Evaluation of cellular viability by quantitative autoradiographic study of myocardial uptake of a fatty acid analogue in isoproterenol-induced focal rat heart necrosis

Previous studies led us to hypothesize that a fatty acid analogue, 15-p-iodophenyl--methyl pentadecanoic acid (IMPPA or BMIPP), which is taken up but not quickly metabolized by heart cells, would be a more suitable tracer of cellular viability than thallium-201. Biodistribution studies of 1-¹⁴C-IMPPA in conscious, freely moving rats showed that the concentration ratio of radioactivity in the heart with respect to the blood was about 8 for at least 60 min after intravenous administration, permitting its use as a putative tracer in these conscious, freely moving rats. Thereafter, the myocardial uptake of¹⁴C-IMPPA was studied in isoproterenol-treated rats (daily treatment for 10 days in order to induce cardiac hypertrophy and necrotic foci) with respect to control ones. Comparison of myocardial localizations by quantitative autoradiography of the uptake of²⁰¹Tl and¹⁴C-IMPPA with that of triphenyltetrazolium chloride (TTC) staining enabled comparative evaluation of nutritional blood flow, localization and uptake of¹⁴C-IMPPA and necrotic foci size. Distributions of¹⁴C-IMPPA and²⁰¹1 T1 in control rats' hearts were homogeneous, like TTC staining. In infarcted hearts, areas of decreased¹⁴C-IMPPA uptake were nearly the same (100%±5%) as those unstained by TTC. These areas were larger than those showing a decrease in thallium uptake (about 70%±5% of the total scar size). Therefore, IMPPA seems to be a more accurate and sensitive indicator of necrosis localization compared with thallium. It may be a useful agent for assessment of myocardial viability by single photon emission tomography (SPET) imaging.     

Iatrogenic Thyrotoxicosis: Causal Circumstances, Pathophysiology, and Principles of Treatment—Review of the Literature

Thyrotoxicosis is the clinical syndrome that results when tissues are exposed to high levels of circulating thyroid hormones. In most instances thyrotoxicosis is due to hyperthyroidism, a term reserved for disorders characterized by overproduction of thyroid hormones by the thyroid gland. Nevertheless, thyrotoxicosis may also result from a variety of conditions other than thyroid hyperfunction. The present report focuses on the etiologies, pathophysiology, and treatment of iatrogenic thyrotoxicosis. Iatrogenic thyrotoxicosis may be caused by (1) subacute thyroiditis (a result of lymphocytic infiltration, cellular injury, trauma, irradiation) with release of preformed hormones into circulation; (2) excessive ingestion of thyroid hormones (“thyrotoxicosis factitia”); (3) iodine-induced hyperthyroidism (radiologic contrast agents, topical antiseptics, other medications). Among these causes of iatrogenic thyrotoxicosis, that induced by the iodine overload and cytotoxicity associated with amiodarone represents a significant challenge. Successful management of amiodarone-induced thyrotoxicosis requires close cooperation between endocrinologists and endocrine surgeons. Surgical treatment may have a leading yet often underestimated role in view of the potential life-threatening severity of this disease, whereas others kinds of iatrogenic thyrotoxicosis are usually treated conservatively.     

Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial.

PURPOSE: This randomized, 2 x 2 factorial study compared a semimonthly (LVFU2) with a monthly (FULV) regimen of fluorouracil and leucovorin and 24 versus 36 weeks of each regimen as adjuvant treatment of patients with stage II (Dukes' B2) and III (Dukes' C) colon cancer. PATIENTS AND METHODS: LVFU2 was administered semi-monthly for 2 consecutive days as dl- or l-leucovorin (200 or 100 mg/m2, respectively) as a 2-hour infusion, followed by a 400 mg/m2 FU bolus and 600 mg/m2 of FU as a 22-hour continuous infusion. FULV was administered monthly for 5 consecutive days as a 15-minute infusion of dl- or l-leucovorin, followed by 400 mg/m2 of FU as a 15-minute infusion. RESULTS: A total of 905 patients were randomly assigned. The median follow-up was 41 months. Disease-free survival was similar between the LVFU2 and FULV groups (127 v 124 events; hazard ratio [HR] = 1.04; P =.74) and between 24 and 36 weeks of therapy (128 v 123 events; HR = 0.94; P =.63). Analysis of overall survival showed a slight excess in the number of deaths in LVFU2 compared with FULV (73 v 59), but this difference was not statistically significant (HR = 1.26; 95% confidence interval, 0.90 to 1.78; P =.18). The most commonly observed grade 3 to 4 toxicities were neutropenia, diarrhea, and mucositis. Toxicities were significantly lower in the LVFU2 group (all toxicities, P <.001). CONCLUSION: Our data confirm that LVFU2 is less toxic than FULV. At a median follow-up of 41 months, no statistically significant difference could be detected in disease-free or overall survival between the treatment groups or treatment durations.     

Analysis of the p21 gene in gliomas

The p21 gene encodes a cyclin dependent kinase inhibitor protein (p21) which has a tumor suppressive activity in a variety of tumor cell lines. Since, the p21 gene is up-regulated by the p53 tumor suppressor gene, which is frequently mutated in gliomas, acting therefore in the same control pathway, it constitutes a good candidate gene to be also inactivated in these tumors. To test this hypothesis, DNAs from 81 gliomas (48 glioblastomas, 11 anaplastic astrocytomas, 10 low-grade astrocytomas, 12 oligodendrogliomas and mixed gliomas), were investigated for mutations in the p21 coding sequence by denaturant gradient gel electrophoresis followed by sequencing. All these tumors have been previously screened for p53 mutations. Three different DNA variants were identified on codon 31 (17 cases), 27 (1 case) and 117 (1 case) and shown to be also present in matching constitutional DNA, suggesting they were polymorphisms. None of the tumors demonstrated a somatic mutation. No significant correlation between the presence of a p21 variant and the p53 mutation tumor status was observed. In conclusion, mutation in the p21 gene unlikely contributes to the development of gliomas.     

Morbid obesity: laparoscopic gastroplasty prior to plastic surgery

OBJECTIVES: Reduction of the weight in obese patients is a pre-condition for the aesthetic improvement of obesity or its after effects by plastic surgery. The aim of this study was to evaluate the effectiveness and advantages of gastric banding, using a ring positioned under laparoscopic guidance. PATIENTS AND METHODS: Thirty-nine patients with morbid obesity were operated on. For the first nine patients, gastric restriction was obtained by Mason's traditional technique. In the remaining thirty, a Kuzmak ring was positioned a few centimeters under the cardia, under laparoscopic guidance. The study concerned the evolution of weight, associated pathologies, and complications. RESULTS: Three months after surgery, all patients had lost weight (mean loss: 15 kg). At six months, a mean weight loss of 26 kg was observed. At one year, the mean weight loss was 35 kg. Two patients experienced postprandial vomiting that justified widening of the ring; one ring was poorly tolerated and was removed 10 days after surgery. CONCLUSION: This new surgical technique is effective for reducing the weight of obese patients. The laparoscopic approach to the stomach reduces parietal complications and enables subsequent abdominal plastic surgery to be performed.     

Irinotecan plus oxaliplatin and leucovorin-modulated fluorouracil in advanced pancreatic cancer--a Groupe Tumeurs Digestives of the Federation Nationale des Centres de Lutte Contre le Cancer study.

PURPOSE: To evaluate response rate and toxicity of irinotecan and oxaliplatin plus fluorouracil (FU) and leucovorin (Folfirinox) in advanced pancreatic adenocarcinoma (APA). PATIENTS AND METHODS: Chemotherapy-naive patients with histologically proven APA and bidimensionally measurable disease were treated with Folfirinox therapy every 2 weeks, which comprised oxaliplatin 85 mg/m(2) and irinotecan 180 mg/m(2) plus leucovorin 400 mg/m(2) followed by bolus FU 400 mg/m(2) on day 1, then FU 2,400 mg/m(2) as a 46-hour continuous infusion. Quality of life (QOL) was assessed using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30). RESULTS: Forty-seven patients were entered, and 46 received treatment. Thirty-five patients (76%) had metastatic disease. A total of 356 cycles were delivered, with a median of eight cycles per patient (range, one to 24 cycles). All patients were assessable for safety. No toxic death occurred. Grade 3 to 4 neutropenia occurred in 52% of patients, including two patients with febrile neutropenia. Other relevant toxicities included grade 3 to 4 nausea (20%), vomiting (17%), and diarrhea (17%) and grade 3 neuropathy (15%; Levi's scale). The confirmed response rate was 26% (95% CI, 13% to 39%), including 4% complete responses. Median time to progression was 8.2 months (95% CI, 5.3 to 11.6 months), and median overall survival was 10.2 months (95% CI, 8.1 to 14.4 months). Between baseline and end of treatment, patients had improvement in all functional scales of the EORTC QLQ-C30, except cognitive functioning. Responders had major improvement in global QOL. CONCLUSION: With a good safety profile, a promising response rate, and an improvement in QOL, Folfirinox will be further assessed in a phase III trial.     

Evaluation of radiation-induced oral mucositis by optical coherence tomography.

PURPOSE: Optical coherence tomography (OCT) imaging was evaluated to determine if radiation-induced mucosal damage could be noninvasively monitored in real time and correlated with histopathologic findings. EXPERIMENTAL DESIGN: Female C3H mice, ages 7 to 9 weeks, four per group, were immobilized in a custom-made Lucite jig and received 0, 15, 22.5, and 25 Gy in a single fraction to their oral cavity. OCT images were acquired of proximal, middle, and distal aspects of the dorsum of the tongue on days 0, 1, 3, 5, and 7 post-irradiation. Animals were sacrificed on day 7 and samples taken for histologic evaluation. OCT images were visually examined and also quantified by image analysis and compared with histologic findings. RESULTS: Tongues removed 7 days post-irradiation showed no visible damage; however, upon staining with toluidine blue, ulcers at the base of the tongue became visible (100% for 25 Gy, 75% after 22.5 Gy, and 0% after 15 Gy). Visual inspection of OCT images qualitatively compared with histologic findings and quantitative image analysis of the OCT images (effective light penetration depth) revealed significant changes 7 days post-irradiation compared with unirradiated controls for the base of the tongue. CONCLUSIONS: OCT allows for direct noninvasive real-time acquisition of digitally archivable images of oral mucosa and can detect radiation-induced changes in the mucosa before visual manifestation. OCT may be a useful technique to quantify subclinical radiation-induced mucosal injury in experimental chemoradiation clinical trials.     

Total soluble HLA class I and soluble HLA-G in multiple myeloma and monoclonal gammopathy of undetermined significance.

Serum beta2-microglobulin, the light chain of the HLA class I molecular complex, remains one of the best survival prognostic factors in multiple myeloma, but other HLA class I molecules might be of interest in monoclonal gammopathies. In this study, we evaluate total soluble HLA class I (HLA-Is) and soluble HLA-G (HLA-Gs) in 103 patients with newly diagnosed multiple myeloma, 30 patients with monoclonal gammopathy of undetermined significance (MGUS), and 30 healthy subjects, studying their prognostic value in multiple myeloma. In multiple myeloma patients, HLA-Is and HLA-Gs median values were 0.8 microg/mL and 28 ng/mL, respectively. Median HLA-Is concentration was higher in stage II and III multiple myeloma patients than in stage I multiple myeloma, MGUS, and control patients. Median HLA-Gs was significantly lower in healthy controls than in MGUS and multiple myeloma patients. A high level of HLA-Is (> or =2.1 microg/mL) was predictive of short survival (P = 0.017). For each given level of beta2-microglobulin, the relative risk of death was higher for patients with HLA-Is > or = 2.1 microg/mL than in patients with a lower level (P = 0.047). HLA-Gs, a marker of monoclonal gammopathy, was of no prognostic value, but the addition of HLA-Is to beta2-microglobulin produced an efficient prognostic score (P < 0.0001). HLA-Is is a new marker of multiple myeloma tumor load and provides additional survival prognostic information to beta2-microglobulin.     

Baseline Brain Metabolism in Resistant Depression and Response to Transcranial Magnetic Stimulation

Neuroimaging studies of patients with treatment-resistant depression (TRD) have reported abnormalities in the frontal and temporal regions. We sought to determine whether metabolism in these regions might be related to response to repetitive transcranial magnetic stimulation (TMS) in patients with TRD. Magnetic resonance images and baseline resting-state cerebral glucose uptake index (gluMI) obtained using ¹⁸F-fluorodeoxyglucose positron emission tomography were analyzed in TRD patients who had participated in a double-blind, randomized, sham-controlled trial of prefrontal 10 Hz TMS. Among the patients randomized to active TMS, 17 responders, defined as having 50% depression score decrease, and 14 nonresponders were investigated for prestimulation glucose metabolism and compared with 39 healthy subjects using a voxel-based analysis. In nonresponders relative to responders, gluMI was lower in left lateral orbitofrontal cortex (OFC), and higher in left amygdala and uncinate fasciculus. OFC and amygdala gluMI negatively correlated in nonresponders, positively correlated in responders, and did not correlate in healthy subjects. Relative to healthy subjects, both responders and nonresponders displayed lower gluMI in right dorsolateral prefrontal (DLPFC), right anterior cingulate (ACC), and left ventrolateral prefrontal cortices. Additionally, nonresponders had lower gluMI in left DLPFC, ACC, left and right insula, and higher gluMI in left amygdala and uncus. Hypometabolisms were partly explained by gray matter reductions, whereas hypermetabolisms were unrelated to structural changes. The findings suggest that different patterns of frontal–temporal–limbic abnormalities may distinguish responders and nonresponders to prefrontal magnetic stimulation. Both preserved OFC volume and amygdala metabolism might precondition response to TMS.