Sameer K. Nath

Induction of angiogenesis in a mouse model using engineered transcription factors

The relationship between the structure of zinc-finger protein (ZFP) transcription factors and DNA sequence binding specificity has been extensively studied. Advances in this field have made it possible to design ZFPs de novo that will bind to specific targeted DNA sequences. It has been proposed that such designed ZFPs may eventually be useful in gene therapy. A principal advantage of this approach is that activation of an endogenous gene ensures expression of the natural array of splice variants. Preliminary studies in tissue culture have validated the feasibility of this approach. The studies reported here were intended to test whether engineered transcription factors are effective in a whole-organism model. ZFPs were designed to regulate the endogenous gene encoding vascular endothelial growth factor-A (Vegfa). Expression of these new ZFPs in vivo led to induced expression of the protein VEGF-A, stimulation of angiogenesis and acceleration of experimental wound healing. In addition, the neovasculature resulting from ZFP-induced expression of Vegfa was not hyperpermeable as was that produced by expression of murine Vegfa164 cDNA. These data establish, for the first time, that specifically designed transcription factors can regulate an endogenous gene in vivo and evoke a potentially therapeutic biophysiologic effect.

Population-Based Study of Competing Mortality in Head and Neck Cancer

PURPOSE Patients with head and neck cancer (HNC) are at high risk of death resulting from noncancer causes and second malignancies (ie, competing mortality). Variation in competing mortality risk complicates individual treatment choices and design and interpretation of clinical studies. METHODS Using the Surveillance, Epidemiology, and End Results registry, we identified 34,568 patients with nonmetastatic squamous cell carcinoma of the head and neck diagnosed between 1994 and 2003. We developed a multivariable competing-risk regression model to stratify patients according to competing mortality risk and evaluate the impact of this risk on power loss in clinical studies. RESULTS The 5-year cumulative incidences of all-cause mortality, HNC-specific mortality, and competing mortality were 51.3% (95% CI, 50.8% to 51.9%), 23.8% (95% CI, 23.3% to 24.2%), and 27.6% (95% CI, 26.8% to 28.3%), respectively. Factors associated with increased competing mortality were increasing age, male sex, black race, unmarried status, localized disease, higher socioeconomic status, nonsurgical treatment, and hypopharyngeal, nasopharyngeal, and oral cavity subsites. The 5-year cumulative incidences of competing mortality for patients in low-, medium-, and high-risk score tertiles were 20.0% (95% CI, 18.8% to 21.3%), 27.7% (95% CI, 26.3% to 29.1%), and 33.7% (95% CI, 32.2% to 35.2%), respectively. Compared with patients with low competing mortality risk, relative sample sizes required to show benefit of a treatment regarding all-cause mortality were 12% and 42% higher in the medium- and high-risk groups, respectively. CONCLUSION Multiple factors affect risk of competing mortality among patients with HNC. Risk stratification would be useful to identify patients most likely to benefit from treatment intensification.

Clinical Outcomes of Intensity-Modulated Pelvic Radiation Therapy for Carcinoma of the Cervix

PURPOSE To evaluate disease outcomes and toxicity in cervical cancer patients treated with pelvic intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS We included all patients with Stage I-IVA cervical carcinoma treated with IMRT at three different institutions from 2000-2007. Patients treated with extended field or conventional techniques were excluded. Intensity-modulated radiation therapy plans were designed to deliver 45 Gy in 1.8-Gy daily fractions to the planning target volume while minimizing dose to the bowel, bladder, and rectum. Toxicity was graded according to the Radiation Therapy Oncology Group system. Overall survival and disease-free survival were estimated by use of the Kaplan-Meier method. Pelvic failure, distant failure, and late toxicity were estimated by use of cumulative incidence functions. RESULTS The study included 111 patients. Of these, 22 were treated with postoperative IMRT, 8 with IMRT followed by intracavitary brachytherapy and adjuvant hysterectomy, and 81 with IMRT followed by planned intracavitary brachytherapy. Of the patients, 63 had Stage I-IIA disease and 48 had Stage IIB-IVA disease. The median follow-up time was 27 months. The 3-year overall survival rate and the disease-free survival rate were 78% (95% confidence interval [CI], 68-88%) and 69% (95% CI, 59-81%), respectively. The 3-year pelvic failure rate and the distant failure rate were 14% (95% CI, 6-22%) and 17% (95% CI, 8-25%), respectively. Estimates of acute and late Grade 3 toxicity or higher were 2% (95% CI, 0-7%) and 7% (95% CI, 2-13%), respectively. CONCLUSIONS Intensity-modulated radiation therapy is associated with low toxicity and favorable outcomes, supporting its safety and efficacy for cervical cancer. Prospective clinical trials are needed to evaluate the comparative efficacy of IMRT vs. conventional techniques.

Dosimetric effects of needle divergence in prostate seed implant using 125I and 103Pd radioactive seeds.

In prostate seed implants, radioactive seeds are implanted into the prostate through a guiding needle with the help of a template and real-time imaging. The ideal locations of the guiding needles and the relative positions of the seeds in each needle are determined before the implantation under the assumption that the needles inserted at different locations will remain parallel. In actual implantation, the direction of the needle is subject variation. In this work, we studied how the dosimetry quality of an implant may be affected when the guiding needles deviate from its planned orientations. Needle divergence of varying degree was simulated on spherical models and actual patient implants. It was found that needle divergence degraded the dosimetric quality of an implant: The minimum target dose, the target dose coverage and therefore the tumor biological effective dose were quantitatively decreased as compared to the reference implant. The magnitude of degradation increased almost linearly with respect to the magnitude of needle divergence. For iodine-125 implants, the average reduction in minimum target dose was about 10% and 20% for needle divergence of standard deviation of 5(0) and 10(0), respectively. The dose coverage in the target was reduced by about 1% and 3% for needle divergence of standard deviation of 5(0) and 10(0), respectively. Implants designed with palladium-103 showed additional 5% reduction in minimum target dose while the effect on dose coverage was about the same as compared to the iodine-125 implants. The degree of dosimetry degradation was shown to be dependent on the size of target volume, the seed spacing used, the use of seeding margin, and on the actual configuration of needle orientations in a given implant. One needs to minimize the physical causes of needle divergence in order to minimize its impact on planned dosimetry. The study suggests that the displacement between a needle image and its planned grid point at the base of prostate should be kept less than 5 mm in order to minimize the reduction in D(min)(<5%) and the increase in cell-survival (< a factor of 10) from the planned dosimetry.

A survey of image‐guided radiation therapy use in the United States

Image‐guided radiation therapy (IGRT) is a novel array of in‐room imaging modalities that are used for tumor localization and patient setup in radiation oncology. The prevalence of IGRT use among US radiation oncologists is unknown.

Toxicity analysis of postoperative image-guided intensity-modulated radiotherapy for prostate cancer.

PURPOSE To report on the acute and late gastrointestinal (GI) and genitourinary (GU) toxicity associated with a unique technique of image-guided radiotherapy (IGRT) in patients undergoing postprostatectomy irradiation. METHODS AND MATERIALS Fifty patients were treated with intensity-modulated radiation therapy (IMRT) after radical prostatectomy. Daily image guidance was performed to localize the prostate bed using kilovoltage imaging or cone-beam computed tomography. The median prescription dose was 68 Gy (range, 62-68 Gy). Toxicity was graded every 3 to 6 months according to the Common Terminology Criteria for Adverse Events version 3.0. RESULTS The median follow-up was 24 months (range, 13-38 months). Grade 2 acute GI and GU events occurred in 4 patients (8%) and 7 patients (14%), respectively. No Grade 3 or higher acute GI or GU toxicities were observed. Late Grade 2 GI and GU events occurred in 1 patient (2%) and 8 patients (16%), respectively. Only a single (2%) Grade 3 or higher late toxicity was observed. CONCLUSIONS Image-guided IMRT in the postprostatectomy setting is associated with a low frequency of acute and late GI/GU toxicity. These results compare more favorably to radiotherapy techniques that do not use in-room image-guidance, suggesting that daily prostate bed localization may reduce the incidence of adverse events in patients undergoing postprostatectomy irradiation.

Evaluation of intra- and inter-fraction movement of the cervix during intensity modulated radiation therapy

BACKGROUND AND PURPOSE To assess the degree of intra- and inter-fraction cervical motion throughout a course of intensity modulated radiation therapy (IMRT) for cervical cancer patients. MATERIALS AND METHODS A retrospective study of 10 women with stage 1B1-3B cervical cancer diagnosed from September 2007 to July 2008 was conducted. All patients were treated with chemoradiation using IMRT followed by intracavitary brachytherapy. Pretreatment, patients had 2 seeds placed at a depth of 10mm into the cervix. On-Board Imaging (OBI) was used to obtain anterior/posterior (AP) and lateral X-rays before and after each treatment. OBI images were rigidly aligned to baseline digitally reconstructed radiographs (DRRs), and movement of cervical seeds was determined in the lateral, vertical, and AP directions. Mean differences in cervical seed position and standard error of the mean (SEM) were calculated. RESULTS A total of 922 images were reviewed, with approximately 90 images per patient. The mean intra-fractional movement in cervical seed position in the lateral, vertical, and AP directions were 1.6mm (SD±2.0), 2.6mm (SD±2.4), and 2.9mm (SD±2.7), respectively, with a range from 0 to 15mm for each direction. The mean inter-fractional movement in the lateral, vertical, and AP directions were 1.9mm (SD±1.9), 4.1mm (SD±3.2), and 4.2mm (SD±3.5), respectively, with a range from 0 to 18mm for each direction. CONCLUSIONS This is the first study to assess intra- and inter-fractional movement of the cervix using daily imaging before and after each fraction. Within and between radiation treatments, cervical motion averages approximately 3mm in any given direction. However, maximal movement of the cervix can be as far as 18mm from baseline. This wide range of motion needs to be accounted for when generating planning treatment volumes.

Locoregional and distant failure following image-guided stereotactic body radiation for early-stage primary lung cancer

PURPOSE To report our institutional experience using image-guided stereotactic body radiation therapy (SBRT) for early stage lung cancer, including an analysis into factors associated with nodal and distant failures (NF, DF). METHODS Forty-eight patients with early-stage primary lung cancer were treated with image-guided SBRT between 2007 and 2009. Median prescription dose was 48 Gy in 4 fractions. Toxicity was graded according to the NCI CTCAE v3.0 scale. RESULTS Local failure was detected in two lesions and actuarial 24-month local control was 95%. At 24 months, the cumulative incidence of NF was 6%, and DF was 29%. Larger lesions (>3 cm) and younger age (<70 years) were the only factors found to be significantly correlated with increased DF (p=0.005 and p=0.015, respectively). A single grade ≥ 3 toxicity was observed. After adjusting for age and lesion size, distant failure was significantly associated with a poorer OS (Cox regression, p=0.0059). CONCLUSION Image-guided SBRT can produce excellent LC rates with minimal toxicity. Distant failure was a major determinant of OS and the most common pattern of failure, indicating a potential role for systemic therapy in younger patients with large lesions.

Single-Isocenter Frameless Intensity-Modulated Stereotactic Radiosurgery for Simultaneous Treatment of Multiple Brain Metastases: Clinical Experience

PURPOSE To describe our clinical experience using a unique single-isocenter technique for frameless intensity-modulated stereotactic radiosurgery (IM-SRS) to treat multiple brain metastases. METHODS AND MATERIALS Twenty-six patients with a median of 5 metastases (range, 2-13) underwent optically guided frameless IM-SRS using a single, centrally located isocenter. Median prescription dose was 18 Gy (range, 14-25). Follow-up magnetic resonance imaging (MRI) and clinical examination occurred every 2-4 months. RESULTS Median follow-up for all patients was 3.3 months (range, 0.2-21.3), with 20 of 26 patients (77%) followed up until their death. For the remaining 6 patients alive at the time of analysis, median follow-up was 14.6 months (range, 9.3-18.0). Total treatment time ranged from 9.0 to 38.9 minutes (median, 21.0). Actuarial 6- and 12-month overall survivals were 50% (95% confidence interval [C.I.], 31-70%) and 38% (95% C.I., 19-56%), respectively. Actuarial 6- and 12-month local control (LC) rates were 97% (95% C.I., 93-100%) and 83% (95% C.I., 71-96%), respectively. Tumors <or=1.5 cm had a better 6-month LC than those >1.5 cm (98% vs. 90%, p = 0.008). New intracranial metastatic disease occurring outside of the treatment volume was observed in 7 patients. Grade >or=3 toxicity occurred in 2 patients (8%). CONCLUSION Frameless IM-SRS using a single-isocenter approach for treating multiple intracranial metastases can produce clinical outcomes that compare favorably with those of conventional SRS in a much shorter treatment time (<40 minutes). Given its faster treatment time, this technique is appealing to both patients and personnel in busy clinics.

Utilization of Advanced Imaging Technologies for Target Delineation in Radiation Oncology

PURPOSE The aim of this study was to evaluate the utilization of advanced imaging technologies for target delineation among radiation oncologists in the United States. METHODS A random sample of 1,600 radiation oncologists was contacted by Internet, e-mail, and fax and questioned regarding the use of advanced imaging technologies, clinical applications, and future plans for use. Advanced imaging technologies were defined as any of the following that were directly incorporated into radiation therapy planning: MRI, PET, single-photon emission CT, 4-D CT, functional MRI, and MR spectroscopy. RESULTS Of 1,089 contactable physicians, 394 (36%) responded. Of respondents, 65% were in private practice and 35% were in academic practice. The proportion using any advanced imaging technology for target delineation was 95%. However, the majority reported only rare (in <25% of their patients; 46.6%) or infrequent (in 25%-50% of their patients; 26.0%) utilization. The most commonly used technologies were 2-[(18)F]fluoro-2-deoxyglucose PET (76%), MRI (72%), and 4-D CT (44%). The most common cancers treated using image-guided target delineation were those of the lung (83%), central nervous system (79%), and head and neck (79%). Among users of advanced imaging technologies, 66% planned to increase use; 30% of nonusers planned to adopt these technologies in the future. CONCLUSIONS Advanced imaging technologies are widely used by US radiation oncologists for target delineation. Although the majority of respondents used them in <50% of their patients, the frequency of utilization is expected to increase. Studies determining the optimal application of these technologies in radiation therapy planning are needed.