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.

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.

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.

Factors Associated With Choriocarcinoma Syndrome Development in Poor-Risk Patients With Germ Cell Tumors.

Background: Germ cell tumors (GCTs) represent a highly curable cancer. However, a small proportion of poor-risk patients can develop choriocarcinoma syndrome (CS) connected with acute respiratory distress syndrome (ARDS) with a high mortality rate. Our retrospective study aimed to determine the risk factors of poor-risk GCTs susceptible to CS development. Patients and Methods: Using a computerized database and a systematic chart review, we identified the records of 532 patients with GCTs treated at the National Cancer Institute from 2000 to 2018. Ninety eligible patients with poor-risk GCTs based on IGCCCG classification were identified. All patients were treated with platinum-based induction chemotherapy. Clinicopathological variables were collected and analyzed in correlation with CS development. Results: Nine (10%) of 90 patients developed CS in a median of 1 day (1-9 days) after chemotherapy administration. All patients died shortly after the chemotherapy start with a median of 4 days (3-35 days) due to ARDS development. In univariate analysis, metastatic lung involvement ≥50% of lung parenchyma, choriocarcinoma elements in histology specimen, dyspnea, cough, hemoptysis, ECOG PS ≥2, weight loss, hemoglobin ≤100 g/l, and NLR ≥3.3 at the time of presentation were associated with CS development. In multivariate analysis, ECOG PS ≥2 and metastatic lung involvement ≥50% were independently associated with CS. All patients with these two characteristics developed CS, compared to 0% with zero or one of these factors (p < 0.000001). Conclusions: In our study, we identified factors associated with CS development. These factors might improve the risk stratification of the patients susceptible to CS and improve their outcome.

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.

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.

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.

Paclitaxel, Ifosfamide, and Cisplatin in Patients with Poor-prognosis Disseminated Nonseminomatous Germ Cell Tumors with Unfavorable Serum Tumor Marker Decline After First Cycle of Chemotherapy. The GCT-SK-003 Phase II Trial.

BACKGROUND: Germ cell tumors represent highly curable disease even in metastatic stage. However, poor-risk patients with an unfavorable serum tumor marker (STM) decline after the first cycle of chemotherapy represent a subgroup with dismal prognosis, with approximately 50% cure rate using bleomycin, etoposide, and cisplatin (BEP). OBJECTIVE: The aim of this study was to determine the efficacy and safety of paclitaxel, ifosfamide, and cisplatin (TIP) in this patient population. DESIGN SETTING AND PARTICIPANTS: This was an open-labeled, nonrandomized, single-center phase II trial to study the efficacy and toxicity of TIP in the first-line treatment of germ cell tumor patients with an unfavorable decline of STMs. Nineteen patients with a poor prognosis according to the International Germ Cell Cancer Collaboration Group classification and an unfavorable STM decline after the first cycle of chemotherapy were included in this phase II study (NCT02414685). The treatment regimen consisted of paclitaxel 250 mg/m2 on day 1, ifosfamide 1200 mg/m2 on days 1-5, and cisplatin 20 mg/m2 on days 1-5, totally for four cycles. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was complete response (CR) rate. An optimal Simon two-stage design was used with a type I error of 5% and study power of 80%. If fewer than six CRs to study therapy have been observed among the first 19 patients, the study was to be terminated. RESULTS AND LIMITATIONS: A CR was achieved in four (21.1%) patients; therefore, the study was terminated in the first stage. A favorable response rate (CR or partial remission with negative tumor markers) was observed in 14 (78.9%) patients. At a median follow-up period of 35.2 mo (range, 5.6-62.1 mo), ten (52.6%) patients experienced disease progression and eight patients (42.1%) died. The 2-yr progression-free and overall survival was 41.2% (95% confidence interval [CI] 16.8-65.7) and 72.7% (95% CI 48.9-96.4), respectively. TIP was well tolerated, and no unexpected toxicity was observed. No informative biomarkers, including miR-371a-3p was identified. CONCLUSIONS: Treatment modification from the BEP to the TIP regimen in patients with an unfavorable STM decline after the first cycle of chemotherapy was not associated with improved outcome, and four cycles of BEP remain the standard treatment option in this patient population. PATIENT SUMMARY: Poor-risk patients with an unfavorable serum tumor marker decline after the first cycle of chemotherapy represent a subgroup with dismal prognosis, with an approximately 50% cure rate using bleomycin, etoposide, and cisplatin (BEP). Treatment modification from the BEP regimen to the paclitaxel, ifosfamide, and cisplatin regimen in patients with an unfavorable serum tumor marker decline after the first cycle of chemotherapy was not associated with improved outcome, and four cycles of BEP remain the standard treatment option in this patient population.

Survival Prediction by Baseline Systemic Immune-inflammation Index (SII) and its Changes During First-line Platinum-based Treatment in a Caucasian Population of Patients With Metastatic Urothelial Carcinoma (MUC).

BACKGROUND/AIM: Systemic immune-inflammation index (SII) predicts survival of patients with various malignancies. This study explored the prognostic value of SII in metastatic urothelial carcinoma (MUC) subjects. PATIENTS AND METHODS: We evaluated 181 consecutive MUC patients treated with first-line platinum-based therapy. Karnofsky performance status <80% and visceral metastasis were present in 18.2% and 46.4% of patients, respectively. SII was based on platelet × neutrophil/lymphocyte counts. Study population was dichotomized by median into high and low SII groups before the initiation of chemotherapy and at week 6. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared with the log-rank test. RESULTS: At median follow-up of 9.6 months, 174 patients experienced disease progression and 173 died. Patients with low SII at baseline and at week 6 had significantly better PFS (HR=0.58; p=0.0002 and HR=0.55; p<0.0001) and OS (HR=0.54; p<0.0001 and HR=0.54; p<0.0001) compared to patients with high SII. Independent prognostic value of SII was confirmed in a multivariate analysis. CONCLUSION: High SII before chemotherapy that persists at week 6 negatively affects survival. SII at baseline can be used in the stratification of patients within clinical trials and in clinical practice.

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.

Prognostic Value of Apoptosis-Inducing Factor (AIF) in Germ Cell Tumors.

Apoptosis is a strictly regulated process essential for preservation of tissue homeostasis. This study aimed to evaluate expression of apoptosis inducing factor (AIF) in testicular germ cell tumors (GCTs) and to correlate expression patterns with clinicopathological variables. Formalin-fixed and paraffin-embedded specimens of non-neoplastic testicular tissue and GCTs obtained from 216 patients were included in the study. AIF expression was detected by immunohistochemistry, scored by the multiplicative quickscore method (QS). Normal testicular tissue exhibits higher cytoplasmic granular expression of AIF compared to GCTs (mean QS = 12.77 vs. 4.80, p < 0.0001). Among invasive GCTs, mean QS was the highest in embryonal carcinoma, yolk sac tumor and seminoma, lower in teratoma and the lowest in choriocarcinoma. No nuclear translocation of AIF was observed. Nonpulmonary visceral metastases were associated with lower AIF expression. Metastatic GCTs patients with high AIF expression had better overall survival compared to patients with low AIF expression (HR = 0.26, 95% CI 0.11-0.62, p = 0.048). We observed significantly lower AIF expression in GCTs compared to normal testicular tissue, which is an uncommon finding in malignant tumors. AIF downregulation might represent one of the mechanisms of inhibition of apoptosis and promotion of cell survival in GCTs.

Squamous cell carcinoma of the colon - a case report.

BACKGROUND: Primary squamous cell carcinomas (SCC) of the colon are extremely rare and occur predominantly in the fifth decade of life, with a slight prevalence in men. The most common anatomical sites are the rectum and the proximal colon. Clinical signs and common dia-gnostic methods cannot clearly distinguish SCC from adenocarcinoma. METHODS: In this case report, we present a case of a 68-year-old patient with SCC of the cecum and colon ascendens, who was treated with resection and systemic gemcitabine- and cisplatin-based chemotherapy. RESULTS: A 68-year-old patient underwent right-sided hemicolectomy for cecal and colon ascendens tumor, histologically poorly differentiated epidermoid carcinoma, grade 3 with an initial stage of pT4aN1aM0. Due to local recurrence at the resection site with suspected infiltration of straight and oblique abdominal muscles, he was treated with systemic gemcitabine and cisplatin based chemotherapy with partial remission. Subsequently, the postchemotherapeutic residual tumor was radically resected, achieving complete remission of the disease, which persists for 10 months after the surgery. CONCLUSION: The case emphasizes the need for a multidisciplinary treatment approach of this rare disease. Early surgery plays a key role. Although the standard chemotherapy regimen is not well defined, the use of a combination of cisplatin and gemcitabine resulted in partial remission in our patient, which in turn allowed a radical resection of the relapse and subsequently achieved complete remission of the disease.

Complete Response to Chemotherapy in Metastatic Pancreatic Carcinoma Associated with Double Heterozygous Germline Mutation in BRCA2 and CHEK2 Genes - a Case Report.

BACKGROUND: Metastatic pancreatic carcinoma is an aggressive disease with adverse prognosis. Despite slight advances in chemotherapy, complete remission of the disease is extremely rare. CASE: In this article we present a case of a patient with initially metastatic pancreatic adenocarcinoma, associated with double heterozygous germline mutation in BRCA2 and CHEK2 genes, with the description of clinical, radiological and histomorphological characteristics of the disease as well as the dia-gnostic and therapeutic procedure. RESULTS: The patient with initially metastatic pancreatic adenocarcinoma with multiple liver involvement achieved complete remission following first-line FOLFIRINOX chemotherapy. The treatment lasted for 12 months but due to increased neurotoxicity since the 9th cycle, oxaliplatin was excluded from the regimen. Given the family history of several malignancies (prostate cancer, seminoma), genetic testing was performed, which confirmed heterozygous germline mutations in BRCA2 and CHEK2 genes. Since the treatment has been completed, the patient remains in complete remission at 30 months. CONCLUSION: Given the low incidence of complete remissions in patients with metastatic pancreatic cancer, the further therapeutic approach is not clearly established, an individual treatment is important. Universal genetic testing is recommended in patients with pancreatic cancer as it may affect the treatment strategy.

DNA damage measured in blood cells predicts overall and progression-free survival in germ cell tumour patients.

Germ cell tumour (GCT) patients who fail to respond to chemotherapy or who relapse have a poor prognosis. Timely and accurately stratifying such patients could optimise their therapy. We identified endogenous DNA damage levels as a prognostic marker for progression-free (PFS) and overall (OS) survival in chemotherapy-naïve GCT patients. In the present study, we have extended our previous results and reviewed the prognostic power of DNA damage level in GCTs. Endogenous DNA damage levels were measured with the comet assay. Receiver operator characteristic analysis was applied to determine the optimal cut-off value and to evaluate its prognostic accuracy. PFS and OS were estimated by the Kaplan-Meier method and compared using the log-rank test. Hazard ratio (HR) estimates were calculated by Cox regression analysis. A cut-off value of 6.34 provided the highest sensitivity and specificity, with area under curve values of 0.813 and 0.814 for disease progression and mortality, respectively. A % DNA in tail > 6.34 was significantly associated with shorter PFS (HR = 9.54, 95 % confidence interval [CI]: 3.43-26.55, p < 0.001) and OS (HR = 14.62, 95 % CI: 3.14-67.95, p = 0.001) by univariate analysis. The prognostic value of DNA damage measurement was confirmed by multivariate models (HR = 6.45, 95 % CI: 2.22-18.75, p = 0.001 for PFS and HR = 9.40, 95 % CI: 1.70-52.09, p = 0.010 for OS), when HR was adjusted for relevant clinical categories. The added prognostic value of DNA damage in combination with International Germ Cell Cancer Collaborative Group (IGCCCG) risk groups has been revealed. Endogenous DNA damage is an independent prognosticator for PFS and OS in GCT patients and its clinical use, particularly in combination with IGCCCG risk groups, may help in stratifying these patients.

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.

Intricacies of Radiographic Assessment in Testicular Germ Cell Tumors.

Testicular germ cell tumors (GCTs) are malignancies with a unique biology, pathology, clinical appearance, and excellent outcomes. A correct radiographic assessment of GCTs is extremely important for the clinical management in several typical scenarios. Advancements in the field of diagnostic medicine bring an increasing number of sophisticated imaging methods to increase the performance of imaging studies. The conventional computed tomography (CT) remains the mainstay of diagnostic imaging in the management of GCTs. While certain improvements in the sensitivity and specificity are suggested with magnetic resonance (MR) imaging with lymphotrophic nanoparticles in evaluating retroperitoneal lymph nodes during the staging procedure, further exploration in larger prospective studies is needed. A common diagnostic dilemma is assessing the post-chemotherapy residual disease in GCTs. Several studies have consistently shown advantages in the utility of positron emission tomography (PET) scanning in post-chemotherapy residual retroperitoneal lymph nodes in patients with seminoma, but not with non-seminoma. Recommendations suggest that seminoma patients with a residual disease in the retroperitoneum larger than 3 cm should be subjected for PET scanning with 18-fluorodeoxyglucose. Relatively high sensitivity, specificity and a negative predictive value (80-95%) may guide clinical decision to spare these patients of high morbidity of an unnecessary surgery. However, a positive predictive value of around 50% renders PET scanning difficult to interpret in the case of positive finding. These patients often require extremely difficult surgical procedures with the high risk of post-operative morbidity. Therefore, seminoma patients with PET positive residual masses larger than 3 cm still remain a serious challenge in the decision making of nuclear medicine specialist, oncologists, and urologic surgeons. In this article, we aim to summarize data on controversial dilemmas in staging procedures, active surveillance, and post-chemotherapy assessment of GCTs based on the available published literature.

High Endogenous DNA Damage Levels Predict Hematological Toxicity in Testicular Germ Cell Tumor Patients Treated With First-Line Chemotherapy.

BACKGROUND: Testicular germ cell tumors (TGCTs) are an excellent example of chemosensitive disease. However, cisplatin-based chemotherapy has significant side effects, including myelosuppression. Previously, we found endogenous DNA damage level in peripheral blood mononuclear cells (PBMCs) to be an independent prognostic marker. In this study, we tested the hypothesis that patients with high endogenous DNA damage levels in PBMCs have an increased risk of developing hematological toxicity. PATIENTS AND METHODS: One hundred twenty chemotherapy-naive TGCT patients treated in the National Cancer Institute and the St Elisabeth Cancer Institute in Bratislava, Slovakia, from 2012 to 2018 were enrolled. All patients received platinum-based chemotherapy with granulocyte colony stimulating factor support. On the day of starting treatment, we measured the DNA damage levels in PBMCs using the comet assay. We used the cutoff level of 5.25, a value previously reported to stratify patients on the basis of their prognosis. We monitored hematological toxicity during the first cycle of chemotherapy. The mean and standard error of the mean were calculated for all variables. RESULTS: Patients with high DNA damage levels (>5.25) had more significant hematological toxicity with significantly lower nadir white blood cell count (P = .001), absolute neutrophil count (P = .013) and absolute lymphocyte count (ALC; P < .001). ALCs on day 0 (P = .005) and day 22 (P = .046) were also significantly lower in patients with high DNA damage levels. CONCLUSION: This study shows that higher endogenous DNA damage levels correlate with increased risk of hematological toxicity in TGCT patients. Hence, the DNA damage levels can be used to select patients for closer monitoring because of a higher risk of acute chemotherapy-related complications.