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1.
Int J Mol Sci ; 23(21)2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36361753

RESUMO

Reactive oxygen species (ROS) are produced by every aerobic cell during mitochondrial oxidative metabolism as well as in cellular response to xenobiotics, cytokines, and bacterial invasion. Superoxide Dismutases (SOD) are antioxidant proteins that convert superoxide anions (O2•-) to hydrogen peroxide (H2O2) and dioxygen. Using the differential in the level of oxidative stress between normal and cancer cells, SOD mimetics can show an antitumoral effect and prevent oxaliplatin-induced peripheral neuropathy. New Pt(IV) conjugate prodrugs (OxPt-x-Mn1C1A (x = 1, 1-OH, 2)), combining oxaliplatin and a Mn SOD mimic (MnSODm Mn1C1A) with a covalent link, were designed. Their stability in buffer and in the presence of sodium ascorbate was studied. In vitro, their antitumoral activity was assessed by the viability and ROS production of tumor cell lines (CT16, HCT 116, KC) and fibroblasts (primary culture and NIH 3T3). In vivo, a murine model of colorectal cancer was created with subcutaneous injection of CT26 cells in Balb/c mice. Tumor size and volume were measured weekly in four groups: vehicle, oxaliplatin, and oxaliplatin associated with MnSODm Mn1C1A and the bis-conjugate OxPt-2-Mn1C1A. Oxaliplatin-induced peripheral neuropathy (OIPN) was assessed using a Von Frey test reflecting chronic hypoalgesia. Tolerance to treatment was assessed with a clinical score including four items: weight loss, weariness, alopecia, and diarrhea. In vitro, Mn1C1A associated with oxaliplatin and Pt(IV) conjugates treatment induced significantly higher production of H2O2 in all cell lines and showed a significant improvement of the antitumoral efficacy compared to oxaliplatin alone. In vivo, the association of Mn1C1A to oxaliplatin did not decrease its antitumoral activity, while OxPt-2-Mn1C1A had lower antitumoral activity than oxaliplatin alone. Mn1C1A associated with oxaliplatin significantly decreased OIPN and also improved global clinical tolerance of oxaliplatin. A neuroprotective effect was observed, associated with a significantly improved tolerance to oxaliplatin without impairing its antitumoral activity.


Assuntos
Antineoplásicos , Doenças do Sistema Nervoso Periférico , Camundongos , Animais , Oxaliplatina/efeitos adversos , Espécies Reativas de Oxigênio/metabolismo , Peróxido de Hidrogênio/metabolismo , Superóxidos , Antineoplásicos/uso terapêutico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/patologia , Superóxido Dismutase , Camundongos Endogâmicos BALB C
2.
Oncol Rep ; 43(6): 1719-1728, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32236638

RESUMO

Targeted therapy and oral chemotherapy indications are increasing in the realm of digestive oncology. Oral intake of cancer agents is sometimes compulsory (no i.v. equivalent) or is preferred by the patient or the physician. Although oral chemotherapy facilitates the treatment of oncology patients, the treatment diversity, risk of pharmaceutical interactions and monitoring of side effects are potentially challenging and need to be fully acknowledged by the physician. We offer here a literature review of the indications, doses, side effects and monitoring of every oral therapy indicated in Digestive Oncology. We suggest a prescription algorithm including therapeutic education by the physician or a trained nurse, and pharmaceutical counseling.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias do Sistema Digestório/tratamento farmacológico , Administração Oral , Algoritmos , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Terapia de Alvo Molecular
3.
Br J Cancer ; 118(3): 325-330, 2018 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-29169182

RESUMO

BACKGROUND: Hepatocholangiocarcinoma (cHCC-ICC) is a rare liver tumour for which no data on chemosensitivity exist. The aims of this multicentre study were to evaluate overall survival (OS), progression-free survival (PFS), and prognostic factors in cHCC-ICC treated by gemcitabine plus platinum as first-line. METHODS: Unresectable cHCC-ICC treated by gemcitabine plus platinum-based chemotherapy between 2008 and 2017 were retrospectively analysed. Diagnosis was based on histology or, in case of ICC or HCC histology, on discordant computerised tomography scan enhancement patterns associated with discordant serum tumour marker elevation suggesting the alternative tumour. OS and PFS were evaluated by Kaplan-Meier method and prognostic factors by Log-rank test and Cox model. RESULTS: Among 30 patients included, cHCC-ICC was histologically proven in 22 (73.3%). 18 (60%) received gemcitabine plus oxaliplatin (GEMOX), 9 (30%) GEMOX plus bevacizumab, and 3 (10%) gemcitabine plus cisplatin. RECIST criteria were reported in 28 patients: 8 (28.6%) showed partial response, 14 (50%) stable disease, and 6 (21.4%) tumour progression at first evaluation. Median PFS and OS were 9.0 and 16.2 months, respectively. Serum bilirubin ⩾30 µmol l-1 (P=0.001) and positive serology for HBV and/or HCV (P=0.014) were independent poor prognostic factors for OS. CONCLUSIONS: Gemcitabine plus platinum-based chemotherapy is effective as first-line for advanced cHCC-ICC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Complexas Mistas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/administração & dosagem , Bilirrubina/sangue , Carcinoma Hepatocelular/patologia , Colangiocarcinoma/patologia , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Progressão da Doença , Feminino , França , Anticorpos Anti-Hepatite B/sangue , Anticorpos Anti-Hepatite C/sangue , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Complexas Mistas/patologia , Oxaliplatina/administração & dosagem , Intervalo Livre de Progressão , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Taxa de Sobrevida , Gencitabina
4.
Semin Arthritis Rheum ; 47(5): 741-748, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29102156

RESUMO

OBJECTIVE: To investigate effectiveness of systematic switching treatment from innovator infliximab to biosimilar infliximab, and its associated factors. METHODS: In this prospective observational study, all adult patients receiving maintenance therapy with innovator infliximab in Cochin University Hospital were systematically switched to biosimilar infliximab. Effectiveness was assessed by the retention rate of biosimilar infliximab at the time of the third infusion. Sensitivity analyses for effectiveness included changes of disease activity parameters and infliximab trough levels between baseline and the last visit as well as the occurrence of adverse events leading to drug discontinuation. Factors associated with biosimilar infliximab discontinuation at the last visit were explored. RESULTS: A total of 260 patients fulfilled the inclusion criteria, including 31 rheumatoid arthritis (RA), 131 axial spondyloarthritis (axSpA) and 64 inflammatory bowel diseases. The retention rate was 85% (221/260 patients) at the time of the third biosimilar infusion. Between baseline and the last visit (mean follow-up of 34 weeks), 59 patients (23%) discontinued biosimilar infliximab, mainly due to experienced inefficacy (n = 47, 80%). No clinical or biological factors were associated with biosimilar discontinuation. No serious adverse events occurred. No change in objective disease activity parameters or infliximab trough levels was detected. However, a significant increase of BASDAI (2.94 ± 2.20 vs. 3.18 ± 2.21, P = 0.046, before vs. after switch, respectively) was observed in patients with axSpA. Innovator infliximab was re-established in 47/59 patients (80%). CONCLUSION: No changes in drug trough levels or objective parameters were observed after the systematic switch to biosimilar infliximab in a real clinical practice setting. Only changes in patient-reported outcomes were observed, suggesting attribution effects rather than pharmacological differences.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Medicamentos Biossimilares/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/uso terapêutico , Espondilartrite/tratamento farmacológico , Adulto , Substituição de Medicamentos , Feminino , França , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão , Resultado do Tratamento
5.
J Gastrointest Oncol ; 8(4): E52-E55, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28890828

RESUMO

Radiation induced gastroparesis as well as the other autonomic nervous system radiation induced neuropathies are poorly described in the literature. A case of gastroparesis associated with phrenic and recurrent laryngeal nerves paralysis was observed in a 69-year old patient. She was already treated two times by rachis radiotherapy in a context of breast cancer with bone metastases. Anatomical and chronological correlation of lesions, concomitant nerve damage in the radiation fields and elimination of the main differential diagnoses allowed us to link this case of gastroparesis with the background of radiotherapy. It confirms the role of vagus nerve lesion in radiation induced gastroparesis. This specific diagnosis led to a successful treatment and a quality of life improvement.

6.
Target Oncol ; 12(3): 301-308, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28540478

RESUMO

Immune checkpoint inhibitors are monoclonal antibodies indicated for an increasing number of malignant diseases. These agents can cause specific side effects, which need to be anticipated while clear patterns of management need to be established. Immune checkpoint inhibitor-mediated gastrointestinal side effects, including diarrhea and colitis, occur in up to 30% of patients. Severe colitis can lead to severe dehydration or intestinal perforation. Endoscopic lesions and histopathological features of immune checkpoint inhibitor-induced colitis are similar to an inflammatory bowel disease (IBD) flare. Patients with immune checkpoint inhibitor-induced diarrhea and colitis are treated with corticosteroids. Infliximab can be used in cases of corticosteroid failure. Rectosigmoïdoscopy or colonoscopy should be performed when severe immune checkpoint inhibitor-induced colitis is suspected, but endoscopic investigations should not delay treatment. Specific patient education as well as co-operation between oncologists and gastroenterologists is essential.


Assuntos
Corticosteroides/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Colite/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Imunoterapia/métodos , Infliximab/uso terapêutico , Neoplasias/terapia , Anticorpos Monoclonais/efeitos adversos , Colite/induzido quimicamente , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Humanos , Imunoterapia/efeitos adversos , Comunicação Interdisciplinar , Neoplasias/imunologia
7.
J Gastrointest Oncol ; 8(1): 173-179, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28280621

RESUMO

BACKGROUND: Few studies with contradictory results have been published on the safety of pelvic radiation therapy (RT) in patients with inflammatory bowel disease (IBD). METHODS: From 1989 to 2015, a single center retrospective analysis was performed including all IBD patients who received pelvic external beam radiation therapy (EBRT) or brachytherapy (BT) for a pelvic malignancy. Treatment characteristics, IBD activity and gastrointestinal (GI) toxicity were examined. RESULTS: Overall, 28 patients with Crohn's disease (CD) (n=13) or ulcerative colitis (n=15) were included in the present study. Median follow-up time after irradiation was 5.9 years. Regarding IBD activity, only one and two patients experienced a severe episode within and after 6 months of follow-up, respectively. Grade 3/4 acute GI toxicity occurred in 3 (11%) patients, whereas one (3.6%) patient experienced late grade 3/4 GI toxicity. Only patients with rectal IBD location (P=0.016) or low body mass index (BMI) (P=0.012) experienced more severe IBD activity within or after 6 months following RT, respectively. CONCLUSIONS: We report an acceptable tolerance of RT in IBD patients with pelvic malignancies. Specifically, a low risk of uncontrolled flare-up was observed.

8.
Presse Med ; 46(4): 374-380, 2017 Apr.
Artigo em Francês | MEDLINE | ID: mdl-28126504

RESUMO

Mucosal healing is the goal to achieve in IBD. Calculating an endoscopic score in IBD is a good reflect of mucosal activity and is useful in therapeutic strategy to assess response to treatment. Calculating endoscopic score, precise description of mucosal lesions, quality of colonic preparation and the number of explored segments are necessary in every endoscopic report.


Assuntos
Colonoscopia , Doenças Inflamatórias Intestinais/patologia , Índice de Gravidade de Doença , Humanos , Mucosa Intestinal/patologia
9.
Presse Med ; 46(1): 4-10, 2017 Jan.
Artigo em Francês | MEDLINE | ID: mdl-28089247

RESUMO

CONTEXT: Mid gut neuroendocrine tumors (NET) are rare tumors whose incidence is increasing. Curative surgery remains the gold standard for the treatment of NETs of the small intestine. Surgery should be considered as soon as possible even if a metastatic stage is diagnosed. The management of unresectable well-differentiated metastatic NETs of the small intestine recently changed with the publication of trials demonstrating the benefit of targeted therapies and metabolic radiotherapy, leading to a change of practices and update of French and international recommendations. OBJECTIVE: The objective of this review is to present the recent data consisting of three phase III studies, which modify the management of well-differentiated metastatic midgut NETs and make an inventory of the available treatment options. DOCUMENTARY SOURCES: The documentary sources used were gathered through the PubMed website using keyword searching (neurendocrine tumor, mid gut, treatment). We also referred to recommendations of the European Society of neuroendocrine tumors (ENETS) trials presented at ESMO Congress 2015 (European Society for Medical Oncology). STUDY SELECTION: We excluded studies of exclusive extra-digestive NETs, poorly differentiated NETs, surgical treatments and phase I studies. RESULTS: We discussed three randomized phase III trials: CLARINET, RADIANT and NETTER studies. These studies demonstrated the efficacy of respectively somatostatin analogues, mTOR inhibitors and metabolic radiotherapy. CONCLUSION: This review highlights the validation by randomized studies of an mTOR inhibitor and metabolic radiotherapy in metastatic non-pancreatic digestive NETs unresectable well-differentiated grade of G1/2 in progression under somatostatin analogues.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Intestinais/tratamento farmacológico , Intestino Delgado/patologia , Tumores Neuroendócrinos/tratamento farmacológico , Terapias em Estudo/tendências , Quimiorradioterapia , Terapia Combinada , Humanos , Neoplasias do Íleo/tratamento farmacológico , Neoplasias do Íleo/patologia , Neoplasias Intestinais/patologia , Neoplasias Intestinais/terapia , Terapia de Alvo Molecular , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/terapia , Terapias em Estudo/métodos
10.
Dig Dis Sci ; 62(2): 473-480, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27853898

RESUMO

BACKGROUND AND AIMS: Mucosal healing (MH) with thiopurines has been poorly investigated in ulcerative colitis (UC). We aimed to assess MH rate in UC patients treated with thiopurine monotherapy. PATIENTS AND METHODS: We retrospectively collected all UC patients treated with thiopurines more than 6 months who have undergone colonoscopy at baseline and after at least 6 months of treatment. Patients were recruited from January 2005 to May 2015 through a personal database and/or standardized hospital inpatient diagnostic dataset. Patients were excluded in case of any use of other immunomodulator or biological agent. MH was defined as a Mayo endoscopic subscore ≤1 and UCEIS ≤ 2. Histological healing (HH) was defined by the absence of epithelial polynuclear infiltrate, cryptic abscesses, or ulcerations. RESULTS: Eighty patients (31 women, median age 43 [IQR 32-58]) were included. Median disease duration was 10.5 [6-16] years. At baseline, median full Mayo score, endoscopic subscore, and UCEIS were 8 [6.8-10], 3 [2-3], and 5 [3-6], respectively. MH was first assessed after a mean follow-up of 38 ± 31 months. Median full Mayo score, endoscopic subscore, and UCEIS decreased to 3.5 [1-6], 2 [0-2.2], and 2 [0-4], respectively. MH was achieved in 43.7%, HH in 38%. In multivariate analysis, predictors of MH were thiopurine exposure duration ≥2 years [odds ratio (OR) 2.9, CI 95% (1.1-7.6), p = 0.03] and a prior acute severe colitis [OR 5.9, CI 95% (1.1-32), p = 0.04]. Factors associated with MH during treatment were partial Mayo score ≤2 (NPV = 100%), BMI ≥ 25 kg/m2 (NPV = 75%), and MCV ≥ 95 fL (NPV = 73%). CONCLUSIONS: In UC, thiopurine monotherapy is associated with MH in 43.7% and HH in 38%.


Assuntos
Azatioprina/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Imunossupressores/uso terapêutico , Mercaptopurina/uso terapêutico , Adulto , Estudos de Coortes , Colite Ulcerativa/patologia , Colonoscopia , Feminino , Humanos , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
12.
Presse Med ; 44(4 Pt 1): 411-7, 2015 Apr.
Artigo em Francês | MEDLINE | ID: mdl-25622513

RESUMO

Crohn's disease is an inflammatory bowel disease that affects the entire digestive tract, from the mouth to the anus. The inflammatory disease is transmural and may be complicated by abscesses, fistulas, strictures. Budesonide is used as first-line treatment for a first episode of ileitis. Thiopurines and methotrexate are used as immunosuppressive maintenance therapy. Anti-tumour necrosis factors (TNF) alpha therapy is used as induction and maintenance therapy in case of severe flares or corticodependence. Combination of immunosuppressive therapy and anti-TNF-alpha (combotherapy) prevents the appearance of specific anti drug antibodies. Combotherapy is used in case of severe disease. The goal of the treatment is to achieve clinical remission, endoscopic mucosal healing, and to prevent the occurrence of complications such as strictures, fistulas or abscesses. Anoperineal lesions are found in 10% of the patients at diagnosis. Surgical treatment is indicated for severe medical treatment-resistant patients or complications such as symptomatic stenosis, fistula or abscess unresponsive to medical treatment or immediately complicated.


Assuntos
Doença de Crohn , Doença de Crohn/complicações , Doença de Crohn/diagnóstico , Doença de Crohn/terapia , Humanos
13.
Presse Med ; 44(2): 144-9, 2015 Feb.
Artigo em Francês | MEDLINE | ID: mdl-25534469

RESUMO

Ulcerative colitis (UC) is a chronic inflammatory bowel disease limited to the mucosa and affecting the rectum and the colon continuously. Salicylates are the first line treatment for moderate forms. Corticosteroids are used to induce remission, but are not given as maintenance therapy. Thiopurines are indicated as maintenance therapy in case of failure of salicylates or cortico-dependence. Anti TNF alpha are indicated in cortico-resistant severe flares or if cortico- dependence. Vedolizumab (anti-integrin) is the first non anti-TNF alpha biotherapy available for the treatment of UC. Severe acute colitis is a medical emergency; diagnosis is based on Lichtiger score. An emergency colectomy for severe acute colitis is indicated in cases of surgical complication or resistance to medical therapy. UC patients with extension beyond splenic flexure are at risk of colorectal cancer, increasing with the duration of the disease, severity of mucosal inflammation, family history of colorectal cancer, and the existence of sclerosing cholangitis. Annual surveillance colonoscopy is required in patients with sclerosing cholangitis regardless of the extension of their UC.


Assuntos
Colite Ulcerativa/diagnóstico , Colite Ulcerativa/terapia , Colite Ulcerativa/epidemiologia , Colite Ulcerativa/etiologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/prevenção & controle , Técnicas de Diagnóstico do Sistema Digestório , Humanos , Indução de Remissão/métodos
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