Patients with Lynch Syndrome Mismatch Repair Gene Mutations Are at Higher Risk for Not Only Upper Tract Urothelial Cancer but Also Bladder Cancer

Background

Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer, is caused by mutations in mismatch repair (MMR) genes. An increased risk for upper tract urothelial carcinoma (UTUC) has been described in this population; however, data regarding the risk for bladder cancer (BCa) are sparse.

Objective

To assess the risk of BCa in MMR mutation carriers and suggest screening and management recommendations.

Design, setting, and participants

Cancer data from 1980 to 2007 were obtained from the Familial Gastrointestinal Cancer Registry in Toronto for 321 persons with known MMR mutations: mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1); mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli) (MSH2); mutS homolog 6 (E. coli) (MSH6); and PMS2 postmeiotic segregation increased 2 (S. cerevisiae) (PMS2).

Outcome measurements and statistical analysis

Standardized incidence ratios from the Ontario Cancer Registry, using the Surveillance Epidemiology and End Results public database, were used to compare cancer risk in patients with MMR mutations with the Canadian population. Microsatellite instability analysis and immunohistochemistry (IHC) of the MMR proteins were also performed and the results compared with matched sporadic bladder tumors.

Results and limitations

Eleven of 177 patients with MSH2 mutations (6.21%, p < 0.001 compared with the Canadian population) were found to have BCa, compared with 3 of 129 patients with MLH1 mutations (2.32%, p > 0.05). Of these 11 tumors, 81.8% lacked expression of MSH2 on IHC, compared with the matched sporadic cases, which all displayed normal expression of MSH2 and MLH1. The incidence of UTUC among MSH2 carriers was 3.95% (p < 0.001), and all tumors were found to be deficient in MSH2 expression on IHC. Mutations in the intron 5 splice site and exon 7 of the MSH2 gene increased the risk of urothelial cancer. Limitations include possible inflated risk estimates due to ascertainment bias.

Conclusions

LS patients with MSH2 mutations are at an increased risk for not only UTUC but also BCa and could be offered appropriate screening.     

Large Diameter Metal on Metal Articulations. Comparison of Total Hip Arthroplasty and Hip Resurfacing Arthroplasty

The use of large diameter metal bearing total hip arthroplasty (THA) and hip resurfacing arthroplasty (HRA) increased in popularity in the last decade. More recent literature has highlighted the effect of head size in patient outcomes. Data was obtained from the Australian Orthopaedic Association National Joint Replacement Registry (AOA-NJRR) to evaluate the Birmingham (MoM) bearing surface when used with THA and HRA. There is no difference in the overall rate of revision between the THA and HRA but head size has a significant effect on revision rate. The data show that small diameter metal bearings in HRA (below 50 mm) have a higher rate of revision than large diameter metal bearings in HRA (equal to and above 50 mm) (P < .001). Conversely the large diameter metal bearings in THA have a higher rate of revision than the small diameter metal bearings in THA (P = .027). The revision rate for large diameter HRA compared to small diameter THA is not significantly different P = .670. We recommend caution when choosing either a large diameter (≥ 50 mm) metal on metal THA or small diameter (< 50 mm) HRA.     

The impact of genotype on outcome in oligodendroglioma: validation of the loss of chromosome arm 1p as an important factor in clinical decision making

OBJECT: Oligodendrogliomas are rare primary brain tumors. They comprise approximately 5 to 33% of all glial tumors but differ from astrocytomas by being associated with a more favorable prognosis, making their correct identification important. Allelic loss of chromosome arms 1p and 19q is found in a substantial subpopulation of tumors with an oligodendroglioma phenotype. Anaplastic oligodendrogliomas with allelic loss of 1p have been associated with chemosensitivity and a longer patient survival period. METHODS: Oligodendroglial neoplasms were studied using fluorescence in situ hybridization of formalin-fixed, paraffin-embedded tissue specimens; reference and target probe sets were used to map the telomeric regions of 1p and 19q. The results were correlated with the clinical characteristics of patients treated at our institution between 1993 and 2003. Data obtained in 96 patients were analyzed. This included 63 patients (65.6%) with World Health Organization (WHO) Grade II oligodendroglioma, 22 (23%) with Grade III oligodendroglioma, and 11 (11.4%) with mixed oligoastrocytoma. Analysis of 1p in patients with pure oligodendroglioma revealed a loss of 1p in 42 patients (49.4%). In 46 of these patients 19q was lost and in 70 (82.3%) there was concordance for combined loss or retention of both 1p and 19q (p < 0.0001). Patients with oligodendroglioma in whom a loss of 1p was present fared significantly better, and this outcome was unrelated to the treatment modality or WHO grade, compared with patients in whom 1p was intact (p < 0.05). CONCLUSIONS: To the authors' knowledge, this study includes the largest published series of WHO Grade II oligodendroglioma and 1p analysis. The results suggest that the association between long-term survival and 1p loss in oligodendroglioma is unrelated to treatment. The authors of further prospective studies may better determine the true value of the allelic loss of 1p and its implication for clinical decision making.     

New drugs in prostate cancer

PURPOSE OF REVIEW: The survival of hormone-refractory metastatic prostate cancer patients has improved with the use of docetaxel-based chemotherapy. The survival benefits, however, are modest suggesting that rationally designed therapeutic approaches are needed. We discuss recent developments in the therapeutic approach to advanced metastatic hormone-refractory prostate cancer, including molecularly targeted therapy, signal transduction inhibitors, stem-cell targeted therapy, anti-angiogenic compounds, vaccines and immunomodulating agents, differentiation agents, cytotoxics, and pro-apoptotic agents. RECENT FINDINGS: Over 200 compounds have entered clinical development for use in advanced prostate cancer, alone or in combination with cytotoxic agents such as docetaxel, or in other combinations. This article will review the results of emerging targets since the approval of docetaxel in 2004, concentrating on some of those compounds that, in our opinion, have the greatest potential and rationale for use. SUMMARY: The growing field of targeted molecular therapy of prostate cancer has opened up numerous opportunities for therapeutic impact. Knowledge of the molecular determinants of progression, relapse after local therapy, chemotherapeutic resistance, and hormone refractoriness remains essential in the rational design of clinical trials of these agents. Given the complexity, heterogeneity, and crosstalk of molecular pathways and the molecular lesions in prostate cancer, combination or sequential therapy may be a necessary step towards significant therapeutic progress. Novel translational clinical trial methodologies may assist in a more rapid identification of active compounds at biologically active doses for phase-III testing.     

Posttransplant diabetes mellitus in kidney transplant recipients receiving calcineurin or mTOR inhibitor drugs

BACKGROUND: The aim of this study was to evaluate the incidence and risk factors for posttransplant diabetes mellitus (PTDM; defined as new insulin use and/or new hyperglycemia) in 528 kidney recipients using different immunosuppressive agents. METHODS: Maintenance therapy included mycophenolate mofetil or azathioprine plus glucocorticoids in combination with Group I cyclosporine (263); Group II tacrolimus (60); or Group III sirolimus (205). RESULTS: The mean follow-up was 39.2 (range 9.0-103.8) months. Overall, the number of patients needing insulin was 7.4% (39/528). The incidences for Groups I, II, and III of 7.6%, 11.7%, and 5.9%, respectively, were not statistically different. Characteristics of patients with PTDM included older age (P=0.007); greater body weight (kg) at transplant, 6 months, and 12 months, respectively (P<0.001); greater BMI (kg/m2) at transplant, 6 months, and 12 months, respectively (P<0.001); more acute rejection episodes 28.2% vs. 13.5% (P=0.012); and increased incidence in African Americans (P=0.03). Multivariable analysis demonstrated increased risk for PTDM (defined as new insulin use) for tacrolimus, (hazard ratio [HR] 3.794, P=0.007); treated rejections (HR 2.491, P=0.0115); age (HR 1.407, P=0.0116); and BMI (HR 1.153, P<0.0001). New insulin use occurred sooner and with less total glucocorticoid dose for tacrolimus patients. If PTDM is defined as all cases of new hyperglycemia, then no immunosuppressive drug group demonstrated an increased risk. CONCLUSION.: The risk for developing PTDM is greatest among older recipients, and those obese at the time of transplant; those given steroid pulse therapy were at exceptionally high-risk. PTDM risk reduction should focus on weight loss in the obese end-stage renal disease population prior to transplant.     

A single surgeon's experience of treatment of Lisfranc joint injuries

This paper assesses the outcomes and complications of Lisfranc joint injuries treated at a regional trauma centre under the care of a single surgeon. We performed a retrospective study of all patients that underwent ORIF of a Lisfranc joint injury over a 5-year period. Case note review, radiology review, and questionnaire assessment were performed. We analysed for correlations between outcome and injury type, mechanism of injury, and presence of other ipsilateral limb injury and pure ligamentous injury. All injuries were classified according to a system described by Myerson et al. (Types A, B1, B2, C1, C2). Radiographs were also assessed for the presence of pure ligamentous injury. Outcome was measured using the American Orthopaedic Foot and Ankle society (AOFAS) midfoot score. Twenty-five injuries (24 patients) were identified and 16 injuries (15 patients) were available for follow. The mean duration of follow up was 42.6 months (11-69). The mean outcome score was 78.3 (38-100). The outcome scores for pure ligamentous injury (74.9) and for mixed bony and ligamentous injury (80.9) had no significant difference (p=0.61). High-energy trauma accounted for 50% of cases, and scored significantly less than low energy trauma (69.1 versus 87.4, p<0.05). There was an associated injury in the ipsilateral limb in 31% of cases and this group had a poorer outcome (63.0 versus 85.3, p<0.035). The most common injury type was B2 (38%). Type C2 injuries (divergent with total displacement) had a worse outcome than the mean outcome of all other categories (60.5 versus 84.4, p<0.01). Our mean outcome from ORIF of Lisfranc joint injuries is comparable to internationally quoted figures. Pure ligamentous injuries did no worse statistically than mixed bony and ligamentous injuries. Poorer outcome was associated with high-energy trauma, associated injury on the ipsilateral limb, and Type C2 injuries.     

Decompression not escharotomy in acute burns

The concept of escharotomy has long been associated with acute burns care. Nevertheless the practice of escharotomy is frequently flawed and there is considerable diversity in the teaching of the procedure. It is proposed that there should be a fundamental change in the teaching of acute burn management and the concept of decompression should be promoted. The justification for this change comes from a review of the present knowledge base using indexed, library and web-based information sources and also a review of a series of patients transferred to a regional burns unit over a five-year period which revealed that 37% of patients who required surgical decompression had not been appropriately treated prior to transfer. Based on relevant compartmental anatomy a change in the surgical decompression of limbs is proposed to allow safer and more effective management.