Oussama M Darwish

University of Texas Southwestern Medical Center, Dallas, Texas, United States

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Publications (15)55.1 Total impact

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    ABSTRACT: Supra-hepatic IVC tumor thrombus in RCC has historically portended a poor prognosis. With advances in perioperative management of patients with high level thrombi, contemporary outcomes are hypothesized to be improved. We evaluated long-term oncologic outcomes of contemporary surgical management of RCC patients with level III-IV IVC thrombi treated at high volume centers. Clinical and pathologic data of RCC patients with level III-IV thrombus who had surgery from January 2000-June 2013 at 4 tertiary referral centers was examined. Survival outcomes and associated prognostic variables were assessed with Kaplan-Meier and multivariable Cox-regression analyses. 166 patients were identified (69 with level III, and 97 with level IV thrombus). Median post-operative follow-up was 27.8 months. Patients with no evidence of nodal or distant metastases (pN0/X,M0) had 5-yr CSS and OS of 49.0% and 42.2% respectively. There were no differences in survival based on the level of tumor thrombus or pathologic tumor stage. Variables associated with increased risk of death from kidney cancer on multivariable analysis were: regional nodal metastases (HR 3.94,p<0.0001), systemic metastases (HR 2.39,p=0.01), tumor grade 4 (HR 2.25,p=0.02), histologic tissue necrosis (HR 3.11,p=0.004), and elevated pre-operative serum alkaline phosphatase level (HR 2.30, p=0.006). Contemporary surgical management achieves nearly 50% 5-year survival in non-metastatic patients with RCC tumor thrombus above the hepatic veins. Factors associated with increased mortality included nodal/distant metastases, advanced grade, histologic necrosis and elevated pre-operative serum alkaline phosphatase. These findings support an aggressive surgical approach to the management of RCC patients with advanced tumor thrombi.
    The Journal of urology 04/2014; · 3.75 Impact Factor
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    ABSTRACT: Objective To evaluate degree of hydronephrosis (HN) as a surrogate for adverse pathological features and oncologic outcomes in patients with high-grade (HG) and low-grade (LG) upper tract urothelial carcinomas (UTUCs). Methods We retrospectively reviewed 141 patients with localized UTUCs that underwent extirpative surgery at a tertiary referral center. Preoperative imaging was used to evaluate presence and degree of ipsilateral HN. We evaluated degree of HN (none/mild vs. moderate/severe), pathological findings, and oncologic outcomes. Results HG UTUC was present in 113 (80%) patients, muscle-invasive disease (≥pT2) in 49 (35%), and non–organ-confined disease (≥pT3) in 41 (29%). At a median follow-up of 34 months, 49 (35%) patients experienced intravesical recurrence, 28 (20%) developed local/systemic recurrence, and 24 (17%) died of UTUC. HN was graded as none/mild in 77 (55%) patients and moderate/severe in 64 (45%). In patients with HG UTUC, but not LG, degree of HN was associated with advanced pathological stage (P<0.001), positive lymph nodes (P = 0.01), local/systemic recurrence-free survival (hazard ratio [HR] = 5.5, P = 0.02), and cancer-specific survival (HR = 5.2, P = 0.02). On multivariable analysis of preoperative factors, degree of HN in patients with HG UTUC was associated with muscle invasion (HR = 9.3; 95% CI: 3.08–28.32; P<0.001), non–organ-confined disease (HR = 4.5; 95% CI: 1.66–12.06; P = 0.003), local/systemic recurrence-free survival (HR = 2.5; 95% CI: 1.07–5.64; P = 0.04), and cancer-specific survival (HR = 2.6; 95% CI: 1.05–6.22; P = 0.04). Conclusions Degree of HN can serve as a surrogate for advanced disease and predict worse oncologic outcomes in HG UTUC. Degree of HN was not predictive of intravesical or local/systemic recurrence in LG UTUC.
    The Journal of Urology 04/2014; · 3.75 Impact Factor
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    ABSTRACT: Purpose We determined the association of the proliferation marker Ki-67 with pathological parameters and oncologic outcomes in patients with high grade upper tract urothelial carcinoma. Materials and Methods Immunohistochemical staining for Ki-67 was done prospectively in 101 consecutive patients undergoing radical nephroureterectomy/ureterectomy for high grade upper tract urothelial carcinoma. Data were compared based on Ki-67 status (normal vs over expressed). Survival was assessed by the Kaplan-Meier method. Cox regression analysis was done to identify independent predictors of time dependent outcomes. Results Median patient age was 70.0 years and median followup was 22.0 months (range 1 to 77). Overall, 30.2% of the population experienced recurrence and 24.8% died of upper tract urothelial carcinoma. Organ confined disease (T2 or less and lymph node negative), lymphovascular invasion and sessile architecture were present in 56.3%, 33.3% and 20.8% of patients, respectively. Ki-67 was over expressed in 73.3% of patients and associated with adverse pathological features. Patients with over expressed Ki-67 had significantly worse recurrence-free survival (43.2 vs 69.0 months, p = 0.006) and cancer specific survival (48.9 vs 68.9 months, p = 0.031) than patients with normal Ki-67. Patients with nonmetastatic disease similarly had worse recurrence-free survival (40.7 vs 71.8 months, p = 0.003) and cancer specific survival (41 months vs not attained, p = 0.008) for over expressed vs normal Ki-67. After adjusting for the effects of organ vs nonorgan confined disease Ki-67 over expression was an independent predictor of recurrence-free survival in the total cohort (HR 4.3, p = 0.05) and in patients with nonmetastatic disease (HR 8.5, p = 0.038). Conclusions Ki-67 over expression was associated with adverse pathological features in cases of upper tract urothelial carcinoma. It was also an independent predictor of recurrence-free survival in patients with high grade upper tract urothelial carcinoma.
    The Journal of Urology. 01/2014; 191(1):28–34.
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    ABSTRACT: Epithelial to mesenchymal transition (EMT) is thought to play a crucial role in cancer progression and metastatic egress. We evaluated association of beta-catenin, an important mediator of EMT, with pathologic parameters and oncologic outcomes in patients with clear cell renal cell carcinoma (ccRCC). Immunohistochemical staining was performed for beta-catenin on tissue microarrays of patients with non-metastatic ccRCC. Membranous and cytoplasmatic beta-catenin expression patterns were assessed separately. Beta-catenin was considered dysregulated if both, membranous and cytoplasmatic expression, were abnormal. Groups were compared based on beta-catenin expression (normal vs. dysregulated). Survival probabilities were assessed with the Kaplan-Meier method. Cox proportional hazard models were used to identify predictors of oncological outcomes. 406 patients with a median follow-up of 58 months were included. Overall, 52 (12.8%) and 25 (6.2%) patients recurred and died of ccRCC. Beta-catenin was dysregulated in 70 (17.2%) patients. Dysregulation of beta-catenin was uniformly associated with adverse pathologic features, including advanced T-stage, larger tumor diameter, nodal positivity, higher Fuhrman grade, presence of tumor thrombus, sarcomatoid features, necrosis and lymphovascular invasion (all p<0.001). Patients with dysregulated beta-catenin had inferior RFS and CSS (both p<0.001). On multivariate analysis adjusting for tumor stage, nodal status and grade, dysregulation of beta-catenin was an independent predictor of RFS (HR 2.2, 95%CI 1.2-3.9, p=0.008) and CSS (HR 2.4, 95%CI 1.1-5.6, p=0.044). Dysregulation of beta-catenin may be an important phenomenon in ccRCC carcinogenesis. These findings support further study of beta-catenin and systematic assessment of beta-catenin and EMT in ccRCC.
    The Journal of urology 11/2013; · 3.75 Impact Factor
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    ABSTRACT: Surgery for renal cell carcinoma (RCC) patients with inferior vena cava (IVC) thrombus above the hepatic veins is technically complex and associated with an increased risk of perioperative morbidity and mortality. However, minimal data exist that describe contemporary perioperative outcomes at major referral centers or the prognostic factors associated with poor outcomes. To determine the preoperative predictors of major complications and 90-d mortality after surgery in RCC patients who have IVC thrombus above the hepatic veins. We reviewed medical records of all RCC patients who had IVC tumor thrombus above hepatic veins and had had surgery between January 2000 and December 2012 at the Mayo Clinic, M.D. Anderson Cancer Center, University of Texas Southwestern Medical Center, and the University of Wisconsin Hospital. Major complications recorded were defined as ≥3A according to the Clavien-Dindo system within 90 d of surgery. Univariate and multivariate analyses were used to evaluate associations of preoperative variables with risk of major complications or 90-d mortality. A total of 162 patients were identified for study (level 3, 4 in 69, 93 patients, respectively, according to the Neves classification). Cardiopulmonary bypass was used in 60 of 162 patients (37.5%), and 40 patients (24.7%) had preoperative angioembolization. Major complications were reported in 55 patients (34.0%), with the most common being respiratory, cardiac, and hematologic issues. After multivariate analysis, preoperative systemic symptoms and level 4 thrombus were independently associated with increased risk of major complications. Mortality was reported in 17 patients (10.5%) within 90 d after surgery. After multivariate analysis, Eastern Cooperative Oncology Group (ECOG) performance status (PS) and low serum albumin were preoperative factors independently associated with increased risk of 90-d mortality. Contemporary perioperative mortality and major complication rates for RCC patients who have upper-level thrombus are 10% and 34%, respectively. Patients who have ECOG PS >1 or low serum albumin have increased risk for perioperative mortality.
    European Urology 11/2013; · 10.48 Impact Factor
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    ABSTRACT: Upper tract urothelial carcinoma (UTUC) is rare and less well studied than bladder cancer (BC). It remains questionable if findings in BC can safely be extrapolated to UTUC. We prospectively evaluate molecular profiles of UTUC and BC using a cell cycle biomarker panel. Immunohistochemical staining for p21, p27, p53, cyclin E and Ki-67 was prospectively performed on 96 UTUC and 159 BC patients with non-metastatic high-grade UC treated with extirpative surgery. Data was compared between two groups according to the pathological stage. Primary outcome was assessment of differences in marker expression. Secondary outcome was difference in survival according to marker status. Over a median follow up of 22.0 months, 31.2% of patients with UTUC and 28.3% of patients with BC recurred and 20.8% and 27.7% died of UTUC and BC, respectively. Number of altered markers was not significantly different between the study groups. 34 patients (35.4%) with UTUC and 62 patients (39.0%) with BC had an unfavorable marker score (MS) (>2 markers altered). There were no significant differences between UTUC and BC in alteration status of markers, number of altered markers and MS when sub-stratified by pathologic stage. There were no significant differences in survival outcomes between UTUC and BC patients, according to number of altered markers and MS. Our results demonstrate molecular similarity of UTUC and BC regarding cell cycle and proliferative tissue markers. These findings have important implications and support further extrapolation of treatment paradigms established in BC to UTUC.
    The Journal of urology 09/2013; · 3.75 Impact Factor
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    ABSTRACT: To determine the association of the proliferative marker Ki-67 with pathologic parameters and oncologic outcomes in patients with high-grade upper tract urothelial carcinoma (UTUC). Immunohistochemical staining for Ki-67 was done prospectively on 101 consecutive patients undergoing radical nephroureterectomy/ureterectomy for high-grade UTUC. Data was compared based on Ki-67 status (normal versus overexpressed). Survival was assessed with Kaplan-Meier method. Cox regression analyses identified independent predictors of time-dependent outcomes. Median patient age and follow up was 70.0 years and 22.0 months (range 1-77 months). Overall, 30.2% and 24.8% of the population recurred and died of UTUC. Organ-confined disease (=T2 and lymph node negative), LVI and sessile architecture were present in 56.3%, 33.3% and 20.8% of patients. Ki-67 was overexpressed in 73.3%, and associated with adverse pathologic features. Patients with overexpressed Ki-67 demonstrated a significantly worse recurrence-free survival (RFS) (43.2 vs. 69.0 months, p=0.006) and cancer-specific survival (CSS) (48.9 months vs. 68.9 months, p=0.031), than patients with normal Ki-67. Similarly, non-metastatic patients revealed worse RFS (40.7 months vs. 71.8 months, p=0.003) and CSS (41 months vs. not reached, p=0.008) for over-expressed compared to normal Ki-67. After adjusting for the effects of organ vs. non-organ confined disease, Ki-67 overexpression was an independent predictor of RFS for the total patient cohort (HR, 4.3; p=0.05) as well as for patients with non-metastatic disease (HR, 8.5; p=0.038). In our study, Ki-67 overexpression was associated with adverse pathologic features for UTUC and was an independent predictor of RFS in patients with high grade UTUC.
    The Journal of urology 07/2013; · 3.75 Impact Factor
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    ABSTRACT: Cell cycle regulatory molecules are implicated in various stages of carcinogenesis. In this proof of principle study we systematically evaluate the association of aberrant expression of cell cycle regulators and proliferative markers on oncological outcomes of patients with clear cell renal carcinoma (ccRCC). Immunohistochemistry for Cyclin D, Cyclin E, p16, p21, p27, p53, p57 and Ki67 was performed on tissue microarray constructs of 452 patients treated with extirpative therapy for ccRCC between 1997-2010. Clinical and pathologic data elements were collected. A prognostic marker score (MS) was defined as unfavorable if >4 biomarkers were altered. The relationship between MS and pathological features and oncological outcomes was evaluated. Median age and follow up was 57 years (range 17-85) and 24 months (range 6-150), respectively. Unfavorable MS was found in 55 (12.2%) patients and was associated with adverse pathological features. A significant correlation between unfavorable MS and DFS (HR 26.62, 95% CI 43.38-100.04, p = 0.000) and with CSS (HR 8.15, 95% CI 74.42-101.56, p = 0.004) was demonstrated in Kaplan Meier survival analysis. In a multivariate analysis, unfavorable MS was an independent predictor of DFS (HR 2.63, CI 1.08-6.38, p = 0.033). The cumulative number of aberrantly expressed cell cycle and proliferative biomarkers correlates with aggressive pathological features and inferior oncologic outcomes in patients with ccRCC. Our findings indicate that interrogation of cell cycle and proliferative markers is feasible and further prospective pathway-based exploration of biomarkers is needed.
    The Journal of urology 06/2013; · 3.75 Impact Factor
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    ABSTRACT: To validate the impact of Ki67 expression on oncological outcomes of patients treated for clinically localized clear-cell renal cell carcinoma (ccRCC). Immunohistochemistry for Ki67 was performed on tissue microarray constructs of patients treated with radical or partial nephrectomy for clinically localized (M0) ccRCC and Ki67 expression >10% was considered abnormal. Clinical and pathological data elements were entered into an institutional review board-approved database. The Kaplan-Meier method and Cox regression models were used to analyse disease-free survival (DFS) and cancer-specific survival (CSS) probabilities. Of 401 patients, 59.6% were males. The median (range) age was 58 (17-85) years, follow-up was 22 (0-150) months and time to death was 27 (0-150) months. A total of 20.2% of patients had advanced stage (pT3-T4) and 31% had advanced grade (3-4) disease. Abnormal expression of Ki67 was seen in 6.5% of our cohort and was associated with adverse pathological features (P < 0.05). Patients with high expression of Ki67 were found to have 5-year DFS and CSS rates of 67 and 84%, respectively, vs 87 and 95%, respectively, in those with normal expression (P < 0.001 and P < 0.05, respectively). In multivariable analyses, adjusting for stage and grade, abnormal Ki67 expression was an independent predictor of DFS (hazard ratio [HR] 3.77, P = 0.011, 95% confidence interval [CI] 1.35-10.52), but not of CSS (HR 3.51 P = 0.137, 95% CI 0.671-18.35). Our findings support the role of Ki67 as a powerful independent predictor of inferior oncological outcomes in patients with ccRCC. Further prospective studies are needed to determine the clinical applicability of these findings.
    BJU International 06/2013; · 3.05 Impact Factor
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    ABSTRACT: OBJECTIVES: The objective is to evaluate the effect of lymphovascular invasion (LVI) on disease-free survival (DFS) and cancer-specific survival (CSS) in patients with clinically localized clear cell renal cell carcinoma (ccRCC). METHODS: Patients with ccRCC who were treated surgically in 1997 to 2010 were identified. Retrospective chart review was performed to identify clinical outcomes. Independent pathologic re-review was performed by a single pathologist to confirm LVI status. Pathologic features were correlated with clinical outcomes using Kaplan-Meier and Cox regression analyses. RESULTS: Four hundred and nineteen patients with nonmetastatic ccRCC comprised the study cohort. Three hundred and thirty-three of these patients had an organ-confined (pT1-2, N any, and M0) disease. LVI was present in 14.3% of all nonmetastatic patients. In all patients with nonmetastatic ccRCC, presence of LVI was correlated with significantly shorter DFS (P <0.001) and CSS (P = 0.001) on Kaplan-Meier analysis. In cases of organ-confined, nonmetastatic ccRCC, presence of LVI was a significant predictor of DFS (hazard ratio = 4.0, P = 0.026) and CSS (hazard ratio = 12.7, P = 0.01) on multivariate analysis. Patients with organ-confined RCC who were LVI positive had similar DFS (P = 0.957) and CSS (P = 0.799) to patients with locally advanced tumors (pT3-pT4, N any, and M0) on Kaplan-Meier analysis. CONCLUSIONS: The presence of LVI is an independent predictor of both DFS and CSS in organ-confined, nonmetastatic ccRCC. LVI positivity in patients with otherwise pathologically organ-confined ccRCC confers oncologic outcomes similar to those of patients with locally advanced disease. If confirmed by others, future revisions to the tumor-node-metastasis staging system may incorporate LVI status into the prognostic algorithm of patients with RCC.
    Urologic Oncology 02/2013; · 3.65 Impact Factor
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    ABSTRACT: OBJECTIVE: To evaluate the association of the altered expression of the mammalian target of rapamycin (mTOR) pathway components with oncologic outcomes in patients with nonmetastatic clear cell renal cell carcinoma (ccRCC). MATERIALS AND METHODS: Immunohistochemistry for phosphorylated-S6, phosphorylated-mTOR, mTOR, phosphorylated-AKT, hypoxia inducible factor-1α, Raptor, phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), and phosphorylated 4E-binding protein-1 was performed on tissue microarray constructs of patients treated for nonmetastatic kidney cancer from 1997 to 2010. The relationship between individual altered marker expression and a prognostic marker score (low, intermediate, and high, defined as ≤3, 4-5, >5 altered biomarkers, respectively) and oncologic outcome was assessed. RESULTS: The study included 419 patients with nonmetastatic ccRCC, with a median follow-up period of 26 months (range 6-150). The tumors were nonorgan confined (pT3-T4) in 86 (20.5%) and high Fuhrman nuclear grade (3-4) in 131 (31%). A low, intermediate, and high prognostic marker score was found in 214 (51%), 152 (36%), and 53 (13%) patients, respectively. Kaplan-Meier analysis demonstrated a statistically significant correlation between the risk groups and disease recurrence and cancer-specific survival. In a multivariate Cox regression analysis controlling for tumor stage and grade, a high marker score was an independent predictor of disease recurrence (hazard ratio 3.3, 95% confidence interval 1.33-8.39, P = .01), and a combination of a high and an intermediate score was an independent predictor of survival (hazard ratio 4.8, 95% confidence interval 1.27-4.78, P = .008). CONCLUSION: The cumulative number of aberrantly expressed biomarkers correlated with aggressive tumor biology and inferior oncologic outcomes in patients with ccRCC. Our data support prospective pathway-based exploration of the mTOR signaling cascade to augment current clinicopathologic predictors of oncologic outcomes in patients with ccRCC.
    Urology 01/2013; · 2.42 Impact Factor
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    ABSTRACT: Small renal masses (SRMs) are frequently encountered due to the ubiquitous use of abdominal cross-sectional imaging. Enhanced risk prediction in the management of SRMs would allow for a more informed decision of which, if any, patients would benefit from the available intervention modalities. Data suggest that a substantial proportion of SRMs are benign and that a significant proportion demonstrate indolent clinical behavior, leading to increased implementation of active surveillance strategies. Extirpative treatment of SRMs may be associated with worse outcomes, particularly in the elderly and infirm. Patient characteristics, including advanced age and comorbidity, and tumor anatomy are being increasingly recognized as having significant prognostic importance in terms of which type of treatment to offer. Further, a recent renewed interest in renal mass biopsy for risk stratification in SRMs has occurred as tumor size, radiographic characteristics, and growth kinetics are limited in their predictive capacity. Within the last decade, the reference standard treatment of SRMs evolved from radical nephrectomy to nephron-sparing approaches. This evolution continues, as we learn more about the complex interplay between patient and tumor characteristics and, as outcomes data mature, to ablative therapies and active surveillance.
    Current opinion in urology 06/2012; 22(5):347-52. · 2.50 Impact Factor
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    ABSTRACT: Objectives Increased knowledge about the molecular pathways involved in tumorigenesis has led to the discovery of new prognostic molecular markers and development of novel targeted therapies for renal cell carcinoma (RCC). In this review we describe the prognostic markers of RCC and highlight the areas of recent discovery with a focus on the mammalian target of rapamycin (mTOR) pathway.Methods We reviewed previous reports, using PubMed with the search terms ‘renal cell carcinoma’, ‘molecular markers’, ‘prognosis’, ‘outcomes’ and ‘mammalian target of rapamycin pathway’ published in the last two decades. We created a library of 100 references and focused on presenting the recent advances in the field.ResultsGrowing evidence suggests that mTOR deregulation is associated with many types of human cancer, including RCC. Consequently, temsirolimus and everolimus, which target mTOR, are approved for treating advanced RCC. There is a demand to integrate clinical, pathological and molecular markers into accurate prognostic models to provide patients with the most personalised cancer care possible.Conclusions The mTOR pathway is highly implicated in RCC tumorigenesis and progression, and its constituents might represent a promising prognostic tool and target for treating RCC. Combining newly discovered molecular markers with classic clinicopathological prognostics might potentially improve the management of RCC.
    Arab Journal of Urology. 06/2012; 10(2):110–117.
  • European Urology 04/2012; 62(1):e27-9. · 10.48 Impact Factor
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    Oussama M Darwish, Ganesh V Raj
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    ABSTRACT: Clinically localized prostate cancer is typically managed by well established therapies like radical prostatectomy, brachytherapy, and external beam radiation therapy. While many patients can be cured with definitive local therapy, some will have biochemical recurrence (BCR) of disease detected by a rising serum prostate-specific antigen (PSA). Management of these patients is nuanced and controversial. The natural history indicates that a majority of patients with BCR will not die from prostate cancer but from other causes. Despite this, a vast majority of patients with BCR are empirically treated with non-curable systemic androgen deprivation therapy (ADT), with its myriad of real and potential side effects. In this review article, we examined the very definition of BCR after definitive local therapy, the current status of imaging studies in its evaluation, the need for additional therapies, and the factors involved in the decision making in the choice of additional therapies. This review aims to help clinicians with the management of patients with BCR. The assessment of prognostic factors including absolute PSA level, time to recurrence, PSA kinetics, multivariable nomograms, imaging, and biopsy of the prostatic bed may help stratify the patients into localized or systemic recurrence. Patients with low-risk of systemic disease may be cured by a salvage local therapy, while those with higher risk of systemic disease may be offered the option of ADT or a clinical trial. An algorithm incorporating these factors is presented.
    Frontiers in Oncology 01/2012; 2:48.