Overview of treatment plan quality in a high dose rate prostate brachytherapy workflow.

PURPOSE: High dose rate brachytherapy (HDR-BT) has been shown to be an effective treatment for prostate cancer, with treatment plan quality dependent on a number of factors. In this work, we report on the overall performance of our ultrasound (US)-based workflow and the impact of several treatment-specific variables. METHODS AND MATERIALS: Patients who underwent HDR-BT (boost, monotherapy, and retreatment) using Varian Bravos/US from 2021 to 2023 were sampled for this study. Treatment plan quality was analyzed and plans were categorized with regard to a number of metrics, including: prostate volume, treating physician, planning physicist, number of needles included, estimated planning time, rectum-prostate separation, and bladder-prostate separation. The performance of this program was compared to the performance of our program using previously used modality combinations: Varian Varisource/US, Elekta microSelectron/CT. RESULTS: Plan quality for our Bravos/US workflow was shown to be consistently above acceptability criteria for all personnel involved; on average: prostate V100%: 98.9% ± 0.1%, rectum V75%: 0.04 ± 0.01 cc, bladder V75%: 0.06 ± 0.01cc, urethra V125%: 0.00 ± 0.00 cc. Prostate coverage was statistically improved with this workflow compared to that using our previous modalities. There was a statistical correlation between organ-at-risk sparing/prostate coverage ratio and prostate volume, number of needles/prostate volume, bladder-prostate separation, and rectum-prostate separation. There was no correlation between plan quality and planning time. CONCLUSIONS: Our US-based HDR-BT program led to target coverage and organ-at-risk sparing that exceeded department thresholds. Results were acceptable regardless of the personnel involved and improved plan quality was obtained using more needles/prostate volume and increased spacing between the prostate and the rectum and bladder.

Opitz syndrome is genetically heterogeneous, with one locus on Xp22, and a second locus on 22q11.2.

Opitz syndrome (OS, McKusick 145410) is a well described genetic syndrome affecting multiple organ systems whose cardinal manifestations include widely spaced eyes and hypospadias (Fig. 1). It was first reported as two separate entities, BBB syndrome, and G syndrome. However, subsequent reports of families in which the BBB and G syndrome segregated within a single kindred suggested that they were a single clinical entity. Although the original pedigrees were consistent with X-linked and autosomal dominant inheritance, male-to-male transmission in subsequent reports suggested that OS was inherited as an autosomal dominant trait. Here we report that OS is a heterogeneous disorder, with an X-linked and an autosomal locus. Three families were linked to DXS987 in Xp22, with a lod score of 3.53 at zero recombination. Five families were linked to D22S345 from chromosome 22q11.2, with a lod score of 3.53 at zero recombination. This represents the first classic multiple congenital anomaly syndrome with an X-linked and an autosomal form.

Esophageal motion during radiotherapy: quantification and margin implications.

The purpose was to evaluate interfraction and intrafraction esophageal motion in the right-left (RL) and anterior-posterior (AP) directions using computed tomography (CT) in esophageal cancer patients. Eight patients underwent CT simulation and CT-on-rails imaging before and after radiotherapy. Interfraction displacement was defined as differences between pretreatment and simulation images. Intrafraction displacement was defined as differences between pretreatment and posttreatment images. Images were fused using bone registries, adjusted to the carina. The mean, average of the absolute, and range of esophageal motion were calculated in the RL and AP directions, above and below the carina. Thirty-one CT image sets were obtained. The incidence of esophageal interfraction motion > or =5 mm was 24% and > or =10 mm was 3%; intrafraction motion > or =5 mm was 13% and > or =10 mm was 4%. The average RL motion was 1.8 +/- 5.1 mm, favoring leftward movement, and the average AP motion was 0.6 +/- 4.8 mm, favoring posterior movement. Average absolute motion was 4.2 mm or less in the RL and AP directions. Motion was greatest in the RL direction above the carina. Coverage of 95% of esophageal mobility requires 12 mm left, 8 mm right, 10 mm posterior, and 9 mm anterior margins. In all directions, the average of the absolute interfraction and intrafraction displacement was 4.2 mm or less. These results support a 12 mm left, 8 mm right, 10 mm posterior, and 9 mm anterior margin for internal target volume (ITV) and can guide margins for future intensity modulated radiation therapy (IMRT) trials to account for organ motion and set up error in three-dimensional planning.

Dosimetric verification of modulated electron radiotherapy delivered using a photon multileaf collimator for intact breasts.

Modulated electron radiotherapy (MERT) may potentially be an effective modality for the treatment of shallow tumors, but dose calculation accuracy and delivery efficiency challenges remain. The purpose of this work is to investigate the dose accuracy of MERT delivery using a photon multileaf collimator (pMLC) on a Siemens Primus accelerator. A Monte Carlo (MC)-based inverse treatment planning system was developed for the 3D treatment planning process. Phase space data of 6, 9, 12 and 15 MeV electron beams were commissioned and used as the input source for MC dose calculations. A treatment plan was performed based on the 3D CT data of a heterogeneous 'breast phantom' that mimics a breast cancer patient, and delivered with 22 segments, each associated with a particular energy and Monitor Unit value. Film and ion chamber dosimetry was carefully performed for the conversion from measurement reading to dose, and the results were employed for plan verification using the heterogeneous breast phantom and a solid water phantom. Dose comparisons between measurements and calculations showed agreement within 2% or 1 mm. We conclude that our in-house MC treatment planning system is capable of performing treatment planning and accurate dose calculations for MERT using the pMLC to deliver radiation therapy to the intact breast.

Analysis of the CONRAD computational problems expressing only stochastic uncertainties: neutrons and protons.

Within the scope of CONRAD (A Coordinated Action for Radiation Dosimetry) Work Package 4 on Computational Dosimetry jointly collaborated with the other research actions on internal dosimetry, complex mixed radiation fields at workplaces and medical staff dosimetry. Besides these collaborative actions, WP4 promoted an international comparison on eight problems with their associated experimental data. A first set of three problems, the results of which are herewith summarised, dealt only with the expression of the stochastic uncertainties of the results: the analysis of the response function of a proton recoil telescope detector, the study of a Bonner sphere neutron spectrometer and the analysis of the neutron spectrum and dosimetric quantity H(p)(10) in a thermal neutron facility operated by IRSN Cadarache (the SIGMA facility). A second paper will summarise the results of the other five problems which dealt with the full uncertainty budget estimate. A third paper will present the results of a comparison on in vivo measurements of the (241)Am bone-seeker nuclide distributed in the knee. All the detailed papers will be presented in the WP4 Final Workshop Proceedings.

Pitfalls and modelling inconsistencies in computational radiation dosimetry: lessons learnt from the QUADOS intercomparison. Part II: Photons, electrons and protons.

'QUADOS', a concerted action of the European Commission, has promoted an intercomparison aimed at evaluating the use of computational codes for dosimetry in radiation protection and medical physics. This intercomparison was open to all users of radiation transport codes. Eight problems were selected for their relevance to the radiation dosimetry community, five of which involved photon and proton transport. This paper focuses on a discussion of lessons learned from the participation in solving the photon and charged particle problems. The lessons learned from the participation in solving the neutron problems are presented in a companion paper (in this issue).

Pitfalls and modelling inconsistencies in computational radiation dosimetry: lessons learnt from the QUADOS intercomparison. Part I: Neutrons and uncertainties.

The QUADOS EU cost shared action conducted an intercomparison on the usage of numerical methods in radiation protection and dosimetry. The eight problems proposed were intended to test the usage of Monte Carlo and deterministic methods by assessing the accuracy with which the codes are applied and also the methods used to evaluate uncertainty in the answer gained through these methods. The overall objective was to spread good practice through the community and give users information on how to assess the uncertainties associated with their calculated results.

Extreme obesity may be linked to markers flanking the human OB gene.

Mice with mutations of the ob gene are extremely obese, and the human homologue (OB) has been cloned and physically mapped. The protein product of the ob gene (leptin) reduces body fat in mice when given exogenously, and leptin has been proposed to provide a lipostatic signal that regulates adiposity. Variation in the OB gene may be one genetically determined cause of obesity in human populations. To test this hypothesis, we genotyped siblings from 78 families at markers flanking the human OB gene. Pairs of siblings with extreme obesity (BMI > or = 40; n = 59) shared haplotypes identical-by-descent for the region containing the OB gene at greater than chance levels (corrected P = 0.04). Furthermore, one haplotype containing the OB gene was transmitted by heterozygous parents to extremely obese (BMI > or = 40) offspring more frequently than expected by chance, indicting significant allelic disequilibrium (corrected P = 0.027). One explanation for these linkage findings is that some individuals with extreme obesity have an allelic variant of the OB gene, although other nearby genes could contribute to obesity in these families.

Genetic polymorphism for human platelet thermostable phenol sulfotransferase (TS PST) activity.

Platelet TS PST basal activity and thermal stability were measured in blood samples from 237 individuals in 50 nuclear families. Significant correlations were found among first degree relatives, confirming the previously reported familial aggregation of TS PST basal activity and thermal stability. Commingling analysis of basal TS PST activity provided evidence for multiple component distributions, and after transformation to remove skewness, segregation analysis supported a major gene hypothesis. For TS PST thermal stability, commingling analysis also provided evidence for multiple component distributions. However, segregation analyses were equivocal with regard to the presence of a major gene for thermal stability, since support for a major gene model depended on skewness. Bivariate commingling analysis, which examined thermal stability by simultaneously considering basal activity and activity after heating, suggested that genotypes, as defined by the inferred component distributions for TS PST activity, differ in thermal stability. A three-allele model is proposed as one hypothesis that may account for the combined results of basal activity and thermal stability. The results of this study indicate that a major gene polymorphism in conjunction with polygenic inheritance plays an important role in the regulation of both level of activity and thermal stability of this important drug-metabolizing enzyme in humans.

Early onset (under age 30 years) and panic disorder as markers for etiologic homogeneity in major depression.

Early onset of major depression (age, less than 30 years) in probands confers high risk to relatives, whereas late-onset depression (age, greater than 40 years) involves no elevation of risk over population rates. Analyses of data from families of probands with early onset from the Yale Family Study (47 three generation and 17 two generation) favored a major gene effect over polygenic inheritance. However, no genetic model was supported unambiguously. The increase in prevalence of depression over the past several decades complicates the genetic interpretation of results. Restriction of analyses to older (age, greater than 18 years) age cohorts appeared to simplify the pattern of transmission, but a consequent reduction of sample size provided only limited power for tests of competing genetic hypotheses. In a subgroup of 28 families in which the proband had both depression and panic disorder, a major gene mode of inheritance was not supported.

A twin study of Tourette syndrome.

In 43 pairs of same-sex twins, in which at least one co-twin had Tourette syndrome (TS), 30 pairs were probably monozygotic (MZ) and 13 were probably dizygotic (DZ). Concordances for TS were 53% and 8% for MZ and DZ pairs, respectively. When diagnostic criteria were broadened to include any tics in co-twins, concordance rates were 77% and 23% for MZ and DZ pairs, respectively. These concordances are consistent with genetic etiology. However, the fact that only 53% of MZ twins were fully concordant indicates nongenetic factors affect expression of TS. Presence of tics in discordant co-twins and timing of onset in partially concordant co-twins support an association between TS and tics in families with TS present. The data are inconclusive on whether some MZ twins with discordant co-twins are etiologically different from those who are concordant.

Neuropsychological functioning in siblings discordant for schizophrenia and healthy volunteers.

OBJECTIVE: To determine whether schizophrenics and their nonschizophrenic siblings have a similar pattern of neuropsychological deficit when compared with normal controls. DESIGN AND PARTICIPANTS: Fifteen probands with schizophrenia, 16 of their nonschizophrenic siblings, and 31 unrelated, demographically balanced, normal individuals underwent evaluation with a comprehensive neuropsychological test battery. All subjects were screened for history of head injury, neurologic illness, major medical conditions, substance use, and axis I psychiatric disorders other than schizophrenia. Probands underwent evaluation twice: once at intake when half had never received neuroleptic medication and the other half had received none for a minimum of 2 weeks, and again at the 2- to 4-week follow-up, after stabilization with neuroleptic medications. RESULTS: Both schizophrenics and their nonschizophrenic siblings were impaired neuropsychologically compared with normal controls, with the nonschizophrenic siblings' performance intermediate between that of the schizophrenic siblings and the normal controls on all measures of functioning. The shapes of the deficit profiles of schizophrenic patients and their siblings were similar; in patients, verbal memory, abstraction, attention, and language functions were significantly more affected compared with spatial abilities, spatial memory, and sensory-motor functions, with a nonsignificant trend in the same direction in siblings. Cognitive functioning in patients was found to be stable across changes in medication status and clinical state. Four fifths of patients obtained more deviant scores than their nonschizophrenic siblings. Among the sibling group, those with probable and certain diagnoses of schizotypal personality disorder were more impaired compared with those without schizophrenia-spectrum symptoms. CONCLUSION: These results support the hypothesis that impaired information processing aggregates in the family members of schizophrenics and may serve as an indicator of genetic vulnerability to the disorder. Further work is needed to establish whether particular areas of functioning are selectively impaired in relatives and to determine whether the performance deficits are mediated by structural and/or metabolic disturbances in specific brain regions.

Elongated beamlets: a simple technique for segment and MU reduction for sMLC IMRT delivery on accelerators utilizing 5 mm leaf widths.

The focus of this work is to demonstrate the effects of using an elongated beamlet to achieve similar dose conformity as achieved with a square beamlet while reducing the number of segments and subsequent MU required. A series of 10 patients were planned for IMRT delivery to the prostate using minimum beamlet sizes of 5x5 mm2 (default scheme), 10x5 mm2 with the short axis parallel to the prostate-rectum interface (scheme 1), and 10x5 mm2 with the short axis perpendicular to the prostate-rectum interface (scheme 2). All other parameters between plans were left unchanged. Plans were appropriately normalized and evaluated for R65, R40, conformity index, total number of segments and MU. All plans were generated using the Corvus inverse planning system. The average number of segments in this study decreased by approximately 49% for both schemes 1 and 2. The subsequent number of MU required decreased by approximately 34.6%. The resultant modified modulation scaling factor (MSFmod) decreased by approximately 34.3%. Additionally, we found that each isodose distribution using scheme 2 would still meet our clinical acceptance criteria with no visible degradation in the dose distribution as compared with the default scheme. In conclusion, we have demonstrated that it is possible to achieve similar results as those obtained using a 5x5 mm2 beamlet with respect to target coverage and critical structure sparing by using strategically oriented elongated beamlets. This technique directly translates to a decreased MSF(mod) allowing for decreased leakage dose to the patient, a decreased risk of exceeding secondary shielding limits in pre-existing vaults, and shorter treatment times.

A genome-wide scan suggests a locus on chromosome 1q21-q23 contributes to normal variation in plasma cholesterol concentration.

To identify genes that influence plasma cholesterol, triglyceride, and high-density and low-density lipoproteins concentrations we conducted a genome-wide scan using 354 polymorphic markers spaced at 10-cM intervals in 75 obese but otherwise normal human families. The results of the genome scan using sibling pair analysis of quantitative phenotypes suggested that 1q21-q23 contains a locus that influences plasma cholesterol concentration. Chromosome 12 gave evidence of linkage to plasma triglyceride concentration (D12SPAH) and chromosomes 3, 6, 7, 10, 11, 17, and 20 yielded additional evidence of linkage for lipid phenotypes at lower levels of statistical significance. Allele sharing for markers near prominent candidate genes was either very weakly related or unrelated to sibling similarity for lipid concentrations. Together these results suggest that genes with important roles in regulating normal cholesterol and triglyceride concentrations do not coincide with the location of previously known candidate genes.

QUADOS intercomparison: a summary of photon and charged particle problems.

QUADOS, a Concerted Action of the European Commission, has promoted an intercomparison aimed at evaluating the use of computational codes for dosimetry in radiation protection and medical physics. This intercomparison was open to all users of radiation transport codes. Eight problems were selected for their relevance to the radiation dosimetry community, five of which involved photon and proton transport. This paper focuses on the analysis of the photon and charged particle problems. The neutron problems were presented in a paper at the NEUDOS9 conference.

Genetic contributions to human fatness: an adoption study.

A strong relationship was found between the degree of fatness of biologic mothers and that of their adult offspring who had been separated from their mothers at birth and adopted during the first year of life. This relationship persisted even after age, height, and possible confounding environmental factors were controlled. There was little evidence for either selective placement on the basis of parental fatness or gene-environment interaction. There was no relationship between the degree of fatness of adoptive parents and that of the adoptees. Two indexes of environmental influence--rural upbringing and disturbance in the adoptive home--predicted fatness among adoptees.

Gilles de la Tourette's syndrome: tics and central nervous system stimulants in twins and nontwins.

Thirty-four of 170 surveyed individuals with Tourette's syndrome (TS) were treated with CNS stimulants before age 18. In 24% of treated individuals, persistent exacerbation of tics was closely associated with treatment. In 3%, tic response was transient, and in 24%, tics were not obviously associated with treatment. Six pairs of monozygotic twins were discordant for stimulant treatment, and all untreated co-twins also developed TS. The number of individuals in whom stimulants permanently exacerbate tics may be small, but the risk appears to be real. Genetic vulnerability and duration and timing of treatment may mediate response.

Childhood oligodendrogliomas presenting with seizures and low-density lesions on computed tomography.

Three children with cerebral oligodendrogliomas causing partial complex or generalized seizures presented with completely normal neurologic examinations. CT showed low-density, nonenhancing surface lesions. Although these CT features are usually associated with infarcts or cysts, neoplasm was suspected because of irregularity of the margins and erosion of the adjacent inner table of the skull. Oligodendrogliomas often enlarge slowly and may cause seizures years before they produce focal neurologic signs. CT of all children with seizures not responsive to anticonvulsant medication and focal clinical or EEG abnormalities will hasten diagnosis of slowly growing intracranial mass lesions.

Dose selection for prostate cancer patients based on dose comparison and dose response studies.

PURPOSE: To better define the appropriate dose for individual prostate cancer patients treated with three-dimensional conformal radiation therapy (3D CRT). METHODS AND MATERIALS: Six hundred eighteen patients treated with 3D CRT between 4/89 and 4/97 with a median follow-up of 53 months are the subject of this study. The bNED outcomes were assessed by the American Society for Therapeutic Radiology and Oncology (ASTRO) definition. The patients were grouped into three groups by prostate-specific antigen (PSA) level (<10 ng/ml, 10-19.9 ng/ml, and 20+ ng/ml) and further subgrouped into six subgroups by favorable (T1, 2A and Gleason score < or =6 and no perineural invasion) and unfavorable characteristics (one or more of T2B, T3, Gleason 7-10, perineural invasion). Dose comparisons for bNED studies were made for each of the six subgroups by dividing patients at 76 Gy for all subgroups except the favorable <10 ng/ml subgroup, which was divided at 72.5 Gy. Five-year bNED rates were compared for the median dose of each dose comparison subgroup. Dose response functions were plotted based on 5-year bNED rates for the six patient groupings, with the data from each of the six subgroups divided into three dose groups. The 5-year bNED rate was also estimated using the dose response function and compares 73 Gy with 78 Gy. RESULTS: Dose comparisons show a significant difference in 5-year bNED rates for three of the six subgroups but not for the favorable <10 ng/ml, the favorable 10-19.9 ng/ml, or the unfavorable > or =20 ng/ml subgroups. The significant differences ranged from 22% to 40% improvement in 5-year bNED with higher dose. Dose response functions show significant differences in 5-year bNED rates comparing 73 Gy and 78 Gy for four of the six subgroups. Again, no difference was observed for the favorable <10 ng/ml group or the unfavorable > or =20 ng/ml group. The significant differences observed in 5-year bNED ranged from 15% to 43%. CONCLUSIONS: Dose response varies by patient subgroup, and appropriate dose can be estimated for up to six subdivisions of prostate cancer patients. The appropriate use of high dose with 3D CRT results in 5-year cure rates that equal or exceed other treatments. The national practice must be upgraded to allow the safe administration of 75-80 Gy with 3D CRT.