Rapid-fractionation preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for resectable pancreatic adenocarcinoma

PURPOSE: To evaluate the toxicities, radiographic and pathologic responses, and event-free outcomes with combined modality treatment that involves preoperative rapid-fractionation chemoradiation, pancreaticoduodenectomy, and electron-beam intraoperative radiation therapy (EB-IORT) for patients with resectable pancreatic adenocarcinoma. PATIENTS AND METHODS: Patients with radiographically resectable localized adenocarcinoma of the pancreatic head were entered onto a preoperative protocol that consisted of a 2-week course of fluorouracil (5-FU) 300 mg/m2 daily 5 days per week and concomitant rapid-fractionation radiation 30 Gy, 3 Gy daily 5 days per week. Radiographic restaging was performed 4 weeks after chemoradiation, and patients with localized disease underwent pancreaticoduodenectomy with EB-IORT 10 to 15 Gy. RESULTS: Thirty-five patients were entered onto the study and completed chemoradiation, 34 (97%) as outpatients. Three patients (9%) experienced grade 3 nausea and vomiting; no other grade 3 or 4 toxicities were observed. Of the 27 patients taken to surgery, 20 patients (74%) underwent pancreaticoduodenectomy with EB-IORT. All patients had a less than grade III pathologic response to preoperative chemoradiation. At a median follow-up of 37 months, the 3-year survival rate in patients who underwent combined modality therapy was 23%. CONCLUSION: Combined modality treatment with preoperative rapid-fractionation chemoradiation, pancreaticoduodenectomy, and EB-IORT is associated with minimal toxicity and excellent locoregional control. This represents one approach to maximize the proportion of patients who receive all components of combined modality therapy and avoids the toxicity of pancreaticoduodenectomy in patients found to have metastatic disease at the time of restaging.     

Canine neosporosis: clinical signs, diagnosis, treatment and isolation of Neospora caninum in mice and cell culture

Clinical signs, diagnosis, treatment and isolation of Neospora caninum from two littermate dogs are described. Three of six pups from a Labrador bitch developed paralysis. Neosporosis was diagnosed ante mortem by serological examination in two of the affected pups. At necropsy, tissue cysts were seen in unstained smears and in histologic sections of their brains. Tissue cysts were often thin-walled (approximately 1 micron) but antigenically and ultrastructurally identified as N. caninum. Furthermore, N. caninum (isolates NC-4, NC-5) was isolated in mice and in cell cultures inoculated with neural tissues of these two dogs. Serological diagnosis of neosporosis using a variety of tests is discussed.     

Identification and characterization of the PutP proline permease that contributes to in vivo survival of Staphylococcus aureus in animal models

Staphylococcus aureus is an important pathogen of humans and other animals, causing bacteremia, abscesses, endocarditis, and other infectious syndromes. A signature-tagged mutagenesis (STM) system was adapted for use in studying the genes required for in vivo survival of S. aureus. An STM library was ultimately created in S. aureus RN6390, with Tn917 being used to create the transposon mutations. Pools of S. aureus RN6390 mutants were screened in mouse abscess, bacteremia, and wound infection models for growth attenuation after in vivo passage. One of the mutants that was identified displayed marked attenuation following large-pool screening in all three animal models, which was confirmed in bacteremia and endocarditis models of infection with a smaller pool of mutants. Sequence analysis of the entire open reading frame showed a 99% identity to the high-affinity proline permease (putP) gene characterized in another strain of S. aureus. In wound and murine abscess infection models, the putP mutant was approximately 10-fold more attenuated than was wild-type strain RN6390. Another S. aureus strain transduced with the putP mutation also displayed an attenuated phenotype after passage in the wound model. A [3H]proline uptake assay showed that less proline was specifically transported into the putP mutant than into strain RN6390. The reduced viability of the bacteria possessing the mutation in the S. aureus high-affinity proline permease suggests that proline scavenging by the bacteria is important for in vivo growth and proliferation and that analogs of proline may serve as potential antistaphylococcal therapeutic agents.     

Endotoxin and cytokines increase hepatic sphingolipid biosynthesis and produce lipoproteins enriched in ceramides and sphingomyelin

Alterations in triglyceride and cholesterol metabolism often accompany inflammatory diseases and infections. We studied the effects of endotoxin (lipopolysaccharide [LPS]) and cytokines on hepatic sphingolipid synthesis, activity of serine palmitoyltransferase (SPT), the first and rate-limiting enzyme in sphingolipid synthesis, and lipoprotein sphingolipid content in Syrian hamsters. Administration of LPS induced a 2-fold increase in hepatic SPT activity. The increase in activity first occurred at 16 hours, peaked at 24 hours, and was sustained for at least 48 hours. Low doses of LPS produced maximal increases in SPT activity, with half-maximal effect seen at approximately 0.3 microg LPS/100 g body weight. LPS increased hepatic SPT mRNA levels 2-fold, suggesting that the increase in SPT activity was due to an increase in SPT mRNA. LPS treatment also produced 75% and 2.5-fold increases in hepatic sphingomyelin and ceramide synthesis, respectively. Many of the metabolic effects of LPS are mediated by cytokines. Interleukin 1 (IL-1), but not tumor necrosis factor, increased both SPT activity and mRNA levels in the liver of intact animals, whereas both IL-1 and tumor necrosis factor increased SPT mRNA levels in HepG2 cells. IL- produced a 3-fold increase in SPT mRNA in HepG2 cells, and the half-maximal dose was 2 ng/mL. IL-1 also increased the secretion of sphingolipids into the medium. Analysis of serum lipoprotein fractions demonstrated that very low density lipoprotein, intermediate density lipoprotein, and low density lipoprotein isolated from animals treated with LPS contained significantly higher amounts of ceramide, glucosylceramide, and sphingomyelin. Taken together, these results indicate that LPS and cytokines stimulate hepatic sphingolipid synthesis, which results in an altered structure of circulating lipoproteins and may promote atherogenesis.     

Managing data caches using selective cache line replacement

As processor performance continues to improve, more demands are being placed on the performance of the memory system. The caches employed in current processor designs are very similar to those described in early cache studies. In this paper, a detailed characterization of data cache behavior for individual load instructions is given. It will be shown that by selectively allocating cache lines according the characteristics of individual load instructions, overall performance can be improved for both the data cache and the memory system. This approach can improve some aspects of memory performance by as much as 60 percent on existing executables. This work was supported by National Science Foundation Grants CCR-94-03651, CCR-92-13651, CCR-92-13627, MIP-92-57259, and generous grants from the SUN Microsystems and Tektronix corporations.     

Prognostic significance of allelic losses in primary melanoma

Loss of genetic material, including loss of loci on chromosome arms 6q, 9p, and 10q, occurs frequently in cutaneous melanoma but infrequently in benign melanocytic nevi or other melanocytic lesions, suggesting that these genetic alterations are important in the development and progression of melanoma. To examine whether allelic loss is of prognostic importance in melanoma, disease-free survival was related to loss of heterozygosity on 6q, 9p and 10q in 83 individuals with sporadic primary cutaneous melanoma. Loss of chromosome arms 6q and 10q were each significantly associated with a poorer clinical outcome (P=0.013 and P=0.001 respectively). In a subgroup of 41 subjects whose primary tumours were allelotyped, the fractional allelic loss (FAL) at 39 autosomal arms also significantly correlated with disease-free survival (P=0.013), with an increase in FAL associated with a poorer outcome; this association remained significant when controlled for tumour thickness (P=0.035). In addition, a greater proportion of cells were immunopositive for Ki67 antigen, p53 and p21WAF1 protein in the primary melanomas than in the benign melanocytic nevi, however, only p53 over-expression was significantly associated with improved survival (P=0.041).     

Radiation-induced temporary epilation after a neuroradiologically guided embolization procedure

A 34-year-old woman underwent embolization of a left paraorbital arteriovenous malformation guided with a bi-plane x-ray system in two sessions separated by 3 days. Imaging included 110 minutes of fluoroscopy and 46 digital subtraction angiography acquisitions. Entrance skin dose rates were determined with measurements performed on a skull phantom. The maximum possible skin dose was estimated to be 6.6 Gy, which is consistent with the temporary epilation in the right occipital region of the skull reported by the patient approximately 5 weeks later.     

Escherichia coli associated cellulitis in broilers: correlation with systemic infection and microscopic visceral lesions, and evaluation for skin trimming

In Alberta, cellulitis condemnations average 0.5% and are among the highest in Canada. Presently, all cellulitis-affected birds are condemned for fear of systemic infections and public health implications. In a slaughterhouse sample of 102 birds condemned with cellulitis, Escherichia coli was isolated from 83.3% of the lesions. All hearts were cultured and from 11.2% E. coli was recovered. Gross lesions of perihepatitis, infected oviducts, and arthritis were found in 11.2%, 6.7%, and 2.9% of the birds, respectively. Serotyping suggested that visceral infection occurs independent of cellulitis in at least half of the cases. There was no correlation between microscopic visceral lesions and positive bacterial cultures. Two E. coli isolates of serogroup 0157 produced no toxin and neither isolate produced CS31A, F107, or F1845 fimbriae. Cellulitis lesions ranged from 0.55 to 218.9 cm2. All lesions under 16 cm2 and 64% of lesions up to 48 cm2 were considered suitable for trimming.     

Quantitative electroencephalographic characteristics of crack cocaine dependence

This study replicates preliminary findings reporting a quantitative electroencephalographic (QEEG) profile of crack cocaine dependence in abstinence. All subjects (n = 52) met criteria for DMS-III-R cocaine dependence (in the form of crack), and were residing in a drug-free therapeutic community. Baseline QEEG evaluations were conducted at intake (5-10 days after last use of crack, and at follow-up (1 month after last reported use). Previous findings of significant excess of relative alpha power and deficit of absolute and relative delta and theta power were replicated in this expanded group. Abnormalities were greater in anterior than posterior regions, and disturbances in interhemispheric relationships were also observed. Further, QEEG showed little change in the interval between the first and second evaluations. This QEEG profile may reflect persistent alterations in neurotransmission as a possible consequence of chronic cocaine exposure.