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1.
Beijing Da Xue Xue Bao Yi Xue Ban ; 52(5): 902-906, 2020 Oct 18.
Artigo em Chinês | MEDLINE | ID: mdl-33047727

RESUMO

OBJECTIVE: To investigate the effects of salinomycin on the proliferation and apoptosis of oral squamous carcinoma cells and to further understand the mechanisms of these effects. METHODS: The human oral squamous carcinoma cell line CAL-27 was cultured in different concentrations of salinomycin and cisplatin. After co-culture with 0, 1, 2, 4, 8, 16 and 32 µmol/L salinomycin or 0, 1.25, 2.5, 5, 10, 20, 40 and 80 µmol/L cisplatin for 24 hours and 48 hours, the proliferation of oral squamous carcinoma cells were detected by cell counting kit-8(CCK-8) assay. After being exposed to 0, 2, 4, 8 µmol/L salinomycin and 0, 5, 10, 20 µmol/L cisplatin for 48 hours, the cell cycle of oral squamous carcinoma cells was detected by flow cytometry assay, and Western blot analysis was performed to analyze the expressions of cysteine-containing aspartate-specific proteases-3(Caspase-3), cysteine-containing aspartate-specific proteases-9(Caspase-9), poly ADP-ribose polymerase (PARP), protein kinase B (Akt) and phosphorylated protein kinase B (p-Akt) protein in oral squamous carcinoma cells. RESULTS: Both salinomycin and cisplatin significantly inhibited the proliferation of oral squamous cell carcinoma CAL-27 cells in a time- and dose-dependent manner. However, compared with the first-line chemotherapeutic drug cisplatin, salinomycin showed stronger anti-proliferation activity in oral squamous carcinoma cells than cisp-latin (P < 0.001). After being exposed to 8 µmol/L salinomycin, CAL-27 cells exhibited markedly higher proportion in quiescent/ first gap phases (40.40%±1.99% vs. 64.46%±0.90%, P < 0.05), and had a significantly lower proportion in synthesis phases and second gap / mitosis phases (24.32%±2.30% vs. 18.73%±0.61%, P < 0.05; 35.01%±1.24% vs. 16.54%±1.31%, P < 0.05) compared with the dimethyl sulfoxide control group; moreover cisplatin didn't show cell-cycle specific effect on CAL-27. Western blot proved that salinomycin could up-regulate the expressions of Caspase-3 and Caspase-9 protein in oral squamous cell carcinoma CAL-27 cells (P < 0.05). At the same time, the levels of PARP, Akt and p-Akt protein were down-regulated (P < 0.05). CONCLUSION: Compared with cisplatin, salinomycin has a better inhibitory effect on the proliferation of oral squamous carcinoma cells and blocks the cell cycle process at the quiescent / first gap phase. At the same time, salinomycin could trigger apoptosis of oral squamous carcinoma cells and the mechanism is associated with the Akt/p-Akt signaling pathway.


Assuntos
Antineoplásicos , Carcinoma de Células Escamosas , Neoplasias Bucais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Bucais/tratamento farmacológico , Piranos
2.
Anticancer Res ; 40(9): 4885-4894, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878776

RESUMO

AIM: The aim of this study was to investigate the antitumor potential of guaiazulene-3-carboxylate derivatives against oral malignant cells. MATERIALS AND METHODS: Twelve guaiazulene-3-carboxylate derivatives were synthesized by introduction of either with alkyl group [1-5], alkoxy group [6, 7], hydroxyl group [8, 9] or primary amine [10-12] at the end of sidechains. Tumor-specificity (TS) was calculated by the ratio of mean 50% cytotoxic concentration (CC50) against 3 human oral mesenchymal cell lines to that against 4 human oral squamous cell carcinoma (OSCC) cell lines. Potency-selectivity expression (PSE) was calculated by dividing TS value by CC50value against OSCC cell lines. Cell cycle analysis was performed by cell sorter. RESULTS: [6, 7] showed the highest TS and PSE values, and induced the accumulation of both subG1 and G2/M cell populations in HSC-2 OSCC cells. Quantitative structure-activity relationship analysis demonstrated that their tumor-specificity was correlated with chemical descriptors that explain the 3D shape, electric state and ionization potential. CONCLUSION: Alkoxyl guaiazulene-3-carboxylates [6, 7] can be potential candidates of lead compound for developing novel anticancer drugs.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Azulenos/química , Azulenos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Bucais/tratamento farmacológico , Sesquiterpenos de Guaiano/química , Sesquiterpenos de Guaiano/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Azulenos/síntese química , Carcinoma de Células Escamosas/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Estrutura Molecular , Neoplasias Bucais/patologia , Relação Quantitativa Estrutura-Atividade , Sesquiterpenos de Guaiano/síntese química
3.
N Engl J Med ; 383(14): 1328-1339, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32997907

RESUMO

BACKGROUND: The efficacy and safety of the anti-programmed death ligand 1 (PD-L1) monoclonal antibody atezolizumab, as compared with those of platinum-based chemotherapy, as first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC) with PD-L1 expression are not known. METHODS: We conducted a randomized, open-label, phase 3 trial involving patients with metastatic nonsquamous or squamous NSCLC who had not previously received chemotherapy and who had PD-L1 expression on at least 1% of tumor cells or at least 1% of tumor-infiltrating immune cells as assessed by the SP142 immunohistochemical assay. Patients were assigned in a 1:1 ratio to receive atezolizumab or chemotherapy. Overall survival (primary end point) was tested hierarchically according to PD-L1 expression status among patients in the intention-to-treat population whose tumors were wild-type with respect to EGFR mutations or ALK translocations. Within the population with EGFR and ALK wild-type tumors, overall survival and progression-free survival were also prospectively assessed in subgroups defined according to findings on two PD-L1 assays as well as by blood-based tumor mutational burden. RESULTS: Overall, 572 patients were enrolled. In the subgroup of patients with EGFR and ALK wild-type tumors who had the highest expression of PD-L1 (205 patients), the median overall survival was longer by 7.1 months in the atezolizumab group than in the chemotherapy group (20.2 months vs. 13.1 months; hazard ratio for death, 0.59; P = 0.01). Among all the patients who could be evaluated for safety, adverse events occurred in 90.2% of the patients in the atezolizumab group and in 94.7% of those in the chemotherapy group; grade 3 or 4 adverse events occurred in 30.1% and 52.5% of the patients in the respective groups. Overall and progression-free survival favored atezolizumab in the subgroups with a high blood-based tumor mutational burden. CONCLUSIONS: Atezolizumab treatment resulted in significantly longer overall survival than platinum-based chemotherapy among patients with NSCLC with high PD-L1 expression, regardless of histologic type. (Funded by F. Hoffmann-La Roche/Genentech; IMpower110 ClinicalTrials.gov number, NCT02409342.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Análise de Sobrevida
4.
PLoS One ; 15(8): e0237453, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32780766

RESUMO

BACKGROUND: Ocular surface squamous neoplasia (OSSN) is the most common ocular surface tumour. Diagnosis and management have traditionally been by excision biopsy. Recently there has been success with the use of topical chemo or immunotherapy, which has resulted in a move from invasive diagnosis by histology to an array of non-invasive diagnostic tests. METHODS: This observational study aims to describe the characteristics of patients with OSSN at St John Eye Hospital in Johannesburg, South Africa. Non-invasive diagnostic tests (impression cytology, anterior segment-OCT, methylene blue staining) will be compared to the gold standard, histology. Treatment success, recurrence and adverse events will be documented between three treatment options that include: surgical excision, topical 5-Fluorouracil (5FU) chemotherapy, and topical 5FU with retinoic acid therapy. DISCUSSION: There is a trend to the use of less invasive diagnosis and management for OSSN. Minimally invasive diagnostic tests include cytology, anterior-segment OCT and methylene blue staining. The study will compare these to the gold standard histology, thereby providing evidence for their use in clinical practice. Interferon alpha 2b is commonly used as immunotherapy for OSSN. The cost of this medication is prohibitive to its adoption in a developing country. We therefore decided to use 5FU as the chemotherapeutic agent of choice in this study. The success, adverse events and recurrence rates with this agent may provide additional evidence for its use in the management of OSSN. Overall, if diagnosis and management can be implemented with good success in the outpatient environment, care can be improved for this condition in a developing country.


Assuntos
Carcinoma de Células Escamosas/diagnóstico , Neoplasias Oculares/diagnóstico , Adulto , Antineoplásicos/uso terapêutico , Área Sob a Curva , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/etiologia , Neoplasias Oculares/tratamento farmacológico , Neoplasias Oculares/etiologia , Feminino , Fluoruracila/uso terapêutico , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Curva ROC , Fatores de Risco , África do Sul , Centros de Atenção Terciária , Tomografia de Coerência Óptica , Resultado do Tratamento , Raios Ultravioleta/efeitos adversos
5.
Bull Cancer ; 107(5S): eS16-eS21, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32620211

RESUMO

Background Metastatic Squamous cell Penile Carcinoma (mSCPC) is an orphan disease with a virally induced oncogenesis. PD-L1 expression rate is around 60% with a strong correlation between PD-L1 in the primary tumour and metastases. The first line systemic treatment relies on platinum-based chemotherapies with a median progression free survival and overall survival around 7.5 and 16 months, respectively. Immunotherapies targeting PD-1/PD-L1 axis are effective in other squamous cell or HPV related cancers. Methods PULSE is a prospective multicenter open label single arm phase II study. Thirty-two patients will be enrolled after a radiological assessment showing a non-progressive disease after 3 to 6 cycles of a first line platinum-based polychemotherapy. Patients will receive Avelumab injections 10mg/ kg every two weeks until progression or unacceptable toxicity. The primary endpoint will be the progression free survival (PFS) according to RECIST v1.1 criteria. Secondary endpoints will include PFS according to iRECIST criteria, overall survival, quality of life, safety. Ancillary explorations will include assessing blood and tissue biomarkers for association with clinical benefit. Discussion After the first line, the prognosis remains poor with no consensus on a second line systemic treatment in locally advanced or mSCPC. PULSE trial is the first study that assess an anti PD-L1 immunotherapy in maintenance among patients with locally advanced or mSCPC. NCT NUMBER : NCT03774901.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto/métodos , Quimioterapia de Manutenção , Estudos Multicêntricos como Assunto/métodos , Neoplasias Penianas/tratamento farmacológico , Compostos de Platina/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma de Células Escamosas/secundário , Quimioterapia Combinada , Humanos , Imunoterapia , Masculino , Neoplasias Penianas/patologia , Intervalo Livre de Progressão , Estudos Prospectivos
6.
Gene ; 757: 144936, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32640301

RESUMO

Oral squamous cell carcinoma (OSCC) accounts for nearly 90 percent of oral cavity malignancies and is one of the most widespread oral cancers in the world. The microRNAs (miRNAs or miRs) have an important role in cellular processes comprising cell cycle, differentiation, and also apoptosis. MiRNAs are also implicated in the progression of cancers, including OSCC, through a variety of signaling pathways. One of the most significant signaling pathways in OSCC is the PI3K / Akt pathway that has been illustrated to be under the tight regulation of miRNAs. Deregulation or activation of the PI3K / Akt pathway due to mutations has been revealed to be implicated in the development of oral cancer. According to studies, more than 47% of HNSCC and around 38% of OSCC samples indicate at least one molecular alteration in this signaling pathway. The potential of miRNAs for their use as therapeutic tools in the diagnosis as well as treatment of numerous diseases have been confirmed. In the current review, we summarize miRNAs and their possible mechanisms as well as their functions in OSCC advancement and progression.


Assuntos
Carcinoma de Células Escamosas/genética , MicroRNAs/genética , Neoplasias Bucais/genética , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/metabolismo , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo
7.
Anticancer Res ; 40(7): 3685-3696, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620607

RESUMO

BACKGROUND/AIM: Although chemotherapy agents, such as oxaliplatin, cisplatin, paclitaxel and bortezomib frequently cause severe peripheral neuropathy, very few studies have reported the effective strategy to prevent this side effect. In this study, we first investigated whether these drugs show higher neuropathy compared to a set of 15 other anticancer drugs, and then whether antioxidants, such as sodium ascorbate, N-acetyl-L-cysteine, and vitamin B12 have any protective effect against them. MATERIALS AND METHODS: Rat PC12 cells were induced to differentiate into neuronal cells by repeated overlay of serum-free medium supplemented with nerve growth factor. The cytotoxic levels of anticancer drugs against four human oral squamous cell carcinoma cell lines, three normal oral cells, and undifferentiated and differentiated PC12 cells were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Cells were sorted for apoptotic cells (distributed into subG1 phase) and cells at different stages of cell cycle (G1, S and G2/M). RESULTS: All 19 anticancer drugs showed higher cytotoxicity against PC12 compared to oral normal cells. Among them, bortezomib showed the highest cytotoxicity against both undifferentiated and differentiated PC12 cell and, committed them to undergo apoptosis. Sodium ascorbate and N-acetyl-L-cysteine, but not vitamin B12, completely reversed the cytotoxicity of bortezomib. CONCLUSION: Bortezomib-induced neuropathy might be ameliorated by antioxidants.


Assuntos
Antioxidantes/farmacologia , Bortezomib/efeitos adversos , Síndromes Neurotóxicas/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Bortezomib/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Fator de Crescimento Neural/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Síndromes Neurotóxicas/metabolismo , Células PC12 , Doenças do Sistema Nervoso Periférico/metabolismo , Ratos
8.
PLoS One ; 15(7): e0236101, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32678829

RESUMO

Dysregulation of histone demethylase Jumonji-C domain-containing protein 5 (JMJD5) has been identified as a great effect on tumorigenesis. Silibinin is a commonly used anti-hepatotoxic drug and exhibits anticancer effect in various cancers. However, the antitumor mechanism between silibinin and JMJD5 in oral squamous cell carcinoma (OSCC) remains unclear. In this study, the clinical significance of JMJD5 on OSCC patients was assessed through tissue microarray. Furthermore, mice bearing patient-derived tumor xenografts (PDTXs) and tongue cancer cell lines were treated with silibinin and evaluated for tumor growth and JMJD5 expression. High expression of JMJD5 in oral cancer was significantly associated with tumor size (P = 0.0241), cervical node metastasis (P = 0.0001) and clinical stage (P = 0.0002), was associated with worse survival rate compared with that of the total cohort (P = 0.0002). Collectively the data indicate that JMJD5 expression may be suitable for detection of unfavorable prognosis in OSCC patients, based in part on its apparent role as a marker of metastasis. In addition, silibinin inhibits cancer growth in vitro and in PDTX models. Furthermore, metastasis-associated protein 1 (MTA1) could regulate the expression for JMJD5 and had a positive correlation with JMJD5. Moreover, silibinin could downregulate JMJD5 and MTA1 in oral cancer. Present study thus identifies that JMJD5 might be an essential prognostic indicator and therapeutic target against OSCC progression. In addition, silibinin is a potential candidate among novel chemotherapeutic agents or adjuvants for modulating JMJD5 in OSCC, through a mechanism likely involving MTA1/JMJD5 axis.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Histona Desmetilases/metabolismo , Neoplasias Bucais/patologia , Proteínas Repressoras/metabolismo , Silibina/farmacologia , Transativadores/metabolismo , Animais , Antineoplásicos Fitogênicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Histona Desmetilases/genética , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Prognóstico , Proteínas Repressoras/genética , Taxa de Sobrevida , Transativadores/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Life Sci ; 257: 118104, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32679143

RESUMO

Halofuginone (HF) from Dichroa febrifuga has shown therapeutic potential in hepatocellular, lung and colorectal cancer cell models. Evidence has also indicated that HF plays roles in caustic induced esophageal strictures and oxidative injury. However, the role of HF in esophageal squamous carcinoma (ESCC) remains unclear. In this study, we investigated HF actions and mechanisms during ESCC cell apoptosis. We observed different HF concentrations (5, 10 and 20 nM) inhibited ESCC cell survival in a time and dose-dependent manner. HF treatment markedly induced KYSE-30 and TE-1 cell apoptosis, and caspase-3 activity. Apoptosis related protein Bax expression was dramatically increased, whereas Bcl-2 levels were reduced in KYSE-30 and TE-1 cells, after HF exposure. Also, we showed that HF treatment induced DNA damage by promoting γH2AX, pATM and pATR expression. HF treatment also reduced hypoxia-inducible factor-1α (HIF-1α) and forkhead box class O 3a (FOXO3a) expression in KYSE-30 and TE-1 cells. We also showed that HF inhibited FOXO3a expression, but this was dependent on HIF-1α inhibition. Finally, FOXO3a overexpression reversed HF induced cell survival inhibition, cell apoptosis and DNA damage. FOXO3a knockdown enhanced the effects of HF on cell survival, cell apoptosis and DNA damage. In summary, HF plays inhibitory roles in ESCC cell apoptosis, via HIF-1α-FOXO3a-dependent signaling. These data support the notion that HF could act as an effective therapeutic reagent towards ESCC.


Assuntos
Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Esofágicas/tratamento farmacológico , Proteína Forkhead Box O3/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Piperidinas/uso terapêutico , Quinazolinonas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Western Blotting , Carcinoma de Células Escamosas/metabolismo , Caspase 3/metabolismo , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Neoplasias Esofágicas/metabolismo , Humanos
10.
Hautarzt ; 71(8): 597-606, 2020 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-32583034

RESUMO

Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers of the Caucasian population and accounts for 20% of all skin tumours. An S3 guideline of the German Guideline Program in Oncology has been available since 2019. The diagnosis is based on the clinical examination. Excision and histological confirmation is required for all clinically suspicious lesions to allow prognostic assessment and correct treatment. The therapy of first choice is complete excision with histological control of the surgical margin. In cSCC with risk factors such as tumor thickness >6 mm, sentinel lymph node biopsy may be discussed, but there is currently no clear evidence of its prognostic and therapeutic relevance. Adjuvant radiation therapy may be considered in cases of high risk of recurrence and should be tested in cases of inoperable tumors. The indication for electrochemotherapy should also be considered in the treatment of local or locoregional recurrence. The immune checkpoint inhibitor cemiplimab is approved for the treatment of inoperable or metastasized cSCC. In case of contraindications, chemotherapeutic agents, epidermal growth factor receptor (EGFR) inhibitors or palliative radiotherapy can be used. Since the evidence is low in these cases, a systemic therapy should be used preferentially within clinical studies. Follow-up care should be risk-adapted and includes a dermatological control, supplemented by ultrasound examinations in high-risk patients.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/cirurgia , Procedimentos Cirúrgicos Dermatológicos/métodos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/cirurgia , Carcinoma de Células Escamosas/patologia , Humanos , Recidiva Local de Neoplasia , Guias de Prática Clínica como Assunto , Prognóstico , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/patologia , Resultado do Tratamento
11.
Bull Cancer ; 107(7-8): 792-799, 2020.
Artigo em Francês | MEDLINE | ID: mdl-32591138

RESUMO

Anal canal cancer is a rare disease that accounts for 2.5% of digestive cancers. Squamous cell carcinomas are the most common histological form. Their incidence is in progression, probably due to the increase in Human Papilloma Virus infections. Metastatic forms account for 20% of anal canal cancers considering synchronous forms or metastatic recurrence of an initially localised disease. Their prognosis remains poor with an estimated 5-year survival rate of 30%. The first-line therapeutic standard based on the combination of cisplatin with 5-Fluorouracil has recently been challenged by carboplatin - paclitaxel and docetaxel, cisplatin and 5-Fluorouracil regimens which are becoming new treatment options. In second-line setting, there is no international consensus. Anti-EGFRs and immunotherapy in combination or not with other molecules are promising but these results need to be confirmed. In this review, we report current and future data in the management of squamous cell carcinomas of the anal canal in unresectable locoregional recurrence or at metastatic stage.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias do Ânus/mortalidade , Carboplatina/administração & dosagem , Carcinoma de Células Escamosas/mortalidade , Cisplatino/administração & dosagem , Docetaxel/administração & dosagem , Receptores ErbB/antagonistas & inibidores , Fluoruracila/administração & dosagem , Humanos , Imunoterapia/métodos , Paclitaxel/administração & dosagem , Prognóstico , Taxa de Sobrevida
12.
J Craniomaxillofac Surg ; 48(7): 685-693, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32507671

RESUMO

This study aimed to investigate the in vitro efficacy of three different SMAC mimetics for pro-apoptotic sensitization of HNSCC cells. We evaluated BV-6 in comparison to Birinapant and LCL161, for which pro-apoptotic sensitization effects have been demonstrated. Concentration-dependent response was measured for BV-6 in each cell line with an average IC50 value 8-fold lower than of aforementioned SMAC mimetics. Combination treatment of FasL (log2) and BV-6 (IC10) showed highly significant cell count reductions even in the lowest applied concentration in five cell lines (PCI-1: p = 0.0002, PCI-13: p = 0.0002, Detroit 562: p: p < 0.0001, FaDu: p < 0.0001, SCC-25: p = 0.0047). Synergistic effects (y < 1) were evident in eight out of 10 cell lines (PCI-1, PCI-9, PCI-13, PCI-68, Detroit 562, FaDu, SCC-25 and HaCaT). Annexin V assays revealed in nine cell lines very highly significant (p < 0.001) pro-apoptotic effects of BV-6. Western blots showed a heterogeneous IAP expression following SMAC mimetic treatment. Except for two cell lines, at least the cellular inhibitor of apoptosis protein 1 (cIAP1) was degraded in response to BV-6. For prospective targeted HNSCC therapy, this study identifies SMAC mimetics, particularly BV-6 as the compound with the highest pro-apoptotic potency, as promising antitumor agents.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço , Intervenção Coronária Percutânea , Carcinoma de Células Escamosas de Cabeça e Pescoço , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proteína Ligante Fas/farmacologia , Proteína Ligante Fas/uso terapêutico , Humanos , Estudos Prospectivos
13.
Am J Surg Pathol ; 44(9): 1184-1191, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32496434

RESUMO

Tumor cell expression of major histocompatibility complex (MHC) class I is required for antigen presentation and adaptive immune recognition. Absent or diminished MHC class I expression is thought to contribute to immunotherapeutic resistance in some epithelial tumors but has not been previously studied in cervical and vulvar carcinoma. Given that anti-programmed cell death 1 (PD-1) checkpoint inhibition is deployed for programmed cell death ligand 1 (PD-L1)-positive recurrent and metastatic cervical squamous carcinomas, identifying tumors with loss of MHC class I is of clinical interest to optimize the selection of immunotherapeutic candidates. Immunohistochemistry for PD-L1 and MHC class I combined A, B, and C heavy chains (MHC class I) was assessed in 58 human papillomavirus-associated cervical and vulvar lesions, including 27 squamous intraepithelial lesions (SILs) and 31 invasive squamous cell carcinoma (SCC). Although 84% of SCC and 22% of SIL were PD-L1-positive, 35.5% (11/31) of SCC and 18.5% (5/27) of SIL also showed clonal or complete loss of MHC class I. Loss of MHC class I expression was more common in PD-L1-positive (10/26, 38%) versus PD-L1-negative SCC (1/5, 20%). In summary, over one third of human papillomavirus-associated cervical and vulvar SCC show clonal or complete loss of MHC class I expression, including many PD-L1-positive cases. This suggests that the efficacy of checkpoint inhibitors targeting the PD-1/PD-L1 axis may be limited in a subset of cervical and vulvar squamous neoplasms due to an impaired ability to engage with the adaptive immune system related to loss of MHC class I expression.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Escamosas/virologia , Resistencia a Medicamentos Antineoplásicos , Antígenos de Histocompatibilidade Classe I/imunologia , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/virologia , Lesões Intraepiteliais Escamosas Cervicais/virologia , Neoplasias do Colo do Útero/virologia , Neoplasias Vulvares/virologia , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Regulação para Baixo , Feminino , Interações Hospedeiro-Patógeno , Humanos , Papillomaviridae/imunologia , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Estudos Retrospectivos , Lesões Intraepiteliais Escamosas Cervicais/tratamento farmacológico , Lesões Intraepiteliais Escamosas Cervicais/imunologia , Lesões Intraepiteliais Escamosas Cervicais/patologia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/patologia , Neoplasias Vulvares/tratamento farmacológico , Neoplasias Vulvares/imunologia , Neoplasias Vulvares/patologia
14.
Anticancer Res ; 40(5): 2467-2474, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366390

RESUMO

BACKGROUND/AIM: The hormonally-active form of vitamin D, 1,25(OH)2D3, demonstrated activity against oral squamous cell carcinoma (OSCC). Cytochrome P450scc (CYP11A1)-derived vitamin D hydroxyderivatives, such as 20(OH)D3 and 1,20(OH)2D3, have overlapping beneficial effects with 1,25(OH)2D3 without causing hypercalcemia. This study sought to determine (i) whether 20(OH)D3 and 1,20(OH)2D3 exhibit antitumor effects against OSCC comparable to those of 1,25(OH)2D3 and (ii) whether these effects may stem from down-regulation of sonic hedgehog (SHH) or WNT/ß-catenin signaling pathways. MATERIALS AND METHODS: Effects on CAL-27 cells were assessed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt and spheroid assays. Signaling pathways were assessed by immunofluorescence and western blotting. RESULTS: 20(OH)D3 and 1,20(OH)2D3 inhibited the growth of CAL-27 and demonstrated inhibition of WNT/ß-catenin and the SHH signaling as evidenced by down-regulation of nuclear translocation of glioma-associated oncogene 1(GLI1) and ß-catenin. CONCLUSION: Noncalcemic vitamin D hydroxyderivatives demonstrated antitumor activities against OSCC comparable to those of 1,25(OH)2D3 Their activities against SHH and the WNT/ß-catenin pathways provide insight for a possible target for OSCC treatment.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/metabolismo , Proteínas Hedgehog/metabolismo , Neoplasias Bucais/metabolismo , Vitamina D/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Biomarcadores , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Núcleo Celular , Imunofluorescência , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/etiologia , Neoplasias Bucais/patologia , Transporte Proteico , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Vitamina D/análogos & derivados , Vitamina D/uso terapêutico , beta Catenina/metabolismo
15.
Hautarzt ; 71(6): 463-475, 2020 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-32472149

RESUMO

The S3 guideline "Actinic keratosis and squamous cell carcinoma of the skin" was published on 30 June 2019. Subsequently, publications, reviews and meta-analyses appeared with new questions regarding the comparability of study data and heterogeneity of the evaluations, which are caused, among other things, by divergent measurement parameters as well as insufficient consideration of pretreatments and combined treatments. This concise overview was written in the context of criticism and in view of necessary developments and research. Topics include epidemiology, pathogenesis, prevention, clinical presentation, therapy and BK5103. Therapy is divided into local destructive procedures and topical applications. Recommendations with quotation marks are based on the actual guideline. Corresponding evidence levels are given. For the implementation in daily routine basic data, side effects and features of therapeutic options are mentioned. The current developments and questions concerning actinic keratoses become clear.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Ceratose Actínica/tratamento farmacológico , Guias de Prática Clínica como Assunto , Neoplasias Cutâneas/tratamento farmacológico , Administração Tópica , Carcinoma de Células Escamosas/patologia , Terapia Combinada , Humanos , Ceratose Actínica/patologia , Neoplasias Cutâneas/patologia
16.
Gan To Kagaku Ryoho ; 47(5): 819-821, 2020 May.
Artigo em Japonês | MEDLINE | ID: mdl-32408327

RESUMO

An 81-year-old man was admitted to our medical center for dyspnea. He underwent right upper lobectomy due to squamous cell lung cancer 5 years ago. Chest computed tomography(CT)revealed stenosis ofthe right main bronchus, and pathological diagnosis ofthe lesion was squamous cell carcinoma and PD-L1 expression was low(tumor proportion score [TPS]: 1%). Because his performance status(PS)was 1, he underwent 4 courses ofnab -paclitaxel(nab-PTX)plus carboplatin( CBDCA)plus pembrolizumab chemotherapy and pembrolizumab maintenance chemotherapy. The stenosis ofthe right main bronchus was clear after chemotherapy, and his dyspnea was improved. Chemotherapy using nab-PTX plus CBDCA plus pembrolizumab may become one of the therapeutic choices for the recurrence after operation of an elderly person with squamous cell lung carcinoma and low PD-L1 expression.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Idoso de 80 Anos ou mais , Albuminas , Anticorpos Monoclonais Humanizados , Antígeno B7-H1 , Carboplatina , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/cirurgia , Células Epiteliais , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Masculino , Recidiva Local de Neoplasia , Paclitaxel
17.
Cell Prolif ; 53(4): e12786, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32301195

RESUMO

OBJECTIVES: Photodynamic therapy (PDT) is a novel non-invasive therapeutic method, which has been widely applied for the treatment of human oral cancers. However, the problems of undesirable singlet oxygen (1 O2 ) quantum yields and long-term phototoxicity were inevitable during the application of traditional photosensitizers. Therefore, it is necessary to explore novel photosensitizers for the improvement of therapeutic effects. In our study, the sulphur-doped carbon dots (S-CDs) of high yield of singlet oxygen (1 O2 ) were synthesized as a nano-photosensitizer for OSCC to improve the PDT efficacy in clinical practice. MATERIALS AND METHODS: After synthesis of the novel S-CDs, the size, morphologic characteristics, surface potential and yield of singlet oxygen (1 O2 ) were determined. In vitro study was performed to compare the therapeutic effect as well as the biocompatibility of the novel S-CDs to those of 5-ALA. Besides, possible mechanism of action was illustrated. RESULTS: After synthesis of the novel S-CDs, the size, morphologic characteristics, surface potential and yield of singlet oxygen (1 O2 ) were determined. In vitro study was performed to compare the therapeutic effect as well as the biocompatibility of the novel S-CDs to those of 5-ALA. Besides, possible mechanism of action was illustrated. CONCLUSIONS: These data from the in vitro study demonstrated the promising safety profile of the low dose (nmol/L) S-CDs, which indicated the novel S-CDs could be used as a promising photodynamic agent for oral cancer therapy.


Assuntos
Carbono/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Bucais/tratamento farmacológico , Fármacos Fotossensibilizantes/farmacologia , Enxofre/farmacologia , Apoptose/efeitos dos fármacos , Carbono/química , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Humanos , Modelos Moleculares , Neoplasias Bucais/patologia , Nanopartículas/química , Nanopartículas/ultraestrutura , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Enxofre/química
18.
Anticancer Res ; 40(4): 2359-2364, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234938

RESUMO

BACKGROUND: The aim of the present study was to evaluate the clinical impact of the perioperative use of antiplatelet/anticoagulation therapy for postoperative bleeding after esophagectomy for esophageal cancer. PATIENTS AND METHODS: Patients were selected from the medical records of consecutive patients who were diagnosed with primary esophageal adenocarcinoma or squamous cell carcinoma and who underwent complete resection at Yokohama City University from January 2005 to September 2018. The patients were divided into the antiplatelet/anticoagulation treatment group and the non-treatment group. We compared the safety and feasibility of esophagectomy between two groups. RESULTS: One hundred and twenty-two patients underwent esophagectomy for esophageal cancer and were analyzed in the present study. Among them, 18 (14.8%) received anti-thrombotic therapy (anticoagulation group). The incidence of postoperative bleeding in patients overall was 8.2% (10/122). The incidence of postoperative bleeding in the anticoagulation group was 22.2% (4/18), while that in the non-anticoagulation group was 5.8% (6/104). Preoperative anticoagulation therapy was identified as a significant independent risk factor for postoperative bleeding (hazard ratio=4.673, 95% confidence interval=1.170-18.519; p=0.029). CONCLUSION: The perioperative use of anti-thrombotic therapy was a significant risk factor for postoperative bleeding after esophagectomy for esophageal cancer. Thus, when patients receive perioperative antiplatelet/anticoagulation treatment, careful attention is required after esophagectomy due to their increased risk of postoperative bleeding.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/cirurgia , Esofagectomia/métodos , Complicações Pós-Operatórias/diagnóstico , Hemorragia Pós-Operatória/diagnóstico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/cirurgia , Terapia Combinada , Esofagectomia/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/efeitos adversos , Complicações Pós-Operatórias/etiologia , Hemorragia Pós-Operatória/etiologia , Fatores de Risco
19.
PLoS One ; 15(4): e0231884, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32343749

RESUMO

BACKGROUND: The overall aim was to investigate the change over time in circulating cell free DNA (cfDNA) in patients with locally advanced non-small cell lung cancer (NSCLC) undergoing concurrent chemo-radiotherapy. Furthermore, to assess the possibility of detecting circulating cell free tumor DNA (ctDNA) using shallow whole genome sequencing (sWGS) and size selection. METHODS: Ten patients were included in a two-phase study. The first four patients had blood samples taken prior to a radiation therapy (RT) dose fraction and at 30 minutes, 1 hour and 2 hours after RT to estimate the short-term dynamics of cfDNA concentration after irradiation. The remaining six patients had one blood sample taken on six treatment days 30 minutes post treatment to measure cfDNA levels. Presence of ctDNA as indicated by chromosomal aberrations was investigated using sWGS. The sensitivity of this method was further enhanced using in silico size selection. RESULTS: cfDNA concentration from baseline to 120 min after therapy was stable within 95% tolerance limits of +/- 2 ng/ml cfDNA. Changes in cfDNA were observed during therapy with an apparent qualitative difference between adenocarcinoma (average increase of 0.69 ng/ml) and squamous cell carcinoma (average increase of 4.0 ng/ml). Tumor shrinkage on daily cone beam computer tomography scans during radiotherapy did not correlate with changes in concentration of cfDNA. CONCLUSION: Concentrations of cfDNA remain stable during the first 2 hours after an RT fraction. However, based on the sWGS profiles, ctDNA represented only a minor fraction of cfDNA in this group of patients. The detection sensitivity of genomic alterations in ctDNA strongly increases by applying size selection.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Ácidos Nucleicos Livres/sangue , Neoplasias Pulmonares/terapia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/radioterapia , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/radioterapia , Quimiorradioterapia , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Radiação Ionizante , Tomografia Computadorizada por Raios X
20.
J Cancer Res Clin Oncol ; 146(7): 1647-1658, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32335720

RESUMO

BACKGROUND: Additional prognostic factors and personalized therapeutic alternatives for vulvar squamous cell carcinoma (VSCC), especially for advanced stages with poor prognosis, are urgently needed. OBJECTIVES: To review and assess literature regarding underlying molecular mechanisms of VSCC target therapeutic and prognostic approaches. METHODS: We performed a narrative literature review from the inception of the database up to January 2020 limited to English language, organizing knowledge in five main fields: extracellular and intracellular cell cycle deregulation, tumor immune microenvironment, tumor angiogenesis and hormones. RESULTS: EGFR immunohistochemical overexpression/gene amplification, representing early events in VSCC carcinogenesis, have been correlated with a worse prognosis and led to inclusion of erlotinib in cancer guidelines. p16 expression and HPV positivity are linked to a better prognosis, while p53 overexpression is linked to a worse prognosis; thus, biomarkers could help tailoring conventional treatment and follow-up. The implications of PD-L1 positivity in reference to HPV status and prognosis are still not clear, even though pembrolizumab is part of available systemic therapies. The role of tumor angiogenesis emerges through data on microvessel density, immunohistochemical VEGF staining and evaluation of serum VEGF concentrations. Few data exist on hormonal receptor expression, even though hormonal therapy showed great manageability. CONCLUSIONS: We suggest adding p16, p53 and HPV status to routine hystopathological examination of vulvar biopsies or surgical specimens. Predictive biomarkers for anti-EGFR and anti-PD-1/PD-L1 drugs are needed. Enough preclinical data supporting anti-angiogenic target therapies in clinical trials are existing. Hormonal receptor expression deserves further investigation.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/metabolismo , Regulação Neoplásica da Expressão Gênica , Transdução de Sinais , Neoplasias Vulvares/etiologia , Neoplasias Vulvares/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Ciclo Celular/genética , Tomada de Decisão Clínica , Suscetibilidade a Doenças , Espaço Extracelular/metabolismo , Feminino , Humanos , Espaço Intracelular/metabolismo , Terapia de Alvo Molecular , Neovascularização Patológica/genética , Neovascularização Patológica/imunologia , Neovascularização Patológica/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Neoplasias Vulvares/tratamento farmacológico , Neoplasias Vulvares/patologia
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