Background

Phase 3 studies of bevacizumab in patients with advanced pancreatic cancer (APCA) demonstrated no improvement in outcome. To the authors' knowledge, no validated predictive biomarkers for bevacizumab exist, although emerging data suggest that subsets of patients with APCA may benefit from treatment with bevacizumab. The authors evaluated baseline serum albumin (b-alb) as a predictive biomarker in a pooled analysis from 7 prospective clinical trials of gemcitabine-based therapy with or without bevacizumab.

Methods

Data were collected from individual databases from 7 prospective clinical trials. Patients were grouped by exposure to bevacizumab and by b-alb level (≥ 3.4 g/L or < 3.4 g/dL). Overall survival (OS), time to disease progression (TTP), overall response rate, and disease control rate (overall response rate plus stable disease lasting ≥ 16 weeks) were compared between groups. Univariate and multivariable analyses of prognostic factors were performed.

Results

A total of 264 patients were included. The median age was 59 years (range, 31 years-85 years) and all patients had stage IV disease per TNM staging. Normal b-alb was associated with significantly improved median OS (10.2 months vs 4.1 months; P = .0001), median TTP (6.2 months vs 3.7 months; P = 0.0488), and disease control rate (71% vs 46%; P = .007) for patients receiving bevacizumab, but not for those treated without bevacizumab. Multivariable analysis revealed a significant influence of normal b-alb on OS (P = .0008) and TTP (P = .033).

Conclusions

Patients with APCA with normal b-alb derive benefit from treatment with bevacizumab. Future prospective investigations of bevacizumab in patients with APCA should consider selecting patients with normal b-alb to maximize potential benefit.

Recent studies have identified oncogenic lesions in Philadelphia chromosome-positive (Ph+)  acute lymphoblastic leukemia (ALL) and ABL1 kinase mutations that confer resistance to tyrosine kinase inhibitors. We sought to determine the prevalence and clinical impact of these lesions in patients on CALGB 10001, a previously reported Phase II study of imatinib, chemotherapy, and hematopoietic cell transplant in adult Ph + ALL. Of the 58 enrolled, 22 relapsed. By direct sequencing, an ABL1 kinase mutation known to induce imatinib resistance was present at relapse in 13 of 20. Using quantitative PCR assays, the mutations were detectable at diagnosis or early during treatment in most (62%) relapsed patients. Aberrations in IKZF1, CDKN2A/B, and PAX5 were assessed in 28 samples using SNP arrays and genomic DNA sequencing. Of these, 22 (79%) had IKZF1 deletion. The combination of IKZF1 deletion and p210 BCR-ABL1 (p < 0.0001), high white blood cell count (p = 0.021), and minimal residual disease (p = 0.013) were associated with worse disease-free survival.

Objective

The phenotypic diversity of type 1 diabetes suggests heterogeneous etiopathogenesis. We investigated the relationship of type 2 diabetes-associated transcription factor 7 like 2 (TCF7L2) single nucleotide polymorphisms (SNPs) with immunologic and metabolic characteristics at type 1 diabetes diagnosis.

Research design and methods

We studied TrialNet participants with newly diagnosed autoimmune type 1 diabetes with available TCF7L2 rs4506565 and rs7901695 SNP data (n = 810; median age 13.6 years; range 3.3-58.6). We modeled the influence of carrying a TCF7L2 variant (i.e., having 1 or 2 minor alleles) on the number of islet autoantibodies and oral glucose tolerance test (OGTT)-stimulated C-peptide and glucose measures at diabetes diagnosis. All analyses were adjusted for known confounders.

Results

The rs4506565 variant was a significant independent factor of expressing a single autoantibody, instead of multiple autoantibodies, at diagnosis (odds ratio [OR] 1.66 [95% CI 1.07, 2.57], P = 0.024). Interaction analysis demonstrated that this association was only significant in participants ≥12 years old (n = 504; OR 2.12 [1.29, 3.47], P = 0.003) but not younger ones (n = 306, P = 0.73). The rs4506565 variant was independently associated with higher C-peptide area under the curve (AUC) (P = 0.008) and lower mean glucose AUC (P = 0.0127). The results were similar for the rs7901695 SNP.

Conclusions

In this cohort of individuals with new-onset type 1 diabetes, type 2 diabetes-linked TCF7L2 variants were associated with single autoantibody (among those ≥12 years old), higher C-peptide AUC, and lower glucose AUC levels during an OGTT. Thus, carriers of the TCF7L2 variant had a milder immunologic and metabolic phenotype at type 1 diabetes diagnosis, which could be partly driven by type 2 diabetes-like pathogenic mechanisms.

Background

Critical injury has been associated with reduction in innate immune function in adults, with infection risk being related to degree of immune suppression. This relationship has not been reported in critically injured children.

Hypothesis

Innate immune function will be reduced in critically injured children, and the degree of reduction will predict the subsequent development of nosocomial infection.

Methods

Children (≤18 years old) were enrolled in this longitudinal, prospective, observational, single-center study after admission to the pediatric intensive care unit following critical injury, along with a cohort of outpatient controls. Serial blood sampling was performed to evaluate plasma cytokine levels and innate immune function as measured by ex vivo lipopolysaccharide-induced tumor necrosis factor α (TNF-α) production capacity.

Results

Seventy-six critically injured children (and 21 outpatient controls) were enrolled. Sixteen critically injured subjects developed nosocomial infection. Those subjects had higher plasma interleukin 6 and interleukin 10 levels on posttrauma days 1-2 compared with those who recovered without infection and outpatient controls. Ex vivo lipopolysaccharide-induced TNF-α production capacity was lower on posttrauma days 1-2 (P = 0.006) and over the first week following injury (P = 0.04) in those who went on to develop infection. A TNF-α response of less than 520 pg/mL at any time in the first week after injury was highly associated with infection risk by univariate and multivariate analysis. Among transfused children, longer red blood cell storage age, not transfusion volume, was associated with lower innate immune function (P < 0.0001). Trauma-induced innate immune suppression was reversible ex vivo via coculture of whole blood with granulocyte-macrophage colony-stimulating factor.

Conclusions

Trauma-induced innate immune suppression is common in critically injured children and is associated with increased risks for the development of nosocomial infection. Potential exacerbating factors, including red blood cell transfusion, and potential therapies for pediatric trauma-induced innate immune suppression are deserving of further study.

Type 1 diabetes is an autoimmune disease arising from the destruction of pancreatic insulin-producing beta cells. The disease represents a continuum, progressing sequentially at variable rates through identifiable stages prior to the onset of symptoms, through diagnosis and into the critical periods that follow, culminating in a variable depth of beta cell depletion. The ability to identify the very earliest of these presymptomatic stages has provided a setting in which prevention strategies can be trialled, as well as furnishing an unprecedented opportunity to study disease evolution, including intrinsic and extrinsic initiators and drivers. This niche opportunity is occupied by Type 1 Diabetes TrialNet, an international consortium of clinical trial centres that leads the field in intervention and prevention studies, accompanied by deep longitudinal bio-sampling. In this review, we focus on discoveries arising from this unique bioresource, comprising more than 70,000 samples, and outline the processes and science that have led to new biomarkers and mechanistic insights, as well as identifying new challenges and opportunities. We conclude that via integration of clinical trials and mechanistic studies, drawing in clinicians and scientists and developing partnership with industry, TrialNet embodies an enviable and unique working model for understanding a disease that to date has no cure and for designing new therapeutic approaches.

Objective

The type 2 diabetes-associated alleles at the TCF7L2 locus mark a type 1 diabetes phenotype characterized by single islet autoantibody positivity as well as lower glucose and higher C-peptide measures. Here, we studied whether the TCF7L2 locus influences progression of islet autoimmunity, from single to multiple (≥2) autoantibody positivity, in relatives of patients with type 1 diabetes.

Research design and methods

We evaluated 244 participants in the Type 1 Diabetes TrialNet Pathway to Prevention study with confirmed single autoantibody positivity at screening and Immunochip single nucleotide polymorphism data (47.5% male; median age 12.8 years, range 1.2-45.9; 90.2% white). We analyzed risk allele frequency at TCF7L2 rs4506565 (in linkage disequilibrium with rs7903146). Altogether, 62.6% participants carried ≥1 risk allele. Univariate and multivariable Cox proportional hazards models and Kaplan-Meier statistical methods were used.

Results

During follow-up (median 5.2 years, range 0.2-12.6), 62% of the single autoantibody-positive participants developed multiple autoantibody positivity. In the overall cohort, the TCF7L2 locus did not significantly predict progression to multiple autoantibody positivity. However, among single GAD65 autoantibody-positive participants (n = 158), those who carried ≥1 risk allele had a lower rate of progression to multiple autoantibody positivity (hazard ratio [HR] 0.65, P = 0.033) than those who did not, after adjustment for HLA risk haplotypes and age. Among subjects who were either IA-2 or insulin autoantibody positive only, carrying ≥1 TCF7L2 risk allele was not a significant factor overall, but in overweight or obese participants, it increased the risk of progression to multiple autoantibody positivity (HR 3.02, P = 0.016) even with adjustment for age.

Conclusions

The type 2 diabetes-associated TCF7L2 locus influences progression of islet autoimmunity, with differential effects by autoantibody specificity and interaction by obesity/overweight.

Objective

We aimed to determine the effect of elevated BMI over time on the progression to type 1 diabetes in youth.

Research design and methods

We studied 1,117 children in the TrialNet Pathway to Prevention cohort (autoantibody-positive relatives of patients with type 1 diabetes). Longitudinally accumulated BMI above the 85th age- and sex-adjusted percentile generated a cumulative excess BMI (ceBMI) index. Recursive partitioning and multivariate analyses yielded sex- and age-specific ceBMI thresholds for greatest type 1 diabetes risk.

Results

Higher ceBMI conferred significantly greater risk of progressing to type 1 diabetes. The increased diabetes risk occurred at lower ceBMI values in children <12 years of age compared with older subjects and in females versus males.

Conclusions

Elevated BMI is associated with increased risk of diabetes progression in pediatric autoantibody-positive relatives, but the effect varies by sex and age.

2000 Background: Craniopharyngiomas, a rare brain tumor along the pituitary-hypothalamic axis, can cause significant clinical sequelae. Surgery and radiation, the only effective treatments, can cause significant morbidity. Genetic analysis of craniopharyngiomas revealed that 95% of papillary craniopharyngiomas (PCP) have BRAF V600E mutations (Brastianos et al. Nature Genetics 2014). We evaluated the efficacy of BRAF/MEK inhibition in patients (pts) with previously untreated PCP. Methods: Eligible pts without prior radiation whose PCP screened positively for BRAF mutations were treated with oral vemurafenib/cobimetinib in 28-day cycles. The primary endpoint of response rate (RR) based on centrally determined volumetric data was evaluated in 16 pts, where a partial response was defined as >20% decrease in volume. This single arm, Simon two-stage phase 2 trial had 89% power to detect a true RR of at least 30% (vs. the null RR 5%; alpha=0.04). In this design, 3 or more observed volumetric responses in 16 evaluable pts would be considered promising activity. Results: In the 16 pts evaluated, 56% were female, and the median age was 49.5 years. Median follow-up was 22 months (95% CI: 16-26.5) and median number of treatment cycles was 8. Three patients progressed after therapy was discontinued and none have died. Based on volumetric response criteria, 14 of 15 pts with volumetric data available for central review had response to therapy (93%; 95% CI: 68% to 99.8%). Of 16 patients evaluable based on local review, 15 had response to therapy (93.75%; 95% CI: 70% to 99.8%). The median tumor reduction was -83% (range: -52% to -99%). The one nonresponder received 2 days of treatment before coming off therapy due to toxicity. Median progression-free survival was not reached. Grade 3 toxicities at least possibly related to treatment occurred in 12 pts (rash in 6 pts). Grade 4 toxicities were observed in two pts: hyperglycemia (n=1) and increased CPK (n=1). Three pts discontinued treatment for adverse events. Conclusions: Vemurafenib/cobimetinib resulted in an objective response in all pts who received 1 or more cycles of therapy. Our study indicates that BRAF/MEK inhibitors could be a powerful tool in the treatment of previously untreated PCP and warrants further evaluation in larger studies. A second arm of this study is enrolling pts with progressive PCP after prior radiotherapy. Support: U10CA180821, U10CA180882; U24CA196171, U10CA180868 (NRG); Genentech; https://acknowledgments.alliancefound.org. Clinical trial information: NCT03224767.

Abstract PURPOSE Standard of care for craniopharyngiomas is surgery with or without radiotherapy (RT). Cohort A of Alliance A071601 evaluated the efficacy of BRAF/MEK inhibition with vemurafenib/cobimetinib in patients with previously untreated papillary craniopharyngiomas (PCP), which carry the BRAF V600E mutation. Cohort B is currently enrolling patients with recurrence after RT. In a correlative analysis, we examined changes in RT volumes after BRAF/MEK therapy in Cohort A. METHODS Previously unirradiated patients with BRAF-mutated PCP were treated with vemurafenib/cobimetinib. Sixteen patients had scans available before starting vemurafenib/cobimetinib (“pre-therapy”) and after completing therapy (“post-therapy”). Two patients went off study treatment after 8 and 9 days due to side-effects and were excluded for this analysis. Gross target volumes (GTV) were contoured on pre-therapy and post-therapy scans. On post-therapy scans, an additional target comprising gross disease and at-risk regions for microscopic residual disease (GTV-micro) was defined and considered the treatment volume. Clinical target volume (CTV) was a 5-mm uniform expansion on pre-therapy GTV and post-therapy GTV-micro. Volumes were independently reviewed by two radiation oncologists. Changes in volumes from pre- versus post-therapy were compared using the Wilcoxon signed rank test. RESULTS In 14 patients evaluated, 57% were female and median age at enrollment was 49.5 years (range 33-83). Median time on treatment was 8.9 months (range 4.0-18.0). Median GTV pre-therapy was 3.8 mL (range 0.2-23.4) versus 0.3 mL (range 0.0-3.2) post-therapy (p=0.0001) and 1.7 mL (range 0.1-8.0) post-therapy GTV-micro (p=0.0001). Median CTV pre-therapy was 13.7 mL (range 2.8-51.8) versus 9.1 mL (range 2.2-27.5) post-therapy (p=0.0001). All tumors abutted the optic chiasm pre-therapy, only 6 did post-therapy. CONCLUSIONS Vemurafenib/cobimetinib resulted in smaller RT volumes. BRAF/MEK inhibitors could reduce RT volumes and spare dose to surrounding normal structures. Enrollment to Cohort B of Alliance A071601 should be considered for patients with recurrent tumors after RT. SUPPORT https://acknowledgments.alliancefound.org