Delayed disease progression after allogeneic cell vaccination in hormone-resistant prostate cancer and correlation with immunologic variables.

PURPOSE: There are a significant number of patients with asymptomatic hormone-resistant prostate cancer who have increasing prostate-specific antigen (PSA) levels but little or no evaluable disease. The immunogenicity and minimal toxicity associated with cell-based vaccine therapy makes this approach attractive for these patients. EXPERIMENTAL DESIGN: We have evaluated a vaccine comprising monthly intradermal injection of three irradiated allogeneic prostate cell lines (8 x 10(6) cells each) over 1 year. The first two doses were supplemented with bacille Calmette-Guérin as vaccine adjuvant. Twenty-eight hormone-resistant prostate cancer patients were enrolled. Patients were assessed clinically and PSA levels were measured monthly. Radiologic scans (X-ray, computed tomography, and bone scan) were taken at baseline and at intervals throughout the treatment period. Comprehensive monthly immunologic monitoring was undertaken including proliferation studies, activation markers, cytokine protein expression, and gene copy number. This longitudinal data was analyzed through predictive modeling using artificial neural network feed-forward/back-propagation algorithms with multilayer perceptron architecture.RESULTS: Eleven of the 26 patients showed statistically significant, prolonged decreases in their PSA velocity (PSAV). None experienced any significant toxicity. Median time to disease progression was 58 weeks, compared with recent studies of other agents and historical control values of around 28 weeks. PSAV-responding patients showed a titratable T(H)1 cytokine release profile in response to restimulation with a vaccine lysate, while nonresponders showed a mixed T(H)1 and T(H)2 response. Furthermore, immunologic profile correlated with PSAV response by artificial neural network analysis. We found predictive power not only in expression of cytokines after maximal stimulation with phorbol 12-myristate 13-acetate, but also the method of analysis (qPCR measurement of IFN-gamma > qPCR measurement tumor necrosis factor-alpha > protein expression of IFN-gamma > protein expression of interleukin 2). CONCLUSIONS: Whole cell allogeneic vaccination in hormone-resistant prostate cancer is nontoxic and improves the natural history of the disease. Longitudinal changes in immunologic function in vaccinated patients may be better interpreted through predictive modeling using tools such as the artificial neural network rather than periodic "snapshot" readouts.     

Biliary dyskinesia: the most common indication for cholecystectomy in children

BACKGROUND: The purpose of this study is to examine the current indications for cholecystectomy in children and to evaluate the results after such surgery. METHODS: Retrospective analysis of 107 consecutive cholecystectomies performed in children at the Children's Hospital of Illinois between October 1998 and September 2003. Hospital medical charts and outpatient clinic charts were reviewed. Patients' families were contacted by telephone to obtain longer-term follow-up. Results were analyzed with SPSS 12.0 for Windows (SPSS Inc, Chicago, Ill). RESULTS: Biliary dyskinesia (BD) was the indication for surgery for 62 (58%) of the 107 children who underwent cholecystectomy during the study period. Gallbladder calculus (GC) disease was the next most common indication with 29 (27%) children. The duration of symptoms was longer for BD. The most common presenting symptom in both groups was abdominal pain. Food intolerance was reported by 45% of patients with BD, significantly higher than patients with GC. Mean length of stay after cholecystectomy was 17 hours and 45 hours for BD and GC, respectively. Short-term follow-up showed relief or improvement of symptoms in 85% of children with BD and in 97% with GC. There were no deaths. Two (1.9%) children of the total of 107 developed complications; both had intra-abdominal abscesses. Most patients had complete or considerable long-term improvement in symptoms. CONCLUSIONS: Biliary dyskinesia was the most common indication for cholecystectomy in children in our study. More than half of the surgeries were performed on an outpatient basis. Morbidity was minimal and mortality was zero. We had satisfactory short- and long-term symptom resolution with long-term patient satisfaction reaching 95%.     

Epilepsy surgery outcome in children with tuberous sclerosis complex evaluated with alpha-[11C]methyl-L-tryptophan positron emission tomography (PET)

Tuberous sclerosis complex is commonly associated with medically intractable seizures. We previously demonstrated that high uptake of alpha-[11C]methyl-L-tryptophan (AMT) on positron emission tomography (PET) occurs in a subset of epileptogenic tubers consistent with the location of seizure focus. In the present study, we analyzed the surgical outcome of children with tuberous sclerosis complex in relation to AMT PET results. Seventeen children (mean age 4.7 years) underwent epilepsy surgery, guided by long-term videoelectroencephalography (EEG) (including intracranial EEG in 14 cases), magnetic resonance imaging (MRI), and AMT PET. AMT uptake values of cortical tubers were measured using regions of interest delineated on coregistered MRI and were divided by the value for normal-appearing cortex to obtain an AMT uptake ratio. Based on surgical outcome data, tubers showing increased AMT uptake (uptake ratio greater than 1.00) were classified into three categories: (1) epileptogenic (tubers within an EEG-defined epileptic focus whose resection resulted in seizure-free outcome), (2) nonepileptogenic (tubers that were not resected but the patient became seizure free), or (3) uncertain (all other tubers). Increased AMT uptake was found in 30 tubers of 16 children, and 23 of these tubers (77%) were located in an EEG-defined epileptic focus. The tuber with the highest uptake was located in an ictal EEG onset region in each patient. Increased AMT uptake indicated an epileptic region not suspected by scalp EEG in four cases. Twelve children (71%) achieved seizure-free outcome (median follow-up 15 months). Based on outcome criteria, 19 of 30 tubers (63%) with increased AMT uptake were epileptogenic, and these tubers had significantly higher AMT uptake than the nonepileptogenic ones (P = .009). Tubers with at least 10% increase of AMT uptake (in nine patients) were all epileptogenic. Using a cutoff threshold of 1.02 for AMT uptake ratio provided an optimal accuracy of 83% for detecting tubers that needed to be resected to achieve a seizure-free outcome. The findings suggest that resection of tubers with increased AMT uptake is highly desirable to achieve seizure-free surgical outcome in children with tuberous sclerosis complex and intractable epilepsy. AMT PET can provide independent complementary information regarding the localization of epileptogenic regions in tuberous sclerosis complex and enhance the confidence of patient selection for successful epilepsy surgery.     

A Ser49Cys variant in the ataxia telangiectasia, mutated, gene that is more common in patients with breast carcinoma compared with population controls

BACKGROUND: Mothers of children who have ataxia telangiectasia have been reported to be at increased risk for development of breast carcinoma. To test whether sequence variants in the ataxia telangiectasia, mutated, gene (ATM) are associated with breast carcinoma, the authors compared the frequency of ATM cDNA sequence changes in patients with breast carcinoma with the corresponding frequency in control patients. METHODS: The authors sequenced ATM cDNA from 91 patients with breast carcinoma and compared the frequencies of sequence changes in these patients with the corresponding frequencies in a control sample of 940 individuals with no history of malignant disease. RESULTS: Thirty-five patients with breast carcinoma had one or more single-base changes in ATM. Three genetic variants were found in at least two patients. These variants resulted in Asp1853Asn, Pro1054Arg, or Ser49Cys amino acid substitutions in the ATM protein. The Ser49Cys variant was more common in patients with breast carcinoma than in the control patients, with respective frequencies of 6.7% (5 of 75 patients) and 1.3% (12 of 940 patients; P=0.006; Fisher two-sided exact test). The subgroup of patients with bilateral breast carcinoma had a Ser49Cys frequency of 11.8% (2 of 17 patients), which again was significantly different from what was observed in the control group (P=0.024; Fisher two-sided exact test). The allele frequencies of the other two variants were not different between case patients and control patients. CONCLUSIONS: Patients with breast carcinoma, particularly those with bilateral disease, were more likely to have a variant in the ATM gene that resulted in a Ser49Cys substitution in the gene product. Additional studies are needed to evaluate the potential functional consequences of the Ser49Cys substitution and confirm the relevance of this variant in the development of breast carcinoma.