Modern Tools for Modern Brachytherapy.

This review aims to showcase the brachytherapy tools and technologies that have emerged during the last 10 years. Soft-tissue contrast using magnetic resonance and ultrasound imaging has seen enormous growth in use to plan all forms of brachytherapy. The era of image-guided brachytherapy has encouraged the development of advanced applicators and given rise to the growth of individualised 3D printing to achieve reproducible and predictable implants. These advances increase the quality of implants to better direct radiation to target volumes while sparing normal tissue. Applicator reconstruction has moved beyond manual digitising, to drag and drop of three-dimensional applicator models with embedded pre-defined source pathways, ready for auto-recognition and automation. The simplified TG-43 dose calculation formalism directly linked to reference air kerma rate of high-energy sources in the medium water remains clinically robust. Model-based dose calculation algorithms accounting for tissue heterogeneity and applicator material will advance the field of brachytherapy dosimetry to become more clinically accurate. Improved dose-optimising toolkits contribute to the real-time and adaptive planning portfolio that harmonises and expedites the entire image-guided brachytherapy process. Traditional planning strategies remain relevant to validate emerging technologies and should continue to be incorporated in practice, particularly for cervical cancer. Overall, technological developments need commissioning and validation to make the best use of the advanced features by understanding their strengths and limitations. Brachytherapy has become high-tech and modern by respecting tradition and remaining accessible to all.

Mutagen sensitivity and risk of second cancer in younger adults with head and neck squamous cell cancer: 15-year results.

PURPOSE: To evaluate the mutagen sensitivity phenotype on the risk of second primary cancer (SPC) in patients with head and neck squamous cell carcinoma (HNSCC), and to estimate the long-term rate of SPC and the outcome with SPC. METHODS: A survey was made regarding SPC among 124 younger (≤ 50 years) adults with HNSCC who were enrolled in a pretreatment mutagen sensitivity investigation during 1996-2006. Mutagen sensitivity was assessed by exposing lymphocytes to bleomycin in vitro and quantifying the bleomycin-induced chromatid breaks per cell (b/c). Patients were classified as hypersensitive (> 1 b/c) or not hypersensitive (≤ 1 b/c). RESULTS: Mean follow-up time for all patients was 68 months (range: 5-288 months), and the 15-year cancer-specific survival was 15%. Twenty patients (16%) developed a SPC (15-year estimated rate: 41%), and half of them was hypersensitive. The crude rate of SPC for hypersensitive (n = 65) or not hypersensitive (n = 59) patients were 15 and 17%, respectively (p = 0.4272). The 15-year estimated rate of SPC for hypersensitive and not hypersensitive patients was 36 and 48%, respectively (p = 0.3743). Gender, UICC stages, anatomical sites of index cancer did not prove to be a significant risk factor for SPC. Forty-five percent of SPC developed after the 10-year follow-up. The 3­year cancer-specific survival was 23% with SPC. CONCLUSION: According to our findings, mutagen hypersensitivity was not associated with an increased SPC risk in HNSCC patients. Patients are at a lifelong risk of developing a SPC. Survival with SPC is very poor.

Enhancing analytical accuracy of intravascular electrochemical oxygen sensors via nitric oxide release using S-nitroso-N-acetyl-penicillamine (SNAP) impregnated catheter tubing.

Implantable medical devices are an integral part of primary/critical care. However, these devices carry a high risk for blood clots, caused by platelet aggregation on a foreign body surface. This study focuses on the development of a simplified approach to create nitric oxide (NO) releasing intravascular electrochemical oxygen (O2) sensors with increased biocompatibility and analytical accuracy. The implantable sensors are prepared by embedding S-nitroso-N-acetylpenacillamine (SNAP) as the NO donor molecule in the walls of the catheter type sensors. The SNAP-impregnated catheters were prepared by swelling silicone rubber tubing in a tetrahydrofuran solution containing SNAP. Control and SNAP-impregnated catheters were used to fabricate the Clark-style amperometric PO2 sensors. The SNAP-impregnated sensors release NO under physiological conditions for 18 d as measured by chemiluminescence. The analytical response of the SNAP-impregnated sensors was evaluated in vitro and in vivo. Rabbit and swine models (with sensors placed in both veins and arteries) were used to evaluate the effects on thrombus formation and analytical in vivo PO2 sensing performance. The SNAP-impregnated PO2 sensors were found to more accurately measure PO2 levels in blood continuously (over 7 and 20 h animal experiments) with significantly reduced thrombus formation (as compared to controls) on their surfaces.

Dosimetric comparison between treatment plans of patients treated with low-dose-rate vs. high-dose-rate interstitial prostate brachytherapy as monotherapy: Initial findings of a randomized clinical trial.

PURPOSE: The aim of this study was to compare the dosimetry of intraoperative dose plans of prostate cancer patients treated with low-dose-rate (LDR) and high-dose-rate (HDR) interstitial brachytherapy (BT). METHODS AND MATERIALS: A randomized clinical trial was initiated at our institution to compare the results and side effects of LDR and HDR BT as monotherapy in the treatment of early, organ-confined prostate cancer patients. Eighty-seven patients were randomly assigned to receive HDR afterloading BT with one fraction of 19 Gy or permanent LDR 125I seed BT with 145 Gy. Inverse optimization algorithms were used for planning. Stranded seeds were implanted using live ultrasound imaging after preimplant treatment planning. Final dosimetry of HDR treatments was based on updated needle and contour positions. Statistical comparisons with nonparametric test were performed between the corresponding dose-volume parameters. RESULTS: The V100 and V150 were 99% and 61%, respectively, for LDR, whereas 98% and 32% for HDR treatments. The D90 was less for HDR (122% vs. 110%). The dose distributions were more homogeneous and conformal with HDR technique (dose homogeneity index, 0.39 vs. 0.67; conformal index, 0.65 vs. 0.80). The urethra and rectum received significantly less dose with HDR. The D10 and D30 for urethra were 133% and 128%, respectively, for LDR and 114% and 111% for HDR treatments. The [Formula: see text] for rectum was 68% and 55% for LDR and HDR technique, respectively. CONCLUSIONS: Both techniques provided acceptable target volume coverage with a slightly higher value with the LDR technique. The dose distributions were more homogeneous and conformal, and both urethra and rectum were better protected with the HDR technique.

Dosimetric and radiobiological comparison of TG-43 and Monte Carlo calculations in 192Ir breast brachytherapy applications.

PURPOSE: To investigate the clinical significance of introducing model based dose calculation algorithms (MBDCAs) as an alternative to TG-43 in 192Ir interstitial breast brachytherapy. MATERIALS AND METHODS: A 57 patient cohort was used in a retrospective comparison between TG-43 based dosimetry data exported from a treatment planning system and Monte Carlo (MC) dosimetry performed using MCNP v. 6.1 with plan and anatomy information in DICOM-RT format. Comparison was performed for the target, ipsilateral lung, heart, skin, breast and ribs, using dose distributions, dose-volume histograms (DVH) and plan quality indices clinically used for plan evaluation, as well as radiobiological parameters. RESULTS: TG-43 overestimation of target DVH parameters is statistically significant but small (less than 2% for the target coverage indices and 4% for homogeneity indices, on average). Significant dose differences (>5%) were observed close to the skin and at relatively large distances from the implant leading to a TG-43 dose overestimation for the organs at risk. These differences correspond to low dose regions (<50% of the prescribed dose), being less than 2% of the prescribed dose. Detected dosimetric differences did not induce clinically significant differences in calculated tumor control probabilities (mean absolute difference <0.2%) and normal tissue complication probabilities. CONCLUSION: While TG-43 shows a statistically significant overestimation of most indices used for plan evaluation, differences are small and therefore not clinically significant. Improved MBDCA dosimetry could be important for re-irradiation, technique inter-comparison and/or the assessment of secondary cancer induction risk, where accurate dosimetry in the whole patient anatomy is of the essence.

Altered Immunogenicity of Donor Lungs via Removal of Passenger Leukocytes Using Ex Vivo Lung Perfusion.

Passenger leukocyte transfer from the donor lung to the recipient is intrinsically involved in acute rejection. Direct presentation of alloantigen expressed on donor leukocytes is recognized by recipient T cells, promoting acute cellular rejection. We utilized ex vivo lung perfusion (EVLP) to study passenger leukocyte migration from donor lungs into the recipient and to evaluate the effects of donor leukocyte depletion prior to transplantation. For this purpose, female pigs received male left lungs either following 3 h of EVLP or retrieved using standard protocols. Recipients were monitored for 24 h and sequential samples were collected. EVLP-reduced donor leukocyte transfer into the recipient and migration to recipient lymph nodes was markedly reduced. Recipient T cell infiltration of the donor lung was significantly diminished via EVLP. Donor leukocyte removal during EVLP reduces direct allorecognition and T cell priming, diminishing recipient T cell infiltration, the hallmark of acute rejection.

A retrospective dosimetric comparison of TG43 and a commercially available MBDCA for an APBI brachytherapy patient cohort.

PURPOSE: To compare dosimetry using a contemporary model based dose calculation algorithm (MBDCA) following TG186 recommendations, and the conventional TG43 method in an (192)Ir high dose rate (HDR) accelerated partial breast irradiation (APBI) patient cohort. METHODS: Data of 38 APBI patients were studied. Dosimetry for the treatment plans was performed using both the TG43 and TG186 dose calculation methods of the Oncentra Brachy v4.4 treatment planning system (TPS). Analysis included indices of clinical interest for the planning target volume (PTV coverage, dose homogeneity, conformity) as well as dose volume histograms (DVH) for the breast, lung, heart, rib and skin. Significance testing of observed differences between TG43 and TG186 results was carried out and the effect of target location to these differences was studied. RESULTS: Statistically significant differences were observed in the values of clinically relevant DVH parameters for the PTV and the organs at risk (OAR), except for the heart. Differences for the PTV are relatively small (<1% for coverage, on the order of 2% for homogeneity and conformity) with a slight TG43 overestimation except for the dose homogeneity. Percentage differences are larger for the rib and lung (on the order of 4% for Dmax and 5% for V10Gy, respectively) and maximum for the skin (on the order of 6% for D10cc), with a correlation of the observed differences with target location. CONCLUSION: While the MBDCA option of the TPS appears to improve dosimetric accuracy, differences from TG43 do not appear to warrant dose prescription changes or treatment protocol amendment..

Compromised bone healing following spacer removal in a rat femoral defect model.

PURPOSE: The clinical demand for bone grafting materials necessitated the development of animal models. Critical size defect model has been criticized recently, mainly for its inaccuracy. Our objective was to develop a dependable animal model that would provide compromised bone healing, and would allow the investigation of bone substitutes. METHODS: In the first group a critical size defect was created in the femur of adult male Wistar rats, and a non-critical defect in the remaining animals (Groups II, III and IV). The defect was left empty in group II, while in groups III and IV a spacer was interposed into the gap. Osteoblast activity was evaluated by NanoSPECT/CT imaging system. New bone formation and assessment of a union or non-union was observed by µCT and histology. RESULTS: The interposition model proved to be highly reproducible and provided a bone defect with compromised bone healing. Significant bone regeneration processes were observed four weeks after removal of the spacer. CONCLUSION: Our results have shown that when early bone healing is inhibited by the physical interposition of a spacer, the regeneration process is compromised for a further 4 weeks and results in a bone defect during the time-course of the study.

Muscle regeneration is undisturbed by repeated polytraumatic injury.

INTRODUCTION: Clinical observations suggest that repeated injury within a week after a traumatic event impairs the regeneration of tissues. Our aim was to investigate the effect of repeated trauma on the proliferation of satellite cells in skeletal muscle tissue. MATERIALS AND METHODS: Cold lesion injury was performed in the soleus muscle and in the motor cortex of anesthetized male Wistar rats 0, 1, or 2 times with 7 day intervals between the interventions. Following the last operation, 5-bromo-2'-deoxyuridine was injected i.p. for 6 or 12 days to label dividing cells. Gut epithelium was used as positive control. Immunohistochemistry was performed 1 and 5 weeks after the last injury and the sections were analyzed with confocal microscopy. RESULTS: In the case of repeated trauma, the percentage of proliferating cells remained the same compared to single hit animals after 1 week (28.0 ± 2.5% and 29.6 ± 3.0%) as well as after 5 weeks (13.9 ± 1.8% and 14.5 ± 2.2%). CONCLUSION: The second hit phenomenon is probably due to systemic factors rather than to a diminished regenerating potential of injured soft tissues.

Evaluation of the thyroid function of healthy pregnant women by five different hormone assays.

A normal function of the thyroid gland during pregnancy is essential. Any change can affect both the pregnant woman and the fetus. Thyroid hormones play a crucial role in the brain development of the fetus, thus proper maternal free thyroid hormone levels are important especially during the first trimester. We compared the free thyroid hormone levels FT3 and FT4 in forty pregnant women with no thyroidal disease by five different assays available on the market. The blood samples were collected between the 8th and 22nd weeks of pregnancy. The correlation coefficient "r" between different assays was 0.908-0.975 for TSH, 0.676-0.892 for FT4 and 0.480-0.789 for FT3. These data show that the inter-assay results varied widely in the studied population. One reasonable explanation may be that during pregnancy the serum levels of the thyroid hormone binding proteins are altered and "free" hormone measurements by immunoassays are influenced by these alterations. Thus, the results may show higher or lower thyroid hormone values depending upon the assay used. Therefore, it is strongly suggested that every laboratory should establish its own pregnant reference ranges for the tests used for the evaluation of thyroid function, based on values of the population served.

Prognosis of patients with local recurrence after mastectomy or conservative surgery for early-stage invasive breast cancer.

Between 1983 and 1987, 1309 women with stage I or II breast cancer underwent mastectomy (n=894) or conservative surgery (CS, n=415). Of these patients, 124 developed an isolated local recurrence (ILR): chest wall, 56 and in-breast, 68. The 10-year actuarial rate of cause-specific survival after treatment for ILR was 52%. On multivariate analysis three independent prognostic factors for the risk of death after ILR were identified: operability of recurrence (operable vs. inoperable, relative risk [RR]: 5.9), age at initial diagnosis (>40 vs. < or = 40 years, RR: 2.2) and time to ILR (>24 vs. < or = 24 months, RR: 2). Initial lymph node stage (negative vs. positive) showed borderline significance (p=0.06), and type of initial surgery (CS vs. mastectomy) and recurrent tumor grade (1-2 vs. 3) were not independent predictors of survival. In the mastectomy group, single surgical scar recurrence with initial node negative stage predicted good prognosis, and the 10-year survival was 85%. In the CS group, the 10-year survival rate was 88% with new primary tumor and 54% with true recurrence (p=0.01), and the type of salvage surgery (mastectomy vs. repeat complete excision) had no significant impact on survival (p=0.2). The majority (n=44) of CS patients developed < or = 2 cm in-breast recurrence, and the 10-year survival was 81% after both salvage excision (n=28) and mastectomy (n=16). The identified unfavorable prognostic factors are pointers of the forthcoming systemic progression. Patients with < or = 2 cm in-breast recurrence might receive a second CS.

Review of radiosurgery of pineal parenchymal tumors. Long survival following 125-iodine brachytherapy of pineoblastomas in 2 cases.

OBJECTIVE: The aim of the present work is to report the volumetric changes of tumor in two pineoblastoma patients treated with stereotactic interstitial irradiation and to present a review on radiosurgery of pineal parenchymal tumors. METHODS: Two of our patients with pineoblastoma were treated with CT and image-fusion guided 125-iodine brachytherapy. The tumor volumes were determined with outlined contours on planning and control CT/MRI images and were compared. RESULTS: Until January 2006, there were 61- and 58-month follow-up periods in the two cases. 56 and 53 months after irradiation the MRI images showed significant tumor shrinkage. In case 1 tumor volume was 0.76 cm (3) on the last control MRI image, compared to the 2.87 cm (3) at the time of interstitial irradiation, which means 73% shrinkage. In case 2, tumor volume measured with the last control MRI examination was 0.29 cm (3), which represents 77% shrinkage of the original tumor volume. In both Cases 1 and 2, PET examinations using (11)C-methionine showed no active tumor mass 56 and 53 months following brachytherapy. CONCLUSION: Two successful treatments of pineoblastoma are reported. The interstitial irradiation of the tumors decreased their volumes significantly. The CT and image fusion-guided 125-iodine stereotactic brachytherapy can be planned well dosimetrically and is surgically precise.

Early European experience with the MammoSite radiation therapy system for partial breast brachytherapy following breast conservation operation in low-risk breast cancer.

Preliminary results of ultrasound studies do exist in the literature on the successful use of the MammoSite Radiation Therapy System (RTS), a new device for delivering brachytherapy following breast-conserving surgery. In Europe, some groups started a prospective multicentre trial to investigate the use of the MammoSite RTS. In this early publication, we analysed the surgical procedure and placement of the MammoSite, treatment planning and radiation delivery complications, and early cosmesis, as well as the comfort of the patients. Between June 2002 and March 2005, a total of 54 low-risk breast cancer patients fulfilling the enrolment criteria were implanted intra- or postoperatively using the MammoSite applicator. After inflating the balloon in the excision cavity, the reference isodose was defined 1cm from the balloon's surface. Twenty-eight patients were treated with primary brachytherapy with a total dose of 34 Gy (2x3.4 Gy) and 16 patients had a boost with a mean dose of 13.3 Gy (range: 7.5-15 Gy; 2x2.5 Gy) combined with external beam radiotherapy (EBRT). Doses ranged between 46 and 50 Gy. We analysed the postimplant anatomic position of the applicator in relation to the skin and chest wall as well as the geometric form of the balloon via ultrasound, computed tomography and X-ray before, during and after the treatment. Forty-four out of 54 patients (81.5%) were eligible for MammoSite RTS brachytherapy. Ten patients were excluded from the trial due to the strict study criteria and received no brachytherapy. Balloon rupture occurred in two cases. We observed seroma in 16 patients (36%); furthermore, an abscess developed in two patients (4.5%) within 3 months of implantation. Postoperative air gaps and haematoma were successfully reduced by draining the operation cavity in one institution. At a mean follow-up of 14 months (range 3-31 months), the skin-related side effects observed were skin discoloration or inflammation in 36 patients (82%) and teleangiectasia in eight patients (18%). The MammoSite RTS is a feasible treatment modality for postoperative partial breast irradiation after breast-conserving surgery for selected low-risk breast cancer patients. The main advantage of the system is the necessity of only one applicator for the delivery of fractionated radiotherapy over a 5-day treatment period. In addition, patient tolerance of the procedure is high. Based on this early experience, the method may serve as a successful alternative to conventional multicatheter brachytherapy for a highly select group of patients, but we have to bear in mind the higher level of acute toxicity.

High co-prevalence of genogroup 1 TT virus and human papillomavirus is associated with poor clinical outcome of laryngeal carcinoma.

BACKGROUND: The aetiology and factors leading to the progression of laryngeal cancer are still unclear. Although human papillomavirus (HPV) has been suggested to play a role, reports concerning the effect of HPV infection on tumour development are controversial. Recently, transfusion transmitted virus (TTV) was suggested to play a role in certain infections as a causative or coinfecting agent. AIMS: To investigate whether the development and progression of laryngeal squamous cell carcinoma is associated with coinfection with TTV and HPV. METHODS: The prevalence of TTV and HPV was investigated using the polymerase chain reaction in tissue samples from 40 healthy individuals, 10 patients with recurrent papillomatosis, five patients with papillomatosis with malignant transformation, and 25 patients with laryngeal carcinoma. The obtained prevalence data were compared and analysed statistically. RESULTS: In the 11 patients with carcinoma who had metastasis or relapse there was a high rate of coinfection with genogroup 1 TTV and HPV (eight of 11), whereas in the 14 without tumour progression no coinfection was found. Coinfection was associated with significantly lower tumour free survival in patients with carcinoma (p < 0.001). Furthermore, four of five patients who had papillomatosis with malignant transformation were coinfected with genogroup 1 TTV and HPV. CONCLUSIONS: Although the nature of cooperation between HPV and TTV needs to be investigated further, coinfection with genogroup 1 TTV and HPV appears to be associated with poor clinical outcome in laryngeal cancer.

The characteristics of human papillomavirus DNA in head and neck cancers and papillomas.

AIM: To determine the prevalence, type, physical state, and viral load of human papillomavirus (HPV) DNA in cases of head and neck cancer and recurrent respiratory papillomatosis (RRP). METHODS: The prevalence and type of HPV DNA was determined in 27 fresh frozen tissue specimens from patients with head and neck cancers and 16 specimens from 10 patients with RRP by MY09/MY11 and GP5+/GP6+ nested polymerase chain reaction (PCR) and subsequent restriction enzyme cleavage. The physical state of HPV DNA was analysed by E1, E2, and E1E2 specific PCRs and Southern blot hybridisation (SBH). RESULTS: HPV DNA was detected in 13 of 27 cancers and 10 of 10 papillomas. Both low risk HPV-6 and HPV-11 and high risk HPV-16 were present in cancers in low copy numbers, whereas papillomas exclusively harboured low risk HPV-6 and HPV-11. E1E2 PCRs failed to determine the physical state of HPV in cancers except one case where HPV-6 DNA was integrated. In contrast to cancers, all papillomas showed the episomal state of HPV DNA and a relatively higher viral load. CONCLUSIONS: Based on the prevalence, type, physical state, and copy number of HPV DNA, cancers and papillomas tend to show a different HPV DNA profile. The 100% positivity rate of low risk HPV types confirms the role of HPV-6 and HPV-11 in the aetiology of RRP.

Complete genome sequence of the genetically tractable hydrogenotrophic methanogen Methanococcus maripaludis.

The genome sequence of the genetically tractable, mesophilic, hydrogenotrophic methanogen Methanococcus maripaludis contains 1,722 protein-coding genes in a single circular chromosome of 1,661,137 bp. Of the protein-coding genes (open reading frames [ORFs]), 44% were assigned a function, 48% were conserved but had unknown or uncertain functions, and 7.5% (129 ORFs) were unique to M. maripaludis. Of the unique ORFs, 27 were confirmed to encode proteins by the mass spectrometric identification of unique peptides. Genes for most known functions and pathways were identified. For example, a full complement of hydrogenases and methanogenesis enzymes was identified, including eight selenocysteine-containing proteins, with each being paralogous to a cysteine-containing counterpart. At least 59 proteins were predicted to contain iron-sulfur centers, including ferredoxins, polyferredoxins, and subunits of enzymes with various redox functions. Unusual features included the absence of a Cdc6 homolog, implying a variation in replication initiation, and the presence of a bacterial-like RNase HI as well as an RNase HII typical of the Archaea. The presence of alanine dehydrogenase and alanine racemase, which are uniquely present among the Archaea, explained the ability of the organism to use L- and D-alanine as nitrogen sources. Features that contrasted with the related organism Methanocaldococcus jannaschii included the absence of inteins, even though close homologs of most intein-containing proteins were encoded. Although two-thirds of the ORFs had their highest Blastp hits in Methanocaldococcus jannaschii, lateral gene transfer or gene loss has apparently resulted in genes, which are often clustered, with top Blastp hits in more distantly related groups.

Predictive value of hysteroscopic examination in intrauterine abnormalities.

STUDY OBJECTIVE: This study was set up to evaluate the predictive value of hysteroscopic examination in patients referred to the Department of Obstetrics and Gynecology at the Medical and Health Science Center, Debrecen, Hungary. STUDY DESIGN: The authors performed 835 biopsies by hysteroscopy over more than 13 years. They compared their findings with histological findings held in a a computerized clinical database. RESULTS: The sensitivity of hysteroscopy was 0.52 for hyperplasia, 0.87 for polyps, 0.85 for myomas, 0.68 for carcinoma, and 0.73 for atrophy. CONCLUSION: It seems that for findings facing into the uterine cavity (such as submucosal myomas and peduncular polyps), hysteroscopy can predict the histological results. The evaluation of endometrial cycles and of the thickness of the endometrium by hysteroscopy is less accurate.

Follow-up study on the effectiveness of transcervical myoma resection (TCRM).

STUDY OBJECTIVE: To measure the efficacy of transcervical hysteroscopic fibroid resection (TCRM) among the authors' patients. STUDY DESIGN: In one department, 73 transcervical hysteroscopic fibroid resections were performed on 68 patients over a 6-year period. Using a computerized database and mailed questionnaires, 58 patients were followed up. RESULTS: Thirty-six of the 58 patients showed no symptoms after the procedure; in 15 cases subsequent fibroid was detected, while in seven cases other types of complaints occurred, not related to the myoma. During the procedures complications happened in four cases; one perforation and three bleeding episodes occurred. CONCLUSION: Our data indicate that TCRM is a safe and successful method of treating submucosal fibroids.