Citations

Abstract Immune checkpoint inhibitors such as ipilimumab and targeted BRAF inhibitors have dramatically altered the landscape of melanoma therapeutics over the past few years. Agents targeting the programmed cell death-1/ligand (PD-1/PD-L1) axis are now being developed and seem to be highly active clinically with favorable toxicity profiles. We report on two patients with BRAF V600E–mutant melanoma who were treated with anti-PD-1 agents as first-line therapy without significant toxicity, followed by vemurafenib at disease progression. Both patients developed severe hypersensitivity drug eruptions with multiorgan injury early in their BRAF inhibitor treatment course. One patient subsequently developed acute inflammatory demyelinating polyneuropathy, and the other developed anaphylaxis upon low-dose vemurafenib rechallenge. Further investigation of the immune response during combination or sequences of melanoma therapeutics is warranted. Furthermore, clinicians should maintain a high index of suspicion for these toxicities when vemurafenib is administered following an anti-PD-1 agent. Cancer Immunol Res; 1(6); 373–7. ©2013 AACR.

Purpose Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O 6 -methylguanine-DNA methyltransferase (MGMT) methylation status may be an important determinant of treatment response. Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM. Patients and Methods This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of ≥ 60 with adequate tissue. Stratification included clinical factors and tumor MGMT methylation status. Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles. The primary end point was OS. Secondary analyses evaluated the impact of MGMT status. Results A total of 833 patients were randomly assigned to either arm 1 or arm 2 (1,173 registered). No statistically significant difference was observed between arms for median OS (16.6 v 14.9 months, respectively; hazard ratio [HR], 1.03; P = .63) or median PFS (5.5 v 6.7 months; HR, 0.87; P = .06). Efficacy did not differ by methylation status. MGMT methylation was associated with improved OS (21.2 v 14 months; HR, 1.74; P < .001), PFS (8.7 v 5.7 months; HR, 1.63; P < .001), and response (P = .012). There was increased grade ≥ 3 toxicity in arm 2 (34% v 53%; P < .001), mostly lymphopenia and fatigue. Conclusion This study did not demonstrate improved efficacy for DD temozolomide for newly diagnosed GBM, regardless of methylation status. However, it did confirm the prognostic significance of MGMT methylation. Feasibility of large-scale accrual, prospective tumor collection, and molecular stratification was demonstrated.

Significance Our data demonstrate that differences in host genotype that affect the carbohydrate landscape of the distal gut interact with diet to alter the composition and function of resident microbes in a diet-dependent manner.

Objectives: TT-TG distance is a commonly used measurement for surgical decision-making in patients with patellofemoral malalignment and instability. This measurement has historically been performed utilizing axial CT scans. More recently, MRI has been proposed as an equivalent test for measurement of TT-TG distance. We sought to determine the reliability of TT-TG measurements on both MRI and CT, and to determine whether the measurements can be used interchangeably. Methods: All patients diagnosed with patellar instability who had received both CT and MRI of the knee between 2003 and 2011 were included (n=59 knees in 54 patients). Two fellowship trained musculoskeletal radiologists measured the TT-TG distances for each patient by CT and MRI in a randomized, blinded fashion for a total of 236 measurements. Inter-observer reliability was calculated between radiologists for both imaging modalities and inter-methods reliability was calculated between the two imagining modalities. The results are reported using intraclass correlation coefficients (ICC) and Bland Altman analysis (BAA). Results: The 59 knees had a mean TT-TG distance of 16.9 mm (range: 8.3-25.8) by CT and 14.7 mm (range: 1.5-25.1) by MRI. Eighteen patients (31%) had a TT-TG ≥ 20 mm by CT, and only 9 (15%) had a TT-TG ≥ 20 mm by MRI. Inter-observer reliability between the radiologists was considered excellent for both CT and MRI (ICC = 0.777 and 0.843 respectively). When comparing CT to MRI, however, the ICC was considered only fair for each of the two raters (0.532 and 0.539). A total of 11 patients (19%) had a TT-TG ≥ 20 mm on CT preoperatively and underwent distal realignment by tibial tubercle osteotomy (TTO). In this surgical subgroup, the mean TT-TG on CT was 22.5 mm (range 19.8-25.8) while the mean TT-TG on MRI was only 18.7 mm (range 14.4-22.8). Conclusion: TT-TG distance can be measured with excellent inter-rater reliability on both MRI and CT scans; however, the values derived from these two tests may not be interchangeable. This observation should be taken into consideration when MRI is used for surgical planning since MRI may underestimate TT-TG distance when compared to CT.