José M. Guillén-Rodríguez

Lack of Effect of a High-Fiber Cereal Supplement on the Recurrence of Colorectal Adenomas

BACKGROUND The risks of colorectal cancer and adenoma, the precursor lesion, are believed to be influenced by dietary factors. Epidemiologic evidence that cereal fiber protects against colorectal cancer is equivocal. We conducted a randomized trial to determine whether dietary supplementation with wheat-bran fiber reduces the rate of recurrence of colorectal adenomas. METHODS We randomly assigned 1429 men and women who were 40 to 80 years of age and who had had one or more histologically confirmed colorectal adenomas removed within three months before recruitment began to a supervised program of dietary supplementation with either high amounts (13.5 g per day) or low amounts (2 g per day) of wheat-bran fiber. The primary end point was the presence or absence of new adenomas at the time of follow-up colonoscopy. Subjects and physicians, including colonoscopists, were unaware of the group assignments. RESULTS Of the 1303 subjects who completed the study, 719 had been randomly assigned to the high-fiber group and 584 to the low-fiber group. The median times from randomization to the last follow-up colonoscopy were 34 months in the high-fiber group and 36 months in the low-fiber group. By the time of the last follow-up colonoscopy, at least one adenoma had been identified in 338 subjects in the high-fiber group (47.0 percent) and in 299 subjects in the low-fiber group (51.2 percent). The multivariate adjusted odds ratio for recurrent adenoma in tile high-fiber group, as compared with the low-fiber group, was 0.88 (95 percent confidence interval, 0.70 to 1.11; P=0.28), and the relative risk of recurrence according to the number of adenomas, in the high-fiber group as compared with the low-fiber group, was 0.99 (95 percent confidence interval, 0.71 to 1.36; P=0.93). CONCLUSIONS As used in this study, a dietary supplement of wheat-bran fiber does not protect against recurrent colorectal adenomas.

A Comparison of the Prehospital Motor Component of the Glasgow Coma Scale (mGCS) to the Prehospital Total GCS (tGCS) as a Prehospital Risk Adjustment Measure for Trauma Patients

Abstract Objective. This study compared the prehospital motor component subscale of the Glasgow Coma Scale (mGCS) to the prehospital total GCS (tGCS) score for its ability to predict the need for intubation, survival to hospital discharge, and neurosurgical intervention in trauma patients. Methods. This is a retrospective analysis of an urban level 1 trauma registry. All trauma patients presenting to the trauma center emergency department via emergency medical services from July 2008 through June 2010 were included. The area under the receiver operating characteristics curve (AUC) analysis was used to compare the predictive ability of the prehospital mGCS to tGCS for three outcomes: intubation, survival to hospital discharge, and neurosurgical intervention. Two subgroups (patients with injury severity score [ISS] ≥ 16 and traumatic brain injury [TBI] [head abbreviated injury score (AIS) ≥ 3]) were analyzed. An a priori statistically significant absolute difference of 0.050 in AUC between mGCS and tGCS for these clinical outcomes was used as a clinically significant difference. Multiple imputation was used for missing prehospital GCS data. Results. There were 9,816 patients, of which 4% were intubated, 3.8% had neurosurgical intervention, and 97.1% survived to hospital discharge. The absolute difference in AUC (prehospital tGCS minus mGCS) for all cases was statistically significant for all three outcomes but did not reach the clinical significance threshold: survival = 0.010 (95% CI: 0.002–0.018), intubation = 0.018 (95% CI: 0.011–0.024), and neurosurgical intervention = 0.019 (95% CI: 0.007–0.029). The difference in AUC between tGCS and mGCS for the subgroups ISS ≥ 16 (n = 1,151) and TBI (n = 1,165) did not reach clinical significance for the three outcomes. The discriminatory ability of the prehospital mGCS was good for survival (AUC: all patients = 0.89, ISS ≥ 16 = 0.84, traumatic brain injury = 0.86) excellent for intubation (AUC: all patients = 0.95, ISS ≥ 16 = 0.91, traumatic brain injury = 0.91), and poor for neurosurgical intervention (AUC: all patients = 0.67, ISS ≥ 16 = 0.57, traumatic brain injury = 0.60). Conclusion. The prehospital mGCS appears have good discriminatory power and is equivalent to the prehospital tGCS for predicting intubation and survival to hospital discharge in this trauma population as a whole, those with ISS ≥ 16, or TBI.

Dietary change in an intervention trial of wheat bran fiber and colorectal adenoma recurrence

PURPOSE The objectives of this study were to determine whether participants in the Wheat Bran Fiber (WBF) trial exhibited changes in diet over time, and whether these changes were differential by assigned treatment group. METHODS The WBF trial was a randomized trial with participants assigned to one of two groups: a low-fiber (2.0 g/d) or high-fiber (13.5 g/d) wheat bran fiber cereal supplement. A total of 685 participants from both treatment groups completed the Arizona Food Frequency Questionnaire (AFFQ) at baseline, year one, and year three of the trial. Means were calculated for nutrient intake, change in nutrient intake, number of food group servings, and change in number of food group servings. RESULTS For both treatment groups combined, significant increases were observed for most micronutrients and vitamins at years one and three, while fat intake significantly decreased. Participants from both groups significantly increased their consumption of cereals, breads, and crackers, but decreased the number of servings from the meat, poultry, and egg group, the fats group, and the salty snacks group. The only differential changes in intake between the treatment groups were for sugar and iron, which increased to a lesser extent among those assigned to the high-fiber treatment as compared with the low-fiber group. CONCLUSIONS Although differential dietary intake was not appreciable in the WBF trial, participants exhibited longitudinal changes. Future intervention studies should carefully monitor dietary changes during the trial with multiple dietary assessment tools to assess potential secular and treatment-related diet changes.

Early Assessment of Biophysical Parameters Predicts Lesion Formation During RF Energy Delivery In Vitro

Background: There is no currently available technology to accurately predict ablation lesion size within seconds of onset of delivery of radiofrequency (RF) energy.

A Phase II Exploratory Study of PXD-101 (Belinostat) Followed by Zevalin in Patients with Relapsed Aggressive High-Risk Lymphoma

Objective: Aggressive lymphomas (aNHL) including diffuse large B-cell lymphoma (DLBCL) have poor outcomes in relapsed refractory patients. Prior studies have demonstrated that loss of major histocompatibility complex class II (MHCII) expression in DLBCL is associated with poor survival. The objective of this single-arm phase II study was to evaluate if PXD-101 would increase MHCII expression, synergize with Zevalin, and improve clinical outcomes. Methods: This was a single-center open-label phase II trial (NCT01686165) geared toward heavily pretreated patients with CD20-positive aNHL. The primary endpoint was overall response rate (ORR) in aNHL patients treated with 2 cycles of PXD-101 followed by restaging CT and 1 cycle of Zevalin. Results: Five patients were enrolled, and all were heavily pretreated. Therapy was well tolerated, with nausea and vomiting being the most frequent adverse events. All patients progressed after receiving therapy; the study did not achieve the required ORR to proceed to the next stage. Conclusion: The pleotropic effects of histone deacetylase inhibition and lack of clinical biomarkers have precluded a priori identification of responding patients. Thus, while we report a negative trial of PXD-101 in combination with Zevalin, this study highlights the importance of a clinically feasible biomarker.

Oesophageal sensation in response to high PCO2 and acidic solutions in nonerosive reflux disease

Eur J Clin Invest 2011

Phase 2 Open-Label Study of Bortezomib, Cladribine, and Rituximab in Advanced, Newly Diagnosed, and Relapsed/Refractory Mantle-Cell and Indolent Lymphomas

Background Mantle‐cell lymphoma (MCL) and indolent non‐Hodgkin lymphoma (iNHL) are incurable heterogeneous diseases characterized by relapse. There is a need for newer treatments in MCL and iNHL, especially in the relapsed/refractory (R/R) setting. We therefore investigated the novel combination of bortezomib (Velcade), cladribine, and rituximab (VCR) in front‐line and R/R settings in MCL and iNHL (NCT00980395). Patients and Methods Eligible patients included adults with biopsy‐proven CD20‐positive MCL and iNHL who met the criteria for treatment. Rituximab 375 mg/m2 intravenous (IV) day 1, cladribine 4 mg/m2 IV days 1 to 5, and bortezomib 1.3 mg/m2 IV days 1 and 4 were administered every 28 days for 6 cycles. Results Twenty‐four patients were enrolled onto the study with a median follow‐up of 38.5 months. Median age was 66.5 years, and 46% had MCL. The most common adverse events were hematologic, with febrile neutropenia in 3 patients. Neuropathy was noted in 17% of patients, of which 8% was grade 3 or above. The overall response rate was 92%. For the entire cohort, and for MCL patients, the median progression‐free survival and the median overall survival were not reached. The 2‐year progression‐free survival was 82% for the MCL group and 54% for the iNHL group; it was 80% for treatment‐naive patients and 57% for R/R patients. Conclusion VCR is effective in MCL and iNHL. Although hematologic toxicity can be an issue, this study demonstrates a high response rate to a novel combination and provides an alternative option in transplant‐ineligible R/R MCL and iNHL. Micro‐Abstract The combination of bortezomib, cladribine, and rituximab is novel and effective in mantle‐cell and indolent non‐Hodgkin lymphomas.

Yttrium-90-Ibritumomab Tiuxetan (Zevalin®) Radioimmunotherapy after Cytoreduction with ESHAP Chemotherapy in Patients with Relapsed Follicular Non-Hodgkin Lymphoma: Final Results of a Phase II Study

Background: Radioimmunotherapy (RIT) is effective in treating relapsed/refractory follicular lymphoma (FL), with durable remissions in first-line consolidation. We hypothesized that RIT with ibritumomab tiuxetan (Zevalin®) would result in durable remissions by eliminating minimal residual disease after cytoreduction. Methods: Patients with FL received 2 cycles of ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) every 28 days, followed by Zevalin 4–6 weeks later if there was no disease progression and bone marrow biopsy showed < 25% involvement. Results: Twenty-eight patients were treated, with a median age of 61 years, median of 3 prior therapies, 49% high-risk disease (Follicular Lymphoma International Prognostic Index, FLIPI), and 39% progressive disease. Three patients did not receive Zevalin due to residual bone marrow involvement. The main toxicities were cytopenias, with 11% febrile neutropenia. The overall response rate (ORR) was 72%, with 45% achieving complete response. With a median follow-up of 73 months, 1-year progression-free survival (PFS) was 38%, and median PFS was 10 months, but median overall survival (OS) was not reached. Conclusion: The study did not reach its primary endpoint of a 1-year PFS of 67.3%. Reasons for this could include low accrual, high-risk disease, and inadequate debulking provided by 2 cycles of ESHAP. However, this protocol was associated with tolerable toxicity, high ORR, and high OS. Further studies would optimize debulking and focus on high-risk FL patients.

Contents Vol. 93, 2017

A.B. Benson, Chicago, Ill. A. Chang, Singapore A.L. Cheng, Taipei J.F. Cleary, Madison, Wis. M. Dietel, Berlin P. Dufour, Strasbourg M.S. Ernstoff , Buff alo, N.Y. M.G. Fakih, Duarte, Calif. J.J. Grau, Barcelona H. Gronemeyer, Illkirch D.F. Hayes, Ann Arbor, Mich. C.S. Johnson, Buff alo, N.Y. M.J. Kelley, Durham, N.C. L. Kumar, New Delhi P.J. Loehrer, Indianapolis, Ind. J.R. Marshall, Buff alo, N.Y. S. Monfardini, Milan R. Nagler, Haifa R. Ohno, Nagoya B. Pestalozzi, Zurich H.M. Pinedo, Amsterdam E.A. Repasky, Buff alo, N.Y. D. Santini, Rome A. Semczuk, Lublin E.F. Smit, Amsterdam C.N. Sternberg, Rome R. Stupp, Zurich M.S. Tallman, New York, N.Y. S. Tanaka, Hiroshima M. Tian, Houston, Tex. D.L. Trump, Buff alo, N.Y. T. Wiegel, Ulm W. Yasui, Hiroshima H. Zhang, Hangzhou City Editor-in-Chief

Kinase-driven metabolic signalling as a predictor of response to carboplatin–paclitaxel adjuvant treatment in advanced ovarian cancers

Background:The biological mechanisms underlying early- and advanced-stage epithelial ovarian cancers (EOCs) are still poorly understood. This study explored kinase-driven metabolic signalling in early and advanced EOCs, and its role in tumour progression and response to carboplatin–paclitaxel treatment.Methods:Tumour epithelia were isolated from two independent sets of primary EOC (n=72 and 30 for the discovery and the validation sets, respectively) via laser capture microdissection. Reverse phase protein microarrays were used to broadly profile the kinase-driven metabolic signalling of EOC with particular emphasis on the LBK1–AMPK and AKT–mTOR axes. Signalling activation was compared between early and advanced lesions, and carboplatin–paclitaxel-sensitive and -resistant tumours.Results:Advanced EOCs were characterised by a heterogeneous kinase-driven metabolic signature and decreased phosphorylation of the AMPK–AKT–mTOR axis compared to early EOC (P<0.05 for AMPKα T172, AMPKα1 S485, AMPKβ1 S108, AKT S473 and T308, mTOR S2448, p70S6 S371, 4EBP1 S65, GSK-3 α/β S21/9, FOXO1 T24/FOXO3 T32, and FOXO1 S256). Advanced tumours with low relative activation of the metabolic signature and increased FOXO1 T24/FOXO3 T32 phosphorylation (P=0.041) were associated with carboplatin–paclitaxel resistance.Conclusions:If validated in a larger cohort of patients, the decreased AMPK–AKT–mTOR activation and phosphorylation of FOXO1 T24/FOXO3 T32 may help identify carboplatin–paclitaxel-resistant EOC patients.