Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma.

PURPOSE: Evaluate efficacy and toxicity of bortezomib in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. PATIENTS AND METHODS: Patients were stratified, based on preclinical data, into arm A (mantle-cell lymphoma) or arm B (other B-cell lymphomas) without limitation in number of prior therapies. Bortezomib was administered as an intravenous push (1.5 mg/m2) on days 1, 4, 8, and 11 every 21 days for a maximum of six cycles. RESULTS: Sixty patients with a median number of prior therapies of 3.5 (range, one to 12 therapies) were enrolled; 33 patients were in arm A and 27 were in arm B, including 12 diffuse large B-cell lymphomas, five follicular lymphomas (FL), three transformed FLs, four small lymphocytic lymphomas (SLL), two Waldenstrom's macroglobulinemias (WM), and one marginal zone lymphoma. In arm A, 12 of 29 assessable patients responded (six complete responses [CR] and six partial responses [PR]) for an overall response rate (ORR) of 41% (95% CI, 24% to 61%), and a median time to progression not reached yet, with a median follow-up of 9.3 months (range, 1.7 to 24 months). In arm B, four of 21 assessable patients responded (one SLL patient had a CR, one FL patient had a CR unconfirmed, one diffuse large B-cell lymphoma patient had a PR, and one WM patient had a PR) for an ORR of 19% (95% CI, 5% to 42%). Grade 3 toxicity included thrombocytopenia (47%), gastrointestinal (20%), fatigue (13%), neutropenia (10%), and peripheral neuropathy (5%). Grade 4 toxicity occurred in nine patients (15%), and three deaths from progression of disease occurred within 30 days of withdrawal from study. CONCLUSION: Bortezomib showed promising activity in relapsed mantle-cell lymphoma and encouraging results in other B-cell lymphomas. Future studies will explore bortezomib in combination with other cytotoxic or biologic agents.     

Midterm Outcomes of Revisional Surgery for Gastric Pouch and Gastrojejunal Anastomotic Enlargement in Patients with Weight Regain After Gastric Bypass for Morbid Obesity

Reoperative surgery for the morbidly obese has become increasingly common due to postoperative weight regain. There are limited studies evaluating the effectiveness of revisional surgery. This study evaluates the weight loss outcomes of revisional surgery over a 2-year period at our University Hospital, USA. Of the 412 patients who underwent laparoscopic bariatric surgery between June 2009 and June 2011, we identified 25 patients who had Roux-en-Y gastric bypass (RYGB) originally, who underwent laparoscopic revisional surgery for weight regain. Preoperative and postoperative data were reviewed. Statistical analysis was performed using paired t test. This study includes 0 male and 25 female patients with an average age of 42 (range min to max: 28–58), mean original body mass index (BMI) of 54.6 kg/m² (r?=?37.3–80.7), average lowest BMI achieved of 32.2 (r?=?20.1–50.9), and average BMI at the time of revision of 41.0 kg/m² (r?=?29.5–60.7, standard deviation (SD)?=?8.5). All laparoscopic revisions consisted of resizing the gastric pouch by resection and recreating the gastrojejunostomy. Average hospital length of stay was 1.28 days (r?=?1–4). Perioperative morbidity was 8 %; one patient developed a trocar site hernia which required repair, and another suffered postoperative bleeding requiring transfusion. There was no mortality. Postoperative BMI averages at 3, 6, 9, 12, and 24 months were 35.0 (SD?=?7.15), 34.7 (SD?=?4.26), 36.2 (SD?=?7.63), 33.0 (SD?=?6.58), and 44.2 (SD?=?12.87), respectively. Statistically significant weight loss was achieved at 3 [t (10)?=?6.74, p?<?0.05], 6 [t (7)?=?4.69, p?<?0.05], 9 [t (9)?=?2.94, p?<?0.05], and 12 [t (6)?=?3.78, p?<?0.05] months. However, there was no statistically significant weight loss at 24 months postoperatively [t (4)?=??0.16, p?>?0.05]. Laparoscopic revisional bariatric surgery can be performed with significant weight loss up to 1 year postoperatively. However, additional studies are required to evaluate longer-term success.     

Novel Mutations in the Amyloid Precursor Protein Gene within Moroccan Patients with Alzheimer's Disease

In Morocco, Alzheimer's disease (AD) affects almost 30,000 individuals, and this number could increase to 75,000 by 2020. To our knowledge, the genes predisposing individuals to AD and predicting disease incidence remain elusive. In this study, we aimed to evaluate the genetic contribution of mutations in the amyloid precursor protein (APP) gene exons 16 and 17 to familial and sporadic AD cases. Seventeen sporadic cases and eight family cases were seen at the memory clinic of the University of Casablanca Neurology Department. These patients underwent standard somatic neurological examination, cognitive function assessment, brain imaging, and laboratory tests. Direct sequencing of exons 16 and 17 of the APP gene was performed on genomic DNA of AD patients. In this original Moroccan study, we identified seven novel frameshift mutations in exons 16 and 17 of the APP gene. Interestingly, only one novel splice mutation was detected in a family case. There is a strong correlation between clinical symptoms and genetic factors in Moroccan patients with a family history of AD. Therefore, mutations in APP gene exons 16 and 17 may eventually become genetic markers for AD predisposition.     

Disrupted local innervation results in less VIP expression in CF mice tissues

Vasoactive Intestinal Peptide (VIP) is the major physiological agonist of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) chloride channel activity. VIP functions as a neuromodulator and neurotransmitter secreted by neurons innervating all exocrine glands. VIP is also a potent vasodilator and bronchodilator that regulates exocrine gland secretions, contributing to local innate defense by stimulating the movement of water and chloride transport across intestinal and tracheobronchial epithelia. Previous human studies have shown that the rich intrinsic neuronal networks for VIP secretion around exocrine glands could be lost in tissues from patients with cystic fibrosis. Our research has since confirmed, in vitro and in vivo, the need for chronic VIP exposure to maintain functional CFTR chloride channels at the cell surface of airways and intestinal epithelium, as well as normal exocrine tissues morphology [1]. The goal of the present study was to examine changes in VIP in the lung, duodenum and sweat glands of 8- and 17-weeks old F508del/F508del mice and to investigate VIPergic innervation in the small intestine of CF mice, before important signs of the disease development. Our data show that a low amount of VIP is found in CF tissues prior to tissue damage. Moreover, we found a specific reduction in VIPergic and cholinergic innervation of the small intestine. The general innervation of the primary and secondary myenteric plexus was lost in CF tissues, with the presence of enlarged ganglionic cells in the tertiary layer. We propose that low amount of VIP in CF tissues is due to a reduction in VIPergic and cholinergic innervation and represents an early defect that constitutes an aggravating factor for CF disease progression.     

Frequency of Mammary Artery Coiling in Single-Ventricle Patients and Future Coronary Artery Grafting

Pre-Fontan coil closure of aorto-pulmonary collaterals decreases single-ventricle volume load and improves outcome. Coiling of right and left internal mammary arteries may present a challenge to cardiothoracic surgery teams caring for these patients when future coronary artery bypass grafting is needed for SV patients. The goal of this study was to determine the frequency of internal mammary artery coil closure in SV patients in a single tertiary care center. A retrospective review of all pediatric single-ventricle patients who underwent cardiac catheterization between March 2009 and October 2015 at Rush Center for Congenital Heart Disease was performed. Fifty-one patients’ charts were reviewed. Twenty-five patients received coil closure of one or more internal mammary artery (coil group) and 26 received no coil closure (no-coil group). In the coil group, 21 (84 %) had their collateral vessels coiled in the pre-Fontan period and 4 (16 %) had their vessels coiled in the post-Fontan period. In the coil group, 18 (72 %) had their right internal mammary artery coiled and 7 (28 %) had both right and left internal mammary arteries coiled. None of the coil group had isolated coil closure of the left internal mammary artery. This study is the first to verify the frequency of right and/or left internal mammary artery coil closure in SV patients and the potential impact on future coronary artery bypass grafting. Extensive peri-Fontan coiling of the internal mammary arteries presents a significant potential challenge for subsequent management of SV patients as older adults.