The Effectiveness and Toxicity of Frameless CyberKnife Based Radiosurgery for Parkinson's Disease-Phase II Study.

Frame-based stereotactic radiosurgery (SRS) has an established role in the treatment of tremor in patients with Parkinson's disease (PD). The low numbers of studies of frameless approaches led to our prospective phase 2 open-label single-arm clinical trial (NCT02406105), which aimed to evaluate the safety and efficacy of CyberKnife frameless SRS. Twenty-three PD patients were irradiated on the area of the thalamic ventral nuclei complex with gradually increasing doses of 70 to 105 Gy delivered in a single fraction. After SRS, patients were monitored for tremor severity and the toxicity of the treatment. Both subjective improvement and dose-dependent efficacy were analysed using standard statistical tests. The median follow-up was 23 months, and one patient died after COVID-19 infection. Another two patients were lost from follow-up. Hyper-response resulting in vascular toxicity and neurologic complications was observed in two patients irradiated with doses of 95 and 100 Gy, respectively. A reduction in tremor severity was observed in fifteen patients, and six experienced stagnation. A constant response during the whole follow-up was observed in 67% patients. A longer median response time was achieved in patients irradiated with doses equal to or less than 85 Gy. Only two patients declared no improvement after SRS. The efficacy of frameless SRS is high and could improve tremor control in a majority of patients. The complication rate is low, especially when doses below 90 Gy are applied. Frameless SRS could be offered as an alternative for patients ineligible for deep brain stimulation; however, studies regarding optimal dose are required.

Safety and Feasibility of Radiation Therapy Combined with CDK 4/6 Inhibitors in the Management of Advanced Breast Cancer.

The addition of CDK4/6 inhibitors to endocrine therapy in advanced hormone receptor-positive HER2-negative breast cancer has led to practice-changing improvements in overall survival. However, data concerning the safety of CDK4/6i combination with radiotherapy (RT) are conflicting. A retrospective evaluation of 288 advanced breast cancer patients (pts) treated with CDK4/6i was performed, and 100 pts also received RT. Forty-six pts received 63 RT courses concurrently and fifty-four sequentially before CDK4/6i initiation (76 RT courses). Neutropenia was common (79%) and more frequent during and after concurrent RT than sequential RT (86% vs. 76%); however, CDK4/6i dose reduction rates were similar. In patients treated with CDK4/6i alone, the dose reduction rate was 42% (79 pts) versus 38% with combined therapy, and 5% discontinued treatment due to toxicity in the combined group. The risk of CDK4/6i dose reduction was correlated with neutropenia grade, RT performed within the first two CDK4/6i cycles, and more than one concurrent RT; a tendency was observed in concurrent bone irradiation. However, on multivariate regression analysis, only ECOG 1 performance status and severe neutropenia at the beginning of the second cycle were found to be associated with a higher risk of CDK4/6i dose reduction. This largest single-center experience published to date confirmed the acceptable safety profile of the CDK4/6i and RT combination without a significantly increased toxicity compared with CDK4/6i alone. However, one might delay RT for the first two CDK4/6i cycles, when myelotoxic AE are most common.

Conventionally fractionated radiotherapy versus CyberKnife hypofractionated radiotherapy for painful vertebral haemangiomas - A randomized clinical trial.

BACKGROUND AND PURPOSE: The outcomes of conventional radiotherapy for painful vertebral haemangiomas have been improved through dose escalation at the expense of overall treatment time. We hypothesized that with the aid of precise hypofractionated radiotherapy, it is possible to safely deliver a similar biological equivalent dose over a significantly shorter course of treatment with a comparable efficacy and safety. MATERIALS AND METHODS: In this prospective, single-institution unblinded randomized clinical trial (NCT02332408) patients with painful vertebral haemangiomas were allocated one-to-one either to 25 Gy delivered in five fractions (CK) or conventionally fractionated radiotherapy up to 36 Gy (conv.). The main endpoint was pain relief at two years, measured on a subjective and numerical scale (NRS). RESULTS: The trial was finished yielding 74 evaluable patients, including 38 in the CK arm. Adverse events were infrequent and the treatment was well tolerated. The overall treatment time was significantly shorter in the CK arm (median of 13 days vs 25 days). At two years, more than half of the patients reported improvement (46; 62.2 %) , in 21 cases the pain symptoms were stable (28.4 %), and in seven cases worse (9.5 %). There were significantly more patients reporting improvement in the CK arm (73.7 % vs 50 %; p = 0.036). The median decrease in NRS was 4 (IQR 1-5) or 59 % (IQR 20-86 %), and the difference between arms was not statistically significant. CONCLUSION: Five fractions hypofractionated radiotherapy for painful vertebral haemangiomas up to a total dose of 25 Gy is a safe treatment modality, significantly shorter compared to conventional fractionation, and possibly more effective.

Ultra-Hypofractionated Stereotactic Body Radiotherapy for Localized Prostate Cancer: Clinical Outcomes, Patterns of Recurrence, Feasibility of Definitive Salvage Treatment, and Competing Oncological Risk.

A cohort of 650 patients treated for localized prostate cancer (PCa) with CyberKnifeTM ultra-hypofractionated radiotherapy between 2011 and 2018 was retrospectively analyzed in terms of survival, patterns of failure, and outcomes of second-line definitive salvage therapies. The analysis was performed using survival analysis including the Kaplan-Meier method and Cox regression analysis. At a median follow-up of 49.4 months, the main pattern of failure was local-regional failure (7.4% in low-, and 13% in intermediate/high-risk group at five years), followed by distant metastases (3.6% in low-, and 6% in intermediate/high-risk group at five years). Five-year likelihood of developing a second malignancy was 7.3%; however, in the vast majority of the cases, the association with prior irradiation was unlikely. The 5-year overall survival was 90.2% in low-, and 88.8% in intermediate/high-risk patients. The independent prognostic factors for survival included age (HR 1.1; 95% CI 1.07-1.14) and occurrence of a second malignancy (HR 3.67; 95% CI 2.19-6.15). Definitive local salvage therapies were feasible in the majority of the patients with local-regional failure, and uncommonly in patients with distant metastases, with an estimated second-line progression free survival of 67.8% at two years. Competing oncological risks and age were significantly more important for patients' survival compared to primary disease recurrence.

Association of Polymorphism CHRNA5 and CHRNA3 Gene in People Addicted to Nicotine.

Smoking is a chronic and relapsing addictive trait that harms public health. Among the many identified genetic variants of nicotine dependence, the variants in the CHRNA5/A3/B4 gene cluster on chromosome 15 that encode the α5, α3, and ß4 subunits have recently received a lot of attention. Importantly, variants in this gene cluster have been associated with nicotine addiction. Among the many significant variants in this cluster, the polymorphism SNP rs16969968 seems to be the most interesting factor in nicotine addiction. This polymorphism causes an amino acid change from aspartate to asparagine at position 398 of the α5 nicotinic receptor protein sequence. Our study aimed to analyze three polymorphic variants: the rs16969968 located in the CHRNA5 gene, the rs578776 and rs1051730 located in the CHRNA3 gene in nicotine-addicted subjects, and in controls. Our study encompasses an association analysis of genotypes and haplotypes. A group of 401 volunteers was recruited for the study and divided into two groups: the study group consisted of addicted smokers and a control group of 200 unrelated non-smokers who were not dependent on any substance and healthy. A statistically significant difference was observed in the frequency of genotypes of the rs1051730 polymorphism of the CHRNA3 gene (χ2 = 6.704 p = 0.035). The T/T genotype was statistically significantly more frequent in the group of nicotine-dependent subjects. The haplotypes rs16969968, rs578776, and rs1051730 were distinguished, of which the G-T-T and G-C-T haplotypes were present only in the study group. With differences in frequencies, statistical significance was noted-for the G-T-T haplotype p = 0.01284 and the G-C-T haplotype p = 0.00775. The research stated that novel haplotypes G-T-T and G-C-T, though with very low-frequency variants in CHRNA3, were associated with nicotine addiction.

The Prognostic Value of PI-RADS Score in CyberKnife Ultra-Hypofractionated Radiotherapy for Localized Prostate Cancer.

Prostate Imaging-Reporting and Data System (PI-RADS) has been widely implemented as a diagnostic tool for significant prostate cancer (PCa); less is known about its prognostic value, especially in the setting of primary radiotherapy. We aimed to analyze the association between PI-RADS v. 2.1 classification and risk of metastases, based on a group of 152 patients treated with ultra-hypofractionated stereotactic CyberKnife radiotherapy for localized low or intermediate risk-group prostate cancer. We found that all distant failures (n = 5) occurred in patients diagnosed with a PI-RADS score of 5, and axial measurements of the target lesion were associated with the risk of developing metastases (p < 0.001). The best risk stratification model (based on a combination of greatest dimension, the product of multiplication of PI-RADS target lesion axial measurements, and age) achieved a c-index of 0.903 (bootstrap-validated bias-corrected 95% CI: 0.848−0.901). This creates a hypothesis that PI-RADS 5 and the size of the target lesion are important prognostic factors in early-stage PCa patients and should be considered as an adverse prognostic measure for patients undergoing early treatment such as radiation or focal therapy.

Therapeutic Strategy in Low-Risk Papillary Thyroid Carcinoma - Long-Term Results of the First Single-Center Prospective Non-Randomized Trial Between 2011 and 2015.

Optimal therapeutic strategy in low advanced papillary thyroid carcinoma (PTC) is still a matter of debate. The management differs depending on the country. A prospective non-randomized study was performed to evaluate whether less extensive surgery could be a safe, acceptable, and sufficient therapeutic option in PTC cT1N0M0 patients. The present paper summarizes the results of over a 5-year follow-up. Material: Our prospective group (PG) treated between 2011 and 2015 consisted of 139 patients with cT1aN0M0 PTC who underwent lobectomy (LT) as initial surgical treatment (PGcT1aN0M0 group) and 102 cT1bN0M0 patients in whom total thyroidectomy (TT) with unilateral central neck dissection (CND) was performed (PGcT1bN0M0). PG was compared with the retrospective group (RG) of patients who underwent TT with bilateral CND between 2004 and 2006: 103 cT1aN0M0 patients (RGcT1aN0M0) and 91cT1bN0M0 (RGcT1bN0M0). The risks of reoperation, cancer relapse and postoperative complications were analyzed. Results: Only 12 cT1aN0M0 patients (7.6%) withdrew from the trial and underwent TT with bilateral CND. Over 90% of patients accepted less extensive surgery. In 4 cT1aN0M0 cases, TT with CND was performed due to lymph node metastases found intraoperatively. The initial clinical stage according to the TNM/AJCC 7th edition was confirmed histologically in 77% of cases in PGT1aN0M0 and in 72% in PGT1bN0M0, respectively. 24 PGcT1aN0M0 patients were reoperated on. In this group, cancer lesions in the postoperative histological specimens were found in 8 cases (32%). Five-year disease-free survival (DFS) was excellent. However, no statistically significant differences were found between PG and RG groups (99.3% in PGcT1aN0M0 and 99.0%, in RGcT1aN0M0; p = 0.41 and 98%, in PGcT1bN0M0 and 94.4% in RGcT1bN0M0; p=0.19). No significant differences were observed in the incidence of early paresis of the recurrent laryngeal nerves between PG and RG. However, as predicted, LT completely eliminated the risk of postoperative hypoparathyroidism. Summary: The results of the prospective clinical trial confirm that less extensive surgery in adequately selected low-advanced PTC patients is both safe and sufficient.

Tandem autologous hematopoietic cell transplantation with sequential use of total marrow irradiation and high-dose melphalan in multiple myeloma.

The goal of this phase II trial was to evaluate safety and efficacy of a tandem autologous hematopoietic cell transplantation (auto-HCT) using sequentially total marrow irradiation (TMI) at the dose of 12 Gy (4 Gy on days -3, -2, and -1) and melphalan 200 mg/m2 for patients with multiple myeloma (MM). TMI was performed using helical tomotherapy. Additional "boosts" (total 24 Gy) were applied for patients with active lesions as revealed by PET-FDG. Fifty patients with median age 58 years (41-64 years) were included and received tandem auto-HCT. TMI resulted in absolute neutropenia in all patients. Grade 3 infections were reported in 30% patients. Other toxicities were rare. Proportion of patients who achieved at least very good partial response increased from 46% before the first auto-HCT to 82% after tandem transplantation. Complete remission rates changed from 10% to 42%, respectively. The probabilities of overall and progression-free survival at 5 years were 74% and 55%, respectively. No patient died without progression. We conclude that conditioning with TMI ± PET-guided "boosts" represents personalized treatment approach in MM and is characterized by very good toxicity profile. Tandem auto-HCT using TMI in sequence with high-dose melphalan appears safe with encouraging early efficacy.

Randomised clinical trial on 7-days-a-week postoperative radiotherapy vs. concurrent postoperative radio-chemotherapy in locally advanced cancer of the oral cavity/oropharynx.

OBJECTIVE: To compare the efficacy and tolerance of 7-days-a-week accelerated postoperative radiotherapy (p-CAIR) vs postoperative radio-chemotherapy (p-RTCT). METHODS: Between September 2007 and October 2013, 111 patients were enrolled and randomly assigned to receive 63 Gy in 1.8 Gy fractions 7-days-a-week (n = 57, p-CAIR) or 63 Gy in 1.8 Gy fractions 5-days-a-week with concurrent cisplatin 80-100 mg per square meter of body-surface area on days 1, 22 and 43 of the radiotherapy course (p-RTCT). It represents approximately 40% of the intended trial size, that was closed prematurely due to slowing accrual. Only high-risk patients with squamous cell cancer of the oropharynx/oral cavity, considered fit for concurrent treatment were enrolled. RESULTS: The rate of locoregional control (LRC) did not differ significantly between treatment arms (p = 0.18, HR = 0.56), 5 year LRC tended, however, to favour p-RTCT (81%) vs p-CAIR (62%). There was no difference in overall survival between treatment arms (p = 0.90, HR = 1.03).The incidence and severity of acute mucosal reactions and late reactions did not differ significantly between treatment arms. Haematological toxicity of p-RTCT was, however, considerably increased compared to p-CAIR. CONCLUSION: Concurrent postoperative RTCT tended to improve locoregional control rate as compared to p-CAIR. This, however, did not transferred into improved overall survival. Postoperative RTCT was associated with a substantial increase in haematological toxicity that negatively affected treatment compliance in this arm. ADVANCES IN KNOWLEDGE: To our knowledge, this is the first trial that compares accelerated radiotherapy and radio-chemotherapy in postoperative treatment for oralcavity/oropharyngeal cancer.

Surgical approach to differentiated thyroid cancers (DTC) in children [Specyfika leczenia chirurgicznego zróznicowanych raków tarczycy (ZRT) u dzieci].

Thyroid cancer in children is rare and accounts for 1-3% of all malignant tumours. Differentiated thyroid cancers (DTC) and particularly papillary thyroid carcinoma (PTC) (90% of cases) are the most prevalent. Surgery is the mainstay of treatment in patients with DTC. The current recommendations are based not on prospective randomised clinical trials, but on retrospective trials and expert opinions. Therefore, it is not easy to choose the optimal therapeutic strategy to obtain the best treatment and to avoid serious complications and adverse events. In children and adolescents, the clinical presentation, course, and prognosis are different from those seen in adults. Children are generally at low risk of death but at higher risk of long-term harm due to overly aggressive treatment. Therefore, optimisation of the therapeutic strategy is particularly important. The present paper provides a summary of the current guidelines on surgical management in thyroid tumours and DTC in children and adolescents.

Stereotactic Ablative Radiotherapy for Prostate Cancer-The Treatment Results of 500 Patients and Analysis of Failures.

OBJECTIVE: Stereotactic ablative radiotherapy is a very promising approach for the treatment of patients with prostate cancer. The aim of this study was to evaluate the clinical tolerance, effectiveness, patterns of failure, and attempt to define predictive factors based on our experience. METHODS: The cohort consists of 264 low-risk and 236 intermediate-risk consecutive patients treated at one institution. Prostate-specific antigen (PSA), adverse effects, and androgen deprivation therapy (ADT) usage were noted. RESULTS: Median follow-up was 31.3 months. Over 90% of the patients reported no gastrointestinal toxicity. There were 4 occurrences of G3+ sequelae. 75% patients had no genitourinary toxicity at first month, and up to 90% during the rest of follow-up, with only 1 case of G3 adverse event. The toxicity was more pronounced in patients with higher PSA concentrations. Prior to stereotactic ablative radiotherapy, the mean PSA was 7.59 and 277 patients used ADT. The PSA decreased for up to 20 months before reaching a plateau. The decline was slower, and PSA levels were higher in patients without ADT. A total of 15 treatment failures occured in a median time of 19.9 months. Higher PSA concentrations were connected with higher failure rates, even in the first month and prior to reaching Phoenix criterion. CONCLUSION: CyberKnife-based stereotactic ablative radiotherapy of low-risk and intermediate-risk prostate cancer patients is an effective and well-tolerated modality of treatment. PSA is the most important predictive factor. The evolution of PSA concentration in a particular subgroup of patients suggests that ADT in intermediate-risk cases could improve long-term results.

Influence of Confounding Factors on Radiation Dose Estimation Using In Vivo Validated Transcriptional Biomarkers.

For triage purposes following a nuclear accident, blood-based gene expression biomarkers can provide rapid dose estimates for a large number of individuals. Ionizing-radiation-responsive genes are regulated through the DNA damage-response pathway, which includes activation of multiple transcription factors. Modulators of this pathway could potentially affect the response of these biomarkers and consequently compromise accurate dose estimation calculations. In the present study, four potential confounding factors were selected: cancer condition, sex, simulated bacterial infection (lipopolysaccharide), and curcumin, an anti-inflammatory/antioxidant agent. Their potential influence on the transcriptional response to radiation of the genes CCNG1 and PHPT1, two biomarkers of radiation exposure ex vivo, was assessed. First, both CCNG1 and PHPT1 were detected in vivo in blood samples from radiotherapy patients and as such were validated as biomarkers of exposure. Importantly, their basal expression level was slightly but significantly affected in vivo by patients' cancer condition. Moreover, lipopolysaccharide stimulation of blood irradiated ex vivo led to a significant modification of CCNG1 and PHPT1 transcriptional response in a dose- and time-dependent manner with opposite regulatory effects. Curcumin also affected CCNG1 and PHPT1 transcriptional response counteracting some of the radiation induction. No differences were observed based on sex. Dose estimations calculated using linear regression were affected by lipopolysaccharide and curcumin. In conclusion, several confounding factors tested in this study can indeed modulate the transcriptional response of CCNG1 and PHPT1 and consequently can affect radiation exposure dose estimations but not to a level which should prevent the biomarkers' use for triage purposes.

Cyberknife Radioablation of Prostate Cancer ­ Preliminary Results for 400 Patients

Objectives: To evaluate the tolerance and effectiveness of stereotactic ablative radiotherapy (SABR) applied in the treatment of low and intermediate risk (LR & IR) prostate cancer patients (PCP) and provide an evaluation of the level of risk group impact on treatment results. In addition, androgen deprivation therapy (ADT) usage and prostatic specific antigen (PSA) decline after SABR were assessed. Material and Methods: A total of 400 PCP (213 LR and 187 IR, including T2c) were irradiated with a CyberKnife using fd 7.25 Gy to TD 36.25 Gy. At the start of treatment, 60.3% of patients were undergoing ADT and this gradually decreased to 0% after 38 months. Follow-up was for a median of 15.0 months. Patients were monitored on SABR completion and 1, 4, 8 months later and then subsequently every 6 months. GI (Gastro-Intestinal) and GU (Genito-Urinary) acute and late adverse effects, PSA and ADT usage were evaluated. Results: Failure was noted in 9 patients (2.25%) (5 in LR and 4 in IR groups) - 4 relapses and 5 nodal metastases. No G3/4 late adverse effects (EORTC/RTOG) were observed. Some 0.5% of G3 GU and 0.3% of G3 GI acute reactions were noted respectively on the SABR completion day and one month later. The median of PSA declined 1.5 ng/ml during the first month and 0.6 ng/ml during the next three months. No impact of risk groups on treatment results was found. An impact of ADT on PSA decline was only confirmed for time point interactions. Conclusions: SABR for LR and IR PCP is a safe and effective treatment. The inclusion of T2c patients and the low percentage of IR patient failure permit us the assumption that this procedure could be utilized in the treatment of more advanced cases. The results do not allow clear definition of the impact of ADT on radioablation results in LR and IR+ T2c cases.

[CyberKnife for prostate cancer patients. Update of 200 patients treatment results].

Introduction: This is an update regarding the treatment results of 200 prostate cancer patients' (PCP) CyberKnife based radioablation (the first group in Poland). The purpose of this study is reevaluation (after 2 years) of this treatment modality results of low (LR) and intermediate risk (IR) (including T2c) PCP and failure analysis. Material and Methods: 200 PCP (95 LR, 86 IR, 19 T2c) 53 ­ 83 y.o. (mean 69) treated between 2011 and 2014. 48% used neoadjuvant ADT. The patients were irradiated every other day with a fraction dose of 7.25 Gy to the total dose 36.25 Gy (5 fractions in 9 days). Fiducials based tracking was performed. The patients were controlled on the treatment completion day, 1, 4, 8 months later and subsequently every 6 months. The PSA concentration, ADT usage, acute and late adverse effects (EORTC/RTOG) and other symptoms were evaluated. FU ranged from 1 to 63.6 months (mean 32.2, median 32.9). Results: The adverse effects percentage was very low; only 1 month after treatment the percentage of acute urinary reaction exceeded 40%. Only single G3 adverse effects were noted. Over 4 months the median PSA concentration declined from 3.75 to 0.27 ng/ml. 9 failures (4.5%) were noted ­ more among IR and patients without neoadjuvant ADT. No failure in the T2c group was found. Median time to failure was 32.4 months. Cox analysis revealed that the failure risk increases with the value of maximal PSA before treatment. Conclusions: CK based radioablation of LR and IR PCP is a safe and highly effective treatment modality. The main prognostic factor of failure after this treatment is probably the maximal PSA concentration before treatment. The neoadjuvant ADT in IR group should be considered. The lack of failures in the T2c group enables us to suggest that even more locally advanced patients (T3) with low PSA and maximal Gleason 3+4 could be treated with this modality.

Cell-cycle gene expression analysis using real time PCR in locally advanced squamous-cell head and neck cancer.

PURPOSE: The analysis of gene expression, especially those involved in cell cycle control, can help to discover mechanisms determining the outcome of radiation treatment. The main purpose of this study was to examine the expression level of genes responsible for cell cycle regulation in samples of the head and neck cancer, obtained during surgery. METHODS: Postsurgical samples of SCC of head and neck region were collected. Over 80 genes were analysed using cell cycle quantitative real-time RT-PCR Array method. Presence of 14 high-risk HPV types DNA in frozen or paraffin-embedded tumour pathological samples was also assessed. To correlate gene expression with selected pathological features and clinical outcome we used different hierarchical clustering method. RESULTS: Hierarchical clustering demonstrated the association between gene expression within certain clusters and gender, tumour site, T stage, N stage, grade, pathological subtype or tumour recurrence. CONCLUSIONS: Despite some limitations we were able to identify gene clusters that allowed to classify patients according to selected clinical features and occurrence of tumour recurrence. The results of the analysis also confirm that the incidence of HPV infection among the patients from Upper Silesia is relatively low, whereas HPV negative tumours, likely associated with smoking, appeared dominant.

Randomized clinical trial on 7-days-a-week post-operative radiotherapy vs concurrent post-operative radiochemotherapy in locally advanced cancer of the oral cavity/oropharynx: a report on acute normal tissue reactions.

OBJECTIVE: The purpose of the study was to evaluate acute normal tissue reactions and treatment compliance in a randomized clinical trial on 7-days-a-week post-operative radiotherapy (p-CAIR) vs post-operative concurrent radiochemotherapy (p-RTCT) in locally advanced cancer of the oral cavity/oropharynx. The sample analyzed at present represents approximately 30% of the intended future trial size. METHODS: The patients were randomly assigned to receive 63 Gy in 1.8-Gy fractions 7 days a week (n = 44) or 63 Gy in 1.8-Gy fractions 5 days a week with concurrent cisplatin 80-100 mg per square metre of body surface area on Days 1, 22 and 43 of the course of radiotherapy (n = 40). Acute mucosal reactions were scored using the modified Dische system. RESULTS: 15 (17.9%) patients, including 5 patients in p-CAIR and 10 patients in p-RTCT, did not comply with the assigned radiation treatment, mostly because of rapid tumour progression or deteriorating general performance. In p-RTCT, 22 (55%) patients received less than the intended three courses of chemotherapy mostly owing to haematological toxicity. The average maximum mucosal severity score was 14.2 in p-CAIR compared with 13.4 in p-RTCT; the difference was not statistically significant (p = 0.31). CONCLUSION: The schedules compared (p-CAIR and p-RTCT) did not differ considerably with respect to acute mucosal reactions. Haematological toxicity in p-RTCT was elevated compared with p-CAIR. Both schedules were considered tolerable with respect to acute toxicity, which justifies further recruitment to the trial. ADVANCES IN KNOWLEDGE: The results show that early mucosal reactions are comparable in both trial arms but haematological toxicity is more pronounced during radiochemotherapy.

CyberKnife-based prostate cancer patient radioablation - early results of irradiation in 200 patients.

INTRODUCTION: Prostrate cancer (PC) is one of the most common malignancies and is frequently treated with an 8-week course of radiotherapy. CyberKnife (CK) based radioablation enables completion of therapy within 5-9 days. The aim of this study is an evaluation of the effectiveness and tolerance of CyberKnife-based radioablation in prostate cancer patients. MATERIAL AND METHODS: 200 PC patients (94 low risk [LR], 106 intermediate risk [IR]) underwent CK irradiation every other day (fraction dose [fd] 7.25 Gy, total dose [TD] 36.25 Gy, time 9 days). PSA varied from 1.1 to 19.5 (median 7.7) and T stage from T1c to T2c. The percentage of patients with Androgen Deprivation Therapy (ADT), GI (gastrointestinal) and GU (genitourinary) toxicity (EORTC/RTOG scale), and PSA were checked at 1, 4 and 8 months, and thereafter every 6 months - up to a total of 26 months - post-treatment. RESULTS: The percentage of patients without ADT increased from 47.5% to 94.1% after 26 months. The maximum percentage of acute G3 adverse effects was 0.6% for GI, 1% for GU and G2 - 2.1% for GI and 8.5% for GU. No late G3 toxicity was observed. The maximum percentage of late G2 toxicity was 0.7% for GI and 3.4% for GU. Median PSA decreased from 7.7 to 0.1 ng/ml during FU. One patient relapsed and was treated with salvage brachytherapy. CONCLUSIONS: We conclude that CK-based radioablation in low and intermediate risk PC patients is an effective treatment modality enabling OTT reduction and presents a very low percentage of adverse effects.

PTEN as a prognostic and predictive marker in postoperative radiotherapy for squamous cell cancer of the head and neck.

BACKGROUND: Tumor suppressor PTEN is known to control a variety of processes related to cell survival, proliferation, and growth. PTEN expression is considered as a prognostic factor in some human neoplasms like breast, prostate, and thyroid cancer. METHODOLOGY/PRINCIPAL FINDINGS: In this study we analyzed the influence of PTEN expression on the outcome of a randomized clinical trial of conventional versus 7-days-a-week postoperative radiotherapy for squamous cell cancer of the head and neck. The patients with cancer of the oral cavity, oropharynx, and larynx were randomized to receive 63 Gy in fractions of 1.8 Gy given 5 days a week (CF) or 7 days a week (p-CAIR). Out of 279 patients enrolled in the study, 147 paraffin blocks were available for an immunohistochemical assessment of PTEN. To evaluate the prognostic value of PTEN expression and the effect of fractionation relative to PTEN, the data on the outcome of a randomized clinical trial were analyzed. Tumors with a high intensity of PTEN staining had significant gain in the loco-regional control (LRC) from p-CAIR (5-year LRC 92.7% vs. 70.8%, for p-CAIR vs. CF, p = 0.016, RR = 0.26). By contrast, tumors with low intensity of PTEN did not gain from p-CAIR (5-year LRC 56.2% vs. 47.2%, p = 0.49, RR = 0.94). The intensity of PTEN highly affected the LRC in a whole group of 147 patients (5-year LRC 80.9% vs. 52.3% for high vs. low PTEN, p = 0.0007, RR = 0.32). In multivariate Cox analysis, including neck node involvement, EGFR, nm23, Ki-67, p53, cyclin D1, tumor site and margins, PTEN remained an independent predictor of LRC (RR = 2.8 p = 0.004). CONCLUSIONS/SIGNIFICANCE: These results suggest that PTEN may serve as a potent prognostic and predictive marker in postoperative radiotherapy for high-risk squamous cell cancer of the head and neck.

Impact of HPV infection on the clinical outcome of p-CAIR trial in head and neck cancer.

The purpose of the study was to analyse the influence of HPV infection on the outcome of a randomized clinical trial of conventional (CF) versus 7-days-a-week postoperative radiotherapy (p-CAIR) for squamous cell cancer of the head and neck (SCCHN). Between 2001 and 2004, 279 patients with high-risk SCC of the larynx or cancer of the oral cavity/oropharynx were randomized to receive 63 Gy in fractions of 1.8 Gy given 5 days a week or 7 days a week (Radiother Oncol 87:155-163, 2008). The presence of HPV DNA in 131 archival paraffin blocks was assessed with multiplex quantitative real-time PCR using five consensus primers for the conservative L1 region and molecular beacon probes targeting 14 high-risk HPV subtypes. Following the RT-PCR procedure, we could determine the presence and type of HPV16, HPV18 and the other 12 less frequent oncogenic subtypes. Out of 131 samples, 9 were positive for HPV infection (6.9%), all of them with HPV16 subtype. None of the 65 laryngeal tumours was HPV positive. The 5-year LRC in HPV-positive patients was 100%, compared to 58% in the HPV-negative group (p = 0.02, log-rank test). Amongst 122 patients with HPV-negative tumours, 5-year LRC was 50.3% in p-CF versus 65.2 in p-CAIR (p = 0.37). HPV infection was associated with low expression of EGFR and cyclin D. This study demonstrates a favourable outcome for HPV-positive patients with SCCHN treated with postoperative radiotherapy. While considering the small number of HPV+ tumours, the data set can be considered as hypothesis generating only, the outcome raises new questions on the necessity of aggressive postoperative treatment in HPV+ patients.

The European sea bass Dicentrarchus labrax genome puzzle: comparative BAC-mapping and low coverage shotgun sequencing.

BACKGROUND: Food supply from the ocean is constrained by the shortage of domesticated and selected fish. Development of genomic models of economically important fishes should assist with the removal of this bottleneck. European sea bass Dicentrarchus labrax L. (Moronidae, Perciformes, Teleostei) is one of the most important fishes in European marine aquaculture; growing genomic resources put it on its way to serve as an economic model. RESULTS: End sequencing of a sea bass genomic BAC-library enabled the comparative mapping of the sea bass genome using the three-spined stickleback Gasterosteus aculeatus genome as a reference. BAC-end sequences (102,690) were aligned to the stickleback genome. The number of mappable BACs was improved using a two-fold coverage WGS dataset of sea bass resulting in a comparative BAC-map covering 87% of stickleback chromosomes with 588 BAC-contigs. The minimum size of 83 contigs covering 50% of the reference was 1.2 Mbp; the largest BAC-contig comprised 8.86 Mbp. More than 22,000 BAC-clones aligned with both ends to the reference genome. Intra-chromosomal rearrangements between sea bass and stickleback were identified. Size distributions of mapped BACs were used to calculate that the genome of sea bass may be only 1.3 fold larger than the 460 Mbp stickleback genome. CONCLUSIONS: The BAC map is used for sequencing single BACs or BAC-pools covering defined genomic entities by second generation sequencing technologies. Together with the WGS dataset it initiates a sea bass genome sequencing project. This will allow the quantification of polymorphisms through resequencing, which is important for selecting highly performing domesticated fish.