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Heparanase is an endo-β-glucuronidase capable of cleaving heparan sulfate (HS), an activity implicated in tumor metastasis. Heparanase expression is upregulated in primary human tumors, correlating with reduced post operative survival and elevated microvessel density. An ELISA method was used to quantify heparanase in urine from 282 individuals. Urine was collected from healthy volunteers (n = 41), patients diagnosed with noncancerous pathologic disorders (n = 90), and bladder cancer patients (n = 92). Fifty-nine bladder carcinoma patients after transurethral resection (TUR) with no evidence of disease (NED) were also included. Heparanase levels were significantly elevated in urine from bladder cancer patients compared with healthy controls (P < .001) and with noncancerous urinary disorders (P < .05). Heparanase elevation strongly correlated with tumor grade (P < .001) and stage (P = .027). An optimal cutoff value of 154 pg/ml was determined. Of 199 individuals enrolled (59 patients after TUR and 24 patients with recurring disease were excluded), 65 had heparanase levels above 154 pg/ml. Only 3 of 65 (4.6%) were healthy individuals. In contrast, 52.3% (34 of 65) of individuals with heparanase levels above 154 pg/ml were bladder cancer patients. The results indicate that urine heparanase levels are elevated during bladder cancer progression, suggesting that the ELISA method may be applied for bladder cancer diagnosis.

Aims: Thymidine kinase 1 (TK1) is an enzyme involved in DNA synthesis and an important proliferation marker. We explored the association of preoperative serum TK1 activity with clinicopathological parameters and prognosis in terms of recurrence-free survival (RFS) in breast cancer (BC) patients. Patients and methods: TK1 activity in serum of 120 healthy women and 161 BC patients was measured by quantitative ELISA. Results: Serum TK1 activity in BC patients was significantly higher than in healthy women (P < 0.0001). In BC patients elevated TK1 activity was significantly associated with advanced T stage (P = 0.015), higher grade (P = 0.013), presence of tumor necrosis (P = 0.006), vascular invasion (P = 0.002), and lack of estrogen receptor (ER) and progesterone receptor (PR) expression (P = 0.0004 and P = 0.003). Higher TK1 activity was found in patients with BRCA1/2 mutations compared to those without the mutation (P = 0.004). Multivariate Cox proportional hazards analyses demonstrated that TK1, adjusted for stage, grade, necrosis, ER and PR negativity was retained as an independent predictor of disease recurrence (Hazard Ratio = 3.9, 95%CI 1.3-11.6, P = 0.013). Conclusion: Elevated serum TK1 is an important risk factor indicating a high proliferation potential of tumors at the time of excision. In multivariate analysis TK1 activity was found to be an independent prognostic factor for RFS. [ABSTRACT FROM AUTHOR]

Heparanase is an endo-β-glucuronidase capable of cleaving heparan sulfate (HS), an activity implicated in tumor metastasis. Heparanase expression is upregulated in primary human tumors, correlating with reduced post operative survival and elevated microvessel density. An ELISA method was used to quantify heparanase in urine from 282 individuals. Urine was collected from healthy volunteers (n = 41), patients diagnosed with noncancerous pathologic disorders (n = 90), and bladder cancer patients (n = 92). Fifty-nine bladder carcinoma patients after transurethral resection (TUR) with no evidence of disease (NED) were also included. Heparanase levels were significantly elevated in urine from bladder cancer patients compared with healthy controls (P < .001) and with noncancerous urinary disorders (P < .05). Heparanase elevation strongly correlated with tumor grade (P < .001) and stage (P = .027). An optimal cutoff value of 154 pg/ml was determined. Of 199 individuals enrolled (59 patients after TUR and 24 patients with recurring disease were excluded), 65 had heparanase levels above 154 pg/ml. Only 3 of 65 (4.6%) were healthy individuals. In contrast, 52.3% (34 of 65) of individuals with heparanase levels above 154 pg/ml were bladder cancer patients. The results indicate that urine heparanase levels are elevated during bladder cancer progression, suggesting that the ELISA method may be applied for bladder cancer diagnosis. [ABSTRACT FROM AUTHOR]

Background: Current standard treatment for metastatic breast cancer (MBC) involves cyclin-dependent kinase 4/6 (CDK4/6) inhibitors with endocrine therapy, showing potential in enhancing anti-tumor immune responses., Case Report: This report details a clinical case of MBC where palbociclib was co-administered with letrozole. The integration of allogeneic tumor vaccination to this treatment led to heightened interferon-γ production, expansion of CD8+ and NK cell populations, and positive delayed-type hypersensitivity reactions, indicating successful development of anti-tumor immunity. The induced production of interferon-γ by tumor vaccination was associated with manageable modulation of sensitivity to palbociclib-letrozole therapy. Administration of the BioNTech/Pfizer Covid-19 vaccine compromised the anti-tumor immune response by reducing cytotoxic cell populations and increasing immunosuppressive cytokine production. The patient undergoing combined treatment achieved a progressive-free survival of 42 months., Conclusion: Incorporating active tumor vaccination with CDK4/6 inhibitor therapy presents a feasible approach for metastatic breast cancer. The precise regulation of the microenvironment emerges as a crucial factor and warrants careful consideration., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Tumor cell lines are essential tools in understanding the molecular mechanisms underlying cancer biology and therapeutic responses. Poly (ADP-ribose) polymerase inhibitors (PARPi) kill tumor cells harboring pathogenic mutations of BRCA DNA repair-associated genes 1/2 (BRCA1/2) and are approved to treat ovarian and metastatic breast cancer. Loss of heterozygosity (LOH) of the wild-type BRCA1/2 locus is suspected to increase cellular response to PARPi. To better elucidate the molecular mechanisms underlying PARPi sensitivity and resistance, this study assessed the responses of various pathogenic BRCA1/2-mutant cell lines to the PARPi talazoparib., Materials and Methods: Mutant cell lines were extracted and cultured from four surgically resected, human breast cancer specimens with different pathogenic BRCA1/2, one normal breast specimen and one ovarian cancer specimen. Mutation analysis was performed on all cell lines using genomic DNA extraction and polymerase chain reaction. Following treatment with talazoparib, cell growth was assessed using tetrazolium salt and half-maximal inhibitory concentration values were determined., Results: A partial correlation between different variants of pathogenic BRCA1/2 mutation and talazoparib susceptibility was found, with five of the cell lines exhibiting sensitivity to talazoparib. The most sensitive cell-line to talazoparib had LOH for BRCA1, while the breast cancer cell line harboring BRCA2 LOH was resistant to talazoparib., Conclusion: This study suggests that LOH does not necessarily correlate with PARPi efficacy. These results lay a foundation for future studies to utilize these novel cell lines to further elucidate the underlying molecular mechanisms of PARPi resistance and reveal new potential drug targets., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Many experimental studies have suggested the importance of thyroid hormones in breast cancer (BC) morphogenesis. The aim of this study was to evaluate the association of thyroid hormone levels in serum of patients with primary BC with morphological presentations of the disease in pathological specimens and prognosis., Patients and Methods: We measured the serum levels of thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4), along with serum thymidine kinase 1 activity and examined their relation to pathological features and prognosis of 158 patients with primary BC., Results: We found a significant positive association of serum FT3 level with the presence of carcinoma in situ component (CIS) (p=0.032) and its size (p=0.047), with the presence (p=0.022) and the number of multifocal/multicentric tumors (MMTs) (p=0.002), as well as with increased proliferative activity in terms of serum thymidine kinase 1 (p=0.002). Moreover, we report that each 1.0 unit rise of FT3/FT4 ratio×10 was associated with an odds ratio of 1.77 (95% confidence interval=1.17-3.30, p=0.007), 1.97 (95% confidence interval=1.17-2.67, p=0.010) and 1.56 (95% confidence interval=1.02-2.37, p=0.039) for the detection of patients with CIS, MMTs and lymphovascular invasion, respectively, after adjusting for age. We did not find statistically significant associations of serum TSH level with breast cancer`s parameters. A Cox regression survival analysis identified serum FT3 level >5.95 pmol/l as a risk factor for BC recurrence (relative risk=2.65, p=0.017), a finding that retained significance in a multivariate model (relative risk=2.52, p=0.027)., Conclusion: The FT3/FT4 ratio is a valuable parameter predicting the presence of CIS, MMTs and lymphovascular invasion in pathological specimens. An elevated serum FT3 level is associated with the presence of CIS, MMTs, increased proliferative activity and poor prognosis., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Thymidine kinase 1 (TK1) is involved in DNA synthesis and is considered a reliable and sensitive marker of cell proliferation. The aim of this study was to investigate the prognostic value of measurements of serum TK1 activity following tumor ablation., Patients and Methods: This study was performed on 32 patients with renal cell carcinoma (RCC) who had undergone nephrectomy and 35 patients with cancer of different histology with metastases to the liver (n=28) and lung (n=7) treated with radiofrequency ablation (RFA). The TK1 activity was measured with DiviTum (Biovica) immunoassay., Results: In patients with RCC with no evidence of disease during their observation, a significant decrease of the TK1 activity was observed on the day following nephrectomy (p<0.0001). The mean calculated half-life ±SEM was 10.8±1.2 h. Taking into account the short half-life, measurements of TK1 were performed 24 h after nephrectomy or RFA of metastases. It was found that elevated TK1 activity (>60 Du/l) on the day after nephrectomy independently predicted poor recurrence-free survival (hazard ratio=5.0, p=0.040), after adjustment for T-stage, age and pretreatment TK1. Patients scheduled for RFA averaged 1.4 lesions and an average lesion diameter of 2.2 cm. Multivariate Cox's regression model demonstrated the significant association of any increase of TK1 activity or decrease not reaching ≤60 Du/l on the day after ablation with poor progression-free survival (hazard ratio=4.6, p=0.001), after adjustment for the type of primary tumor, the number and size of metastases., Conclusion: The half-life for serum TK1 activity is 10.8±1.2 h. The measurements of TK1 activity following nephrectomy or RFA of metastases could be an important tool in prognostic evaluation., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Aim: To investigate the prognostic significance of cancer antigen 15-3 (CA15-3) in primary breast cancer (BC)., Patients and Methods: This prospective study included 368 women: 62 patients with benign breast disease (BBD), 159 patients with invasive BC and 88 healthy blood donors (control). The median follow-up was 76 months (range, 43-99 months). Serum CA15-3 was measured with LIAISON® CA15-3® chemilluminescence immunoassay., Results: Significantly high levels of CA15-3 were found in patients with BC compared to controls (p=0.029), but not to the BBD group (p=0.16). Preoperative CA15-3 in patients with BC was significantly associated with tumor size (p=0.003), TNM stage (p=0.005), vascular invasion (p=0.018) and tumor necrosis (p<0.05). Increased CA15-3 (>30 U/ml) concentrations were more often found in patients with larger tumors (p<0.05), advanced stage (p=0.004) and node-positive disease (p=0.007). Patients with normal levels of CA15-3 had better recurrence-free survival (RFS) than those with elevated levels (p<0.001). After adjustment for T-stage, grade, tumor necrosis, estrogen receptor (ER) and progesterone receptor (PR) status, CA15-3 remained an important preoperative characteristic with independent impact on RFS (hazard ratio=4.4, 95% confidence interval=1.5-13.1, p=0.007). The independent prognostic contribution of CA15-3, considered on a continuous scale was significant among subgroups of the BC patients with ER/PR-positive (p=0.002), node-positive (p=0.028), node-negative (p=0.003), T1-stage node-negative (p=0.017), luminal-A (p=0.003), luminal-B (p=0.028) and human epidermal growth factor receptor-2 (HER2)/non-luminal disease (p=0.045)., Conclusion: Preoperative measurement of CA15-3 allowed identifying high-risk of recurrence for patients with primary BC and might be combined with existing prognostic factors in planning adjuvant treatment.

Aim: To investigate the diagnostic and prognostic significance of pro-gastrin-releasing peptide (ProGRP) in non-small cell (NSCLC) and small cell lung cancer (SCLC) and compare this marker with other known serum markers in lung cancer., Patients and Methods: Serum levels of ProGRP, neuron-specific enolase (NSE), CYFRA 21-1 and carcinoembryonic antigen (CEA) were measured in 37 patients with benign pulmonary disease (BPD), 88 with advanced NSCLC and 37 with SCLC., Results: The ProGRP assay showed a better clinical performance than that of NSE in discriminating between SCLC and BPD or NSCLC, especially at specificity higher than 90%. ProGRP and NSE sensitivity in SCLC at 95% specificity versus the BPD group was 78.4% and 48.6%, (p=0.001) and at 97.7% specificity versus NSCLC, 75.7% and 37.8%, respectively (p=0.001). A significant association of low ProGRP levels with high-grade NSCLC tumors was found (p=0.002). A univariate analysis showed a significant association of ProGRP with survival both in NSCLC and SCLC (p=0.03 and p=0.04, respectively). In multivariate analysis, performance status (PS) and CYFRA 21-1 in NSCLC, and PS, CYFRA 21-1 and serum lactic dehydrogenase in SCLC were found as significant variables with an independent impact on survival., Conclusion: ProGRP is a useful marker in SCLC, with diagnostic performance better than that of NSE and demonstrating association with survival in NSCLC and SCLC limited to univariate analysis.

Aim: This study aimed to evaluate the accuracy of urine cytology, bladder ultrasound (US), urine cytokeratin 19 fragment assay (CYFRA 21-1) and the combination of these noninvasive modalities in the detection of recurrent bladder cancer., Patients and Methods: In a total of 154 patients that were followed with cystoscopy after endoscopic resection of non-muscle-invasive bladder cancer, we performed and analyzed results of 311 observations that included cytology, CYFRA 21-1, US. The urine concentration of CYFRA 21-1 was measured by an immunoradiometric assay., Results: Cystoscopy and biopsy revealed recurrent bladder tumors in 21 patients. Most of the tumors (77%) were less than 10 mm in their largest diameter. Urine cytology, US and urine CYFRA 21-1 resulted in overall sensitivity of 19.1, 52.4 and 71.4% and specificity of 96.6, 99.7 and 68.6%, respectively. Each of these methods used alone yielded false-negative results in patients harboring tumors at high risk of progression. The combination of all three methods had sensitivity and specificity of 90.5 and 67.2%, respectively. All three tests were negative in 197 of 311 observations (63.3%), missing only 2 low-risk tumors., Conclusion: The combined use of US, urinary CYFRA 21-1 and cytology appears to be an effective, noninvasive approach for the detection of recurrent bladder tumors.

The prognostic value of various demographic, clinical and laboratory characteristics was investigated in 54 patients with metastatic breast cancer during first-line paclitaxel chemotherapy. As a single-agent treatment, paclitaxel (175 mg/m2) was given by 3-hour infusion every three weeks. The overall response rate was 30%. The follow-up ranged from 3 to 65 months (median 17 months). The most important pretreatment prognostic factors for survival were found to be hemoglobin (Relative Risk-2.26; p = 0.02) and serum lactic dehydrogenase (RR-1.81; p = 0.04) levels. The survival showed a strong association to the type of response. The median survival for responders was 5-fold greater than for patients with progressive disease (30.2 months and 5.7 months, respectively). Following the first-line paclitaxel treatment the estimates of tumor response became the major predictor of survival (RR-12.3; p < 0.0001).