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1.
Nat Commun ; 12(1): 5006, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408135

RESUMO

Obesity is a strong risk factor for cancer progression, posing obesity-related cancer as one of the leading causes of death. Nevertheless, the molecular mechanisms that endow cancer cells with metastatic properties in patients affected by obesity remain unexplored.Here, we show that IL-6 and HGF, secreted by tumor neighboring visceral adipose stromal cells (V-ASCs), expand the metastatic colorectal (CR) cancer cell compartment (CD44v6 + ), which in turn secretes neurotrophins such as NGF and NT-3, and recruits adipose stem cells within tumor mass. Visceral adipose-derived factors promote vasculogenesis and the onset of metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming CRC cells into a highly metastatic phenotype. Notably, obesity-associated tumor microenvironment provokes a transition in the transcriptomic expression profile of cells derived from the epithelial consensus molecular subtype (CMS2) CRC patients towards a mesenchymal subtype (CMS4). STAT3 pathway inhibition reduces ZEB2 expression and abrogates the metastatic growth sustained by adipose-released proteins. Together, our data suggest that targeting adipose factors in colorectal cancer patients with obesity may represent a therapeutic strategy for preventing metastatic disease.


Assuntos
Tecido Adiposo/citologia , Reprogramação Celular , Neoplasias do Colo/fisiopatologia , Células-Tronco Neoplásicas/citologia , Nicho de Células-Tronco , Tecido Adiposo/metabolismo , Animais , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos SCID , MicroRNAs/genética , MicroRNAs/metabolismo , Metástase Neoplásica , Células-Tronco/citologia , Células-Tronco/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo
2.
Biomedicines ; 9(7)2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34356835

RESUMO

Cisplatin is one of the chemotherapeutic drugs used for the management of oral carcinoma, in which combined therapies are estimated to exert superior therapeutic efficacy compared with monotherapy. It is known that poly(ADP-ribosyl)ation is implicated in a multiplicity of cellular activities, such as DNA repair and cell death. Based on these, PARP inhibitors are used for the treatment of cancers; however, the capacity of PARP inhibitors associated to anti-cancer drugs have not been completely assessed in oral carcinoma. Here, we evaluated the effects of PARPi veliparib (ABT888) in combination with cisplatin on the survival of three human oral cancer cell lines HSC-2, Ca9-22 and CAL27 and we observed the effects of ABT888 alone or in combination with cisplatin on apoptosis and DNA damage repair mechanism. The results obtained showed that ABT888 induces a cytotoxicity effect on cell viability increasing the apoptotic pathway as well as DNA strand break; moreover, our results displayed the effects with cisplatin in a dose-dependent manner. Therefore, our results indicate PARP inhibitors as adjuvants for therapeutic strategy of oral cancer.

3.
Int J Mol Sci ; 22(8)2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33920318

RESUMO

Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics, such as oxaliplatin (L-OHP). The aim of the present work was to evaluate the potential beneficial effects of 2-pentadecyl-2-oxazoline (PEA-OXA) in a murine model of oxaliplatin-induced peripheral neuropathy (OIPN). OIPN was induced by an intraperitoneally injection of L-OHP in rats on five consecutive days (D0-4) for a final cumulative dose of 10 mg/kg. PEA-OXA and ultramicronized palmitoylethanolamide (PEAum), both 10 mg/kg, were given orally 15-20 min prior (L-OHP) and sacrifice was made on day 25. Our results demonstrated that PEA-OXA, more than PEAum, reduced the development of hypersensitivity in rats; this was associated with the reduction in hyperactivation of glia cells and the increased production of proinflammatory cytokines in the dorsal horn of the spinal cord, accompanied by an upregulation of neurotrophic factors in the dorsal root ganglia (DRG). Moreover, we showed that PEA-OXA reduced L-OHP damage via a reduction in NF-κB pathway activation and a modulation of Nrf-2 pathways. Our findings identify PEA-OXA as a therapeutic target in chemotherapy-induced painful neuropathy, through the biomolecular signaling NF-κB/Nrf-2 axis, thanks to its abilities to counteract L-OHP damage. Therefore, we can consider PEA-OXA as a promising adjunct to chemotherapy to reduce chronic pain in patients.


Assuntos
Fator 2 Relacionado a NF-E2/genética , Oxaliplatina/farmacologia , Oxazóis/farmacologia , Dor/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Animais , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/patologia , Humanos , Camundongos , NF-kappa B/genética , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Oxaliplatina/efeitos adversos , Dor/induzido quimicamente , Dor/genética , Dor/patologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/patologia , Ratos , Transdução de Sinais/efeitos dos fármacos
4.
J Geriatr Oncol ; 12(1): 163-167, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32653216

RESUMO

AIM: This paper aims to analyze the usefulness of the G8 geriatric oncology questionnaire in patients with advanced/metastatic pancreatic adenocarcinoma (aPAC) and its possible association with different clinical outcomes. METHODS: Patients age > 70 years were screened with the G8 tool and treated with intravenous nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 for 3 consecutive weeks followed by one-week rest as prescribed after clinical evaluation by treating oncologists. Patient's charts were evaluated for type and severity of toxicity, 2 cycle rate of completion, discontinuation rate, delays, dose reductions, and other outcomes response rates, progression-free, and overall survival. Sensitivity, specificity, and possible correlations were analyzed. RESULTS: Sensitivity and specificity of the G8 score for severe toxicity were respectively 55.9% and 50%. No association between all types of severe grade 3-4 toxicity, delays, or dose reductions, and the G8 score was present (p=0.622). ORR was 32.5% with no complete responses. Median PFS and OS were 4.5 months and 8.1 months, respectively. Correlation between G8 score and PFS was not statistically significant (p=0.0652). Correlation between G8 score and OS was statistically significant (p=0.0251). Although median survival of G8 fit patients was superior to that of G8 vulnerable patients (6.5 versus 4 months), the difference was not statistically different (p=0.1975). CONCLUSION: Clinical results in terms of response rate, survival outcomes, and side-effects were in the range reported by others. However, the G8 questionnaire is not a reliable diagnostic tool to predict the risk of severe toxicity, and clinical outcomes in older patients with aPAC.

5.
Cancers (Basel) ; 12(12)2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33297488

RESUMO

Neo-adjuvant radiotherapy is frequently employed in the therapeutic management of locally advanced rectal cancer (LARC). Radiotherapy can both reduce local recurrence and improve the success of surgical procedures by reducing tumor mass size. However, some patients show a poor response to treatment, which results in primary resistance or relapse after apparent curative surgery. In this work, we report in vitro and in vivo models based on patient-derived cancer stem cells (CSCs); these models are able to predict individual responses to radiotherapy in LARC. CSCs isolated from colorectal cancer biopsies were subjected to in vitro irradiation with the same clinical protocol used for LARC patients. Animal models, generated by CSC xenotransplantation, were also obtained and treated with the same radiotherapy protocol. The results indicate that CSCs isolated from rectal cancer needle biopsies possess an intrinsic grade of sensitivity to treatment, which is also maintained in the animal model. Notably, the specific CSCs' in vitro and in vivo sensitivity values correspond to patients' responses to radiotherapy. This evidence suggests that an in vitro radiotherapy response predictivity assay could support clinical decisions for the management of LARC patients, thus avoiding radiation toxicity to resistant patients and reducing the treatment costs.

6.
Anticancer Res ; 27(4C): 2871-5, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17695463

RESUMO

BACKGROUND: Capecitabine is considered the treatment of choice for anthracycline- and taxane-pretreated metastatic breast cancer. Mitomycin C seems to improve the activity of capecitabine by up-regulation of thymidine phosphorylase. PATIENTS AND METHODS: Fifty-five women with metastatic breast cancer previously treated with anthracyclinetaxane were treated with mitomycin C 10 mg/m2 on day 1 every six weeks and capecitabine 1000 mg/m2 on days 2-15 every three weeks. RESULTS: An overall response rate of 38% was found, consisting of 3 (5%) complete responses (CR) and 18 (33%) partial responses (PR); 8 patients (14%) had a stable disease (SD) for more than 4 months. The combination was well-tolerated, with the main toxicities being neutropenia, diarrhea and fatigue; other toxicities were of mild to moderate intensity without impairment in the quality of life of the patients. CONCLUSION: Capecitabine is confirmed as the drug of choice in the treatment of anthracycline- and taxane-pretreated metastatic breast cancer and its combination with mitomycin appears to improve its efficacy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Antraciclinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Capecitabina , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/análogos & derivados , Humanos , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Mitomicina/efeitos adversos , Metástase Neoplásica , Taxoides/uso terapêutico
7.
Anticancer Res ; 25(6C): 4513-7, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16334135

RESUMO

BACKGROUND: No standard chemotherapy has been defined for metastatic breast cancer patients pretreated with anthracyclines and taxanes. In preclinical studies, mitomycin C (MMC) and capecitabine showed a synergistic effect by up-regulation of thymidine phosphorylase, and both drugs were active against breast cancer with a lack of overlapping toxicity, making their combination a well-tolerated regimen. PATIENTS AND METHODS: A dose-finding study was carried out in order to determine the maximum tolerable dose of MMC combined with fixed-dose capecitabine and to describe the dose-limiting toxicities. RESULTS: Twenty-one patients were enrolled, with metastatic breast cancer pretreated at least with anthracyclines and taxanes (3 at dose level I, 15 at dose level II, 3 at dose level III). At dose level III (MMC 12 mg/m2 and capecitabine 1000 mg/m2 days 2-15) dose-limiting toxicities were recorded in 2 patients (G4 thrombocytopenia, neutropenic fever, G4 neutropenia); dose level II (MMC 10 mg/m2 and capecitabine 1000 mg/m2 days 2-15) was extended for a better safety evaluation. No severe toxicity was noted at this dose level, and therefore this dose was recommend for the phase II study. With regard to activity, 4 partial responses and 2 stable diseases (28%) were recorded. CONCLUSION: Our data show that the combination is feasible, well tolerated and active in this set of patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Neoplasias da Mama/patologia , Capecitabina , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Fluoruracila/análogos & derivados , Humanos , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Mitomicina/efeitos adversos , Metástase Neoplásica
8.
Support Care Cancer ; 11(9): 587-92, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12905055

RESUMO

GOALS: The aim of this prospective study was to assess the quality of pain management hospitalized cancer patients. PATIENTS AND METHODS: In a quantitative and qualitative evaluation from six oncology centers in Italy, all consecutive cancer patients complaining of pain and hospitalized during the same 2 weeks were requested to fill in a McGill pain questionnaire (MPQ), a present pain intensity scale (PPI), and a hospital anxiety and depression acale (HADS), and to answer a questionnaire focused (QF) on the quality of medical and nursing care. The healthcare provider's antalgic prescriptions were assessed by an index of pain management (IPM). MAIN RESULTS: Of 120 patients with pain admitted to oncology divisions (65 men and 52 women; mean age 57 years, range 21-79 years), 117 completed the questionnaires. The quantitative evaluation (PPI) showed a significant pain reduction between admission and discharge pain levels-from 2.65 to 1.50 ( p<0.001). While a significant reduction of anxiety (HADS) was also found-from 10.24 to 9.11 ( p<0.001)-depression did not improve (9.83 and 9.72). The most relevant information from qualitative evaluation (QF) was: in 37.6% of patients, pain level was higher overnight; 47% waited for spontaneous decrease of pain intensity before asking for nurse or physician intervention; 69% asked for nurse help when pain level was really high. The health care response to patients' pain was not completely satisfactory, since analgesic prescription was adequate in 56.52% but inadequate in 43.47%. CONCLUSIONS: Pain control in hospitalized cancer patients is not completely satisfactory. The physician's attitude is to underestimate and undertreat pain, while nurses are not adequately trained for timely intervention despite published guidelines for pain management. The findings of this study support the concern of inadequate knowledge and inappropriate attitudes regarding pain management, even in cancer patients hospitalized in medical oncology divisions.


Assuntos
Pacientes Internados , Neoplasias/complicações , Manejo da Dor , Dor/enfermagem , Adulto , Idoso , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Medição da Dor , Estudos Prospectivos , Inquéritos e Questionários
9.
Anticancer Res ; 23(2C): 1923-6, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12820480

RESUMO

BACKGROUND: Docetaxel is a very active drug against breast cancer, but at the standard dose causes severe myelosuppression. In order to reduce the toxicity while maintaining the activity, weekly docetaxel administration was tested. PATIENTS AND METHODS: We enrolled 30 patients with metastatic breast cancer, who had been treated with intravenous infusion of weekly docetaxel 35 mg/m2 in 100 ml of normal saline over 30 minutes for six weeks, followed by two weeks' rest from docetaxel therapy (one cycle). RESULTS: The overall response rate was 33% (95% CI +/- 16.8%) and the estimated time to progression was 8 months. Acute toxicity was mild. Nail loss, excessive tearing and dysgeusia worsened the quality of life of the patients. CONCLUSION: Weekly docetaxel is an active schedule for treating metastatic breast cancer patients, particularly the elderly and those unsuited to anthracycline-based regimens.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Paclitaxel/análogos & derivados , Paclitaxel/administração & dosagem , Taxoides , Adulto , Idoso , Antineoplásicos Fitogênicos/efeitos adversos , Docetaxel , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos
10.
Anticancer Res ; 22(4): 2521-3, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12174955

RESUMO

BACKGROUND: Peripheral lung lesions are difficult to diagnose with conventional methods: ultrasound-guided aspiration biopsy is an interesting prospect having been reported to have good sensitivity and specificity. PATIENTS AND METHODS: From January 1991 to August 2001 we investigated, in 268 patients, the role of ultrasound-guided transthoracic fine needle aspiration for cytological diagnosis of peripheral lung lesions. Nodule sizes ranged from 1 to 10 cm. RESULTS: From 268 patients, we obtained 174 positive specimens for malignancy, of which 155 were positive for primary lung tumors and 19 for metastasis; 76 negative; 9 inadequate; and 9 aspecific. One patient developed pneumothorax after needle aspiration and one patient emophtoe. The nodule size did not affect complication rate and diagnostic outcome. CONCLUSION: This diagnostic procedure appears to be effective, safe and feasible, even in bedridden patients. The cost is low (70Euro), the examination is fast (5-6 minutes) and well-tolerated and, if the specimen is inadequate or non-specific, it is possible to repeat the examination. Ultrasound-guided aspiration biopsy can replace the TC-guided biopsy in patients with peripheral lung nodules.


Assuntos
Biópsia por Agulha/métodos , Neoplasias Pulmonares/patologia , Nódulo Pulmonar Solitário/patologia , Ultrassonografia/métodos , Carcinoma Pulmonar de Células não Pequenas/classificação , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Pequenas/diagnóstico por imagem , Carcinoma de Células Pequenas/patologia , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Nódulo Pulmonar Solitário/diagnóstico por imagem
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