Zelig Tochner

Surgery with or without radiation therapy in the management of craniopharyngiomas in children and young adults

PURPOSE The optimal management of craniopharyngiomas remains controversial, especially in children and young adults. This study reports a single institutions experience with such patients. METHODS AND MATERIALS Between 1974 and 2001, 76 patients were treated for craniopharyngioma at the Childrens Hospital of Philadelphia and the Hospital of University of Pennsylvania (HUP). Of these, 75 patients (97%) were evaluable with long-term follow-up. Although all patients underwent attempted gross total resection, 27 had documentation of less than total resection with 18 of these patients receiving immediate postoperative radiotherapy (RT). An additional 22 patients received RT at HUP after failing surgery alone. RESULTS Median follow-up for all patients was 7.6 years. The 10-year actuarial overall survival, relapse-free survival, and local control (LC) rates for all patients were 85%, 48%, and 53%, respectively. When comparing the 57 patients treated with surgery alone to the 18 treated with subtotal resection (STR) followed by RT, a significant difference in LC rates at 10 years (42% vs. 84%, respectively; p = 0.004) was noted. However, no statistically significant difference in overall survival was found between the two groups, because RT was highly effective as salvage therapy. Twenty-two patients at HUP treated with RT after relapse had a 10-year ultimate LC rate comparable to that of patients who received RT immediately after STR. CONCLUSION RT given either immediately after STR or at relapse is effective in controlling craniopharyngiomas.

Late cognitive and radiographic changes related to radiotherapy Initial prospective findings

BackgroundAssumptions about the damaging effects of radiotherapy (XRT) are based on studies in which total dose, dose fraction, treatment volume, degree of malignancy, chemotherapy, tumor recurrence, and neurologic comorbidity interact with XRT effects. This is a prospective, long-term study of XRT effects in adults, in which total dose and dose fraction were constrained and data related to tumor recurrence and neurologic comorbidity (e.g., hypertension) were excluded. MethodsThe effects of XRT on the cognitive and radiographic outcomes of 26 patients with low-grade, supratentorial, brain tumors yearly from baseline (6 weeks after surgery and immediately before XRT) and yearly to 6 years were examined. Radiographic findings were examined regionally. ResultsSelective cognitive declines (in visual memory) emerged only at 5 years, whereas ratings of clinical MRI (T2 images) showed mild accumulation of hyperintensities with post-treatment onset from 6 months to 3 years, with no further progression. White matter atrophy and total hyperintensities demonstrated this effect, with subcortical and deep white matter, corpus callosum, cerebellar structures, and pons accounting for these changes over time. About half of the patients demonstrated cognitive decline and treatment-related hyperintensities. ConclusionsThere was no evidence of a general cognitive decline or progression of white matter changes after 3 years. Results argue for limited damage from XRT at this frequently used dose and volume in the absence of other clinical risk factors.

Phase I study of debulking surgery and photodynamic therapy for disseminated intraperitoneal tumors

PURPOSE Phase I study designed to determine the maximum tolerated dose of intraoperative photodynamic therapy (PDT) at laparotomy/debulking surgery in patients with refractory or recurrent, disseminated intraperitoneal tumors. METHODS AND MATERIALS Patients received dihematoporphyrin ethers (DHE) 1.5-2.5 mg/kg by i.v. injection prior to surgery. Patients resected to < or = 5 mm of residual disease underwent laser light delivery to all peritoneal surfaces. RESULTS Fifty-four patients entered the study. Thirty-nine underwent resection and light delivery/PDT. PDT dose was escalated by increasing DHE from 1.5 to 2.5 mg/kg, shortening the interval between DHE injection and surgery from 72 to 48 hr, and increasing the light dose. Initially, 630 nm red light alone was used. In this group, PDT of 2.8-3.0 J/cm2 induced small bowel edema and resulted in 3 small bowel perforations after bowel resection or enterotomy. Further light dose escalation, however, was achieved by switching to less penetrating 514 nm green light to the bowel/mesentery. In later patients, whole peritoneal PDT was supplemented with boost doses of 10-15 J/cm2 red light or 5-7.5 J/cm2 green light to high risk areas. Small bowel complications were not seen after switching to less penetrating green light. Dose limiting toxicities occurred in 2 of 3 patients at the highest light dose of 5.0 J/cm2 green light with boost. These patients had pleural effusions that required thoracentesis and postoperative respiratory support for 7-9 days, while one had a gastric perforation. At potential follow-up times of 3.8-43.1 months (median 22.1 months), 30/39 patients are alive and 9/39 are free of disease. CONCLUSION The maximum tolerated dose of intraoperative PDT following debulking surgery performed 48 hr after intravenous administration 2.5 mg/kg DHE is 3.75 J/cm2 of 514 nm green light to the entire peritoneal surface with boosts to 5.0-7.5 J/cm2 of 514 nm green light or 10-15 J/cm2 of 630 nm red light to sites of gross disease encountered at surgery.

Short-Term and Long-Term Health Risks of Nuclear-Power-Plant Accidents

Recent natural disasters in Japan led to a partial meltdown at the Fukushima nuclear power plant. This article reviews the history of such accidents, along with the short-term and long-term health risks associated with environmental exposure to nuclear fission products.

A Critical Review of the Clinical Effects of Therapeutic Irradiation Damage to the Brain: The Roots of Controversy

We critically examined the damaging affects of therapeutic irradiation by comparing results from cross-disciplinary studies of early- and late-delayed radiotherapy effects. Focus is attained by concentrating on clinical treatment issues (volume of brain, dose, timing of effects, age, modality types, and stereotactic treatment techniques), rather than on methodological means or problems, which is necessary to understand the mechanisms and characteristics of radiotherapy-induced behavioral dysfunction including cognition. We make observations and hypotheses about the actual risks from radiotherapy that could be informative in the treatment decision process, and which may lessen the concerns of some patients and their families about the risks they take when receiving radiation. Conditions that predispose to radiation injury are reviewed: (1) higher doses even to part of the brain versus lower doses to the whole brain, (2) combined treatment modalities, (3) malignancy itself, (4) radiation early during postnatal brain development, and (5) late-delayed effects (more than 3 years posttreatment). Current neurocognitive frameworks for understanding cognitive change over time in children and adults are summarized, along with the literature on effects of brain tumors and treatment on depression. No studies have as yet identified candidate brain regions that are more sensitive to radiotherapy. Two studies have provided early, preliminary evidence for a specific vulnerability of visual attention/memory to the early stage of late radiation damage. Furthermore, radiation effects appear severe only in a minority of patients. Risk is related to direct and indirect effects of cancer type, concurrent clinical factors, and premorbid risk factors.

Intrapleural Photodynamic Therapy: Results of a Phase I Trial

AbstractBackground: The management of pleural neoplasms, specifically mesothelioma, remains difficult. We performed a phase I trial in 54 patients with isolated hemithorax pleural malignancy to determine (a) the feasibility of intraoperative, intrapleural photodynamic therapy after debulking surgery; (b) the influence of light dose/sensitizer interval on postoperative morbidity in order to define the photodynamic therapy (PDT) maximal tolerated dose (MTD); and (c) whether first order dosimetry could be applied to this complex geometry. Methods: Cohorts of three patients were given escalating intraoperative light doses of 15–35 J/cm2 48 h after i.v. delivery of 2.0 mg/kg Photofrin II (Quadra Logic Technologies, Vancouver, British Columbia, Canada), and then escalating light doses of 30–32.5 J/cm2 after a 24-h sensitizer/operation interval. Twelve patients could not be debulked to the prerequisite 5 mm residual tumor thickness. The remaining 42 patients underwent 19 modified pleuropneumonectomies, five lobectomy-pleurectomies, and 18 pleurectomies. Intrapleural PDT was delivered using 630 nm light from two argon pump-dye lasers, and real-time and cumulative light doses were monitored using seven uniquely designed, computer-interfaced photodiodes. Results: There was one 30-day mortality from intraoperative hemorrhage. In the 48-h sensitizer/operation group (n=33), possible PDT-related complications included an empyema with late hemorrhage in one of three patients at 17.5 J/cm2 and a bronchopleural fistula at 35 J/cm2. At each of these light doses, three additional patients were treated without complication. Two patients subjected to 24-h sensitizer dosing and 32.5 J/cm2 developed esophageal perforations after pleuropneumonectomy at identical sites. The MTD was declared as 30 J/cm2 light with a 24-h dosing interval when none of the six patients (three original, three repeat) at that level developed toxicity. Conclusions: These data demonstrate that resection and intrapleural PDT can be performed safely with currently available sensitizers and lasers. Phase II and III trials are now warranted at this MTD in a homogeneous population of patients with pleural malignancies.

Optical Properties of Human Prostate at 732 nm Measured In Vivo During Motexafin Lutetium–mediated Photodynamic Therapy¶

Abstract Characterization of the tissue light penetration in prostate photodynamic therapy (PDT) is important to plan the arrangement and weighting of light sources so that sufficient light fluence is delivered to the treatment volume. The optical properties (absorption [μa], transport scattering [μs′] and effective attenuation [μeff] coefficients) of 13 patients with locally recurrent prostate cancer were measured in situ using interstitial isotropic detectors. Measurements were made at 732 nm before and after motexafin lutetium (MLu)–mediated PDT in four quadrants. Optical properties were derived by applying the diffusion theory to the fluence rates measured at several distances (0.5–5 cm) from a point source. μa and μs′ varied between 0.07 and 1.62 cm−1 (mean 0.37 ± 0.24 cm−1) and 1.1 and 44 cm−1 (mean 14 ± 11 cm−1), respectively. μa was proportional to the concentration of MLu measured by an ex vivo fluorescence assay. We have observed, on average, a reduction of the MLu concentration after PDT, presumably due to the PDT consumption of MLu. μeff varied between 0.91 and 6.7 cm−1 (mean 2.9 ± 0.7 cm−1), corresponding to an optical penetration depth (δ = 1/μeff) of 0.1–1.1 cm (mean 0.4 ± 0.1 cm). The mean penetration depth at 732 nm in human prostate is at least two times smaller than that found in normal canine prostates, which can be explained by a four times increase of the mean value of μs′ in human prostates. The mean light fluence rate per unit source strength at 0.5 cm from a point source was 1.5 ± 1.1 cm−2, excluding situations when bleeding occurs. The total number of measurements was N = 121 for all mean quantities listed above. This study showed significant inter- and intraprostatic differences in the optical properties, suggesting that a real-time dosimetry measurement and feedback system for monitoring light fluences during treatment should be considered for future PDT studies.

THE ROLES OF INTRACELLULAR GLUTATHIONE IN ANTINEOPLASTIC CHEMOTHERAPY

Glutathione is a sulfhydryl containing tripeptide that participates in detoxification of xenobiotic compounds, including the alkylating agents melphalan, cyclophosphamide, and BCNU. The role of glutathione in the detoxification of these compounds, both in terms of initial tumor response, and drug-induced resistance to these alkylating agents is examined. Since glutathione disulfide and glutathione are a pivotal redox pair, the modulation of intracellular glutathione levels is shown to change the cytotoxicity of drugs dependent on the redox cycle, such as adriamycin and bleomycin, as well as the oxygen dependent drug neocarzinostatin. Areas of further research are discussed.

Childhood intracranial ependymoma : Twenty-year experience from a single institution

Because few large studies of pediatric ependymoma treatment are available, the authors believed that a retrospective review of treatment outcomes from a single institution would yield potentially valuable information regarding potential prognostic factors. In this article, they report their 20‐year institutional experience with this disease.

Real-time study of prostate intrafraction motion during external beam radiotherapy with daily endorectal balloon.

PURPOSE To prospectively investigate intrafraction prostate motion during radiofrequency-guided prostate radiotherapy with implanted electromagnetic transponders when daily endorectal balloon (ERB) is used. METHODS AND MATERIALS Intrafraction prostate motion from 24 patients in 787 treatment sessions was evaluated based on three-dimensional (3D), lateral, cranial-caudal (CC), and anterior-posterior (AP) displacements. The mean percentage of time with 3D, lateral, CC, and AP prostate displacements>2, 3, 4, 5, 6, 7, 8, 9, and 10 mm in 1 minute intervals was calculated for up to 6 minutes of treatment time. Correlation between the mean percentage time with 3D prostate displacement>3 mm vs. treatment week was investigated. RESULTS The percentage of time with 3D prostate movement>2, 3, and 4 mm increased with elapsed treatment time (p<0.05). Prostate movement>5 mm was independent of elapsed treatment time (p=0.11). The overall mean time with prostate excursions>3 mm was 5%. Directional analysis showed negligible lateral prostate motion; AP and CC motion were comparable. The fraction of time with 3D prostate movement>3 mm did not depend on treatment week of (p>0.05) over a 4-minute mean treatment time. CONCLUSIONS Daily endorectal balloon consistently stabilizes the prostate, preventing clinically significant displacement (>5 mm). A 3-mm internal margin may sufficiently account for 95% of intrafraction prostate movement for up to 6 minutes of treatment time. Directional analysis suggests that the lateral internal margin could be further reduced to 2 mm.