Jan Rajec

Phase II study of everolimus in refractory testicular germ cell tumors

BACKGROUND Testicular germ cell tumors (TGCTs) represent a highly curable disease; however, a small proportion of patients develop disease recurrence. Loss of the tumor-suppressor gene phosphatase and tensin homolog marks the transition from intratubular germ cell neoplasia to invasive GCT and is correlated with disease progression. Inactivation of phosphatase and tensin homolog is associated with deregulation of the PI3K/Akt pathway and increased mammalian target of rapamycin signaling. This study aimed to determine the efficacy and toxicity of a mammalian target of rapamycin inhibitor, everolimus, in patients with refractory TGCTs. METHODS From December 2011 to February 2015, 15 patients with refractory GCTs were enrolled in the phase II study. All patients were pretreated with at least 2 cisplatin-based therapies; 4 tumors (26.7%) were absolutely refractory to cisplatin and 9 patients (60.0%) had visceral nonpulmonary metastases. Everolimus was administered at a dose of 10mg daily until progression or unacceptable toxicity. The primary end point was the objective response rate, according to Response Evaluation Criteria in Solid Tumors. RESULTS No objective response was observed, but 6 patients (40.0%) achieved 12-week progression-free survival. During a median follow-up period of 3.6 months (range: 1-35.1mo), all patients experienced disease progression and 11 patients (80.0%) died. Median progression-free survival was 1.7 months (95% CI: 1.1-4.0mo) and median overall survival was 3.6 months (95% CI: 2.0-11.0mo). CONCLUSIONS This study failed to achieve its primary end point and our data suggest limited efficacy of everolimus against unselected heavily pretreated refractory TGCTs. CONDENSED ABSTRACT Everolimus showed limited efficacy in unselected heavily pretreated refractory TGCTs. Prolonged disease stabilization could be achieved in selected patients.

Plasma Cytokines Correlated With Disease Characteristics, Progression-Free Survival, and Overall Survival in Testicular Germ-Cell Tumor Patients

Micro‐Abstract We performed a translational study and found a correlation among overall survival, progression‐free survival, and circulating cytokines in metastatic testicular germ‐cell tumor patients. Association between baseline clinicopathologic features and plasma cytokines was also assessed. Plasma cytokines could be a potential biomarker for identification of high‐risk patients. Background: Cytokines are the communicators of immune system and are involved in all immune responses. The aim of this study was to assess the correlation among plasma cytokines, patient and tumor characteristics, and clinical outcome in chemonaive testicular germ‐cell tumor (TGCT) patients. Patients and Methods: This study included 92 metastatic chemotherapy‐naive TGCT patients treated with platinum‐based chemotherapy from July 2010 to March 2014. Plasma was isolated before first administration of chemotherapy, and the concentration of 51 plasma cytokines were analyzed using multiplex bead arrays. Results: At a median follow‐up of 33.2 months (range, 0.1‐54.8 months), 10.9% of patients experienced disease progression, and 7.6% died. Several cytokines were associated with different baseline clinicopathologic features. Elevated plasma levels of interferon (IFN)‐&agr;2, interleukin (IL)‐2R&agr;, IL‐16, hepatocyte growth factor (HGF), and monocyte chemotactic protein (MCP)‐3 were significantly associated with worse progression‐free survival and overall survival (OS). Moreover, elevated levels of stem‐cell growth factor (SCGF)‐&bgr; were also associated with worse OS. Patients with elevated levels of all 6 cytokines experienced significantly worse outcomes compared to patients who had fewer than 6 cytokines elevated (hazard ratio = 12.06; 95% confidence interval, 7.39‐19.49; P = .002 for progression‐free survival, and hazard ratio = 39.65; 95% confidence interval, 25.03‐62.18; P < .00001 for OS, respectively). Results were independent of International Germ Cell Cancer Collaborative Group criteria. Conclusion: We found a correlation among progression free‐survival, OS, and circulating cytokines in TGCT. This suggests the existence an association between plasma cytokines and baseline clinicopathologic features in TGCT. Plasma cytokines could be used for identification of high‐risk patients who are candidates for new therapeutic approaches.

Prognostic value of intratumoral carbonic anhydrase IX expression in testicular germ cell tumors

Testicular germ cell tumors (TGCTs) represent a highly curable malignancy, however a small proportion of patients fails to be cured with cisplatin-based chemotherapy. Carbonic anhydrase IX (CA IX) is upregulated by hypoxia in several cancer types and correlates with a poor prognosis. The present translational study evaluated expression and prognostic value of CA IX in TGCTs. Surgical specimens from 228 patients with TGCTs were processed by the tissue microarray method and subjected to immunohistochemistry with the M75 monoclonal antibody. CA IX expression was evaluated in tumors vs. adjacent normal testicular tissues and correlated with clinicopathological characteristics and clinical outcome. CA IX expression was detected in 62 (30.2%) of TGCTs compared to 0 (0%) of normal tissue adjacent to testicular tumor (P<0.001). The highest frequency of the CA IX expression was detected in teratoma (39.0%), followed by seminoma (22.7%), yolk sac tumor (22.2%), embryonal carcinoma (11.9%) and choriocarcinoma (7.7%). None of germ cell neoplasias in situ (GCNIS) exhibited CA IX expression. Patients without the CA IX tumor expression showed significantly better progression-free survival, but not overall survival, compared to patients with the CA IX expression [hazard ratio (HR), 0.57; 95% CI, 0.32–1.02; P=0.037 and HR, 0.58; 95% CI, 0.29–1.16; P=0.088, respectively]. There was no significant correlation between the CA IX expression and clinicopathological variables. The intratumoral CA IX expression can serve as a prognostic marker in the TGCT patients. These results suggest that activation of the hypoxia-induced pathways may be important in the treatment failure in TGCTs patients.

Prognostic value of serum carbonic anhydrase IX in testicular germ cell tumor patients

Despite the fact that testicular germ cell tumors (TGCTs) are one of the most chemosensitive solid tumors, a small proportion of patients fail to be cured following cisplatin-based first line chemotherapy. Upregulation of carbonic anhydrase IX (CA IX) in various solid tumors is associated with poor outcome. The current prospective study investigated the prognostic value of serum CA IX level in TGCTs. In total, 83 patients (16 non-metastatic following orchiectomy with no evidence of disease, 57 metastatic chemotherapy-naïve and 10 metastatic relapsed chemotherapy-pretreated) starting adjuvant and/or new line of chemotherapy and 35 healthy controls were enrolled in the study. Serum CA IX values were determined using an enzyme-linked immunosorbent assay, and intratumoral CA IX was analyzed by immunohistochemistry. Metastatic chemotherapy-naïve patients had significantly higher mean CA IX serum levels than healthy controls (490.6 vs. 249.6 pg/ml, P=0.005), while there was no difference in serum CA IX levels in non-metastatic or relapsed TGCT patients compared with healthy controls. There was no significant difference in the mean serum CA IX levels between different groups of patients and between the first and second cycle of chemotherapy, nor association with patients/tumor characteristics. Serum CA IX was not prognostic for progression-free survival [hazard ratio (HR)=0.81, P=0.730] or overall survival (HR=0.64, P=0.480). However, there was a significant association between intratumoral CA IX expression and serum CA IX concentration (rho=0.51, P=0.040). These results suggest that serum CA IX level correlates with tumor CA IX expression in TGCT patients, but fails to exhibit either a prognostic value or an association with patients/tumor characteristics.

[Is the same tyrosine kinase inhibitor still effective after development of brain metastases? A Case report].

There is a new era of treatment options since introduction of new biological targeted therapies (tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors) in renal cell cancer. However, in patients who developed brain metastases, there is still treatment dilemma about an optimal therapeutic scenario, particularly in the subgroup of patients with-out disease progression outside the central nervous system. The objective of this case report is to present that it is possible to continue the same targeted therapy after development of brain metastasis after application of local whole brain irradiation with meaningful overall survival.

Antioxidant stimulation as the adaptation mechanism in patients with metastatic urothelial cancers (MUC) treated with gemcitabine and cisplatin (GC).

281 Background: The role of oxidative stress inpatients with MUC treated with GC is unknown. The objective of this ongoing study is to determinate plasma antioxidants, lipid peroxidation, and lipids in pts. with MUC before and after GC treatment, and to compare them with control. METHODS From May 2010 - January 2012, 42 MUC patients were enrolled into this study. The median of age was 65 years (range 44-81), median of metastasis sites was 2 (range 1-7). All patients were treated with gemcitabine 1000 mg/m2 i.v. days 1 and 8 with cisplatin 75 mg/m2 i.v. day 1, the new cycle of treatment started on day 22. Plasma samples were collected before and after 3 cycles of chemotherapy with GC. The control consisted of 22 subjects without cancer with age median 61 years (range 39-66). RESULTS In MUC patients, plasma γ-tocopherol before treatment were significantly lower (1.77±0.70 vs 2.13±0.70 μmol/L, P<0.04) and plasma TBARS higher vs control (5.76±1.32 vs 4.51±0.56 μmol/L, P<0.001). When compared baseline plasma levels to values after 3 cycles of GC, significant changes were noticed: γ-tocopherol (1.77±0.70 vs 2.29±1.14 μmol/L, P<0.04), α-tocopherol (24.23±5.14 vs 29.25±6.24 μmol/L, P<0.003), CoQ10-TOTAL (0.43±0.15 vs 0.56±0.16 μmol/L, P=0.003). TBARS concentrations were significantly decreased (5.76±1.32 vs 4.85±1.08 μmol/L, P=0.01). The concentrations of plasma lipids after GC were increased: Cholesterol (4.61±0.99 vs 5.47±1.21 mmol/L, P<0.004), TAG (1.30±0.65 vs 1.74±0.81 mmol/L, P<0.02), LDL cholesterol (2.94±0.73 vs 3.46±0.86 mmol/L, P<0.02), VLDL cholesterol (0.59±0.30 vs 0.81±0.37 mmol/L, P<0.02), and HDL cholesterol (1.08±0.39 vs 1.24±0.43 mmol/L, NS). CONCLUSIONS GC in patients with MUC stimulated antioxidant defence system, increased plasma lipids, and decreased lipid peroxidation. The antioxidant stimulation might be one of the adaptation mechanisms that protect organism and might prevent or reduce chemotherapy side-effects. Acknowledgement: Study is supported by VEGA 1/0614/12 and Ministry of Health, Slovakia, grant 2007/29-UK-06.

Adjuvant high-dose IFN-alfa2b real life treatment outcome in the patients with malignant melanoma.

e19037 Background: Kirkwoods studies found that adjuvant HD IFNa reduced 24%-38% relapse rate of malignant melanoma. This study findings want to confirm safety of HD regimen in terms of keeping th...