Faculty Bibliography

ABSTRACT: BACKGROUND: Brain metastases afflict approximately half of patients with metastatic melanoma (MM) and small cell lung cancer (SCLC) and represent the direct cause of death in 60 to 70% of those affected. Standard of care remains ineffective in both types of cancer with the challenge of overcoming the blood brain barrier (BBB) exacerbating the clinical problem. Our purpose is to determine and characterize the potential of albendazole (ABZ) as a cytotoxic and radiosensitizing agent against MM and SCLC cells. METHODS: Here, ABZ's mechanism of action as a DNA damaging and microtubule disrupting agent is assessed through analysis of histone H2AX phosphorylation and cell cyle progression. The cytotoxicity of ABZ alone and in combination with radiation therapy is determined though clonogenic cell survival assays in a panel of MM and SCLC cell lines. We further establish ABZ's ability to act synergistically as a radio-sensitizer through combination index calculations and apoptotic measurements of poly (ADP-ribose) polymerase (PARP) cleavage. RESULTS: ABZ induces DNA damage as measured by increased H2AX phosphorylation. ABZ inhibits the growth of MM and SCLC at clinically achievable plasma concentrations. At these concentrations, ABZ arrests MM and SCLC cells in the G2/M phase of the cell cycle after 12 hours of treatment. Exploiting the notion that cells in the G2/M phase are the most sensitive to radiation therapy, we show that treatment of MM and SCLC cells treated with ABZ renders them more sensitive to radiation in a synergistic fashion. Additionally, MM and SCLC cells co-treated with ABZ and radiation exhibit increased apoptosis at 72 hours. CONCLUSIONS: Our study suggests that the orally available antihelminthic ABZ acts as a potent radiosensitizer in MM and SCLC cell lines. Further evaluation of ABZ in combination with radiation as a potential treatment for MM and SCLC brain metastases is warranted

This study demonstrates the feasibility of using a novel 2D spectrum ultrasonic tissue characterization (UTC) technique for prostate-cancer diagnosis. Normalized 2D spectra are computed by performing Fourier transforms along the range (beam) and the cross-range directions of the digital radio-frequency echo data, then dividing by a reference spectrum. This 2D spectrum method provides axial and lateral information of tissue microstructures, an improvement over the current 1D spectrum analysis which only provides axial information. A pilot study was conducted on four prostate-cancer patients who underwent radical prostatectomies. Cancerous and noncancerous regions of interest, identified through histology, were compared using four 2D spectral parameters: peak value and 3 dB width of the radially integrated spectral power (RISP), slope and intercept of the angularly integrated spectral power (AISP). For noncancerous and cancerous prostatic tissues, respectively, our investigation yielded 23 +/- 1 and 26 +/- 1 dB for peak value of RISP, 7.8 +/- 0.5 degrees and 7.6 +/- 0.6 degrees for 3 dB of RISP, -2.1 +/- 0.2 and -2.7 +/- 0.4 dB/MHz for slope of AISP, and 92 +/- 5 and 112 +/- 6 dB for intercept of AISP. Preliminary results indicated that 2D spectral UTC has the potential for identifying tumor-bearing regions within the prostate gland.

The goal of this study was to implement and validate a noninvasive, quantitative ultrasonic technique for accurate and reproducible measurement of normal-tissue toxicity in radiation therapy. The authors adapted an existing ultrasonic tissue characterization (UTC) technique that used a calibrated 1D spectrum based on region-of-interest analysis. They modified the calibration procedure by using a reference phantom instead of a planar reflector. This UTC method utilized ultrasonic radiofrequency echo signals to generate spectral parameters related to the physical properties (e.g., size, shape, and relative acoustic impedance) of tissue microstructures. Three spectral parameters were investigated for quantification of normal-tissue injury: Spectral slope, intercept, and midband fit. They conducted a tissue-mimicking phantom study to verify the reproducibility of UTC measurements and initiated a clinical study of radiation-induced breast-tissue toxicity. Spectral parameter values from measurements on two phantoms were reproducible within 1% of each other. Eleven postradiation breast-cancer patients were studied and significant differences between the irradiated and untreated (contralateral) breasts were observed for spectral intercept (p = 0.003) and midband fit (p < 0.001) but not for slope (p = 0.14). In comparison to the untreated breast, the average difference in the spectral intercept was 2.99 +/- 0.75 dB and the average difference in the midband fit was 3.99 +/- 0.65 dB. The preliminary clinical study demonstrated the feasibility of using the quantitative ultrasonic method to evaluate normal-tissue toxicity in radiation therapy

OBJECTIVE: The optimal management of stage II endometrial cancer remains uncertain. We examined the role of radical hysterectomy and adjuvant radiotherapy for stage II endometrial cancer. STUDY DESIGN: The Surveillance, Epidemiology, and End Results database was used to identify 1577 women with stage II endometrioid type endometrial adenocarcinoma who underwent surgical staging. RESULTS: The cohort included 1198 women who underwent simple hysterectomy (76%) and 379 who underwent radical hysterectomy (24%). Radical hysterectomy had no effect on survival (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.61-1.23). Patients who did not receive radiation were 48% (HR, 1.48; 95% CI, 1.14-1.93) more likely to die than those who underwent adjuvant radiotherapy. The survival benefit from radiation was most pronounced in women who underwent radical hysterectomy. CONCLUSION: Adjuvant radiation improves survival. Although the routine performance of radical hysterectomy does not appear to be justified, patients with high-risk stage II tumors appear to benefit from combination therapy with radical hysterectomy and radiotherapy

BACKGROUND: Black women with endometrial cancer have been more likely to die than white patients. The authors examined factors associated with the poor outcome for black women with uterine corpus tumors and analyzed whether these characteristics have changed over time based on year of diagnosis. METHODS: The authors examined women with uterine neoplasms recorded from 1988-2004 in the Surveillance, Epidemiology and End Results (SEER) Database. The authors developed Cox proportional hazards models to examine the effect of race on survival and stratified women by year of diagnosis into 3 groups: 1988-1993, 1994-1998, 1999-2004. RESULTS: A total of 80,915 patients including 5564 (7%) black women were identified. Black patients were significantly younger, had more advanced stage tumors, and had more aggressive, nonendometrioid histologic variants (P<.001). Black women were 60% more likely to die from their tumors than white women when matched for other prognostic variables (hazards ratio, 1.60; 95% confidence interval, 1.51-1.69). For each of the 3 time periods, survival was worse for blacks even when stratified by stage and histology. Over time, the incidence of serous and clear-cell tumors increased, and the use of radiation decreased for both races. Staging lymphadenectomy was performed more commonly in both blacks (45%) and whites (48%) who had been treated more recently. CONCLUSIONS: Black women with uterine corpus tumors were more likely to die from their disease. This survival difference has persisted over time. The clinical characteristics of blacks and whites have remained relatively constant. The proportion of women who undergo surgical staging has increased with time and was well matched between races

PURPOSE: Oophorectomy is commonly performed in premenopausal women with endometrial cancer who undergo hysterectomy. The benefits of oophorectomy in this setting are unknown, and the procedure subjects women to the long-term sequelae of estrogen deprivation. We examined the safety of ovarian preservation in young women with endometrial cancer who underwent hysterectomy. PATIENTS AND METHODS: Women < or = 45 years of age with stage I endometrial cancer recorded from 1988 to 2004 in the Surveillance, Epidemiology, and End Results Database were examined. We developed Cox proportional hazards models and Kaplan-Meier curves to compare women who underwent oophorectomy with those who had ovarian preservation. RESULTS: A total of 3,269 women, including 402 patients (12%) who had ovarian preservation, were identified. Younger age (P < .0001), later year of diagnosis (P = .04), residence in the eastern United States (P = .02), and low tumor grade (P < .0001) were associated with ovarian preservation. In a multivariate Cox model, ovarian preservation had no effect on either cancer-specific (hazard ratio [HR] = 0.58; 95% CI, 0.14 to 2.44) or overall (HR = 0.68; 95% CI, 0.34 to 1.35) survival. The findings were unchanged when women who received pelvic radiotherapy were excluded. CONCLUSION: Ovarian preservation in premenopausal women with early-stage endometrial cancer may be safe and not associated with an increase in cancer-related mortality