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 ␣ (PPAR␣) should aggravate steatohepatitis produced by feeding a methionine and choline deficient (MCD) diet. Conversely, we assessed dietary steatohepatitis in PPAR␣ ؊/؊ mice that cannot up-regulate Cyp4a. Male wild type (wt) or PPAR␣ ؊/؊ mice (C57BL6 background) were fed the MCD diet with or without Wy-14,643 (0.1% wt/wt), a potent PPAR␣ 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 ␤-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. PPAR␣ ؊/؊ mice fed the MCD diet developed more severe steatohepatitis than wt mice, and were unaffected by Wy-14,643. In conclusion, PPAR␣ 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. (HEPATOLOGY 2003;38:123-132.)

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The underlying mechanisms that perpetuate liver inflammation in nonalcoholic steatohepatitis are poorly understood. We explored the hypothesis that cyclooxygenase-2 (COX-2) can exert pro-inflammatory effects in metabolic forms of fatty liver disease. Male wild-type (WT) C57BL6/N or peroxisome proliferator-activated receptor ␣ knockout (PPAR-␣ ؊/؊ ) mice were fed a lipogenic, methionine-and choline-deficient (MCD) diet or the same diet with supplementary methionine and choline (control). COX-2 was not expressed in livers of mice fed the control diet. In mice fed the MCD diet, hepatic expression of COX-2 messenger RNA and protein occurred from day 5, continued to rise, and was 10-fold higher than controls after 5 weeks, thereby paralleling the development of steatohepatitis. Upregulation of COX-2 was even more pronounced in PPAR

PURPOSE: To identify the approximately 12% with inherited cancer predisposition, all men with metastatic prostate cancer (mPC) should be offered germline genetic testing. This guides treatment choices and impacts cancer prevention in the family. Limited genetic services globally present a barrier to testing. This study tested a potential solution, “mainstreaming,” where counseling and testing are performed by the patient’s oncologist. PATIENTS AND METHODS: Men with mPC at three Australian sites were offered germline genetic testing at their medical oncology appointment. Panel testing ( ATM, BRCA1, BRCA2, BRIP1, CHEK2, EPCAM, FANCA, HOXB13, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, RAD51D, and TP53) was performed on saliva/blood (Invitae, San Francisco, CA). Primary outcomes were clinician and patient satisfaction. Secondary outcomes included mutation rates and resource allocation. RESULTS: Of 66 men offered testing, 63 (95%) accepted. Four pathogenic variants were identified (two BRCA2, one NBN, and one MSH6). Fifty patients and nine clinicians completed questionnaires. Satisfaction was high. All patients were pleased to have had testing overall, 98% (46 of 47) to have had testing at their usual oncology appointment, and all to receive results from their usual specialist, rather than a separate genetics appointment. A total of 88% (7 of 8) of clinicians felt confident, and all were satisfied with mainstreaming. Mainstreaming was resource efficient, requiring 87% fewer genetic consultations than traditional genetic counseling. CONCLUSION: This study demonstrates that mainstreaming of men with mPC is feasible, resource efficient, and satisfactory for clinicians and patients. Widespread implementation as standard of care would facilitate timely access to genetic testing for men with mPC.

Introduction: Mainstream genetic testing refers to genetic testing arranged by a patient's treating specialist. The aim of this study was to retrospectively review a Sydney-based ovarian cancer mainstream genetic testing program. Methods: A Cancer Genetics Service (CGS)-supported mainstream genetic testing program was commenced in 2015. The CGS provided training, paperwork and ongoing and adaptable advice regarding appropriate genes for testing and interpretation of results. Written and electronic medical records were reviewed until August 2019 to assess patient and family history characteristics, genetic testing eligibility, results and posttest management for women who had testing coordinated via mainstreaming or by the CGS.Results: Genetic testing was arranged for 289 women with ovarian cancer. Prior to 2017, 44% of genetic tests were mainstreamed, compared with 76% of tests from 2017 onwards. CGS was more likely to arrange testing for women with a strong family history of cancer and nonserous pathology. Germline pathogenic variants were detected in 13.7% (19/138) of women who had mainstream testing and 20.3% (14/69) of women tested by the CGS. Referral for posttest counseling occurred for pathogenic variant carriers identified through mainstreaming. Conclusion:This study demonstrated successful uptake of a mainstream ovarian cancer genetic testing program by medical oncologists, as evidenced by higher proportion and absolute numbers of eligible ovarian cancer patients accessing genetic testing through this pathway over time. The genetic testing criteria were appropriately assessed by oncologists and posttest referral occurred where required.

A quarter of patients 80 years and older received first-line palliative chemotherapy. Despite most receiving a modified dose, one third were hospitalised during treatment. These findings highlight the need for careful clinical assessment and selection of older cancer patients for chemotherapy.

Aims: There is limited data on health-related quality of life (HRQoL) in locally advanced rectal cancer. We assessed HRQoL before, during and after neoadjuvant chemoradiation, correlated this to corresponding clinician-reported adverse events (CR-AEs) and explored disparities between patients of Asian ethnicity versus Caucasians. Correlation between HRQoL and treatment response was also assessed. Methods: A consecutive sample of patients was recruited. HRQoL was assessed with the EORTC QLQ-C30 before chemoradiation, week three of chemoradiation and one-week pre-surgery. Clinical variables including CR-AEs were recorded at these time-points. Patients self-reported socio-demographic variables. Treatment response was assessed by the tumour regression grade. HRQoL data were analysed with multilevel models. Results: Fifty-one patients were recruited. HRQoL completion rates were ≥86%. Cognitive and role functioning worsened significantly during treatment. Emotional, role and social functioning improved significantly at pre-surgery. Fatigue and nausea/vomiting worsened during treatment while fatigue, appetite loss, diarrhoea and financial difficulties improved from treatment to pre-surgery. Almost 30% of the cohort were Asian ethnicity. Differences were found in multiple HRQoL domains between Asians and Caucasians, with Asians faring worse. Significant differences were evident in physical, role and cognitive functioning, and in seven out of the 8 symptom scales. The correlation between patient-reported outcomes and clinician-reported outcomes was weak, with diarrhoea having the strongest correlation (r = 0.58). Vomiting during treatment correlated with poor response, whilst baseline constipation correlated with good response. Conclusion: Chemoradiation for locally advanced rectal cancer affects multiple HRQoL domains. Our findings highlight the importance of psychological aspects of treatment. Significant differences were identified between the Asian and Caucasian populations, with Asians consistently performing worse. Poor correlations between patient and clinician reporting strongly support the inclusion of patient-reported outcomes in clinical studies. HRQoL domains of vomiting and constipation are potential biomarkers of treatment response.

Objective: 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. Methods: 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. 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 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. Advances in knowledge: 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.