Gender-specific Differences in Clinicopathologic Outcomes Following Radical Cystectomy: An International Multi-institutional Study of More Than 8000 Patients

Background

The impact of gender on the staging and prognosis of urothelial carcinoma of the bladder (UCB) is insufficiently understood.

Objective

To assess gender-specific differences in pathologic factors and survival of UCB patients treated with radical cystectomy (RC).

Design, setting, and participants

Data from 8102 patients treated with RC (6497 men [80%] and 1605 women [20%]) for UCB between 1971 and 2012 were analyzed.

Outcome measurements and statistical analysis

Multivariable competing-risk regression analyses were performed to evaluate the relationship of gender on disease recurrence (DR) and cancer-specific mortality (CSM). We also tested the interaction of gender and tumor stage, nodal status, and lymphovascular invasion (LVI).

Results and limitations

Female patients were older at the time of RC (p = 0.033) and had higher rates of pathologic stage T3/T4 disease (p < 0.001). In univariable, but not in multivariable analysis, female gender was associated with a higher risk of DR (p = 0.022 and p = 0.11, respectively). Female gender was an independent predictor for CSM (p = 0.004). We did not find a significant interaction between gender and stage, nodal metastasis, or LVI (all p values >0.05).

Conclusions

We found female gender to be associated with a higher risk of CSM following RC. However, these findings do not appear to be explained by gender differences in pathologic stage, nodal status, or LVI. This gender disparity may be due to differences in care and/or the biology of UCB.     

The lipoprotein-associated coagulation inhibitor that inhibits the factor VII-tissue factor complex also inhibits factor Xa: insight into its possible mechanism of action

Blood coagulation is initiated when plasma factor VII(a) binds to its essential cofactor tissue factor (TF) and proteolytically activates factors X and IX. Progressive inhibition of TF activity occurs upon its addition to plasma. This process is reversible and requires the presence of VII(a), catalytically active Xa, Ca2+, and another component that appears to be associated with the lipoproteins in plasma, a lipoprotein-associated coagulation inhibitor (LACI). A protein, LACI(HG2), possessing the same inhibitory properties as LACI, has recently been isolated from the conditioned media of cultured human liver cells (HepG2). Rabbit antisera raised against a synthetic peptide based on the N-terminal sequence of LACI(HG2) and purified IgG from a rabbit immunized with intact LACI(HG2) inhibit the LACI activity in human serum. In a reaction mixture containing VIIa, Xa, Ca2+, and purified LACI(HG2), the apparent half-life (t1/2) for TF activity was 20 seconds. The presence of heparin accelerated the initial rate of inhibition threefold. Antithrombin III alpha alone had no effect, but antithrombin III alpha with heparin abrogated the TF inhibition. LACI(HG2) also inhibited Xa with an apparent t1/2 of 50 seconds. Heparin enhanced the rate of Xa inhibition 2.5-fold, whereas phospholipids and Ca2+ slowed the reaction 2.5-fold. Xa inhibition was demonstrable with both chromogenic substrate (S-2222) and bioassays, but no complex between Xa and LACI(HG2) could be visualized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Nondenaturing PAGE, however, showed that LACI(HG2) bound to Xa but not to X or Xa inactivated by diisopropyl fluorophosphate. Thus, LACI(HG2) appears to bind to Xa at or near its active site. Bovine factor Xa lacking its gamma-carboxyglutamic acid-containing domain, BXa(-GD), through treatment with alpha-chymotrypsin, was used to further investigate the Xa requirement for VIIa/TF inhibition by LACI(HG2). LACI(HG2) bound to BXa(-GD) and inhibited its catalytic activity against a small molecular substrate (Spectrozyme Xa), though at a rate approximately sevenfold slower than native BXa. Preincubation of LACI(HG2) with saturating concentrations of BXa(-GD) markedly retarded the subsequent inhibition of BXa. The VII(a)/TF complex was not inhibited by LACI(HG2) in the presence of BXa(-GD), and further, preincubation of LACI(HG2) with BXa(-GD) slowed the inhibition of VIIa/TF after the addition of native Xa. The results are consistent with the hypothesis that inhibition of VII(a)/TF involves the formation of a VIIa-TF-XA-LACI complex that requires the GD of XA.(ABSTRACT TRUNCATED AT 400 WORDS)     

Kinematics and kinetics with an adaptive ankle foot system during stair ambulation of transtibial amputees

Conventional prosthetic feet cannot adapt to specific conditions such as walking on stairs or ramps. Amputees are therefore forced to compensate their prosthetic deficits by modifying the kinematics and kinetics of their lower limbs. The Proprio-Foot™ (Ossur) intends to reduce these compensation mechanisms by automatically increasing dorsiflexion during stair ambulation thanks to an adaptive microprocessor-controlled ankle. The present investigation proposes to analyze the biomechanical effects of the dorsiflexion adaptation in transtibial (TT) amputees during stair ambulation.Sixteen TT amputees and sixteen healthy controls underwent conventional 3D gait analysis. Kinematics and kinetics of the lower limbs were compared during stair ascent and descent performed by patients with the prosthetic foot set to a neutral ankle angle and with an adapted dorsiflexion ankle angle of 4°. Norm distance as well as minimum and maximal values of sagittal kinematics and kinetics were calculated for comparisons between patients and control subjects.For both stair ascent and descent, an improvement of the knee kinematics and kinetics could particularly be noticed on the involved side with an increase of the knee flexion and an increase of the knee moment during stance.Therefore, despite its additional weight compared to a conventional prosthetic ankle, the Proprio-Foot™ should be beneficial to active TT amputees whose knee musculature strength does not constitute a handicap.     

High frequency of MAGE‐A4 and MAGE‐A9 expression in high‐risk bladder cancer

Cancer‐testis (CT) genes encode proteins that are ideal targets for cancer immunotherapy because of their restricted expression in normal tissues and frequent expression in cancers. We previously observed that MAGE‐A9 was one of the CT genes most frequently expressed in bladder tumors. To confirm that observation and evaluate the potential prognostic value of MAGE‐A9 protein, we analyzed its expression by immunohistochemistry in 493 primary bladder tumors and 33 lymph node metastases, in comparison with MAGE‐A4 protein, also frequently expressed in bladder tumors. Overall, MAGE‐A4 and MAGE‐A9 were observed, respectively, in 38% and 63% of nonmuscle‐invasive tumors, 48% and 57% of muscle‐invasive tumors, 65% and 84% of carcinomas in situ and in 73% and 85% of lymph node metastases. Expression was associated with higher grade (MAGE‐A4, p = 0.007; MAGE‐A9, p = 0.012). In multivariate Cox regression analyses, expression of MAGE‐A9 in pTa tumors was associated with recurrence (HR = 1.829; p = 0.010). In univariate analyses, MAGE‐A4 expression in these same tumors was associated with progression to muscle‐invasive cancer (HR = 7.417, p = 0.013). MAGE‐A9 expression was even more predictive of progression as all tumors that progressed expressed this antigen. In muscle‐invasive bladder tumors, no association was found between expression of either MAGE and bladder cancer‐specific death. In conclusion, MAGE‐A9 is a target of choice for bladder cancer immunotherapy as it is expressed in 60% of bladder tumors, predominantly high‐grade tumors, and at higher frequency in pTis and metastatic tumors. Moreover, in pTa tumors, an immunotherapy targeting MAGE‐A9 could be protective against recurrence and progression to more advanced cancer. © 2009 UICC     

Use of markers in defining urothelial premalignant and malignant conditions

Markers have revealed the presence of phenotypically abnormal areas in histologically benign urothelium in bladders containing transitional cell carcinomas. This finding strongly suggests that at least some bladder cancers are associated with changes in the field and that markers can detect these lesions before they reach a grossly malignant stage. Markers have been used clinically for the detection of cancer in patients who are under regular surveillance for recurrence of bladder cancer. Much less information is available regarding the use of markers to detect bladder cancer without a prior history of the disease and for the prediction of which tumors are biologically more aggressive. However, ongoing clinical trials are addressing the latter issue. The type of specimen and its preparation will determine what type of markers can be analyzed. Although marker performance is based upon sensitivity and specificity, the prevalence of bladder cancer in the population being tested will dramatically affect the positive predictive value of an assay. Markers with high positive predictive value are indicators for interventions, such as biopsy, while markers with high negative specific values are useful for avoiding interventions. Cytology is used to detect occult high-grade neoplasms such as carcinoma in situ. While not yet clinically validated, tests with high negative predictive value could be used to decrease the frequency of cystoscopic evaluation. Markers must be validated by testing them prospectively using previously defined cut-off values. Furthermore, markers that will be used to alter treatment should be tested prospectively to determine the safety and cost-effectiveness of this strategy. Recommendations for future work include: (1) evaluation of markers in patients with dysplasia defined by the current pathologic classification; (2) evaluation of markers as indicators of tumor recurrence; (3) evaluation of markers as indicators of tumor progression; and (4) evaluation of markers in chemoprevention studies.     

Does the potassium stimulation test predict cystometric,cystoscopic outcome in interstitial cystitis?

PURPOSE: We establish the relationship among symptom duration, cystometric and cystoscopic findings and potassium stimulation test in patients with interstitial cystitis. MATERIALS AND METHODS: A retrospective chart review was performed of 189 patients treated at an ambulatory clinic between 1992 and 1998. Urodynamic parameters, potassium stimulation test results and subjective response to treatment were evaluated. Fisher's exact test was used for statistical analysis. RESULTS: Of the 189 patients diagnosed with interstitial cystitis 173 (92%) were female and 16 (8%) were male. The potassium stimulation test was positive in 105 (83%) patients, negative in 16 (13%) and equivocal in 6 (4%). A cystometrogram and potassium stimulation test were done in 118 patients. Bladder capacity averaged 259 ml. in patients with tests potassium positive and negative, while average bladder volume at first sensation to void was 85 ml. and 148 ml. in those with negative and positive tests, respectively. Among the 102 patients with a positive potassium stimulation test 52 had normal cystoscopic findings. CONCLUSIONS: The potassium stimulation test is not correlated with either bladder capacity or cystoscopic findings.     

Currarino triad: Characteristic appearances on magnetic resonance imaging and plain radiography

The Currarino triad is a complex anomaly consisting of an anorectal malformation, a sacral bone defect and a presacral mass. It was first described in 1981 and since then, approximately 250 cases have been reported. Radiology has an important part to play in the diagnosis of this entity, as the imaging features are characteristic. We report a case of Currarino triad in an infant who presented with intractable constipation and discuss relevant MRI and plain radiography findings.     

Risk factors for deaths in under-age-five children attending a diarrhoea treatment centre

Few case-control studies have examined possible risk factors for diarrhoeal deaths in under-age-five children in the developing countries. We analysed data from the surveillance system of our diarrhoea treatment centre/hospital for the period 1990-94 on 928 children less than 5 years of age. In univariate analysis, 11 factors were significantly associated with death: lack of breastfeeding, severe malnutrition, complicated diarrhoea, pneumonia, xerophthalmia, duration of diarrhoea 7-14 days, moderate or severe dehydration, recent history of measles, Shigella flexneri infection, maternal illiteracy, and very low household income. Rotavirus diarrhoea was negatively associated with fatal outcome. In the assessment of severe malnutrition, weight-for-height measurement discriminated mortality risk better than weight-for-age or height-for-age indices. Only two factors retained their significance, severe malnutrition and non-breastfeeding in the multivariate analysis with adjusted odds ratio (95% confidence interval) of 84.2 (9.1, 775.9) and 4.2 (1.3, 13.2) respectively.