RESUMEN
BACKGROUND: Insulinomas are found in 10-15 per cent of patients with multiple endocrine neoplasia type 1 (MEN1) and lead to life-threatening hypoglycaemia. Surgical outcome and the optimal surgical strategy for MEN1-related insulinoma are unknown. METHODS: Patients with MEN1-related insulinomas were identified in 46 centres in Europe and North America between 1990 and 2016. Insulinomas were considered localized if the lesion was in the pancreatic head or body/tail. Patients with pancreatic neuroendocrine tumours throughout the pancreas were suspected of having multifocal insulinoma. The primary outcome was postoperative hypoglycaemia, defined as persistent hypoglycaemia, or recurrent hypoglycaemia caused by a new insulinoma or insulin-producing liver metastases. Hypoglycaemia-free survival was estimated by the Kaplan-Meier method. RESULTS: Ninety-six patients underwent resection for MEN1-related insulinoma. Sixty-three and 33 patients had localized and multifocal insulinomas respectively. After a median follow-up of 8 (range 1-22) years, one patient (1 per cent) had persistent disease and six (6 per cent) had developed recurrent disease, of whom four had a new insulinoma. The 10-year hypoglycaemia-free survival rate was 91 (95 per cent c.i. 80 to 96) per cent. Of those with localized disease, 46 patients underwent pancreatic resection and 17 enucleation. One of these patients had persistent disease and one developed recurrent insulinoma. Among patients with multifocal disease, three developed new insulinomas and two developed insulin-producing liver metastases. CONCLUSION: Surgery for MEN1-related insulinoma is more successful than previously thought.
ANTECEDENTES: Del 10% al 15% de los pacientes con MEN1 presentan insulinomas que pueden desencadenar una hipoglucemia potencialmente mortal. Se desconoce el resultado de la cirugía y la estrategia quirúrgica óptima para el tratamiento del insulinoma relacionado con el MEN1. MÉTODOS: Se identificaron los pacientes con insulinomas relacionados con el MEN1 en 46 centros de Europa y América del Norte entre 1990 y 2016. Los insulinomas se consideraron localizados si el tumor se localizaba en la cabeza o en el cuerpo/cola del páncreas. Se sospechó la existencia de un insulinoma multifocal en los pacientes con tumores neuroendocrinos pancreáticos (pNETs). El objetivo primario de este estudio fue evaluar la hipoglucemia postoperatoria, definida como hipoglucemia persistente, hipoglucemia recidivante causada por un nuevo insulinoma o debida a metástasis hepáticas productoras de insulina. La supervivencia libre de hipoglucemia se estimó mediante el método de Kaplan-Meier. RESULTADOS: A 96 se les realizó una resección por insulinoma en el contexto del MEN1. Un total de 63 y 33 pacientes presentaron insulinomas localizados y multifocales, respectivamente. Después de una mediana de seguimiento de 7,8 años (rango 1-22), un paciente (1%) tenía enfermedad persistente y seis pacientes (6%) presentaron enfermedad recidivante, de los cuales cuatro desarrollaron un nuevo insulinoma. La supervivencia libre de hipoglucemia fue del 91% a los 10 años (i.c. del 95%, 80%-96%). De los pacientes con enfermedad localizada, 46 fueron sometidos a resección pancreática y 17 pacientes a enucleación. Entre éstos, un paciente tenía enfermedad persistente y uno desarrolló insulinoma recidivante, respectivamente. De los pacientes con enfermedad multifocal, tres desarrollaron nuevos insulinomas y dos desarrollaron metástasis hepáticas productoras de insulina. CONCLUSIÓN: La cirugía para el insulinoma en el contexto del MEN1 es más exitosa de lo que parecía en principio.
Asunto(s)
Insulinoma/cirugía , Neoplasia Endocrina Múltiple Tipo 1/cirugía , Pancreatectomía , Neoplasias Pancreáticas/cirugía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Toma de Decisiones Clínicas , Femenino , Estudios de Seguimiento , Humanos , Hipoglucemia/epidemiología , Hipoglucemia/etiología , Insulinoma/complicaciones , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasia Endocrina Múltiple Tipo 1/complicaciones , Recurrencia Local de Neoplasia/epidemiología , Neoplasias Pancreáticas/complicaciones , Complicaciones Posoperatorias/epidemiología , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Patients with peritoneal metastases from colorectal cancer have a poor prognosis. If the intraperitoneal tumour load is limited, patients may be eligible for cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC). This treatment has improved overall survival, but recurrence rates are high. The aim of this study was to create a preclinical platform for the development of more effective intraperitoneal chemotherapy strategies. METHODS: Using organoid technology, five tumour cultures were generated from malignant ascites and resected peritoneal metastases. These were used in an in vitro HIPEC model to assess sensitivity to mitomycin C (MMC) and oxaliplatin, the drugs used most commonly in HIPEC. The model was also used to test a rational combination treatment involving MMC and inhibitors of the checkpoint kinase ATR. RESULTS: MMC was more effective in eliminating peritoneal metastasis-derived organoids than oxaliplatin at clinically relevant concentrations. However, the drug concentrations required to eliminate 50 per cent of the tumour cells (IC50) were higher than the median clinical dose in two of five organoid lines for MMC, and all five lines for oxaliplatin, indicating a general resistance to monotherapy. ATR inhibition increased the sensitivity of all peritoneal metastasis-derived organoids to MMC, as the IC50 decreased 2·6-12·4-fold to well below concentrations commonly attained in clinical practice. Live-cell imaging and flow cytometric analysis showed that ATR inhibition did not release cells from MMC-induced cell cycle arrest, but caused increased replication stress and accelerated cell death. CONCLUSION: Peritoneal metastasis-derived organoids can be used to evaluate existing HIPEC regimens on an individual-patient level and for development of more effective treatment strategies. Surgical relevance Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) has improved prognosis of patients with peritoneal metastases from colorectal cancer, but disease recurrence is common. More effective and personalized HIPEC is urgently needed. Organoid technology is frequently used for drug screens, as patient-derived organoids can accurately predict clinical therapeutic response in vitro. A panel of organoids was established from peritoneal metastases from colorectal cancer and used to develop a model for testing HIPEC regimens in vitro. Patient-derived organoids differed in sensitivity to commonly used chemotherapeutics, in line with variable clinical outcomes following cytoreductive surgery-HIPEC. Combining MMC with an ATR inhibitor improved the efficacy of MMC. Peritoneal metastasis-derived organoids can be used as a platform to test novel (combination) strategies that increase HIPEC efficacy. In the future, organoids could be used to select patent-tailored HIPEC regimens.
ANTECEDENTES: Los pacientes con metástasis peritoneales (peritoneal metastasis, PM) de cáncer colorrectal tienen un mal pronóstico. Si la carga tumoral intraperitoneal es reducida, los pacientes pueden ser candidatos a cirugía citorreductora seguida de quimioterapia intraperitoneal hipertérmica (hyperthermic intraperitoneal chemotherapy, HIPEC). Este tratamiento ha mejorado la supervivencia global, pero las tasas de recidiva son altas. El objetivo de este estudio fue crear una plataforma preclínica para el desarrollo de las estrategias de quimioterapia intraperitoneal más efectivas. MÉTODOS: Mediante la utilización de la tecnología de organoides, se generaron cinco cultivos tumorales a partir de ascitis maligna y PM resecadas. Se utilizó un modelo de HIPEC in vitro para evaluar la sensibilidad a la mitomicina C (mitomycin C, MMC) y al oxaliplatino, los fármacos más utilizados en la HIPEC. El modelo también se usó para probar un tratamiento combinado de MMC e inhibidores de control inmunitario de la quinasa ATR. RESULTADOS: A concentraciones clínicamente relevantes, la MMC fue más efectiva que el oxaliplatino para eliminar los organoides derivados de PM. Sin embargo, las concentraciones de fármaco necesarias para eliminar el 50% de las células tumorales (IC50) fueron más elevadas que la mediana de la dosis clínica en 2/5 (MMC) o 5/5 (oxaliplatino) de las líneas de organoides, lo que indica una resistencia general a la monoterapia. La inhibición de ATR aumentó la sensibilidad a MMC de todos los organoides derivados de PM, ya que la IC50 disminuyó (2,6-12,4 veces) a concentraciones muy por debajo de las que se alcanzan comúnmente en la práctica clínica. Los análisis de viabilidad celular y de citometría de flujo (FACS) mostraron que la inhibición de ATR no liberaba células tras la detención del ciclo celular inducida por la MMC, sino que causaba un aumento en el estrés replicativo y muerte celular acelerada. CONCLUSIÓN: Se pueden usar los organoides derivados de PM para evaluar los regímenes HIPEC existentes a nivel del paciente individual y para desarrollar estrategias terapéuticas más efectivas.
Asunto(s)
Neoplasias Colorrectales , Hipertermia Inducida/métodos , Organoides , Neoplasias Peritoneales/terapia , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mitomicina/uso terapéutico , Oxaliplatino/uso terapéutico , Neoplasias Peritoneales/secundario , Recolección de Tejidos y Órganos/métodosRESUMEN
BACKGROUND: Recurrences are reported in 70% of all patients after resection of colorectal liver metastases (CRLM), in which half are confined to the liver. Adjuvant hepatic arterial infusion pump (HAIP) chemotherapy aims to reduce the risk of intrahepatic recurrence. A large retrospective propensity score analysis demonstrated that HAIP chemotherapy is particularly effective in patients with low-risk oncological features. The aim of this randomized controlled trial (RCT) --the PUMP trial-- is to investigate the efficacy of adjuvant HAIP chemotherapy in low-risk patients with resectable CRLM. METHODS: This is an open label multicenter RCT. A total of 230 patients with resectable CRLM without extrahepatic disease will be included. Only patients with a clinical risk score (CRS) of 0 to 2 are eligible, meaning: patients are allowed to have no more than two out of five poor prognostic factors (disease-free interval less than 12 months, node-positive colorectal cancer, more than 1 CRLM, largest CRLM more than 5 cm in diameter, serum Carcinoembryonic Antigen above 200 µg/L). Patients randomized to arm A undergo complete resection of CRLM without any adjuvant treatment, which is the standard of care in the Netherlands. Patients in arm B receive an implantable pump at the time of CRLM resection and start adjuvant HAIP chemotherapy 4-12 weeks after surgery, with 6 cycles of floxuridine scheduled. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, hepatic PFS, safety, quality of life, and cost-effectiveness. Pharmacokinetics of intra-arterial administration of floxuridine will be investigated as well as predictive biomarkers for the efficacy of HAIP chemotherapy. In a side study, the accuracy of CT angiography will be compared to radionuclide scintigraphy to detect extrahepatic perfusion. We hypothesize that adjuvant HAIP chemotherapy leads to improved survival, improved quality of life, and a reduction of costs, compared to resection alone. DISCUSSION: If this PUMP trial demonstrates that adjuvant HAIP chemotherapy improves survival in low-risk patients, this treatment approach may be implemented in the standard of care of patients with resected CRLM since adjuvant systemic chemotherapy alone has not improved survival. TRIAL REGISTRATION: The PUMP trial is registered in the Netherlands Trial Register (NTR), number: 7493 . Date of registration September 23, 2018.
Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Neoplasias Colorrectales/patología , Floxuridina/administración & dosificación , Hepatectomía , Neoplasias Hepáticas/terapia , Recurrencia Local de Neoplasia/prevención & control , Adulto , Quimioterapia Adyuvante/instrumentación , Quimioterapia Adyuvante/métodos , Ensayos Clínicos Fase III como Asunto , Neoplasias Colorrectales/mortalidad , Humanos , Bombas de Infusión Implantables , Infusiones Intraarteriales/instrumentación , Infusiones Intraarteriales/métodos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/secundario , Estudios Multicéntricos como Asunto , Países Bajos , Supervivencia sin Progresión , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Patients with colorectal peritoneal carcinomatosis have a very poor prognosis. The recently developed consensus molecular subtype (CMS) classification of primary colorectal cancer categorizes tumours into four robust subtypes, which could guide subtype-targeted therapy. CMS4, also known as the mesenchymal subtype, has the greatest propensity to form distant metastases. CMS4 status and histopathological features of colorectal peritoneal carcinomatosis were investigated in this study. METHODS: Fresh-frozen tissue samples from primary colorectal cancer and paired peritoneal metastases from patients who underwent cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy were collected. Histopathological features were analysed, and a reverse transcriptase-quantitative PCR test was used to assess CMS4 status of all collected lesions. RESULTS: Colorectal peritoneal carcinomatosis was associated with adverse histopathological characteristics, including a high percentage of stroma in both primary tumours and metastases, and poor differentiation grade and high-grade tumour budding in primary tumours. Furthermore, CMS4 was significantly enriched in primary tumours with peritoneal metastases, compared with unselected stage I-IV tumours (60 per cent (12 of 20) versus 23 per cent; P = 0.002). The majority of peritoneal metastases (75 per cent, 21 of 28) were also classified as CMS4. Considerable intrapatient subtype heterogeneity was observed. Notably, 15 of 16 patients with paired tumours had at least one CMS4-positive tumour location. CONCLUSION: Significant enrichment for CMS4 was observed in colorectal peritoneal carcinomatosis. Surgical relevance Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) improves survival of selected patients with colorectal peritoneal carcinomatosis, but recurrence is common. Histopathological and molecular analysis of colorectal peritoneal carcinomatosis could provide clues for development of novel therapies. In this study, colorectal peritoneal carcinomatosis was found to be enriched for tumours with high stromal content and CMS4-positive status. To further improve prognosis for patients with colorectal peritoneal carcinomatosis, therapies that target tumour-stroma interaction could be added to CRS-HIPEC.
Asunto(s)
Neoplasias Colorrectales/patología , Procedimientos Quirúrgicos de Citorreducción/métodos , Hipertermia Inducida/métodos , Neoplasias Peritoneales/secundario , Adulto , Anciano , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/terapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Países Bajos , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/terapia , Peritoneo/patología , Pronóstico , ADN Polimerasa Dirigida por ARN , Análisis de SupervivenciaRESUMEN
PURPOSE: Pancreatic neuroendocrine tumors are a major manifestation of multiple endocrine neoplasia type 1 (MEN1). This tumor syndrome is caused by germline mutations in MEN1, encoding menin. Insight into pathogenesis of these tumors might lead to new biomarkers and therapeutic targets for these patients. Several lines of evidence point towards a role for p27Kip1 and p18Ink4c in MEN1-related tumor development in animal models for MEN1, but their contribution to human MEN1-related pancreatic neuroendocrine tumor development is not known. METHODS: In this study, we characterized protein expression of p27Kip1 and p18Ink4c in human MEN1-related PanNETs by immunohistochemistry. From the nationwide DutchMEN1 Study Group database including > 90% of the Dutch MEN1 population, MEN1-patients, who underwent pancreatic surgery, were selected. A tissue micro-array was constructed with available paraffin tissue blocks, and PanNETs from 61 MEN1 patients were eligible for analysis. RESULTS: Expression of p27Kip1 was high in 57 (93%) PanNETs and 67% of the tumors showed low expression of p18Ink4c (67.3%). No association was found between expression of either p27Kip1 or p18Ink4c and clinic-pathological characteristics. CONCLUSIONS: These findings indicate that loss of p18Ink4c, but not p27Kip1, is a common event in the development of MEN1-related PanNETs. Restoration of p18Ink4c function through CDK4/6 inhibitors could be a therapeutic option for MEN1-related PanNETs.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Inhibidor p18 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Neoplasia Endocrina Múltiple Tipo 1/complicaciones , Tumores Neuroendocrinos/metabolismo , Neoplasias Pancreáticas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/etiología , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/etiología , Pronóstico , Adulto JovenRESUMEN
BACKGROUND: The identification of four Consensus Molecular Subtypes (CMS1-4) of colorectal cancer forms a new paradigm for the design and evaluation of subtype-directed therapeutic strategies. The most aggressive subtype - CMS4 - has the highest chance of disease recurrence. Novel adjuvant therapies for patients with CMS4 tumours are therefore urgently needed. CMS4 tumours are characterized by expression of mesenchymal and stem-like genes. Previous pre-clinical work has shown that targeting Platelet-Derived Growth Factor Receptors (PDGFRs) and the related KIT receptor with imatinib is potentially effective against mesenchymal-type colon cancer. In the present study we aim to provide proof for the concept that imatinib can reduce the aggressive phenotype of primary CMS4 colon cancer. METHODS: Tumour biopsies from patients with newly diagnosed stage I-III colon cancer will be analysed with a novel RT-qPCR test to pre-select patients with CMS4 tumours. Selected patients (n = 27) will receive treatment with imatinib (400 mg per day) starting two weeks prior to planned tumour resection. To assess treatment-induced changes in the aggressive CMS4 phenotype, RNA sequencing will be performed on pre- and post-treatment tissue samples. DISCUSSION: The development of effective adjuvant therapy for primary colon cancer is hindered by multiple factors. First, new drugs that may have value in the prevention of (early) distant recurrence are almost always first tested in patients with heavily pre-treated metastatic disease. Second, measuring on-target drug effects and biological consequences in tumour tissue is not commonly a part of the study design. Third, due to the lack of patient selection tools, clinical trials in the adjuvant setting require large patient populations. Finally, the evaluation of recurrence-prevention requires a long-term follow-up. In the ImPACCT trial these issues are addressed by including newly diagnosed pre-selected patients with CMS4 tumours prior to primary tumour resection, rather than non-selected patients with late-stage disease. By making use of the pre-operative window period, the biological effect of imatinib treatment on CMS4 tumours can be rapidly assessed. Delivering proof-of-concept for drug action in early stage disease should form the basis for the design of future trials with subtype-targeted therapies in colon cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02685046 . Registration date: February 9, 2016.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Mesilato de Imatinib/uso terapéutico , Quimioterapia Adyuvante , Ensayos Clínicos Fase II como Asunto , Neoplasias Colorrectales/patología , Humanos , Estudios Multicéntricos como Asunto , Periodo Preoperatorio , Pronóstico , Proyectos de Investigación , Resultado del TratamientoRESUMEN
BACKGROUND: Ostomies are being placed in 35 % of patients after colorectal cancer surgery. As decision-making regarding colorectal surgery is challenging in the older patients, it is important to have insight in the potential impact due to ostomies. METHODS: An internet-based survey was sent to all members with registered email addresses of the Dutch Ostomy Patient Association. RESULTS: The response rate was 49 %; 932 cases were included of whom 526 were aged <70 years old ("younger respondents"), 301 were aged between 70 and 79 years old ("the elderly"), and 105 were aged ≥80 years old ("oldest old"). Ostomy-related limitations were similar in the different age groups, just as uncertainty (8-10 %) and dependency (18-22 %) due to the ostomy. A reduced quality of life was experienced least in the oldest old group (24 % vs 37 % of the elderly and 46 % of the younger respondents, p < 0.001). Over time, a decrease of limitations and impact due to the ostomy was observed. CONCLUSION: Older ostomates do not experience more limitations or psychosocial impact due to the ostomy compared to their younger counterparts. Over the years, impact becomes less distinct. Treatment decision-making is challenging in the older colorectal cancer patients but ostomy placement should not be withheld based on age alone.
Asunto(s)
Neoplasias Colorrectales/cirugía , Estomía , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/psicología , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida , Factores de TiempoRESUMEN
PURPOSE: There has been an increased utilization of the posterior retroperitoneal approach (PRA) for adrenalectomy alongside the "classic" laparoscopic transabdominal technique (LTA). The aim of this study was to compare both procedures based on outcome variables at various ranges of tumor size. METHODS: A retrospective analysis was performed on 204 laparoscopic transabdominal (UMC Groningen) and 57 retroperitoneal (UMC Utrecht) adrenalectomies between 1998 and 2013. We applied a univariate and multivariate regression analysis. Mann-Whitney and chi-squared tests were used to compare outcome variables between both approaches. RESULTS: Both mean operation time and median blood loss were significantly lower in the PRA group with 102.1 (SD 33.5) vs. 173.3 (SD 59.1) minutes (p < 0.001) and 0 (0-200) vs. 50 (0-1000) milliliters (p < 0.001), respectively. The shorter operation time in PRA was independent of tumor size. Complication rates were higher in the LTA (19.1%) compared to PRA (8.8%). There was no significant difference in recovery time between both approaches. CONCLUSIONS: Application of the PRA decreases operation time, blood loss, and complication rates compared to LTA. This might encourage institutions that use the LTA to start using PRA in patients with adrenal tumors, independent of tumor size.
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Neoplasias de las Glándulas Suprarrenales/cirugía , Adrenalectomía/métodos , Laparoscopía/métodos , Pérdida de Sangre Quirúrgica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tempo Operativo , Complicaciones Posoperatorias/epidemiología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
INTRODUCTION: Adequate decision-making in elderly colorectal cancer patients requires accurate information regarding risks of treatment. We analysed the outcome and survival of colorectal resections in the oldest old (≥85 years). METHODS: An analysis of the 2011-2012 data from two large nationwide registries: the Dutch Surgical Colorectal Audit (DSCA), containing all colorectal cancer resections, and the Netherlands Cancer Registry (NCR), containing survival data for all newly diagnosed malignancies. RESULTS: The study included more than 1200 patients aged ≥85 years (DSCA n = 1232, NCR n = 1206). The postoperative complication rate was 41 % in the oldest old. The frequency of cardiopulmonary complications rose rapidly with age, from 11 % in those <70 years to 38 % for the oldest old (p < 0.001). Postoperative 30-day mortality rate was 10 % in the oldest old. Three-month mortality was 14 % (compared with 3 % of patients <85 years; p < 0.001). One-year mortality was 24 % and 2-year mortality 36 %. After correction for expected mortality in the general population, excess mortality for the oldest old was 12 % in the first year and 3 % in the second year. CONCLUSIONS: In this study of more than 1200 colorectal cancer patients aged ≥85 years undergoing surgical resection, we found high rates of cardiopulmonary complications and excess mortality, particularly in the first year after surgery. We propose that these data could be incorporated into individualized treatment algorithms, which also include detailed information regarding the patients' health status.
Asunto(s)
Colectomía/mortalidad , Neoplasias Colorrectales/mortalidad , Complicaciones Posoperatorias/mortalidad , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/cirugía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Pronóstico , Sistema de Registros , Tasa de Supervivencia , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: Invasive surgery remains the standard for diagnosis of pathological nipple discharge (PND). Only a minority of patients with nipple discharge and an unsuspicious finding on conventional breast imaging have cancer. Ductoscopy is a minimally invasive alternative for evaluation of PND. This systematic review and meta-analysis was designed to evaluate the diagnostic accuracy of ductoscopy in patients with PND. METHODS: A systematic search of electronic databases for studies addressing ductoscopy in patients with PND was conducted. Two classification systems were assessed. For DSany , all visualized ductoscopic abnormalities were classified as positive, whereas for DSsusp , only suspicious findings were considered positive. After checking heterogeneity, pooled sensitivity and specificity of DSany and DSsusp were calculated. RESULTS: The search yielded 4642 original citations, of which 20 studies were included in the review. Malignancy rates varied from 0 to 27 per cent. Twelve studies, including 1994 patients, were eligible for meta-analysis. Pooled sensitivity and specificity of DSany were 94 (95 per cent c.i. 88 to 97) per cent and 47 (44 to 49) per cent respectively. Pooled sensitivity and specificity of DSsusp were 50 (36 to 64) and 83 (81 to 86) per cent respectively. Heterogeneity between studies was moderate to large for sensitivity (DSany : I2 = 17·5 per cent; DSsusp : I2 = 37·9 per cent) and very large for specificity (DSany : I2 = 96·8 per cent; DSsusp : I2 = 92·6 per cent). CONCLUSION: Ductoscopy detects about 94 per cent of all underlying malignancies in patients with PND, but does not permit reliable discrimination between malignant and benign findings.
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Neoplasias de la Mama/diagnóstico , Endoscopía/métodos , Secreción del Pezón , Pezones/patología , Neoplasias de la Mama/patología , Exudados y Transudados , Femenino , Humanos , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Health-related quality of life (QoL) is of major importance in pancreatic cancer, owing to the limited life expectation. The aim of this prospective longitudinal study was to describe QoL in patients undergoing resection for pancreatic or periampullary malignancy. METHODS: QoL was measured on a scale of 0-100 in patients who underwent pancreatic resection for malignancy or premalignancy at the University Medical Centre Utrecht before resection, and 1, 3, 6 and 12 months after surgery. Measures consisted of the RAND-36, the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and the EORTC pancreatic cancer-specific module (QLQ-PAN26). RESULTS: Between March 2012 and November 2013, 68 consecutive patients with a malignancy (59 patients) or premalignancy (9) were included. Physical role restriction, social and emotional domains showed a significant and clinically relevant deterioration directly after operation in 53 per cent (RAND-36, P < 0.001), 63 and 78 per cent (QLQ-C30 and RAND-36 respectively, P < 0.001) and 37 per cent (RAND-36, P < 0.001) of patients respectively. Most domains demonstrated recovery to preoperative values or better at 3 months, except for physical functioning. Emotional functioning at 3, 6 and 12 months was better than at baseline (P < 0.001). Symptom scores revealed a deterioration in vitality, pain (P = 0.002), fatigue (P < 0.001), appetite loss (P < 0.001), altered bowel habit (P = 0.001) and side-effects (P < 0.001) after 1 month. After 3 months, only side-effects were worse than preoperative values (P < 0.001). CONCLUSION: QoL after pancreatic resection for malignant and premalignant tumours decreased considerably in the early postoperative phase. Full recovery of QoL took up to 6 months after the operation.
Asunto(s)
Estado de Salud , Pancreatectomía/métodos , Neoplasias Pancreáticas/cirugía , Calidad de Vida , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pancreatectomía/psicología , Neoplasias Pancreáticas/psicología , Estudios Prospectivos , Encuestas y CuestionariosRESUMEN
BACKGROUND: Open transthoracic esophagectomy is the worldwide gold standard in the treatment of resectable esophageal cancer. Robot-assisted minimally invasive thoraco-laparoscopic esophagectomy (RAMIE) for esophageal cancer may be associated with reduced blood loss, shorter intensive care unit (ICU) stay, and less cardiopulmonary morbidity; however, long-term oncologic results have not been reported to date. METHODS: Between June 2007 and September 2011, a total of 108 patients with potentially resectable esophageal cancer underwent RAMIE at the University Medical Centre Utrecht, with curative intent. All data were recorded prospectively. RESULTS: Median duration of the surgical procedure was 381 min (range 264-636). Pulmonary complications were most common and were observed in 36 patients (33 %). Median ICU stay was 1 day, and median overall postoperative hospital stay was 16 days. In-hospital mortality was 5 %. The majority of patients (78 %) presented with T3 and T4 disease, and 68 % of patients had nodal-positive disease (cN1-3). In 65 % of patients, neoadjuvant treatment (chemotherapy 57 %, chemoradiotherapy 7 %, radiotherapy 1 %) was administered, and in 103 (95 %) patients, a radical resection (R0) was achieved. The median number of lymph nodes was 26, median follow-up was 58 months, 5-year overall survival was 42 %, median disease-free survival was 21 months, and median overall survival was 29 months. Tumor recurrence occurred in 51 patients and was locoregional only in 6 (6 %) patients, systemic only in 31 (30 %) patients, and combined in 14 (14 %) patients. CONCLUSION: RAMIE was shown to be oncologically effective, with a high percentage of R0 radical resections and adequate lymphadenectomy. RAMIE provided good local control with a low percentage of local recurrence at long-term follow up.
Asunto(s)
Neoplasias Esofágicas/cirugía , Esofagectomía/métodos , Laparoscopía/métodos , Escisión del Ganglio Linfático/métodos , Complicaciones Posoperatorias , Robótica/métodos , Toracoscopía , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Adulto , Anciano , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , Neoplasias Esofágicas/patología , Femenino , Estudios de Seguimiento , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Perioperative epirubicin, cisplatin, and capecitabine (ECC) chemotherapy was evaluated in patients who underwent esophageal resection for adenocarcinoma of the esophagus or gastroesophageal junction (GEJ). METHODS: A cohort of 93 consecutive patients was analyzed. The median follow-up period was 60 months. Source data verification of adverse events was performed by two independent observers. RESULTS: All three planned preoperative chemotherapy cycles were administered to 65 patients (69.9 %). Only 27 % of the patients completed both pre- and postoperative chemotherapy. The reasons for not receiving postoperative adjuvant chemotherapy could be separated in two main problems: toxicity of the preoperative chemotherapy and postoperative problems involving difficulty in recovery and postoperative complications. Finally, 25 patients (27 %), completed three preoperative and three postoperative cycles. Grades 3 and 4 nonhematologic adverse events of preoperative chemotherapy mainly consisted of thromboembolic events (16.2 %) and cardiac complications (7.5 %). A history of cardiac and vascular disease was independently associated with discontinuation of preoperative chemotherapy and the occurrence of grade 3 or higher adverse events. Surgery was performed for 94 % of all the patients who started with ECC chemotherapy. A radical resection (R0) was achieved in 93 % of the patients. A complete pathologic response was observed in 8 % of the patients. During a median follow-up period of 60 months, the median disease-free survival time was 28 months, and the median overall survival time was 36 months. The 3-year overall survival rate was 50 %, and the 5-year overall survival rate was 42 %. CONCLUSION: For patients with adenocarcinoma of the esophagus or GEJ, six cycles of ECC-based perioperative chemotherapy is associated with a relatively high number of adverse events. Although this toxicity did not affect the esophageal resectability rate, this regimen should be used with caution in this patient population.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Unión Esofagogástrica/efectos de los fármacos , Atención Perioperativa , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Adulto , Anciano , Capecitabina/administración & dosificación , Cisplatino/administración & dosificación , Terapia Combinada , Epirrubicina/administración & dosificación , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/cirugía , Unión Esofagogástrica/patología , Unión Esofagogástrica/cirugía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Seguridad , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugía , Tasa de Supervivencia , Factores de TiempoRESUMEN
BACKGROUND: Surgery is the intervention of choice for definitive diagnosis and treatment in women with pathological nipple discharge (PND). Ductoscopy has been reported to improve diagnosis, but as an interventional procedure it may also reduce the need for surgery. This study evaluated interventional ductoscopy in patients with PND. METHODS: A prospective study on ductoscopy was conducted in consecutive patients with PND, but without a suspected malignancy on routine diagnostic evaluation. Intraductal lesions were removed by ductoscopic extraction. Surgery was undertaken if there were suspicious ductoscopic findings or at the patient's request. Therapeutic efficacy was determined by cannulation success, detection and removal rates, symptom resolution and avoided surgery. RESULTS: Ductoscope introduction was successful in 71 (87 per cent) of 82 patients, with abnormalities visualized in 53 (65 per cent); these were mostly polypoid lesions (29 patients). The lesion was removed in 27 of 34 attempted ductoscopic extractions. Twenty-six (32 per cent) of the 82 patients underwent surgery, whereas surgery was avoided in 56 (68 per cent). After a median follow-up of 17 (range 3-45) months, 40 patients (49 per cent) no longer experienced symptoms of PND, 13 of 34 patients experienced an insufficient therapeutic effect after attempted ductoscopic extraction, and the outcome was unknown in two (2 per cent). Malignancy was diagnosed in four patients (5 per cent); two had been missed at ductoscopy and two at initial surgery after ductoscopy. CONCLUSION: Interventional ductoscopy is technically feasible and may help to avoid surgery in the majority of patients. As endoscopic removal of intraductal lesions is not always possible and malignancy can be the underlying cause of PND, ductoscopic instruments should be further optimized to allow definitive histological diagnosis.
Asunto(s)
Neoplasias de la Mama/patología , Endoscopía/métodos , Pezones/patología , Adulto , Diagnóstico Diferencial , Exudados y Transudados , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Pezones/metabolismo , Pronóstico , Estudios Prospectivos , Adulto JovenRESUMEN
BACKGROUND: Transthoracic oesophagectomy requires prolonged one-lung ventilation causing systemic and local inflammatory responses. Application of continuous positive airway pressure (CPAP) to the collapsed lung potentially reduces pulmonary damage, hypoxia, and consequent inflammation. This randomized controlled trial studied the influence of CPAP applied to the collapsed right lung during thoracoscopic oesophagectomy on local and systemic inflammatory response. METHODS: Broncho-alveolar lavage fluid (BALF) from the right collapsed and left ventilated lung and serum samples were obtained during surgery from 30 patients undergoing thoracolaparoscopic oesophagectomy for cancer who were randomized for one-lung ventilation with or without CPAP applied to the collapsed right lung. Concentrations of cytokines and chemokines, in BALF and serum, were determined with Luminex. RESULTS: Patients from the control (no CPAP) group had significantly increased concentrations of interleukin (IL)-1α, IL-1ß, IL-10, tumour necrosis factor-alpha, macrophage inflammatory protein (MIP)-1α, pulmonary and activation-regulated chemokine (PARC), and IL-8 in the collapsed (right) lung when compared with patients from the CPAP group (P<0.05). The ventilated (left) lung of the control group showed increased concentrations of monocyte chemoattractant protein (MCP)-1 and MIP-1α (P<0.05). Serum concentrations of cytokines and chemokines increased during surgery, but did not differ between the control and CPAP groups. CONCLUSIONS: A significantly lower local immune response was observed during one-lung ventilation when CPAP was applied to the collapsed lung. The findings suggest a beneficial effect of CPAP on the collapsed lung during oesophagectomy with one-lung ventilation.
Asunto(s)
Quimiocinas/inmunología , Presión de las Vías Aéreas Positiva Contínua/métodos , Citocinas/inmunología , Esofagectomía/métodos , Inflamación/inmunología , Ventilación Unipulmonar/métodos , Anciano , Quimiocina CCL3/inmunología , Quimiocinas CC/inmunología , Femenino , Humanos , Inmunidad , Interleucina-1/inmunología , Interleucina-10/inmunología , Interleucina-8/inmunología , Masculino , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
AIM: Most patients with colorectal cancer are elderly, but there are few data on the optimal surgical treatment for this age group and most studies are observational. We have reviewed the characteristics of randomized trials reporting laparoscopic surgery for colorectal cancer to determine the degree to which the elderly are represented. METHOD: A search was conducted of the NIH clinical trial registry and the ISRCTN register for randomized trials on laparoscopic surgery for colorectal cancer. Trial characteristics and end-points were extracted from the registry website and supplemented by published results where available. RESULTS: Of 52 trial protocols the majority did not state any restrictions regarding cardiac [40 (77%)] or pulmonary function [41 (79%)]. More than half [30 (58%)] had no restrictions regarding American Society of Anesthesiologists score. Twenty-three (44%) trials excluded the elderly either simply on age or by comorbidity or organ function. When an upper age limit was set, half of the studies had no restriction regarding organ function, indicating that chronological age rather than physical condition was taken as the reason for exclusion. In 45 (86%) of the trials the average age of participants was < 70 years, and no details of concurrent disease were given. CONCLUSION: Participation of the elderly in trials of laparoscopic surgery for colorectal cancer is very limited. This should be remedied in future trials if adequate information on the majority of patients with colorectal cancer is to be obtained.
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Ensayos Clínicos como Asunto , Neoplasias Colorrectales/cirugía , Laparoscopía , Selección de Paciente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Comorbilidad , Indicadores de Salud , Corazón/fisiología , Humanos , Pulmón/fisiología , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Current European guidelines recommend routine enteral feeding after pancreato-duodenectomy (PD), whereas American guidelines do not. The aim of this study was to determine the optimal feeding route after PD. METHODS: A systematic search was performed in PubMed, Embase and the Cochrane Library. Included were studies on feeding routes after PD that reported length of hospital stay (primary outcome). RESULTS: Of 442 articles screened, 15 studies with 3474 patients were included. Data on five feeding routes were extracted: oral diet (2210 patients), enteral nutrition via either a nasojejunal tube (NJT, 165), gastrojejunostomy tube (GJT, 52) or jejunostomy tube (JT, 623), and total parenteral nutrition (TPN, 424). Mean(s.d.) length of hospital stay was shortest in the oral diet and GJT groups (15(14) and 15(11) days respectively), followed by 19(12) days in the JT, 20(15) days in the TPN and 25(11) days in the NJT group. Normal oral intake was established most quickly in the oral diet group (mean 6(5) days), followed by 8(9) days in the NJT group. The incidence of delayed gastric emptying varied from 6 per cent (3 of 52 patients) in the GJT group to 23.2 per cent (43 of 185) in the JT group, but definitions varied widely. The overall morbidity rate ranged from 43.8 per cent (81 of 185) in the JT group to 75 per cent (24 of 32) in the GJT group. The overall mortality rate ranged from 1.8 per cent (3 of 165) in the NJT group to 5.4 per cent (23 of 424) in the TPN group. CONCLUSION: There is no evidence to support routine enteral or parenteral feeding after PD. An oral diet may be considered as the preferred routine feeding strategy after PD.
Asunto(s)
Nutrición Enteral/métodos , Pancreaticoduodenectomía , Nutrición Parenteral Total/métodos , Métodos Epidemiológicos , Vaciamiento Gástrico , Humanos , Tiempo de Internación , Fístula Pancreática/etiología , Complicaciones Posoperatorias/etiología , Resultado del TratamientoRESUMEN
AIM: Anastomotic leakage is a frequent postoperative complication of colorectal resection. This nonrandomized study assessed the feasibility and safety of applying a haemostatic tissue sealant (TachoSil®) to colorectal anastomoses following resection. METHOD: TachoSil was applied as reinforcement of the anastomotic line after laparoscopic or open colorectal resection. The primary endpoint was the proportion of patients for whom TachoSil application was considered feasible by both the investigator and an independent external assessor. Application was considered feasible if TachoSil fully adhered, covered ≥1cm beyond the margin of the anastomotic line and patches overlapped by ≥1cm. Individual investigator assessment of feasibility and adverse events 30 days after surgery were also recorded. RESULTS: Twenty-five patients underwent anterior resection (seven open lower, nine open middle-upper, four laparoscopic lower and five laparoscopic middle-upper). In six cases a video-recording was not available because of technical problems. The primary endpoint was met in 12 of the remaining 19 patients (63%; 95% CI 38-84%), while in the other seven the application was recorded as not feasible because the assessor was unable to see the entire anastomosis. No application was assessed as unfeasible on the basis of visual evidence. When assessed by the investigator alone, TachoSil was considered feasible in all but one instance (96%; 95% CI 80-100%). There were 45 adverse events, of which 10 were serious. None was considered related to TachoSil. No deaths were reported. CONCLUSION: Application of TachoSil to reinforce the anastomotic line in colorectal resections appears to be feasible and well tolerated.
Asunto(s)
Anastomosis Quirúrgica/métodos , Fuga Anastomótica/prevención & control , Cirugía Colorrectal/métodos , Fibrinógeno/uso terapéutico , Trombina/uso terapéutico , Anciano , Anastomosis Quirúrgica/efectos adversos , Cirugía Colorrectal/efectos adversos , Combinación de Medicamentos , Estudios de Factibilidad , Femenino , Humanos , Laparoscopía , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Patients with liver metastases from colon carcinoma show highly variable responses to chemotherapy and tumor recurrence is frequently observed. Therapy-resistant cancer stem cells have been implicated in drug resistance and tumor recurrence. However, the factors determining therapy resistance and tumor recurrence are poorly understood. The aim of this study was to gain insight into these mechanisms by comparing the proteomes of patient-derived cancer stem cell cultures and their differentiated isogenic offspring. We established colonosphere cultures derived from resection specimens of liver metastases in patients with colon cancer. These colonospheres, enriched for colon cancer stem cells, were used to establish isogenic cultures of stably differentiated nontumorigenic progeny. Proteomics based on one-dimensional gel electrophoresis coupled to nano liquid chromatography tandem MS was used to identify proteome differences between three of these paired cultures. The resulting data were analyzed using Ingenuity Pathway Software. Out of a total data set of 3048 identified proteins, 32 proteins were at least twofold up-regulated in the colon cancer stem cells when compared with the differentiated cells. Pathway analysis showed that "cell death " regulation is strikingly different between the two cell types. Interestingly, one of the top-up-regulated proteins was BIRC6, which belongs to the class of Inhibitor of Apoptosis Proteins. Knockdown of BIRC6 sensitized colon cancer stem cells against the chemotherapeutic drugs oxaliplatin and cisplatin. This study reveals that differentiation of colon cancer stem cells is accompanied by altered regulation of cell death pathways. We identified BIRC6 as an important mediator of cancer stem cell resistance against cisplatin and oxaliplatin. Targeting BIRC6, or other Inhibitors of Apoptosis Proteins, may help eradicating colon cancer stem cells.
Asunto(s)
Adenocarcinoma/secundario , Diferenciación Celular , Neoplasias del Colon/patología , Proteínas Inhibidoras de la Apoptosis/metabolismo , Neoplasias Hepáticas/secundario , Células Madre Neoplásicas/metabolismo , Adenocarcinoma/metabolismo , Antineoplásicos/farmacología , Cisplatino/farmacología , Neoplasias del Colon/metabolismo , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas Inhibidoras de la Apoptosis/genética , Neoplasias Hepáticas/metabolismo , Anotación de Secuencia Molecular , Terapia Molecular Dirigida , Células Madre Neoplásicas/efectos de los fármacos , Compuestos Organoplatinos/farmacología , Mapas de Interacción de Proteínas , Proteómica , Piridinas/farmacología , Esferoides Celulares , Espectrometría de Masas en Tándem , Células Tumorales Cultivadas , Regulación hacia ArribaRESUMEN
BACKGROUND: This study investigates the possible benefits of radiofrequency ablation (RFA) in patients with non-resectable colorectal liver metastases. METHODS: This phase II study, originally started as a phase III design, randomly assigned 119 patients with non-resectable colorectal liver metastases between systemic treatment (n = 59) or systemic treatment plus RFA ( ± resection) (n = 60). Primary objective was a 30-month overall survival (OS) rate >38% for the combined treatment group. RESULTS: The primary end point was met, 30-month OS rate was 61.7% [95% confidence interval (CI) 48.2-73.9] for combined treatment. However, 30-month OS for systemic treatment was 57.6% (95% CI 44.1-70.4), higher than anticipated. Median OS was 45.3 for combined treatment and 40.5 months for systemic treatment (P = 0.22). PFS rate at 3 years for combined treatment was 27.6% compared with 10.6% for systemic treatment only (hazard ratio = 0.63, 95% CI 0.42-0.95, P = 0.025). Median progression-free survival (PFS) was 16.8 months (95% CI 11.7-22.1) and 9.9 months (95% CI 9.3-13.7), respectively. CONCLUSIONS: This is the first randomized study on the efficacy of RFA. The study met the primary end point on 30-month OS; however, the results in the control arm were in the same range. RFA plus systemic treatment resulted in significant longer PFS. At present, the ultimate effect of RFA on OS remains uncertain.