Prognostic Factors for Treatment Failure of Photodynamic Therapy and 5-Fluorouracil in Bowen's Disease.

INTRODUCTION: Little is known about prognostic factors that may influence the response to non-invasive treatments of patients with Bowen's disease. The aim of this study was to identify patient and lesion characteristics that are associated with a higher risk of treatment failure after 5-fluorouracil and photodynamic therapy in Bowen's disease. The hypothesis that the thickness of the Bowen's lesion and extension along the hair follicle is associated with the risk of treatment failure after noninvasive treatment was also explored. METHODS: Data were derived from a non-inferiority randomized trial in which 169 patients were treated with 5% 5-fluorouracil cream twice daily for 4 weeks or 2 sessions of methylaminolevulinate photodynamic therapy with 1-week interval. All patients had histologically confirmed Bowen's disease of 4-40 mm. The initial 3 mm biopsy specimens were re-examined to measure the maximum histological lesion thickness and extension along the hair follicle. To evaluate the association between potential risk factors for treatment failure at 1-year follow-up, univariate and multivariate logistic regression analyses were used to calculate odds ratios (ORs) with 95% confidence intervals and p values. RESULTS: Histological lesion thickness was not significantly associated with treatment failure (OR: 0.84, p = 0.806), nor was involvement of the hair follicle (OR: 1.12, p = 0.813). Lesion diameter was the only risk factor that was significantly associated with 1-year risk of treatment failure (OR = 1.08 per mm increase, p = 0.021). When using the median value of 10 mm as cut-off point, the risk of treatment failure was 23.4% for lesions >10 mm compared to 10.3% for lesions ≤10 mm (OR: 2.66, p = 0.028). CONCLUSIONS: Only clinical lesion diameter was identified as a prognostic factor for response to non-invasive therapy in Bowen's disease.

Dramatic Alteration of 3ILCT Lifetimes Using Ancillary Ligands in [Re(L)(CO)3(phen-TPA)] n+ Complexes: An Integrated Spectroscopic and Theoretical Study.

The ground and excited state photophysical properties of a series of fac-[Re(L)(CO)3(α-diimine)] n+ complexes, where L = Br-, Cl-, 4-dimethylaminopyridine (dmap) and pyridine (py) have been extensively studied utilizing numerous electronic and vibrational spectroscopic techniques in conjunction with a suite of quantum chemical methods. The α-diimine ligand consists of 1,10-phenanthroline with the highly electron donating triphenylamine (TPA) appended in the 5 position. This gives rise to intraligand charge transfer (ILCT) states lying lower in energy than the conventional metal-to-ligand charge transfer (MLCT) state, the energies of which are red and blue-shifted, respectively, as the ancillary ligand, L becomes more electron withdrawing. The emitting state is 3ILCT in nature for all complexes studied, characterized through transient absorption and emission, transient resonance Raman (TR2), time-resolved infrared (TRIR) spectroscopy and TDDFT calculations. Systematic modulation of the ancillary ligand causes unanticipated variation in the 3ILCT lifetime by 2 orders of magnitude, ranging from 6.0 µs for L = Br- to 27 ns for L = py, without altering the nature of the excited state formed or the relative order of the other CT states present. Temperature dependent lifetime measurements and quantum chemical calculations provide no clear indication of close lying deactivating states, MO switching, contributions from a halide-to-ligand charge transfer (XLCT) state or dramatic changes in spin-orbit coupling. It appears that the influence of the ancillary ligand on the excited state lifetime could be explained in terms of energy gap law, in which there is a correlation between ln( knr) and Eem with a slope of -21.4 eV-1 for the 3ILCT emission.

Germline findings in cancer predisposing genes from a small cohort of chordoma patients.

INTRODUCTION: Chordoma is a rare slow-growing tumor that occurs along the length of the spinal axis and arises from primitive notochordal remnants (Stepanek et al., Am J Med Genet 75:335-336, 1998). Most chordomas are sporadic, but a small percentage of cases are due to hereditary cancer syndromes (HCS) such as tuberous sclerosis 1 and 2 (TSC1/2), or constitutional variants in the gene encoding brachyury T (TBXT) (Pillay et al., Nat Genet 44:1185-1187, 2012; Yang et al., Nat Genet 41:1176-1178, 2009). PURPOSE: The genetic susceptibility of these tumors is not well understood; there are only a small number of studies that have performed germline genetic testing in this population. METHODS: We performed germline genetic in chordoma patients using genomic DNA extracted by blood or saliva. CONCLUSION: We report here a chordoma cohort of 24 families with newly found germline genetic mutations in cancer predisposing genes. We discuss implications for genetic counseling, clinical management, and universal germline genetic testing for cancer patients with solid tumors.

Longitudinal Natural History Study of Children and Adults with Rare Solid Tumors: Initial Results for First 200 Participants.

Understanding of tumor biology and identification of effective therapies is lacking for many rare tumors. My Pediatric and Adult Rare Tumor (MyPART) network was established to engage patients, advocates, and researchers and conduct a comprehensive longitudinal Natural History Study of Rare Solid Tumors. Through remote or in-person enrollment at the NIH Clinical Center, participants with rare solid tumors ≥4 weeks old complete standardized medical and family history forms, patient reported outcomes, and provide tumor, blood and/or saliva samples. Medical records are extracted for clinical status and treatment history, and tumors undergo genomic analysis. A total of 200 participants (65% female, 35% male, median age at diagnosis 43 years, range = 2-77) enrolled from 46 U.S. states and nine other countries (46% remote, 55% in-person). Frequent diagnoses were neuroendocrine neoplasms (NEN), adrenocortical carcinomas (ACC), medullary thyroid carcinomas (MTC), succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (sdGIST), and chordomas. At enrollment, median years since diagnosis was 3.5 (range = 0-36.6), 63% participants had metastatic disease and 20% had no evidence of disease. Pathogenic germline and tumor mutations included SDHA/B/C (sdGIST), RET (MTC), TP53 and CTNNB1 (ACC), MEN1 (NEN), and SMARCB1 (poorly-differentiated chordoma). Clinically significant anxiety was observed in 20%-35% of adults. Enrollment of participants and comprehensive data collection were feasible. Remote enrollment was critical during the COVID-19 pandemic. Over 30 patients were enrolled with ACC, NEN, and sdGIST, allowing for clinical/genomic analyses across tumors. Longitudinal follow-up and expansion of cohorts are ongoing to advance understanding of disease course and establish external controls for interventional trials. SIGNIFICANCE: This study demonstrates that comprehensive, tumor-agnostic data and biospecimen collection is feasible to characterize different rare tumors, and speed progress in research. The findings will be foundational to developing external controls groups for single-arm interventional trials, where randomized control trials cannot be conducted because of small patient populations.

Adrenocortical carcinoma masquerading as pheochromocytoma: a histopathologic dilemma.

SUMMARY: Adrenocortical carcinoma (ACC) is an aggressive cancer that originates in the cortex of the adrenal gland and generally has a poor prognosis. ACC is rare but can be more commonly seen in those with cancer predisposition syndromes (e.g. Li-Fraumeni and Lynch Syndrome). The diagnosis of ACC is sometimes uncertain and it requires the use of precise molecular pathology; the differential diagnosis includes pheochromocytoma, adrenal adenoma, renal carcinoma, or hepatocellular carcinoma. We describe a case of a 57-year-old woman with Lynch Syndrome and metastatic ACC who was initially diagnosed as having pheochromocytoma. The tumor was first identified at 51 years of age by ultrasound followed by a CT scan. She underwent a left adrenalectomy, and the histopathology identified pheochromocytoma. Two years later, she had tumor recurrence with imaging studies showing multiple lung nodules. Following a wedge resection by video-assisted thoracoscopic surgery (VATS), histopathology was read as metastatic pheochromocytoma at one institution and metastatic ACC at another institution. She later presented to the National Institutes of Health (NIH) where the diagnosis of ACC was confirmed. Following her ACC diagnosis, she was treated with mitotane and pembrolizumab which were stopped due to side effects and progression of disease. She is currently receiving etoposide, doxorubicin, and cisplatin (EDP). This case highlights the importance of using a multi-disciplinary approach in patient care. Thorough evaluation of the tumor's pathology and analysis of the patient's genetic profile are necessary to obtain the correct diagnosis for the patient and can significantly influence the course of treatment. LEARNING POINTS: Making the diagnosis of ACC can be difficult as the differential diagnosis includes pheochromocytoma, adrenal adenoma, renal carcinoma, or hepatocellular carcinoma. Patients with Lynch Syndrome should undergo surveillance for ACC as there is evidence of an association between Lynch Syndrome and ACC. Conducting a complete tumor immunoprofile and obtaining a second opinion is very important in cases of suspected ACC in order to confirm the proper diagnosis. A multi-disciplinary approach including genetic testing and a thorough evaluation of the tumor's pathology is imperative to ensuring that the patient receives an accurate diagnosis and the appropriate treatment.

Early pattern formation in the developing Drosophila eye.

The formation of complex cellular arrays from unpatterned epithelia is a widespread developmental phenomenon. Insights into the mechanisms regulating this transformation have come from studying the development of the Drosophila compound eye. Pattern formation in the eye primordium is a highly ordered process in which the onset of differentiation is coordinated with synchronization of cell cycle progression. Recent studies have identified a number of genes that are required for early patterning events, and provide a link between the regulation of proliferation and pattern formation.

Further observations, mainly serological, on a cohort of women with or without pelvic inflammatory disease.

An analysis was undertaken of data pertaining to over 100 women with lower abdominal pain who were laparoscoped. Prior to laparoscopy, 11 of the women were considered to almost certainly have salpingitis, of whom six (55%) had salpingitis at laparoscopy; 17 to probably have salpingitis, of whom six (35%) did; 28 to possibly have salpingitis, of whom five (18%) did; and 56 to be very unlikely to have salpingitis, of whom five (9%) did. Of the 22 women who had salpingitis at laparoscopy, 14 (64%) had a Chlamydia trachomatis IgG antibody titre of >or=1:128 and might reasonably be regarded as having chlamydial disease on this basis; six without such a titre probably did not have chlamydial disease as C. trachomatis could not be detected at any genital site. At laparoscopy, 18 women had adhesions without obvious tubal inflammation; clinically, 15 of them had been regarded as possibly having salpingitis or unlikely to have it, with 12 having chronic pelvic pain. Twelve (67%) of the 18 women had a chlamydial IgG antibody titre of >or=1:128. IgM antibody was also detected most often in the 'salpingitis' group. Of 49 women without any abnormality detected at laparoscopy, nine (18%) had a high chlamydial IgG antibody titre. Overall, a woman who had a high titre of chlamydial IgG antibody and acute pelvic pain, together with a clinical picture of pelvic inflammation, was more likely to have salpingitis than adhesions alone. Likewise, a woman who had a high titre of chlamydial IgG antibody and chronic pelvic pain, together with a clinical picture suggesting that salpingitis was unlikely, was more likely to have adhesions alone than acute chlamydial salpingitis. However, while antibody measurement and seeking cervical C. trachomatis may help in formulating a diagnosis, there seems no simple way of detecting the small proportion of women who are infected by C. trachomatis in the upper genital tract but whose laparoscopic findings indicate normality. So far as patient care is concerned, the only way of preventing damage to the upper genital tract is to treat early on the basis of suspicion.

Synthesis of Cyclopenta-HBCs and their Regioselective Chlorination During Oxidative Cyclodehydrogenation.

Hexa-peri-hexabenzocoronenes with a bay-fused five-membered ring are synthesized from fluorenyl precursors. The key oxidative cyclodehydrogenation step is accompanied by regioselective chlorination that is enhanced by methylation at the cyclopenta-ring or increased reaction concentration. The CpHBC products undergo mild electrophilic aromatic bromination, without catalyst, to afford adducts suitable for π-extension by cross-coupling.

A fly's eye view of biology.

Determining how genes function in developmentally complex multicellular organisms can be a formidable task. Obstacles arise from the fact that inactivation of most genes results in subtle or undetectable phenotypic alterations, and when phenotypes are observed they are often difficult to interpret because most genes play multiple roles in development. New techniques that have been applied to studying genes in the developing Drosophila eye promise to circumvent these obstacles. The advent of these techniques combined with the existing wealth of information about cellular pattern formation in the Drosophila eye make the eye a powerful model system for deciphering the function of genes in biological processes.

Roughex mediates G(1) arrest through a physical association with cyclin A.

Differentiation in the developing Drosophila eye requires synchronization of cells in the G(1) phase of the cell cycle. The roughex gene product plays a key role in this synchronization by negatively regulating cyclin A protein levels in G(1). We show here that coexpressed Roughex and cyclin A physically interact in vivo. Roughex is a nuclear protein, while cyclin A was previously shown to be exclusively cytoplasmic during interphase in the embryo. In contrast, we demonstrate that in interphase cells in the eye imaginal disk cyclin A is present in both the nucleus and the cytoplasm. In the presence of ectopic Roughex, cyclin A becomes strictly nuclear and is later degraded. Nuclear targeting of both Roughex and cyclin A under these conditions is dependent on a C-terminal nuclear localization signal in Roughex. Disruption of this signal results in cytoplasmic localization of both Roughex and cyclin A, confirming a physical interaction between these molecules. Cyclin A interacts with both Cdc2 and Cdc2c, the Drosophila Cdk2 homolog, and Roughex inhibits the histone H1 kinase activities of both cyclin A-Cdc2 and cyclin A-Cdc2c complexes in whole-cell extracts. Two-hybrid experiments suggested that the inhibition of kinase activity by Roughex results from competition with the cyclin-dependent kinase subunit for binding to cyclin A. These findings suggest that Roughex can influence the intracellular distribution of cyclin A and define Roughex as a distinct and specialized cell cycle inhibitor for cyclin A-dependent kinase activity.

Alkylation of DNA in rats by N-nitrosomethyl-(2-hydroxyethyl)amine: dose response and persistence of the alkylated lesions in vivo.

The in vivo alkylation of DNA by N-nitrosomethyl-(2-hydroxyethyl)amine (NMHEA) was examined in male and female F-344/N rats. NMHEA is a strong hepatocarcinogen in female rats when administered by gavage but a weaker hepatocarcinogen in male rats. Groups of 5 rats of each sex were treated by gavage with various doses of NMHEA dissolved in corn oil. After 4 h the animals were sacrificed and the livers, lungs, and kidneys were removed. The DNA from each liver was isolated and the neutral thermal and mild acid hydrolysates were separated by high-performance liquid chromatography. The alkylated guanines were quantified by fluorescence spectroscopy. NMHEA gives rise to four fluorescent alkylated guanines, 7- and O6-methylguanines, and 7- and O6-hydroxyethylguanines. The dose-response data revealed that all four lesions increased with dose. There was approximately 10x more methylation than hydroxyethylation at the 7 position of guanine. There was less O6 alkylation, but both methylation and hydroxyethylation were observed at all of the doses studied. The overall alkylation was the same in males and females at the 10- and 20-mg/kg doses, but at higher doses the females exhibited significantly higher levels of alkylation than males. The level of alkylation of DNA isolated from non-target tissues, lung, and kidney was low. The persistence of these lesions in vivo was studied at a dose of 25 mg/kg. Groups of five animals each were sacrificed at various times from 0 to 96 h. There was no significant difference between the sexes in persistence of any of the lesions in the liver. The 7-alkylguanines disappeared slowly over the observation period. 7-Methylguanine was present at 30% of the maximum level after 96 h, while 7-hydroxyethylguanine appeared to be more stable. The O6-alkylguanines were removed rapidly from the liver, being at base level by 48 h. The rapid removal of O6-hydroxyethylguanine suggests a repair process independent of O6-alkylguanine-DNA guanine alkyl transferase: an excision repair is postulated. In vitro alkylation of calf thymus DNA by N-nitrosomethyl-(2-tosyloxyethyl)amine, a surrogate for the putative O-sulfate conjugate of NMHEA, resulted in exclusive methylation of DNA-guanine at both the 7 and O6 positions; no hydroxyethylation was detected. In vitro alkylation of calf thymus DNA with 2-hydroxyethyl-ethylnitrosourea resulted in exclusive hydroxyethylation of DNA-guanine at the 7 and O6 positions.(ABSTRACT TRUNCATED AT 400 WORDS)

The genetic control of direct-repeat recombination in Saccharomyces: the effect of rad52 and rad1 on mitotic recombination at GAL10, a transcriptionally regulated gene.

We have previously shown direct-repeat recombination events leading to loss of a plasmid integrated at the GAL10 locus in Saccharomyces cerevisiae are stimulated by transcription of the region. We have examined the role of two recombination- and repair-defective mutations, rad1 and rad52, on direct repeat recombination in transcriptionally active and inactive sequences. We show that the RAD52 gene is required for transcription-stimulated recombination events leading to loss of the integrated plasmid. Similarly, Gal+ events between the duplicated repeats that retain the integrated plasmid DNA (Gal+ Ura+ replacement events) are reduced 20-fold in the rad52 mutant in sequences that are constitutively expressed. In contrast, in sequences that are not expressed, the rad52 mutation reduces plasmid loss events by only twofold and Gal+ Ura+ replacements by fourfold. We also observe an increase in disome-associated plasmid loss events in the rad52 mutant, indicative of chromosome gain. This event is not affected by expression of the region. Plasmid loss events in rad1 mutant strains are reduced only twofold in transcriptionally active sequences and are not affected in sequences that are repressed. However, the rad1 and rad52 double mutant shows a decrease in plasmid loss events greater than the sum of the decreases in the rates of this event displayed by either single mutant in both constitutive and repressed DNA, indicating a synergistic interaction between these two genes. The synergism is limited to recombination since the rad1 rad52 double mutant is no more sensitive when compared with either single mutant in its ability to survive radiation damage. Finally, the recombination pathway that remains in the double mutant is positively affected by transcription of the region.

The effect of recombinant human osteogenic protein-1 on growth plate repair in a sheep model.

Injuries to the growth plate in children can result in bone bridge formation, which ultimately lead to limb length and angular deformities. The histological and molecular changes associated with growth plate repair following the Langenskiöld procedure, a surgical technique used to remove impeding bone bridges, in conjunction with administration of recombinant human osteogenic protein-1 (rhOP-1) were examined using a sheep model. Following treatment with rhOP-1 there was an increase in the height of the growth plate immediately adjacent to the defect compared to untreated animals. The expression of type I collagen, osteopontin and decorin were observed in the growth plate adjacent to the defect in the untreated animals at day 56, but this response was accelerated in the rhOP-1 treated animals, with these molecules seen as early as day 7. Therefore, treatment with rhOP-1 initiated a complex response that was both chondrogenic and osteogenic in nature.

Body composition in myelomeningocele.

Body composition and measures of obesity were evaluated in 59 subjects with myelomeningocele (MMC), aged 0.3-29 y, by anthropometry and measures of body cell mass (BCM) and intra- and extracellular water (ICW and ECW), derived from total body potassium and deuterium-isotope dilution; these results were compared with reference data. Body composition was normal in preambulatory children with MMC. Beyond ages 3-4 y there was significant depletion of BCM and total body water, with maldistribution of water (increased ECW and decreased ICW) and increased percentage body fat above that expected for age and sex. These findings were more pronounced in females and in those with high lesions, and were less pronounced in those who remained ambulatory. These changes may result in metabolic and nutritional maladaption during stress. The relation of BCM, total body water depletion and increased ECW to decreasing ambulatory activity suggests that early nutritional and mobility programs warrant further study.

Altered body composition and muscle protein degradation in nutritionally growth-retarded children with cystic fibrosis.

To investigate nutritional growth retardation and the adaptive response to malnutrition in cystic fibrosis (CF), body composition and muscle protein catabolism were studied in nine malnourished CF children and eight healthy controls by anthropometry, measurement of whole body potassium, urinary creatinine excretion, creatinine height index, and urinary 3-methylhistidine excretion, an index of myofibrillar protein catabolism. CF children had a significant deficit of body mass (p less than 0.001), derived from both the body fat and the fat-free compartments, including a deficit in muscle mass (p less than 0.005). A deficit of muscle mass in CF was also reflected by a lower creatinine height index (mean +/- 1 SEM = 0.66 +/- 0.04 in CF, versus 0.85 +/- 0.5 in controls, p less than 0.02). Urinary 3-methylhistidine excretion was elevated in CF children and the mean (+/- 1 SEM) rate of muscle protein catabolism was 0.82 +/- 0.06 versus 0.53 +/- 0.04 kg-1 24 h-1 in CF and controls, respectively (p less than 0.01). 3-Methylhistidine excretion rates did not correlate with severity of disease as assessed by clinical score. We conclude that nutritional growth retardation in CF is characterized by a protein energy deficit resembling that of protein-energy malnutrition, but that in contrast to the normal adaptive response to protein-energy malnutrition, muscle protein catabolism is markedly increased. These data may have important implications regarding the clinical course and prognosis of CF and the design of optimal therapy.

Nutritional support in children with end-stage liver disease: a randomized crossover trial of a branched-chain amino acid supplement.

Malnutrition is common in children with end-stage liver disease (ESLD) awaiting orthotopic liver transplantation (OLT), and nutritional support is assuming an important role in preoperative management. To evaluate preoperative nutritional therapy, 19 children (median age 1.25 y) with ESLD awaiting OLT were prospectively studied. Two high-energy, isoenergetic and isonitrogenous nutritional formulations delivered nasogastrically were compared: a branched-chain amino acid (BCAA)-enriched semielemental formulation and a matched standard semielemental formation. Twelve of 19 patients completed a randomized controlled study before OLT and 10 of 19 completed a full crossover study. Improvements in weight and height occurred during the BCAA supplements, with no statistical change on the standard formulation. Significant increases in total body potassium, midupper arm circumference, and subscapular skinfold thickness occurred during the BCAA supplements, whereas no significant changes occurred during the standard formulation period. Significantly fewer albumin infusions were required during the BCAA supplement. These findings suggest that BCAA-enriched formulas have advantages over standard semielemental formulas in improving nutritional status in children with ESLD, and are deserving of wider application and study.

The nature of malnutrition in children with end-stage liver disease awaiting orthotopic liver transplantation.

To evaluate malnutrition in chronic liver disease, and its relationship to nutrient deficiencies and hepatic dysfunction, 27 children with end-stage liver disease were studied. Mean protein-energy intakes were 70% of recommended daily intakes. The patients were underweight and stunted with reduced mean triceps and subscapular skinfold thicknesses and midupper arm circumference. Mean total body potassium was only 63 +/- 18% of that expected for age and sex. Deficiency of essential fatty acids (32%), and low concentrations of fat-soluble vitamins (A, 92%; E, 32%), iron (32%), zinc (42%), and selenium (13%) were common. Serum ammonia concentrations were raised in all patients, and increased methionine, tyrosine, and glutamic acid, and reduced glutamine concentrations were noted. There was no correlation between the degree of malnutrition and the degree of liver synthetic function, the degree of cholestasis, or the degree of liver injury. We suggest that potentially correctable factors in addition to liver failure (eg, inadequate absorbed intake) were important determinants of malnutrition in these patients.

The use of postoperative irradiation for the prevention of heterotopic bone formation after total hip replacement.

Formation of heterotopic bone (HTB) following total hip replacement may partially or completely ankylose the joint space, causing pain and/or limiting the range of motion. Patients at high risk for formation of HTB postoperatively include those with previous HTB formation, heterotopic osteoarthritis, and active rheumatoid spondylitis. Patients in these high risk groups have a 63-69% incidence of post-operative HTB formation, usually seen radiographically by 2 months post-operation. From 1980-1986 twenty-nine hips in 28 consecutively treated patients were irradiated post-operatively at the UCLA Center for the Health Sciences. The indication for irradiation was documented HTB formation previously in 26 of the 27 hips presented below. From 1980-1982 patients received 20 Gray (Gy) in 2 Gy fractions; from 1982-1986 the dose was reduced to 10 Gy in 2 Gy fractions. Twenty-seven hips in 26 patients completed therapy and were available for evaluation, with a minimum of 2 month follow-up, and a median follow-up of 12 months. Three of 27 hips developed significant HTB (Brooker grade III or IV) post-operatively, whereas 5 of 27 hips developed minor, nonsymptomatic HTB (Brooker grade I). When irradiation was begun by postoperative day 4, 0 of 17 hips formed significant HTB. If irradiation began after post-operative day 4, 3 of 10 hips formed significant HTB (Brooker grade III or IV). These 3 hips received doses of 10 Gy in one hip and 20 Gy in the other 2 hips. There were no differences in the incidence or severity of side effects in the 10 Gy vs. the 20 Gy treatment groups. Eighteen hips received 10 Gy, 8 hips 20 Gy and, 1 hip 12 Gy. In conclusion, 10 Gy in 5 fractions appears as effective as 20 Gy in 10 fractions at preventing post-operative formation of HTB. For optimal results, treatment should begin as early as possible prior to post-operative day 4.

Postoperative irradiation for the prevention of heterotopic bone: analysis of different dose schedules and shielding considerations.

Ninety-seven high risk hips were irradiated postoperatively for prevention of heterotopic bone (HTB) in the UCLA Department of Radiation Oncology from 1980 to 1988. Ninety-two hips in 82 patients were eligible for analysis with a minimum follow-up of 2 months and a median follow-up of 10 months. Forty-nine of the hips had porous coated ingrowth prostheses. From 1980 to 1986, 2 Gy fractions were used to deliver 20 Gy (8 hips), 12 Gy (1 hip), and 10 Gy (27 hips). Since December of 1986, 38 hips received 8 Gy in two increments and 18 hips received a single 7 Gy fraction. All porous ingrowth components were shielded with custom blocks. Six out of 92 hips developed clinically significant (Brooker grade 3 or 4 heterotopic bone). There was one clinically significant failure in 78 hips (1.3%) when irradiation was initiated before post-operative day (POD) #6 and shielding was properly placed. One clinical failure occurred in 38 hips which received 8 Gy in two increments. One clinical failure occurred out of the 18 hips treated with 7 Gy in one fraction. This failure could be related to block malposition. There were four clinical failures in the 36 hips treated with 2 Gy fractions to total doses of 10 Gy, 12 Gy, or 20 Gy. Three of these failures were associated with initiation of treatment after POD #5, and the fourth was related to block malposition. Unshielded trochanteric osteotomies resulted in five migrations and seven fibrous unions for a total non-osseous union rate of 12/36 (33%). Shielding of the remaining 28 trochanteric osteotomies resulted in a non-osseous union rate of 7% (0 migrations and 2 fibrous unions). There were no failures of union of components, and the only side effects noted in the series were the five trochanteric migrations. In conclusion, the use of 8 Gy in two increments or 7 Gy in one fraction was found to be as efficacious as conventional 2 Gy fractionation schemes with no increase in side effects. For optimal results, treatment should be implemented prior to POD #5 with shielding of the trochanteric osteotomy. Postoperative irradiation to prevent HTB can be used in hips with porous components using properly placed blocks to shield the porous region.