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BACKGROUND: KRAS mutations in metastatic colorectal cancer (mCRC) are used as predictive biomarkers to select therapy with EGFR monoclonal antibodies (mAbs). Other factors may be significant determinants of benefit. METHODS: Individual patient data from randomised trials with a head-to-head comparison between EGFR mAb versus no EGFR mAb (chemotherapy alone or best supportive care) in mCRC, across all lines of therapy, were pooled. Overall survival (OS) and progression-free survival (PFS) were compared between groups. Treatment effects within the predefined KRAS biomarker subsets were estimated by adjusted hazard ratio (HRadj) and 95% confidence interval (CI). EGFR mAb efficacy was measured within the KRAS wild-type subgroup according to BRAF and NRAS mutation status. In both KRAS wild-type and mutant subgroups, additional factors that could impact EGFR mAb efficacy were explored including the type of chemotherapy, line of therapy, age, sex, tumour sidedness and site of metastasis. RESULTS: 5675 patients from 8 studies were included, all with known mCRC KRAS mutation status. OS (HRadj 0.90, 95% CI 0.84-0.98, p = 0.01) and PFS benefit (HRadj 0.73, 95% CI 0.68-0.79, p < 0.001) from EGFR mAbs was observed in the KRAS wild-type group. PFS benefit was seen in patients treated with fluorouracil (HRadj 0.75, 95% CI 0.68-0.82) but not with capecitabine-containing regimens (HRadj 1.04, 95% CI 0.86-1.26) (pinteraction = 0.002). Sidedness also interacted with EGFR mAb efficacy, with survival benefit restricted to left-sided disease (pinteraction = 0.038). PFS benefits differed according to age, with benefits greater in those under 70 (pinteraction = 0.001). The survival benefit was not demonstrated in those patients with mutations found in the KRAS, NRAS or BRAF genes. The presence of liver metastases interacted with EGFR mAb efficacy in patients with KRAS mutant mCRC (pinteraction = 0.004). CONCLUSION: The benefit provided by EGFR mAbs in KRAS WT mCRC is associated with left-sided primary tumour location, younger patient age and absence of NRAS or BRAF mutations. Survival benefit is observed with fluorouracil but not capecitabine. Exploratory results support further research in KRAS mutant mCRC without liver metastases.
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Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias Hepáticas , Neoplasias del Recto , Humanos , Anticuerpos Monoclonales/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Fluorouracilo , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Recto/tratamiento farmacológico , Receptores ErbB/genética , Neoplasias Hepáticas/tratamiento farmacológico , Mutación , CetuximabRESUMEN
STUDY DESIGN: This is a prospective observational study. OBJECTIVES: The objective of this study was to determine time-dependent changes in diurnal blood pressure (BP) and urine production in acute spinal cord injury (SCI). SETTING: This study was conducted in a specialist, state-based spinal cord service in Victoria, Australia. METHODS: Consenting patients admitted consecutively with acute SCI were compared with patients confined to bed rest while awaiting surgery and with mobilising able-bodied controls. Participants underwent ambulatory BP monitoring (ABPM), measurement of diurnal urine production and rated orthostatic symptoms over 1 year. Participants with night:day systolic BP (SBP) <90% were classified as dippers, 90-100% as non-dippers and >100% as reverse dippers. RESULTS: Participants comprised tetraplegics (n=47, 40.0±17.3 years), paraplegics (n=35, 34.4±13.9 years), immobilised (n=18, 30.9±11.3 years) and mobilising (n=44, 33.1±13.5 years) controls. At baseline, 24-h BP was significantly lower in tetraplegics (111.8±1.9/62.1±1.1 mm Hg) but not in paraplegics (116.7± 1.4/66.0±1.1 mm Hg), compared with controls (117.1 ±1.3/69.1±1.1 mm Hg), adjusting for gender. This difference was not observed at 1 year. The average night:day SBP in mobilising controls was 86.1±0.7%, differing from paraplegics (94.0±1.5%, P<0.001) and tetraplegics (101.5±1.5%, P<0.001). Urine production in tetraplegics and paraplegics did not fall at night compared with the day. Abnormal diurnal BP and orthostatic symptoms in tetraplegics persisted throughout the study. Nocturnal hypertension was observed in 27% (n=9) of tetraplegics, of whom only 2 had day hypertension. All mobilising controls with nocturnal hypertension (n=6, 14%) had day hypertension. CONCLUSION: People with SCI have a high prevalence of isolated nocturnal hypertension, reverse dipping, orthostatic intolerance and nocturnal polyuria. Cardiovascular risk management and assessment of orthostatic symptoms should include ABPM.
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Presión Sanguínea/fisiología , Ritmo Circadiano/fisiología , Traumatismos de la Médula Espinal/sangre , Traumatismos de la Médula Espinal/orina , Enfermedad Aguda , Adolescente , Adulto , Anciano , Monitoreo Ambulatorio de la Presión Arterial , Femenino , Humanos , Hipertensión/sangre , Hipertensión/epidemiología , Hipertensión/etiología , Hipertensión/orina , Masculino , Persona de Mediana Edad , Parálisis/sangre , Parálisis/epidemiología , Parálisis/etiología , Parálisis/orina , Fotoperiodo , Poliuria/sangre , Poliuria/epidemiología , Poliuria/etiología , Poliuria/orina , Prevalencia , Caracteres Sexuales , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/epidemiología , Toma de Muestras de Orina , Adulto JovenRESUMEN
Studies of germline polymorphisms as predictors of tumor response to anti-epidermal growth factor receptor (EGFR) monoclonal antibody agents in metastatic colorectal cancer have reported inconsistent results. We performed a systematic review of studies from 1990 to September 2015, followed by random-effects meta-analyses for polymorphisms examined in at least three studies. Of 87 studies, 40 passed the criteria for systematic review and 23 for meta-analysis. The polymorphisms suitable for meta-analysis were CCND1 (rs17852153), COX2 (rs20417), EGF (rs4444903), EGFR (rs712829, rs11543848, 3'UTR CA repeat), FCGR2A (rs1801274), FCGR3A (rs396991), IL8 (rs4073), KRAS (rs61764370) and VEGFA (rs3025039). Meta-analysis yielded nominal significance (at α=0.05) for rs4444903 and rs11543848, but showed no significant results after multiple testing correction; this was unchanged by sensitivity analyses to address subgroups, funnel-plot asymmetries, and study quality. This highlights a tendency for lack of replication in the face of initial positive results, and possibly the unsuitability of relying on tumor response as a surrogate marker in this setting.
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Anticuerpos Monoclonales/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Receptores ErbB/antagonistas & inhibidores , Polimorfismo Genético , Neoplasias Colorrectales/mortalidad , Humanos , Resultado del TratamientoRESUMEN
BACKGROUND: There is insufficient information regarding the prognostic significance of baseline and change in quality of life (QoL) scores on overall survival (OS) in advanced pancreatic cancer. METHODS: QoL was assessed prospectively using the EORTC QLQ-C30 as part of the PA.3 trial of gemcitabine + erlotinib (G + E) vs. gemcitabine + placebo (G + P). Relevant variables and QoL scores at baseline and change at 8 weeks were analyzed by Cox stepwise regression to determine predictors of OS. RESULTS: 222 of 285 patients (pts) treated with G + E and 220 of 284 pts treated with G + P completed baseline QoL assessments. In a multivariable Cox analysis combining all pts, better QoL physical functioning (PF) score independently predicted longer OS (HR 0.86; CI: 0.80-0.93), as did non-white race (HR 0.64; CI: 0.44-0.95), PS 0-1 (HR 0.65; CI: 0.50-0.85), locally advanced disease (HR 0.55; CI: 0.43-0.71) and G + E (HR 0.78; CI: 0.64-0.96). Improvement in physical function at week 8 also predicted for improved survival (HR 0.89; CI: 0.81-0.97 for 10 point increase in score, p = 0.02). CONCLUSION: In addition to clinical variables, patient reported QoL scores at baseline and change from baseline to week 8 added incremental predictive information regarding survival for advanced pancreatic cancer patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pancreáticas/psicología , Neoplasias Pancreáticas/terapia , Calidad de Vida , Resultado del Tratamiento , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antibióticos Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Preescolar , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Clorhidrato de Erlotinib/administración & dosificación , Femenino , Humanos , Lactante , Estado de Ejecución de Karnofsky , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Grupos Raciales , Análisis de Supervivencia , Adulto Joven , GemcitabinaRESUMEN
BACKGROUND: Cost avoidance occurs when, because of provision of a drug therapy [drug cost avoidance (dca)] or a pathology test [pathology cost avoidance (pca)] during trial participation, health care payers need not pay for standard treatments or testing. The aim of our study was to estimate the total dca and pca for Canadian patients enrolled in relevant phase iii trials conducted by the ncic Clinical Trials Group. METHODS: Phase iii trials that had completed accrual and resulted in dca or pca were identified. The pca was calculated based on the number of patients screened and the test cost. The dca was estimated based on patients randomized, the protocol dosing regimen, drug cost, median dose intensity, and median duration of therapy. Costs are presented in Canadian dollars. No adjustment was made for inflation. RESULTS: From 1999 to 2011, 4 trials (1479 patients) resulted in pca and 17 trials (3195 patients) resulted in dca. The total pca was estimated at $4,194,849, which included testing for KRAS ($141,058), microsatellite instability ($18,600), and 21-gene recurrence score ($4,035,191). The total dca was estimated at $27,952,512, of which targeted therapy constituted 43% (five trials). The combined pca and dca was $32,147,361. CONCLUSIONS: Over the study period, trials conducted by the ncic Clinical Trials Group resulted in total cost avoidance (pca and dca) of approximately $7,518 per patient. Although not all trials lead to cost avoidance, such savings should be taken account when the financial impact of conducting clinical research is being considered.
RESUMEN
Surgical injury to the pancreas is thought to occur commonly during procurement. The UK Transplant Registry was analyzed to determine the frequency of pancreatic injuries, identify factors associated with damage, and assess the impact of injuries on graft survival. Twelve hundred ninety-six pancreata were procured from donation after brain death donors, with 314 (19.5%) from donation after circulatory death donors. More than 50% of recovered pancreata had at least one injury, most commonly a short portal vein (21.5%). Liver donation, procurement team origin, hepatic artery (HA) arising from the superior mesenteric artery (SMA), and increasing donor BMI were associated with increased rates of pancreas damage on univariate analyses; on multivariate analysis only the presence of an HA from the SMA remained significant (p = 0.02). Six hundred forty solid organ pancreas transplants were performed; 238 had some form of damage. Overall, there was no difference in graft survival between damaged and undamaged organs (p = 0.28); however, graft loss was significantly more frequent in pancreata with arterial damage (p = 0.04) and in those with parenchymal damage (p = 0.05). Damage to the pancreas during organ recovery is more common than other organs, and meticulous surgical technique and awareness of damage risk factors are essential to reduce rates of procurement-related injuries.
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Muerte Encefálica , Trasplante de Páncreas/efectos adversos , Páncreas/lesiones , Pancreatectomía/efectos adversos , Adolescente , Adulto , Niño , Preescolar , Femenino , Estudios de Seguimiento , Rechazo de Injerto , Supervivencia de Injerto , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Trasplante de Páncreas/métodos , Pancreatectomía/métodos , Sistema de Registros , Estudios Retrospectivos , Medición de Riesgo , Estadísticas no Paramétricas , Tasa de Supervivencia , Obtención de Tejidos y Órganos , Resultado del Tratamiento , Reino Unido , Adulto JovenRESUMEN
AIM: To examine the usage and value of computed tomography (CT) following simultaneous pancreas and kidney (SPK) transplantation. MATERIALS AND METHODS: Indications for postoperative CT, key findings, and their influence on management were determined by retrospective analysis. RESULTS: Ninety-eight patients underwent 313 CT examinations. Common indications for the examinations included suspected intra-abdominal collection (31.1%) and elevated serum amylase/lipase (24.1%). CT findings most frequently showed non-specific mild inflammation (27.6%), a normal scan (17.1%) and fluid collections (16.3%). High capillary blood glucose (CBG) was associated with resultant CT demonstration of graft vascular abnormalities, but otherwise, particular clinical indications were not associated with specific CT findings. CONCLUSION: Clinical findings in patients with SPK transplants are non-specific. The pattern of abnormalities encountered is significantly different to those seen in native pancreatic disease and demands a tailored protocol. CT enables accurate depiction of vascular abnormalities and fluid collections, thus reducing the number of surgical interventions that might otherwise be required. Elevated CBG should prompt urgent CT to exclude potentially reversible vascular complications.
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Trasplante de Páncreas/métodos , Páncreas/diagnóstico por imagen , Adulto , Aloinjertos/diagnóstico por imagen , Glucemia/metabolismo , Femenino , Supervivencia de Injerto , Humanos , Estimación de Kaplan-Meier , Trasplante de Riñón/métodos , Masculino , Cuidados Posoperatorios/métodos , Complicaciones Posoperatorias/diagnóstico por imagen , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Trasplante Homólogo/métodosRESUMEN
Most kidneys from potential elderly circulatory death (DCD) donors are declined. We report single center outcomes for kidneys transplanted from DCD donors over 70 years old, using preimplantation biopsy Remuzzi grading to inform implantation as single or dual transplants. Between 2009 and 2012, 43 single transplants and 12 dual transplants were performed from elderly DCD donors. Remuzzi scores were higher for dual than single implants (4.4 vs. 3.4, p < 0.001), indicating more severe baseline injury. Donor and recipient characteristics for both groups were otherwise similar. Early graft loss from renal vein thrombosis occurred in two singly implanted kidneys, and in one dual-implanted kidney; its pair continued to function satisfactorily. Death-censored graft survival at 3 years was comparable for the two groups (single 94%; dual 100%), as was 1 year eGFR. Delayed graft function occurred less frequently in the dual-implant group (25% vs. 65%, p = 0.010). Using this approach, we performed proportionally more kidney transplants from elderly DCD donors (23.4%) than the rest of the United Kingdom (7.3%, p < 0.001), with graft outcomes comparable to those achieved nationally for all deceased-donor kidney transplants. Preimplantation biopsy analysis is associated with acceptable transplant outcomes for elderly DCD kidneys and may increase transplant numbers from an underutilized donor pool.
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Enfermedades Cardiovasculares/mortalidad , Funcionamiento Retardado del Injerto/epidemiología , Trasplante de Riñón/métodos , Donantes de Tejidos/estadística & datos numéricos , Obtención de Tejidos y Órganos/métodos , Factores de Edad , Anciano , Biopsia con Aguja , Estudios de Cohortes , Funcionamiento Retardado del Injerto/patología , Femenino , Rechazo de Injerto/epidemiología , Supervivencia de Injerto , Humanos , Inmunohistoquímica , Cuidados Intraoperatorios/métodos , Estimación de Kaplan-Meier , Trasplante de Riñón/efectos adversos , Masculino , Pronóstico , Sistema de Registros , Estudios Retrospectivos , Estadísticas no Paramétricas , Tasa de Supervivencia , Receptores de Trasplantes/estadística & datos numéricos , Resultado del Tratamiento , Reino UnidoRESUMEN
BACKGROUND: Right- and left-sided colon cancers (RC, LC) differ with respect to biology, pathology and epidemiology. Previous data suggest a mortality difference between RC and LC. We examined if primary tumour side also predicts for outcome in chemotherapy refractory, metastatic colon cancer (MCC). We also compared RC versus LC as a predictor of efficacy of epidermal growth factor receptor (EGFR) inhibition with cetuximab. METHODS: Reanalyzing NCIC CO.17 trial (cetuximab versus best supportive care [BSC]), we coded the primary tumour side as RC (caecum to transverse colon) or LC (splenic flexure to rectosigmoid). The association between tumour side and baseline characteristics was assessed. Cox regression models determined factors affecting overall survival (OS) and progression free survival (PFS). RESULTS: Patients with RC (150/399) had more poorly differentiated, mutant KRAS, mutated PIK3CA and wild-type BRAF tumours, fewer liver and lung metastases, and shorter interval between diagnosis and study entry. Among BSC patients, tumour side was not prognostic for PFS (hazard ratios (HR) 1.07 [0.79-1.44], p = 0.67) or OS (HR 0.96 [0.70-1.31], p = 0.78). Among wild-type KRAS patients, those with LC had significantly improved PFS when treated with cetuximab compared to BSC (median 5.4 versus 1.8 months, HR 0.28 [0.18-0.45], p < 0.0001), whereas those with RC did not (median 1.9 versus 1.9 months, HR 0.73 [0.42-1.27], p = 0.26), [interaction p = 0.002]. CONCLUSION: In refractory MCC, tumour location within the colon is not prognostic, but is strongly predictive of PFS benefit from cetuximab therapy. Additional research is needed to understand the molecular differences between RC and LC and their interaction with EGFR inhibition.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Cetuximab , Neoplasias Colorrectales/metabolismo , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cuidados Paliativos/métodos , Pronóstico , Análisis de Regresión , Tasa de SupervivenciaRESUMEN
STUDY DESIGN: Retrospective study. OBJECTIVES: To quantify diurnal blood pressure (BP) patterns and nocturnal hypertension and to measure diurnal urine production in spinal cord injury (SCI) patients with clinically significant disorders of BP control. SETTING: A specialist state-based spinal cord service in Victoria, Australia. METHODS: Medical records of patients with traumatic SCI who were referred to a specialist service for management of a BP disorder were examined. Ambulatory BP and nocturnal urine production were compared between groups of patients classified according to level, completeness and chronicity of SCI. Patients with night:day systolic BP <90% were classified as dippers, 90-100% as non-dippers and >100% as reversed dippers. RESULTS: Patients (44 tetraplegic, 10 paraplegic) were predominantly males (92.6%) aged 41±2.5 years (mean±s.e.m.). Referral was for orthostatic intolerance (n=37), autonomic dysreflexia (n=6), nocturnal polyuria (n=4), elevated BP (n=1) and peripheral oedema (n=1). The average BP was 111.1±1.4/65.0±1.2 mm Hg. In 56% of patients (n=30), BP at night was higher than during the day and another 37% (n=20) were non-dippers. Nocturnal hypertension was present in 31% (n=17) of the patients. In the tetraplegic patients, urine flow rate was greater during the night than day (121±9.5 ml h(-1) vs 89±8.2 ml h(-1), P=0.025). CONCLUSION: Ambulatory BP monitoring in patients with SCI and clinically significant BP disorders detected a high incidence of reversed dipping and nocturnal hypertension. We postulate elevated nocturnal BP may contribute to nocturnal diuresis that might cause relative volume depletion and thereby contribute to daytime orthostatic hypotension.
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Presión Sanguínea/fisiología , Ritmo Circadiano/fisiología , Traumatismos de la Médula Espinal/clasificación , Traumatismos de la Médula Espinal/complicaciones , Trastornos Urinarios/etiología , Adulto , Monitoreo Ambulatorio de la Presión Arterial , Femenino , Humanos , Hipertensión/etiología , Masculino , Cuadriplejía/etiología , Estudios Retrospectivos , Traumatismos de la Médula Espinal/terapia , Factores de Tiempo , Micción/fisiologíaRESUMEN
BACKGROUND: Anti-EGFR antibody, cetuximab, improves overall survival (OS) in K-ras wild-type chemotherapy-refractory colorectal cancer. Epidermal growth factor receptor ligand epiregulin (EREG) gene expression may further predict cetuximab benefit. METHODS: Tumour samples from a phase III clinical trial of cetuximab plus best supportive care (BSC) vs BSC alone (CO.17) were analysed for EREG mRNA gene expression. Predictive effects of high vs low EREG on OS and progression-free survival (PFS) were examined for treatment-biomarker interaction. RESULTS: Both EREG and K-ras status were ascertained in 385 (193 cetuximab, 192 BSC) tumour samples. Within the high EREG and K-ras wild-type status ('co-biomarker')-positive group (n=139, 36%), median PFS was 5.4 vs 1.9 months (hazard ratio (HR) 0.31; P<0.0001), and median OS was 9.8 vs 5.1 months (HR 0.43; P<0.001) for cetuximab vs BSC, respectively. In the rest (n=246, 64%), PFS (HR 0.82; P=0.12) and OS (HR 0.90; P=0.45) were not significantly different. Test for treatment interaction showed a larger cetuximab effect on OS (HR 0.52; P=0.007) and PFS (HR 0.49; P=0.001) in the co-biomarker-positive group. CONCLUSION: In pre-treated K-ras wild-type status colorectal cancer, patients with high EREG gene expression appear to benefit more from cetuximab therapy compared with low expression. Epiregulin as a selective biomarker requires further evaluation.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Factor de Crecimiento Epidérmico/biosíntesis , Proteínas ras/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Cetuximab , Ensayos Clínicos Fase III como Asunto , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Factor de Crecimiento Epidérmico/genética , Epirregulina , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Mutación , Estadificación de NeoplasiasRESUMEN
BACKGROUND: The ACCENT database, with individual patient data for 20 898 patients from 18 colon cancer clinical trials, was used to support Food and Drug Administration (FDA) approval of 3-year disease-free survival as a surrogate for 5-year overall survival. We hypothesised substantive differences in survival estimation with log-normal modelling rather than standard Kaplan-Meier or Cox approaches. METHODS: Time to relapse, disease-free survival, and overall survival were estimated using Kaplan-Meier, Cox, and log-normal approaches for male subjects aged 60-65 years, with stage III colon cancer, treated with 5-fluorouracil-based chemotherapy regimens (with 5FU), or with surgery alone (without 5FU). RESULTS: Absolute differences between Cox and log-normal estimates with (without) 5FU varied by end point. The log-normal model had 5.8 (6.3)% higher estimated 3-year time to relapse than the Cox model; 4.8 (5.1)% higher 3-year disease-free survival; and 3.2 (2.2)% higher 5-year overall survival. Model checking indicated greater data support for the log-normal than the Cox model, with Cox and Kaplan-Meier estimates being more similar. All three model types indicate consistent evidence of treatment benefit on both 3-year disease-free survival and 5-year overall survival; patients allocated to 5FU had 5.0-6.7% higher 3-year disease-free survival and 5.3-6.8% higher 5-year overall survival. CONCLUSION: Substantive absolute differences between estimates of 3-year disease-free survival and 5-year overall survival with log-normal and Cox models were large enough to be clinically relevant, and warrant further consideration.
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Neoplasias del Colon/mortalidad , Modelos Estadísticos , Anciano , Ensayos Clínicos Fase III como Asunto , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/cirugía , Terapia Combinada , Bases de Datos como Asunto , Supervivencia sin Enfermedad , Determinación de Punto Final , Fluorouracilo/administración & dosificación , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Ensayos Clínicos Controlados Aleatorios como AsuntoAsunto(s)
Causas de Muerte , Trasplante de Páncreas , Choque , Donantes de Tejidos , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: Cetuximab-induced hypomagnesemia has been associated with improved clinical outcomes in advanced colorectal cancer (CRC). We explored this relationship from a randomized clinical trial of cetuximab plus best supportive care (BSC) versus BSC alone in patients with pretreated advanced CRC. PATIENTS AND METHODS: Day 28 hypomagnesemia grade (0 versus ≥1) and percent reduction (<20% versus ≥20%) of Mg from baseline was correlated with outcome. RESULTS: The median percentage Mg reduction at day 28 was 10% (-42.4% to 63.0%) for cetuximab (N = 260) versus 0% (-21.1% to 25%) for BSC (N = 251) [P < 0.0001]. Grade ≥1 hypomagnesemia and ≥20% reduction from baseline at day 28 were associated with worse overall survival (OS) [hazard ratio, HR 1.61 (95% CI 1.12-2.33), P = 0.01 and 2.08 (95% CI 1.32-3.29), P = 0.002, respectively] in multivariate analysis including grade of rash (0-1 versus 2+). Dyspnea (grade ≥3) was more common in patients with ≥20% versus < 20% Mg reduction (68% versus 45%; P = 0.02) and grade 3/4 anorexia were higher in patients with grade ≥1 hypomagnesemia (81% versus 63%; P = 0.02). CONCLUSIONS: In contrast to prior reports, cetuximab-induced hypomagnesemia was associated with poor OS, even after adjustment for grade of rash.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/metabolismo , Magnesio/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Cetuximab , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/inducido químicamente , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Receptores ErbB/metabolismo , Femenino , Humanos , Hipercalciuria/inducido químicamente , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Nefrocalcinosis/inducido químicamente , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas p21(ras) , Defectos Congénitos del Transporte Tubular Renal/inducido químicamente , Resultado del Tratamiento , Proteínas ras/genética , Proteínas ras/metabolismoRESUMEN
BACKGROUND: Adult whole-organ donation after circulatory death (DCD) and 'split' extended right lobe donation after brain death (ERL-DBD) liver transplants are considered marginal, but direct comparison of outcomes has rarely been performed. Such a comparison may rationalize the use of DCD livers, which varies widely between UK centres. METHODS: Outcomes for adult ERL-DBD livers and 'controlled' DCD liver transplantations performed at the Cambridge Transplant Centre between January 2004 and December 2010 were compared retrospectively. RESULTS: None of the 32 patients in the DCD cohort suffered early graft failure, compared with five of 17 in the ERL-DBD cohort. Reasons for graft failure were hepatic artery thrombosis (3), progressive cholestasis (1) and small-for-size syndrome (1). Early allograft dysfunction occurred in a further five patients in each group. In the DCD group, ischaemic cholangiopathy developed in six patients, resulting in graft failure within the first year in two; the others remained stable. The incidence of biliary anastomotic complications was similar in both groups. Kaplan-Meier survival analysis confirmed superior graft survival in the DCD liver group (93 per cent at 3 years versus 71 per cent in the ERL-DBD cohort; P = 0·047), comparable to that of contemporaneous whole DBD liver transplants (93 per cent at 3 years). Patient survival was similar in all groups. CONCLUSION: Graft outcomes of DCD liver transplants were better than those of ERL-DBD liver transplants. Redefining DCD liver criteria and refining donor-recipient selection for ERL-DBD transplants should be further explored.
Asunto(s)
Trasplante de Hígado/métodos , Choque , Obtención de Tejidos y Órganos/métodos , Adolescente , Adulto , Anciano , Muerte Encefálica , Selección de Donante , Enfermedad Hepática en Estado Terminal , Femenino , Supervivencia de Injerto , Paro Cardíaco , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Cuidados Posoperatorios/métodos , Resultado del Tratamiento , Isquemia Tibia/métodos , Adulto JovenRESUMEN
BACKGROUND: Organ scarcity has prompted increased use of organs from donation after circulatory death (DCD) donors. An early single-centre experience of simultaneous pancreas-kidney (SPK) transplantation from controlled DCD donors is described here. METHODS: Outcomes of SPK transplants from DCD and donation after brain death (DBD) donors between August 2008 and January 2011 were reviewed retrospectively. RESULTS: SPK transplants from 20 DCD and 40 DBD donors were carried out. Donor and recipient characteristics were similar for both groups, although pancreas cold ischaemia times were shorter in DCD recipients: median (range) 8·2 (5·9-10·5) versus 9·5 (3·8-12·5) h respectively (P = 0·004). Median time from treatment withdrawal to cold perfusion was 24 (range 16-110) min for DCD donors. There were no episodes of delayed pancreatic graft function in either group; the graft thrombosis rates were both 5 per cent. Similarly, there were no differences in haemoglobin A1c level at 12 months: median (range) 5·4 (4·9-7·7) per cent in DCD group versus 5·4 (4·1-6·2) per cent in DBD group (P = 0·910). Pancreas graft survival rates were not significantly different, with Kaplan-Meier 1-year survival estimates of 84 and 95 per cent respectively (P = 0·181). CONCLUSION: DCD SPK grafts had comparable short-term outcomes to DBD grafts, even when procured from selected donors with a prolonged agonal phase.
Asunto(s)
Muerte Encefálica , Trasplante de Riñón/métodos , Trasplante de Páncreas/métodos , Choque , Obtención de Tejidos y Órganos/métodos , Adolescente , Adulto , Funcionamiento Retardado del Injerto , Selección de Donante , Femenino , Supervivencia de Injerto , Humanos , Estimación de Kaplan-Meier , Tiempo de Internación , Masculino , Persona de Mediana Edad , Cuidados Posoperatorios/métodos , Estudios Prospectivos , Resultado del Tratamiento , Isquemia Tibia/métodos , Adulto JovenRESUMEN
BACKGROUND: The effect of comorbidity, age and performance status (PS) on treatment of advanced pancreatic cancer is poorly understood. We examined these factors as predictors of outcome in advanced pancreatic cancer patients treated with gemcitabine +/- erlotinib. PATIENTS AND METHODS: Comorbidity was evaluated by two physicians using the Charlson Comorbidity Index (CCI) and correlated with clinical outcome data from the NCIC Clinical Trials Group (NCIC CTG) PA.3 clinical trial. RESULTS: Five hundred and sixty-nine patients were included; 47% were aged ≥ 65 years old, 36% had comorbidity (CCI>0). In multivariate analysis, neither age (p=0.22) nor comorbidity (p=0.21) was associated with overall survival. The baseline presence of better PS and lower pain intensity scores was associated with better overall survival (p < 0.0001 and p=0.01, respectively). An improvement in survival with the addition of erlotinib therapy was seen in patients age < 65 (adjusted hazard ratio (HR) 0.73, p=0.01) or in the presence of comorbidity (adjusted HR 0.72, p=0.03). However, neither age nor CCI score was predictive of erlotinib benefit after test for interaction. Patients treated with gemcitabine plus erlotinib who were ≥ 65 years of age or those with comorbidity had a higher rate of infections ≥ grade 3. CONCLUSION: Low baseline pain intensity and better PS were associated with improved overall survival, while age and comorbidity were not independent prognostic factors for patients treated with gemcitabine-based therapy.
Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinazolinas/administración & dosificación , Factores de Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Comorbilidad , Desoxicitidina/administración & dosificación , Clorhidrato de Erlotinib , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Metástasis de la Neoplasia , Evaluación de Resultado en la Atención de Salud , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/epidemiología , Placebos , Modelos de Riesgos Proporcionales , Riesgo , GemcitabinaRESUMEN
BACKGROUND: the interplay between comorbidity, age and performance status (PS) as predictors of outcome in advanced colorectal cancer (ACRC) is poorly understood. We examined these factors as predictors of treatment toxicity and outcome in cetuximab-treated patients with ACRC. PATIENTS AND METHODS: comorbidity was independently evaluated using the Charlson Comorbidity Index (CCI), a validated measure of comorbidity based on the presence of medical conditions weighted according to their effect on mortality. CCI score was correlated with clinical and outcome data. RESULTS: five hundred and seventy-two patients were included; 41% were ≥ 65 years and 25% had comorbidities at randomization. In multivariate analysis (MVA) of all covariates, only older age was associated with greater comorbidity (P = 0.008). Overall survival (OS) was significantly better for patients with greater comorbidity in univariate analysis (P = 0.047). Conversely, better PS was associated with better OS in MVA (hazard ratio 1.92 for PS = 2 versus PS = 0, P < 0.0001). Age was not associated with OS (P = 0.13). Elderly patients had significantly less grade ≥ 3 vomiting (P = 0.034) but more dyspnea (P = 0.005). Patients with greater comorbidity had significantly less grade ≥ 3 vomiting (P = 0.002) but more non-neutropenic fever (P = 0.005). CONCLUSION: better PS was associated with improved OS. For patients with good PS, restricting cetuximab use in the setting of significant comorbidity does not appear justified.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/terapia , Cuidados Paliativos/métodos , Factores de Edad , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Antineoplásicos/efectos adversos , Cetuximab , Comorbilidad , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Análisis Multivariante , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
Solid organ transplant recipients are at risk of infection from cytomegalovirus (CMV). A wide range of disease is associated with CMV infection and we report two cases of CMV cholecystitis in patients following renal transplantation. Both patients presented with severe hemorrhagic cholecystitis, which required immediate resuscitation and emergency cholecystectomy. The diagnosis of CMV infection was confirmed in both cases using CMV-specific staining of the gallbladder. The diagnosis of CMV cholecystitis must be considered in all patients with upper abdominal pain after renal transplantation.