Hemispheric asymmetries in arousal affect outcome of the intracarotid amobarbital test.

OBJECTIVE: To evaluate changes in arousal and their impact on memory performance during the intracarotid amobarbital test (IAT). METHODS: Along with memory measures, level of arousal was evaluated through clinical ratings and nonverbal self-ratings in epilepsy patients undergoing IAT before anterior temporal lobectomy. RESULTS: Irrespective of seizure focus, left-sided amobarbital injection resulted in decreased objective and subjective arousal more often than right-side injection. Impaired objective arousal was greater when the left hemisphere was injected second, because of the presumed additive effects of systemic amobarbital residual from the first injection. Decreased objective arousal was related to poorer performance on memory testing following left-hemisphere injection. CONCLUSIONS: The IAT, as practiced in most centers, is biased, so patients with right temporal lobe seizure focus are more likely to "pass" the test, whereas patients with left seizure focus are more likely to "fail" the test. The significant impact of changes in arousal on memory testing needs to be considered when using IAT results to select patients for temporal lobectomy.     

Surgical repair of retinal detachment secondary to cytomegalovirus retinitis

BACKGROUND AND OBJECTIVE: This study was conducted to determine preoperative predictors of postoperative visual acuity in patients with acquired immunodeficiency syndrome (AIDS) and cytomegalovirus (CMV) retinitis and retinal detachment. PATIENTS AND METHODS: The study design was a retrospective chart review of 38 eyes in 33 patients with AIDS and CMV retinitis who had retinal reattachment surgery by pars plana vitrectomy with the use of silicone oil tamponade. Factors considered included: preoperative visual acuity, macular attachment status and CMV activity at the time of surgery, and length of time from diagnosis of retinal detachment to surgical repair. RESULTS: Retinal reattachment was achieved in 37 of 38 eyes. Mean interval from surgery to best corrected visual acuity (VA) was 9 weeks. The mean best corrected post-op VA was 20/70. Approximately half of the patients died within 7 months of the surgery. There was good correlation between preoperative VA and best attained postoperative VA (Spearman's: r = 0.5139, P = 0.001). The interval from retinal detachment to surgery, and best attained postoperative VA did not correlate (Spearman's: r = 0.2339, P=0.158). The lack of macular CMV retinitis correlated well with postoperative VA (P = 0.0066, Wilcoxon rank-sum test). CONCLUSIONS: Preoperative visual acuity and macular attachment status correlates with better postoperative visual acuity results, whereas early surgical repair of retinal detachment does not.     

Synthesis and pharmacology of site-specific cocaine abuse treatment agents: 2-(aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane dopamine uptake inhibitors

As part of a program to develop site-specific medications for cocaine abuse, a series of 2-(aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane derivatives was synthesized and tested for inhibitory potency in [3H]WIN 35,428 binding and [3H]dopamine uptake assays using rat striatal tissue. Selected compounds were tested for their ability to substitute for cocaine in rat drug discrimination tests. Synthesis was accomplished by a series of Diels-Alder reactions, using cis- and trans-cinnamic acid derivatives (nitrile, acid, acid chloride) with cyclohexadiene and cyclopentadiene. Standard manipulations produced the aminomethyl side chain. Many of the compounds bound with high affinity (median IC50 = 223 nM) to the cocaine binding site as marked by [3H]WIN 35,428. Potency in the binding assay was strongly enhanced by chlorine atoms in the 3- and/or 4-position on the aromatic ring and was little affected by corresponding methoxy groups. In the [2.2.2] series there was little difference in potency between cis and trans compounds or between N, N-dimethylamines and primary amines. In the [2.2.1] series the trans exo compounds tended to be least potent against binding, whereas the cis exo compounds were the most potent (4-Cl cis exo: IC50 = 7.7 nM, 27-fold more potent than 4-Cl trans-exo). Although the potencies of the bicyclic derivatives in the binding and uptake assays were highly correlated, some of the compounds were 5-7-fold less potent at inhibiting [3H]dopamine uptake than [3H]WIN 35,428 binding (for comparison, cocaine has a lower discrimination ratio (DR) of 2.5). The DR values were higher for almost all primary amines and for the trans-[2.2.2] series as compared to the cis-[2.2.2]. Most of the compounds had Hill coefficients approaching unity, except for the [2. 2.2] 3,4-dichloro derivatives, which all had nH values of about 2.0. Two of the compounds were shown to fully substitute for cocaine in drug discrimination tests in rats, and one had a very long duration of action.     

Laser Induced Autofluorescence Diagnosis of Bladder Cancer

Purpose

We assessed the ability of laser induced autofluorescence to differentiate malignant from nonmalignant bladder lesions.

Materials and Methods

We studied 53 patients with bladder cancer undergoing mucosal biopsies or transurethral resection of a bladder tumor. A quartz optical fiber was advanced through the working channel of a cystoscope and placed in gentle contact with the bladder. Tissue fluorescence was excited by 337 nm. light pulses (nitrogen laser). One fiber was used for transmission of the excitation and emission (fluorescence) light. An optical multichannel analyzer system was used to record fluorescence spectra of the sites of interest.

Results

We analyzed the fluorescence spectra of 114 bladder areas (1 carcinoma in situ as well as 28 malignant, 35 inflammatory, 7 dysplastic, 1 squamous metaplastic and 42 normal areas). These lesions included 44 difficult to diagnose suspicious tumors (11 malignant and 33 nonmalignant). We developed an algorithm that used the I385:I455 nm. fluorescence ratio to distinguish malignant from nonmalignant lesions, including inflammatory areas. By analyzing the data on all 114 lesions, we noted the sensitivity, specificity, and positive and negative predictive values of this method for differentiating malignant from nonmalignant bladder lesions to be 97, 98, 93 and 99 percent, respectively.

Conclusions

Under excitation with 337 nm. light a clear differentiation between malignant and nonmalignant bladder tissues can be made using the I385:I455 nm. autofluorescence ratio.     

Accumulation of exogenous polyamines in gerbil brain after ischemia

Regionally selective delayed neuronal degeneration is a characteristic sequel of cerebral ischemia. Recent evidence indicates that changes in brain polyamine metabolism may be critical for nerve cell survival after ischemia. Within hours after ischemia, intracellular putrescine levels are greatly increased and remain elevated for days, whereas only minor changes are noted in the levels of the polyamines spermine and spermidine. In contrast, the extracellular levels of all polyamines are low after ischemia. Injections of polyamines following ischemia, however, can protect neurons in the gerbil brain from delayed cell death, with spermine being the most potent of the polyamines. In the present study, therefore, we sought to determine if increased polyamine uptake occurs in the brain after ischemia. In the hippocampal slice preparation, temperature-dependent uptake was unique for spermine, but not for spermidine or putrescine. Uptake of [¹⁴C]spermine was transiently increased after ischemia, peaking at 150% of control by 12–13 h and subsiding by 24 h. Intravenous injections of [³H]spermidine resulted in a postischemic accumulation of this polyamine throughout the forebrain parenchyma. We conclude that:

1. Active cellular uptake of spermine is transiently increased early after ischemia;
2. A nonspecific accumulation of exogenous polyamines occurs early after ischemia probably owing to a compromised blood-brain barrier, and
3. The findings indicate that exogenous polyamines can exert their effect directly in the brain after ischemia.

     

Decision-making process in abdominal surgery in the geriatric patient

The high rates of abdominal disorders in a growing population of geriatric patients and the greater willingness of the surgeon to cope with major problems in the elderly are factors contributing to a steady increase in abdominal procedures in this group. Four hundred consecutive major abdominal surgical procedures in patients over 70 years of age were submitted for computer analysis, the purpose of which was to determine the principal factors affecting mortality and morbidity. The etiological profile of abdominal surgery in the elderly was characterized by a high percentage of procedures related to the biliary tract, with the second largest group being those for intestinal obstruction due to benign and malignant conditions. The decision-making process in geriatric surgery is of great importance, requiring consideration of ethical, medico-legal and economic factors in addition to the purely medical ones. Analysis of data presented in this series leads to the following conclusions:

1. There is a declining mortality rate in all elective operations in the elderly, in the absence of widespread malignancy.
2. Timing is all important in abdominal emergencies in the elderly, and early operations are usually more successful than either immediate or delayed operations.
3. Definitive procedures are sometimes both safer and more cost effective than minimal procedures performed under such circumstances.
4. The principal factors leading to high mortality rates are the presence of malignancy, generalized peritonitis, and moderate-to-severe involvement of life-support systems.

     

Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II Trial.

PURPOSE: To determine the response rate, time to disease progression, survival duration and rate, and toxicity with the combination of cetuximab and gemcitabine in patients with epidermal growth factor receptor (EGFR)-expressing advanced pancreatic cancer. PATIENTS AND METHODS: Patients with measurable locally advanced or metastatic pancreatic cancer who had never received chemotherapy for their advanced disease and had immunohistochemical evidence of EGFR expression were eligible for the multicenter phase II trial. Patients were treated with cetuximab at an initial dose of 400 mg/m(2), followed by 250 mg/m(2) weekly for 7 weeks. Gemcitabine was administered at 1,000 mg/m(2) for 7 weeks, followed by 1 week of rest. In subsequent cycles, cetuximab was administered weekly, and gemcitabine was administered weekly for 3 weeks every 4 weeks. RESULTS: Sixty-one patients were screened for EGFR expression, 58 patients (95%) had at least 1+ staining, and 41 were enrolled onto the trial. Five patients (12.2%) achieved a partial response, and 26 (63.4%) had stable disease. The median time to disease progression was 3.8 months, and the median overall survival duration was 7.1 months. One-year progression-free survival and overall survival rates were 12% and 31.7%, respectively. The most frequently reported grade 3 or 4 adverse events were neutropenia (39.0%), asthenia (22.0%), abdominal pain (22.0%), and thrombocytopenia (17.1%). CONCLUSION: Cetuximab in combination with gemcitabine showed promising activity against advanced pancreatic cancer. Further clinical investigation is warranted.     

A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer.

PURPOSE: Preclinical and clinical studies have demonstrated that inhibition of prenylation can radiosensitize cell lines with activation of Ras and produce clinical response in patients with cancer. The aim of this study was to determine the maximally tolerated dose of the dual farnesyltransferase and geranylgeranyltransferase I inhibitor L-778,123 in combination with radiotherapy for patients with locally advanced pancreatic cancer. EXPERIMENTAL DESIGN: L-778,123 was given by continuous intravenous infusion with concomitant radiotherapy to 59.4 Gy in standard fractions. Two L-778,123 dose levels were tested: 280 mg/m2/day over weeks 1, 2, 4, and 5 for dose level 1; and 560 mg/m2/day over weeks 1, 2, 4, 5, and 7 for dose level 2. RESULTS: There were no dose-limiting toxicities observed in the eight patients treated on dose level 1. Two of the four patients on dose level 2 experienced dose-limiting toxicities consisting of grade 3 diarrhea in one case and grade 3 gastrointestinal hemorrhage associated with grade 3 thrombocytopenia and neutropenia in the other case. Other common toxicities were mild neutropenia, dehydration, hyperglycemia, and nausea/vomiting. One patient on dose level 1 showed a partial response of 6 months in duration. Both reversible inhibition of HDJ2 farnesylation and radiosensitization of a study patient-derived cell line were demonstrated in the presence of L-778,123. K-RAS mutations were found in three of the four patients evaluated. CONCLUSIONS: The combination of L-778,123 and radiotherapy at dose level 1 showed acceptable toxicity in patients with locally advanced pancreatic cancer. Radiosensitization of a patient-derived pancreatic cancer cell line was observed.