Treatment of fecal impaction in children using combined polyethylene glycol and sodium picosulphate

Background and Aim: Polyethylene glycol (PEG) is the gold standard for fecal disimpaction in constipation. A regimen of PEG combined with the stimulant laxative sodium picosulphate (SPS) produced fecal disimpaction in chronically constipated children in the community, but it is unknown if it is effective for more severe constipation. To determine the stool output and effect of a combined PEG and SPS regimen on fecaloma in children with severe constipation and impaction. Methods: Children with symptoms for a duration of >= 2 years, a palpable fecaloma, and enlarged rectum on X-ray (rectal: pelvic ratio > 0.6) were recruited from a tertiary hospital. Daily diaries recorded laxative dose, stool frequency, volume, and consistency (Bristol stool scale, BSS). Abdominal X-rays were taken on day 1 and day 8, and stool loading was assessed using the Leech score. Laxative doses were based on the child's age. The dose of PEG with electrolytes taken was 2-8 sachets (14.7 g/sachet) on days 1-2, reducing to 2-6 sachets on day 3. The SPS dose was 15-20 drops on days 2-3. Results: Eighty-nine children (4-18 years) produced a large volume of soft stool (median/inter-quartile-range: 2.2/1.6-3.1 L) over 7 days. Stool volume on X-rays decreased significantly in the colon (P <0.001). Fecalomas resolved in 40 of 89 children, while 49 needed a second high dose. Rectal: pelvic ratios did not change. Conclusions: A combined high dose of PEG and SPS on days 1 and 2 was effective in removing the fecaloma in half of the children. Administering high doses for a longer period should be tested to provide outpatient disimpaction for severe fecalomas. Rectums remained flaccid after emptying

Optimising colorectal cancer therapies using clinical registries

© 2020 Siavash ForoughiColorectal cancer (CRC) remains one of the leading causes of cancer deaths worldwide. Advances in therapy have resulted in significant gains in survival, particularly in the metastatic setting. While the discovery of biomarkers, such as RAS mutations, have helped refine treatment selection to some degree, more accurate biomarkers are urgently needed. Comparison of existing treatments, as well as the evaluation of the efficacy of new therapies, are informed by randomised controlled trials (RCTs), which form the evidentiary backbone of clinical practice guidelines and represent the gold standard of assessment. Despite their high internal validity, they can lack generalisability due to their highly selective inclusion criteria. Prospective, registry-based, randomised controlled trials (RRCTs) have the potential to bridge the gap between RCTs and real-world clinical practice in oncology. The objective of this thesis is to explore how clinical registries can help to advance biomarker research. This thesis applies real-world data to examine the clinical utility and validity of emerging CRC biomarkers, and explores the feasibility of RRCTs in the oncology setting. In a cohort of 99 metastatic colorectal cancer (mCRC) patients, the role of the epidermal growth factor receptor (EGFR) and its ligands, amphiregulin and epiregulin, as potential prognostic and predictive biomarkers for mCRC patients is explored (Chapter 5). This study examines protein expression by immunohistochemistry and includes patients who were not treated with EGFR inhibitors, representing the largest such cohort reported to date. The real-world validity of biomarker trials is explored in Chapter 6, where the characteristics of patients enrolled in these studies are compared to real-world patients. Using an established multi-centre CRC registry as the reference real-world cohort, clinical data was analysed for participants in three types of biomarker trials (retrospective, prospective observational and prospective interventional). This study provides novel insights into recruitment to, and potential validity of, biomarker trials. Finally, Chapter 7 examines the feasibility of an Australian-first RRCT in oncology. This ongoing study is exploring chemotherapy sequencing in first-line treatment of mCRC and leverages an established multi-centre registry as the data collection platform. This study demonstrates the potential of RRCTs to accelerate progress in optimising patient treatments and outcomes. This thesis demonstrates the power of high-quality clinical registries to facilitate prospective randomised trials, while providing opportunities to investigate and validate biomarkers in real-world settings

BRCA-deficient metastatic prostate cancer has an adverse prognosis and distinct genomic phenotypeResearch in context

Summary: Background: Genomic alterations in DNA damage response (DDR) genes are common in metastatic castration-resistant prostate cancer (mCRPC). Understanding how these genomic events impact prognosis and/or treatment response is vital for optimising clinical outcomes. Methods: Targeted sequencing was performed on 407 plasma samples from 375 men with mCRPC. Using the CLIA-certified PredicineCARE™ cell-free DNA (cfDNA) assay, pathogenic alterations in 152 key genes (including 27 DDR-related genes) were assessed, as was the presence and mechanisms of biallelic loss in BRCA2. Findings: At least one DDR alteration was present in 34.5% (129/375) of patients (including monoallelic alterations). The most frequently altered DDR genes were BRCA2 (19%), ATM (13%), FANCA (5%), CHEK2 (5%) and BRCA1 (3%). Patients with BRCA alterations, especially BRCA2, had significantly worse progression-free survival (PFS) (Hazard ratio (HR) 3.3 [95% CI 1.9–6.0]; Cox regression p < 0.001), overall survival (HR 2.2 [95% CI 1.1–4.5]; Cox regression p = 0.02) and PSA response rates to androgen receptor (AR) pathway inhibitors (32% vs 60%, chi-square p = 0.02). BRCA-deficient tumours were also enriched for alterations within multiple genes including in the AR and PI3K pathways. Zygosity of BRCA2 alterations had no discernible impact on clinical outcomes, with similarly poor PFS for monoallelic vs biallelic loss (median 3.9 months vs 3.4 months vs copy neutral 9.8 months). Interpretation: These data emphasise that the BRCA genes, in particular BRCA2, are key prognostic biomarkers in mCRPC. The clinical utility of BRCA2 as a marker of poor outcomes may, at least in cfDNA assays, be independent of the zygosity state detected. Enrichment of actionable genomic alterations in cfDNA from BRCA-deficient mCRPC may support rational co-targeting strategies in future clinical trials. Funding: Several funding sources have supported this study. A full list is provided in the Acknowledgments. No funding was received from Predicine, Inc. during the conduct of the study