Clinical Profile and Outcome of 806 Pediatric Oncology Patients Treated With Radiotherapy at the Serbian National Cancer Center.

Radiotherapy plays an important role in the multimodal treatment of childhood cancer. Our objective was to provide an analysis of pediatric oncology patients treated with radiotherapy in a national referral institution in Serbia. A retrospective chart review of children treated with radiotherapy between January 2007 and July 2018 was conducted. Of the 806 patients who were identified, 767 formed the basis of this study. CNS tumors (31.2%) were the most common tumors followed by leukemias (17.3%) and bone tumors (14.3%). The most common indication for radiotherapy was in adjuvant setting (69.1%). Anesthesia or sedation was performed on 115 patients. The 5-year and 10-year overall survival rates were 65.7% and 62.1%, respectively. A significant difference in survival in relation to tumor type was seen. The best survival rates were obtained in patients with retinoblastoma, followed by lymphomas and nephroblastoma, while patients with bone sarcomas had the worst survival. The intent of radiotherapy treatment was also a parameter associated with survival. Patients treated with palliative and definitive intent lived shorter than patients treated with prophylactic and adjuvant intent. Our study showed that good treatment outcomes can be achieved in specialized centers with an experienced team of professionals who are dedicated to pediatric oncology.

Total diagnostic interval in children with brain tumours in a middle-income country: national experience from Serbia.

PURPOSE: The aim was to evaluate the total diagnostic interval (TDI) and presenting complaints in children with brain tumours in Serbia. METHODS: This study retrospectively analysed 212 children aged 0-18 years newly diagnosed with brain tumours in two tertiary centres from mid-March 2015 to mid-March 2020 covering virtually all children with brain tumours in Serbia. TDI was calculated as the difference between the date of diagnosis and the date of symptom onset presented as a median in weeks. This variable has been evaluable for 184 patients. RESULTS: Overall TDI was 6 weeks. TDI was significantly longer in patients with low-grade tumours (11 weeks) than in patients with high-grade tumours (4 weeks). Children with the most frequent complaints (headache, nausea/vomiting and gait disturbance) were more likely to be diagnosed sooner. Patients with a single complaint had significantly longer TDI (12.5 weeks) contrasted to patients with multiple complaints (5 weeks). CONCLUSION: TDI with a median of 6 weeks is similar to other developed countries. Our study supports the view that low-grade tumours will present later than high-grade tumours. Children with the commonest complaints and children with multiple complaints were more likely to be diagnosed sooner.

Germline Variants in Cancer Predisposition Genes in Pediatric Patients with Central Nervous System Tumors.

Central nervous system (CNS) tumors comprise around 20% of childhood malignancies. Germline variants in cancer predisposition genes (CPGs) are found in approximately 10% of pediatric patients with CNS tumors. This study aimed to characterize variants in CPGs in pediatric patients with CNS tumors and correlate these findings with clinically relevant data. Genomic DNA was isolated from the peripheral blood of 51 pediatric patients and further analyzed by the next-generation sequencing approach. Bioinformatic analysis was done using an "in-house" gene list panel, which included 144 genes related to pediatric brain tumors, and the gene list panel Neoplasm (HP:0002664). Our study found that 27% of pediatric patients with CNS tumors have a germline variant in some of the known CPGs, like ALK, APC, CHEK2, ELP1, MLH1, MSH2, NF1, NF2 and TP53. This study represents the first comprehensive evaluation of germline variants in pediatric patients with CNS tumors in the Western Balkans region. Our results indicate the necessity of genomic research to reveal the genetic basis of pediatric CNS tumors, as well as to define targets for the application and development of innovative therapeutics that form the basis of the upcoming era of personalized medicine.

Circulating levels of IL-6 and TGF-ß1 in patients with prostate cancer undergoing radiotherapy: associations with acute radiotoxicity and fatigue symptoms.

BACKGROUND: The goal of research was to investigate the possible relations between serum concentrations of IL-6 and TGF-ß1, individual and clinical characteristics, and adverse effects of radiotherapy in patients with prostate cancer: acute and late genitourinary and gastrointestinal toxicity, and fatigue. METHODS: Thirty-nine patients with localized or locally advanced prostate cancer who were treated with radiotherapy were enrolled in this study. The acute radiotoxicity grades and fatigue levels were assessed during the radiotherapy and 1 month after the radiotherapy. Estimation of the late radiotoxicity was performed every three months in the first year, every four months in the second year, and then every six months. Serum levels of IL-6 and TGF-ß1 were determined before radiotherapy and after the 25th radiotherapy fraction by ELISA. RESULTS: The significant positive association between diabetes mellitus and changes in acute genitourinary toxicity grades during the radiotherapy was observed in prostate cancer patients. In addition, patients who were smokers had significantly higher maximum fatigue levels in comparison with patients who were non-smokers. The circulating IL-6 levels were significantly higher after the 25th radiotherapy fraction in comparison with levels determined before radiotherapy. The significant positive correlations between pretreatment TGF-ß1 levels and maximum genitourinary toxicity grades and between TGF-ß1 levels after the 25th fraction and genitourinary toxicity grades after the 25th fraction, were found. The pretreatment IL-6 concentrations and TGF-ß1 concentrations after the 25th fraction were positively correlated with maximum genitourinary toxicity grades. The IL-6 levels after the 25th fraction were positively associated with genitourinary toxicity grades after this fraction. The pretreatment IL-6 concentrations were significantly positively correlated with maximum fatigue scores. The significant positive correlation between IL-6 concentrations and fatigue scores after the 25th fraction was determined. The positive correlations between IL-6 and TGF-ß1 concentrations measured after the 25th fraction and maximum fatigue scores were observed. CONCLUSIONS: Our results suggest that serum levels of IL-6 and TGF-ß1 might influence the severity of acute genitourinary radiotoxicity and fatigue in patients with prostate cancer. Combining clinical parameters and circulating cytokine levels might be useful for the prediction of adverse reactions to radiotherapy.

Evaluation of In Vitro Cytotoxic Potential of Avarol towards Human Cancer Cell Lines and In Vivo Antitumor Activity in Solid Tumor Models.

The goal of this study was to determine the activity in vitro and in vivo of avarol, a sesquiterpene hydroquinone originating from the Dysidea avara sponge from the south Adriatic Sea, against different cancer cell lines and two types of mouse carcinoma. To investigate the in vitro cytotoxicity, a human cervix adenocarcinoma cell line (HeLa), human colon adenocarcinoma (LS174), human non-small-cell lung carcinoma (A549), and a normal human fetal lung fibroblast cell line (MRC-5) were used. The in vivo antitumor activity was investigated against two transplantable mouse tumors, the Ehrlich carcinoma (EC) and cervical cancer (CC-5). The effect of avarol on cancer cell survival, which was determined by the microculture tetrazolium test, confirmed a significant in vitro potency of avarol against the investigated cell lines, without selectivity towards MRC-5. The highest cytotoxicity was exhibited against HeLa cancer cells (10.22 ± 0.28 µg/mL). Moreover, potent antitumor activity against two tumor models was determined, as the intraperitoneal administration of avarol at a dose of 50 mg/kg resulted in a significant inhibition of tumor growth in mice. After three administrations of avarol, a 29% inhibition of the EC growth was achieved, while in the case of CC-5, a 36% inhibition of the tumor growth was achieved after the second administration of avarol. Therefore, the results indicate that this marine sesquiterpenoid hydroquinone could be a promising bioactive compound in the development of new anticancer medicine.

The Association of Polymorphisms in Genes Encoding Antioxidant Enzymes GPX1 (rs1050450), SOD2 (rs4880) and Transcriptional Factor Nrf2 (rs6721961) with the Risk and Development of Prostate Cancer.

Background and Objectives: Mounting evidence implicates oxidative damage in prostate carcinogenesis, contributing to modifications of macromolecules that drive cellular malignant transformation. Functional single-nucleotide polymorphisms (SNPs) of enzymes involved in redox homeostasis can disrupt pro-oxidant-antioxidant balance, leading to accumulation of reactive oxygen species and oxidative damage. We investigated the potential role of genetic polymorphisms of antioxidant enzymes glutathione peroxidase 1 (GPX1 rs1050450) and superoxide dismutase 2 (SOD2 rs4880) and regulatory antioxidant protein nuclear factor erythroid 2-related factor 2 (Nrf2 rs6721961) in the susceptibility to prostate cancer development (PC) and prognosis. Materials and Methods: We conducted a case-control study consisting of 235 patients with PC and 240 controls. Gene polymorphisms were determined by quantitative polymerase chain reaction (qPCR) and polymerase chain reaction with confronting two-pair primers (PCR-CTTP) methods. Multiple risk models were composed to inspect the separate and mutual effect of multiple genes and in combination with acquired contributory factors on the risk of PC development. Results: Independently, carriers of at least one SOD2*C allele had increased risk of PC development, which was significantly further amplified in advanced statistical models. When tested in combination, individuals with both SOD2*C allele and Nrf2*C/C genotype were also at increased risk of PC development, which was augmented when combined with acquired contributory factors. During the mean 75 ± 25 months of follow-up, investigated gene polymorphisms did not affect overall survival. Conclusion: Our results suggest that these gene polymorphisms could be used as risk biomarkers of PC evolution.

Prevalence of burnout among healthcare professionals at the Serbian National Cancer Center.

OBJECTIVE: The aim of this study was to investigate the level of burnout and identify who is at highest risk among healthcare professionals (HCPs) working at the largest referent national institution. METHODS: A cross-sectional survey was conducted at the Institute of Oncology and Radiology of Serbia from May 2019 to July 2019, evaluating the level of burnout, depression, fatigue, socio-demographic, behavioral and professional characteristics, and quality of life among healthcare professionals. Of the 576 distributed questionnaires among physicians, nurses/technicians and healthcare coworkers, 432 participants returned their questionnaires (75%). All instruments used in our study had been validated and cross-culturally adapted to Serbian language. RESULTS: The overall prevalence of burnout was 42.4%, with the greatest proportion of burned out in emotional exhaustion domain (66.9%). The multivariable-adjusted model analysis showed that nurses/technicians had a 1.41 times greater chance of experiencing burnout, compared to physicians (OR = 1.41, 95% CI 1.16-7.10), and that with each year of work experience, the chance of burnout increased by about 2% (OR = 1.02, 95% CI 1.00-1.92). Furthermore, it was shown that, with each point in the PHQ-9 score for depression, probability of burnout increased by 14% (OR = 1.14, 95% CI 1.07-1.94). Finally, after controlling all these potential confounders, the Mental Composite Score of SF-36 score showed an independent prognostic value in exploring the burnout presence among HCPs (OR = 1.17, 95% CI 1.03-2.47). CONCLUSION: Our research showed a significant level of burnout among healthcare professionals working in oncology, especially among nurses/technicians. The development of effective interventions at both individual and organizational level toward specific risk groups is needed.

Assessment of health-related quality of life among parents of children with solid tumors in Serbia.

PURPOSE: The aim of the study was to assess health-related quality of life (HRQoL) and contributing factors among parents of children with solid tumors in Serbia. METHODS: The cross-sectional study included 51 parents of children treated for different solid tumors at the Institute of Oncology and Radiology of Serbia. Parents filled out validated Serbian version of SF-36 questionnaire. Hierarchical multiple regression analysis was conducted to identify predictors of total score of SF-36. RESULTS: Almost all parents (94.1%) were mothers and average age was 38.6 ± 6.7 years. Majority of children had brain tumors (43.1%), followed by bone tumors (37.3%). The hierarchical regression analysis showed that socio-demographic characteristics explained 26% of the variance (p > 0.05) of the total score of SF-36. Addition of quality of life of children assessed by parents in the second model caused an increase of 21% in the variance explained (p < 0.05). After adding the Beck Depression Inventory score in the third block, an additional 18% of the variance in total score was explained (p < 0.05). CONCLUSIONS: This study showed that HRQoL measured by SF-36 in parents of children with cancer is strongly influenced by depression and quality of life of children assessed by parents.

GSTP1 rs1138272 Polymorphism Affects Prostate Cancer Risk.

Background and Objectives: One of the most frequent genetic alterations reported to date in prostate cancer (PC) is aberrant methylation of glutathione transferase P1 (GSTP1). Taking into consideration the involvement of oxidative stress in PC pathogenesis and recent advances in scientific understanding of the role of GSTP1*Ala114Val rs1138272 polymorphism in carcinogenesis, we hypothesized that this single-nucleotide polymorphism (SNP) influences the risk of PC independently of, or in combination with, other GST polymorphisms, including GSTP1*IIe105Val rs1695 or GSTM1 and GSTT1 deletion polymorphisms. Materials and Methods: Genotyping was performed in 237 PC cases and in 236 age-matched controls by multiplex polymerase chain reaction (PCR) for deletion of GST polymorphisms and by quantitative PCR for SNPs. Results: We found that carriers of either GSTP1*Val (rs1138272) or GSTP1*Val (rs1695) variant alleles had a PC risk compared to individuals with both referent alleles (OR = 4.93, 95%CI: 2.89-8.40, p < 0.001 and OR = 1.8, 95%CI: 1.19-2.73, p = 0.006, respectively). Additionally, in a haplotype analysis we found that individuals with GSTP1*C haplotype, represented by both variant alleles (GSTP1*Val rs1695 + GSTP1*Val rs1138272), had a 5.46 times higher risk of PC development compared to individuals with the most frequent haplotype (95%CI = 2.56-11.65, p < 0.001), suggesting a potential role of those variants in PC susceptibility. A regression analysis on the number of risk-associated alleles per individual (GSTM1*active, GSTT1*null, GSTP1*Val rs1695 and GSTP1*Val rs1138272) showed a significant increase in the risk of developing PC, from 3.65-fold in carriers of two risk alleles (95%CI = 1.55-8.61, p = 0.003) to an approximately 12-fold increase in carriers of all four risk alleles (95%CI = 3.05-44.93, p < 0.001). Conclusion: Prostate cancer may be influenced by multiple glutathione transferase (GST) polymorphic genes, especially GSTP1, highlighting the role of gene-gene interactions in human susceptibility to this cancer.

Severe hematologic temozolomide-related toxicity and lifethreatening infections.

Glioblastoma is the most frequent primary malignant brain tumor in adults. With the number of symptoms and signs, it belongs to diseases where a lot of treatment modalities are often applied. A standard treatment for patients with glioblastoma includes surgical resection followed by radiotherapy with concomitant and adjuvant temozolomide. Each type of treatment has its own toxicity. Temozolomide is an oral alkylating cytotoxic drug and like any other alkylating agent can induce side effects. Although temozolomide is generally a well tolerated drug, with rare severe toxic effects, sometimes certain toxicities can overcome the life risk of the underlying malignancy. By reviewing the literature, we have selected the cases with severe clinical presentation where some of them had a lethal outcome and we have chosen to present them in this article. In some patients with noticeable hematological toxic effects, as well as those with serious infections, attention must be paid to their treatment, as toxic effects can deepen and develop new toxicity, which all lead to a vicious circle without a favorable outcome. Preventive use of antiviral drugs should be considered before the treatment with temozolomide in patients with a positive history of viral infections such as Hepatitis B infection. In order to prevent rare but possible opportunistic infections, it is necessary to familiarize the patients with the treatment, toxicity and rare opportunistic infections. These infections can be triggered by various factors from the nearest environment, including both domestic and wild animals and pets.

Treatment results of childhood Ewing's sarcoma of the bone in Serbia.

PURPOSE: The purpose of this study was to present treatment results of childhood Ewing's sarcoma (ES) of the bone in Serbia and to analyze prognostic factors. METHODS: We performed a detailed analysis on a series of 107 patients with ES of the bone treated at the Institute for Oncology and Radiology of Serbia between 2000 and 2014, using modern multimodal therapy. RESULTS: Median age at the time of diagnosis was 14 years, with 56.07% of the patients being ≤14 years. There was a male predominance (59.81%). The most common primary sites were pelvis (25.23%), femur (17.76%) and tibia (12.15%). Thirty-four patients (31.78%) had metastatic disease, 17 of which had isolated lung metastases, 9 bone metastases and 8 patients had both. Tumor size ≤ 8 cm had 38.32% and >8 cm had 61.68% patients. Overall, 51.4% patients underwent surgery and radiotherapy as a local treatment modality after neoadjuvant chemotherapy. Radiotherapy alone was performed in 24 patients. The 5-year overall survival (OS) was 43.8%. For patients with localized disease, the 5-year OS was 56.4% and for patients with metastatic disease 17.6%. In patients with initially nonmetastatic disease, age under 14 years, with tumor size <8 cm and a good response to the neoadjuvant chemotherapy, the OS correlated with better outcome. CONCLUSIONS: Modern multidisciplinary approach in treatment of childhood ES of the bone in accordance with the recommended pediatric protocols, gives good treatment results. Therapy should be performed in referral centers.

Management and treatment of children with medulloblastoma in Serbia, a middle-income country.

PURPOSE: The aim of this study was to present the management and treatment of children with medulloblastoma in Serbia, a middle-income country (MIC). METHODS: The data of 87 children diagnosed with medulloblastoma and treated at the Institute for Oncology and Radiology of Serbia from 2000 to 2013 were analyzed. RESULTS: The children's median age was 8.3 years (range 2.5-17.3). Eighty-two (94.2%) were 3 years or older. Sixtytwo (71.3%) patients had stage M0 medulloblastoma, 12 (13.8%) had stage M1 and 13 (14.9%) had stage M2 or M3. As of October 2015, 51 (58.6%) patients were alive and 31 (35.6%) had died. Five patients (5.7%) were lost to followup. Twenty-six patients relapsed. The median follow-up time was 58 months (range 4-187). Mean overall survival (OS) was 76.4% at 3 years, 66.2% at 5 years and 59.2% at 10 years. Mean disease-free survival (DFS) was 75.8% at 3 years, 62.8% at 5 years and 56.6% at 10 years. Mean OS of stage M0 patients was 86.4% at 3 years, 74% at 5 years and 63.1% at 10 years. The OS of stage M1, M2 and M3 patients combined was 48.9% at 3 years, 44.0% at 5 years and 37.7% at 10 years. CONCLUSION: In Serbia, a MIC, it is possible to achieve good treatment results in children with medulloblastoma using international treatment guidelines and recommendations, available resources and an experienced team of professionals dedicated to pediatric neurooncology.

Curative intent for unresectable advanced squamous cell esophageal cancer: Overall survival after chemoradiation.

PURPOSE: To analyse the overall survival (OS) of patients with locally advanced, unresectable esophageal cancer treated with chemoradiation (CRT) with or without surgery. METHODS: CRT was administered to 63 patients with locally advanced (T3-4, N0-1), initially unresectable squamous cell esophageal cancer. After the assessment of tumor response to treatment, medically fit patients converted to operable stage were subjected to surgery. Regular follow-up was performed every 3 months during first 2 years, and then every 6 months. RESULTS: All 63 patients completed the whole radiotherapy course. Forty patients (63%) received complete 4 cycles of chemotherapy. In the remaining 23 patients (37%) chemotherapy was interrupted due to toxicity. Clinical response to CRT was: complete response (CR) in 4 patients (6%), partial response (PR in 27 (43%), stable disease (SD) in 22 (35%) patients, and 10 patients (16%) had disease progression (PD). After reevaluation, 23 patients (15 PR and 8 SD after CRT) underwent surgery (37%), all with R0 resection. OS in the whole group was 53% at one year, and 36% at two years. OS was significantly better in the operated group of patients than in the non-operated group. No statistically significant difference in OS was observed comparing operated to CR patients with no surgery (70 vs 50%). In the non-operated group of patients there was no difference in OS between CR, PR, and SD patients. CONCLUSIONS: With appropriate selection, patients with advanced squamous cell esophageal cancer should be considered for potentially effective treatment.

Pediatric glioblastoma: a single institution experience.

PURPOSE: The aim of this study was to evaluate characteristics of childhood glioblastoma multiforme, effectiveness of treatment modalities, and detect factors related to outcome. METHODS: A detailed analysis was performed on a series of 15 patients treated between 2000 and 2013, based on their clinical, radiologic, pathologic, treatment, and follow-up data. RESULTS: Median survival time of children with glioblastoma was 13.5 months. One- and 2-year overall survival probabilities were 66.7 and 20 %, respectively. There were no significant differences in survival based on patients' gender, age, disease presentation with or without epileptic seizures, signs/symptoms of increased intracranial pressure, or tumor location. The presence of neurological deficit initially, as well as prior to radiotherapy, which was quantified by neurologic function score (NFS), had an impact on overall survival. Children with NFS 0 lived longer compared to others (p = 0.001). Survival of children that underwent gross total resection was longer than that of children that underwent subtotal resection (p = 0.030). Mean survival time of children with gross total resection was 73.5 months, compared to 13 months in children with subtotal resection. There was no significant correlation between outcome and type of radiotherapy. In four patients with gigantocellular glioblastoma, we found no evidence of a better prognosis. Two long-term survivors were recorded. Both of them underwent gross total resection and were assigned a NFS 0. CONCLUSIONS: Gross total resection is essential for longer overall survival among pediatric patients with glioblastoma and offers a possibility for long-term survival. Severity of neurologic symptoms quantified by NFS can be considered as a potential predictor of outcome.

Toxicity of the lower gastrointestinal tract and its predictive factors after 72Gy conventionally fractionated 3D conformal radiotherapy of localized prostate cancer.

PURPOSE: To estimate the incidence of acute and late lower gastrointestinal tract toxicity (LGIT) in patients treated with 3D conformal radiotherapy (3DCRT) for localized prostate cancer (PC) and estimate the influence of dosimetric parameters and other possible factors. METHODS: Ninety-four patients with localized PC treated with 3DCRT, with an estimated risk of lymph node involvement ?15%, according to the Roach formula, were evaluated in this study. All patients received a total dose of 72Gy in 36 fractions. Acute and late lower gastrointestinal tract (LGIT) toxicity were graded according to the EORTC radiation morbidity scoring scale. Characteristics such as alcohol intake, gastrointestinal (GI) co-morbidities, hemorrhoids, previous abdominal or pelvic surgery (PAPS), diabetes mellitus (DM), the use of antiaggregants, and dosimetric parameters, were analyzed as possible predictive factors of radiation (RT) toxicity. RESULTS: Grade ?1 acute LGIT toxicity during 3DCRT developed in 41 of 94 patients (43.6%). At univariate logistic regression analysis (UVA) using the baseline model, alcohol consumption (p=0.068), hemorrhoids (p=0.004), GI co-morbidities (p=0.018), PAPS (p=0.033), V60 (p=0.070), V65 (p=0.046) and V70 (P=0.056) were significant predictive factors for any grade of acute LGIT toxicity. Predictive factors of grade ?1 acute toxicity in the multivariate logistic regression analysis (MVA) were current hemorrhoids (p=0.007), and the GI co-morbidities (p=0.025). Late grade 1 LGIT toxicity occurred in 17 (18.1%) patients. Late grade ?2 LGIT toxicity as a maximum toxicity score occurred in 9 (9.57%) patients during a median follow-up of 27 months. Following UVA, hemorrhoids (p=0.001) and use of antiaggregants (p=0.034) were significant predictive factors for any grade of late LGIT toxicity. In the MVA, hemorrhoids were significantly associated with late grade ?1 LGIT toxicity (p=0.005). CONCLUSION: Hemorrhoids and GI co-morbidities had a significant impact on the occurrence of acute grade ?1 LGIT toxicity. Hemorrhoids had significant influence on the development of any grade of late LGIT toxicity.

Bone metastases in medulloblastoma--single institution experience.

BACKGROUND: Medulloblastoma has one of the highest rates of metastasis outside the central nervous system (CNS). Bone metastases are the most common lesions, although lymph node and visceral spread have also been reported. OBJECTIVE: To present patients with bone metastasis in medulloblastoma and discuss their radiologic appearances and treatment approach. PATIENTS AND METHODS: From 1993 to 2008, 82 patients diagnosed with medulloblastoma were treated at the Institute for Oncology and Radiology of Serbia. Three (3.6%) developed extraneural metastasis (ENM). In primary treatment, patients were treated with surgery, craniospinal radiotherapy with local boost to tumor bed, and adjuvant chemotherapy [lomustine (CCNU) and vincristine]. Of the three patients with ENM, all developed bone metastases at the time of relapse. Relapse occurred within 17 to 42 months of initial diagnosis. Patients received secondary chemotherapy and palliative radiotherapy to the affected bone in two cases. RESULTS: Among these three patients, case 1 had initially a solitary lytic lesion. Case 2 had diffuse blastic lesions and also bone marrow involvement. Case 3 had multiple mixed lytic-sclerotic lesions but later developed lymph node metastasis and metastases to both breasts, as well. All patients were without concurrent CNS involvement at the time of ENM. Unfortunately, after initial partial response, the three patients died at 24, 13, and 18 months after detection of metastases, respectively. CONCLUSION: With prolonged survival times in children with medulloblastoma, more emphasis should be placed on the possibility of systemic involvement. A greater understanding of the pathogenesis of the systemic metastases may be valuable in designing future, more aggressive multimodal therapy.

What did COVID-19 pandemics teach us about single-fraction radiotherapy for painful bone metastases-State of the art or undertreatment?

BACKGROUND: Choosing the optimal treatment approach for patients with painful bone metastases during the COVID-19 pandemic became challenging. A simple technique, single fraction radiotherapy was recommended for these patients usually referring to bone metastases as a single entity, although it is a very heterogeneous group of patients. AIM: This study aimed to analyze the response to palliative single fraction radiotherapy in relation to age, performance status, primary tumor, histopathology, and bone localization in the group of patients with painful bone metastases. METHODS: A clinical, prospective, non-randomized study was conducted at the Institute for Oncology and Radiology of Serbia, which included 64 patients with noncomplicated, painful bone metastases who underwent palliative, pain-relieving radiation therapy with a single tumor dose of 8Gy in a single hospital visit. Response to treatment was patient reported via telephone interview using visual analog scale. The response assessment was based on the international consensus panel of radiation oncologists. RESULTS: In the entire group of patients, 83% responded to radiotherapy. No statistically significant difference was observed in response to therapy, time to reach the maximum response, degree of pain reduction, nor in response duration depending on the patient's age, performance status, the primary origin of the tumor, histopathology, or location of the metastasis (bone) that was irradiated. CONCLUSION: Regardless of clinical parameters, palliative radiotherapy with a single dose of 8Gy can be considered very effective in quick pain relief in patients with noncomplicated painful bone metastases. Single fraction radiotherapy in a single hospital visit, as well as patient-reported outcome for these patients may be considered favorable beyond Covid pandemics.

MicroRNAs in Prostate Cancer Following Radiotherapy: Towards Predicting Response to Radiation Treatment.

Prostate cancer (PCa) is the second most frequently diagnosed male cancer worldwide. Early diagnosis of PCa, response to therapy, and prognosis still represent a challenge. Nearly 60% of PCa patients undergo radiation therapy (RT) which might cause side effects. Despite numerous researches in this field, predictive biomarkers for radiation toxicity are still not elucidated. MicroRNAs as posttranscriptional regulators of gene expression are shown to be changed during and after irradiation. MicroRNA level changes might be utilized to predict response to RT in the near future, which might help clinicians to make the decision on treatment regimens if needed. Individual radiation response results from the interactions among radiation treatment parameters and the biological background of each patient. In this review, we have listed and described miRNAs involved in response to RT in PCa and highlighted potential candidates for future biological tests predicting radiation response to RT, with the special focus on side effects of RT. According to described literature, we concluded that let-7, miR-21, miR-34a, miR-146a, miR-155, and members of miR-17/92 cluster might be promising candidates for biological tests predicting radiosensitivity of PCa patients undergoing radiation treatment. Predictive miRNA panels, especially for acute and late side effects of RT, can serve as a starting point for decisions for individualized RT planning. We believe that this review might be one step closer to understanding molecular mechanisms underlying individual radiation response of patients with PCa.

Association between microRNAs 10b/21/34a and acute toxicity in glioblastoma patients treated with radiotherapy and temozolomide.

A personalized approach to chemoradiation is important in reducing its potential side effects and identifying a group of patients prone to toxicity. MicroRNAs have been shown to have a predictive potential for radiotoxicity. The goal of the study was to test if levels of miRNA in peripheral blood mononuclear cells of glioblastoma patients are associated with toxicity and to identify the peak time point for toxicity. MicroRNA-10b/21/34a levels were measured in 43 patients with and without toxicity, at baseline, at the 15th, and at the 30th fraction by Real-Time quantitative Polymerase Chain Reaction. MicroRNA-10b/21 levels increased with toxicity grade (p = 0.014; p = 0.013); miR-21/34a levels were significantly different between patients with and without toxicity at the 15th fraction (p = 0.030; p = 0.045), while miR-34a levels significantly changed during treatment (p < 0.001). All three miRNAs showed a significantly high positive correlation with one another. MiR-34a might be considered as a predictive factor for toxicity due to its changes during treatment, and differences between the groups with and without toxicity; miR-10b might be used to predict toxicity; miR-10b/21 might be used for predicting the grade of toxicity in GB patients.

Association of polymorphisms in TGFB1, XRCC1, XRCC3 genes and CD8 T-lymphocyte apoptosis with adverse effect of radiotherapy for prostate cancer.

The genetic background of each person might affect the severity of radiotherapy (RT)-induced normal tissue toxicity. The aim of study was to evaluate the influence of TGFB1 C-509T and Leu10Pro, XRCC1 Arg280His and XRCC3 Thr241Met polymorphisms as well as the level of radiation-induced CD8 T-lymphocyte apoptosis (RILA) on adverse effects of RT for prostate cancer (PCa). The study included 88 patients with localized or locally advanced PCa who were treated with RT. The polymorphisms were determined by PCR-RFLP analysis on DNA from peripheral blood mononuclear cells. RILA values were measured by flow cytometry. We found that CT genotype of TGFB1 C-509T could be protective biomarker for acute genitourinary (GU) and gastrointestinal (GI) radiotoxicity, while Thr variant of XRCC3 Thr241Met could predict the risk for acute GU radiotoxicity. Correlation between RILA values and toxicity was not detected. Univariate logistic regression analysis showed that Gleason score and risk group were risk factors for late GU, while for late GI radiotoxicity it was diabetes mellitus type 2. However, in multivariate model those were not proven to be significant and independent risk factors. Identification of assays combination predicting individual radiosensitivity is a crucial step towards personalized RT approach.