Radiation-Induced Imaging Changes and Cerebral Edema following Stereotactic Radiosurgery for Brain AVMs.

BACKGROUND AND PURPOSE: T2 signal and FLAIR changes in patients undergoing stereotactic radiosurgery for brain AVMs may occur posttreatment and could result in adverse radiation effects. We aimed to evaluate outcomes in patients with these imaging changes, the frequency and degree of this response, and factors associated with it. MATERIALS AND METHODS: Through this retrospective cohort study, consecutive patients treated with stereotactic radiosurgery for brain AVMs who had at least 1 year of follow-up MR imaging were identified. Logistic regression analysis was used to evaluate predictors of outcomes. RESULTS: One-hundred-sixty AVMs were treated in 148 patients (mean, 35.6 years of age), including 42 (26.2%) pediatric AVMs. The mean MR imaging follow-up was 56.5 months. The median Spetzler-Martin grade was III. The mean maximal AVM diameter was 2.8 cm, and the mean AVM target volume was 7.4 mL. The median radiation dose was 16.5 Gy. New T2 signal and FLAIR hyperintensity were noted in 40% of AVMs. T2 FLAIR volumes at 3, 6, 12, 18, and 24 months were, respectively, 4.04, 55.47, 56.42, 48.06, and 29.38 mL Radiation-induced neurologic symptoms were encountered in 34.4%. In patients with radiation-induced imaging changes, 69.2% had new neurologic symptoms versus 9.5% of patients with no imaging changes (P = .0001). Imaging changes were significantly associated with new neurologic findings (P < .001). Larger AVM maximal diameter (P = .04) and the presence of multiple feeding arteries (P = .01) were associated with radiation-induced imaging changes. CONCLUSIONS: Radiation-induced imaging changes are common following linear particle accelerator-based stereotactic radiosurgery for brain AVMs, appear to peak at 12 months, and are significantly associated with new neurologic findings.

Immunohistochemical localization of parathyroid hormone-related protein in human breast cancer.

Parathyroid hormone-related protein (PTHrP) is known to be a causative factor in humoral hypercalcemia of malignancy. A polyclonal rabbit antiserum directed against the amino-terminal region of the protein and immunoperoxidase methods have been used to locate the presence of PTHrP in a series of 102 consecutive invasive breast tumors removed surgically from normocalcemic women. Positive PTHrP staining was detected in 60% of the tumors but not in the accompanying normal breast tissue. Positive staining was related to the progesterone receptor status of the tumor (P = 0.039) and to the prognostic index of the patient (P = 0.046) and not to estrogen receptor status, patient age, tumor size, histological grade, or nodal status.

Localization of parathyroid hormone-related protein in breast cancer metastases: increased incidence in bone compared with other sites.

Parathyroid hormone-related protein (PTHrP) has recently been identified in 60% of a series of primary breast cancers. The detection of a bone-resorbing factor in tumors with a propensity to metastasize to bone prompted study of PTHrP in breast cancer metastasis. PTHrP was localized by immunohistology in 12 of 13 (92%) breast cancer metastases in bone and in 3 of 18 (17%) metastases in non-bone sites. The statistical difference was highly significant (P less than 0.0001). Production of PTHrP as a bone-resorbing agent may contribute to the ability of breast cancers to grow as bone metastases.

Patient preferences concerning the trade-off between the risks and benefits of routine radiation therapy after conservative surgery for early-stage breast cancer.

PURPOSE: To assess patients' preferences regarding the trade-off between risks and benefits of radiation therapy after conservative surgery for early-stage breast cancer. PATIENTS AND METHODS: Utilities (measures of preference) of 97 early-stage breast cancer patients treated with conservative surgery and radiation therapy and 20 medical oncology nurses were assessed for five health states using standard gambles. RESULTS: Patients had the highest mean utility for treatment with conservative surgery and radiation therapy without a local recurrence (0.92), intermediate utilities for treatment with conservative surgery alone followed either by no local recurrence or by a local recurrence salvaged by conservative surgery and radiation therapy (0.88 and 0.87, respectively), and the lowest utilities for treatment with or without radiation therapy followed by a local recurrence salvaged by mastectomy and reconstructive surgery (0.82 and 0.81, respectively). All differences between health states' utilities were significant (P < .0001), except between the two intermediate and two lowest rated health states. None of the clinical or sociodemographic factors examined explained more than 5% of the variability in the patients' utilities or their differences. Nurses' utilities were similar to those of the patients. CONCLUSIONS: These results strongly suggest that fear of a local recurrence and an actual local recurrence leading to mastectomy have such a negative impact on quality of life that patients are willing to accept the risks and inconvenience of radiation therapy to avoid them. There is also considerable interpatient variability that was not explained by the clinical or sociodemographic factors examined.

Cost-effectiveness of routine radiation therapy following conservative surgery for early-stage breast cancer.

PURPOSE: To examine the cost-effectiveness of radiation therapy following conservative surgery for early-stage breast cancer. METHODS: Using a Markov model, a cost-utility analysis was performed to compare a strategy of radiation therapy versus no radiation therapy in a hypothetical cohort of 60-year-old women following conservative surgery. Local recurrence, distant recurrence, and survival rates used in the model were derived from randomized trial data. Utilities for the nonmetastatic health states were collected from actual patients. Direct medical costs were estimated using data from a single institution. Transportation and time costs were also estimated. Years of life, quality-adjusted life-years (QALYs), costs, and incremental cost/QALY over a 10-year time horizon were calculated by the model for each strategy. RESULTS: The addition of radiation therapy results in a cost increase of $9,800 per patient, no change in life expectancy, and an increase of 0.35 QALYs per patient, which leads to an incremental cost-effectiveness ratio of $28,000/QALY, which is well below $50,000/QALY, a commonly cited threshold for cost-effective care. Sensitivity analysis shows the ratio to be heavily influenced by the cost of radiation therapy and the quality-of-life benefit that results from decreased risk of local recurrence. CONCLUSION: Radiation therapy following conservative surgery is cost-effective compared with other accepted medical interventions. This study illustrates the importance of considering an intervention's effect on quality of life, as well as survival in defining cost-effectiveness.

Cost-effectiveness of adding an electron-beam boost to tangential radiation therapy in patients with negative margins after conservative surgery for early-stage breast cancer.

PURPOSE: Electron-beam boosts (EBB) are routinely added after conservative surgery and tangential radiation therapy (TRT) for early-stage breast cancer. We performed an incremental cost-utility analysis to evaluate their cost-effectiveness. METHODS: A Markov model examined the impact of adding an EBB to TRT from a societal perspective. Outcomes were measured in quality-adjusted life years (QALYs). On the basis of the Lyon trial, the EBB was assumed to reduce local recurrences by approximately 2% at 10 years but to have no impact on survival. Patients' utilities were used to adjust for quality of life. Given the small absolute benefit of the EBB, baseline utilities were assumed to be the same with or without it, an assumption evaluated by Monte Carlo simulation. Direct medical, time, and travel costs were considered. RESULTS: Adding the EBB led to an additional cost of $2,008, an increase of 0.0065 QALYs and, therefore, an incremental cost-effectiveness ratio of over $300,000/QALY. In a sensitivity analysis, the ratio was moderately sensitive to the efficacy and cost of the EBB and highly sensitive to patients' utilities for treatment without it. Even if patients do value a small risk reduction, the mean cost-effectiveness ratio estimated by the Monte Carlo simulation remains high, at $70,859/QALY (95% confidence interval, $53,141 to $105,182/QALY). CONCLUSION: On the basis of currently available data, the cost-effectiveness ratio for the EBB is well above the commonly cited threshold for cost-effective care ($50,000/QALY). The EBB becomes cost-effective only if patients place an unexpectedly high value on the small absolute reduction in local recurrences achievable with it.

Estimating the cost of informal caregiving for elderly patients with cancer.

PURPOSE: As the United States population ages, the increasing prevalence of cancer is likely to result in higher direct medical and nonmedical costs. Although estimates of the associated direct medical costs exist, very little information is available regarding the prevalence, time, and cost associated with informal caregiving for elderly cancer patients. MATERIALS AND METHODS: To estimate these costs, we used data from the first wave (1993) of the Asset and Health Dynamics (AHEAD) Study, a nationally representative longitudinal survey of people aged 70 or older. Using a multivariable, two-part regression model to control for differences in health and functional status, social support, and sociodemographics, we estimated the probability of receiving informal care, the average weekly number of caregiving hours, and the average annual caregiving cost per case (assuming an average hourly wage of $8.17) for subjects who reported no history of cancer (NC), having a diagnosis of cancer but not receiving treatment for their cancer in the last year (CNT), and having a diagnosis of cancer and receiving treatment in the last year (CT). RESULTS: Of the 7,443 subjects surveyed, 6,422 (86%) reported NC, 718 (10%) reported CNT, and 303 (4%) reported CT. Whereas the adjusted probability of informal caregiving for those respondents reporting NC and CNT was 26%, it was 34% for those reporting CT (P <.05). Those subjects reporting CT received an average of 10.0 hours of informal caregiving per week, as compared with 6.9 and 6.8 hours for those who reported NC and CNT, respectively (P <.05). Accordingly, cancer treatment was associated with an incremental increase of 3.1 hours per week, which translates into an additional average yearly cost of $1,200 per patient and just over $1 billion nationally. CONCLUSION: Informal caregiving costs are substantial and should be considered when estimating the cost of cancer treatment in the elderly.

Dose escalation in non-small-cell lung cancer using three-dimensional conformal radiation therapy: update of a phase I trial.

PURPOSE: High-dose radiation may improve outcomes in non-small-cell lung cancer (NSCLC). By using three-dimensional conformal radiation therapy and limiting the target volume, we hypothesized that the dose could be safely escalated. MATERIALS AND METHODS: A standard phase I design was used. Five bins were created based on the volume of normal lung irradiated, and dose levels within bins were chosen based on the estimated risk of radiation pneumonitis. Starting doses ranged from 63 to 84 Gy given in 2.1-Gy fractions. Target volumes included the primary tumor and any nodes >or= 1 cm on computed tomography. Clinically uninvolved nodal regions were not included purposely. More recently, selected patients received neoadjuvant cisplatin and vinorelbine. RESULTS: At the time of this writing, 104 patients had been enrolled. Twenty-four had stage I, four had stage II, 43 had stage IIIA, 26 had stage IIIB, and seven had locally recurrent disease. Twenty-five received chemotherapy, and 63 were assessable for escalation. All bins were escalated at least twice. Although grade 2 radiation pneumonitis occurred in five patients, grade 3 radiation pneumonitis occurred in only two. The maximum-tolerated dose was only established for the largest bin, at 65.1 Gy. Dose levels for the four remaining bins were 102.9, 102.9, 84 and 75.6 Gy. The majority of patients failed distantly, though a significant proportion also failed in the target volume. There were no isolated failures in clinically uninvolved nodal regions. CONCLUSION: Dose escalation in NSCLC has been accomplished safely in most patients using three-dimensional conformal radiation therapy, limiting target volumes, and segregating patients by the volume of normal lung irradiated.

Immunohistochemical detection of parathyroid hormone-related protein in human fetal epithelia.

PTH-related protein (PTHrP) is commonly produced by squamous cell carcinomata and is the mediator of the PTH-like features of humoral hypercalcemia of malignancy. It has also been implicated in calcium regulation during fetal development. In this study immunohistochemical techniques, using rabbit polyclonal antibodies to synthetic PTHrP peptides, have been used to localize PTHrP in human fetal tissues from one fetus of 7 weeks and two of approximately 18 and 20 weeks gestation, respectively, in order to identify sites of potential functional significance. PTHrP immunoreactivity was identified in epithelia from many sources, including skin, bronchus, pancreas, pharynx, gut, stomach, and renal pelvis. Thyroid and parathyroid glands, which develop from epithelial origins, also stained positive for PTHrP, as did kidney collecting tubules, adrenal tissue, and skeletal and smooth muscle. PTHrP immunoreactivity was also located in developing long bones and calvaria, where it may have relevance in bone turnover during fetal development. The role of PTHrP at these locations remains to be elucidated, but the identification of specific PTHrP immunoreactivity in fetal epithelia is consistent with PTHrP production by cancers of epithelial origin and supports the hypothesis that PTHrP may have a role in epithelial growth and differentiation.

Is the use of radiation therapy after mastectomy cost-effective?

With the publication of two randomized trials showing an improvement in overall survival after the use of postmastectomy radiation therapy, interest in the use of radiation therapy in this setting has been rekindled. These results are in contrast to those reported in the most recent meta-analysis of the Early Breast Cancer Trialists' Collaborative Group, in which a statistically significant survival benefit was not detected. Although evidence of a survival benefit was sufficient in the past for an intervention to gain acceptance, payers are increasingly interested in knowing whether its use is also cost-effective. This article briefly reviews the methods used in performing cost-effectiveness analyses, summarizes the results of one published and a second preliminary cost-effectiveness analysis of postmastectomy radiation therapy, and highlights several areas for future research.

Do dose-volume metrics predict pulmonary function changes in lung irradiation?

PURPOSE: To examine the ability of standard dose-volume metrics to predict pulmonary function changes as measured by pulmonary function tests (PFTs) in a group of patients with non-small-cell lung cancer treated with nonconventional beam arrangements on a Phase I dose-escalation study. In addition, we wanted to examine the correlation between these metrics. MATERIALS AND METHODS: Forty-three patients received a median treatment dose of 76.9 Gy (range 63-102.9). Eight patients also received induction chemotherapy with cisplatin and vinorelbine. They all had pre- and posttreatment PFTs >/=3 months (median 6.2) after treatment. The volume of normal lung treated to >20 Gy, effective volume, and mean lung dose were calculated for both lungs for all patients. Linear regression analysis was performed to determine whether correlations existed between the metrics and changes in the PFTs. Additionally, the three metrics were compared with each other to assess the degree of intermetric correlation. RESULTS: No correlation was found between the volume of normal lung treated to >20 Gy, effective volume, and mean lung dose and changes in the PFTs. Subgroup analyses of patients without atelectasis before irradiation, Stage I and II disease, or treatment without induction chemotherapy were also performed. Again, no correlation was found between the dose-volume metrics and the PFT changes. The intermetric correlation was good among all three dose-volume metrics. CONCLUSIONS: In this relatively small series of patients, dose-volume metrics that correlate with the risk of pneumonitis did not provide a good model to predict early changes in pulmonary function as measured with PFTs.

A comparison of two methods for estimating the technical costs of external beam radiation therapy.

PURPOSE: To accurately assess the cost-effectiveness of treatment with external beam radiation, it is necessary to have accurate estimates of its cost. One of the most common methods for estimating technical costs has been to convert Medicare charges into costs using Medicare Cost-to-Charge Ratios (CCR). More recently, health care organizations have begun to invest in sophisticated cost-accounting systems (CAS) that are capable of providing procedure-specific cost estimates. The purpose of this study was to examine whether these competing approaches result in similar cost estimates for four typical courses of external beam radiation therapy (EBRT). METHODS AND MATERIALS: Technical costs were estimated for the following treatment courses: 1) a palliative "simple" course of 10 fractions using a single field without blocks; 2) a palliative "complex" course of 10 fractions using two opposed fields with custom blocks; 3) a curative course of 30 fractions for breast cancer using tangent fields followed by an electron beam boost; and 4) a curative course of 35 fractions for prostate cancer using CT-planning and a 4-field technique. Costs were estimated using the CCR approach by multiplying the number of units of each procedure billed by its Medicare charge and CCR and then summing these costs. Procedure-specific cost estimates were obtained from a cost-accounting system, and overall costs were then estimated for the CAS approach by multiplying the number of units billed by the appropriate unit cost estimate and then summing these costs. All costs were estimated using data from 1997. The analysis was also repeated using data from another academic institution to estimate their costs using the CCR and CAS methods, as well as the appropriate relative value units (RVUs) and conversion factor from the 1997 Medicare Fee Schedule to estimate Medicare reimbursement for the four treatment courses. RESULTS: The estimated technical costs for the CCR vs. CAS approaches for the four treatment courses were as follows: palliative "simple" $1,285 vs. $1,195; palliative "complex" $2,345 vs. $1,769; curative breast $6,757 vs. $4,850; and curative prostate $9,453 vs. $7,498. Accordingly, the CCR estimates were 8%, 33%, 39%, and 26% higher than the CAS cost estimates, respectively. The primary cause of the difference between the estimates was the daily cost of delivering a "complex" treatment. In fact, if corrected the difference between the estimates fell to 0%, 1%, 4%, and 0%, respectively. Similar results were observed for both methods when the analysis was repeated using data from another academic institution. Medicare reimbursement was also slightly lower than, but remarkably close to, the costs estimated by the CAS approach. CONCLUSIONS: For "complex" treatment courses, which represent the vast majority of external beam treatments, technical costs estimated using the CCR approach appear to be significantly higher than those estimated using procedure-specific cost estimates. Because cost-effectiveness analyses of radiation therapy tend to be sensitive to the cost of treatment, the use of higher costs will result in radiation therapy appearing less cost-effective.

Overall survival after prostate-specific-antigen-detected recurrence following conformal radiation therapy.

PURPOSE: To study the significance, in terms of overall and cause-specific survival, of biochemical failure after conformal external-beam radiation therapy (RT) for prostate cancer. METHODS AND MATERIALS: Of the 1844 patients in the Radiation Oncology prostate cancer database, 718 were deemed eligible. Patients excluded were those with N1 or M1 disease, those treated after radical prostatectomy, those who received hormone therapy before radiation therapy, and those who died, failed clinically, or had no PSA response in the first 6 months after RT. Patients included were required to have a minimum of 2 post-RT PSAs separated by at least 1 week. Biochemical relapse was defined as 3 consecutive PSA rises. This resulted in 154 patients with biochemical failure. Survival was calculated from the third PSA elevation. The rate of rise of PSA was calculated by fitting a regression line to the four rising PSAs on a ln PSA vs. time plot. RESULTS: There were 41 deaths among the 154 patients with failure in 23 of the 41 due to prostate cancer. The overall survival after failure was 58% at 5 years, while the cause-specific failure was 73% at 5 years. Among the 154 failures, several factors were evaluated for an association with overall survival: age at failure, pre-RT PSA, PSA at second rise, PSA nadir, time from RT to failure, time to nadir, Gleason score, T-stage, and rate of rise, both from the nadir and from the beginning of the rise. None of these factors were significantly associated with an increased risk of death. As expected, the group of patients with biochemical failure have significantly worse prognostic factors than those without biochemical failure: median pre-RT PSA 15.9 vs. 9.0 (p < 0.001), and Gleason score of 7 or greater for 48% of subjects vs. 40% (p = 0.1). Relative PSA rise and slope of ln PSA vs. time were associated with cause-specific mortality (p < 0.001 and p = 0.007, respectively). CONCLUSION: Overall survival after conformal radiotherapy for prostate cancer remains high 5 years after biochemical failure. This high survival rate occurs even though the group of patients with biochemical failure has worse than average adverse preradiation prognostic factors. Thus, although biochemical failure can identify patients who have recurrent disease after RT, the ultimate relationship between this endpoint and death remains to be better defined.

Stereotactic radiosurgery of cerebral arteriovenous malformations with a multileaf collimator and a single isocenter.

OBJECTIVE: To prospectively demonstrate the safety and efficacy of stereotactic radiosurgery for arteriovenous malformations (AVMs) of the brain with a linear accelerator fitted with a multileaf collimator. METHODS: A novel radiosurgery system was developed at the University of Michigan Medical Center with a standard multileaf collimator and a computer-controlled radiotherapy system. Data were accumulated prospectively on all patients undergoing treatment with this system since treatment began in 1995. RESULTS: Thirty-six patients with 37 AVMs have undergone treatment to date. At more than 3 years since treatment, 15 of 16 AVMs with a volume of less than 10 cc were proven to be obliterated by angiography or magnetic resonance imaging, and one was considered a treatment failure. At more than 24 months since therapy, all four AVMs with a volume of 10 to 25 cc were obliterated. Four patients with AVMs with a volume of more than 25 cc have undergone staged therapy, treating the entire volume to 10 Gy twice, but none has been followed long enough to demonstrate a final outcome. There were four transient and no permanent complications. CONCLUSION: Our early data indicate that stereotactic radiosurgery of cerebral AVMs with a linear accelerator and a multileaf collimator is safe and effective. Large AVMs may be especially suitable for this mode of therapy. Staged treatment of very large AVMs seems to be a promising addition to standard treatment, but longer follow-up is necessary to confirm that complete obliteration can be achieved.

Parathyroid hormone related protein in breast cancers of widely varying prognosis.

Parathyroid hormone related protein (PTHrP) is a novel calcium regulating hormone that may have a significant role in the pathophysiology of breast cancer. We have previously demonstrated a relationship between immunohistochemically detectable PTHrP in primary breast tumours and the subsequent development of bone metastases and hypercalcaemia. The aim of this study was to compare the PTHrP status in the primary tumours from three groups of patients with widely varying prognosis. (1) The favourable outcome group; all patients had a favourable prognosis and minimum 3 years disease free follow up (n = 30). (2) The unfavourable outcome group; all patients presented with localized breast cancer but developed distant disease within 3 years (n = 26). (3) The unfavourable presentation group; all had distant disease at first presentation (n = 26). No differences in PTHrP status of the primary tumour amongst the three patient groups were found (66%, 65% and 61% positive respectively). The development of bone with liver metastases and hypercalcaemia was associated with increased positive PTHrP status of the primary tumor.

Ovarian mucinous tumour with a focus of anaplastic carcinoma: a case report.

A 50-yr-old patient presented with abdominal symptoms due to the presence of cystic ovarian tumours. After hysterectomy and bilateral salpingo-oophorectomy, the diagnosis of a mucinous tumour with a focus of anaplastic carcinoma in one ovary and a dermoid cyst in the other was made. Further treatment was refused and the patient died 12 mth after operation with disseminated anaplastic carcinoma. The case is the first reported when adjuvant therapy has not been given and illustrates the poor natural history of this disease.

Fatal dissecting aneurysm of the aorta in a diver.

A 20-yr-old trained sports diver developed severe chest pain shortly after decompressing from a 40 m repetitive freshwater sinkhole dive, and died 6 h later. An autopsy examination showed a dissecting aneurysm of the aorta with rupture into the left pleural cavity. The relationship between the fatal event and the diving is discussed.

Malignant pulmonary lymphoid disease: case reports illustrating anatomical pattern of disease as a prognostic marker.

Although a well documented phenomenon in Hodgkin's disease, malignant pulmonary lymphoid disease in other lymphoproliferative diseases, such as non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL), is less frequently described. We present 3 patients, 2 with NHL and one with CLL, all demonstrating pulmonary malignant lymphoid involvement. We briefly review the probable mechanism underlying the development of this disease process and identify anatomical distribution of malignant pulmonary lymphoid disease as a prognostic marker in this condition.

Pseudoepitheliomatous hyperplasia in Mycobacterium ulcerans infection.

Pseudoepitheliomatous hyperplasia of the epidermis occurring with Mycobacterium ulcerans skin infection may result in localization of the infected area with discharge of necrotic material, followed by healing leaving a depressed scar. The process represents more than simple re-epithelization of an ulcerated skin surface; it is a mechanism which produces active extrusion of necrotic material containing viable mycobacteria and should be seen as part of a protective physiological response to the infection.

Ectopic pituitary with pregnancy changes in a benign cystic teratoma of the ovary.

We report on the rare finding of pituitary tissue, including both adenohypophysis and neurohypophsis, in a mature cystic teratoma of the ovary removed from a 26 year old female at the time of cesarean section. Immunocytochemistry of the ectopic anterior pituitary component showed pregnancy-related changes that have previously only been described in pituitaries obtained at autopsy.