Citations

Abstract Early gastric cancer comprises more than 30 per cent of gastric carcinomas treated in Japan but remains an uncommon entity in the western hemisphere. A retrospective review of 48 patients with early gastric cancer undergoing operative treatment between 1965 and 1984 was carried out. The mean patient age was 70 years, in 31 men and 17 women. Preoperative diagnosis was made in 88 per cent of patients undergoing oesophagogastroduodenoscopy with biopsy but upper gastrointestinal radiography was diagnostic in only 20 per cent. Surgical management consisted of subtotal gastrectomy (86 per cent), total gastrectomy (10 per cent) and wide local excision (4 per cent). The operative mortality and morbidity rates were 0 and 38 per cent, respectively. Mean follow-up was 7.7 years, with 44 per cent of patients still alive. Multivariate analysis disclosed only a healthy. Eastern Cooperative Oncology Group score (P = 0.002) and a diploid DNA tumour pattern (P = 0.05) as significant prognostic variables of survival. The overall survival rate of patients with early gastric cancer (70 per cent at 5 years) was equivalent to that of an age- and sex-matched control population.

Abstract We reviewed our recent experience with management of 23 consecutive patients with acute necrotizing pancreatitis. All patients had documented necrotizing pancreatitis with parenchymal or peripancreatic necrosis. Our method of treatment has evolved from our previous approach of controlled open lesser sac drainage (marsupialization) to staged necrosectomy I debridement with delayed primary closure over drains. With this latter approach, hospital mortality was 4 of 23 patients (17 per cent), but significant morbidity still occurred in 12 of 23 patients (52 per cent). However, recurrent intra-abdominal abscess before discharge occurred in only one patient. We believe that this operative approach toward the severely ill patient with acute necrotizing pancreatitis who requires operative intervention will minimize the occurrence of intra-abdominal sepsis.

AbstractThe aim was to determine whether changes in enteric bacteriology, absorption, morphology, and emptying occur after ileal pouch–anal anastomosis for ulcerative colitis, and to relate any changes to the clinical result. Twenty patients were studied 26 ± 2 months (mean ± s.e.m.) after operation. Eight patients had a good result, six a poor result, and six a history of recurrent pouch ileitis. Anaerobic and aerobic overgrowth occurred in the jejunum of patients with a poor result, but not in those with a good result or with pouch ileitis. In contrast, ileal pouch bacterial overgrowth occurred in all patients regardless of the clinical result. Patients with jejunal overgrowth had increased 24 h stool volume and stool nitrogen, but other patients did not. The larger the stool volume, the greater the anaerobic overgrowth. Pouch biopsies showed chronic inflammation in all patients, while 45 per cent had colonic metaplasia. Neither the inflammation nor the metaplasia correlated with the clinical result, nor did the clinical result correlate with the efficiency of pouch emptying. In conclusion, jejunal bacterial overgrowth after ileal pouch–anal anastomosis was associated with an increased stool output, azotorrhoea, and a poor clinical result. A distinguishing bacterial, absorptive, morphological, or emptying abnormality was not found in patients with a history of recurrent pouch ileitis.

AbstractBackground: Zn-α2 glycoprotein (ZAG) is a relatively abundant glycoprotein that has potential as a biomarker for prostate cancer. We present a high-flow liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for measuring serum ZAG concentrations by proteolytic cleavage of the protein and quantification of a unique peptide.Methods: We selected the ZAG tryptic peptide 147EIPAWVPEDPAAQITK162 as the intact protein for quantification and used a stable isotope-labeled synthetic peptide with this sequence as an internal standard. Standards using recombinant ZAG in bovine serum albumin, 50 g/L, and a pilot series of patient sera were denatured, reduced, alkylated, and digested with trypsin. The concentration of ZAG was calculated from a dose–response curve of the ratio of the relative abundance of the ZAG tryptic peptide to internal standard.Results: The limit of detection for ZAG in serum was 0.08 mg/L, and the limit of quantification was 0.32 mg/L with a linear dynamic range of 0.32 to 10.2 mg/L. Replicate digests from pooled sera run during a period of 3 consecutive days showed intraassay imprecision (CV) of 5.0% to 6.3% and interassay imprecision of 4.4% to 5.9%. Mean (SD) ZAG was higher in 25 men with prostate cancer [7.59 (2.45) mg/L] than in 20 men with nonmalignant prostate disease [6.21 (1.65) mg/L, P = 0.037] and 6 healthy men [3.65 (0.71) mg/L, P = 0.0007].Conclusions: This LC-MS/MS assay is reproducible and can be used to evaluate the clinical utility of ZAG as a cancer biomarker.

Abstract Aberrant DNA methylation occurs early in oncogenesis, is stable, and can be assayed in tissues and body fluids. Therefore, genes with aberrant methylation can provide clues for understanding tumor pathways and are attractive candidates for detection of early neoplastic events. Identification of sequences that optimally discriminate cancer from other diseased and healthy tissues is needed to advance both approaches. Using well-characterized specimens, genome-wide methylation techniques were used to identify candidate markers specific for colorectal neoplasia. To further validate 30 of these candidates from genome-wide analysis and 13 literature-derived genes, including genes involved in cancer and others with unknown functions, a high-throughput methylation-specific oligonucleotide microarray was used. The arrays were probed with bisulfite-converted DNA from 89 colorectal adenocarcinomas, 55 colorectal polyps, 31 inflammatory bowel disease, 115 extracolonic cancers, and 67 healthy tissues. The 20 most discriminating markers were highly methylated in colorectal neoplasia (area under the receiver operating characteristic curve > 0.8; P < 0.0001). Normal epithelium and extracolonic cancers revealed significantly lower methylation. Real-time PCR assays developed for 11 markers were tested on an independent set of 149 samples from colorectal adenocarcinomas, other diseases, and healthy tissues. Microarray results could be reproduced for 10 of 11 marker assays, including eight of the most discriminating markers (area under the receiver operating characteristic curve > 0.72; P < 0.009). The markers with high specificity for colorectal cancer have potential as blood-based screening markers whereas markers that are specific for multiple cancers could potentially be used as prognostic indicators, as biomarkers for therapeutic response monitoring or other diagnostic applications, compelling further investigation into their use in clinical testing and overall roles in tumorigenesis. (Mol Cancer Res 2007;5(2):153–63)

Increasing application of expensive medical technologies, including joint replacement, is of concern in the current economic climate. Successful upper limb joint replacements (ULJRs) are being performed, but few detailed data about their utilization are available. To explore the resource implications of such surgery, the utilization of total shoulder replacement (TSR), total elbow replacement (TER) and total wrist replacement (TWR) were examined from the time these procedures first became available at the Mayo Clinic up to 1990. The age- and sex-adjusted utilization rate for TSR among Olmsted County, Minnesota, residents was 1.8 per 100000 person-years (p-y), 0.8 per 100000 p-y for TER and 1.1 per 100000 p-y for TWR. Overall utilization of primary ULJR among Olmsted County residents during the 19-year study period was 3.8 per 100000 p-y. The commonest indication for TSR was osteoarthritis (46 per cent) and for TER and TWR was rheumatoid arthritis (50 and 81 per cent respectively). There was no consistent trend in the utilization of these procedures among Olmsted County residents, but the number of referral patients receiving a ULJR at the Mayo Clinic increased steadily during the study period. The Mayo Clinic experience suggests an increasing demand for ULJR, particularly TSR and TER. With continued advances in, and diffusion of, the technology this demand may increase further.

Abstract Germ line inactivating mutations in BRCA1 confer susceptibility for breast and ovarian cancer. However, the relevance of the many missense changes in the gene for which the effect on protein function is unknown remains unclear. Determination of which variants are causally associated with cancer is important for assessment of individual risk. We used a functional assay that measures the transactivation activity of BRCA1 in combination with analysis of protein modeling based on the structure of BRCA1 BRCT domains. In addition, the information generated was interpreted in light of genetic data. We determined the predicted cancer association of 22 BRCA1 variants and verified that the common polymorphism S1613G has no effect on BRCA1 function, even when combined with other rare variants. We estimated the specificity and sensitivity of the assay, and by meta-analysis of 47 variants, we show that variants with <45% of wild-type activity can be classified as deleterious whereas variants with >50% can be classified as neutral. In conclusion, we did functional and structure-based analyses on a large series of BRCA1 missense variants and defined a tentative threshold activity for the classification missense variants. By interpreting the validated functional data in light of additional clinical and structural evidence, we conclude that it is possible to classify all missense variants in the BRCA1 COOH-terminal region. These results bring functional assays for BRCA1 closer to clinical applicability. [Cancer Res 2007;67(4):1494–501]

Abstract FKBP52 is a member of the FK506-binding family of immunophilins and serves as a co-chaperone for steroid hormone nuclear receptors to govern appropriate hormone action in target tissues. Male mice missing Fkbp52 are infertile, and this infertility has been ascribed to compromised sensitivity of the anterior prostate, external genitalia, and other accessory sex organs to androgen. Here, we show additional defects contributing to infertility. We found that epididymal Fkbp52−/− sperm are sparse often with aberrant morphology, and they have reduced fertilizing capacity. This phenotype, initially observed in null males on a C57BL/6/129 background, is also maintained on a CD1 background. Expression studies show that while FKBP52 and androgen receptor are co-expressed in similar cell types in the epididymis, FKBP52 is also present in epididymal sperm flagella. Collectively, our results suggest that reduced number and abnormal morphology contribute to compromised fertilizing capacity of Fkbp52−/− sperm. This study is clinically relevant because unraveling the role of immunophilin signaling in male fertility will help identify new targets for male contraceptives and/or alleviate male infertility.