Low-molecular-weight heparin prophylaxis is not associated with decreased incidence of venous thromboembolism in testicular germ cell tumor patients receiving chemotherapy.

Venous thromboembolism (VTE), commonly occurring in patients with testicular germ cell tumors (GCTs), is associated with increased morbidity and mortality. Prophylactic anticoagulation has been shown to decrease the risk of VTE in patients with malignancies. The objective was to evaluate the effect of low-molecular-weight heparin (LMWH) prophylaxis on the incidence of VTE and outcome in patients with GCT treated with first-line chemotherapy. In this retrospective study, 353 chemotherapy-naive GCT patients were treated with first-line chemotherapy at the National Cancer Institute, Bratislava, Slovakia (2000-2017). Median follow-up was 71 months. VTE was defined as any venous thrombosis or pulmonary embolism, confirmed by imaging, occurring during first-line chemotherapy. Exclusion criteria were LMWH use before starting chemotherapy and VTE on initial staging. We observed 14 (4.0%) VTE events. No visceral thromboses were observed. The difference in VTE incidence between patients with and without prophylaxis was not statistically significant (5.8% vs. 3.2%, p=0.37). We observed a trend toward longer overall survival in patients without prophylaxis (hazard ratio = 0.61, 95% confidence interval = 0.32-1.13, p=0.08). Patients with extragonadal GCT receiving VTE prophylaxis had significantly shorter survival (hazard ratio = 0.29, 95% confidence interval = 0.08-1.12, p=0.04). This effect was most likely driven by a higher incidence of treatment-related deaths in patients with extragonadal GCT receiving LMWH (p=0.06). LMWH prophylaxis was not associated with decreased VTE incidence. Moreover, there was a higher incidence of treatment-related deaths in patients with extragonadal tumor location. Low-molecular-weight heparin prophylaxis during hospitalization should not be used routinely in patients with testicular germ cell tumors receiving chemotherapy.

Changes in CoQ10/Lipids Ratio, Oxidative Stress, and Coenzyme Q10 during First-Line Cisplatin-Based Chemotherapy in Patients with Metastatic Urothelial Carcinoma (mUC).

Oxidative stress plays an important role in cancer pathogenesis, and thiobarbituric acid-reactive substance level (TBARS)­a parameter of lipid peroxidation­has prognostic significance in chemotherapy-naive patients with metastatic urothelial carcinoma (mUC). However, the effect of cisplatin (CDDP)-based chemotherapy on oxidative stress, coenzyme Q10, and antioxidants remains unknown. The objective of this prospective study was to determine possible changes in the CoQ10 (coenzyme Q10)/lipids ratio, antioxidants (α-tocopherol, γ-tocopherol, ß-carotene, CoQ10), total antioxidant status (TAS), and TBARS in plasma at baseline and during first-line chemotherapy based on CDDP in mUC subjects. In this prospective study, 63 consecutive patients were enrolled. The median age was 66 years (range 39−84), performance status according to the Eastern Cooperative Oncology Group (ECOG) was 2 in 7 subjects (11.1%), and visceral metastases were present in 31 (49.2%) patients. Plasma antioxidants were determined by HPLC and TAS and TBARS spectrophotometrically. After two courses of chemotherapy, we recorded significant enhancements compared to baseline for total cholesterol (p < 0.0216), very low-density lipoprotein (VLDL) cholesterol (p < 0.002), triacylglycerols (p < 0.0083), α-tocopherol (p < 0.0044), and coenzyme Q10-TOTAL (p < 0.0001). Ratios of CoQ10/total cholesterol, CoQ10/HDL-cholesterol, and CoQ10/LDL-cholesterol increased during chemotherapy vs. baseline (p < 0.0048, p < 0.0101, p < 0.0032, respectively), while plasma TBARS declined (p < 0.0004). The stimulation of antioxidants could be part of the defense mechanism during CDDP treatment. The increased index of CoQ10-TOTAL/lipids could reflect the effect of CDDP protecting lipoproteins from peroxidation.

Are Changes in the Percentage of Specific Leukocyte Subpopulations Associated with Endogenous DNA Damage Levels in Testicular Cancer Patients?

Chemoresistance of germ cell tumors (GCTs) represents an intensively studied property of GCTs that is the result of a complicated multifactorial process. One of the driving factors in this process is the tumor microenvironment (TME). Intensive crosstalk between the DNA damage/DNA repair pathways and the TME has already been reported. This study aimed at evaluating the interplay between the immune TME and endogenous DNA damage levels in GCT patients. A cocultivation system consisting of peripheral blood mononuclear cells (PBMCs) from healthy donors and GCT cell lines was used in an in vitro study. The patient cohort included 74 chemotherapy-naïve GCT patients. Endogenous DNA damage levels were measured by comet assay. Immunophenotyping of leukocyte subpopulations was performed using flow cytometry. Statistical analysis included data assessing immunophenotypes, DNA damage levels and clinicopathological characteristics of enrolled patients. The DNA damage level in PBMCs cocultivated with cisplatin (CDDP)-resistant GCT cell lines was significantly higher than in PBMCs cocultivated with their sensitive counterparts. In GCT patients, endogenous DNA damage levels above the cutoff value were independently associated with increased percentages of natural killer cells, CD16-positive dendritic cells and regulatory T cells. The crosstalk between the endogenous DNA damage level and specific changes in the immune TME reflected in the blood of GCT patients was revealed. The obtained data contribute to a deeper understanding of ongoing interactions in the TME of GCTs.

Increased levels of XPA might be the basis of cisplatin resistance in germ cell tumours.

BACKGROUND: Germ cell tumours (GCTs) represent a highly curable malignity as they respond well to cisplatin (CDDP)-based chemotherapy. Nevertheless, a small proportion of GCT patients relapse or do not respond to therapy. As this might be caused by an increased capacity to repair CDDP-induced DNA damage, identification of DNA repair biomarkers predicting inadequate or aberrant response to CDDP, and thus poor prognosis for GCT patients, poses a challenge. The objective of this study is to examine the expression levels of the key nucleotide excision repair (NER) factors, XPA, ERCC1 and XPF, in GCT patients and cell lines. METHODS: Two hundred seven GCT patients' specimens with sufficient follow-up clinical-pathological data and pairwise combinations of CDDP-resistant and -sensitive GCT cell lines were included. Immunohistochemistry was used to detect the ERCC1, XPF and XPA protein expression levels in GCT patients' specimen and Western blot and qRT-PCR examined the protein and mRNA expression levels in GCT cell lines. RESULTS: GCT patients with low XPA expression had significantly better overall survival than patients with high expression (hazard ratio = 0.38, 95% confidence interval: 0.12-1.23, p = 0.0228). In addition, XPA expression was increased in the non-seminomatous histological subtype, IGCCCG poor prognosis group, increasing S stage, as well as the presence of lung, liver and non-pulmonary visceral metastases. Importantly, a correlation between inadequate or aberrant CDDP response and XPA expression found in GCT patients was also seen in GCT cell lines. CONCLUSIONS: XPA expression is an additional independent prognostic biomarker for stratifying GCT patients, allowing for improvements in decision-making on treatment for those at high risk of refractoriness or relapse. In addition, it could represent a novel therapeutic target in GCTs.

Increased Stromal Infiltrating Lymphocytes Are Associated with the Risk of Disease Progression in Mesenchymal Circulating Tumor Cell-Positive Primary Breast Cancer Patients.

Circulating tumor cells (CTCs) and the immune infiltration of tumors are closely related to clinical outcomes. This study aimed to verify the influence of stromal lymphocyte infiltration and the immune context of tumor microenvironment on the hematogenous spread and prognosis of 282 chemotherapy naïve primary BC patients. To detect the presence of mesenchymal CTCs, RNA extracted from CD45-depleted peripheral blood was interrogated for the expression of mesenchymal gene transcripts. Tumor-infiltrating lymphocytes (TILs) were detected in the stromal areas by immunohistochemistry, using CD3, CD8, and CD45RO antibodies. The concentrations of 51 plasma cytokines were measured by multiplex bead arrays. TILs infiltration in mesenchymal CTC-positive patients significantly decreased their progression-free survival (HR = 4.88, 95% CI 2.30-10.37, p < 0.001 for CD3high; HR = 6.17, 95% CI 2.75-13.80, p < 0.001 for CD8high; HR = 6.93, 95% CI 2.86-16.81, p < 0.001 for CD45ROhigh). Moreover, the combination of elevated plasma concentrations of transforming growth factor beta-3 (cut-off 662 pg/mL), decreased monocyte chemotactic protein-3 (cut-off 52.5 pg/mL) and interleukin-15 (cut-off 17.1 pg/mL) significantly increased the risk of disease recurrence (HR = 4.838, 95% CI 2.048-11.427, p < 0.001). Our results suggest a strong impact of the immune tumor microenvironment on BC progression, especially through influencing the dissemination and survival of more aggressive, mesenchymal CTC subtypes.

Clinical utility of plasma miR-371a-3p in germ cell tumors.

Germ cell tumours predominantly of the testis ((T)GCTs) are remarkably chemotherapy sensitive. However, a small proportion of patients fail to be cured with cisplatin-based combination chemotherapy. miR-371a-3p is a new liquid biopsy biomarker for (T)GCTs. The aim of this study was to evaluate clinical utility of plasma miR-371a-3p level in patients starting systemic chemotherapy. Patients were included before the first cycle (N = 180) and second cycle (N = 101) of systemic first line chemotherapy, treated between July 2010 and May 2017. Plasma miR-371a-3p levels were measured with the ampTSmiR test and compared to disease characteristics and outcome. Pretreatment plasma miR-371a-3p levels were increased in 51.7% of cases and associated with number of metastatic sites, presence of lung, retroperitoneal, and mediastinal lymph node metastases, S - stage, IGCCCG risk group, and response to therapy. Patients with a negative pretreatment plasma level had better progression-free survival (PFS) and overall survival (OS) compared to patients being positive for miR-371a-3p (hazard ratio [HR] = 0.26, 95% confidence interval [CI] 0.09-0.71, P = 0.02 for PFS and HR = 0.21, 95% CI 0.07-0.67, P = 0.03 for OS, respectively). Patients negative for miR-371a-3p in both samples had a superior PFS (HR = 0.10, 95% CI 0.01-21.49, P = 0.02) and OS (HR = 0.08, 95% CI 0.01-27.81, P = 0.008) compared to patients with miR-371a-3p positive in both samples (multivariate analyses were non-significant). In total 68% of the patients were S0. This study demonstrates clinical value of plasma miR-371a-3p level in chemotherapy naïve (T)GCT patients starting first line of chemotherapy to predict prognosis.

Systemic immune-inflammation index in germ-cell tumours.

BACKGROUND: We evaluated systemic immune-inflammation index (SII) and its association with patient outcome in germ-cell tumours (GCTs). METHODS: Two independent cohorts of patients were analysed; the discovery set (n=171) from a single institution and the validation set (n=181) previously included in a study evaluating PD-L1 in GCTs. The SII was calculated using platelet (P), neutrophil (N) and lymphocyte (L) counts before chemotherapy and correlated with survival using regression analyses and Kaplan-Meier method. RESULTS: In the discovery cohort, the SII was associated with poor risk clinical features. Patients with low SII had significantly longer progression-free survival (HR=0.22, 95% CI 0.12-0.41, P<0.001) and overall survival (OS) (HR=0.16, 95% CI 0.08-0.32, P<0.001) compared to high SII. This index was independent of International Germ Cell Cancer Collaborative Group criteria in multivariable Cox regression analysis for OS and was validated in an independent cohort. When combining PD-L1 expression on tumour infiltrating lymphocytes (TILs) and SII, we identified three distinctive prognostic groups. CONCLUSIONS: High SII was associated with poor outcome in GCTs. Combination of PD-L1 positive TILs and SII could further refine prognosis in GCTs.

Long-Term Cognitive Functioning in Testicular Germ-Cell Tumor Survivors.

BACKGROUND: Treatment for cancer may lead to development of cognitive difficulties in cancer survivors. This study aimed to evaluate long-term cognitive functioning (CogF) in germ-cell tumor (GCT) survivors. SUBJECTS, MATERIALS, AND METHODS: GCT survivors (n = 155) from the National Cancer Institute of Slovakia completed the Functional Assessment of Cancer Therapy Cognitive Function at a median of 10 years of follow-up (range: 5-32). The study group consisted of survivors receiving a cisplatin-based chemotherapy, radiotherapy to the retroperitoneal lymph nodes, or both, whereas the control group included survivors treated with orchiectomy only. RESULTS: Of the total survivors, 138 received treatment beyond orchiectomy and 17 controls had orchiectomy alone. Any treatment resulted in significantly greater cognitive difficulties on the overall cognitive function score. Treatment with radiotherapy was associated with cognitive declines in overall cognitive functioning and in subscales for perceived cognitive impairment and cognitive impairment perceived by others (both p < .05). The burden of chemotherapy plus radiotherapy or radiotherapy versus controls resulted in the impairment in all cognitive functioning domains (all p < .05). Overall long-term cognitive impairment was independent of age in the multivariable analysis. CONCLUSION: This prospective study shows that GCT survivors suffer from a long-term CogF impairment. These results may help guide clinicians' decisions in treatment and follow-up of GCTs. IMPLICATIONS FOR PRACTICE: In this study, long-term survivors of germ-cell tumors have reported cognitive impairment after curative treatment with radiotherapy and chemotherapy compared with controls who had treatment with orchiectomy only. These data provide an argument against the use of adjuvant radiotherapy for stage I seminoma. Unnecessary overtreatment with chemotherapy and additional radiotherapy after chemotherapy should be avoided.

ßcatenin is a marker of poor clinical characteristics and suppressed immune infiltration in testicular germ cell tumors.

BACKGROUND: WNT/ßcatenin (WNTß) pathway is activated in early stages of embryonic development. We aimed to evaluate the significance of ßcatenin in germ cell tumors (GCTs) and explore associations with the inflamed environment. METHODS: Surgical specimens from 247 patients were analyzed. Βcatenin expression was detected in the tumor tissue by immunohistochemistry and correlated with clinical characteristics, outcome, PD-L1 expression and systemic immune-inflammation index (SII). The Ingenuity Pathway Analysis (IPA) was used to investigate the immune-cell related effects of ßcatenin and PD-L1 encoding genes. RESULTS: ßcatenin was expressed in 86.2% of GCTs. The expression in seminomas was significantly lower compared to all subtypes of non-seminoma (all P <  0.0001). A high expression (weighted histoscore > 150) was associated with primary mediastinal non-seminoma (P = 0.035), intermediate/poor risk disease (P = 0.033) and high tumor markers (P = 0.035). We observed a positive correlation with the PD-L1 in tumor and an inverse correlation with the SII. IPA uncovered relationships of CTNNB (ßcatenin) and CD274 (PD-L1) genes and their effects on differentiation, proliferation and activation of lymphocyte subtypes. CONCLUSION: Herein, we showed that ßcatenin is associated with male adult GCT characteristics as well as supressed immune environment.

Cancer Control in Central and Eastern Europe: Current Situation and Recommendations for Improvement.

: The incidence of many cancers is higher in Western European (WE) countries, but mortality is frequently higher in Central and Eastern European (CEE) countries. A panel of oncology leaders from CEE countries participating in the South Eastern European Research Oncology Group (SEEROG) was formed in 2015, aiming to analyze the current status and trends of oncology care in CEE and to propose recommendations leading to improved care and outcomes. The SEEROG panel, meeting during the 11th Central European Oncology Congress, proposed the following: (a) national cancer control plans (NCCPs) required in all CEE countries, defining priorities in cancer care, including finance allocation considering limited health care budgets; (b) national cancer registries, describing in detail epidemiological trends; (c) efforts to strengthen comprehensive cancer centers; (d) that multidisciplinary care should be mandated by the NCCPs; (e) that smaller hospitals should be connected to multidisciplinary tumor boards via the Internet, providing access to specialized expertise; (f) nationwide primary prevention programs targeting smoking, obesity, and alcohol consumption and centrally evaluated secondary prevention programs for cervical, colorectal, and breast cancers; (g) prioritize education for all involved in cancer care, including oncology nurses, general practitioners, and palliative care providers; (h) establish outpatient care in day hospitals to reduce costs associated with the current inpatient model of care in CEE countries and to improve patients' quality of life; (i) long-term pharmacoeconomic evaluations of new therapies in CEE countries; (j) increase national oncology budgets in view of the higher mortality rates in CEE compared with WE countries; and (k) CEE countries urgently need help from the European Union to increase and monitor overall investment in cancer care. IMPLICATIONS FOR PRACTICE: Significant differences in cancer incidence and mortality have been observed between European countries. While the incidence of many cancer types is higher in Western European (WE) countries, the mortality is generally higher in Central and Eastern Europe (CEE). The primary purpose of this review was to describe the current status and trends of oncology care in the CEE region, to raise awareness among physicians, regulators, and payers, and to propose the most needed changes in order to make the oncology care in CEE closer to the WE standards.

Relationship between circulating tumor cells, blood coagulation, and urokinase-plasminogen-activator system in early breast cancer patients.

Cancer is a risk factor for venous thromboembolism (VTE) and plasma d-dimer (DD) and tissue factor (TF) are established VTE associated markers. Circulating tumor cells (CTCs) are associated with the risk of VTE in metastatic breast cancer. This study aimed to correlate CTCs, blood coagulation and the urokinase plasminogen activator (uPA) system in primary breast cancer (PBC) patients. This prospective study included 116 PBC patients treated by primary surgery. CTCs were detected by quantitative RT-PCR assay for expression of epithelial (CK19) or epithelial-mesenchymal transition (EMT) genes (TWIST1, SNAIL1, SLUG, ZEB1, FOXC2). Plasma DD, TF, uPA system proteins were detected by enzyme-linked immunosorbent assays, while expressions of uPA system in surgical specimens were evaluated by immunohistochemistry. CTCs were detected in 27.6% patients. Patients with CTCs had a significantly higher mean plasma DD (ng/mL) than those of patients without CTCs (632.4 versus 365.4, p = 0.000004). There was no association between plasma TF and CTCs. Epithelial CTCs exhibit higher expression of uPA system genes compared to EMT_CTCs. Patients with CTCs had higher plasma uPA proteins than those of patients without CTCs; there was no correlation between tissue expression of uPA system, CTCs, DD or TF levels. In multivariate analysis CTCs and patients age were independent factors associated with plasma DD. We found association between plasma DD and CTCs indicating a potential role for activation of the coagulation cascade in the early metastatic process. CTCs could be directly involved in coagulation activation or increased CTCs could be marker of aggressive disease and increased VTE risk.

Matrix metalloproteinase 1 and circulating tumor cells in early breast cancer.

BACKGROUND: Matrix metalloproteinases (MMPs) are involved in cancer invasion and metastasis. Circulating tumor cells (CTCs) play role in tumor dissemination and are an independent survival predictor in breast cancer (BC) patients. The aim of this study was to assess correlation between CTCs and tumor MMP1 in BC. METHODS: Study included 149 primary BC patients treated by surgery from March 2012 to March 2013. Peripheral blood mononuclear cells (PBMC) were depleted of hematopoietic cells using RossetteSep(TM) selection kit. RNA extracted from CD45-depleted PBMC was interrogated for expression of EMT (TWIST1, SNAIL1, SLUG, ZEB1) and epithelial (CK19) gene transcripts by qRT-PCR. Patient samples with higher epithelial and/or mesenchymal gene transcripts than those of healthy donors (n = 60) were considered as CTC positive. Expression of MMP1 in surgical specimens was evaluated by immunohistochemistry. RESULTS: CTCs were detected in 24.2% patients. CTCs exhibiting only epithelial markers were present in 8.7% patients, whereas CTCs with epithelial-mesenchymal transition (EMT) markers (CTC_EMT) were observed in 13.4% of patients and CTCs co-expressing both markers were detected in 2.0% patients. Patients with CTC_EMT in peripheral blood had significantly increased expression of MMP1 in tumor cells (p = 0.02) and tumor associated stroma (p = 0.05) than those of patients without CTC_EMT. In multivariate analysis, CTC_EMT and tumor grade were independently associated with MMP1 expression in cancer cells, while CTC_EMT and Ki67 were independently associated with MMP1 expression in cancer associated stroma. CONCLUSION: Our data suggest link between MMP1 and CTCs with EMT phenotype and support role of MMPs and EMT in tumor dissemination.

Delays in diagnosis and treatment of breast cancer: a multinational analysis.

BACKGROUND: Reducing treatment delay improves outcomes in breast cancer. The aim of this study was to determine factors influencing patient- and system-related delays in commencing breast cancer treatment in different countries. METHODS: A total of 6588 female breast cancer patients from 12 countries were surveyed. Total delay time was determined as the sum of the patient-related delay time (time between onset of the first symptoms and the first medical visit) and system-related delay time (time between the first medical visit and the start of therapy). RESULTS: The average patient-related delay time and total delay time were 4.7 (range: 3.4-6.2) weeks and 14.4 (range: 11.5-29.4) weeks, respectively. Longer patient-related delay times were associated with distrust and disregard, and shorter patient-related delay times were associated with fear of breast cancer, practicing self-examination, higher education level, being employed, having support from friends and family and living in big cities. The average system-related delay time was 11.1 (range: 8.3-24.7) weeks. Cancer diagnosis made by an oncologist versus another physician, higher education level, older age, family history of female cancers and having a breast lump as the first cancer sign were associated with shorter system-related delay times. Longer patient-related delay times and higher levels of distrust and disregard were predictors of longer system-related delay times. CONCLUSIONS: The delay in diagnosis and treatment of breast cancer remains a serious problem. Several psychological and behavioural patient attributes strongly determine both patient-related delay time and system-related delay time, but their strength is different in particular countries.

Chemotherapy-Induced Peripheral Neuropathy (CIPN) as a Predictor of Decreased Quality of Life in Testicular Germ Cell Tumor Survivors.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) after curative treatment for testicular germ cell tumors (GCTs) has been previously reported. It has been shown that CIPN can contribute to impaired quality of life (QOL) in cancer survivors. Herein, we aimed to evaluate CIPN in association with QOL in GCT survivors. PATIENTS AND METHODS: European Organization for Research and Treatment of Cancer (EORTC) Quality of Life - Chemotherapy-Induced Peripheral Neuropathy questionnaire (QLQ-CIPN20) and Quality of Life Questionnaire (QLQ-C30) were prospectively completed by GCT survivors (N = 151) at National Cancer Institute in Slovakia during their annual follow-up. The median follow-up was 10 years (range 4-30). Upon obtaining the scores from each questionnaire, each score from QLQ-C30 was correlated with CIPN defined as high or low (above and below median) as obtained from CIPN20. RESULTS: GCT survivors with high overall CIPN score reported impaired QOL in QLQ-C30. The global health status was lower in survivors with high CIPN versus low CIPN (mean score ± SEM: 67.17 ± 2.00 vs. 86.18 ± 1.76, P < .00001). Survivors with high CIPN reported worse physical, role, emotional, cognitive, and social functioning compared to survivors with low CIPN (all P < .00001). CIPN high survivors perceived more fatigue, nausea, pain, dyspnea, sleeping disorders, and appetite loss compared to CIPN low survivors (all P < .004). Higher burden of CIPN was associated with more financial problems vs CIPN low (mean score ± SEM: 19.70 ± 2.64 vs. 6.67 ± 2.32, P = .00025). Spearman analysis has confirmed negative correlation of overall CIPN20 score with QLQ-C30 global health status (R = -0.53, P < .0001). CONCLUSION: CIPN is a strong predictor of impairment in QOL among GCT survivors. Molecular mechanisms of neurotoxicity should be intensively studied to find preventive and therapeutic strategies.

Prognostic role of plasma vitamin D and its association with disease characteristics in germ cell tumours.

Background: Testicular cancer is the most common malignancy among young men. Vitamin D has pluripotent effects on cancer pathogenesis and plays a role in the metastatic cascade. The aim of this study is to analyze plasma vitamin D in association with clinico-pathological findings and prognosis in patients with germ-cell tumors (GCTs). Methods: This study included 120 newly diagnosed and/or relapsed GCT patients treated from April 2013 to July 2020, for whom plasma was available in the biobank. Blood samples were drawn the 1st chemotherapy cycle as well as before the 2nd cycle. Plasma vitamin D was measured using ELISA and correlated with disease characteristics and the outcome. For survival analysis, the cohort was dichotomized into "low" and "high" based on median vitamin D. Results: There was no significant difference in vitamin D plasma levels between healthy donors and GCT patients (p = 0.71). Vitamin D level was not associated with disease characteristics except for brain metastases, where patients with brain metastases had a vitamin D level that was 32% lower compared to patients without brain metastases, p = 0.03. Vitamin D was also associated with response to chemotherapy, with an approximately 32% lower value in patients with an unfavorable response compared to a favorable response, p = 0.02. Moreover, low plasma levels of vitamin D were significantly associated with disease recurrence and inferior progression-free survival (PFS), but not with overall survival (OS) (HR = 3.02, 95% CI 1.36-6.71, p = 0.01 for PFS and HR = 2.06, 95% CI 0.84-5.06, p = 0.14 for OS, respectively). Conclusion: Our study suggests the prognostic value of pretreatment vitamin D concentrations in GCT patients. Low plasma vitamin D was associated with an unfavorable response to therapy and disease recurrence. However, it remains to be determined whether the biology of the disease confirms a causative role for low vitamin D and whether its supplementation affects the outcome.

Cognitive impairment and biomarkers of gut microbial translocation in testicular germ cell tumor survivors.

Background: Survivors of testicular germ cell tumors (GCT) may suffer from late cognitive impairment. We hypothesized that disruption of intestinal barrier during chemotherapy and/or radiotherapy may be a contributing factor of cognitive dysfunction within the gut-blood-brain axis. Methods: GCT survivors (N = 142) from National Cancer Institute of Slovakia completed the Functional Assessment of Cancer Therapy Cognitive Function questionnaires during their annual follow-up visit at 9-year median (range 4-32). Biomarkers of gut microbial translocation and dysbiosis high mobility group box-1 (HMGB-1), lipopolysaccharide, d-lactate and sCD14 were measured from peripheral blood obtained during the same visit. Each questionnaire score was correlated with biomarkers. Survivors were treated with orchiectomy only (N = 17), cisplatin-based chemotherapy (N = 108), radiotherapy to the retroperitoneum (N = 11) or both (N = 6). Results: GCT survivors with higher sCD14 (above median) had worse cognitive function perceived by others (CogOth domain) (mean ± SEM; 14.6 ± 0.25 vs 15.4 ± 0.25, p = 0.019), lower perceived cognitive abilities (CogPCA domain) (20.0 ± 0.74 vs 23.4 ± 0.73, p = 0.025) and lower overall cognitive function score (109.2 ± 0.74 vs 116.7 ± 1.90, p = 0.021). There were no significant cognitive declines associated with HMGB-1, d-lactate and lipopolysaccharide. Survivors treated with ≥ 400mg/m2 vs < 400mg/m2 of cisplatin-based chemotherapy had a higher lipopolysaccharide (567.8 µg/L ± 42.7 vs 462.9 µg/L ± 51.9, (p = 0.03). Conclusions: sCD14 is a marker of monocytic activation by lipopolysaccharide and may also serve as a promising biomarker of cognitive impairment in long-term cancer survivors. While chemotherapy and radiotherapy-induced intestinal injury may be the underlying mechanism, further research using animal models and larger patient cohorts are needed to explore the pathogenesis of cognitive impairment in GCT survivors within the gut-brain axis.

Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial.

PURPOSE: Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). PATIENTS AND METHODS: Adult patients with measurable, locally advanced, and/or metastatic RCC were randomly assigned 2:1 to receive oral pazopanib or placebo. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response rate (Response Evaluation Criteria in Solid Tumors), and safety. Radiographic assessments of tumors were independently reviewed. RESULTS: Of 435 patients enrolled, 233 were treatment naive (54%) and 202 were cytokine pretreated (46%). PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < .0001), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < .0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < .001). The objective response rate was 30% with pazopanib compared with 3% with placebo (P < .001). The median duration of response was longer than 1 year. The most common adverse events were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. There was no evidence of clinically important differences in quality of life for pazopanib versus placebo. CONCLUSION: Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC.

Comprehensive Assessment of Selected Immune Cell Subpopulations Changes in Chemotherapy-Naïve Germ Cell Tumor Patients.

The pattern of immune cell distribution in testicular germ cell tumors (GCT) significantly differs from the immune environment in normal testicular tissues. The present study aimed to evaluate the role of different leukocyte subpopulation in GCTs. A cohort of 84 chemotherapy-naïve GCT patients was analyzed. Immunophenotyping of peripheral blood leukocyte subpopulations was carried out by flow cytometry. In addition, the data assessing the immunophenotypes and the baseline clinicopathological characteristics of the included subjects were statistically evaluated. Their prognostic value for the assessment of progression-free survival (PFS) and overall survival (OS) was estimated. The percentage of different innate/adaptive immune cell subpopulations was significantly associated with poor risk-related clinical features, including the number of metastatic sites, presence of retroperitoneal, mediastinal, lung, brain and non-pulmonary visceral metastases as well as with the S-stage and International Germ Cell Consensus Classification Group (IGCCCG) risk groups. In univariate analysis, the percentages of neutrophils, eosinophils, dendritic cells type 2, lymphocytes and T cytotoxic cells were significantly associated with PFS, while the neutrophil, non-classical monocyte and lymphocyte percentage were associated with OS. However, all these outcome correlations were not independent of IGCCCG in multivariate analysis. The data indicated a link among different innate/adaptive peripheral immune cell subpopulations in GCT patients. In addition, the association between these subpopulations and tumor characteristics was also investigated. The findings of the present study may contribute to a deeper understanding of the interactions between cancer and innate/adaptive immune response in GCT patients.

Detection of Specific Immune Cell Subpopulation Changes Associated with Systemic Immune Inflammation-Index Level in Germ Cell Tumors.

The tumor microenvironment (TME) and the host inflammatory response are closely interconnected. The interplay between systemic inflammation and the local immune response may influence tumor development and progression in various types of cancer. The systemic immune-inflammation index (SII) represents a prognostic marker for germ cell tumors (GCTs). The aim of the present study was to detect specific immune cell subpopulation changes which were associated with the SII level in chemotherapy-naïve GCT patients. In total, 51 GCT patients, prior to cisplatin-based chemotherapy, were included in the present study. Immunophenotyping of peripheral blood leukocyte subpopulations was performed using flow cytometry. The SII level was correlated with the percentage of various leukocyte subpopulations. The obtained results demonstrated that SII levels above the cut-off value of SII ≥ 1003 were associated with higher neutrophil percentages. An inverse correlation was found between the SII and the peripheral lymphocyte percentage that logically reflects the calculations of the SII index. Furthermore, the presented data also showed that in the lymphocyte subpopulation, the association with the SII was driven by T-cell subpopulations. In innate immunity-cell subpopulations, we observed a correlation between SII level and neutrophils as well as associations with eosinophil, basophil, natural killer cell and dendritic cell percentages. We suppose that the described interactions represent a manifestation of cancer-induced immune suppression. The results of the present study contribute to the elucidation of the interrelationship between tumor cells and the innate/adaptive immune system of the host.

Effects of primary granulocyte-colony stimulating factor prophylaxis on the incidence of febrile neutropenia in patients with germ cell tumors.

Testicular germ cell tumors (GCTs) are the most common solid malignancy in males aged 15-35 years. Febrile neutropenia (FN) is a serious complication of chemotherapy that frequently occurs in patients with GCTs. The present retrospective study aimed to evaluate the effect of primary granulocyte-colony stimulating factor (G-CSF) prophylaxis on the incidence of FN in patients with GCTs. The present study included a review of the medical records of patients diagnosed with GCTs treated with first-line/adjuvant chemotherapy between January 2000 and December 2017 at the National Cancer Institute (Bratislava, Slovakia). In January 2006, a decision was made to administer G-CSF prophylaxis (filgrastim or pegfilgrastim) to patients after every cycle of chemotherapy. The present study included 385 patients, and out of these, 264 patients received primary G-CSF prophylaxis, while 121 patients did not. A total of 71 patients (18.4%) suffered from FN events. In the subgroup that did not receive primary prophylaxis, 42 patients exhibited FN, while only 29 patients with primary prophylaxis suffered from FN (34.7 vs. 11.0%; P=0.00000003). According to the subgroup analysis, FN incidence was decreased in all groups that received primary prophylaxis, except for patients with stage I GCT receiving adjuvant chemotherapy, without affecting overall survival. Primary G-CSF prophylaxis was associated with markedly reduced FN incidence in patients treated with first-line chemotherapy for metastatic disease. Therefore, the results of the present study suggested that primary G-CSF prophylaxis should be considered in patients with GCT receiving first-line chemotherapy.