Microstructure Modeling of High b-Value Diffusion-Weighted Images in Glioblastoma

Apparent diffusion coefficient has limits to differentiate solid tumor from normal tissue or edema in glioblastoma (GBM). This study investigated a microstructure model (MSM) in GBM using a clinically available diffusion imaging technique. The MSM was modified to integrate with bi-polar diffusion gradient waveforms, and applied to 30 patients with newly diagnosed GBM. Diffusion-weighted (DW) images acquired on a 3 T scanner with b-values from 0 to 2500 s/mm2 were fitted in volumes of interest (VOIs) of solid tumor to obtain the apparent restriction size of intracellular water (ARS), the fractional volume of intracellular water (Vin), and extracellular (Dex) water diffusivity. The parameters in solid tumor were compared with those of other tissue types by Students’ t test. For comparison, DW images were fitted by conventional mono-exponential and bi-exponential models. ARS, Dex, and Vin from the MSM in tumor VOIs were significantly greater than those in WM, GM, and edema (P values of .01–.001). ARS values in solid tumors (from 21.6 to 34.5 um) had absolutely no overlap with those in all other tissue types (from 0.9 to 3.5 um). Vin values showed a descending order from solid tumor (from 0.32 to 0.52) to WM, GM, and edema (from 0.05 to 0.25), consisting with the descending cellularity in these tissue types. The parameters from mono-exponential and bi-exponential models could not significantly differentiate solid tumor from all other tissue types, particularly from edema. Further development and histopathological validation of the MSM will warrant its role in clinical management of GBM

Developing a Pipeline for Multiparametric MRI-Guided Radiation Therapy: Initial Results from a Phase II Clinical Trial in Newly Diagnosed Glioblastoma

Quantitative mapping of hyperperfused and hypercellular regions of glioblastoma has been proposed to improve definition of tumor regions at risk for local recurrence following conventional radiation therapy. As the processing of the multiparametric dynamic contrast-enhanced (DCE-) and diffusion-weighted (DW-) magnetic resonance imaging (MRI) data for delineation of these subvolumes requires additional steps that go beyond the standard practices of target definition, we sought to devise a workflow to support the timely planning and treatment of patients. A phase II study implementing a multiparametric imaging biomarker for tumor hyperperfusion and hypercellularity consisting of DCE-MRI and high b-value DW-MRI to guide intensified (75 Gy/30 fractions) radiation therapy (RT) in patients with newly diagnosed glioblastoma was launched. In this report, the workflow and the initial imaging outcomes of the first 12 patients are described. Among all the first 12 patients, treatment was initiated within 6 weeks of surgery and within 2 weeks of simulation. On average, the combined hypercellular volume and high cerebral blood volume/tumor perfusion volume were 1.8 times smaller than the T1 gadolinium abnormality and 10 times smaller than the FLAIR abnormality. Hypercellular volume and high cerebral blood volume/tumor perfusion volume each identified largely distinct regions and showed 57% overlap with the enhancing abnormality, and minimal-to-no extension outside of the FLAIR. These results show the feasibility of implementing a workflow for multiparametric magnetic resonance-guided radiation therapy into clinical trials with a coordinated multidisciplinary team, and the unique and complementary tumor subregions identified by the combination of high b-value DW-MRI and DCE-MRI

Low pre-diagnosis attrition but high pre-treatment attrition among patients with MDR-TB: An operational research from Chennai, India

Background: Worldwide, there’s concern over high pre-diagnosis and pre-treatment attritions or delays in Multidrug resistant tuberculosis (MDR-TB) diagnosis and treatment pathway (DTP). We conducted this operational research among patients with presumptive MDR-TB in north and central Chennai, India to determine attrition and turnaround times (TAT) at various steps of DTP and factors associated with attrition. Methods: Study was conducted in Revised National Tuberculosis Control Programme setting. It was a retrospective cohort study involving record review of all patients with presumptive MDR-TB (eligible for DST) in 2014. Results: Of 628 eligible for DST, 557 (88%) underwent DST and 74 (13%) patients were diagnosed as having MDR-TB. Pre-diagnosis and pre-treatment attrition was 11% (71/628) and 38% (28/74) respectively. TAT [median (IQR)] to test from eligibility for DST and initiate DR-TB treatment from diagnosis were 14 (9,27) and 18 (13,36) days respectively. Patients with smear negative TB and detected in first quarter of 2014 were less likely to undergo DST. Patients in first quarter of 2014 had significantly lower risk of pre-treatment attrition. Conclusion: There was high uptake of DST. However, urgent attention is required to reduce pre-treatment attrition, improve TAT to test from eligibility for DST and improve DST among patients with smear-negative TB

Whole Brain Radiotherapy and RRx-001: Two Partial Responses in Radioresistant Melanoma Brain Metastases from a Phase I/II Clinical Trial

BACKGROUND: Kim et al. report two patients with melanoma metastases to the brain that responded to treatment with RRx-001 and whole brain radiotherapy (WBRT) without neurologic or systemic toxicity in the context of a phase I/II clinical trial. RRx-001 is an reactive oxygen and reactive nitrogen species (ROS/RNS)-dependent systemically nontoxic hypoxic cell radiosensitizer with vascular normalizing properties under investigation in patients with various solid tumors including those with brain metastases. SIGNIFICANCE: Metastatic melanoma to the brain is historically associated with poor outcomes and a median survival of 4 to 5 months. WBRT is a mainstay of treatment for patients with multiple brain metastases, but no significant therapeutic advances for these patients have been described in the literature. To date, candidate radiosensitizing agents have failed to demonstrate a survival benefit in patients with brain metastases, and in particular, no agent has demonstrated improved outcome in patients with metastatic melanoma. Kim et al. report two patients with melanoma metastases to the brain that responded to treatment with novel radiosensitizing agent RRx-001 and WBRT without neurologic or systemic toxicity in the context of a phase I/II clinical trial

A Phase 2 Study of Dose-intensified Chemoradiation Using Biologically Based Target Volume Definition in Patients With Newly Diagnosed Glioblastoma

PURPOSE: We hypothesized that dose-intensified chemoradiation therapy targeting adversely prognostic hypercellular (TV) and hyperperfused (TV) tumor volumes would improve outcomes in patients with glioblastoma. METHODS AND MATERIALS: This single-arm, phase 2 trial enrolled adult patients with newly diagnosed glioblastoma. Patients with a TV/TV \u3e1 cm, identified using high b-value diffusion-weighted magnetic resonance imaging (MRI) and dynamic contrast-enhanced perfusion MRI, were treated over 30 fractions to 75 Gy to the TV/TV with temozolomide. The primary objective was to estimate improvement in 12-month overall survival (OS) versus historical control. Secondary objectives included evaluating the effect of 3-month TV/TV reduction on OS using Cox proportional-hazard regression and characterizing coverage (95% isodose line) of metabolic tumor volumes identified using correlative C-methionine positron emission tomography. Clinically meaningful change was assessed for quality of life by the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C30, for symptom burden by the MD Anderson Symptom Inventory for brain tumor, and for neurocognitive function (NCF) by the Controlled Oral Word Association Test, the Trail Making Test, parts A and B, and the Hopkins Verbal Learning Test-Revised. RESULTS: Between 2016 and 2018, 26 patients were enrolled. Initial patients were boosted to TV alone, and 13 patients were boosted to both TV/TV. Gross or subtotal resection was performed in 87% of patients; 22% were O-methylguanine-DNA methyltransferase (MGMT) methylated. With 26-month follow-up (95% CI, 19-not reached), the 12-month OS rate among patients boosted to the combined TV/TV was 92% (95% CI, 78%-100%; P = .03) and the median OS was 20 months (95% CI, 18-not reached); the median OS for the whole study cohort was 20 months (95% CI, 14-29 months). Patients whose 3-month TV/TV decreased to less than the median volume (3 cm) had superior OS (29 vs 12 months; P = .02). Only 5 patients had central or in-field failures, and 93% (interquartile range, 59%-100%) of the C-methionine metabolic tumor volumes received high-dose coverage. Late grade 3 neurologic toxicity occurred in 2 patients. Among non-progressing patients, 1-month and 7-month deterioration in quality of life, symptoms, and NCF were similar in incidence to standard therapy. CONCLUSIONS: Dose intensification against hypercellular/hyperperfused tumor regions in glioblastoma yields promising OS with favorable outcomes for NCF, symptom burden, and quality of life, particularly among patients with greater tumor reduction 3 months after radiation therapy

BRAINSTORM: A Multi-Institutional Phase 1/2 Study of RRx-001 in Combination With Whole Brain Radiation Therapy for Patients With Brain Metastases

© 2020 The Author(s) Purpose: To determine the recommended phase 2 dose of RRx-001, a radiosensitizer with vascular normalizing properties, when used with whole-brain radiation therapy (WBRT) for brain metastases and to assess whether quantitative changes in perfusion magnetic resonance imaging (MRI) after RRx-001 correlate with response. Methods and Materials: Five centers participated in this phase 1/2 trial of RRx-001 given once pre-WBRT and then twice weekly during WBRT. Four dose levels were planned (5 mg/m2, 8.4 mg/m2, 16.5 mg/m2, 27.5 mg/m2). Dose escalation was managed by the time-to-event continual reassessment method algorithm. Linear mixed models were used to correlate change in 24-hour T1, Ktrans (capillary permeability), and fractional plasma volume with change in tumor volume. Results: Between 2015 and 2017, 31 patients were enrolled. Two patients dropped out before any therapy. Median age was 60 years (range, 30-76), and 12 were male. The most common tumor types were melanoma (59%) and non-small cell lung cancer (18%). No dose limiting toxicities were observed. The most common severe adverse event was grade 3 asthenia (6.9%, 2 of 29). The median intracranial response rate was 46% (95% confidence interval, 24-68) and median overall survival was 5.2 months (95% confidence interval, 4.5-9.4). No neurologic deaths occurred. Among 10 patients undergoing dynamic contrast-enhanced MRI, a reduction in Vp 24 hours after RRx-001 was associated with reduced tumor volume at 1 and 4 months (P ≤.01). Conclusions: The addition of RRx-001 to WBRT is well tolerated with favorable intracranial response rates. Because activity was observed across all dose levels, the recommended phase 2 dose is 10 mg twice weekly. A reduction in fractional plasma volume on dynamic contrast-enhanced MRI 24 hours after RRx-001 suggests antiangiogenic activity associated with longer-term tumor response