Infectious exposure in the first years of life and risk of central nervous system tumours in children: analysis of birth order, childcare attendance and seasonality of birth.

BACKGROUND: An infective, mostly viral basis has been found in different human cancers. To test the hypothesis of a possible infectious aetiology for central nervous system (CNS) tumours in children, we investigated the associations with proxy measures of exposure to infectious disease. METHODS: In a large case-control study nested in the populations of Denmark, Norway, Sweden, and Finland of 4.4 million children, we studied the association of birth order and seasonal variation of birth with subsequent risk for CNS tumours. We identified 3983 children from the national cancer registries, and information on exposure was obtained from the high-quality national administrative health registries. We investigated the association between childcare attendance during the first 2 years of life and the risk for CNS tumours in a subset of Danish children with CNS tumours, using information from the Danish Childcare database. RESULTS: We observed no association between birth order and risk of CNS tumours overall (odds ratio (OR) for second born or later born vs first born, 1.03; 95% confidence interval (CI), 0.96-1.10) or by histological subgroup, and children with CNS tumours did not show a seasonal variation of birth that was distinct from that of the background population. Childcare attendance compared with homecare showed a slightly increased OR (1.29; 95% CI, 0.90-1.86) for CNS tumours, with the highest risk observed in children attending a crèche. The strongest association was observed for embryonal CNS tumours. We found no effect of age at enrolment or duration of enrolment in childcare. CONCLUSION: These results do not support the hypothesis that the burden of exposure to infectious disease in early childhood has an important role in the aetiology of paediatric CNS tumours.

Inhibition of bone resorption in vitro by serine-esterase inhibitors.

The effect of two synthetic serine esterase inhibitors, N-alpha-dansyl(p-guanidino)phenylalaninepiperidine hydrochloride (I 2581) and D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (D-Phe-Pro-Arg-CH2Cl), on bone resorption in organ cultured mouse calvaria from neonatal mice has been examined. Mineral mobilization was assessed by analyzing the release of 45Ca, stable calcium (Ca2+) and inorganic phosphate (Pi). Organic matrix degradation was studied by analyzing the release of 3H from [3H]proline-labelled bones, and by quantifying the amounts of hydroxyproline in bone after culture. It was found that I 2581, at and above 30 mumol/l, dose-dependently inhibited 45Ca release induced by thrombin, parathyroid hormone (PTH), prostaglandin E2 and 1-alpha-hydroxyvitamin D-3. I 2581 (50 mumol/l) inhibited PTH-stimulated release of 3H from [3H]proline-labelled bones, and this effect was reversible after withdrawal of I 2581. I 2581 (50 mumol/l) inhibited the release of Ca2+, Pi, beta-glucuronidase and beta-N-acetylglucosaminidase in bones stimulated by PTH and 1-alpha-hydroxyvitamin D-3, without affecting the release of lactate dehydrogenase. In parallel, I 2581 decreased PTH and 1-alpha-hydroxyvitamin D-3 induced reduction of hydroxyproline levels in bones after culture. I 2581 (50 mumol/l) did not affect the basal release of 45Ca, Ca2+, beta-glucuronidase and beta-N-acetylglucosaminidase, nor the basal amounts of hydroxyproline in bones after culture. D-Phe-Pro-Arg-CH2Cl (100 mumol/l) significantly inhibited PTH- and PGE2-induced release of 45Ca without affecting basal release of radioactive calcium. These data indicate that activation of serine proteinase(s) may be a necessary step in the mechanism of action of several stimulators of bone resorption.

Blood coagulation and bone metabolism: some characteristics of the bone resorptive effect of thrombin in mouse calvarial bones in vitro.

Chronic inflammatory processes are often associated with bone resorption. Stimulated by the current great interest in the role of coagulation factors in inflammation and immune injury, we have studied the effect of thrombin on mouse calvarial bones in vitro. Thrombin caused a dose-dependent (0.1-7 U/ml) stimulation of 45Ca release from neonatal mouse calvarial bones. Thrombin also stimulated the mobilization of stable calcium and inorganic phosphate, the release of 3H from [3H]proline-labelled calvaria, the production of lactate and the release of the lysosomal enzymes, beta-glucuronidase and beta-N-acetylglucosaminidase. Thrombin also enhanced 45Ca release from fetal rat long bones, although this bone resorption assay was less sensitive to thrombin than the mouse calvarial system. The bone resorption stimulatory activity of thrombin in mouse calvaria could be inhibited by calcitonin and an increased concentration of phosphate in the culture medium. Thrombin-induced 45Ca release in mouse calvaria was sensitive to inhibition by hydrocortisone and dexamethasone. By contrast, 45Ca release response to parathyroid hormone was insensitive to corticosteroids. The prostaglandin synthetase inhibitors indomethacin, meclofenamic acid and naproxen and 5,8,11,14-eicosatetraynoic acid reduced 45Ca release from thrombin-stimulated calvaria. However, significant stimulation by thrombin could be achieved also in bones treated with inhibitors of arachidonate metabolism. The results obtained suggest that thrombin can stimulate cell-mediated bone resorption by an osteoclast-dependent mechanism. The mechanism of action may involve both prostaglandin-dependent and prostaglandin-independent pathways. Our findings indicate that thrombin may contribute to the bone resorptive processes seen in periodontal disease and rheumatoid arthritis.

Matched-pair analysis of conformal high-dose-rate brachytherapy boost versus external-beam radiation therapy alone for locally advanced prostate cancer.

PURPOSE: We performed a matched-pair analysis to compare our institution's experience in treating locally advanced prostate cancer with external-beam radiation therapy (EBRT) alone to EBRT in combination with conformal interstitial high-dose-rate (HDR) brachytherapy boosts (EBRT + HDR). MATERIALS AND METHODS: From 1991 to 1998, 161 patients with locally advanced prostate cancer were prospectively treated with EBRT + HDR at William Beaumont Hospital, Royal Oak, Michigan. Patients with any of the following characteristics were eligible for study entry: pretreatment prostate-specific antigen (PSA) level of >/= 10.0 ng/mL, Gleason score >/= 7, or clinical stage T2b to T3c. Pelvic EBRT (46.0 Gy) was supplemented with three (1991 through 1995) or two (1995 through 1998) ultrasound-guided transperineal interstitial iridium-192 HDR implants. The brachytherapy dose was escalated from 5.50 to 10.50 Gy per implant. Each of the 161 EBRT + HDR patients was randomly matched with a unique EBRT-alone patient. Patients were matched according to PSA level, Gleason score, T stage, and follow-up duration. The median PSA follow-up was 2.5 years for both EBRT + HDR and EBRT alone. RESULTS: EBRT + HDR patients demonstrated significantly lower PSA nadir levels (median, 0.4 ng/mL) compared with those receiving EBRT alone (median, 1.1 ng/mL). The 5-year biochemical control rates for EBRT + HDR versus EBRT-alone patients were 67% versus 44%, respectively (P <.001). On multivariate analyses, pretreatment PSA, Gleason score, T stage, and the use of EBRT alone were significantly associated with biochemical failure. Those patients in both treatment groups who experienced biochemical failure had a lower 5-year cause-specific survival rate than patients who were biochemically controlled (84% v 100%; P <.001). CONCLUSION: Locally advanced prostate cancer patients treated with EBRT + HDR demonstrate improved biochemical control compared with those who are treated with conventional doses of EBRT alone.

Recurrent myocardial infarction associated with cocaine abuse in a young man with normal coronary arteries: evidence for coronary artery spasm culminating in thrombosis.

Myocardial infarction is increasingly recognized as a complication of cocaine abuse. A significant number of persons suffering from myocardial infarction associated with cocaine abuse do not have significant coronary atherosclerosis, and the mechanism for infarction in these patients has remained obscure. This report describes a young man with angiographically normal coronary arteries in whom cocaine abuse produced coronary artery spasm leading to coronary thrombosis and infarction.

Activation of arachidonic acid metabolism in mouse macrophages by bacterial amphiphiles.

The relative activities of lipoteichoic acid (LTA) from four Gram-positive bacteria were compared to different lipopolysaccharide (LPS) preparations for activation of arachidonic acid metabolism in mouse peritoneal macrophages. Total eicosanoid was determined in cultures labeled with [3H]-arachidonic acid. Prostaglandin E2 (PGE2) and leukotriene C4 (LTC4) were determined by EIA analysis. The relative potencies of the different preparations were: smooth LPS from Salmonella abortus > or = Re-LPS from Salmonella minnesota (R-595) > or = LTA from Streptococcus pyogenes approximately Streptococcus faecalis approximately Staphylococcus aureus > or = monophosphoryl lipid A derived from the Re-LPS >> LTA from Bacillus subtilis. Activation of eicosanoid release was inhibited by staurosporin for all of the amphiphiles tested. Treatment of the macrophage cultures with LTA from S. pyogenes, S. faecalis, and S. aureus, either in the presence or absence of indomethacin, desensitized the cells to eicosanoid release on subsequent challenge with LPS. The desensitized cells remained responsive to the phorbol ester phorbol myristate acetate. LPS from Gram-negative bacteria has immunostimulatory and endotoxic activities which result, in part, from the release of eicosanoids and other mediators from activated macrophages. The similarities in the patterns of cell activation by LPS and LTA suggest that lipoteichoic acids might contribute to the pathogenicities of Gram-positive bacteria.

Normalization of fasting hyperglucagonemia and excessive glucagon responses to intravenous arginine in human diabetes mellitus by prolonged infusion of insulin.

Infusion of insulin (1 U/hr) for 14 hr suppressed basal glucagon levels and normalized previously excessive glucagon responses to arginine in juvenile-onset, insulin-dependent diabetic subjects, indicating that abnormal pancreatic alpha-cell function in human juvenile-onset diabetes mellitus may be a consequence of insulin lack.

Active bacterial luciferase from a fused gene: expression of a Vibrio harveyi luxAB translational fusion in bacteria, yeast and plant cells.

The luxA and luxB genes encoding the luciferase from Vibrio harvey were fused by site-directed mutagenesis so that one polypeptide was encoded by the fused gene. The fused gene facilitated light production in Escherichia coli, Saccharomyces cerevisiae, and Nicotiana plumbaginifolia when the substrates decanal and reduced flavin mononucleotide were present. The specific activity of the encoded enzyme is not known. In E. coli and S. cerevisiae cells the light emission could be measured in viable, intact cells. The luxAB fusion provides a simple reporter gene for in vivo measurement of promoter strength in these species and may be useful in other systems as well.

A new model for "accept or reject" strategies in off-line and on-line megavoltage treatment evaluation.

PURPOSE: With megavoltage on-line imaging, a temporal record of the treatment setup variation is made available during the course of radiotherapy. This work describes the theoretical framework where the imaging data is incorporated as feedback for deriving off-line and on-line "accept or reject" decisions to improve the quality of radiotherapy on an individual patient basis. METHODS AND MATERIALS: A dynamic model of treatment setup variation is developed to describe: (a) the variations of multifraction treatment position and (b) the variation of measurement. Based on this model, a confidence region of subsequent treatment position is estimated from measurements of previous treatment position. The confidence region is compared with an allowance region of the treatment position, representing the acceptable margin of setup variation. The difference of the two regions are then evaluated to derive off-line and on-line "accept or reject" treatment decisions. RESULTS: The model was simulated retrospectively using sequential daily images from different treatment sites. "Accept or reject" decisions were produced for on-line and off-line applications. The results also demonstrate the ability of the model to include the effects of setup variation that drifted during the course of treatment. CONCLUSION: The preliminary result demonstrates that "accept or reject" treatment decisions can be derived quantitatively from on-line imaging data. The model shows potential to guide the physician and therapist in implementing efficient and accurate treatment adjustments. Further work is required to test the model in the clinical setting.

The use of iodine-125 seeds as a substitute for iridium-192 seeds in temporary interstitial breast implants.

PURPOSE: We have previously reported that the use of iodine-125 seeds in temporary plastic tube interstitial implants may be more advantageous than iridium-192 seeds due to less patient and personnel radiation exposure, reduced shielding requirements, and significant dosimetric advantages. The impact of this isotope on the rate of local control and cosmetic outcome in patients with early stage breast cancer treated with interstitial implants for their irradiation "boost" remains to be defined. METHODS AND MATERIALS: We reviewed the treatment outcome of 402 consecutive cases of Stage I and II breast cancer undergoing breast conserving therapy between 1/1/80 and 12/31/87. All patients underwent excisional biopsy and received 45-50 Gy to the entire breast followed by a boost to the tumor bed using either electrons (104 patients), photons (15 patients), or an interstitial implant with either iridium-192 (197 patients) or iodine-125 (86 patients) to at least 60 Gy. Iodine-125 implants were primarily performed in patients with significant risk factors for local recurrence (71%) or in patients with large breasts (17%). Local tumor control and cosmetic outcome were assessed and contrasted between patients boosted with each modality. RESULTS: With a median follow-up of 59.3 months, 18 (4.5%) patients developed a recurrence of the tumor in the treated breast (4.4% 5-year actuarial rate). No statistically significant differences in the 5-year actuarial rate of local recurrence were noted between patients boosted with either iodine-125 (3.0%), iridium-192 (3.8%), electrons (5.4%), or photons (0%). Likewise, no significant differences in the percentage of patients obtaining good/excellent cosmetic results were noted between iodine-125 (93%), iridium-192 (88%), electrons (90%), or photons (82%). CONCLUSION: We conclude that patients with Stage I and II breast cancer undergoing breast conserving therapy and judged to be candidates for boosts with interstitial implants can be effectively treated with iodine-125 seeds. Use of this isotope results in less patient and personnel irradiation exposure and a better dose distribution than iridium-192, since dose optimization can be routinely employed. Overall, local control and cosmetic outcome have been excellent and are similar to either iridium-192, electrons, or photons.

A comprehensive review of prostate cancer brachytherapy: defining an optimal technique.

PURPOSE: A comprehensive review of prostate cancer brachytherapy literature was performed to determine if an optimal method of implantation could be identified, and to compare and contrast techniques currently in use. METHODS AND MATERIALS: A MEDLINE search was conducted to obtain all articles in the English language on prostate cancer brachytherapy from 1985 through 1998. Articles were reviewed and grouped to determine the primary technique of implantation, the method or philosophy of source placement and/or dose specification, the technique to evaluate implant quality, overall treatment results (based upon pretreatment prostate specific antigen, (PSA), and biochemical control) and clinical, pathological or biochemical outcome based upon implant quality. RESULTS: A total of 178 articles were identified in the MEDLINE database. Of these, 53 studies discussed evaluable techniques of implantation and were used for this analysis. Of these studies, 52% used preoperative ultrasound to determine the target volume to be implanted, 16% used preoperative computerized tomography (CT) scans, and 18% placed seeds with an open surgical technique. An additional 11% of studies placed seeds or needles under ultrasound guidance using interactive real-time dosimetry. The number and distribution of radioactive sources to be implanted or the method used to prescribe dose was determined using nomograms in 27% of studies, a least squares optimization technique in 11%, or not stated in 35%. In the remaining 26%, sources were described as either uniformly, differentially, or peripherally placed in the gland. To evaluate implant quality, 28% of studies calculated some type of dose-volume histogram, 21% calculated the matched peripheral dose, 19% the minimum peripheral dose, 14% used some type of CT-based qualitative review and, in 18% of studies, no implant quality evaluation was mentioned. Six studies correlated outcome with implant dose. One study showed an association of implant dose with the achievement of a PSA nadir < or = 0.5. Two studies showed an improvement in biochemical control with a D90 (dose to 90% of the prostate volume) of 120 to 140 Gy or higher, and 2 additional studies found an association of clinical outcome with implant dose. One study correlated implant quality with biopsy results. Of the articles, 33 discussed evaluable treatment results, but only 16 reported findings based upon pretreatment PSA and biochemical control. Three- to 5-year biochemical control rates ranged from 48% to 100% for pretreatment PSAs < or = 4, 55% to 90% for PSAs between 4 and 10, 30% to 89% for PSAs > 10, < or = 20 and < 10% to 100% for PSAs > 20. Due to substantial differences in patient selection criteria (e.g., median Gleason score, clinical stage, pretreatment PSA), number of patients treated, median follow-up, definitions of biochemical control, and time points for analysis, no single technique consistently produced superior results. CONCLUSIONS: Our comprehensive review of prostate cancer brachytherapy literature failed to identify an optimal treatment approach when studies were analyzed for treatment outcome based upon pretreatment PSA and biochemical control. Although several well-designed studies showed an improvement in outcome with total dose or implant quality, the numerous techniques for implantation and the varied and inconsistent methods to specify dose or evaluate implant quality suggest that standardized protocols should be developed to objectively evaluate this treatment approach. These protocols have recently been suggested and, when implemented, should significantly improve the reporting of treatment data and, ultimately, the efficacy of prostate brachytherapy.

Phase II prospective study of the use of conformal high-dose-rate brachytherapy as monotherapy for the treatment of favorable stage prostate cancer: a feasibility report.

PURPOSE: To evaluate the technical feasibility and tolerance of image-guided transperineal conformal high-dose-rate (C-HDR) brachytherapy as the sole treatment modality for favorable, localized cancer of the prostate, and to analyze possible intrafraction and interfraction volume changes in the prostate gland which may affect dosimetric quality. METHODS AND MATERIALS: Patients were eligible for this prospective Phase II trial if they had biopsy proven adenocarcinoma of the prostate with favorable prognostic factors (Gleason score < or =7, PSA < or =10 ng/ml and Stage < or =T2a). The technique consisted of a transperineal implant procedure using a template with transrectal ultrasound (TRUS) guidance. An interactive on-line real-time planning system was utilized with geometric optimization. This allowed dosimetry to be generated and modified as required intraoperatively. Prescription was to the minimum dose point in the implanted volume, assuring conformal coverage of the prostate at its widest dimension with no margin. Total dose was 3800 cGy in 4 fractions of 950 cGy each, delivered twice a day over 2 days. The dose to any segment of rectum and urethra was limited to < or =75% and < or =125% of the prescription dose, respectively. Before each fraction, needle positions were verified under fluoroscopy and adjusted as required. For the last 10 patients, the adjustments required were measured in a prospective fashion in representative extrema of the gland. TRUS images were recorded for all patients before any needle manipulation, again just before delivering the first fraction and immediately after the last fraction. This typically meant approximately 36 h to pass between the first and last measurements. Implant quality was assessed via dose-volume histograms (DVH). RESULTS: Between 3/99 and 6/00, 41 patients received C-HDR interstitial brachytherapy as their only treatment for prostate cancer at our institution. Median age was 64 years (range 51-79). Stage distribution was 27 T1c patients and 14 T2a patients. Three patients had Gleason score (GS) of 5; 34 had GS of 6; 4 patients had GS of 7. Median pretreatment PSA was 4.7 ng/ml (range 0.8-13.3). All patients tolerated the treatment well with minimal discomfort. For 23 patients, data on volume changes in the gland during the implant were tabulated. They demonstrated a mean prostate volume of 30.7 cc before any manipulation with needles, 37.0 cc at the end of fraction 1, and 38.2 cc at the end of fraction 4. In addition, for those 10 patients prospectively evaluated for required adjustments, the overall mean adjustment between fraction 1 and fraction 2 was 2.0 cm, between fraction 2 and 3 was 0.4 cm, and between fractions 3 and 4 was 0.4 cm. For 10 consecutive patients, the average prescriptions dose -D90 for fractions 1 and 4 were 104% and 100%, respectively. The corresponding average urethral D10 for fractions 1 and 4 were 122% and 132%. CONCLUSION: Our protocol using C-HDR interstitial brachytherapy as monotherapy for early cancer of the prostate was feasible and well tolerated by 41 patients treated. Changes in interfraction prostate volume do not appear to be significant enough to warrant modification of dosimetry for each fraction. Both excellent dose coverage of the prostate gland and low urethral dose are achieved as measured by DVH. However, paramount attention should be given to needle displacement before each fraction. Needle movement is most significant between fractions 1 and 2. Acute toxicity (RTOG) has been modest. Late toxicity and tumor control rates will be reported as longer follow-up allows.

Long-term outcome with interstitial brachytherapy in the management of patients with early-stage breast cancer treated with breast-conserving therapy.

PURPOSE: We reviewed our institution's experience with interstitial implant boosts to determine their long-term impact on local control and cosmetic results. METHODS AND MATERIALS: Between January 1, 1980 and December 31, 1987, 390 women with 400 cases of Stage I and II breast cancer were managed with breast-conserving therapy (BCT) at William Beaumont Hospital. All patients were treated with an excisional biopsy and 253 (63%) underwent reexcision. Radiation consisted of 45-50 Gy external beam irradiation to the whole breast followed by a boost to the tumor bed to at least 60 Gy using either electrons [108], photons [15], or an interstitial implant [277] with either 192Ir [190] or 125I [87]. Long-term local control and cosmetic outcome were assessed and contrasted between patients boosted with either interstitial implants, electrons, or photons. RESULTS: With a median follow-up of 81 months, 25 patients have recurred in the treated breast for a 5- and 8-year actuarial rate of local recurrence of 4 and 8%, respectively. There were no statistically significant differences in the 5- or 8-year actuarial rates of local recurrence using either electrons, photons, or an interstitial implant. Greater than 90% of patients obtained a good or excellent cosmetic result, and no statistically significant differences in cosmetic outcome were seen whether electrons, photons, or implants were used. CONCLUSIONS: We conclude that patients with Stage I and II breast cancer undergoing BCT and judged to be candidates for boosts can be effectively managed with LDR interstitial brachytherapy. Long-term local control and cosmetic outcome are excellent and similar to patients boosted with either electrons or photons.

A multileaf collimator field prescription preparation system for conventional radiotherapy.

PURPOSE: The purpose of this work is to develop a prescription preparation system for efficient field shaping using a multileaf collimator that can be used in community settings as well as research institutions. The efficiency advantage of the computer-controlled multileaf collimator, over cerrobend blocks, to shape radiation fields has been shown in conformal treatments, which typically require complete volumetric computerized tomographic data for three-dimensional radiation treatment planning--a utility not readily available to the general community. As a result, most patients today are treated with conventional radiation therapy. Therefore, we believe that it is very important to fully use the same efficiency advantage of multileaf collimator as a block replacement in conventional practice. METHODS AND MATERIAL: The multileaf collimator prescription preparation system developed by us acquires prescription images from different sources, including film scanner and radiation treatment planning systems. The multileaf collimator angle and leaf positions are set from the desired field contour defined on the prescription image, by minimizing the area discrepancies. Interactive graphical tools include manual adjustment of collimator angle and leaf positions, and definition of portions of the field edges that require maximal conformation. Data files of the final leaf positions are transferred to the multileaf collimator controller via a dedicated communication link. RESULTS: We have implemented the field prescription preparation system and a network model for integrating the multileaf collimator and other radiotherapy modalities for routine treatments. For routine plan evaluation, isodose contours measured with film in solid water phantom at prescription depth are overlaid on the prescription image. Preliminary study indicates that the efficiency advantage of the MLC over cerrobend blocks in conformal therapy also holds true for conventional treatments. CONCLUSION: Our model of computer-controlled prescription, evaluation, and treatment using multileaf collimators can be effectively implemented in both community settings and research institutions. The resultant increase in treatment efficiency and accuracy is now available for conventional radiotherapy.

Outcome and prognostic factors for local recurrence in mammographically detected ductal carcinoma in situ of the breast treated with conservative surgery and radiation therapy.

PURPOSE: We have retrospectively reviewed our institution's experience treating a predominantly mammographically detected population of ductal carcinoma in situ (DCIS) patients with conservative surgery and radiation therapy (CSRT) to determine outcome and prognostic factors for local recurrence. METHODS AND MATERIALS: Between January 1, 1982 and December 31, 1988, 52 consecutive cases of DCIS of the breast were treated with CSRT at William Beaumont Hospital. Forty-six (88%) were mammographically detected nonpalpable lesions. All patients underwent at least an excisional biopsy and 28 (54%) were reexcised. The axilla was surgically staged in 41 (79%) and all were N0. The entire breast was irradiated to 45-50 Gy over 5-6 weeks. The tumor bed was boosted in 49 (94%) so that the minimum dose was 60 Gy. The three patients not boosted received a minimum dose of 50 Gy to the entire breast. Pathologic materials were reviewed by one of the authors. RESULTS: The predominant DCIS pattern was comedo in 40%, cribriform in 28%, solid in 17%, and micropapillary in 15%. The predominant nuclear grade was Grade I in 51%, Grade II in 49%, and Grade III in 0%. The median follow-up is 68 months. There have been three recurrences in the treated breast at a median time to failure of 30 months. The 5- and 8-year actuarial local recurrence rate is 6%. One patient recurred with invasive ductal cancer at 28 months, and the other two recurrences were DCIS at 30 and 50 months. All three patients were treated with salvage mastectomy. The patient who recurred locally with an invasive cancer developed metastasis and died at 64 months. The 5- and 8-year actuarial cause-specific survival rates are 100% and 97%, respectively. The following pathologic factors were analyzed for an association with local recurrence: predominant DCIS histology, predominant nuclear grade, and highest nuclear grade. Of these, the predominant nuclear grade was the best predictor of local recurrence (p = 0.070). No clinical or treatment related factor analyzed was associated with local recurrence. CONCLUSION: Our results indicate that excellent local control (94%) at 8 years is obtainable after CSRT in a mammographically detected population of patients with DCIS. The predominant nuclear grade was the only factor found that may be associated with local recurrence.

Ultrasound-guided high dose rate conformal brachytherapy boost in prostate cancer: treatment description and preliminary results of a phase I/II clinical trial.

PURPOSE: To improve results for locally advanced prostate cancer, a prospective clinical trial of concurrent external beam irradiation and fractionated iridium-192 (Ir-192) high dose rate (HDR) conformal boost brachytherapy was initiated. METHODS AND MATERIALS: Between November 1991 and February 1994, 99 implants were performed on 33 patients with prostatic adenocarcinoma at William Beaumont Hospital. Using AJCC staging criteria, 9 patients had T2b tumors, 17 patients had T2c tumors, and 7 patients had T3 disease. Patients were treated with (a) 45.6 Gy whole pelvis external irradiation and (b) three HDR fractions of 5.5 Gy each (18 patients) or 6 Gy each (15 patients) to the prostate. Transperineal needle implants using real-time ultrasound guidance with interactive on-line isodose distributions were performed on an outpatient basis during weeks 1, 2, and 3 of external irradiation. Acute toxicity was scored using the Radiation Therapy Oncology Group (RTOG) morbidity grading system. RESULTS: This technique of concurrent external pelvic irradiation and conformal HDR brachytherapy was well tolerated. No significant intraoperative or perioperative complications occurred. Three patients (9%) experienced Grade 3 acute toxicity (two dysuria and one diarrhea). All toxicities were otherwise Grades 1 or 2 and were primarily as expected from pelvic external irradiation. Persistent implant-related toxicities included Grades 1-2 perineal pain (12%) and hematospermia (15%). Median follow-up time was 13 months. Serum prostatic-specific antigen (PSA) levels normalized in 91% of patients (29 out of 32) within 1-14 months (median 2.8 months) after irradiation. PSA levels were progressively decreasing in the other three patients at last measurement. Prospectively planned prostatic rebiopsies done at 18 months in the first 10 patients were negative in 9 out of 10 (90%). CONCLUSIONS: Acute toxicity has been acceptable with this unique approach using conformal high dose rate Ir-192 boost brachytherapy with concurrent external irradiation. The initial tumor response as assessed by serial PSA measurement and rebiopsy is extremely encouraging. Dose escalation will proceed in accordance with the protocol guidelines. Further patient accrual and longer follow-up will allow comparison to other techniques.

Interim report of image-guided conformal high-dose-rate brachytherapy for patients with unfavorable prostate cancer: the William Beaumont phase II dose-escalating trial.

PURPOSE: We analyzed our institution's experience treating patients with unfavorable prostate cancer in a prospective Phase II dose-escalating trial of external beam radiation therapy (EBRT) integrated with conformal high-dose-rate (HDR) brachytherapy boosts. This interim report discusses treatment outcome and prognostic factors using this treatment approach. METHODS AND MATERIALS: From November 1991 through February 1998, 142 patients with unfavorable prostate cancer were prospectively treated in a dose-escalating trial with pelvic EBRT in combination with outpatient HDR brachytherapy at William Beaumont Hospital. Patients with any of the following characteristics were eligible: pretreatment prostate-specific antigen (PSA) >/= 10.0 ng/ml, Gleason score >/= 7, or clinical stage T2b or higher. All patients received pelvic EBRT to a median total dose of 46.0 Gy. Pelvic EBRT was integrated with ultrasound-guided transperineal conformal interstitial iridium-192 HDR implants. From 1991 to 1995, 58 patients underwent three conformal interstitial HDR implants during the first, second, and third weeks of pelvic EBRT. After October 1995, 84 patients received two interstitial implants during the first and third weeks of pelvic EBRT. The dose delivered via interstitial brachytherapy was escalated from 5.50 Gy to 6.50 Gy for each implant in those patients receiving three implants, and subsequently, from 8.25 Gy to 9.50 Gy per fraction in those patients receiving two implants. To improve implant quality and reduce operator dependency, an on-line, image-guided interactive dose optimization program was utilized during each HDR implant. No patient received hormonal therapy unless treatment failure was documented. The median follow-up was 2.1 years (range: 0.2-7.2 years). Biochemical failure was defined according to the American Society for Therapeutic Radiology and Oncology Consensus Panel definition. RESULTS: The pretreatment PSA level was >/= 10.0 ng/ml in 51% of patients. The biopsy Gleason score was >/= 7 in 58% of cases, and 75% of cases were clinical stage T2b or higher. Despite the high frequency of these poor prognostic factors, the actuarial biochemical control rate was 89% at 2 years and 63% at 5 years. On multivariate analysis, a higher pretreatment PSA level, higher Gleason score, higher PSA nadir level, and shorter time to nadir were associated with biochemical failure. In the entire population, 14 patients (10%) experienced clinical failure at a median interval of 1.7 years (range: 0.2-4.5 years) after completing RT. The 5-year actuarial clinical failure rate was 22%. The 5-year actuarial rates of local failure and distant metastasis were 16% and 14%, respectively. For all patients, the 5-year disease-free survival, overall survival, and cause-specific survival rates were 89%, 95%, and 96%, respectively. The 5-year actuarial rate of RTOG Grade 3 late complications was 9% with no patient experiencing Grade 4 or 5 acute or late toxicity. CONCLUSION: Pelvic EBRT in combination with image-guided conformal HDR brachytherapy boosts appears to be an effective treatment for patients with unfavorable prostate cancer with minimal associated morbidity. Our dose-escalating trial will continue.

A multileaf collimator field prescription preparation system for conventional radiotherapy.

PURPOSE: The purpose of this work is to develop a prescription preparation system for efficient field shaping using a multileaf collimator that can be used in community settings as well as research institutions. The efficiency advantage of the computer-controlled multileaf collimator, over cerrobend blocks, to shape radiation fields has been shown in conformal treatments, which typically require complete volumetric computerized tomographic data for three-dimensional radiation treatment planning--a utility not readily available to the general community. As a result, most patients today are treated with conventional radiation therapy. Therefore, we believe that it is very important to fully use the same efficiency advantage of multileaf collimator as a block replacement in conventional practice. METHODS AND MATERIAL: The multileaf collimator prescription preparation systems developed by us acquires prescription images from different sources, including film scanner, and radiation treatment planning systems. The multileaf collimator angle and leaf positions are set from the desired field contour defined on the prescription image, by minimizing the area discrepancies. Interactive graphical tools include manual adjustment of collimator angle and leaf positions, and definition of portions of the field edges that require maximal conformation. Data files of the final leaf positions are transferred to the multileaf collimator controller via a dedicated communication link. RESULTS: We have implemented the field prescription preparation system and a network model for integrating the multileaf collimator and other radiotherapy modalities for routine treatments. For routine plan evaluation, isodose contours measured with film in solid water phantom at prescription depth are overlaid on the prescription image. Preliminary study indicates that the efficiency advantage of the MLC over cerrobend blocks in conformal therapy also holds true for conventional treatments. CONCLUSION: Our model of computer-controlled prescription, evaluation, and treatment using multileaf collimators can be effectively implemented in both community settings and research institutions. The resultant increase in treatment efficiency and accuracy is now available for conventional radiotherapy.

Use of three-dimensional radiation therapy planning tools and intraoperative ultrasound to evaluate high dose rate prostate brachytherapy implants.

PURPOSE: We performed a pilot study to evaluate the quality of high dose rate (HDR) prostate implants using a new technique combining intraoperative real-time ultrasound images with a commercially available 3-dimensional radiation therapy planning (3D RTP) system. METHODS AND MATERIALS: Twenty HDR prostate implants performed by four different physicians on a phase I/II protocol were evaluated retrospectively. Radiation therapy (RT) consisted of pelvic external beam RT (EBRT) to a dose of 46 Gy in 2-Gy fractions over 5 weeks and 2 HDR implants (prescribed dose of 950 cGy per implant). Our in-house real-time geometric optimization technique was used in all patients. Each HDR treatment was delivered without moving the patient. Ultrasound image sets were acquired immediately after needle placement and just prior to HDR treatment. The ultrasound image sets, needle and source positions and dwell times were imported into a commercial computerized tomography (CT) based 3D RTP system. Prostate contours were outlined manually caudad to cephalad. Dose-volume histograms (DVHs) of the prostate were evaluated for each implant. RESULTS: Four patients with stage T2a carcinoma, 4 with stage T2b, and 3 with stage T1c were studied. The median number of needles used per implant was 16 (range 14-18). The median treated volume of the implant (volume of tissue covered by the 100% isodose surface) was 82.6 cc (range 52.6-96.3 cc). The median target volume based on the contours entered in the 3D RTP system was 44.83 cc (range 28.5-67.45 cc). The calculated minimum dose to the target volume was 70% of the prescribed dose (range 45-97%). On average 92% of the target volume received the prescribed dose (range 75-99 %). The mean homogeneity index (fraction of the target volume receiving between 1.0 to 1.5 times the prescribed dose) was 80% or 0.8 (range 0.55-0.9). These results compare favorably to recent studies of permanent implants which report a minimum target volume dose of 43% (range 29-50%) and an average of 85% of the target volume (range 76-92%) receiving the prescribed dose. CONCLUSIONS: The feasibility of evaluating HDR prostate implants using ultrasound images (acquired immediately prior to treatment) with a commercially available 3D RTP system was established. The dosimetric characteristics of these HDR implants appear to be substantially different compared to permanent implants. These developments allow quantitative evaluation of the dosimetric quality of HDR prostate treatments. Future studies will examine any correlation between the dosimetric quality of the implant and clinical/biochemical outcomes.

Iridium-192 transperineal interstitial brachytherapy for locally advanced or recurrent gynecological malignancies.

PURPOSE: To assess treatment outcome for patients with locally advanced or recurrent gynecological malignancies treated with continuous low-dose-rate (LDR) remote afterloading brachytherapy using the Martinez Universal Perineal Interstitial Template (MUPIT). MATERIALS AND METHODS: Between 7/85 and 6/94, 69 patients with either locally advanced or recurrent malignancies of the cervix, endometrium, vagina, or female urethra were treated by 5 different physicians using the MUPIT with (24 patients) or without (45 patients) interstitial hyperthermia. Fifty-four patients had no prior treatment with radiation and received a combination of external beam irradiation (EBRT) and an interstitial implant. The combined median dose was 71 Gy (range 56-99 Gy), median EBRT dose was 39 Gy (range 30-74 Gy), and the median implant dose was 32 Gy (range 17-40 Gy). Fifteen patients with prior radiation treatment received an implant alone. The total median dose including previous EBRT was 91 Gy (range 70-130 Gy) and the median implant dose was 35 Gy (range 25-55 Gy). RESULTS: With a median follow-up of 4.7 yr in survivors, the 3-yr actuarial local control (LC), disease-specific survival (DSS), and overall survival (OS) for all patients was 60%, 55%, and 41% respectively. The clinical complete response rate was 78% and in these patients the 3-year actuarial LC, DSS, and OS was 78%, 79%, and 63% respectively. On univariate analysis for local control, disease volume and hemoglobin were found to be statistically significant. On multivariate analysis, however, only disease volume remained significant (p = 0.011). There was no statistically significant difference in local control whether patients had received any prior treatment with radiation (p = 0.34), had recurrent disease (p = 0.13), or which physician performed the implant (p = 0.45). The grade 4 complication rate (small bowel obstruction requiring surgery, fistulas, soft tissue necrosis) for all patients was 14%. With a dose rate less than 70 cGy/hour, the grade 4 complication rate was 3% vs. 24% with dose rate > or = 70 cGy/hour (p = 0.013). CONCLUSION: Patients with locally advanced or recurrent gynecological malignancies treated with the remote afterloader LDR MUPIT applicator can expect reasonable rates of local control that are not operator-dependent. Complication rates with this approach are acceptable and appear to be related to the dose rate.