Purpose To assess the safety and efficacy of combining oncolytic adenovirus-mediated cytotoxic gene therapy (OAMCGT) with intensity modulated radiation therapy (IMRT) in intermediate-risk prostate cancer. Methods and Materials Forty-four men with intermediate-risk prostate cancer were randomly assigned to receive either OAMCGT plus IMRT (arm 1; n=21) or IMRT only (arm 2; n=23). The primary phase 2 endpoint was acute (≤90 days’) toxicity. Secondary endpoints included quality of life (QOL), prostate biopsy (12-core) positivity at 2 years, freedom from biochemical/clinical failure (FFF), freedom from metastases, and survival. Results Men in arm 1 exhibited a greater incidence of low-grade influenza-like symptoms, transaminitis, neutropenia, and thrombocytopenia than men in arm 2. There were no significant differences in gastrointestinal or genitourinary events or QOL between the two arms. Two-year prostate biopsies were obtained from 37 men (84%). Thirty-three percent of men in arm 1 were biopsy-positive versus 58% in arm 2, representing a 42% relative reduction in biopsy positivity in the investigational arm (P=.13). There was a 60% relative reduction in biopsy positivity in the investigational arm in men with <50% positive biopsy cores at baseline (P=.07). To date, 1 patient in each arm exhibited biochemical failure (arm 1, 4.8%; arm 2, 4.3%). No patient developed hormone-refractory or metastatic disease, and none has died from prostate cancer. Conclusions Combining OAMCGT with IMRT does not exacerbate the most common side effects of prostate radiation therapy and suggests a clinically meaningful reduction in positive biopsy results at 2 years in men with intermediate-risk prostate cancer.

Background-Women with benign breast diseases (BBD), particularly those with lesions classified as proliferative, have previously been reported to be at increased risk for subsequent development of breast cancer (BC).

Summary Background The majority of studies have reported risks of breast cancer from benign breast disease (BBD) in essentially homogenous Caucasian populations. Information on breast cancer risk factors in larger, multi-ethnic populations should facilitate the development of appropriate and targeted risk reduction strategies. Design Cases and controls were drawn from a parent BBD cohort of 4,970 women, 1,341 African Americans (AA) and 3,629 non-AA who were diagnosed with BBD after examination of an excisional breast biopsy. Risk factors (34 variables) included demographics, lesion types, and epidemiological variables. Results The final multivariable model retained significance (p<0.05) for lesion risk-level, fibroadenoma, and the interaction of age-by-race. Women with proliferative lesions (no atypia, risk level 2) were 1.7 times more likely to develop BC when compared with women with non-proliferative lesions (OR=1.7, 95% CI 1.13, 2.42, p=0.009). Women with atypia (risk level 3) were 3.75 times more likely to develop BC compared to women with non-proliferative lesions (OR= 3.75, 95% CI 1.99, 7.06, p<.001). The odds of breast cancer was approximately 35% lower among women with fibroadenoma as compared to women without fibroadenoma (OR=0.65, 95% CI 0.46, 0.94, p=0.020). African-American women with BBD who were 50 years or older were 2.28 times more likely to develop breast cancer as compared to non African-American women who were less than 50 years old (OR=2.28, 95% CI 1.34, 3.88, p=0.002). Conclusion Women with fibroadenoma (nonproliferative or proliferative) were less likely to progress to BC. Older African American women are at greater risk for progression to breast cancer from BBD.

Purpose: Benign breast disease (BBD) in women encompasses a broad spectrum of histopathologic lesions. Studies on BBD have focused on the risks for subsequent breast cancer associated with three broad categories of lesions, classified as nonproliferative, proliferative, or proliferative with atypia, without addressing the issue of the contribution of concurrent multiple BBD lesions. There is very limited information with regard to the issue of BBD lesion multiplicity and breast cancer risk. Experimental Design: We evaluated a detailed microscopic spectrum of 18 BBD lesions from fibrosis to atypical hyperplasia in a BBD cohort of 4,544 subjects, within which 4.5% (n = 201) developed breast cancer during an average follow-up period of 10.3 years. Lesions were defined as nonproliferative (8 diagnoses; risk level 1 = no risk or low risk), proliferative without atypical hyperplasia (8 diagnoses; risk level 2 = intermediate risk), and proliferative with atypical hyperplasia (2 diagnoses; risk level 3 = highest risk level). Twenty variables including age (z50 or <50 years) at the time of BBD diagnosis and race (African American or non^African American) were assessed. A categorical variable, surrogate for lesion type and number, was represented initially by four levels: 1, nonproliferative = 1 (reference); 2, nonproliferative > 1; 3, proliferative = 1; and 4, proliferative > 1.Results: The majority of BBD subjects in our cohort (almost 70%) had more than one BBD lesion. Concurrent multiple nonproliferative or proliferative BBD lesions with or without atypia in a BBD biopsy and age are significant predictors of risk for progression of BBD to breast cancer. The presence of atypical hyperplasia in a BBD biopsy alone or in conjunction with other lesions without atypia conferred higher risks.Women with fibrosis had a reduced risk for progression to breast cancer. Race was not a significant predictor of progression to breast cancer. The effect of age, fibrosis, and multiple lesions (whether nonproliferative, proliferative, or atypia) on breast cancer progression was not influenced by race. Conclusion: BBD lesion multiplicity is frequent, and teasing out the heterogeneity of multiple concurrent BBD lesions is warranted to refine and improve risk estimates for progression of breast cancer from BBD.Benign breast disease (BBD) in women encompasses a spectrum of histopathologic lesions. Of the many types of benign entities found in the human breast, only a few have been shown to have clinically significant premalignant potential. Currently, the best-characterized premalignant lesions are atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ (1). Ductal carcinoma in situ is considered a preinvasive malignant lesion. Many BBD studies (2 -7) have focused on the risks for subsequent breast cancer associated with lesions classified into three broad pathologic categories: nonproliferative, proliferative, and proliferative with atypia. When different but concurrent BBD lesions (Table 1) are pre...

We have developed a replication-competent adenovirus (Ad5-yCD/mutTK(SR39)rep-hNIS) armed with two suicide genes and the human sodium iodide symporter (hNIS) gene. In this context, hNIS can be used as a reporter gene in conjunction with nuclear imaging and as a potentially therapeutic gene when combined with (131)I radioiodine therapy. Here, we quantified the volume and magnitude of hNIS gene expression in the human prostate following injection of a high Ad5-yCD/mutTK(SR39)rep-hNIS dose using a standardized injection algorithm, and estimated the radiation dose that would be delivered to the prostate had men been administered (131)I with curative intent. Six men with clinically localized prostate cancer received an intraprostatic injection of Ad5-yCD/mutTK(SR39)rep-hNIS under transrectal ultrasound guidance. All men received 2 × 0.5 ml deposits (5 × 10(11) vp/deposit) in each of the four base and midgland sextants and 2 × 0.25 ml deposits (2.5 × 10(11) vp/deposit) in each of the two apex sextants for a total of 12 deposits (5 × 10(12) vp) in 5 ml. On multiple days after the adenovirus injection, men were administered sodium pertechnetate (Na(99m)TcO(4)) and hNIS gene expression in the prostate was quantified by single photon emission computed tomography (SPECT). hNIS gene expression was detected in the prostate of six of six (100%) men. On average, 45% (range 18-83%) of the prostate volume was covered with gene expression. Had men been administered 200 mCi (131)I, we estimate that the mean absorbed dose to the prostate would be 7.2 ± 4.8 Gy (range 2.1-13.3 Gy), well below that needed to sterilize the prostate. We discuss the obstacles that must be overcome before adenovirus-mediated hNIS gene transfer and (131)I radioiodine therapy can be used as a definitive treatment for localized prostate cancer.