Citations

Abstract Background The aim was to evaluate outcomes in patients with ulcerative colitis complicated by primary sclerosing cholangitis (PSC) who required ileal pouch–anal anastomosis (IPAA) and orthotopic liver transplantation (OLT). Methods A retrospective analysis was performed of 32 patients undergoing both IPAA and OLT between 1980 and 2006. Data were collected regarding demographics, indication for surgery, postoperative complications, and outcome of IPAA and OLT. Results Thirty-day mortality after either procedure was nil. The median preoperative Model for End-stage Liver Disease (MELD) score for the group with initial IPAA was 8 (range 6–20) and the postoperative score was 11 (range 6–19). At 1 and 10 years, 32 and 26 of the 32 liver grafts had survived, and 31 and 30 of the 32 pouches, respectively. Fourteen patients require daily medical therapy for chronic pouchitis. At a median follow-up of 3·6 (range 0·2–16·2) years after the second of two procedures, responding patients reported a median of 5·5 stools per day and 2 stools per night. Conclusion IPAA and OLT are feasible and safe in patients requiring both procedures for ulcerative colitis and PSC. Functional outcomes are stable over time, despite an increased risk of chronic pouchitis.

Abstract Rationale Patients with severe chronic obstructive pulmonary disease (COPD) may have varying levels of disability despite similar levels of lung function. This variation may reflect different COPD subtypes, which may have different genetic predispositions. Objectives To identify genetic associations for COPD-related phenotypes, including measures of exercise capacity, pulmonary function, and respiratory symptoms. Methods In 304 subjects from the National Emphysema Treatment Trial, we genotyped 80 markers in 22 positional and/or biologically plausible candidate genes. Regression models were used to test for association, using a test–replication approach to guard against false-positive results. For significant associations, effect estimates were recalculated using the entire cohort. Positive associations with dyspnea were confirmed in families from the Boston Early-Onset COPD Study. Results The test–replication approach identified four genes—microsomal epoxide hydrolase (EPHX1), latent transforming growth factor-β binding protein-4 (LTBP4), surfactant protein B (SFTPB), and transforming growth factor-β1 (TGFB1)—that were associated with COPD-related phenotypes. In all subjects, single-nucleotide polymorphisms (SNPs) in EPHX1 (p ⩽ 0.03) and in LTBP4 (p ⩽ 0.03) were associated with maximal output on cardiopulmonary exercise testing. Markers in LTBP4 (p ⩽ 0.05) and SFTPB (p = 0.005) were associated with 6-min walk test distance. SNPs in EPHX1 were associated with carbon monoxide diffusing capacity (p ⩽ 0.04). Three SNPs in TGFB1 were associated with dyspnea (p ⩽ 0.002), one of which replicated in the family study (p = 0.02). Conclusions Polymorphisms in several genes seem to be associated with COPD-related traits other than FEV1. These associations may identify genes in pathways important for COPD pathogenesis.

Purpose Most patients with colorectal liver metastases present to general surgeons and oncologists without a specialist interest in their management. Since treatment strategy is frequently dependent on the response to earlier treatments, our aim was to create a therapeutic decision model identifying appropriate procedure sequences. Methods We used the RAND Corporation/University of California, Los Angeles Appropriateness Method (RAM) assessing strategies of resection, local ablation and chemotherapy. After a comprehensive literature review, an expert panel rated appropriateness of each treatment option for a total of 1,872 ratings decisions in 252 cases. A decision model was constructed, consensus measured and results validated using 48 virtual cases, and 34 real cases with known outcomes. Results Consensus was achieved with overall agreement rates of 93.4 to 99.1%. Absolute resection contraindications included unresectable extrahepatic disease, more than 70% liver involvement, liver failure, and being surgically unfit. Factors not influencing treatment strategy were age, primary tumor stage, timing of metastases detection, past blood transfusion, liver resection type, pre-resection carcinoembryonic antigen (CEA), and previous hepatectomy. Immediate resection was appropriate with adequate radiologically-defined resection margins and no portal adenopathy; other factors included presence of ≤ 4 or > 4 metastases and unilobar or bilobar involvement. Resection was appropriate postchemotherapy, independent of tumor response in the case of ≤ 4 metastases and unilobar liver involvement. Resection was appropriate only for > 4 metastases or bilobar liver involvement, after tumor shrinkage with chemotherapy. When possible, resection was preferred to local ablation. Conclusion The results were incorporated into a decision matrix, creating a computer program (OncoSurge). This model identifies individual patient resectability, recommending optimal treatment strategies. It may also be used for medical education.

Abstract Purpose: The purpose of this research was to identify promiscuous T-helper cell determinants (THd) from carcinoembryonic antigen (CEA) to be used to prime T-cell help for cancer therapy. CEA was selected because this antigen is expressed in an important variety of carcinomas. Experimental Design: Potential promiscuous THd from CEA were predicted using available computer algorithms. Predicted peptides were synthesized and tested in binding experiments to different HLA-DR molecules. Binder peptides were then used to prime T-cell responses both in vitro and in vivo. Results: Twenty 15-mer peptides from CEA were predicted to bind to different HLA-DR molecules. The promiscuous character of these peptides was demonstrated in binding experiments. Fifteen of 20 peptides tested were able to bind to HLA-DR4, but only CEA (625–639) was shown to be presented after processing of recombinant CEA. CEA (625–639) was also found to be presented by HLA-DR53. Moreover, immunization of HLA-DR4 transgenic mice with CEA (625–639) in conjunction with class I epitope OVA (257–264), induced a CTL response specific of OVA (257–264). Conclusions: CEA (625–639) might be a relevant promiscuous THd peptide for cancer therapy.

Purpose There is a need for a simple, reliable staging system for multiple myeloma that can be applied internationally for patient classification and stratification. Patients and Methods Clinical and laboratory data were gathered on 10,750 previously untreated symptomatic myeloma patients from 17 institutions, including sites in North America, Europe, and Asia. Potential prognostic factors were evaluated by univariate and multivariate techniques. Three modeling approaches were then explored to develop a staging system including two nontree and one tree survival assessment methodologies. Results Serum beta 2 -microglobulin (Sβ 2 M), serum albumin, platelet count, serum creatinine, and age emerged as powerful predictors of survival and were then used in the tree analysis approach. A combination of Sβ 2 M and serum albumin provided the simplest, most powerful and reproducible three-stage classification. This new International Staging System (ISS) was validated in the remaining patients and consists of the following stages: stage I, Sβ 2 M less than 3.5 mg/L plus serum albumin ≥ 3.5 g/dL (median survival, 62 months); stage II, neither stage I nor III (median survival, 44 months); and stage III, Sβ 2 M ≥ 5.5 mg/L (median survival, 29 months). The ISS system was further validated by demonstrating effectiveness in patients in North America, Europe, and Asia; in patients less than and ≥ 65 years of age; in patients with standard therapy or autotransplantation; and in comparison with the Durie/Salmon staging system. Conclusion The new ISS is simple, based on easy to use variables (Sβ 2 M and serum albumin), and recommended for early adoption and widespread use.

Abstract Background Primary sarcomas of the liver are extremely rare in adults. Optimal therapeutic approaches remain unclear. Methods Twenty consecutive adult patients who had surgical treatment for primary hepatic sarcomas were reviewed. Patient age ranged from 23 to 80 years. Other than one patient with primary hepatic angiosarcoma who had a history of thorium dioxide colloid (Thorotrast) exposure 23 years before diagnosis, no predisposing causes were apparent. Nineteen patients had hepatic resection and one patient had an orthotopic liver transplant. No patient received neoadjuvant chemotherapy or radiotherapy but radiotherapy was delivered intraoperatively in one patient. Results Leiomyosarcoma was the most common histological type of sarcoma diagnosed (five of 20 patients), followed by malignant solitary fibrous tumour (four) and epithelioid haemangioendothelioma (three). Fourteen tumours were high-grade sarcomas and six were low grade malignancies. Thirteen patients developed a recurrence. Distant metastases (ten patients) and intrahepatic recurrence (six) were the predominant sites of initial treatment failure. Six patients received salvage chemotherapy. Histological grade was the only factor significantly associated with overall patient survival (P = 0·03). With complete resection, patients with high-grade tumours had a 5-year survival rate of 18 (95 per cent confidence interval 5–62) per cent compared with 80 (52–100) per cent for patients with low-grade tumours. The 5-year survival rate for all 20 patients was 37 (20–60) per cent. Conclusion Surgical resection is the only effective therapy for primary hepatic sarcomas at present. Better adjuvant therapy is necessary, especially for high-grade malignancies, owing to the high failure rate with operation alone.

Scientifically, it has been questioned if the coracoacromial ligament has a significant role of serving as a pulley for the supraspinatus tendon. The purpose of this study was to examine the changes of abduction moment arms of the rotator cuff and deltoid muscle after anterior acromioplasty. In normal condition and after sectioning of the coracoacromial ligament and acromioplasty, abduction moment arms of four cuff tendons and three portions of the deltoid were obtained with four cadaver shoulders by computing the slope of the tendon excursion versus the glenohumeral abduction angle curve using a magnetic tracking device. In intact joints, the abduction moment arms of the supraspinatus increased from 20 mm to 27 mm with the arm abducted from 0° to 30°, which showed a better condition of the glenohumeral abduction. Then, they decreased to 23 mm with arm in 60° abduction. After sectioning of the coracoacromial ligament and acromioplasty less than 4 mm thick, the abduction moment arms of supraspinatus did not increase. This finding suggested that the coracoacromial ligament and acromion, anatomically, did not serve as pulleys for the supraspinatus tendon. However, the abduction moment arm of the middle deltoid decreased after an acromioplasty.