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1.
Clin Nutr ESPEN ; 48: 370-377, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35331516

RESUMO

INTRODUCTION: Critically ill patients in the Intensive Care Unit (ICU) should receive nutritional support matched to their metabolic needs as both under- and overfeeding energy has been shown to increase mortality. Critical illness can significantly affect metabolism. Consequently, resting energy expenditure (REE) can vary markedly during critical illness. Therefore, indirect calorimetry to estimate REE is recommended to determine energy requirements in individual ICU patients and to guide optimal nutritional support. Currently, the Quark metabolic monitor is considered the gold standard in our ICU, but novel mechanical support devices are also equipped with indirect calorimetry functionalities. This study aimed to evaluate the performance of a currently unevaluated device. METHODS: A cross-sectional analysis in mechanically ventilated patients was conducted in a mixed medical-surgical ICU. The primary outcome was a numerical and visual comparison of the performance of the Beacon indirect calorimeter to calculate REE compared to the Quark device using Bland Altman plots. Performance was evaluated using bias, precision, accuracy, and reliability. Secondary analysis included a comparison with REE estimated by predictive equations. RESULTS: Seventy-one measurements were obtained in 27 mechanically ventilated subjects. An underestimation by the Beacon device in calculated REE of -96.2 kcal/day (4.5%) was found. There was a bias towards higher VCO2 and lower VO2 values with Beacon as compared to Quark. The reliability of the Beacon was good, with an absolute intraclass correlation coefficient of 0.897 (95%CI 0.751-0.955; p = 0.000). There was a poor correlation (<0.40) between the separate indirect calorimetry devices and most predictive equations. Only the Faisy predictive equations had good reliability (ICC 0.687, p = 0.002). CONCLUSIONS: Beacon indirect calorimetry accurately determined REE in mechanically ventilated critically ill patients compared to the gold standard in our ICU (Quark indirect calorimeter), although confidence intervals were wide. There was low bias and good reliability. On the other hand, predictive equations performed poorly compared to both devices, underestimating the true metabolic needs of mechanically ventilated ICU patients.


Assuntos
Metabolismo Energético , Respiração Artificial , Calorimetria Indireta , Estudos Transversais , Humanos , Unidades de Terapia Intensiva , Reprodutibilidade dos Testes
2.
ESMO Open ; 6(3): 100103, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33887686

RESUMO

BACKGROUND: Organoid technology has recently emerged as a powerful tool to assess drug sensitivity of individual patient tumors in vitro. Organoids may therefore represent a new avenue for precision medicine, as this circumvents many of the complexities associated with DNA- or transcriptional-profiling. MATERIALS AND METHODS: The SENSOR trial was a single-arm, single-center, prospective intervention trial to evaluate the feasibility of patient-derived organoids to allocate patients for treatment with off-label or investigational agents. The primary endpoint was an objective response rate of ≥20%. Patients underwent a biopsy for culture before commencing their last round standard of care. Organoids were exposed to a panel of eight drugs and patients were treated after progression on standard-of-care treatment and when a clear signal of antitumor activity was identified in vitro. RESULTS: Sixty-one patients were included and we generated 31 organoids of 54 eligible patients. Twenty-five cultures were subjected to drug screening and 19 organoids exhibited substantial responses to one or more drugs. Three patients underwent treatment with vistusertib and three with capivasertib. Despite drug sensitivity of organoids, patients did not demonstrate objective clinical responses to the recommended treatment. CONCLUSIONS: Organoid technology had limited value as a tool for precision medicine in this patient population because a large fraction of patients could not undergo treatment or because the recommended treatment did not elicit an objective response. We identified several essential parameters, such as the culture success rate, clinical deterioration of patients during standard of care, and rational design of drug panels that need to be accounted for in organoid-guided clinical studies.


Assuntos
Neoplasias Colorretais , Preparações Farmacêuticas , Neoplasias Colorretais/tratamento farmacológico , Humanos , Organoides , Medicina de Precisão , Estudos Prospectivos
3.
Eur J Surg Oncol ; 47(2): 486-489, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32800401

RESUMO

In the PERISCOPE I study, gastric cancer patients with limited peritoneal dissemination were treated with systemic chemotherapy followed by (sub)total gastrectomy, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with 460 mg/m2 hyperthermic oxaliplatin followed by normothermic docetaxel in escalating doses (0, 50, 75 mg/m2). In total, 25 patients completed the study protocol. Plasma samples were collected before the start of the HIPEC procedure, after oxaliplatin washing, after docetaxel washing and the following morning. Median peak plasma concentrations were 5.5∗10-3 mg/ml for oxaliplatin, 89∗10-6 mg/ml for docetaxel (dose 50 mg/m2) and 113∗10-6 mg/ml for docetacel (dose 75 mg/m2). The following morning median plasma concentrations were 32% and 4% of the measured peak concentrations for oxaliplatin and docetaxel, respectively. For both cytostatic agents, no correlation was found between intraperitoneal fluid concentration and peak plasma concentration. High doses oxaliplatin and docetaxel can be given intraperitoneally without causing potentially toxic systemic concentrations.


Assuntos
Docetaxel/administração & dosagem , Oxaliplatina/administração & dosagem , Neoplasias Peritoneais/terapia , Peritonite/terapia , Neoplasias Gástricas/terapia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Terapia Combinada , Docetaxel/farmacocinética , Relação Dose-Resposta a Droga , Gastrectomia , Humanos , Injeções Intraperitoneais , Oxaliplatina/farmacocinética , Neoplasias Peritoneais/complicações , Neoplasias Peritoneais/metabolismo , Peritonite/etiologia , Neoplasias Gástricas/complicações , Neoplasias Gástricas/metabolismo
4.
Br J Surg ; 107(11): 1520-1528, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32277764

RESUMO

BACKGROUND: The role of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in gastric cancer is unknown. This non-randomized dose-finding phase I-II study was designed to assess the safety and feasibility of HIPEC, following systemic chemotherapy, in patients with gastric cancer and limited peritoneal dissemination. The maximum tolerated dose of normothermic intraperitoneal docetaxel in combination with a fixed dose of intraperitoneal oxaliplatin was also explored. METHODS: Patients with resectable cT3-cT4a gastric adenocarcinoma with limited peritoneal metastases and/or tumour-positive peritoneal cytology were included. An open HIPEC technique was used with 460 mg/m2 hyperthermic oxaliplatin for 30 min followed by normothermic docetaxel for 90 min in escalating doses (0, 50, 75 mg/m2 ). RESULTS: Between 2014 and 2017, 37 patients were included. Of 25 patients who completed the full study protocol, four were treated at dose level 1 (0 mg/m2 docetaxel), six at dose level 2 (50 mg/m2 ) and four at dose level 3 (75 mg/m2 ). At dose level 3, two dose-limiting toxicities occurred, both associated with postoperative ileus. Thereafter, another 11 patients were treated at dose level 2, with no more dose-limiting toxicities. Based on this, the maximum tolerated dose was 50 mg/m2 intraperitoneal docetaxel. Serious adverse events were scored in 17 of 25 patients. The reoperation rate was 16 per cent (4 of 25) and the treatment-related mortality rate was 8 per cent (2 patients, both in dose level 3). CONCLUSION: Gastrectomy combined with cytoreductive surgery and HIPEC was feasible using 460 mg/m2 oxaliplatin and 50 mg/m2 normothermic docetaxel.


ANTECEDENTES: El papel de la cirugía citorreductora (cytoreductive surgery, CRS) combinado con la quimioterapia intraperitoneal hipertérmica (hyperthermic intraperitoneal chemotherapy, HIPEC) en el cáncer gástrico no está definido. Este estudio fase I-II no aleatorizado de escalado de dosis fue diseñado para evaluar la seguridad y la viabilidad de HIPEC, después de la quimioterapia sistémica, en pacientes con cáncer gástrico con diseminación peritoneal limitada. Además, se exploró la máxima dosis tolerada (maximum tolerated dose, MTD) de docetaxel intraperitoneal normotérmico en combinación con una dosis fija de oxaliplatino intraperitoneal. MÉTODOS: Se incluyeron pacientes con adenocarcinoma gástrico cT3-cT4a resecable con metástasis peritoneales limitadas y/o citología peritoneal positiva. Se utilizó una técnica HIPEC abierta con 460 mg/m2 de oxaliplatino hipertérmico (30 minutos) seguido de docetaxel normotérmico (90 minutos) en dosis crecientes (0, 50, 75 mg/m2 ). RESULTADOS: Entre 2014 y 2017, se incluyeron 37 pacientes. De los 25 pacientes que completaron la totalidad del protocolo del estudio, 4 pacientes fueron tratados en el nivel de dosis 1 (0 mg/m2 de docetaxel), 6 pacientes en el nivel de dosis 2 (50 mg/m2 ) y 4 pacientes en el nivel de dosis 3 (75 mg/m2 ). En el nivel de dosis 3, se produjeron dos casos de toxicidad limitante de dosis (dose-limiting toxicities, DLTs), ambas asociadas con un íleo postoperatorio. Posteriormente, otros 11 pacientes fueron tratados con el nivel de dosis 2, y no se produjeron más DLTs. La MTD de docetaxel intraperitoneal fue de 50 mg/m2 . Se registraron efectos adversos graves en 17 de 25 pacientes. La tasa de reoperación fue del 16% (n = 4) y la mortalidad relacionada con el tratamiento fue del 8% (n = 2; ambos en el nivel de dosis 3).


Assuntos
Adenocarcinoma/secundário , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia do Câncer por Perfusão Regional/métodos , Procedimentos Cirúrgicos de Citorredução/métodos , Hipertermia Induzida/métodos , Neoplasias Peritoneais/secundário , Neoplasias Gástricas/patologia , Adenocarcinoma/mortalidade , Adenocarcinoma/terapia , Idoso , Antineoplásicos/uso terapêutico , Terapia Combinada , Docetaxel/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Estudos de Viabilidade , Feminino , Gastrectomia , Humanos , Masculino , Pessoa de Meia-Idade , Oxaliplatina/uso terapêutico , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/terapia , Neoplasias Gástricas/mortalidade , Resultado do Tratamento
5.
BJS Open ; 3(3): 376-386, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31183454

RESUMO

Background: Pseudomyxoma peritonei (PMP) is a rare disease, most commonly of appendiceal origin. Treatment consists of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). The aim of this study was to identify prognostic factors for recurrence and survival. Methods: This was an observational study using a prospectively designed database containing consecutive patients with PMP originating from the appendix, undergoing CRS-HIPEC at a tertiary referral centre between 1996 and 2015. Histopathological slides were reassessed. Cox regression was used for multivariable analyses. Results: Of 225 patients identified, 36 (16·0 per cent) were diagnosed with acellular mucin, 149 (66·2 per cent) had disseminated peritoneal adenomucinosis (DPAM) and 40 (17·8 per cent) had peritoneal mucinous carcinomatosis (PMCA). The 5-year overall survival (OS) rates were 93, 69·8 and 55 per cent respectively. Recurrence was observed in 120 patients (53·3 per cent), 39 of whom (17·3 per cent) were treated with a second CRS-HIPEC procedure. Factors independently associated with poor disease-free survival were six or seven affected regions (hazard ratio (HR) 6·01, 95 per cent c.i. 2·04 to 17·73), incomplete cytoreduction (R2a resection: HR 1·67, 1·05 to 2·65; R2b resection: HR 2·00, 1·07 to 3·73), and more than threefold raised carcinoembryonic antigen (CEA) and/or carbohydrate antigen (CA) 19-9 level (HR 2·31, 1·30 to 4·11). Factors independently associated with poorer OS were male sex (HR 1·74, 1·09 to 2·77), incomplete cytoreduction (R2a resection: HR 1·87, 1·14 to 3·08; R2b resection: HR 2·28, 1·19 to 4·34), and more than threefold raised CEA and/or CA19-9 level (HR 2·89, 1·36 to 6·16). Conclusion: CEA and CA19-9 levels raised more than threefold above the upper limit identify patients with PMP of appendiceal origin and poorer survival.


Assuntos
Neoplasias do Apêndice/complicações , Procedimentos Cirúrgicos de Citorredução/métodos , Hipertermia Induzida/métodos , Pseudomixoma Peritoneal/tratamento farmacológico , Pseudomixoma Peritoneal/etiologia , Adenocarcinoma Mucinoso/epidemiologia , Adenocarcinoma Mucinoso/patologia , Assistência ao Convalescente , Idoso , Antígenos Glicosídicos Associados a Tumores/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Apêndice/epidemiologia , Antígeno Carcinoembrionário/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Países Baixos/epidemiologia , Neoplasias Peritoneais/epidemiologia , Neoplasias Peritoneais/patologia , Peritônio/patologia , Prognóstico , Estudos Prospectivos , Pseudomixoma Peritoneal/mortalidade , Pseudomixoma Peritoneal/patologia , Taxa de Sobrevida , Centros de Atenção Terciária
6.
BMC Cancer ; 19(1): 420, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31060544

RESUMO

BACKGROUND: At present, palliative systemic chemotherapy is the standard treatment in the Netherlands for gastric cancer patients with peritoneal dissemination. In contrast to lymphatic and haematogenous dissemination, peritoneal dissemination may be regarded as locoregional spread of disease. Administering cytotoxic drugs directly into the peritoneal cavity has an advantage over systemic chemotherapy since high concentrations can be delivered directly into the peritoneal cavity with limited systemic toxicity. The combination of a radical gastrectomy with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promising results in patients with gastric cancer in Asia. However, the results obtained in Asian patients cannot be extrapolated to Western patients. The aim of this study is to compare the overall survival between patients with gastric cancer with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with palliative systemic chemotherapy, and those treated with gastrectomy, CRS and HIPEC after neoadjuvant systemic chemotherapy. METHODS: In this multicentre randomised controlled two-armed phase III trial, 106 patients will be randomised (1:1) between palliative systemic chemotherapy only (standard treatment) and gastrectomy, CRS and HIPEC (experimental treatment) after 3-4 cycles of systemic chemotherapy.Patients with gastric cancer are eligible for inclusion if (1) the primary cT3-cT4 gastric tumour including regional lymph nodes is considered to be resectable, (2) limited peritoneal dissemination (Peritoneal Cancer Index < 7) and/or tumour positive peritoneal cytology are confirmed by laparoscopy or laparotomy, and (3) systemic chemotherapy was given (prior to inclusion) without disease progression. DISCUSSION: The PERISCOPE II study will determine whether gastric cancer patients with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with systemic chemotherapy, gastrectomy, CRS and HIPEC have a survival benefit over patients treated with palliative systemic chemotherapy only. TRIAL REGISTRATION: clinicaltrials.gov NCT03348150 ; registration date November 2017; first enrolment November 2017; expected end date December 2022; trial status: Ongoing.


Assuntos
Procedimentos Cirúrgicos de Citorredução/métodos , Hipertermia Induzida/métodos , Cuidados Paliativos/métodos , Neoplasias Peritoneais/terapia , Neoplasias Gástricas/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioterapia Adjuvante/economia , Quimioterapia Adjuvante/métodos , Ensaios Clínicos Fase III como Assunto , Análise Custo-Benefício , Procedimentos Cirúrgicos de Citorredução/economia , Intervalo Livre de Doença , Feminino , Gastrectomia/economia , Gastrectomia/métodos , Humanos , Hipertermia Induzida/economia , Estimativa de Kaplan-Meier , Masculino , Estudos Multicêntricos como Assunto , Países Baixos/epidemiologia , Cuidados Paliativos/economia , Neoplasias Peritoneais/economia , Neoplasias Peritoneais/secundário , Peritônio/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Gástricas/economia , Neoplasias Gástricas/patologia
7.
Ned Tijdschr Geneeskd ; 1622018 Jun 22.
Artigo em Holandês | MEDLINE | ID: mdl-30040257

RESUMO

An immunocompromised 78-year-old woman had a painful hip and subacute fever. An abdominal CT scan revealed a diverticular sigmoid stenosis fistulating to the presacral space, with free gas in the paravertebral musculature and spinal canal. Because a deep necrotising infection was suspected, she underwent surgery and was treated with antibiotics. She recovered completely.


Assuntos
Artralgia/diagnóstico , Colo Sigmoide , Fístula do Sistema Digestório , Divertículo do Colo , Febre/diagnóstico , Gangrena Gasosa , Articulação do Quadril/fisiopatologia , Idoso , Colo Sigmoide/diagnóstico por imagem , Colo Sigmoide/patologia , Diagnóstico Diferencial , Fístula do Sistema Digestório/complicações , Fístula do Sistema Digestório/diagnóstico , Divertículo do Colo/complicações , Divertículo do Colo/diagnóstico , Feminino , Gangrena Gasosa/diagnóstico , Gangrena Gasosa/etiologia , Humanos , Canal Medular/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos
8.
Br J Surg ; 105(6): 728-735, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29652082

RESUMO

BACKGROUND: Studies investigating the association between hospital volume and quality of gastric cancer surgery are lacking. In the present study, the effect of hospital volume on quality of gastric cancer surgery was evaluated by analysing data from the CRITICS (ChemoRadiotherapy after Induction chemotherapy In Cancer of the Stomach) trial. METHODS: Patients who underwent gastrectomy with curative intent in the Netherlands were selected from the CRITICS trial database. Annual hospital volume of participating centres was derived from the Netherlands Cancer Registry. Hospital volume was categorized into very low (1-10 gastrectomies per year per institution), low (11-20), medium (21-30) and high (31 or more), and linked to the CRITICS database. Quality of surgery was analysed by surgicopathological compliance (removal of at least 15 lymph nodes), surgical compliance (removal of indicated lymph node stations) and the Maruyama Index. Postoperative morbidity and mortality were also compared between hospital categories. RESULTS: Between 2007 and 2015, 788 patients were included in the CRITICS study, of whom 494 were analysed. Surgicopathological compliance was higher (86·7 versus 50·4 per cent; P < 0·001), surgical compliance was greater (52·9 versus 19·8 per cent; P < 0·001) and median Maruyama Index was lower (0 versus 6; P = 0·006) in high-volume hospitals compared with very low-volume hospitals. There was no statistically significant difference in postoperative complications or mortality between the hospital volume categories. CONCLUSION: Surgery performed in high-volume hospitals was associated with better surgical quality than surgery carried out in lower-volume hospitals.


Assuntos
Hospitais/estatística & dados numéricos , Qualidade da Assistência à Saúde , Neoplasias Gástricas/cirurgia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Gastrectomia/normas , Gastrectomia/estatística & dados numéricos , Hospitais/normas , Humanos , Excisão de Linfonodo/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Indicadores de Qualidade em Assistência à Saúde , Qualidade da Assistência à Saúde/organização & administração , Qualidade da Assistência à Saúde/estatística & dados numéricos , Sistema de Registros , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia
9.
Br J Surg ; 105(5): 561-569, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29465746

RESUMO

BACKGROUND: Textbook outcome is a multidimensional measure representing an ideal course after oesophagogastric cancer surgery. It comprises ten perioperative quality-of-care parameters and has been developed recently using population-based data. Its association with long-term outcome is unknown. The objectives of this study were to validate the clinical relevance of textbook outcome at a hospital level, and to assess its relation with long-term survival after treatment for oesophagogastric cancer. METHODS: All patients with oesophageal or gastric cancer scheduled for surgery with curative intent between January 2009 and June 2015 were selected from an institutional database. A Cox model was used to study the association between textbook outcome and survival. RESULTS: A textbook outcome was achieved in 58 of 144 patients (40·3 per cent) with oesophageal cancer and in 48 of 105 (45·7 per cent) with gastric cancer. Factors associated with not achieving a textbook outcome were failure to achieve a lymph node yield of at least 15 (after oesophagectomy) and postoperative complications of grade II or more. After oesophagectomy, median overall survival was longer for patients with a textbook outcome than for patients without (median not reached versus 33 months; P = 0·012). After gastrectomy, median survival was 54 versus 33 months respectively (P = 0·018). In multivariable analysis, textbook outcome was associated with overall survival after oesophagectomy (hazard ratio 2·38, 95 per cent c.i. 1·29 to 4·42) and gastrectomy (hazard ratio 2·58, 1·25 to 5·32). CONCLUSION: Textbook outcome is a clinically relevant measure in patients undergoing oesophagogastric cancer surgery as it can identify underperforming parameters in a hospital setting. Overall survival in patients with a textbook outcome is better than in patients without a textbook outcome.


Assuntos
Neoplasias Esofágicas/cirurgia , Esofagectomia/normas , Gastrectomia/normas , Indicadores de Qualidade em Assistência à Saúde/normas , Neoplasias Gástricas/cirurgia , Resultado do Tratamento , Idoso , Comorbidade , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/mortalidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Países Baixos/epidemiologia , Complicações Pós-Operatórias , Estudos Retrospectivos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/mortalidade , Taxa de Sobrevida/tendências , Fatores de Tempo
10.
Eur J Surg Oncol ; 44(2): 220-227, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29258720

RESUMO

BACKGROUND: Colorectal peritoneal carcinomatosis (PC) is commonly treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). There is an ongoing international debate about which intraperitoneal chemotherapeutic agent is preferred, Mitomycin C (MMC) or oxaliplatin. We questioned whether the type of chemotherapeutic agent influenced postoperative complication rates or short-term survival. METHODS: In this retrospective cohort study patients with colorectal PC who underwent CRS-HIPEC between January 2010 and December 2016 were included. Until March 2014 patients had preferentially been treated with MMC and thereafter with oxaliplatin in an iso-osmotic glucose/electrolyte dialysis (Dianeal®) carrier solution. Main outcomes were postoperative complications, disease free survival (DFS) and overall survival (OS). Survival analyses and multivariable analyses were performed. RESULTS: One hundred four patients received MMC and 73 patients oxaliplatin. Postoperative complications did not differ between groups (44.2% (MMC) versus 43.8% (oxaliplatin); P = 0.958). Median DFS was 12.5 months (IQR 6.4-32.4) in the MMC-group and 13.1 months (IQR 6.1-NA) in the oxaliplatin-group (P = 0.669). Median OS was 37.2 months (IQR 17.2-NA) in the MMC-group and 29.4 months (IQR 17.0-NA) in the oxaliplatin-group (P = 0.764). The type of chemotherapeutic agent did not influence OS in multivariable analysis (oxaliplatin versus MMC HR 1.09 (95%CI 0.58-2.06)). The HIPEC-phase was shorter for oxaliplatin (median 32 (IQR 31-34) versus 91 min (IQR 90-92) for MMC (P < 0.001)). CONCLUSION: Intraperitoneal oxaliplatin reduced the chemoperfusion time when compared to intraperitoneal MMC without adversely influencing complication rates or short-term survival. It may therefore be the preferential drug in CRS-HIPEC procedures for colorectal PC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma/terapia , Neoplasias Colorretais/terapia , Hipertermia Induzida/métodos , Mitomicina/uso terapêutico , Compostos Organoplatínicos/uso terapêutico , Neoplasias Peritoneais/terapia , Idoso , Carcinoma/secundário , Estudos de Coortes , Neoplasias Colorretais/patologia , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução/métodos , Intervalo Livre de Doença , Feminino , Humanos , Infusões Parenterais , Masculino , Pessoa de Meia-Idade , Oxaliplatina , Neoplasias Peritoneais/secundário , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos
11.
Int J Clin Oncol ; 23(3): 482-489, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29204933

RESUMO

BACKGROUND: The RECOURSE trial showed clinical efficacy for trifluridine/tipiracil for refractory metastatic colorectal cancer patients. We assessed the feasibility and effectiveness of trifluridine/tipiracil in daily clinical practice in The Netherlands. METHODS: Medical records of patients from 17 centers treated in the trifluridine/tipiracil compassionate use program were reviewed and checked for RECOURSE eligibility criteria. Baseline characteristics, safety, and survival times were compared, and prespecified baseline characteristics were tested in multivariate analyses for prognostic significance on overall survival (OS). RESULTS: A total of 136 patients with a median age of 62 years were analyzed. Forty-three patients (32%) did not meet the RECOURSE eligibility criteria for not having received all prior standard treatments (n = 35, 26%) and/or ECOG performance status (PS) 2 (n = 12, 9%). The most common grade ≥3 toxicities were neutropenia (n = 44, 32%), leukopenia (n = 8, 6%), anemia (n = 7, 5%), and fatigue (n = 7, 5%). Median progression-free survival (PFS) and median OS were 2.1 (95% CI, 1.8-2.3) and 5.4 months (95% CI, 4.0-6.9), respectively. Patients with ECOG PS 2 had a worse median OS (3.2 months) compared to patients with ECOG PS 0-1 (5.9 months). ECOG PS, KRAS-mutation status, white blood cell count, serum lactate dehydrogenase, and alkaline phosphatase were prognostic factors for OS. CONCLUSIONS: Our data show that treatment with trifluridine/tipiracil in daily clinical practice is feasible and safe. Differences in patient characteristics between our population and the RECOURSE study population should be taken into account in the interpretation of survival data. Our results argue against the use of trifluridine/tipiracil in patients with ECOG PS 2. FUNDING: Johannes J.M. Kwakman received an unrestricted research grant from Servier.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Combinação de Medicamentos , Feminino , Humanos , Leucopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Países Baixos , Neutropenia/induzido quimicamente , Prognóstico , Pirrolidinas , Timina , Resultado do Tratamento , Trifluridina/efeitos adversos , Uracila/efeitos adversos , Uracila/uso terapêutico
13.
Dis Esophagus ; 29(8): 1100-1106, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26541751

RESUMO

The process of preparing endoscopic esophageal adenocarcinoma samples for next-generation DNA/RNA sequencing is poorly described. Therefore, we assessed the feasibility and pitfalls of preparing esophageal adenocarcinoma endoscopic biopsies toward DNA/RNA samples suitable for next-generation sequencing. In this prospective study, four tumor biopsy samples were collected from consecutive esophageal cancer patients during esophagogastroduodenoscopy and fresh-frozen in liquid nitrogen. DNA and RNA were isolated from samples with a tumor percentage of at least 50%. For next-generation sequencing, double-stranded DNA (dsDNA) is required and high-quality RNA preferred. The quantity dsDNA and RNA quantity and quality were assessed with the Nanodrop 2000 spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA) and Agilent 2100 Bioanalyzer (Agilent, Santa Clara, CA, USA). Biopsy samples of 69 consecutive patients with esophageal adenocarcinoma were included. In five patients (7%), the tumor percentage was less than 50% in all four biopsies. Using a protocol allowing simultaneous DNA and RNA isolation, the median dsDNA yield was 2.4 µg (range 0.1-12.0 µg) and the median RNA yield was 0.5 µg (range 0.01-2.05 µg). The median RNA integrity number of samples that were fresh-frozen within 30 minutes after sampling was 6.7 (range 4.2-8.9) compared with 2.5 (1.8-4.5) for samples that were fresh-frozen after 2 hours. The results from this study show that obtaining dsDNA and RNA for next-generation sequencing from endoscopic esophageal adenocarcinoma samples is feasible. Tumor percentage and dsDNA/RNA yield and quality emphasize the need for sampling multiple biopsies and minimizing the delay before fresh-freezing.


Assuntos
Adenocarcinoma/patologia , Neoplasias Esofágicas/patologia , Esôfago/patologia , Secções Congeladas/métodos , Bancos de Tecidos , Adenocarcinoma/genética , Biópsia/métodos , Endoscopia do Sistema Digestório , Neoplasias Esofágicas/genética , Estudos de Viabilidade , Humanos , Estudos Prospectivos , Análise de Sequência de DNA/métodos , Análise de Sequência de RNA/métodos
14.
Crit Rev Oncol Hematol ; 95(3): 282-96, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25921419

RESUMO

PURPOSE: Several studies have shown the potential benefit of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in gastric cancer patients. At present the most effective chemotherapeutic regime in HIPEC for gastric cancer is unknown. The aim of this review was to provide a comprehensive overview of chemotherapeutic agents used for HIPEC in gastric cancer. METHODS: A literature search was conducted using the PubMed database to identify studies on chemotherapy used for HIPEC in gastric cancer patients. RESULTS AND CONCLUSION: The chemotherapeutic regime of choice in HIPEC for gastric cancer has yet to be determined. The wide variety in studies and study parameters, such as chemotherapeutic agents, dosage, patient characteristics, temperature of perfusate, duration of perfusion, carrier solutions, intraperitoneal pressure and open or closed perfusion techniques, warrant more experimental and clinical studies to determine the optimal treatment schedule. A combination of drugs probably results in a more effective treatment.


Assuntos
Antineoplásicos/administração & dosagem , Quimioterapia do Câncer por Perfusão Regional , Hipertermia Induzida , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/secundário , Neoplasias Gástricas/tratamento farmacológico , Humanos , Neoplasias Gástricas/patologia
15.
Cancer Chemother Pharmacol ; 75(4): 763-72, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25677447

RESUMO

PURPOSE: This work was initiated to extend data on the effect of pharmacogenetics and chemotherapy pharmacokinetics (PK) on clinical outcome in patients with gastrointestinal malignancies. METHODS: We assessed 44 gene polymorphisms in 16 genes (TYMS, MTHFR, GSTP1, GSTM1, GSTT1, DPYD, XRCC1, XRCC3, XPD, ERCC1, RECQ1, RAD54L, ABCB1, ABCC2, ABCG2 and UGT2B7) in 64 patients with metastatic colorectal cancer (CRC) receiving capecitabine/oxaliplatin and 76 patients with advanced gastroesophageal cancer (GEC) receiving epirubicin/cisplatin/capecitabine, respectively. Plasma concentrations of anticancer drugs were measured for up to 24 h, and results were submitted to population PK analysis. We calculated the association between gene polymorphisms, chemotherapy exposure, tumor response, progression-free survival (PFS), overall survival (OS) and chemotherapy-related toxicity using appropriate statistical tests. RESULTS: Patients with a low clearance of 5FU were at increased risk of neutropenia (P < 0.05) and hand-foot syndrome (P = 0.002). DPYD T85C, T1896C and A2846T mutant variants were associated with diarrhea (P < 0.05) and HFS (P < 0.02), and IVS14+1G>A additionally with diarrhea (P < 0.001). The TYMS 2R/3G, 3C/3G or 3G/3G promoter variants were associated with worse PFS in the CRC (HR = 2.0, P < 0.01) and GEC group (HR = 5.4, P < 0.001) and worse OS in the GEC group (HR = 4.7, P < 0.001). The GSTP1 A313G mutant variant was associated with a higher PFS (HR = 0.55, P = 0.001) and OS (HR = 0.60, P = 0.002) in the CRC group. CONCLUSIONS: Germline polymorphisms of DPYD, TYMS and GSTP1 have a significant effect on toxicity and clinical outcome in patients receiving capecitabine-based chemotherapy for advanced colorectal or gastroesophageal cancer. These data should further be validated in prospective clinical studies.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Desoxicitidina/análogos & derivados , Di-Hidrouracila Desidrogenase (NADP)/genética , Fluoruracila/análogos & derivados , Neoplasias Gastrointestinais/tratamento farmacológico , Glutationa S-Transferase pi/genética , Polimorfismo de Nucleotídeo Único , Timidilato Sintase/genética , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Capecitabina , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/farmacocinética , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/farmacocinética , Fluoruracila/uso terapêutico , Neoplasias Gastrointestinais/enzimologia , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Genótipo , Mutação em Linhagem Germinativa , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , Metástase Neoplásica , Valor Preditivo dos Testes
16.
Gynecol Oncol ; 136(3): 562-6, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25560808

RESUMO

OBJECTIVE: About 5-15% of all malignant ovarian tumors are metastases from other malignancies such as gastrointestinal tumors, breast cancer or melanoma. Also other gynecological tumors can metastasize to the ovaries. It is crucial to differentiate between primary epithelial ovarian cancer (EOC) and ovarian metastases because different treatment is required. The clinical value of human epididymal secretory protein 4 (HE4) as a serum biomarker in primary ovarian cancer has been established. The use of HE4 in the differentiation between primary ovarian cancer and ovarian metastases from other malignancies has never been investigated. METHODS: HE4, CA125 and CEA were measured in 192 patients with EOC (n=147) or ovarian metastases (n=40). Univariate and multivariate logistic regression analyses were done. Sensitivity, specificity and area under the curve (AUC) were calculated for all markers and ratios hereof using receiver operating characteristics methodology. RESULTS: Median serum HE4 concentration was significantly higher in patients with EOC compared to patients with ovarian metastases (431 pmol/L vs 68 pmol/L, p<0.001). HE4 and CEA were independent factors in differentiating between EOC and ovarian metastases (both p<0.001) while CA125 was not (p=0.33). The HE4(2.5)/CEA ratio demonstrated the highest discriminative value (ROC-AUC 0.94) compared to HE4, CEA, CA125 or CA125/CEA ratio (0.88, 0.78, 0.80 and 0.89 respectively) and showed a specificity of 82.5% at set sensitivity of 90% in discriminating EOC from ovarian metastases. CONCLUSION: HE4 can be used in combination with CEA to make the distinction between EOC and ovarian metastases from gastrointestinal origin.


Assuntos
Adenocarcinoma/secundário , Biomarcadores Tumorais/sangue , Neoplasias Gastrointestinais/patologia , Neoplasias Epiteliais e Glandulares/diagnóstico , Neoplasias Ovarianas/secundário , Proteínas/metabolismo , Adenocarcinoma/sangue , Adenocarcinoma/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Antígeno Ca-125/sangue , Antígeno Carcinoembrionário/sangue , Carcinoma Epitelial do Ovário , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Neoplasias Gastrointestinais/sangue , Neoplasias Gastrointestinais/diagnóstico , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias Epiteliais e Glandulares/sangue , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/diagnóstico , Estudos Retrospectivos , Sensibilidade e Especificidade , Proteína 2 do Domínio Central WAP de Quatro Dissulfetos
17.
J Cancer Res Clin Oncol ; 141(8): 1343-51, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25544671

RESUMO

PURPOSE: Primary tumor classification of gastric or esophageal cancer has changed significantly with recent alterations of the tumor-node-metastasis (TNM) staging system. Considering these alterations, human epidermal growth factor receptor 2 (HER2) positivity rates were determined and compared in gastric and esophageal adenocarcinoma. Additionally, HER2 positivity in relation to other clinicopathological characteristics was evaluated. METHODS: A total of 321 patients with histologically confirmed invasive gastric or esophageal adenocarcinoma were examined for HER2 by immunohistochemy (IHC) and chromogenic in situ hybridization (CISH). IHC 3+ or IHC 2+/CISH-positive tumors were considered HER2 positive. Clinicopathological characteristics were retrospectively retrieved from the patient records. RESULTS: HER2 positivity was found in 50 of 321 patients (15.6 %). In univariate and multivariate logistic models, HER2 positivity rates were significantly higher in esophageal primary tumors (esophageal 25.0 % vs. gastric 7.4 %) and in intestinal histological tumor type (intestinal 22.6 % vs. diffuse/mixed 5.7 %). No significant differences in HER2 positivity were found between males and females, age below and above 65 years, biopsies and surgical specimens or advanced and early-stage disease. Using the 7th TNM edition, many tumors (30.5 % of all included tumors and 64.5 % of all esophageal primary tumors) previously classified as gastric cancer are now classified as esophageal cancer. CONCLUSIONS: HER2 positivity occurs in 15.6 % of invasive gastroesophageal adenocarcinoma in Western patients, of which the majority is esophageal primary tumors and of the intestinal tumor type. With the introduction of the 7th TNM edition, a large number of tumors previously classified as gastric are now classified as esophageal tumors instead, with relatively high HER2 positivity rates in these esophageal primary tumors.


Assuntos
Adenocarcinoma/genética , Neoplasias Esofágicas/genética , Receptor ErbB-2/genética , Neoplasias Gástricas/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Feminino , Dosagem de Genes , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
18.
Euro Surveill ; 19(16): 20776, 2014 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-24786261

RESUMO

We describe a mumps outbreak in a highly-vaccinated population attending a party at a youth club. In a retrospective cohort study with 60 of approximately 100 participants responding, vaccination status was verified for 58/59 respondents, of whom 54 were vaccinated twice and four once. The attack rate was 22% (13 cases, all vaccinated), with smoking at the party (risk ratio (RR) 3.1; 95% confidence interval (CI): 1.6­6.0, p=0.001) and age ≥21 years (RR 4.7; 95% CI: 2.1­10.2, p<0.0001) as risk factors for disease in the binominal regression analysis. Mild upper respiratory illness was also highly prevalent in those who did not meet the mumps case definition (n=46) after the party, suggesting that mumps virus infection may cause mild disease in vaccinated individuals. Our investigation adds toevidence that crowded social events and smoking may facilitate spread of mumps virus among vaccinated populations, with waning immunity playing a role. The suggestion that mumps virus infection in vaccinated individuals may manifest as mild upper respiratory illness could have implications for transmission and warrants further investigation.


Assuntos
Aglomeração , Surtos de Doenças , Vacina contra Caxumba/administração & dosagem , Caxumba/epidemiologia , Fumar/epidemiologia , Vacinação/estatística & dados numéricos , Adolescente , Adulto , Distribuição por Idade , Intervalos de Confiança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Caxumba/diagnóstico , Caxumba/transmissão , Vacina contra Caxumba/imunologia , Vírus da Caxumba/imunologia , Países Baixos/epidemiologia , Prevalência , Análise de Regressão , Infecções Respiratórias/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Fatores Socioeconômicos , Inquéritos e Questionários , Adulto Jovem
19.
Eur J Surg Oncol ; 40(8): 937-42, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24630923

RESUMO

AIM: To compare outcome of women with ovarian metastasis who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) to outcome of women without ovarian metastasis who underwent CRS-HIPEC. METHODS: A prospective CRS-HIPEC database was searched to identify women with surgically treated colorectal carcinoma between 2000 and 2012. Patients with ovarian metastasis were identified and patients with peritoneal carcinomatosis but without ovarian metastasis were included as control cases. RESULTS: 75 patients with macroscopic ovarian metastasis underwent CRS-HIPEC with curative intent, while 50 female patients without ovarian metastasis were identified who underwent CRS-HIPEC. Patients with ovarian metastasis more often had a primary appendiceal tumour and had a more extensive intra-abdominal tumour load compared to patients without ovarian metastases. Median follow-up time was 45 months (95% confidence interval (CI): 37-53 months). Overall survival (OS) did not differ significantly between the two groups with a median OS in the ovarian metastasis group of 40 months (95% CI 26-54) compared to 64 months (95% CI 17-111, P = 0.478) in the non-ovarian metastasis group. Recurrence patterns did not differ significantly between groups (p = 0.183). CONCLUSIONS: Patients with ovarian metastasis of colorectal and appendiceal origin who underwent CRS-HIPEC had similar outcome compared to patients without ovarian metastasis. Given the findings of high coincidence of peritoneal metastases with ovarian metastases and ovarian metastases not being an independent factor for survival after CRS-HIPEC, this procedure should be recommended for patients with peritoneal metastases and ovarian metastases of colorectal and appendiceal carcinoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias do Apêndice/patologia , Carcinoma/tratamento farmacológico , Carcinoma/cirurgia , Neoplasias Colorretais/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/cirurgia , Adulto , Idoso , Carcinoma/metabolismo , Quimioterapia Adjuvante , Quimioterapia do Câncer por Perfusão Regional/métodos , Bases de Dados Factuais , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Hipertermia Induzida , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/metabolismo , Cavidade Peritoneal , Neoplasias Peritoneais/metabolismo , Estudos Prospectivos , Estudos Retrospectivos , Resultado do Tratamento
20.
Ann Oncol ; 25(4): 864-869, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24667719

RESUMO

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is the preferred treatment of peritoneal carcinomatosis (PC) of colorectal carcinoma. Patients with positive lymph node status have worse survival after CRS-HIPEC, which is probably due to higher rates of systemic failure. In this study, we analysed the effect of administration and timing of systemic chemotherapy on the outcome of lymph node positive colorectal carcinoma patients treated with CRS-HIPEC. PATIENTS AND METHODS: A prospective database was reviewed to identify lymph node positive patients with PC treated with CRS-HIPEC within 1 year after primary tumour diagnosis between 2004 and 2012. Medical history of the patients was studied for the administration of perioperative systemic chemotherapy and follow-up. Outcome parameters were progression-free survival (PFS), overall survival (OS) and pattern of recurrence. RESULTS: Seventy-three patients treated with CRS-HIPEC for PC from lymph node positive colorectal carcinoma were identified. Fourteen patients received pre-CRS-HIPEC chemotherapy only, 32 patients underwent post-CRS-HIPEC chemotherapy only, 9 patients received chemotherapy both pre- and post-CRS-HIPEC and 16 patients did not receive any systemic chemotherapy. Of the 47 patients who did not receive pre-CRS-HIPEC chemotherapy, 11 (23%) did not receive any chemotherapy due to major postoperative complications. PFS and OS were significantly higher in patients who received systemic chemotherapy (PFS: median 15 versus 4 months, P = 0.024; OS: median 30 versus 14 months, P = 0.015), although this difference was attenuated after adjustment for major complications. Different chemotherapy timings did not differ significantly in either survival or recurrence patterns. CONCLUSIONS: In patients with PC from lymph node positive colorectal carcinoma, perioperative systemic chemotherapy is associated with increased OS and PFS, although this difference may be partly explained by the occurrence of major postoperative complication; with no evidence of difference in PFS, OS and systemic recurrence rate by timing of systemic chemotherapy.


Assuntos
Carcinoma/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Carcinoma/patologia , Quimioterapia do Câncer por Perfusão Regional , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Hipertermia Induzida , Estimativa de Kaplan-Meier , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Assistência Perioperatória , Neoplasias Peritoneais/patologia , Neoplasias Peritoneais/cirurgia
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