A novel expression vector for human ABCR, a protein expressed in the photoreceptor outer segments

Includes bibliographical references (pages [94]-104)M.S. (Master of Science

Pre-Clinical Assessment of 177Lu-Labeled Trastuzumab Targeting HER2 for Treatment and Management of Cancer Patients with Disseminated Intraperitoneal Disease

Studies from this laboratory have demonstrated the potential of targeting HER2 for therapeutic and imaging applications with medically relevant radionuclides. To expand the repertoire of trastuzumab as a radioimmunoconjugate (RIC) vector, use of 177Lu was investigated. The combination of a 6.7 d half-life, lower energy β−-emissions (500 keV max; 130 keV ave), and an imagable γ-emission make 177Lu an attractive candidate for radioimmunotherapy (RIT) regimens for treatment of larger tumor burdens not possible with α-particle radiation. Radiolabeling trastuzumab-CHX-A″-DTPA with 177Lu was efficient with a specific binding of 60.8 ± 6.8% with HER2 positive SKOV-3 cells. Direct quantitation of tumor targeting and normal tissue uptake was performed with athymic mice bearing subcutaneous and intraperitoneal LS-174T xenografts; a peak tumor %ID/g of 24.70 ± 10.29 (96 h) and 31.70 ± 16.20 (72 h), respectively, was obtained. Normal tissue uptake of the RIC was minimal. Tumor targeting was also demonstrated by γ-scintigraphy. A therapy study administering escalating doses of 177Lu-trastuzumab to mice bearing three day LS-174T i.p. xenografts established the effective therapeutic dose of i.p. administered 177Lu-trastuzumab at 375 μCi with a median survival of 124.5 d while a median survival of 10 d was noted for the control (untreated) group. In conclusion, trastuzumab radiolabeled with 177Lu has potential for treatment of disseminated, HER2 positive, peritoneal disease

Effect of bra use during radiation therapy for large-breasted women: Acute toxicity and treated heart and lung volumes.

PURPOSE: Large breast size presents special problems during radiation simulation, planning, and patient treatment, including increased skin toxicity, in women undergoing breast-conserving surgery and radiation therapy (BCT). We report our experience using a bra during radiation in large-breasted women and its effect on acute toxicity and heart and lung dosimetry. METHODS AND MATERIALS: From 2001 to 2006, 246 consecutive large-breasted women (bra size ≥38 or ≥D cup) were treated with BCT using either 3-dimensional conformal radiation therapy (3DCRT) or intensity modulated radiation therapy (IMRT). In 58 cases, at the physicians\u27 discretion, a custom-fit bra was used during simulation and treatment. Endpoints were acute radiation dermatitis and dosimetric comparison of heart and lung volumes in a subgroup of 12 left-sided breast cancer patients planned with and without a bra. RESULTS: The majority of acute skin toxicities were grade 2 and were experienced by 90% of patients in a bra compared with 70% of patients not in a bra (P = .003). On multivariate analysis significant predictors of grade 2 or 3 skin toxicity included the use of 3DCRT instead of IMRT (odds ratio, 3.9; 95% confidence interval, 1.8-8.5) and the use of a bra (odds ratio, 5.5; 95% confidence interval, 1.6-18.8). For left-sided patients, the use of a bra was associated with a volume of heart in the treatment fields decreased by 63.4% (P = .002), a volume of left lung decreased by 18.5% (P = .25), and chest wall separation decreased by a mean of 1 cm (P = .03). CONCLUSIONS: The use of a bra to augment breast shape and position in large-breasted women is an alternative to prone positioning and associated with reduced chest wall separation and reduced heart volume within the treatment field

Five-year results of whole breast intensity modulated radiation therapy for the treatment of early stage breast cancer: the Fox Chase Cancer Center experience.

PURPOSE: To report the 5-year outcomes using whole-breast intensity-modulated radiation therapy (IMRT) for the treatment of early-stage-breast cancer at the Fox Chase Cancer Center. METHODS AND MATERIALS: A total of 946 women with early-stage breast cancer (stage 0, I, or II) were treated with IMRT after surgery with or without systemic therapy from 2003-2010. Whole-breast radiation was delivered via an IMRT technique with a median whole-breast radiation dose of 46 Gy and median tumor bed boost of 14 Gy. Endpoints included local-regional recurrence, cosmesis, and late complications. RESULTS: With a median follow-up of 31 months (range, 1-97 months), there were 12 ipsilateral breast tumor recurrences (IBTR) and one locoregional recurrence. The 5-year actuarial IBTR and locoregional recurrence rates were 2.0% and 2.4%. Physician-reported cosmestic outcomes were available for 645 patients: 63% were considered excellent , 33% good , and \u3c1.5% fair/poor . For physician-reported cosmesis, boost doses≥16 Gy, breast size\u3e900 cc, or boost volumes\u3e34 cc were significantly associated with a fair/poor cosmetic outcome. Fibrosis, edema, erythema, and telangectasia were also associated with fair/poor physician-reported cosmesis; erythema and telangectasia remained significant on multivariate analysis. Patient-reported cosmesis was available for 548 patients, and 33%, 50%, and 17% of patients reported excellent , good , and fair/poor cosmesis, respectively. The use of a boost and increased boost volume: breast volume ratio were significantly associated with fair/poor outcomes. No parameter for patient-reported cosmesis was significant on multivariate analysis. The chances of experiencing a treatment related effect was significantly associated with a boost dose≥16 Gy, receipt of chemotherapy and endocrine therapy, large breast size, and electron boost energy. CONCLUSIONS: Whole-breast IMRT is associated with very low rates of local recurrence at 5 years, 83%-98% good/excellent cosmetic outcomes, and minimal chronic toxicity, including late fibrosis

Stamp test delivers message on erectile dysfunction after high-dose intensity-modulated radiotherapy for prostate cancer.

OBJECTIVE: To evaluate erectile function after high-dose radiotherapy for prostate cancer using the International Index of Erectile Function, Expanded Prostate Cancer Index Composite, and stamp test. METHODS: Men with favorable and intermediate-risk prostate cancer were assigned to receive prostate intensity-modulated radiotherapy (IMRT) versus an erectile tissue-sparing IMRT technique in a Phase III randomized, prospective study. The stamp test and International Index of Erectile Function and Expanded Prostate Cancer Index Composite questionnaires were completed at baseline and 6 months, 1 year, and 2 years after IMRT. The Sexual Health Inventory for Men scores were abstracted from the International Index of Erectile Function questionnaire. A partner questionnaire, designated IIEF-P, modeled after the International Index of Erectile Function questionnaire but from the perspective of the partner, was also collected. RESULTS: The data from 94 men who were enrolled in the trial and who had completed ≥1 questionnaire or 1 stamp test were analyzed. The median age of the patient population was 62.5 years. The median radiation dose was 76 Gy (range 74-80). At 6 months and 1 year after high-dose IMRT, a positive stamp result correlated significantly with the median Expanded Prostate Cancer Index Composite sexual summary, sexual function, and bother subscale scores. Additionally, 6 months after IMRT, the stamp test correlated with the median International Index of Erectile Function, International Index of Erectile Function sexual function domain, and Sexual Health Inventory for Men scores. Robust concordance for the International Index of Erectile Function and Sexual Health Inventory for Men scores was appreciated between responding patient and partner pairs. CONCLUSION: Nocturnal tumescence, as indicated by a positive stamp test, correlated well with established quality of life questionnaires after IMRT. The stamp test should strongly be considered as an objective measure of erectile function in future studies of erectile dysfunction in patients with prostate cancer

Prostate bed motion during intensity-modulated radiotherapy treatment.

PURPOSE: Conformal radiation therapy in the postprostatectomy setting requires accurate setup and localization of the prostatic fossa. In this series, we report prostate bed localization and motion characteristics, using data collected from implanted radiofrequency transponders. METHODS AND MATERIALS: The Calypso four-dimensional localization system uses three implanted radiofrequency transponders for daily target localization and real-time tracking throughout a course of radiation therapy. We reviewed the localization and tracking reports for 20 patients who received ultrasonography-guided placement of Calypso transponders within the prostate bed prior to a course of intensity-modulated radiation therapy at Fox Chase Cancer Center. RESULTS: At localization, prostate bed displacement relative to bony anatomy exceeded 5 mm in 9% of fractions in the anterior-posterior (A-P) direction and 21% of fractions in the superior-inferior (S-I) direction. The three-dimensional vector length from skin marks to Calypso alignment exceeded 1 cm in 24% of all 652 fractions with available setup data. During treatment, the target exceeded the 5-mm tracking limit for at least 30 sec in 11% of all fractions, generally in the A-P or S-I direction. In the A-P direction, target motion was twice as likely to move posteriorly, toward the rectum, than anteriorly. Fifteen percent of all treatments were interrupted for repositioning, and 70% of patients were repositioned at least once during their treatment course. CONCLUSION: Set-up errors and motion of the prostatic fossa during radiotherapy are nontrivial, leading to potential undertreatment of target and excess normal tissue toxicity if not taken into account during treatment planning. Localization and real-time tracking of the prostate bed via implanted Calypso transponders can be used to improve the accuracy of plan delivery

Stamp Test Delivers Message on Erectile Dysfunction After High-dose Intensity-modulated Radiotherapy for Prostate Cancer

OBJECTIVES: To evaluate erectile function following high dose radiotherapy for prostate cancer using the international index of erectile function (IIEF), expanded prostate cancer index composite (EPIC), and stamp test. METHODS: Men with favorable and intermediate risk prostate cancer were assigned to receive prostate intensity modulated radiotherapy (IMRT) vs. an erectile tissue-sparing IMRT technique on a phase III randomized prospective study. The stamp test, IIEF, and EPIC questionnaires were completed at baseline, 6 months, one year, and two years after IMRT. Sexual Health Inventory for Men (SHIM) scores were abstracted from IIEF questionnaires. A partner questionnaire, designated IIEF-P, modeled after the IIEF but from the perspective of the partner, was collected. RESULTS: Ninety four men enrolled on the trial who completed at least one questionnaire or one stamp test were analyzed. The median age of the patient population was 62.5 years. The median RT dose was 76 Gy (range: 74–80 Gy). At 6-months and one year after high-dose IMRT, a positive stamp result significantly correlated with median EPIC sexual summary, sexual function (EF), and bother subscale scores. Additionally, 6-months after IMRT the stamp test correlated with median IIEF, IIEF EF domain, and SHIM scores. Robust concordance for the IIEF and SHIM results was appreciated between responding patients: partner pairs. CONCLUSIONS: Nocturnal tumescence indicated by a positive stamp test correlates well with established quality of life questionnaires after IMRT. The stamp test should strongly be considered as an objective measure of erectile function in future studies of ED in prostate cancer patients