Platinum Accumulation and Cancer-Related Fatigue, Correlation With IL-8, TNF-α and Hemocytes

Platinum-based chemotherapy drugs cause platinum accumulation and result in cancer-related fatigue (CRF), which is related to immune response through still ambiguous mechanisms. We aimed to explore the correlation between platinum and CRF from the perspective of platinum accumulation. After allowing for complete metabolism of the administered platinum drugs, we collected blood samples from 135 patients who had at least two platinum chemotherapy rounds, correlated the platinum concentration (C-Pt), pro-inflammatory cytokines IL-8 and TNF-α, hematological index with therapeutic effect, adverse reactions and fatigue. The median platinum concentration was higher in patients treated with cisplatin than oxaliplatin (424.0 vs 211.3 μg/L), and the occurrence of fatigue was 64.4% in all subjects. Separately, the incidence and degree of fatigue were 74.1% and 9.5 in the patients with higher platinum concentration compared to 57.1% and 2.0 in the lower group. C-Pt, IL-8 and TNF-α were positively correlated with the degree of CRF, while erythrocyte count and hemoglobin were negatively correlated with the degree of CRF. Mediating effect analysis showed that increased IL-8 concentration mediated 57.4%, while decreased erythrocyte count mediated 24.1% of the C-Pt effect on CRF. Platinum accumulation may involve increasing IL-8, cause inflammation or aggravate anemia, which in combination lead to CRF.

Synergistic Cisplatin-induced cell death by ultrasound-microbubble mediated intracellular delivery in breast cancer cells.

Ultrasound-microbubble (USMB) potentiated cisplatin (CDDP) therapy was assessed in human breast cancer cells. Cells, MDA-MB-231, in suspension were exposed to USMB and CDDP at varying conditions, during which microbubble cavitation activity was measured using passive cavitation detection and 48 hours post-treatment cell viability and intracellular platinum concentration were measured using MTT assay and mass cytometry, respectively. USMB synergistically enhanced cell death (~20 fold) when combined with CDDP and significantly increased intracellular CDDP concentration (~8 fold) compared to CDDP treatment alone. Cell death and intracellular CDDP concentration were correlated to microbubble cavitation activity, which increased with peak negative pressure and microbubble concentration. Combined treatment of USMB and CDDP at relatively lower integrated cavitation dose (ICD) induced a synergistic effect on cell death whereas ICD greater than 10 induced an additive effect. USMB mediated CDDP intracellular accumulation synergistically enhances cell death in CDDPresistant breast cancer cells.

Synergistic Cisplatin-induced cell death by ultrasound-microbubble mediated intracellular delivery in breast cancer cells.

Ultrasound-microbubble (USMB) potentiated cisplatin (CDDP) therapy was assessed in human breast cancer cells. Cells, MDA-MB-231, in suspension were exposed to USMB and CDDP at varying conditions, during which microbubble cavitation activity was measured using passive cavitation detection and 48 hours post-treatment cell viability and intracellular platinum concentration were measured using MTT assay and mass cytometry, respectively. USMB synergistically enhanced cell death (~20 fold) when combined with CDDP and significantly increased intracellular CDDP concentration (~8 fold) compared to CDDP treatment alone. Cell death and intracellular CDDP concentration were correlated to microbubble cavitation activity, which increased with peak negative pressure and microbubble concentration. Combined treatment of USMB and CDDP at relatively lower integrated cavitation dose (ICD) induced a synergistic effect on cell death whereas ICD greater than 10 induced an additive effect. USMB mediated CDDP intracellular accumulation synergistically enhances cell death in CDDPresistant breast cancer cells.

Assessment of Silicone Rubber Properties Using Dynamic Modelling Simulation

The investigation of silicone rubber properties with the presence of platinum catalyst at different temperature using molecular dynamic simulation was conducted. Visual observation shows that structuring of silicone rubber occurs in the cell where the molecules aggregates closer compared to at the beginning of the simulation and at higher platinum concentration, silicone rubber molecules are more closely packed together. The diffusion coefficient of silicone rubber are the highest in a 10% platinum concentration followed by 25% and lastly 50% indicating that it is harder for the silicone rubber molecules to move from its original position in the system as the platinum concentration increases. Structural changes was also investigated through radial distribution function (RDF) where the position of peaks did not change with time but there is changes observed in the intensity of the peak. At a constant temperature 50°C, it was observed that the intensity of the peak at 1.10Å radius was the highest in the presence of 50%Pt followed by 25%Pt and 10%Pt. This indicates that higher numbers of silicone rubber molecules are present in a 1.10Å radius from the reference molecules in a system with higher concentration of platinum.

Persistence of platinum in semen of cisplatin-treated survivors of advanced testicular cancer.

5056 Background: Cisplatin is highly curative treatment for testicular cancer. Most survivors develop azoospermia immediately after cisplatin with recovery expected in 50% at 2 years and 80% at 5 years. Platinum is a heavy metal that can be detected at low levels in serum many years after treatment, however, it is not known whether platinum also persists in semen and if platinum persistence in semen is associated with impaired fertility. Methods: Testicular cancer survivors previously treated with cisplatin were enrolled, relapsed disease treated with salvage chemotherapy was excluded. Semen samples were collected to assess semen quality. Repeat semen collections were performed if azoo- or oligospermia was noted. Serum and semen Platinum levels were determined using HPLC-tandem mass spectrometry. DNA Fragmentation Index (DFI) was measured. Results: From 11/2017 to 12/2019, 38 pts (median age 32 years; range: 19-52; median BSA 2.03; range: 1.81-2.61) were enrolled, 31 were treated with 3 cycles of Bleomycin, Etoposide, Cisplatin. Median cumulative cisplatin dose was 300 mg/m2 (range: 274-404). Median serum platinum concentration was 0.1 ng/mL (range: 0-22.6) at a median of 11 months (range 0.5-36) post treatment completion. Median semen platinum concentration was 0.5 ng/mL (range: 0.2-28.7) at a median of 14 months (range: 1.3-40) post treatment completion. Semen platinum levels were higher in semen than in blood drawn at the same time (p = 0.03). Semen platinum levels were associated with time from last cisplatin dosing (r = -0.34; p = 0.09) but not cumulative cisplatin dose (r = -0.10, p = 0.63). Sperm concentration was correlated with time from last cisplatin dosing (r = 0.58, p < 0.001) but not with semen platinum level (r = -0.15, p = 0.46). DFI was associated with time from last cisplatin dosing (r = 0.55, p = 0.08) but not with semen platinum level (r = -0.32, p = 0.33). In 4 pts with serial semen samples available, semen platinum level decreased with time, sperm concentration and motility increased. Conclusions: Platinum can be detected in semen in long-term testicular cancer survivors at higher levels than matched blood samples. Our preliminary findings may have important implications for reproductive health of survivors of advanced testicular cancer, further studies are needed to assess the relationship between platinum persistence in semen and recovery of fertility post chemotherapy.

P6239Late adverse effects of residual platinum concentrations on cardiac function in testicular cancer survivors: a 30-year follow-up study

Background Cisplatin-based chemotherapy (CBCT) is essential in the treatment of testicular cancer (TC), and platinum can be detected in TC survivors decades after cessation of treatment. CBCT has been implicated as a risk factor in cardiovascular morbidity and mortality. Purpose Our study aimed to assess the relationship between residual serum platinum concentrations and changes in cardiac function and morphology in TC survivors 30 years after CBCT. Methods Seventy TC survivors diagnosed and treated with CBCT (1980–1994) were recruited from the longitudinal Norwegian Cancer Study in Testicular Cancer Survivors. Serum platinum concentration was measured twenty years after CBCT. Patients were then allocated to either a high or low platinum concentration group. Echocardiography was performed in all subjects. Results The participants were on average 60±9 years old. There was a trend towards smaller left ventricular (LV) volumes in the high residual platinum concentration group (Table). No intergroup difference in cardiac function was found. Six (9%) participants had reduced EF (<52%) and 14 (20%) participants had reduced LV global longitudinal strain (> −18.0%), however, there was no intergroup difference. Neither cumulative cisplatin dose nor residual serum platinum concentration showed any correlation with LV or right ventricular functional parameters. Table 1 Low residual Pt concentration >85 ng/L (n=35) High residual Pt concentration <85 ng/L (n=35) p-value Cumulative cisplatin dose, mg/m2 680±249 814±271 <0.05 Residual Pt concentration, ng/L 44±22 136±44 <0.001 3D LV end-diastolic volume, ml/m2 66±17 60±8 0.07 3D LV end-systolic volume, ml/m2 29±15 24±5 0.08 3D ejection fraction, % 57±9 59±6 0.24 LV global longitudinal strain, % −19.2±3.3 −20.0±2.0 0.26 LV global circumferential strain, % −21.1±4.2 −22.1±1.8 0.30 E/e' 10.6±4.4 9.2±2.2 0.10 TAPSE, mm 2.2±0.4 2.3±0.4 0.22 RV fractional area change, % 40±7 41±7 0.67 Data are presented as mean ± SD. The P-values were derived from the Student's t-test. LV, left ventricle; MV, mitral valve; Pt, platinum; RV, right ventricle; TAPSE, tricuspid annular plane systolic excursion. Conclusion Our 30-year follow-up study of testicular cancer patients could not demonstrate impact on cardiac function caused by cumulative cisplatin dose or residual serum platinum concentrations. Acknowledgement/Funding South-Eastern Norway Regional Health Authority

Biomineralization of Platinum by Escherichia coli

The widespread use of platinum in many industrial applications has led to its release into the environment at elevated concentrations with potential adverse effects on human and environmental health. However, the nature of interactions between mobile platinum complexes and the biotic components of the environment, which are increasingly being exposed to platinum, is poorly studied. The aim of this study was to assess the impact of Pt(IV)-chloride on the growth and activity of the well-characterized bacteria Escherichia coli. Bacterial survival and viability in the presence of different concentrations of Pt(IV)-chloride were assessed in liquid culture, while platinum retention was assessed using experimentation with sand-filled columns with the residual platinum concentration measured by atomic absorption spectroscopy. Bacterial biomineralization of platinum was studied with scanning electron microscopy. The results showed that E. coli tolerated PtCl4 at concentrations of up to 10,000 µM over 21 days and remained viable after 112 days of incubation with PtCl4 at 10,000 µM in sand columns. Overall, 74 wt.% and 50 wt.% of platinum was mineralized in E. coli and blank sand columns, respectively. The results of this study confirm that E. coli is capable of biomineralizing platinum. The results confirm that the interaction of platinum with bacteria is not limited to known metal-resistant bacterial species.

Persistence of platinum in semen of cisplatin-treated survivors of advanced testicular cancer.

519 Background: Even in patients (pts) with widely metastatic germ cell tumors cure rates are high with cisplatin based chemotherapy. Survivors of testicular cancer often have impaired gonadal function possibly related to chemotherapy. Most pts develop temporary azoospermia with recovery in about 50% after 2 years and 80% after 5 years. Platinum persists in blood in these pts, however, it is not known whether platinum also persists in semen. Methods: Pts who completed cisplatin > 3 months previously were enrolled. Age, total cisplatin dose and date of completion of treatment were collected. A semen sample was collected from each patient for analysis to assess semen quality. A blood sample was collected to assess FSH/LH/testosterone/creatinine. Serum and semen platinum levels were measured using HPLC-tandem mass spectrometry. Results: Between 11/2017 and 09/2018, 9 pts (median age 32 years; range: 18-52) were enrolled to the study, all were treated with standard Bleomycin, Etoposide, Cisplatin regimen. Blood samples were collected from 7 pts, and semen samples from 4 pts. Median total cisplatin dose given was 658 mg (range: 570-780). Median serum platinum concentration was 0.395 ng/mL (range: 0.10-0.94) at a median of 10 months (range 4.5-13) post completion of treatment. Median semen platinum concentration was 1.06 ng/mL (range: 0.25-1.47) at a median of 10 months (range: 6-14) post completion of treatment. Semen platinum levels were associated with total cisplatin dose administered (Pearson correlation, r = 0.645) and time from completion of treatment (Pearson correlation, r = 0.386). In all 4 pts with matched samples, the semen platinum level was higher than the serum platinum level. Semen analysis showed 2 pts were azoospermic post treatment, 1 of these was also azoospermic prior to treatment; 1 pt had normal semen analysis post treatment and 1 had a low sperm count post treatment. Conclusions: This is the first study demonstrating that platinum persists in semen > 6 months post completion of cisplatin-containing chemotherapy. Platinum levels are higher in semen than in blood following treatment. Our preliminary findings may have important implications for reproductive health of survivors of advanced testicular cancer.