Joseph Herman

Gamma knife stereotactic radiosurgery for patients with glioblastoma multiforme

OBJECTIVE Stereotactic radiosurgery (SRS) has become an effective therapeutic modality for the treatment of patients with glioblastoma multiforme (GBM). This retrospective review evaluates the impact of SRS delivered on a gamma knife (GK) unit as an adjuvant therapy in the management of patients with GBM. METHODS Between August 1993 and December 1998, 82 patients with pathologically confirmed GBM received external beam radiotherapy (EBRT) at the University of Maryland Medical Center. Of these 82 patients, 64 with a minimum follow-up duration of at least 1 month are the focus of this analysis. Of the 64 assessable patients, 33 patients were treated with EBRT alone (Group 1), and 31 patients received both EBRT plus a GK-SRS boost (Group 2). GK-SRS was administered to most patients within 6 weeks of the completion of EBRT. The median EBRT dose was 59.7 Gy (range, 28–70.2 Gy), and the median GK-SRS dose to the prescription volume was 17.1 Gy (range, 10–28 Gy). The median age of the study population was 50.4 years, and the median pretreatment Karnofsky performance status was 80. Patient-, tumor-, and treatment-related variables were analyzed by Cox regression analysis, and survival curves were generated by the Kaplan-Meier product limit. RESULTS Median overall survival for the entire cohort was 16 months, and the actuarial survival rate at 1, 2, and 3 years were 67, 40, and 26%, respectively. When comparing age, Karnofsky performance status, extent of resection, and tumor volume, no statistical differences where discovered between Group 1 versus Group 2. When comparing the overall survival of Group 1 versus Group 2, the median survival was 13 months versus 25 months, respectively (P = 0.034). Age, Karnofsky performance status, and the addition of GK-SRS were all found to be significant predictors of overall survival via Cox regression analysis. No acute Grade 3 or Grade 4 toxicity was encountered. CONCLUSION The addition of a GK-SRS boost in conjunction with surgery and EBRT significantly improved the overall survival time in this retrospective series of patients with GBM. A prospective, randomized validation of the benefit of SRS awaits the results of the recently completed Radiation Therapy Oncology Group’s trial RTOG 93-05.

Radiosurgical treatment of trigeminal neuralgia: evaluating quality of life and treatment outcomes

PURPOSEnTo assess the safety, efficacy, and quality of life (QOL) associated with radiosurgical treatment for trigeminal neuralgia (TN).nnnMETHODS AND MATERIALSnBetween June 1996 and June 2001, 112 patients with TN refractory to medical or surgical management were treated with gamma knife radiosurgery (GKRS) at the University of Maryland Medical Center. A median prescription dose of 75 Gy (range: 70-80 Gy) was delivered to the involved trigeminal nerve root entry zone. Treatment outcomes were assessed through patient self-reports of pain control and medication usage during follow-up visits. In addition, patients responded to a standard questionnaire containing the Barrow Neurologic Institute Pain Scale (BNI) and selected sections of the McGill Pain Scale. Treatment outcomes and objective quality of life measures were also addressed.nnnRESULTSnNinety-six patients (86%) completed questionnaires for a median follow-up of 30 months (range: 8-66 months). Seventy-four patients (77%) reported pain relief occurring after a median of 3 weeks (range: 0-24 weeks) after GKRS. A decrease in medication usage was noted in 66% of patients. Actuarial analysis demonstrated 1-year, 2-year, and 3-year recurrence rates of 23%, 33%, and 39%, respectively. Response to treatment was associated with lack of prior surgical treatment (p = 0.03) and less than 50 months pain duration before GKRS (p = 0.04). Patients who described their TN pain as more severe than their worst non-TN headache pain (McGill Pain Scale IV-V vs. I-III) were also more likely to respond to treatment (p < 0.001). Seven (7.3%) patients reported new or increased trigeminal dysfunction; however, only 3.1% reported these symptoms as bothersome (BNI III-IV). Patients with sustained pain relief reported an average of 100% improvement in their QOL as a direct result of pain relief after GKRS, and 100% believed that the procedure was successful. Furthermore, among those patients with temporary pain relief and subsequent recurrence, 65% felt their treatment was a success with an average of 80% improvement in their QOL.nnnCONCLUSIONSnGKRS provides significant pain relief and improves QOL in the majority of patients treated for TN, with few bothersome side effects. Patients with both temporary and sustained responses to treatment realized significant improvements in QOL after GKRS, and considered their treatment successful. Longer follow-up of these patients may reveal additional recurrences highlighting the importance of studies evaluating repeat GKRS and optimization of current treatment techniques and patient selection.

Combined-Modality Therapy With Gemcitabine and Radiotherapy As a Bladder Preservation Strategy: Results of a Phase I Trial

PURPOSEnWe conducted a phase I trial of gemcitabine given twice weekly with concurrent radiotherapy in patients with muscle-invasive bladder cancer.nnnPATIENTS AND METHODSnEligible patients underwent maximal transurethral resection of their bladder tumors followed by twice-weekly infusion of gemcitabine with 2 Gy/d concurrent radiotherapy to the bladder, for a total of 60 Gy over 6 weeks. The starting dose of gemcitabine was 10 mg/m(2) with subsequent dose levels of 20, 27, 30, and 33 mg/m(2). The primary end point was the determination of the maximum-tolerated dose (MTD) of twice weekly gemcitabine with concurrent radiotherapy. Secondary end points included assessment of toxicity associated with combined-modality therapy and initial assessment of the rate of bladder preservation.nnnRESULTSnTwenty-four patients were enrolled and 23 were assessable for toxicity and response. No significant toxicity was demonstrated at the 10 or 20 mg/m(2) twice-weekly doses. Dose-limiting toxicity (DLT) occurred in two of three patients treated at 33 mg/m(2). Intermediate dose levels of 27 and 30 mg/m(2) were then evaluated. The MTD of gemcitabine was 27 mg/m(2). The DLT was systemic, manifested as an elevation in liver function tests, malaise, and edema. Fifteen of 23 patients (65%) are alive with bladders intact and no evidence of recurrent disease at a median follow-up of 43 months.nnnCONCLUSIONnTwice-weekly gemcitabine with concurrent radiotherapy at 2 Gy/d to a total dose of 60 Gy is well-tolerated. The MTD of gemcitabine is 27 mg/m(2). There is a high rate of bladder preservation in this selected group of patients.

Primary versus Radiation-Associated Craniofacial Osteosarcoma Biologic and Clinicopathologic Comparisons

Craniofacial osteosarcoma differs from long bone osteosarcoma in that patients are older, tumors are often low grade, and prognosis is more favorable. Although most are sporadic, some tumors occur in association with prior radiation therapy. The purpose of the current study was to compare clinicopathologic and prognostic features of primary and radiation‐associated osteosarcoma.

Specifics on the refinement and application of two serological assays for the detection of antibodies to HHV-8

BACKGROUNDnSerologic assays for the detection of antibodies to human herpesvirus type 8 (HHV-8) are important for epidemiological studies and to further investigate the proposed pathogenesis of the virus in cancer. Although a variety of assays are available, a lack of optimization and standardization makes their usefulness uncertain, and may be responsible for the controversy concerning the prevalence of infection.nnnOBJECTIVESnTo refine an indirect immunofluorescent assay (IFA) for the detection of latent antibodies and a recombinant ORF 65 ELISA for the detection of lytic antibodies in order to increase their ability to differentiate individuals at higher and lower risk for HHV-8 infection.nnnSTUDY DESIGNnSera from Kaposis sarcoma (KS) patients and blood donors (BDs) were used to modify assay parameters in an attempt to better discriminate between the two populations. Modifications included methods of substrate fixation, incubation times, sample dilution, and antigen/conjugate concentrations.nnnRESULTSnOptimal modifications to the latent IFA included acetone fixation of substrate, and dilution of sera to 1:64 which enhanced detection of HHV-8 antibodies from 68 to 92% in the KS population. Similarly, successful refinement of the ORF 65 ELISA to increase the signal-to-noise ratio included the use of 88 ng of ORF 65 antigen per well and serum dilutions of 1:50. Optical density-to-cut-off ratios directly correlated with titers, thereby introducing a strategy to predict antibody concentrations. The ORF 65 ELISA and the latent IFA were both able to discriminate between the two populations but with different efficiencies.nnnCONCLUSIONSnAlthough neither the latent IFA nor the ORF 65 ELISA produced perfect test indices, improvement in their performances was noted following the optimization strategies. The ELISA produced better detection of antibodies to the virus than the IFA and permitted prediction of sample titers, thus improving cost and time effectiveness.

Radiotherapy using a water bath in the treatment of Bowen's disease of the digit.

PURPOSEnBowens disease (BD), a form of squamous cell carcinoma in situ, can transform into invasive squamous cell carcinoma and should be treated aggressively. Although standard treatment for BD is electrodessication and curettage, radiotherapy (RT) can be used for those patients who are poor surgical candidates or when surgery could result in a poor cosmetic and functional outcome. Surgical treatment of BD of the digit can result in poor function and sometimes amputation. Here, we report our experience using a unique water bath technique to treat BD of the digit.nnnMATERIALS AND METHODSnThis retrospective review evaluates the outcomes and toxicity of nine consecutive patients with BD of the digit treated with RT between 1999 and 2004. Fourteen digit lesions were immersed in a water bath and treated with photon irradiation. The median radiation dose delivered was 50Gy (range 25-66Gy) in 2.5Gy fractions (range 2-3Gy).nnnRESULTSnThe median age of the patients treated was 77 years (range 29-87 years). Three patients (33%) had more than one digit treated. With a median follow-up of 25 months (range 0.4-52 months), all 14 digit lesions are locally controlled. The majority of lesions demonstrated mild to moderate erythema, desquamation, or edema (grade 1-2) acutely following RT which resolved within one month of treatment. Two digits (14%) developed ulcers (grade 4) which healed following RT. The only long-term toxicity was decreased sensation and strength in one patient who had three circumferential lesions. This toxicity was limited and did not appear to influence the patients daily activities (grade 2).nnnCONCLUSIONSnThese preliminary results demonstrate high rates of tumor control with minimal morbidity following definitive RT in the treatment of BD of the digit, and suggest that RT may be a viable treatment alternative to surgery for selected lesions. Through a multidisciplinary assessment, treatment of BD of the digit can be individualized to optimize patient care.

Repeat gamma knife radiosurgery for refractory or recurrent trigeminal neuralgia

PURPOSEnStereotactic radiosurgery (SRS) has become a minimally invasive treatment modality for patients with refractory trigeminal neuralgia. It is unclear, however, how best to treat patients with pain that is refractory or recurrent after initial SRS. We report on treatment outcomes and quality of life for patients treated with repeated SRS for refractory or recurrent trigeminal neuralgia.nnnMETHODS AND MATERIALSnBetween June 1996 and June 2001, 112 patients with trigeminal neuralgia were treated with SRS at the University of Maryland Medical Center. Eighteen patients underwent repeat SRS 3-42 months (median, 8 months) after initial radiosurgery because of unsatisfactory or unsustained pain relief. Patients received a median prescription dose of 75 and 70 Gy, respectively, for the first and second treatments. Self-reports of pain control were assessed with a standard questionnaire containing the complete Barrow Neurologic Institute Pain Scale.nnnRESULTSnThe median follow-up was 37.5 months (range, 12-68 months) after initial SRS and 24.5 months (range, 6-65 months) after repeat SRS. For the 18 patients in this series, the percentage of patients reporting excellent, good, fair, and poor responses after the initial and repeat SRS was 50%, 28%, 6%, and 16% and 45%, 33%, 0%, and 22%, respectively. None of the 3 patients with pain refractory to initial SRS responded to repeat SRS. Among those with recurrent pain after initial SRS, 14 patients (93%) achieved excellent or good pain outcomes after repeat SRS. The actuarial analysis revealed a 1-year recurrence rate of 22%, with no patients reporting recurrent pain after 9 months of follow-up. Two patients (11%) reported new or increased facial numbness after retreatment, which was described as bothersome by one. Repeat SRS resulted in a median 60% improvement in quality of life, and 56% of patients believed that the procedure was successful.nnnCONCLUSIONnDespite a modest dose reduction, repeat SRS provided similar rates of complete pain control as the initial procedure, but was not effective for patients with no response to initial treatment. Repeat SRS was more efficacious for those patients who experienced longer periods of pain relief after the initial SRS. The incidence of complications was not significantly different from that observed for initial SRS. In this series, most patients had significant improvements in quality of life.

Manganese in Gasoline: Are We Repeating History?

I N 1995, TETRAETHYL LEAD WAS FINALLY phased out of gasoline in the United States. That same year, however, the Ethyl Corporation began selling another metal-based gasoline additive in this country. Ethyl is the same company which previously made and sold tetraethyllead (fEL). The new additive, methylcyclopentadienyl manganese tricarbonyl (MMT) is used for the same purpose as TEL: it enhances octane and thereby acts as an anti-knock agent in gasoline. The Environmental Protection Agency (EPA) had refused for years to allow Ethyl to market MMT for addition to unleaded gasoline in the U.S. on the grounds that there is a reasonable basis for concern about the effects on public health that could result [from manganese in gasoline). (1) The company challenged this EPA ruling in court and won. The court of appeals held that the EPA had exceeded its authority under the Clean Air Act (CAA), and directed the agency to grant the necessary license. Thus, the court ruling has removed any barrier to introduction of this additive into our fuel supply. Manganese, unlike lead, is an essential trace element and is usually present in the human diet. In addition, predicted ambient levels of manganese are expected to remain fairly low despite inclusion of manganese in fuel. Nonetheless, major concerns remain. Inhalation is an abnormal route of intake for manganese and may be associated with increased risk of toxicity, particularly to the central nervous system and the lungs. Certain susceptible subpopulations, such as the young, the old, and the malnourished, may be at greatly increased risk of ad verse effects from exposure to manganese in the environment. As is the case with lead, manganese may accumulate over time in the environment and in the body leading to potential overexposures. There are also significant occupational health concerns for workers in the mining, manufacturing, and blending stages. Although less concentrated, exposures in gas stations and garages may also lead to significant health sequelae. Finally, MMT may damage emission control systems in automobiles, thereby potentially leading to increased air pollution and increased repair costs to consumers. Given that there are viable alternatives to MMT use, it is unwise to proceed with the marketing and addition of MMT into the fuel supply of the United States.