Rajni A. Sethi

Prospective neuraxis MRI surveillance reveals a high risk of leptomeningeal dissemination in diffuse intrinsic pontine glioma

Prognosis of diffuse intrinsic pontine gliomas (DIPGs) remains poor. Failure has been predominantly local, with leptomeningeal dissemination (LD) occurring in 4–33% of patients in pre-MRI era series. Routine craniospinal imaging after initial treatment may reveal other relapse patterns relapse. Sixteen consecutive pediatric patients with DIPG treated between 2006 and 2009 were retrospectively reviewed. Treatment regimens, recurrence patterns, survival, and pathologic diagnosis were recorded. Fourteen patients received involved-field radiotherapy to 54xa0Gy, and two patients received craniospinal irradiation for LD at presentation. Neuraxis MRI was performed at diagnosis and at 4xa0month intervals following radiotherapy. Fifteen patients have had progression of disease (median progression-free survival 5.0xa0±xa01.2xa0months), and 13 patients have died (median survival 9.0xa0±xa01.4xa0months). Local failure occurred in 12 patients (75%). LD occurred in nine patients (56%). LD was present at diagnosis in three patients, after initial staging and treatment in six patients, and during autopsy in two patients. Median overall survival was 12.0xa0±xa03.3xa0months without LD and 8.0xa0±xa02.1xa0months with LD (Pxa0=xa00.059, log rank test). Median progression-free survival was 9.5xa0±xa03.9xa0months without LD and 3.0xa0±xa02.1xa0months with LD (Pxa0=xa00.012, log rank test). The high incidence of LD probably reflects liberal use of spine MRI surveillance. All patients should undergo routine craniospinal imaging at diagnosis and follow-up. Central nervous system prophylaxis should be considered in future clinical trials.

Dyskerin depletion increases VEGF mRNA internal ribosome entry site-mediated translation

Dyskerin is a nucleolar protein encoded by the DKC1 gene that (i) stabilizes the RNA component of the telomerase complex, and (ii) drives the site-specific pseudouridilation of rRNA. It is known that the partial lack of dyskerin function causes a defect in the translation of a subgroup of mRNAs containing internal ribosome entry site (IRES) elements such as those encoding for the tumor suppressors p27 and p53. In this study, we aimed to analyze what is the effect of the lack of dyskerin on the IRES-mediated translation of mRNAs encoding for vascular endothelial growth factor (VEGF). We transiently reduced dyskerin expression and measured the levels of the IRES-mediated translation of the mRNA encoding for VEGF in vitro in transformed and primary cells. We demonstrated a significant increase in the VEGF IRES-mediated translation after dyskerin knock-down. This translational modulation induces an increase in VEGF production in the absence of a significant upregulation in VEGF mRNA levels. The analysis of a list of viral and cellular IRESs indicated that dyskerin depletion can differentially affect IRES-mediated translation. These results indicate for the first time that dyskerin inhibition can upregulate the IRES translation initiation of specific mRNAs.

Comparison of three-dimensional versus intensity-modulated radiotherapy techniques to treat breast and axillary level III and supraclavicular nodes in a prone versus supine position

BACKGROUND AND PURPOSEnTo determine the optimal method of targeting breast and regional nodes in selected breast cancer patients after axillary dissection, we compared the results of IMRT versus no IMRT, and CT-informed versus clinically-placed fields, in supine and prone positions.nnnMATERIALS AND METHODSnTwelve consecutive breast cancer patients simulated both prone and supine provided the images for this study. Four techniques were used to target breast, level III axilla, and supraclavicular fossa in either position: a traditional three-field three-dimensional conformal radiotherapy (3DCRT) plan, a four-field 3DCRT plan using a posterior axillary boost field, and two techniques using a CT-informed target volume consisting of an optimized 3DCRT plan (CT-planned 3D) and an intensity-modulated radiotherapy (IMRT) plan. The prescribed dose was 50 Gy in 25 fractions.nnnRESULTSnCT-planned 3D and IMRT techniques improved nodal PTV coverage. Supine, mean nodal PTV V50 was 50% (3-field), 59% (4-field), 92% (CT-planned 3D), and 94% (IMRT). Prone, V50 was 29% (3-field), 42% (4-field), 97% (CT-planned 3D), and 95% (IMRT). Prone positioning, compared to supine, and IMRT technique, compared to 3D, lowered ipsilateral lung V20.nnnCONCLUSIONSnTraditional 3DCRT plans provide inadequate nodal coverage. Prone IMRT technique resulted in optimal target coverage and reduced ipsilateral lung V20.

Six-month depot formulation of leuprorelin acetate in the treatment of prostate cancer

Hormonal deprivation therapy is well established for the treatment of locally advanced and metastatic prostate cancer, as well as the adjuvant treatment of some patients with localized disease. Long-acting gonadotropin releasing hormone (GnRH) agonists have become a mainstay of androgen deprivation therapy, due to their efficacy, tolerability, and convenience of use. One-month, 3-month, and 4-month depot leuprorelin formulations are well established and widely used to this end. Recently, a 6-month depot leuprorelin has been approved for use in advanced and metastatic prostate cancer patients. With similar efficacy and side effect profiles to earlier formulations, 6-month depot leuprorelin is a convenient treatment option for these patients. This review will highlight the role of GnRH agonists in the treatment of prostate cancer with a focus on the clinical efficacy, pharmacology, and patient-focused outcomes of the newer 6-month 45 mg depot leuprorelin formulation in comparison to available shorter-acting products.

Is there a role for an external beam boost in cervical cancer radiotherapy

Objectives: Some patients are medically unfit for or averse to undergoing a brachytherapy boost as part of cervical cancer radiotherapy. In order to be able to definitively treat these patients, we assessed whether we could achieve a boost plan that would mimic our brachytherapy plans using external beam radiotherapy. Methods: High dose rate brachytherapy plans of 20 patients with stage IIB cervical cancer treated with definitive chemoradiotherapy were included in this study. Patients had undergone computer tomography (CT) simulations with tandem and ovoids in place. Point “A” dose was 600–700 cGy. We attempted to replicate the boost dose distribution from brachytherapy plans using intensity-modulated radiotherapy (Varian Medical Systems, Palo Alto, CA, USA), volumetric modulated arc therapy (Rapid Arc, Varian Medical Systems, Palo Alto, CA, USA), or TomoTherapy (Accuray, Inc., Sunnyvale, CA, USA) with the brachytherapy 100% isodose line as our target. Target coverage, normal tissue dose, and brachytherapy point doses were compared with ANOVA. Two-sided p-values ≤0.05 were considered significant. Results: External beam plans had excellent planning target volume (PTV) coverage, with no difference in mean PTV V95% among planning techniques (range 98–100%). External beam plans had lower bladder Dmax, small intestine Dmax, and vaginal mucosal point dose than brachytherapy plans, with no difference in bladder point dose, mean bladder dose, mean small intestine dose, or rectal dose. Femoral head dose, parametria point dose, and pelvic sidewall point dose were higher with external beam techniques than brachytherapy. Conclusions: External beam plans had comparable target coverage and potential for improved sparing of most normal tissues compared to tandem and ovoid brachytherapy.

Dose-Response Relationships for Meningioma Radiosurgery.

Objective:Dose-response relationships for meningioma radiosurgery are poorly characterized. We evaluated determinants of local recurrence for meningiomas treated with Gamma Knife radiosurgery (GKRS), to guide future treatment approaches to optimize tumor control. Materials and Methods:A total of 101 consecutive patients (108 tumors) who underwent GKRS for benign, atypical, or malignant meningiomas between 1998 and 2011 were studied. Local recurrence was assessed. Cox proportional hazards and logistic regression analyses were used to determine the association of patient-related, tumor-related, and treatment-related characteristics with local recurrence. Acute and late toxicity was evaluated. Results:World Health Organization (2007 classification) tumor grade was I (82%), II (11%), or III (7%). Median dose was 14 Gy (range, 10 to 18 Gy) for grade I tumors and 16 Gy (range, 12 to 20 Gy) for grade II and III tumors. Median follow-up was 25 months (maximum, 17 y). Two- /5-year actuarial local control rates were 100%/98% for grade I tumors and 76%/56% for grade II/III tumors. Higher tumor grade and lower GKRS dose were associated with local failure. In this cohort, there was a 42% relative reduction in local recurrence for each 1 Gy of dose escalation. Conclusions:Treatment was well tolerated with no moderate or severe toxicity. Tumor control was excellent in benign tumors and suboptimal in higher grade tumors. Because the main determinant of local recurrence was GKRS dose, we recommend dose escalation for atypical or malignant tumors to doses between 16 and 20 Gy where critical structures allow.