SummaryBackgroundTrastuzumab duocarmazine is a novel HER2-targeting antibody–drug conjugate comprised of trastuzumab covalently bound to a linker drug containing duocarmycin. Preclinical studies ...showed promising antitumour activity in various models. In this first-in-human study, we assessed the safety and activity of trastuzumab duocarmazine in patients with advanced solid tumours. MethodsWe did a phase 1 dose-escalation and dose-expansion study. The dose-escalation cohort comprised patients aged 18 years or older enrolled from three academic hospitals in Belgium, the Netherlands, and the UK with locally advanced or metastatic solid tumours with variable HER2 status who were refractory to standard cancer treatment. A separate cohort of patients were enrolled to the dose-expansion phase from 15 hospitals in Belgium, the Netherlands, Spain, and the UK. Dose-expansion cohorts included patients aged 18 years or older with breast, gastric, urothelial, or endometrial cancer with at least HER2 immunohistochemistry 1+ expression and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST). Trastuzumab duocarmazine was administered intravenously on day 1 of each 3-week cycle. In the dose-escalation phase, trastuzumab duocarmazine was given at doses of 0·3 mg/kg to 2·4 mg/kg (3 + 3 design) until disease progression or unacceptable toxicity. The primary endpoint of the dose-escalation phase was to assess safety and ascertain the recommended phase 2 dose, which would be the dose used in the dose-expansion phase. The primary endpoint of the dose-expansion phase was the proportion of patients achieving an objective response (complete response or partial response), as assessed by the investigator using RECIST version 1.1. This ongoing study is registered with ClinicalTrials.gov, number NCT02277717, and is fully recruited. FindingsBetween Oct 30, 2014, and April 2, 2018, 39 patients were enrolled and treated in the dose-escalation phase and 146 patients were enrolled and treated in the dose-expansion phase. One dose-limiting toxic effect (death from pneumonitis) occurred at the highest administered dose (2·4 mg/kg) in the dose-escalation phase. One further death occurred in the dose-escalation phase (1·5 mg/kg cohort) due to disease progression, which was attributed to general physical health decline. Grade 3–4 treatment-related adverse events reported more than once in the dose-escalation phase were keratitis (n=3) and fatigue (n=2). Based on all available data, the recommended phase 2 dose was set at 1·2 mg/kg. In the dose-expansion phase, treatment-related serious adverse events were reported in 16 (11%) of 146 patients, most commonly infusion-related reactions (two 1%) and dyspnoea (two 1%). The most common treatment-related adverse events (grades 1–4) were fatigue (48 33% of 146 patients), conjunctivitis (45 31%), and dry eye (45 31%). Most patients (104 71% of 146) had at least one ocular adverse event, with grade 3 events reported in ten (7%) of 146 patients. No patients died from treatment-related adverse events and four patients died due to disease progression, which were attributed to hepatic failure (n=1), upper gastrointestinal haemorrhage (n=1), neurological decompensation (n=1), and renal failure (n=1). In the breast cancer dose-expansion cohorts, 16 (33%, 95% CI 20·4–48·4) of 48 assessable patients with HER2-positive breast cancer achieved an objective response (all partial responses) according to RECIST. Nine (28%, 95% CI 13·8–46·8) of 32 patients with HER2-low, hormone receptor-positive breast cancer and six (40%, 16·3–67·6) of 15 patients with HER2-low, hormone receptor-negative breast cancer achieved an objective response (all partial responses). Partial responses were also observed in one (6%, 95% CI 0·2–30·2) of 16 patients with gastric cancer, four (25%, 7·3–52·4) of 16 patients with urothelial cancer, and five (39%, 13·9–68·4) of 13 patients with endometrial cancer. InterpretationTrastuzumab duocarmazine shows notable clinical activity in heavily pretreated patients with HER2-expressing metastatic cancer, including HER2-positive trastuzumab emtansine-resistant and HER2-low breast cancer, with a manageable safety profile. Further investigation of trastuzumab duocarmazine for HER2-positive breast cancer is ongoing and trials for HER2-low breast cancer and other HER2-expressing cancers are in preparation. FundingSynthon Biopharmaceuticals.
SummaryBackgroundPathological complete response to preoperative treatment in adults with soft-tissue sarcoma can be achieved in only a few patients receiving radiotherapy. This phase 2–3 trial ...evaluated the safety and efficacy of the hafnium oxide (HfO 2) nanoparticle NBTXR3 activated by radiotherapy versus radiotherapy alone as a pre-operative treatment in patients with locally advanced soft-tissue sarcoma. MethodsAct.In.Sarc is a phase 2–3 randomised, multicentre, international trial. Adults (aged ≥18 years) with locally advanced soft-tissue sarcoma of the extremity or trunk wall, of any histological grade, and requiring preoperative radiotherapy were included. Patients had to have a WHO performance status of 0–2 and a life expectancy of at least 6 months. Patients were randomly assigned (1:1) by an interactive web response system to receive either NBTXR3 (volume corresponding to 10% of baseline tumour volume at a fixed concentration of 53·3 g/L) as a single intratumoural administration before preoperative external-beam radiotherapy (50 Gy in 25 fractions) or radiotherapy alone, followed by surgery. Randomisation was stratified by histological subtype (myxoid liposarcoma vs others). This was an open-label study. The primary endpoint was the proportion of patients with a pathological complete response, assessed by a central pathology review board following European Organisation for Research and Treatment of Cancer guidelines in the intention-to-treat population full analysis set. Safety analyses were done in all patients who received at least one puncture and injection of NBTXR3 or at least one dose of radiotherapy. This study is registered with ClinicalTrials.gov, number NCT02379845, and is ongoing for long-term follow-up, but recruitment is complete. FindingsBetween March 3, 2015, and Nov 21, 2017, 180 eligible patients were enrolled and randomly assigned and 179 started treatment: 89 in the NBTXR3 plus radiotherapy group and 90 in the radiotherapy alone group. Two patients in the NBTXR3 group and one patient in the radiotherapy group were excluded from the efficacy analysis because they were subsequently discovered to be ineligible; thus, a total of 176 patients were analysed for the primary endpoint in the intention-to-treat full analysis set (87 in the NBTXR3 group and 89 in the radiotherapy alone group). A pathological complete response was noted in 14 (16%) of 87 patients in the NBTXR3 group and seven (8%) of 89 in the radiotherapy alone group (p=0·044). In both treatment groups, the most common grade 3–4 treatment-emergent adverse event was postoperative wound complication (eight 9% of 89 patients in the NBTXR3 group and eight 9% of 90 in the radiotherapy alone group). The most common grade 3–4 adverse events related to NBTXR3 administration were injection site pain (four 4% of 89) and hypotension (four 4%) and the most common grade 3–4 radiotherapy-related adverse event was radiation skin injury in both groups (five 6% of 89 in the NBTXR3 group and four 4% of 90 in the radiotherapy alone group). The most common treatment-emergent grade 3–4 adverse event related to NBTXR3 was hypotension (six 7% of 89 patients). Serious adverse events were observed in 35 (39%) of 89 patients in the NBTXR3 group and 27 (30%) of 90 patients in the radiotherapy alone group. No treatment-related deaths occurred. InterpretationThis trial validates the mode of action of this new class of radioenhancer, which potentially opens a large field of clinical applications in soft-tissue sarcoma and possibly other cancers. FundingNanobiotix SA and PharmaEngine, Inc.
Summary Background Poly(ADP-ribose) polymerase (PARP) is implicated in DNA repair and transcription regulation. Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that ...induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. We investigated the safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumour activity of niraparib. Methods In a phase 1 dose-escalation study, we enrolled patients with advanced solid tumours at one site in the UK and two sites in the USA. Eligible patients were aged at least 18 years; had a life expectancy of at least 12 weeks; had an Eastern Cooperative Oncology Group performance status of 2 or less; had assessable disease; were not suitable to receive any established treatments; had adequate organ function; and had discontinued any previous anticancer treatments at least 4 weeks previously. In part A, cohorts of three to six patients, enriched for BRCA1 and BRCA2 mutation carriers, received niraparib daily at ten escalating doses from 30 mg to 400 mg in a 21-day cycle to establish the maximum tolerated dose. Dose expansion at the maximum tolerated dose was pursued in 15 patients to confirm tolerability. In part B, we further investigated the maximum tolerated dose in patients with sporadic platinum-resistant high-grade serous ovarian cancer and sporadic prostate cancer. We obtained blood, circulating tumour cells, and optional paired tumour biopsies for pharmacokinetic and pharmacodynamic assessments. Toxic effects were assessed by common toxicity criteria and tumour responses ascribed by Response Evaluation Criteria in Solid Tumors (RECIST). Circulating tumour cells and archival tumour tissue in prostate patients were analysed for exploratory putative predictive biomarkers, such as loss of PTEN expression and ETS rearrangements. This trial is registered with ClinicalTrials.gov , NCT00749502. Findings Between Sept 15, 2008, and Jan 14, 2011, we enrolled 100 patients: 60 in part A and 40 in part B. 300 mg/day was established as the maximum tolerated dose. Dose-limiting toxic effects reported in the first cycle were grade 3 fatigue (one patient given 30 mg/day), grade 3 pneumonitis (one given 60 mg/day), and grade 4 thrombocytopenia (two given 400 mg/day). Common treatment-related toxic effects were anaemia (48 patients 48%), nausea (42 42%), fatigue (42 42%), thrombocytopenia (35 35%), anorexia (26 26%), neutropenia (24 24%), constipation (23 23%), and vomiting (20 20%), and were predominantly grade 1 or 2. Pharmacokinetics were dose proportional and the mean terminal elimination half-life was 36·4 h (range 32·8–46·0). Pharmacodynamic analyses confirmed PARP inhibition exceeded 50% at doses greater than 80 mg/day and antitumour activity was documented beyond doses of 60 mg/day. Eight (40% 95% CI 19–64) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% 7–93) of four mutation carriers with breast cancer. Antitumour activity was also reported in sporadic high-grade serous ovarian cancer, non-small-cell lung cancer, and prostate cancer. We recorded no correlation between loss of PTEN expression or ETS rearrangements and measures of antitumour activity in patients with prostate cancer. Interpretation A recommended phase 2 dose of 300 mg/day niraparib is well tolerated. Niraparib should be further assessed in inherited and sporadic cancers with homologous recombination DNA repair defects and to target PARP-mediated transcription in cancer. Funding Merck Sharp and Dohme.
Background Ventilator-associated pneumonia (VAP) is one of the most common health care–associated infections in pediatric intensive care units (PICUs). Practice bundles have been shown to reduce VAP ...rates in PICUs in developed countries; however, the impact of a multidimensional approach, including a bundle, has not been analyzed in PICUs from developing countries. Methods This was a before-after study to determine rates of VAP during a period of active surveillance without the implementation of the multidimensional infection control program (phase 1) to be compared with rates of VAP after implementing such a program, which included the following: bundle of infection control interventions, education, outcome surveillance, process surveillance, feedback on VAP rates, and performance feedback on infection control practices (phase 2). This study was conducted by infection control professionals applying the National Health Safety Network's definitions of health care—associated infections and the International Nosocomial Infection Control Consortium's surveillance methodology. Results During the baseline period, we recorded a total of 5,212 mechanical ventilator (MV)-days, and during implementation of the intervention bundle, we recorded 9,894 MV-days. The VAP rate was 11.7 per 1,000 MV-days during the baseline period and 8.1 per 1,000 MV-days during the intervention period (relative risk, 0.69; 95% confidence interval, 0.5-0.96; P = .02), demonstrating a 31% reduction in VAP rate. Conclusions Our results show that implementation of the International Nosocomial Infection Control Consortium's multidimensional program was associated with a significant reduction in VAP rate in PICUs of developing countries.
The results of a surveillance study conducted by the International Nosocomial Infection Control Consortium (INICC) from January 2004 through December 2009 in 422 intensive care units (ICUs) of 36 ...countries in Latin America, Asia, Africa, and Europe are reported. During the 6-year study period, using Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network (NHSN; formerly the National Nosocomial Infection Surveillance system NNIS) definitions for device-associated health care-associated infections, we gathered prospective data from 313,008 patients hospitalized in the consortium’s ICUs for an aggregate of 2,194,897 ICU bed-days. Despite the fact that the use of devices in the developing countries’ ICUs was remarkably similar to that reported in US ICUs in the CDC’s NHSN, rates of device-associated nosocomial infection were significantly higher in the ICUs of the INICC hospitals; the pooled rate of central line-associated bloodstream infection in the INICC ICUs of 6.8 per 1,000 central line-days was more than 3-fold higher than the 2.0 per 1,000 central line-days reported in comparable US ICUs. The overall rate of ventilator-associated pneumonia also was far higher (15.8 vs 3.3 per 1,000 ventilator-days), as was the rate of catheter-associated urinary tract infection (6.3 vs. 3.3 per 1,000 catheter-days). Notably, the frequencies of resistance of Pseudomonas aeruginosa isolates to imipenem (47.2% vs 23.0%), Klebsiella pneumoniae isolates to ceftazidime (76.3% vs 27.1%), Escherichia coli isolates to ceftazidime (66.7% vs 8.1%), Staphylococcus aureus isolates to methicillin (84.4% vs 56.8%), were also higher in the consortium’s ICUs, and the crude unadjusted excess mortalities of device-related infections ranged from 7.3% (for catheter-associated urinary tract infection) to 15.2% (for ventilator-associated pneumonia).
Left atrial (LA) and left ventricular (LV) diastolic function analysis can yield new strategies to recognize early cardiac involvement and prognostic indicators in Chagas disease.
Patients with ...Chagas disease with the indeterminate (n = 69) or with the cardiac form (32 with changes limited to electrocardiography stage A, 25 with changes in LV systolic function but no heart failure HF; stage B, and 26 with HF) underwent evaluation of LV diastolic function (mitral inflow, pulmonary vein flow, color M-mode echocardiography, and tissue Doppler analysis), and LA function by three-dimensional echocardiography and strain analysis and were prospectively followed for the occurrence of clinical events. Echocardiograms were also obtained from 32 controls.
LV diastolic dysfunction was gradually more prevalent and severe across groups from patients with the indeterminate form of Chagas disease to patients with HF. Tissue Doppler was the best tool to demonstrate the worsening of LV diastolic function across the groups (E' velocity: controls, 12.6 ± 2.3 cm/sec; patients with the indeterminate form, 12.1 ± 3.1 cm/sec; stage A, 10.3 ± 2.9 cm/sec; stage B, 8.3 ± 2.8 cm/sec; patients with HF, 5.6 ± 1.9; P < .0001). Although maximum LA volume was increased only in patients with HF, minimum LA volume (controls, 8 ± 2 mL/m(2); patients with the indeterminate form, 8 ± 2 mL/m(2); stage A, 9 ± 3 mL/m(2); stage B, 11 ± 4 mL/m(2); patients with HF, 27 ± 17 mL/m(2); P < .0001) and precontraction LA volume (controls, 11 ± 3 mL/m(2); patients with the indeterminate form, 12 ± 3 mL/m(2); stage A, 13 ± 4 mL/m(2); stage B, 16 ± 5 mL/m(2); patients with HF, 32 ± 19 mL/m(2); P < .0001) were increased in all cardiac form groups. LA conductive function was depressed in all cardiac form groups, while LA contractile function was depressed only in patients with HF. Cox proportional-hazards regression analysis revealed that end-systolic LV diameter (hazard ratio, 1.6; 95% confidence interval, 0.9-2.8; P = .09), E' velocity (hazard ratio, 0.5; 95% confidence interval, 0.3-0.8; P = .001), and peak negative global LA strain (hazard ratio, 1.21; 95% confidence interval, 1.02-1.4; P = .03), were independent predictors of clinical events.
LV diastolic dysfunction was found in all forms of chronic Chagas disease, including those without LV systolic dysfunction. LV diastolic dysfunction may contribute to changes in LA volume and conductive function found in early stages of the cardiac form. Both LV diastolic function and LA contractile function were independent predictors of clinical events.
Background Surgical site infections (SSIs) are a threat to patient safety. However, there are no available data on SSI rates stratified by surgical procedure (SP) in Colombia. Methods From January ...2008-December 2010, a prospective surveillance study on SSIs was conducted by the International Nosocomial Infection Control Consortium (INICC) in 4 hospitals in 4 cities within Colombia using the definitions of the Centers for Disease Control and Prevention-National Healthcare Safety Network (CDC-NHSN). SPs were classified into 10 types, according to ICD-9 criteria. Results We recorded 193 SSIs associated with 5,063 SPs. SSI rates per type of SP were the following, compared with INICC and CDC-NHSN rates, respectively: 9.1% for laminectomy (vs 1.7% and 1.0%), 8.3% for cardiac surgery (vs 5.6% and 1.3%), 3.9% for appendix surgery (vs 2.9% and 1.4%), 5.5% for abdominal hysterectomy (vs 2.7% and 1.6%), 4.4% for prostate surgery (vs 2.1% and 1.2%), 4.5% for spleen surgery (vs 5.6% and 2.3%), 4.3% for vaginal hysterectomy (vs 2.0% and 0.9%), and 3.0% for gallbladder surgery (vs 2.5% and 0.6%). Conclusions Compared with CDC-NHSN rates, SSIs rates in our study hospitals were higher in most types of SPs, whereas compared with INICC, they were similar in 5 of the analyzed types, and higher in 4 types. This study represents an important advance toward knowledge of epidemiology in Colombia that will allow us to introduce targeted interventions.
Introducción: La asociación entre sedentarismo y enfermedades crónicas no transmisibles (ECNT) requiere décadas de exposición. Es posible que esta se manifieste más tempranamente, por algunos ...hallazgos clínicos en adultos jóvenes. Objetivo: Probar la hipótesis de que en adultos jóvenes el sedentarismo se asocia con algunos signos o síntomas de alarma para el desarrollo posterior de ECNT. Metodología: Usando la evaluación inicial (años 2000-2003) del proyecto CHICAMOCHA, en 1539 donantes de sangre clínicamente saludables con pruebas de tamización negativas (edad media 36, DE 8,3 años, 66% hombres) se estudió la asociación entre sedentarismo y una serie de hallazgos clínicos. Se definió sedentarismo como reportar actividad física moderada-intensa ≤150 minutos/semana (incluyendo el trabajo). El desenlace primario fue el compuesto de 11 hallazgos (5 síntomas y 6 signos) de alarma encontrados en la valoración médica. La asociación fue estimada usando un modelo regresión logística ajustado por covariables. Resultados: Se encontró que 56.9% (IC95% 54.3 – 59.3) de los participantes eran sedentarios. En el análisis multivariado, el sedentarismo se asoció positivamente con el estado civil soltero y negativamente con estar empleado. No se encontraron asociaciones significativas en el compuesto agregado de 5 síntomas (OR ajustado 1.07, IC95% 0.90 – 1.26), 6 signos (OR ajustado 1.01, IC95% 0.79 – 1.28). Sin embargo, se observó un gradiente positivo no significativo por el número de hallazgos presentes (1 hallazgo OR=0.91, IC95% 0.61 – 1.35), 2 hallazgos (OR=1.20, IC95% 0.84 – 1.73), 3 o más hallazgos (OR=1.31, IC95% 0.91 – 1.89). Conclusiones: Más de la mitad de la población estudiada se encontró sedentaria. Aunque este factor no se encontró asociado con signos o síntomas individualmente, se identificó un gradiente no significativo con el número de estos hallazgos, posiblemente relacionado con el tiempo de exposición relativamente breve. Villar JC, Herrera VM, Moreno-Medina KJ, Castellanos-Domínguez YZ, Martínez LX, Cortés OL. ¿Puede asociarse el sedentarismo con hallazgos clínicos de alarma de enfermedad crónica en adultos jóvenes? Un análisis en el proyecto CHICAMOCHA. MedUNAB 2015; 18 (1): 42-50 Introduction: The association between Sedentary Lifestyle (SL) and Chronic Non-Communicable Diseases (NCD) takes decades of exposure. It is possible to be seen at an early stage in young adults due to some clinical findings. Objective: Test the hypothesis that a sedentary lifestyle in young adults is associated with some signs or symptoms of alarm for the further development of NCD. Methodology: Using the initial evaluation (years 2000-2003) of CHICAMOCHA project, it was found that 1539 blood donors were healthy with negative screening test results (mean age 36, SD 8.3 years, 66% male). The association between sedentary lifestyle and a series of clinical findings was studied. Sedentary Lifestyle was defined as moderate-intense physical activity of ≤150 minutes/week (including work). The primary outcome was the composite of 11 findings (5 symptoms and 6 signs) found in the medical assessment. We computed multivariate logistic regression models for both individual and pooled outcomes. Results: SL was found in 56.9% (IC95% 54.3–59.3) participants. In multivariate analysis SL was positively associated with single marital status and negatively associated with being employed. There were no significant associations between SL and the composite of 5 symptoms (Covariate-adjusted pooled OR 1.07, 95%CI 0.90–1.26), or 6 signs (Covariate-adjusted pooled OR 1.01, 95%CI 0.79–1.28). However, a positive non-significant gradient in association with the number of findings (Covariate-adjusted OR for any one clinical finding OR=0.91, 95%CI 0.61–1.35; any two findings OR=1.20, 95%CI 0.84 – 1.73, or 3 or more findings OR=1.31, 95%CI 0.91–1.89) was observed. Conclusions: It was found that more than half of the studied population presented a sedentary lifestyle. Even though this factor was not associated with individual signs and symptoms, a non-significant gradient was found, possibly related to a short exposure that may explain these results. Villar JC, Herrera VM, Moreno-Medina KJ, Castellanos-Domínguez YZ, Martínez LX, Cortés OL. Can Sedentarism be Associated with Alarm Clinical Findings of Chronic Diseases in Young Adults?. An Analysis in CHICAMOCHA Project. CHICAMOCHA. MedUNAB 2015; 18 (1): 42-50 Introdução: A associação entre sedentarismo e doenças crônicas não transmissíveis (DCNT) requer décadas de exposição. É possível que esta se manifeste mais cedo, pelo que se tem observado clinicamente em alguns adultos jovens. Objetivo: Testar a hipótese de que um estilo de vida sedentário em adultos jovens está associada com alguns sinais ou sinais de alerta para o desenvolvimento de doenças não transmissíveis. Metodologia: Usando a avaliação inicial (2000-2003) do projeto CHICAMOCHA, em 1539 doadores de sangue clinicamente saudáveis com testes de rastreio negativos (idade média de 36 anos, 8.3 anos, 66% do sexo masculino), estudou-se a associação entre sedentarismo e uma série de achados clínicos. O sedentarismo foi definido como atividade física moderada-intensa ≤150 minutos / semana (incluindo trabalho). O desfecho primário foi o composto de 11 resultados (cinco sintomas e 6 sinais) de alarme encontrados na avaliação médica. A associação foi estimada utilizando um modelo de regressão logística ajustado para co-variáveis. Resultados: Verificou-se que 56.9% (IC 95% 54.3-59.3) dos participantes eram sedentários. Na análise multivariada, o sedentarismo foi positivamente associado com o estado civil de solteiro e negativamente ao fato de estar empregado. Não foram encontradas associações significativas no agregado composto por 5 sintomas (OR ajustado 1,07, IC95% 0,90-1,26), 6 sinais (OR ajustado 1.01, IC95% 0.79 – 1.28). No entanto, é observado, um gradiente positivo, nada significativo pela descoberta presente (1 resultado OR = 0.91, IC 95% 0.61-1.35), 2 resultados (OR = 1.20, IC95% 0.84-1.73), 3 ou mais resultados (OR = 1.31, IC 95% 0.91 – 1.89). Conclusões: Mais da metade da população do estudo foi encontrada sedentária. Embora este fator não foi encontrado associado com sinais ou sintomas individualmente, foi identificado um gradiente não significativo com o número destes achados, possivelmente relacionada com o tempo de exposição relativamente curto. Villar JC, Herrera VM, Moreno-Medina KJ, Castellanos-Dominguez YZ,Martinez LX, Cortés OL. Poderia associar-se o sedentarismo às conclusões clínicas de alarme de doenças crônicas em adultos jovens?. Análise no projeto CHICAMOCHA. MedUNAB 2015; 18 (1): 42-50.
Highlights • We analyzed the impact of the International Nosocomial Infection Control Consortium multidimensional infection control approach on central line–associated bloodstream infection. • We ...used the International Nosocomial Infection Control Consortium Surveillance Online System in 2,988 intensive care unit patients in 2 cities of Colombia. • The central line–associated bloodstream infection (CLABSI) rate was reduced by 73%, from 12.9 to 3.5 CLABSIs per 1,000 central line days.
Management of locally advanced rectal cancer (RC) consists of neoadjuvant chemoradiotherapy (CRT) with fluoropyrimidines, followed by total mesorectal excision. We sought to evaluate the expression ...of selected genes, some of which were derived from a previous undirected SAGE (serial analysis of gene expression)-based approach, before and after CRT, to identify mechanisms of resistance.
This retrospective cohort study included 129 consecutive patients. Quantitative polymerase chain reaction of 53 candidate genes was performed on the biopsy specimen before treatment and on the surgical specimen after CRT. A paired-samples t test was performed to determine genes that were significantly changed after CRT. The result was correlated with patients' disease-free survival.
Twenty-two genes were significantly upregulated, and two were significantly downregulated. Several of the upregulated genes have roles in cell cycle control; these include CCNB1IP1, RCC1, EEF2, CDKN1, TFF3, and BCL2. The upregulation of TFF3 was associated with worse disease-free survival on multivariate analyses (hazard ratio, 2.64; P=.027). Patients whose surgical specimens immunohistochemically showed secretion of TFF3 into the lumen of the tumoral microglands had a higher risk of relapse (hazard ratio, 2.51; P=.014). In vitro experiments showed that DLD-1 cells stably transfected with TFF3 were significantly less sensitive to 5-fluorouracil and showed upregulation of genes involved in the transcriptional machinery and in resistance to apoptosis.
Upregulation of TFF3 after CRT for RC is associated with a higher risk of relapse. The physiological role of TFF3 in restoring the mucosa during CRT could be interfering with treatment efficacy. Our results could reveal not only a novel RC prognostic marker but also a therapeutic target.
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