Search

Purpose: Germline genetic testing results can guide treatment decisions for oncology patients and are now offered to many cancer patients. Mainstream testing refers to genetic testing arranged by a non‐genetics specialist. This repeated cross‐sectional study aimed: (1) to capture clinician views on the existing mainstreaming genetic testing program for ovarian, breast, prostate, and endometrial cancer patients, and (2) to ascertain the interest of clinicians to consider changing practice to adopt mainstream testing. Methods: Mainstreaming has occurred since 2015 for patients with ovarian and some breast cancer patients, expanding to include prostate cancer patients in 2019, and endometrial cancer patients in 2020. Two web‐based surveys were administered within two health districts, covering seven hospitals in NSW. Results: Fifty‐four clinicians (70% response rate) participated. Clinicians who had arranged mainstream genetic testing (n = 30) were overall satisfied (76%), viewed the process as time‐efficient and accessible for patients, and desired continuation of the program. Of those clinicians yet to engage in the program (n = 24), 88% expressed an interest in learning about mainstream testing. These clinicians identified time constraints, maintenance of current genetic knowledge, and completing the consenting and counseling process as barriers to mainstreaming. Future mainstreaming models are discussed. Conclusion: From the clinician's perspective, the mainstreaming program is considered a desirable pathway for germline testing of oncology patients. Access to ongoing education and resources is needed for the ongoing success of the program. [ABSTRACT FROM AUTHOR]

Fanconi anaemia due to biallelic loss of BRCA2 (Fanconi anaemia subtype D1) is traditionally diagnosed during childhood with cancer rates historically reported as 97% by 5.2 years. This report describes an adult woman with a history of primary ovarian failure, who was diagnosed with gastrointestinal adenocarcinoma and BRCA2-associated Fanconi anaemia at 23 years of age, only after she suffered severe chemotherapy toxicity. The diagnostic challenges include atypical presentation, initial false-negative chromosome fragility testing and variant classification. It highlights gastrointestinal adenocarcinoma as a consideration for adults with biallelic BRCA2 pathogenic variants with implications for surveillance. After over 4 years, the patient has no evidence of gastrointestinal cancer recurrence although the tumour was initially considered only borderline resectable. The use of platinum-based chemotherapy, to which heterozygous BRCA2 carriers are known to respond, may have had a beneficial anticancer effect, but caution is advised given its extreme immediate toxicity at standard dosing. Fanconi anaemia should be considered as a cause for women with primary ovarian failure of unknown cause and referral to cancer genetic services recommended when there is a family history of cancer in the hereditary breast/ovarian cancer spectrum. [ABSTRACT FROM AUTHOR]

This study explored the value of serial 18-fludeoxyglucose-positron emission tomography (18F-FDG-PET/CT) in predicting disease-free survival (DFS) in locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiation (NCRT) and surgery. We prospectively studied 46 patients with LARC who underwent NCRT and surgery. 18F-FDG-PET/CT scans were performed at three time-points before surgery (pre-NCRT-PET1, during NCRT-PET2 and following completion of NCRT-PET3). The following semi-quantitative PET parameters were analysed at each time point: maximum standardized uptake value (SUVmax), SUVmean, metabolic tumour volume (MTV) and tumour lesion glycolysis (TLG). Absolute and percentage changes in these parameters were analysed between time points. Statistical analysis consisted of median tests, Cox regression and Kaplan–Meier analysis for DFS. The median follow-up time was 24 months. A reduction in PET parameters showed statistically significant differences for patients with recurrence compared to those without; percentage changes in MTV between PET1 and PET3 (cut-off: 87%, p = 0.023), percentage changes in TLG between PET1 and PET3 (cut-off: 94%, p = 0.02) and absolute change in MTV PET1 and PET2 (cut-off: 10.25, p = 0.001). An absolute reduction in MTV between PET1 and PET3 (p=0.013), a percentage reduction in TLG between PET1 and PET2 (p=0.021), SUVmax and SUVmean at PET2 (p = 0.01, p = 0.027 respectively)were also prognostic indicators of recurrence. MTV percentage change between PET1 and PET2 and SUVmean percentage change between PET1 and PET3 were also trending towards significance (p = 0.052, p = 0.053 respectively). Serial 18F-FDG-PET/CT is a potentially reliable non-invasive method to predict recurrence in patients with LARC. Volumetric parameters were the best predictors. This could allow risk-stratification in patients who may benefit from conservative management. This paper will add to the literature in risk-stratifying patients with LARC based on prognosis, using 18F-FDG-PET/CT. This may improve patient outcomes by selecting suitable candidates for conservative management. [ABSTRACT FROM AUTHOR]

Background: MLH1 epimutation is characterised by constitutional monoallelic MLH1 promoter hypermethylation, which can cause colorectal cancer (CRC). Tumour molecular profiles of MLH1 epimutation CRCs were used to classify germline MLH1 promoter variants of uncertain significance and MLH1 methylated early-onset CRCs (EOCRCs). Genome-wide DNA methylation and somatic mutational profiles of tumours from two germline MLH1: c.-11C > T and one MLH1: c.-[28A > G; 7C > T] carriers and three MLH1 methylated EOCRCs (< 45 years) were compared with 38 reference CRCs. Methylation-sensitive droplet digital PCR (ddPCR) was used to detect mosaic MLH1 methylation in blood, normal mucosa and buccal DNA., Results: Genome-wide methylation-based Consensus Clustering identified four clusters where the tumour methylation profiles of germline MLH1: c.-11C > T carriers and MLH1 methylated EOCRCs clustered with the constitutional MLH1 epimutation CRCs but not with the sporadic MLH1 methylated CRCs. Furthermore, monoallelic MLH1 methylation and APC promoter hypermethylation in tumour were observed in both MLH1 epimutation and germline MLH1: c.-11C > T carriers and MLH1 methylated EOCRCs. Mosaic constitutional MLH1 methylation in MLH1: c.-11C > T carriers and 1 of 3 MLH1 methylated EOCRCs was identified by methylation-sensitive ddPCR., Conclusions: Mosaic MLH1 epimutation underlies the CRC aetiology in MLH1: c.-11C > T germline carriers and a subset of MLH1 methylated EOCRCs. Tumour profiling and ultra-sensitive ddPCR methylation testing can be used to identify mosaic MLH1 epimutation carriers., (© 2023. The Author(s).)

Objective: This study explored the value of serial 18-fludeoxyglucose-positron emission tomography ( 18 F-FDG-PET/CT) in predicting disease-free survival (DFS) in locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiation (NCRT) and surgery., Methods: We prospectively studied 46 patients with LARC who underwent NCRT and surgery. 18 F-FDG-PET/CT scans were performed at three time-points before surgery (pre-NCRT-PET1, during NCRT-PET2 and following completion of NCRT-PET3). The following semi-quantitative PET parameters were analysed at each time point: maximum standardized uptake value (SUVmax), SUVmean, metabolic tumour volume (MTV) and tumour lesion glycolysis (TLG). Absolute and percentage changes in these parameters were analysed between time points. Statistical analysis consisted of median tests, Cox regression and Kaplan-Meier analysis for DFS., Results: The median follow-up time was 24 months. A reduction in PET parameters showed statistically significant differences for patients with recurrence compared to those without; percentage changes in MTV between PET1 and PET3 (cut-off: 87%, p = 0.023), percentage changes in TLG between PET1 and PET3 (cut-off: 94%, p = 0.02) and absolute change in MTV PET1 and PET2 (cut-off: 10.25, p = 0.001).An absolute reduction in MTV between PET1 and PET3 (p=0.013), a percentage reduction in TLG between PET1 and PET2 (p=0.021), SUVmax and SUVmean at PET2 ( p = 0.01, p = 0.027 respectively)were also prognostic indicators of recurrence.MTV percentage change between PET1 and PET2 and SUVmean percentage change between PET1 and PET3 were also trending towards significance ( p = 0.052, p = 0.053 respectively)., Conclusion: Serial 18 F-FDG-PET/CT is a potentially reliable non-invasive method to predict recurrence in patients with LARC. Volumetric parameters were the best predictors. This could allow risk-stratification in patients who may benefit from conservative management., Advances in Knowledge: This paper will add to the literature in risk-stratifying patients with LARC based on prognosis, using 18 F-FDG-PET/CT. This may improve patient outcomes by selecting suitable candidates for conservative management.

We have proposed that steatohepatitis results from reactive oxygen species (ROS) acting on accumulated fatty acids to form proinflammatory lipoperoxides. Cytochrome P450 4a (Cyp4a) and Cyp2e1 are potential hepatic sources of ROS. We tested the hypothesis that increasing Cyp4a through activation of peroxisome proliferator-activated receptor alpha (PPARalpha) should aggravate steatohepatitis produced by feeding a methionine and choline deficient (MCD) diet. Conversely, we assessed dietary steatohepatitis in PPARalpha(-/-) mice that cannot up-regulate Cyp4a. Male wild type (wt) or PPARalpha(-/-) mice (C57BL6 background) were fed the MCD diet with or without Wy-14,643 (0.1% wt/wt), a potent PPARalpha agonist. Controls were fed the same diet supplemented with methionine and choline. After 5 weeks, wt mice fed the MCD diet developed moderate steatohepatitis and alanine aminotransferase (ALT) levels were increased. Wy-14,643 prevented rather than increased liver injury; ALT levels were only mildly elevated whereas steatohepatitis was absent. Wy-14,643 up-regulated mRNA for liver fatty acid binding protein and peroxisomal beta-oxidation enzymes (acyl-CoA oxidase, bifunctional enzyme, and ketothiolase), thereby reducing hepatic triglycerides and preventing steatosis. In wt mice, dietary feeding up-regulated Cyp4a14 mRNA 2.7-fold and increased hepatic lipoperoxides compared with controls. Wy-14,643 prevented hepatic lipoperoxides from accumulating despite an 18-fold increase in both Cyp4a10 and Cyp4a14 mRNA. PPARalpha(-/-) mice fed the MCD diet developed more severe steatohepatitis than wt mice, and were unaffected by Wy-14,643. In conclusion, PPARalpha activation both increases Cyp4a expression and enhances hepatic lipid turnover; the latter effect removes fatty acids as substrate for lipid peroxidation and is sufficiently powerful to prevent the development of dietary steatohepatitis.