Introduction

Basic science results suggest that abnormalities of the endocrine pancreas in cystic fibrosis (CF) occur earlier than hitherto estimated (1). All stages of the abnormal glucose tolerance (AGT) spectrum are associated with declining pulmonary function and increased mortality which could be reduced by early recognition and treatment (2-4). Despite, screening for AGT is recommended only from 10 years of age (yoa) according to the current guidelines (5,6). Accurate knowledge of the prevalence of AGT and its subtypes is essential to develop a better screening strategy, therefore we conducted a systematic review and meta-analysis in the topic.

Aims & Methods

Our systematic review and meta-analysis (PROSPERO number: CRD42021282516) was conducted on studies that reported data on the prevalence of AGT or its subtypes in CF populations. Literature search was conducted in MEDLINE (via PubMed), Embase and Cochrane Register of Controlled Trials (CENTRAL). General and superselected populations (e.g.: pancreas exocrine insufficient, ΔF508 homozygous) were separately analyzed. Pooled proportions, risk and odds ratios with 95% confidence intervals (CI) were calculated in at least three age subgroups (pediatric, adult, mixed/unknown). One-stage dose-response random effect meta-analysis was used to assess the effect of age on CF- related diabetes (CFRD).

Results

The quantitative analysis included 457 studies and data from 520,544 patients. More than one third of children with CF (chwCF) were affected by AGT (0.31 [95% CI 0.25-0.37]), even under 10 yoa 0.33 [95% CI 0.23-0.44], and half of the adults with CF (awCF) had AGT (0.51 [95% CI 0.45-0.57]). The prevalence of prediabetes remained unchanged (impaired glucose tolerance in chwCF: 0.14 [95% CI 0.10-0.18]) vs. awCF: 0.19 [95% CI 0.14-0.25]), while the proportion of CFRD increased by age (<5 yoa: 0.005 [95% CI 0.0001-0.15]; 5-10 yoa: 0.05 [95% CI 0.01-0.27]; 10-18 yoa: 0.11 [95% CI 0.08-0.14]; >18 yoa: 0.27 [95% CI 0.24-0.30]).

Conclusion

CF-related AGT is common under 10 years of age. Reconsideration of the current guidelines and better awareness are needed for screening and treating AGT in CF, especially under 10 yoa, to delay the disease progression and maintain a better life quality.

References

1. Olivier AK, Yi Y, Sun X, Sui H, Liang B, Hu S, et al. Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets. J Clin Invest. 2012;122(10):3755-68.
2. Ode KL, Moran A. New insights into cystic fibrosis-related diabetes in children. Lancet Diabetes Endocrinol. 2013;1(1):52-8.
3. Lewis C, Blackman SM, Nelson A, Oberdorfer E, Wells D, Dunitz J, et al. Diabetes-related mortality in adults with cystic fibrosis. Role of genotype and sex. Am J Respir Crit Care Med. 2015;191(2):194-200.
4. Moran A, Pekow P, Grover P, Zorn M, Slovis B, Pilewski J, et al. Insulin therapy to improve BMI in cystic fibrosis-related diabetes without fasting hyperglycemia: results of the cystic fibrosis related diabetes therapy trial. Diabetes Care. 2009;32(10):1783-8.
5. Moran A, Brunzell C, Cohen RC, Katz M, Marshall BC, Onady G, et al. Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care. 2010;33(12):2697-708.
6. Balfour-Lynn I. Clinical Guidelines: Care of Children with Cystic Fibrosis. UK: Royal Brompton and Harefield Hospital, NHS Trust Foundation; 2023.

Introduction

Although there is growing interest on prognostic and therapeutic value of KRAS mutations detection in pancreatic ductal adenocarcinoma (PDAC) patients’, the limited availability of sensitive, cost-effective and efficient molecular technologies has restricted its use. We present the fast single-step methodology utilizing amplification refractory mutation system (ARMS) coupled with high-resolution melting analysis (HRMA) to evaluate KRAS mutations and their prognostic value.

Aims & Methods

This is a prospective bicentric cohort study including PDAC patients with tumor samples collected at diagnosis. Codon-12/13 KRAS mutations were tested by Sanger Sequencing (SS) and the most frequent mutations were tested by ARMS/HRMA (G12D, G12V, G12R and G12C). Primary endpoint was the frequency of KRAS mutations by both techniques and their concordance. Secondary endpoints were the association of KRAS mutations and progression free survival (PFS) and overall survival (OS).

Results

83 patients, 57% male, with median-age at diagnosis of 70 (IQR 63-75) years-old, 55% submitted to upfront-surgery, 45% to palliative-chemotherapy or best-supportive care were included. SS detected KRAS mutations in 67% of tumor samples (G12D=47%, G12V=30%, G12R=13%, G12C=4%, G13V=4%, G12A=2%) and ARMS/HRMA in 82% (G12D=48%, G12V=35%, G12R=10%, G12C=2%, G12V/G12D=3%, G12D/G12C=2%) with a moderate concordance in mutation detection (kappa=0.517, p<0.001). Operated patients with G12C-mutated tumors had lower PFS (0 vs 8.5 months, HR=14.08 95%CI 1.435-138.207, p=0.023) and OS (0 vs 10 months, HR=11.49 95%CI 1.190-110.988, p=0.035) compared with wildtype tumors. No other differences were found in PFS and OS between KRAS-mutated and wildtype patients.

Conclusion

ARMS/HRMA appears to offer greater accuracy than SS in evaluating KRAS mutations in PDAC tumor samples, with the added benefits of speed and reduced costs. The presence of the G12C mutation was associated to lower OS and PFS, with early relapse after surgery. As such and with the recent emergence of drugs targeting G12C mutation (adagrasib), even resectable tumors might have indication for medical therapy, opening new avenues for personalized therapy in PDAC patients.