Sean Sachdev

Regulator of Calcineurin (RCAN1-1L) Is Deficient in Huntington Disease and Protective against Mutant Huntingtin Toxicity in Vitro

Our work suggests an important new link between the RCAN1 gene and Huntington disease. Huntington disease is caused by expansion of glutamine repeats in the huntingtin protein. How the huntingtin protein with expanded polyglutamines (mutant huntingtin) causes the disease is still unclear, but phosphorylation of huntingtin appears to be protective. Increased huntingtin phosphorylation can be produced either by inhibition of the phosphatase calcineurin or by activation of the Akt kinase. The RCAN1 gene encodes regulators of calcineurin, and we now demonstrate, for the first time, that RCAN1-1L is depressed in Huntington disease. We also show that RCAN1-1L overexpression can protect against mutant huntingtin toxicity in an ST14A cell culture model of Huntington disease and that increased phosphorylation of huntingtin via calcineurin inhibition, rather than via Akt induction or activation, is the likely mechanism by which RCAN1-1L may be protective against mutant huntingtin. These findings suggest that RCAN1-1L “deficiency” may actually play a role in the etiology of Huntington disease. In addition, our results allow for the possibility that controlled overexpression of RCAN1-1L in the striatal region of the brain might be a viable avenue for therapeutic intervention in Huntington disease patients (and perhaps other polyglutamine expansion disorders).

Stereotactic radiosurgery yields long-term control for benign intradural, extramedullary spinal tumors.

BACKGROUND:The role of stereotactic radiosurgery in the treatment of benign intracranial lesions is well established. Although a growing body of evidence supports its role in the treatment of malignant spinal lesions, a much less extensive dataset exists for treatment of benign spinal tumors. OBJECTIVE:To examine the safety and efficacy of stereotactic radiosurgery for treatment of benign, intradural extramedullary spinal tumors. METHODS:From 1999 to 2008, 87 patients with 103 benign intradural extramedullary spinal tumors (32 meningiomas, 24 neurofibromas, and 47 schwannomas) were treated with stereotactic radiosurgery at Stanford University Medical Center. Forty-three males and 44 females had a median age of 53 years (range, 12-86). Twenty-five patients had neurofibromatosis. Treatment was delivered in 1 to 5 sessions (median, 2) with a mean prescription dose of 19.4 Gy (range, 14-30 Gy) to an average tumor volume of 5.24 cm3 (range, 0.049-54.52 cm3). RESULTS:After a mean radiographic follow-up period of 33 months (range, 6-87), including 21 lesions followed for ≥ 48 months, 59% were stable, 40% decreased in size, and a single tumor (1%) increased in size. Clinically, 91%, 67%, and 86% of meningiomas, neurofibromas, and schwannomas, respectively, were symptomatically stable to improved at last follow-up. One patient with a meningioma developed a new, transient myelopathy at 9 months, although the tumor was smaller at last follow-up. CONCLUSION:As a viable alternative to microsurgical resection, stereotactic radiosurgery provides safe and efficacious long-term control of benign intradural, extramedullary spinal tumors with a low rate of complication.

Thyroid V50 Highly Predictive of Hypothyroidism in Head-and-Neck Cancer Patients Treated With Intensity-modulated Radiotherapy (IMRT).

Objectives: Radiation-induced hypothyroidism affects a significant number of patients with head-and-neck squamous cell cancer (HNSCC). We examined detailed dosimetric and clinical parameters to better determine the risk of hypothyroidism in euthyroid HNSCC patients treated with intensity-modulated radiation therapy (IMRT). Materials and Methods: From 2006 to 2010, 75 clinically euthyroid patients with HNSCC were treated with sequential IMRT. The cohort included 59 men and 16 females with a median age of 55 years (range, 30 to 89 y) who were treated to a median dose of 70 Gy (range, 60 to 75 Gy) with concurrent chemotherapy in nearly all (95%) cases. Detailed thyroid dosimetric parameters including maximum dose, mean dose, and other parameters (eg, V50—percent volume receiving at least 50 Gy) were obtained. Freedom from hypothyroidism was evaluated using the Kaplan-Meier method. Univariate and multivariate analyses were conducted using Cox regression. Results: After a median follow-up period of 50 months, 25 patients (33%) became hypothyroid. On univariate analysis, thyroid V50 was highly correlated with developing hypothyroidism (P=0.035). Other dosimetric paramaters including mean thyroid dose (P=0.11) and maximum thyroid dose (P=0.39) did not reach statistical significance. On multivariate analysis incorporating patient, tumor, and treatment variables, V50 remained highly statistically significant (P=0.037). Regardless of other factors, for V50>60%, the odds ratio of developing hypothyroidism was 6.76 (P=0.002). Conclusions: In HNSCC patients treated with IMRT, thyroid V50 highly predicts the risk of developing hypothyroidism. V50>60% puts patients at a significantly higher risk of becoming hypothyroid. This can be a useful dose constraint to consider during treatment planning.

Hyperthermia and radiation therapy for locally advanced or recurrent breast cancer.

INTRODUCTION This study aims to report the outcome and toxicity of combined hyperthermia (HT) and radiation therapy (RT) in treatment of locally advanced or loco-regionally recurrent breast cancer. PATIENTS AND METHODS Patients treated with HT and RT from January 1991 to December 2007 were reviewed. RT doses for previously irradiated patients were > 40 Gy and for RT naïve patients > 60 Gy, at 1.8-2 Gy/day. HT was planned for 2 sessions/week, immediately after RT, for a minimum of 20 min and for > 4 sessions. Superficial or interstitial applicators were used with temperature measured by superficial or interstitial thermistors based on target thickness. HT treatment was assessed by thermal equivalent dose (TED), > 42.5 °C and > 43 °C. Endpoints included treatment response, lack of local progression (local control), and survival. RESULTS 127 patients received HT and RT to 167 sites. These included the intact breast (24.4%), chest wall/skin (67.7%), and breast/chest wall and nodes (7.9%). At a median follow-up of 13 months (mean 30 ± 38), improved overall survival was significantly associated with increasing RT dose (p < 0.0001), median TED 42.5 °C ≥ 200 min (p = 0.003), and local control (p = 0.0002). Local control at last follow-up was seen in 55.1% of patients. Complete response was significantly associated with median TED 42.5 °C ≥ 200 min (p = 0.002) and median TED 43 °C ≥ 100 min (p = 0.03). CONCLUSION HT and RT are effective for locally advanced or recurrent breast cancer in patients that have been historically difficult to treat by RT alone. Over 50% of patients achieved control of locoregional disease. Overall survival was improved with local control.

Splenic rupture after uncomplicated colonoscopy.

Colonoscopy is a commonly performed medical procedure generally considered safe and effective. Rare complications include postpolypectomy bleeding and perforation. A far less common and more unusual complication is splenic injury. We present the case of a patient who developed this very outcome, presenting to the emergency department with abdominal pain several hours after the procedure. The mechanism of such injury is not known but has been hypothesized to be either traction on the splenocolic ligament or previously formed adhesions, direct blunt injury, or special maneuvers used to advance the colonoscope. Patients typically present with severe abdominal pain less than 24 hours after the procedure and may demonstrate Kehrs sign. Computed tomographic imaging is the diagnostic method of choice, and suspicion of splenic injury should necessitate careful observation with potential for operative intervention.

c-Met Overexpression in Cervical Cancer, a Prognostic Factor and a Potential Molecular Therapeutic Target.

Purpose: This study aimed to assess the association between pretreatment c-Met overexpression in local-regional advanced cervical cancer patients treated definitively with concurrent chemoradiation therapy (CRT) and treatment outcomes including overall survival (OS), progression-free survival (PFS), distant metastases (DM) control, and local-regional control (LC). Patients and Methods: This Institutional Review Board–approved study included cervical cancer patients treated definitively and consecutively with CRT. Evaluation of cytoplasmic immunoreactivity for c-Met was performed and scored semiquantitatively by 3 pathologists, blinded to the treatment outcomes, and incorporated both the intensity and percentage of immunoreactivity in invasive carcinoma (H score). Treatment outcomes were reviewed and reported. Outcomes were stratified by c-Met overexpression and tumor characteristics. OS, PFS, LC, and DC rates were obtained via the Kaplan-Meier method and differences between groups were evaluated by the log-rank test. Hazard ratios were obtained via Cox regression for both univariate and multivariate analyses. Results: The 5-year OS, PFS, LC, and DC were 57.18%, 48.07%, 72.11%, and 62.85%, respectively. Ten (35.7%) and 18 patients (64.3%) had c-Met H index >30 and<30, respectively. c-Met overexpression was significantly associated with worse 3- and 5-year OS (P=0.003), PFS (P=0.002), LC (P=0.01), and DC (P=0.0003). Patients with c-Met overexpression had a hazard ratio of 6.297, 5.782, 6.28, and 18.173 for the risks of death, disease progression, local recurrence, and DM, respectively. Conclusion: c-Met overexpression could be a potential predictive marker and therapeutic target for local-regional advanced cervical cancer patients treated definitively with CRT.

Gamma Knife Stereotactic Radiosurgery for Grade 2 Meningiomas

Purpose This study aims to report long‐term clinical outcomes after Gamma Knife radiosurgery (GKRS) for intracranial grade 2 meningiomas. Methods In this Institutional Review Board approved study, we reviewed records of all patients with grade 2 meningiomas treated with GKRS between 1998 and 2014. Results A total of 97 postoperative histopathologically confirmed grade 2 meningiomas in 75 patients were treated and are included in this study. After a mean follow‐up of 41 months, 28 meningiomas had local recurrence (29.79%). Median time to local recurrence was 89 months (mean: 69, range: 47‐168). The 3‐ and 5‐year actuarial local control (LC) rates were 68.9 and 55.7%, respectively. The 3‐ and 5‐year overall survival rates were 88.6 and 81.1%, respectively. There was a trend toward worse LC with tumors treated with radiation doses ≤ 13 versus > 13 Gy. There was no radiation necrosis or second malignant tumors noted in our series. Conclusion This report, one of the largest GKRS series for grade 2 meningiomas, demonstrates that GKRS is a safe and effective treatment modality for patients with grade 2 meningiomas with durable tumor control and minimal toxicity. Adjuvant GKRS could be considered as a reasonable treatment approach for patients with grade 2 meningiomas.

Gross total resection and adjuvant radiotherapy most significant predictors of improved survival in patients with atypical meningioma

Atypical and malignant meningiomas are far less common than benign meningiomas. As aggressive lesions, they are prone to local recurrence and may lead to decreased survival. Although malignant meningiomas typically are treated with maximal surgical resection and adjuvant radiotherapy (RT), to the authors’ knowledge the optimal treatment for atypical lesions remains to be defined. There are limited prospective data in this setting.

Quantifying radiation dose delivered to individual shoulder muscles during breast radiotherapy

BACKGROUND AND PURPOSE Radiotherapy is an effective treatment for managing breast cancer, but patients may experience shoulder morbidity after completing radiotherapy. There is a knowledge gap regarding how the inclusion of the regional lymphatics in radiation treatment regimens influence the radiation dose delivered to the underlying shoulder musculature. MATERIAL AND METHODS Five standardized radiation treatment regimens were developed from the computed tomography (CT) scans of 11 patients: tangent fields only (T), high tangent fields (HT), T+supraclavicular fossa and axillary apex with an anterior oblique beam (SCV), T+SCV+axillary nodes with an anterior oblique beam (SCV+AX), and T+SCV+AX with the nodal regions treated with a directly opposed beam configuration (DO). The muscle volumes for nine shoulder muscles anatomically located with the treatment regimens were segmented from the same CT scans. The effect of the nine muscles and five treatment regimens on the percentage of each muscle receiving at least 48Gy (V48Gy) was analyzed with two-way and one-way repeated measures ANOVAs. RESULTS A statistically significant interaction existed between the nine shoulder muscles and five treatment regimens (p<0.001) on the V48Gy dose. Subsequent one-way analyses found statistically significant main effects of treatment plan on the V48Gy dose for each muscle (p<0.001). The pectoralis major and minor had the greatest V48 doses across the five treatments regimens. The HT, SCV+AX and DO treatment regimens produced statistically significant increases in the V48 dose of the latissimus dorsi and teres major. The infraspinatus, subscapularis, supraspinatus, teres minor, and trapezius only observed statistically significant V48 doses when treated with a DO plan. CONCLUSIONS These findings highlight the muscles (pectoralis major, pectoralis minor, latissimus dorsi, and teres major) that may exhibit future morbidity after radiation, and indicate that nodal RT delivered with a DO beam arrangement delivers the highest muscle dose.

Dejerine-Roussy syndrome from thalamic metastasis treated with stereotactic radiosurgery

Dejerine-Roussy syndrome (central thalamic pain) is associated with damage to the ventral posterior sensory nuclei of the thalamus. We report a patient with breast cancer who developed contralateral hemibody paresthesias and dysesthesias. MR imaging revealed limited volume intracranial metastatic disease including a right posterior thalamic lesion. Stereotactic radiosurgery was utilized to selectively treat the lesion while preserving the remaining thalamus. Two months following treatment, the patient reported vastly improved to complete resolution of her sensory symptoms. This is the first reported case of thalamic tumor directed radiosurgical treatment leading to resolution of central neuropathic pain.