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1.  The Total Number of Retroperitoneal Lymph Nodes Resected Impacts Clinical Outcome Following Chemotherapy for Metastatic Testicular Cancer 
Urology  2010;75(6):1431-1435.
Background
Following the multidisciplinary management of metastatic germ cell tumor, approximately 10 to 15% of patients with the histologic finding of fibrosis or teratoma will suffer disease recurrence. We evaluated the prognostic significance of the total number of lymph nodes obtained at post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND).
Materials and Methods
From 1989 to 2006, a total of 628 patients underwent PC-RPLND and were found to have either fibrosis or teratoma. Following Institutional Review Board approval, complete clinical and pathologic data were obtained from our prospective testis cancer surgical database. A Cox proportional hazards regression model was constructed to evaluate the association of the total number of lymph nodes obtained at PC-RPLND on disease recurrence.
Results
On pathologic evaluation, 248 (57%) patients had fibrosis and 184 (43%) patients had teratoma. The median number of lymph nodes resected was 25 (IQ range 15, 37). On multivariable analysis, increasing post-chemotherapy nodal size and decreasing lymph node counts were significant predictors of disease recurrence (p=0.01, 0.04, respectively). For patients with 10 nodes removed, the predicted 2 year relapse free probability was 90%, compared to 97% when 50 nodes were removed.
Conclusion
Our data suggests that the total number of lymph nodes removed and analyzed is an independent predictor of disease recurrence following PC-RPLND. This has implications both for the urologist to assure completeness of resection and for the pathologist to meticulously assess the pathologic specimens.
doi:10.1016/j.urology.2009.11.076
PMCID: PMC3654386  PMID: 20299079
testis cancer; surgery; chemotherapy; lymph node count
2.  A Review of Second-line Chemotherapy and Prognostic Models for Disseminated Germ Cell Tumors 
doi:10.1016/j.hoc.2011.03.007
PMCID: PMC3230321  PMID: 21570609
Testis Cancer; Germ Cell Neoplasm; Salvage Therapy; Chemotherapy
3.  TI-CE High-Dose Chemotherapy for Patients With Previously Treated Germ Cell Tumors: Results and Prognostic Factor Analysis 
Journal of Clinical Oncology  2010;28(10):1706-1713.
Purpose
We previously reported a dose-finding and phase II trial of the TI-CE regimen (paclitaxel [T] plus ifosfamide [I] followed by high-dose carboplatin [C] plus etoposide [E] with stem-cell support) in germ cell tumor (GCT) patients predicted to have a poor prognosis with conventional-dose salvage therapy. We now report the efficacy of TI-CE with prognostic factors for disease-free survival (DFS) and overall survival (OS) in our full data set of 107 patients.
Patients and Methods
Eligible patients had advanced GCTs with progressive disease following chemotherapy and unfavorable prognostic features (extragonadal primary site, incomplete response [IR] to first-line therapy, or relapse/IR to ifosfamide-cisplatin–based conventional-dose salvage). Univariate and multivariate analyses (MVAs) of prognostic factors were performed. The predictive ability of the Einhorn and Beyer prognostic models was assessed.
Results
Most patients were platinum refractory and had an IR to first-line chemotherapy. There were 54 (5%) complete and eight (8%) partial responses with negative markers; 5-year DFS was 47% and OS was 52% (median follow-up, 61 months). No relapses occurred after 2 years. Five (24%) of 21 primary mediastinal nonseminomatous GCTs are continuously disease free. On MVA, primary mediastinal site (P < .001), two or more lines of prior therapy (P < .001), baseline human chorionic gonadotropin ≥ 1,000 U/L (P = .01), and lung metastases (P = .02) significantly predicted adverse DFS. Poor-risk patients did worse than good- or intermediate-risk patients according to both Beyer (P < .002) and Einhorn (P < .05) models.
Conclusion
TI-CE is effective salvage therapy for GCT patients with poor prognostic features. Mediastinal primary site and two or more lines of prior therapy were most predictive of adverse DFS. Beyer and Einhorn models can assist in predicting outcome.
doi:10.1200/JCO.2009.25.1561
PMCID: PMC3651604  PMID: 20194867
4.  Identification and Validation of a Gene Expression Signature That Predicts Outcome in Adult Men With Germ Cell Tumors 
Journal of Clinical Oncology  2009;27(31):5240-5247.
Purpose
Germ cell tumor (GCT) is the most common malignancy in young adult men. Currently, patients are risk-stratified on the basis of clinical presentation and serum tumor markers. The introduction of molecular markers could improve outcome prediction.
Patients and Methods
Expression profiling was performed on 74 nonseminomatous GCTs (NSGCTs) from cisplatin-treated patients (ie, training set) and on 34 similarly treated patients with NSGCTs (ie, validation set). A gene classifier was developed by using prediction analysis for microarrays (PAM) for the binary end point of 5-year overall survival (OS). A predictive score was developed for OS by using the univariate Cox model.
Results
In the training set, PAM identified 140 genes that predicted 5-year OS (cross-validated classification rate, 60%). The PAM model correctly classified 90% of patients in the validation set. Patients predicted to have good outcome had significantly longer survival than those with poor predicted outcome (P < .001). For the OS end point, a 10-gene model had a predictive accuracy (ie, concordance index) of 0.66 in the training set and a concordance index of 0.83 in the validation set. Dichotomization of the samples on the basis of the median score resulted in significant differences in survival (P = .002). For both end points, the gene-based predictor was an independent prognostic factor in a multivariate model that included clinical risk stratification (P < .01 for both).
Conclusion
We have identified gene expression signatures that accurately predict outcome in patients with GCTs. These predictive genes should be useful for the prediction of patient outcome and could provide novel targets for therapeutic intervention.
doi:10.1200/JCO.2008.20.0386
PMCID: PMC3651602  PMID: 19770384
5.  A Phase I Study of Flavopiridol Administered with Oxaliplatin and Fluorouracil/Leucovorin (FOLFOX) in Advanced Solid Tumors: Encouraging Activity in Refractory Germ Cell Tumors 
Purpose
Flavopiridol, a cyclin-dependent kinase inhibitor, has promising clinical activity when combined with chemotherapy. Preclinical data indicate that flavopiridol enhances oxaliplatin (OX)- and fluorouracil (5FU)-induced apoptosis in a sequence-dependent manner.
Experimental Design
We conducted a phase I trial of flavopiridol + FOLFOX (folinic acid, 5FU, and OX) for advanced solid tumors. Flavopiridol was administered every two weeks with OX before 5FU, based on sequence-dependent growth inhibition. Flavopiridol pharmacokinetics and p53 status were evaluated.
Results
Forty-eight patients were treated on study. With dose escalation of OX (85 mg/m2) and 5FU (2400 mg/m2), dose-limiting toxicities (DLT) included hyponatremia, thrombocytopenia, and neutropenia. 5FU was subsequently reduced to allow for dose escalation of flavopiridol. DLTs with escalation of flavopiridol were nausea, vomiting, and neutropenia. The maximum tolerated dose (MTD) was flavopiridol 70 mg/m2, oxaliplatin 85 mg/m2, and 5FU 1800 mg/m2 continuous infusion over 48 hours. Clinical activity was noted in platinum-refractory germ cell tumors (GCTs): 3 out of 9 (33%) evaluable patients demonstrated a partial response on imaging, and 7 out of 10 (70%) had a decline in serum tumor markers. Responses were also observed in pancreatic, gastric, and sweat gland tumors. Flavopiridol pharmacokinetics had significant interpatient variability. At the MTD, tumor samples were p53 mutant (>30% positive cells) for responders and p53 wild-type for non-responders.
Conclusions
Flavopiridol with FOLFOX is a safe and tolerable regimen. Promising clinical activity was seen across tumor types. Encouraging results in the platinum-refractory GCT population has prompted a phase II trial which is currently open for accrual.
doi:10.1158/1078-0432.CCR-09-1502
PMCID: PMC2787644  PMID: 19934304
flavopiridol; FOLFOX; germ cell tumor; solid tumor; refractory
6.  Clinical Outcome and Predictors of Survival in Late Relapse of Germ Cell Tumor 
Journal of Clinical Oncology  2008;26(34):5524-5529.
Purpose
Late relapse (LR) of germ cell tumor (GCT) is a well recognized entity associated with poor survival. We report on our experience with LR and determine predictors of survival.
Patients and Methods
From 1990 to 2004, 75 patients were managed for LR of GCT at our institution. Clinical and pathologic parameters were reviewed. Estimates of cancer-specific survival were generated using the Kaplan-Meier method, and a Cox proportional hazards model was used to assess potential predictors of outcome.
Results
The median time to LR was 6.9 years (range, 2.1 to 37.7 years). Overall, 56 patients (75%) had LR in the retroperitoneum, including 25 (93%) of 27 patients initially managed without retroperitoneal lymph node dissection. The 5-year cancer-specific survival (CSS) was 60% (95% CI, 46% to 71%). Patients who underwent complete surgical resection at time of LR (n = 45) had a 5-year CSS of 79% versus 36% for patients without complete resection (n = 30; P < .0001). The 5-year CSS for chemotherapy-naive patients was significantly greater than patients with a prior history of chemotherapy as part of their initial management (5-year CSS, 93% v 49%, respectively). In multivariable analysis of pretreatment parameters available at the time of LR, the presence of symptoms (hazard ratio [HR] = 4.9) and multifocal disease (HR = 3.0) were associated with an inferior CSS.
Conclusion
The data suggest that meticulous control of the retroperitoneum is critical to prevent LR in the retroperitoneum. In multivariable analysis, patients with a symptomatic presentation and those with multifocal disease have a significantly decreased survival. Survival is greatly improved if complete surgical excision of disease is attained.
doi:10.1200/JCO.2007.15.7453
PMCID: PMC2651099  PMID: 18936477
7.  Treatment of stage I seminoma: is it time to change your practice? 
At the plenary session of the 2008 annual meeting of the American Society of Clinical Oncology, updated results were presented from a large randomized phase III trial comparing adjuvant radiation therapy (RT) and one cycle of Carboplatin for the adjuvant treatment of Stage I seminoma. Results of this Medical Research Council (MRC) trial led its investigators to conclude that one cycle of carboplatin was equivalent in safety and efficacy and less toxic than RT. In this editorial, the trial's design, statistics, toxicity, and length of follow-up are discussed within the context of historical treatments of this disease. With a 1.3% increase in relapse rate (5.3% with carboplatin vs. 4.0% with radiation), a 3% or greater increase in relapse rate could not be excluded, the primary endpoint of the study. A decrease in second testicular germ cell tumors was observed, but was equivalent to the increase in relapse rate. Acute toxicity was generally less with carboplatin. However, the extent of late toxicity, including late second neoplasms, cannot be evaluated because of the short median follow-up. Carboplatin is not yet a standard of care. Surveillance-based strategies, including risk-adapted policies that limit RT to patients with the greatest likelihood of relapse remain prudent at this time.
doi:10.1186/1756-8722-1-22
PMCID: PMC2588624  PMID: 18992162
8.  Characteristic promoter hypermethylation signatures in male germ cell tumors 
Molecular Cancer  2002;1:8.
Background
Human male germ cell tumors (GCTs) arise from undifferentiated primordial germ cells (PGCs), a stage in which extensive methylation reprogramming occurs. GCTs exhibit pluripotentality and are highly sensitive to cisplatin therapy. The molecular basis of germ cell (GC) transformation, differentiation, and exquisite treatment response is poorly understood.
Results
To assess the role and mechanism of promoter hypermethylation, we analyzed CpG islands of 21 gene promoters by methylation-specific PCR in seminomatous (SGCT) and nonseminomatous (NSGCT) GCTs. We found 60% of the NSGCTs demonstrating methylation in one or more gene promoters whereas SGCTs showed a near-absence of methylation, therefore identifying distinct methylation patterns in the two major histologies of GCT. DNA repair genes MGMT, RASSF1A, and BRCA1, and a transcriptional repressor gene HIC1, were frequently methylated in the NSGCTs. The promoter hypermethylation was associated with gene silencing in most methylated genes, and reactivation of gene expression occured upon treatment with 5-Aza-2' deoxycytidine in GCT cell lines.
Conclusions
Our results, therefore, suggest a potential role for epigenetic modification of critical tumor suppressor genes in pathways relevant to GC transformation, differentiation, and treatment response.
doi:10.1186/1476-4598-1-8
PMCID: PMC149411  PMID: 12495446
Germ cell tumor; promoter hypermethylation; MGMT; RASSF1A; BRCA1; gene expression
9.  Management of Unresectable Malignant Tumors at the Skull Base Using Concomitant Chemotherapy and Radiotherapy with Accelerated Fractionation 
Skull base surgery  1994;4(3):127-131.
Between January 1988 and June 1992, 20 patients with unresectable malignant tumors at the skull base were treated. Eleven had T4 lesions of the paranasal sinus/cavity complex, and 9 had T4 nasopharynx cancer. All patients had stage IV disease by the American Joint Committee on Staging Criteria. The histology was squamous cell cancer in 15 patients and other minor salivary gland histologies in 5. There was brain and/or dural invasion in 11 patients and orbital invasion in 9. All patients received radiation therapy with accelerated fractionation to a total of 70 Gy in 6 weeks. Concomitant cisplatin (100 mg/m2) was given on days 1 and 22 of radiation. Seven patients received mitomycin C (7.5 mg/m2) on days 1 and 22, plus adjuvant chemotherapy with cisplatin and vinblastine. Median follow-up was 11 (range: 1 to 43) months. At 2 years, local progression-free survival was 94%, distant metastases-free survival was 57%, and overall survival was 80%. Complications occurred in 20% and caused the death of 1 patient. Treatment of this group of patients with aggressive chemotherapy and radiation therapy produced excellent local control in our early experience, but longer follow-up is needed. There is a high rate of distant failure. Future strategies are outlined.
PMCID: PMC1661798  PMID: 17171161
10.  Reduced Proficiency in Homologous Recombination Underlies the High Sensitivity of Embryonal Carcinoma Testicular Germ Cell Tumors to Cisplatin and Poly (ADP-Ribose) Polymerase Inhibition 
PLoS ONE  2012;7(12):e51563.
Testicular Germ Cell Tumors (TGCT) and patient-derived cell lines are extremely sensitive to cisplatin and other interstrand cross-link (ICL) inducing agents. Nevertheless, a subset of TGCTs are either innately resistant or acquire resistance to cisplatin during treatment. Understanding the mechanisms underlying TGCT sensitivity/resistance to cisplatin as well as the identification of novel strategies to target cisplatin-resistant TGCTs have major clinical implications. Herein, we have examined the proficiency of five embryonal carcinoma (EC) cell lines to repair cisplatin-induced ICLs. Using γH2AX staining as a marker of double strand break formation, we found that EC cell lines were either incapable of or had a reduced ability to repair ICL-induced damage. The defect correlated with reduced Homologous Recombination (HR) repair, as demonstrated by the reduction of RAD51 foci formation and by direct evaluation of HR efficiency using a GFP-reporter substrate. HR-defective tumors cells are known to be sensitive to the treatment with poly(ADP-ribose) polymerase (PARP) inhibitor. In line with this observation, we found that EC cell lines were also sensitive to PARP inhibitor monotherapy. The magnitude of sensitivity correlated with HR-repair reduced proficiency and with the expression levels and activity of PARP1 protein. In addition, we found that PARP inhibition strongly enhanced the response of the most resistant EC cells to cisplatin, by reducing their ability to overcome the damage. These results point to a reduced proficiency of HR repair as a source of sensitivity of ECs to ICL-inducing agents and PARP inhibitor monotherapy, and suggest that pharmacological inhibition of PARP can be exploited to target the stem cell component of the TGCTs (namely ECs) and to enhance the sensitivity of cisplatin-resistant TGCTs to standard treatments.
doi:10.1371/journal.pone.0051563
PMCID: PMC3520950  PMID: 23251575
11.  Role of promoter hypermethylation in Cisplatin treatment response of male germ cell tumors 
Molecular Cancer  2004;3:16.
Background
Male germ cell tumor (GCT) is a highly curable malignancy, which exhibits exquisite sensitivity to cisplatin treatment. The genetic pathway(s) that determine the chemotherapy sensitivity in GCT remain largely unknown.
Results
We studied epigenetic changes in relation to cisplatin response by examining promoter hypermethylation in a cohort of resistant and sensitive GCTs. Here, we show that promoter hypermethylation of RASSF1A and HIC1 genes is associated with resistance. The promoter hypermethylation and/or the down-regulated expression of MGMT is seen in the majority of tumors. We hypothesize that these epigenetic alterations affecting MGMT play a major role in the exquisite sensitivity to cisplatin, characteristic of GCTs. We also demonstrate that cisplatin treatment induce de novo promoter hypermethylation in vivo. In addition, we show that the acquired cisplatin resistance in vitro alters the expression of specific genes and the highly resistant cells fail to reactivate gene expression after treatment to demethylating and histone deacetylase inhibiting agents.
Conclusions
Our findings suggest that promoter hypermethylation of RASSF1A and HIC1 genes play a role in resistance of GCT, while the transcriptional inactivation of MGMT by epigenetic alterations confer exquisite sensitivity to cisplatin. These results also implicate defects in epigenetic pathways that regulate gene transcription in cisplatin resistant GCT.
doi:10.1186/1476-4598-3-16
PMCID: PMC420487  PMID: 15149548

Results 1-11 (11)