Shannon Kahn

Finger extensor variability in TMS parameters among chronic stroke patients

BackgroundThis study determined the reliability of topographic motor cortical maps and MEP characteristics in the extensor digitorum communis (EDC) evoked by single-pulse TMS among patients with chronic stroke.MethodsEach of ten patients was studied on three occasions. Measures included location of the EDC hotspot and center of gravity (COG), threshold of activation and average amplitude of the hotspot, number of active sites, map volume, and recruitment curve (RC) slope.ResultsConsistent intrahemispheric measurements were obtained for the three TMS mapping sessions for all measured variables. No statistically significant difference was observed between hemispheres for the number of active sites, COG distance or the RC slope. The magnitude and range of COG movement between sessions were similar to those reported previously with this muscle in able-bodied individuals. The average COG movement over three sessions in both hemispheres was 0.90 cm. The average COG movement in the affected hemisphere was 1.13 (± 0.08) cm, and 0.68 (± 0.04) cm) for the less affected hemisphere. However, significant interhemispheric variability was seen for the average MEP amplitude, normalized map volume, and resting motor threshold.ConclusionThe physiologic variability in some TMS measurements of EDC suggest that interpretation of TMS mapping data derived from hemiparetic patients in the chronic stage following stroke should be undertaken cautiously. Irrespective of the muscle, potential causes of variability should be resolved to accurately assess the impact of pharmacological or physical interventions on cortical organization as measured by TMS among patients with stroke.

Does the Addition of Involved Field Radiotherapy to High-dose Chemotherapy and Stem Cell Transplantation Improve Outcomes for Patients with Relapsed/Refractory Hodgkin Lymphoma?

PURPOSE To evaluate the value of adding involved field radiotherapy (IFRT) to patients with relapsed/refractory Hodgkin lymphoma (HL) undergoing high-dose chemotherapy (HDCT) and stem cell transplantation (SCT). METHODS AND MATERIALS Ninety-two patients with relapsed/refractory HL undergoing HDCT and SCT from 1995 to 2008 were analyzed in a case-control design. Forty-six HL patients treated with IFRT within 2 months of SCT were matched to 46 HL patients who did not receive IFRT based on age, stage at relapse, timing of relapse, histology, and year of SCT. All were evaluated for response, survival, and toxicity with a median followup of 63.5 months. RESULTS There was a trend for better disease control in patients receiving IFRT. Specifically, 10/46 IFRT patients (22%) relapsed/progressed after SCT compared with 17/46 control patients (37%). Of the failures after IFRT, 70% were inside the radiation field, all in sites of bulky disease. In patients with nonbulky disease, IFRT also resulted in significantly improved outcomes (failure rate 6% vs. 33%, respectively). When stratified by disease bulk, the use of IFRT was found to significantly improve DFS (p=0.032), but did not affect OS. In addition, IFRT and nonbulky disease were found to be positive prognostic indicators for DFS with hazard ratios of 0.357 (p=0.032) and 0.383 (p=0.034), respectively. Grade IV/V toxicities were significantly higher in the IFRT vs. non-IFRT group (28% vs. 2%; p<0.001), observed only in patients receiving a busulfan-based conditioning regimen. CONCLUSION Patients with refractory or relapsed HL undergoing HDCT and SCT have a high risk of relapse in sites of prior disease involvement, especially in sites of bulky disease. The use of IFRT is associated with a lower risk of disease progression in these sites; however bulky disease sites are still difficult to control. Toxicity risk is significant, particularly when busulfan-based conditioning is combined with IFRT, and alternative chemotherapy conditioning regimens should be considered.

Silencing CDK4 radiosensitizes breast cancer cells by promoting apoptosis

BackgroundThe discovery of molecular markers associated with various breast cancer subtypes has greatly improved the treatment and outcome of breast cancer patients. Unfortunately, breast cancer cells acquire resistance to various therapies. Mounting evidence suggests that resistance is rooted in the deregulation of the G1 phase regulatory machinery.MethodsTo address whether deregulation of the G1 phase regulatory machinery contributes to radiotherapy resistance, the MCF10A immortalized human mammary epithelial cell line, ER-PR-Her2+ and ER-PR-Her2- breast cancer cell lines were irradiated. Colony formation assays measured radioresistance, while immunocytochemistry, Western blots, and flow cytometry measured the cell cycle, DNA replication, mitosis, apoptosis, and DNA breaks.ResultsMolecular markers common to all cell lines were overexpressed, including cyclin A1 and cyclin D1, which impinge on CDK2 and CDK4 activities, respectively. We addressed their potential role in radioresistance by generating cell lines stably expressing small hairpin RNAs (shRNA) against CDK2 and CDK4. None of the cell lines knocked down for CDK2 displayed radiosensitization. In contrast, all cell lines knocked down for CDK4 were significantly radiosensitized, and a CDK4/CDK6 inhibitor sensitized MDA-MB-468 to radiation induced apoptosis. Our data showed that silencing CDK4 significantly increases radiation induced cell apoptosis in cell lines without significantly altering cell cycle progression, or DNA repair after irradiation. Our results indicate lower levels of phospho-Bad at ser136 upon CDK4 silencing and ionizing radiation, which has been shown to signal apoptosis.ConclusionBased on our data we conclude that knockdown of CDK4 activity sensitizes breast cancer cells to radiation by activating apoptosis pathways.

Matched Cohort Analysis of Outcomes of Definitive Radiotherapy for Prostate Cancer in Human Immunodeficiency Virus-Positive Patients

PURPOSE To compare the biochemical outcome and toxicity scores of men with human immunodeficiency virus (HIV) and prostate cancer with a matched control population with negative or unknown HIV status when treated with external-beam radiotherapy (EBRT). METHODS AND MATERIALS A single-institution database of men with prostate cancer treated with EBRT from 1999 to 2009 was reviewed. Thirteen men with HIV were identified and matched to 2 control patients according to age, race, T stage, prostate-specific antigen level, Gleason score, RT dose, intensity-modulated RT vs. three-dimensional conformal RT, and whole-pelvis vs. prostate-only RT, for a total of 39 cases. The median follow-up time was 39 months (range, 3-110 months). RESULTS The 4-year biochemical failure (BF)-free survival rate was 87% in the HIV-positive group vs. 89% in the controls (p = 0.94). Pre- and post-RT viral loads were found to be predictive of BF (p = 0.04 and p = 0.04, respectively). No men with HIV died, whereas 2 in the control group died of causes unrelated to prostate cancer. Acute and chronic genitourinary and gastrointestinal toxicity were less in the HIV-positive patients than in controls (p < 0.001, p < 0.001, p = 0.003, and p < 0.001, respectively). The HIV-positive men experienced an average decline in CD4 count of 193 cells/mm(3). CONCLUSIONS Our findings suggest that men with HIV treated with EBRT have a similar risk of BF; however, high viral loads may contribute to an increased risk. This analysis supports that HIV-positive men with prostate cancer can be treated with definitive EBRT with similar disease control and toxicity outcomes as in the general population.

Benefit of adjuvant radiotherapy after breast‐conserving therapy among elderly women with T1‐T2N0 estrogen receptor‐negative breast cancer

The purpose of the current study was to evaluate the impact of radiotherapy (RT) among women aged ≥ 70 years with T1‐2N0 estrogen receptor (ER)‐negative breast cancer using Surveillance, Epidemiology, and End Results (SEER)‐Medicare‐linked data.

Refractory or Relapsed Hodgkin's Disease and Non-hodgkin's Lymphoma: Optimizing Involved-field Radiotherapy in Transplant Patients

ABSTRACTThis study assessed efficacy, optimal dosage and timing, and toxicity of involved-field radiotherapy used in conjunction with high-dose chemotherapy and stem cell transplantation for patients with refractory/relapsed Hodgkins disease and non-Hodgkins lymphoma. METHODS AND MATERIALS306 patients with refractory or relapsed Hodgkins disease and non-Hodgkins lymphoma were analyzed. Forty-one patients underwent involved-field radiotherapy in conjunction with high-dose chemotherapy and bone marrow or peripheral stem cell transplantation. Thirty-three patients received involved-field radiotherapy prior to stem cell transplantation directed at symptomatic and/or bulky sites; eight patients received involved-field radiotherapy after stem cell transplantation directed at sites of persistent disease. The other 265 patients with refractory/relapsed non-Hodgkins lymphoma and Hodgkins disease received high-dose chemotherapy/stem cell transplantation, but not involved-field radiotherapy. Data were analyzed using Cox proportional hazards regression to determine the risk of death among patients treated with stem cell transplantation compared with that among patients treated with stem cell transplantation and involved-field radiotherapy. RESULTSThere were 124 deaths during the follow-up period, including 17% of the patients treated with involved-field radiotherapy and 44.2% of the patients receiving chemotherapy without involved-field radiotherapy. Multivariate analysis found that patients who did not receive involved-field radiotherapy were 2.09 times more likely to die during the follow-up period than patients who received involved-field radiotherapy (P = 0.066; adjusted for age, stem cell transplantation type, stage I/II vs stage III/IV, refractory vs relapsed, and Hodgkins disease vs non-Hodgkins lymphoma). When patients were treated with involved-field radiotherapy prior to stem cell transplantation, 27 (79.4%) of the 34 patients achieved local control; when involved-field radiotherapy followed stem cell transplantation, 6 (85.7%) of the 7 patients experienced local control. Timing of involved-field radiotherapy prior to or following stem cell transplantation did not affect patient survival. Five of the 41 patients treated with involved-field radiotherapy developed toxicity subsequent to treatment. All but one of these patients had been treated with doses greater than 30 Gy. CONCLUSIONSAlthough of borderline significance in this small sample, results of this study suggest that patients who receive involved-field radiotherapy in conjunction with stem cell transplantation may have increased survival when compared with patients who do not receive involved-field radiotherapy. Further follow-up of this cohort is necessary to confirm these findings.

Current strategies and challenges in treatment of childhood rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, affecting very young patients. These tumors often cause significant functional damage because of their aggressive growth pattern. In addition, their metastatic potential can present as a complex and challenging situation. RMS can present in various anatomical sites and often pose significant obstacle in choosing local control modalities. When feasible, surgery plays an important role for initial diagnosis and complete tumor removal; delayed primary re-excision and second-look surgery after initial chemotherapy are gaining more acceptance. Because of high-metastatic risk, systemic chemotherapy is also necessary. Novel agents are emerging which may alter the disease course in high-risk disease where the cure rate is still low. Radiation therapy is an important tool in the management of RMS and has gone through significant evolution during past four decades. This review will outline treatment strategies adopted in children RMS. The primary focus will be the North American approach with attention to advancements in radiation therapy, surgical techniques, and systemic therapies.

The role of postmastectomy radiotherapy in women with pathologic T3N0M0 breast cancer

The authors determined the impact of postmastectomy radiotherapy (PMRT) on overall survival (OS) among patients with pT3N0M0 breast cancer in the National Cancer Data Base.

Targeted sequencing and intracranial outcomes of patients with lung adenocarcinoma brain metastases treated with radiotherapy: Sequencing Outcomes in Lung Brain Metastases

Treatment for advanced lung adenocarcinoma (AC) has become increasingly personalized based on molecular results. However, for patients with AC brain metastases (BMs), intracranial outcomes based on molecular subtype and the frequency of molecular aberrations are less well defined. This study sought to report targeted next‐generation sequencing results and investigate molecularly based outcomes for patients with AC‐BMs treated with radiotherapy.