Shariat SF, Park S, Trinh Q-D, Roehrborn CG, Slawin KM, Karakiewicz PI. Plasminogen activation inhibitor-1 improves the predictive accuracy of prostate cancer nomograms. J Urol. 2007;178 (4 Pt 1) :1229-36; discussion 1236-7.Abstract
PURPOSE: We tested whether the addition of preoperative circulating plasminogen activator inhibitor type I levels improves the accuracy of standard preoperative and postoperative models for prediction of biochemical recurrence after radical prostatectomy. MATERIALS AND METHODS: Preoperative plasma levels of plasminogen activator inhibitor type I were measured in 429 consecutive patients treated with radical prostatectomy for clinically localized prostate cancer. The patients were randomly divided into a development (67%, 286) and a split sample validation cohort (33%, 143). Cox regression analysis was used to develop prognostic nomograms for prediction of biochemical recurrence. RESULTS: In standard univariate analyses categorically coded preoperative plasminogen activator inhibitor type I was significantly associated with biochemical recurrence (p <0.001). In standard preoperative and postoperative multivariate analyses preoperative plasminogen activator inhibitor type I was independently associated with biochemical recurrence (p <0.001 and p = 0.002, respectively). In the split sample validation cohort the addition of plasminogen activator inhibitor type I increased the predictive accuracy of the preoperative multivariate model by 1.2%, 7.7%, 10.3%, 6.7% and 5.4% at 1, 2, 3, 4 and 5 years, respectively (p values <0.001). Moreover, the addition of plasminogen activator inhibitor type I increased the predictive accuracy of the postoperative model by 0.5%, 1.1%, 4.0%, 2.4% and 3.6% at 1, 2, 3, 4 and 5 years, respectively (p values <0.001). CONCLUSIONS: Preoperative circulating plasminogen activator inhibitor type I is a predictor of biochemical recurrence, and it enhances the accuracy of preoperative and postoperative nomograms. After external validation these nomograms may assist clinical decision making regarding treatment choice and followup as well as identification of patients at high risk for biochemical recurrence who may benefit from neoadjuvant and/or adjuvant treatment.
Rioux-Leclercq N, Karakiewicz PI, Trinh Q-D, Ficarra V, Cindolo L, de la Taille A, Tostain J, Zigeuner R, Mejean A, Patard J-J. Prognostic ability of simplified nuclear grading of renal cell carcinoma. Cancer. 2007;109 (5) :868-74.Abstract
BACKGROUND: The Fuhrman grading system is an established predictor of survival in patients with renal cell carcinoma (RCC). The predictive accuracy of various Fuhrman grading schemes was tested with the intent of improving the prediction of RCC-specific survival (RCC-SS). METHODS: The analyses targeted 5453 patients from 14 institutions. Univariable, multivariable, and predictive accuracy analyses addressed RCC-SS. The statistical significance of the gain in predictive accuracy was quantified with the Mantel-Haenszel test. RESULTS: The median follow-up time was 4.5 years. In both univariable and multivariable analyses, Fuhrman grade achieved independent predictor status regardless of the coding scheme. When Fuhrman grade was not considered in multivariable analyses, the predictive accuracy was 83.8%. Addition of Fuhrman grade to the multivariable model resulted in predictive accuracy gains of 0.8% for all 3 grading schemes tested. CONCLUSION: Fuhrman grade must to be considered when RCC-SS is assessed. However, modified or conventional Fuhrman grading schemes perform equally well as the conventional grading system.
Karakiewicz P, Perrotte P, Trinh Q-D, Patard J-J. Rebuttal from authors re: Edward M. Messing. Node positive renal cell cancer. Who can be helped? Eur Urol 2007;51:1477-8. Eur Urol. 2007;51 (6) :1478-80.
Karakiewicz PI, Trinh Q-D, Bhojani N, Bensalah K, Salomon L, de la Taille A, Tostain J, Cindolo L, Altieri V, Ficarra V, et al. Renal cell carcinoma with nodal metastases in the absence of distant metastatic disease: prognostic indicators of disease-specific survival. Eur Urol. 2007;51 (6) :1616-24.Abstract
OBJECTIVES: Outcome of patients with exclusive renal cell carcinoma (RCC) nodal metastases without distant metastases is not extensively described. We explored the ability of standard risk factors such as tumour size, Fuhrman grade, histologic subtype and symptom classification to predict renal cell carcinoma-specific survival (RCC-SS). METHODS: Analyses targeted 171 patients with RCC nodal metastases and absence of distant metastases. Univariable, multivariable, and predictive accuracy analyses addressed RCC-SS with the intent of identifying independent and most informative predictors of RCC-SS in this cohort of patients. RESULTS: Median RCC-SS was 2.3 yr. Symptom classification (61.3%, p<0.001) demonstrated the highest univariable accuracy. In multivariable analyses, symptom classification contributed the most to the combined predictive accuracy of all variables (+4.2%, p<0.001), followed by Fuhrman grade (+2.3%) and histologic subtype (+1.0%). CONCLUSIONS: Renal cell carcinoma-specific survival of patients with exclusive nodal metastases may show important variability. In presence of systemic symptoms, survival is extremely poor. Substantially better survival may be expected in patients with local or no symptoms. This observation has important implications when adjuvant therapies are considered.
Trinh Q-D, Cardinal E, Gallina A, Perrotte P, Saad F, Karakiewicz PI. Sunitinib relieves renal cell carcinoma spinal cord compression. Eur Urol. 2007;51 (6) :1741-3.Abstract
A 66-year-old previously healthy female was diagnosed with renal cell carcinoma (RCC) metastic to the 4th, 6th and 12th thoracic vertebrae. Despite external beam radiotheraphy (20G in 5 fractions), she progressed to spinal cord compression within 4 weeks and was wheelchair bound. Radiation and surgery were not considered suitable, but sunitinib was initiated. After two 6-week sunitinib cycles, she is fully ambulatory. She reports grade I fatigue and occasional epistaxis, as sole side effects. This case demonstrates that despite the rapid progression of the disease, which escaped the effect of radiation within four weeks, sunitinib resulted in complete clinical symptom resolution, which was confirmed radiographically. Moreover, it appears that the novel therapies for metastatic RCC may restore quality and quantity of life to many of those, whose disease previously appeared too advanced to treat.
Karakiewicz PI, Hutterer GC, Trinh Q-D, Pantuck AJ, Klatte T, Lam JS, Guille F, de la Taille A, Novara G, Tostain J, et al. Unclassified renal cell carcinoma: an analysis of 85 cases. BJU Int. 2007;100 (4) :802-8.Abstract
OBJECTIVES: To compare cancer-specific mortality in patients with unclassified renal cell carcinoma (URCC) vs clear cell RCC (CRCC) after nephrectomy, as URCC is a rare but very aggressive histological subtype. PATIENTS AND METHODS: Eighty-five patients with URCC and 4322 with CRCC were identified within 6530 patients treated with either radical or partial nephrectomy at 18 institutions. Of 85 patients with URCC, 55 were matched with 166 of 4322 for grade, tumour size, and Tumour, Node and Metastasis stages. Kaplan-Meier and life-table analyses were used to address RCC-specific survival. Subsequently, multivariate Cox regression analyses were used to test for differences in RCC-specific survival in unmatched samples. RESULTS: Of patients with URCC, 80% had Fuhrman grades III or IV, vs 37.8% for CRCC. Moreover, 36.5% of patients with URCC had pathologically confirmed nodal metastases, vs 8.6% with CRCC. Finally, 54.1% of patients with URCC had distant metastases at the time of nephrectomy, vs 16.8% with CRCC. Despite these differences in the overall analyses, after matching for tumour characteristics, the URCC-specific mortality rate was 1.6 times higher (P = 0.04) in matched analyses and 1.7 times higher (P = 0.001) in multivariate analyses. CONCLUSIONS: These findings indicate that URCC presents with a higher stage and grade, and even after controlling for the stage and grade differences, predisposes patients to 1.6-1.7 times the mortality of CRCC.
Lavoie H, Debeane F, Trinh Q-D, Turcotte J-F, Corbeil-Girard L-P, Dicaire M-J, Saint-Denis A, Pagé M, Rouleau GA, Brais B. Polymorphism, shared functions and convergent evolution of genes with sequences coding for polyalanine domains. Hum Mol Genet. 2003;12 (22) :2967-79.Abstract
Mutations causing expansions of polyalanine domains are responsible for nine hereditary diseases. Other GC-rich sequences coding for some polyalanine domains were found to be polymorphic in human. These observations prompted us to identify all sequences in the human genome coding for polyalanine stretches longer than four alanines and establish their degree of polymorphism. We identified 494 annotated human proteins containing 604 polyalanine domains. Thirty-two percent (31/98) of tested sequences coding for more than seven alanines were polymorphic. The length of the polyalanine-coding sequence and its GCG or GCC repeat content are the major predictors of polymorphism. GCG codons are over-represented in human polyalanine coding sequences. Our data suggest that GCG and GCC codons play a key role in polyalanine-coding sequence appearance and polymorphism. The grouping by shared function of polyalanine-containing proteins in Homo sapiens, Drosophila melanogaster and Caenorhabditis elegans shows that the majority are involved in transcriptional regulation. Phylogenetic analyses of HOX, GATA and EVX protein families demonstrate that polyalanine domains arose independently in different members of these families, suggesting that convergent molecular evolution may have played a role. Finally polyalanine domains in vertebrates are conserved between mammals and are rarer and shorter in Gallus gallus and Danio rerio. Together our results show that the polymorphic nature of sequences coding for polyalanine domains makes them prime candidates for mutations in hereditary diseases and suggests that they have appeared in many different protein families through convergent evolution.