression model demonstrated that RD (hazard ratio(HR)=2.45, 95% confidence interval(CI)=1.067-6.116, p=0.035) and nasopharynx/oropharynx as center of the irradiated area (HR=2.56, 95% CI=1.072-5.604, p=0.034) were significantly associated with the incidence of severe OM (grade 3). CONCLUSION: In patients with pharyngeal cancer treated with CCRT including radiation to the oral cavity, RD at baseline can be a risk factor for developing severe OM.
Assuntos
Neoplasias Faríngeas/tratamento farmacológico , Neoplasias Faríngeas/radioterapia , Estomatite/tratamento farmacológico , Estomatite/radioterapia , Idoso , Quimiorradioterapia/efeitos adversos , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Faríngeas/patologia , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Estomatite/patologiaRESUMO
The main objective of this study was to evaluate the effect of metformin, statins and anti-inflammatory drugs (NSAIDs) on head and neck cancer (HNC). Specifically, the potential beneficial effects on risk, survival and recurrence based on epidemiological studies. PRISMA guidelines were followed. After searching MEDLINE (PubMed), IBECS, LILACS and the Cochrane Central Register for Controlled Trials, 13 studies met the inclusion criteria and so underwent qualitative synthesis (six studies for metformin and seven for NSAIDs). No studies were found for statins. Studies varied in their methodological quality. Meta-analyses showed that metformin exerts significant beneficial effects on HNC risk (RRâ¯=â¯0.71 95% CI 0.61-0.84) and overall survival (RRâ¯=â¯1.71 95% CI 1.20-2.42). Qualitative synthesis also suggests an apparently dose-response relationship and increased benefit when administered alone. The pooled-analyses yielded an almost significant effect of NSAIDs on HNC risk (RRâ¯=â¯0.86 95% CI 0.74-1.01). No associations were found between aspirin use and the risk of HNC (RRâ¯=â¯0.98 95% CI 0.77-1.24) and overall survival (RRâ¯=â¯1.10 95% CI 0.89-1.36). Metformin appears to have beneficial effects on HNC risk and overall survival, with an apparently dose-response relationship and increased benefit when administered alone. NSAIDs also seem to have a modest beneficial effect on HNC risk. No definitive conclusions can be reached for aspirin as the evidence available was proved inconsistent. Further research by means of well designed and conducted studies are needed to determine firm clinical implications. Standardized assessment methods for HNC outcomes should be established and account for known confounding factors such as smoking and alcohol consumption.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Anticarcinógenos/uso terapêutico , Neoplasias de Cabeça e Pescoço/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Metformina/uso terapêutico , Anti-Inflamatórios não Esteroides/farmacologia , Anticarcinógenos/farmacologia , Estudos de Casos e Controles , Estudos de Coortes , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Suscetibilidade a Doenças , Relação Dose-Resposta a Droga , Medicina Baseada em Evidências , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/etiologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inflamação , Metformina/farmacologia , Modelos Teóricos , Recidiva Local de Neoplasia/epidemiologia , Doenças Periodontais/etiologia , Doenças Periodontais/fisiopatologia , Neoplasias Faríngeas/tratamento farmacológico , Neoplasias Faríngeas/epidemiologia , Neoplasias Faríngeas/prevenção & controle , RiscoRESUMO
Although human papillomavirus (HPV) positive oral and oropharyngeal cancers have distinct epidemiologic and molecular characteristics compared to HPV-negative cancers, all patients with oral and oropharyngeal cancers received same standard regimen regardless of HPV status. For these reasons, specific regimens for patients with HPV-positive oral and oropharyngeal cancer are needed. Differentially expressed genes (DEG) between HPV-positive and HPV-negative oropharyngeal cancers were re-analyzed and categorized from public database. Then, druggable targets to HPV-positive oral and oropharyngeal cancer were identified and were validated with E6/E7, which is oncogene of HPV, transfected oral and oropharyngeal cancer cell lines and HPV infected cell lines. In DEG analysis, HPV-positive oral and oropharyngeal cancer showed distinct disease entity from HPV-negative cancers. Unlike HPV-negative oral and oropharyngeal cancer, thymidylate synthase (TS) and topoisomerase II (Topo II) were overexpressed in HPV-positive cancers. Transfection of Lenti-virus containing E6/ E7 to HPV-negative oral and oropharyngeal cancer cells induced upregulation of TS and Topo II in those cells. Although cisplatin, which is standard regimen in head and neck cancers, showed more effectiveness in HPV-negative cells, 5-FU and pemetrexed, which are TS inhibitors, or etoposide, which is Topo II inhibitors, worked more effectively in HPV-positive cells. In addition, cisplatin/etoposide and cisplatin/pemetrexed combination regimens showed synergic effects in HPV-positive cells. Pemetrexed or etoposide alone, or in combination with other chemotherapeutic agents such as cisplatin, can be used as novel substitutes in a regimen of concurrent chemoradiotherapy or a palliative regimen for HPV-positive oral and oropharyngeal cancer patients. However, a well-designed clinical trial is needed.