Daniel R. Simpson

Nerve growth factor promotes survival of new neurons in the adult hippocampus

Exogenously provided NGF enhances cognitive performance in impaired rodents and humans and is currently a promising compound for the treatment of dementia. To investigate whether NGF-dependent cognitive improvement may be due in part to increased hippocampal neurogenesis, adult and aged male rats were treated with NGF or vehicle intracerebroventricularly for 6 or 20 days followed by evaluation of cholinergic parameters and hippocampal neurogenesis. We show that NGF increases hippocampal cholinergic activity as rapidly as 3 days after initiation of treatment. NGF treatment for 6 days did not affect proliferation of progenitor cells in the dentate gyrus granule cell layer (GCL). However, continuous NGF infusion enhanced survival of new neurons in the GCL of young adult, but not aged rats. Taken together, these findings suggest that NGF, likely mediated through increased cholinergic tone, promotes neurogenesis in the adult hippocampus, which may relate to the nootropic action of NGF.

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.

Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck

Despite recent advances in novel therapies, the prognosis for patients with squamous cell carcinoma of the head and neck (SCCHN) remains poor. Progress in understanding the biology of cancer has led to the development of personalized therapy targeted at blocking defective signaling pathways of cancer cells. These drugs aim to act selectively to reduce the adverse effects associated with systemic therapy. Cetuximab (Erbitux®), an anti-epidermal growth factor receptor gene (EGFR)-targeted agent, is the only approved targeted therapy for patients with SCCHN. However, resistance to EGFR therapy remains a major obstacle to achieving a positive clinical outcome with cetuximab. Other therapies that offer better clinical outcomes in patients with advanced SCCHN are urgently needed. The phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway, which is downstream of EGFR, has also been implicated in SCCHN development and progression, and therefore, targeting this pathway offers another rational treatment approach. This review discusses the potential role of PI3K pathway inhibitors in the treatment of patients with advanced SCCHN, both alone and in combination with other therapies.

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.

Clinical practice patterns of lung stereotactic body radiation therapy in the United States: a secondary analysis.

Objectives:Stereotactic body radiation therapy (SBRT) is a technique used to deliver high, ablative doses of radiation in a limited number of fractions to ≥1 extracranial target(s). Although recent studies have shown that SBRT provides effective local tumor control in medically inoperable early-stage lung cancer patients, its implementation in clinical practice is unknown. Methods:A random sample of 1600 American radiation oncologists was surveyed regarding lung SBRT usage, including year adopted, most common prescription, respiratory motion management, and target localization. A biological equivalent dose (BED) was calculated using the linear quadratic model with &agr;/&bgr;=10. Spearman rank correlation coefficients (rs) were calculated to identify factors associated with BED. Results:Of 1373 contactable physicians, 551 responses (40%) were received. Of 510 evaluable responses, 275 physicians (54%) reported using lung SBRT, over half of whom adopted it in 2008 or later. The most commonly reported prescriptions were 20 Gy×3 (22%), 18 Gy×3 (21%), and 12 Gy×4 (17%). Three fraction regimens were most common (48%), with nearly all (89%) prescribing ≥18 Gy/fraction. The median BED was 132 Gy, with 95% of reported prescriptions having BED≥100 Gy. Factors associated with increased BED included use of fiducial markers (rs=0.26, P<0.001), use of planar imaging (rs=0.18, P<0.01), and years of experience with lung SBRT (rs=0.13, P=0.04). Conclusions:Lung SBRT has rapidly become a widely adopted treatment approach in the United States with a range of varying implementations. Further research and additional prospective trials are necessary to optimize this novel approach.

Normal tissue complication probability analysis of acute gastrointestinal toxicity in cervical cancer patients undergoing intensity modulated radiation therapy and concurrent cisplatin.

PURPOSE To test the hypothesis that increased bowel radiation dose is associated with acute gastrointestinal (GI) toxicity in cervical cancer patients undergoing concurrent chemotherapy and intensity-modulated radiation therapy (IMRT), using a previously derived normal tissue complication probability (NTCP) model. METHODS Fifty patients with Stage I-III cervical cancer undergoing IMRT and concurrent weekly cisplatin were analyzed. Acute GI toxicity was graded using the Radiation Therapy Oncology Group scale, excluding upper GI events. A logistic model was used to test correlations between acute GI toxicity and bowel dosimetric parameters. The primary objective was to test the association between Grade ≥2 GI toxicity and the volume of bowel receiving ≥45 Gy (V(45)) using the logistic model. RESULTS Twenty-three patients (46%) had Grade ≥2 GI toxicity. The mean (SD) V(45) was 143 mL (99). The mean V(45) values for patients with and without Grade ≥2 GI toxicity were 176 vs. 115 mL, respectively. Twenty patients (40%) had V(45) >150 mL. The proportion of patients with Grade ≥2 GI toxicity with and without V(45) >150 mL was 65% vs. 33% (p = 0.03). Logistic model parameter estimates V50 and γ were 161 mL (95% confidence interval [CI] 60-399) and 0.31 (95% CI 0.04-0.63), respectively. On multivariable logistic regression, increased V(45) was associated with an increased odds of Grade ≥2 GI toxicity (odds ratio 2.19 per 100 mL, 95% CI 1.04-4.63, p = 0.04). CONCLUSIONS Our results support the hypothesis that increasing bowel V(45) is correlated with increased GI toxicity in cervical cancer patients undergoing IMRT and concurrent cisplatin. Reducing bowel V(45) could reduce the risk of Grade ≥2 GI toxicity by approximately 50% per 100 mL of bowel spared.

Clinical Outcomes of Computed Tomography-Based Volumetric Brachytherapy Planning for Cervical Cancer

PURPOSE/OBJECTIVES A report of clinical outcomes of a computed tomography (CT)-based image guided brachytherapy (IGBT) technique for treatment of cervical cancer. METHODS AND MATERIALS Seventy-six women with International Federation of Gynecology and Obstetrics stage IB to IVA cervical carcinoma diagnosed between 2007 and 2014 were treated with definitive external beam radiation therapy (EBRT) with or without concurrent chemotherapy followed by high-dose-rate (HDR) IGBT. All patients underwent planning CT simulation at each implantation. A high-risk clinical target volume (HRCTV) encompassing any visible tumor and the entire cervix was contoured on the simulation CT. When available, magnetic resonance imaging (MRI) was performed at implantation to assist with tumor delineation. The prescription dose was prescribed to the HRCTV. RESULTS The median follow-up time was 17 months. Thirteen patients (17%) had an MRI done before brachytherapy, and 16 patients (21%) were treated without MRI guidance. The mean EBRT/IGBT sum 2-Gy equivalent dose (EQD2) delivered to the 90% volume of the HRCTV was 86.3 Gy. The mean maximum EQD2s delivered to 2 cm(3) of the rectum, sigmoid, and bladder were 67.5 Gy, 66.2 Gy, and 75.3 Gy, respectively. The 2-year cumulative incidences of local, locoregional, and distant failure were 5.8% (95% confidence interval [CI]: 1.4%-14.8%), 15.1% (95% CI: 5.4%-29.4%), and 24.3% (95% CI: 12.1%-38.9%), respectively. The 2-year overall and disease-free survival rates were 75% (95% CI, 61%-91%) and 73% (95% CI, 60%-90%), respectively. Twenty-nine patients (38%) experienced grade ≥ 2 acute toxicity, with 5 cases of acute grade 3 toxicity and no grade ≥ 4 toxicities. One patient experienced grade 3 gastrointestinal toxicity. No other late grade ≥ 3 events were observed. CONCLUSIONS This is the largest report to date of CT/MRI-based IGBT for the treatment of cervical cancer. The results are promising, with excellent local control and acceptable toxicity. Further investigation is needed to assess the long-term safety and efficacy of this treatment.

Recent Advances in Image-Guided Radiotherapy for Head and Neck Carcinoma

Radiotherapy has a well-established role in the management of head and neck cancers. Over the past decade, a variety of new imaging modalities have been incorporated into the radiotherapy planning and delivery process. These technologies are collectively referred to as image-guided radiotherapy and may lead to significant gains in tumor control and radiation side effect profiles. In the following review, these techniques as they are applied to head and neck cancer patients are described, and clinical studies analyzing their use in target delineation, patient positioning, and adaptive radiotherapy are highlighted. Finally, we conclude with a brief discussion of potential areas of further radiotherapy advancement.