141 Background: Retrospective clinical studies and preclinical studies demonstrated that statin use during preoperative (chemo)radiation (pCRT) for rectal cancer is associated with improved survival, response, and toxicity. Tumor regression following pCRT has strong prognostic significance and can be assessed using MRI-based tumor regression grading (mrTRG), including with non-operative management. SPAR was designed to prospectively evaluate the benefits of adding simvastatin (SIM) to pCRT on tumor regression and gastrointestinal (GI) adverse events (AE). Methods: SPAR is a double-blind randomized phase 2 trial investigating SIM/placebo (PBO) in addition to long-course fluoropyrimidine-based pCRT for rectal adenocarcinoma. Stratification included trial site, clinical T stage (<4 vs 4), clinical N stage (<2 vs 2), either mesorectal fascia involvement (MRFI) or extramural venous invasion (EMVI) on MRI (yes vs no), and total neoadjuvant therapy (TNT): induction vs consolidation chemotherapy vs none. Study treatment was SIM 40mg/PBO daily for 90 days, starting 1 week prior to pCRT; recent statin use was excluded. Pelvic MRI was repeated 6-8 weeks after pCRT to determine mrTRG. An amendment in January 2022 allowed TNT with either induction or consolidation chemotherapy; the timing of post-pCRT MRI remained unchanged. The design was amended to open-label due to PBO supply issues. Primary objective: rate of centrally assessed grade 1-2 mrTRG. Secondary objectives include centrally assessed favorable pathologic TRG (pathTRG), safety and cancer outcomes. Analysis was by intention-to-treat. Results: Between April 2018 - November 2023, 135 of 222 planned participants from 17 sites in Australia and New Zealand were randomized (68 SIM; 67 no SIM). Recruitment was hampered by the COVID-19 pandemic and adoption of TNT as standard care before the protocol amendment. Participant characteristics: median age 59 years; 85 (63%) males; 118 (87%) T2-3 disease, 80 (59%) N0-1 disease; 55 (41%) MRFI or EMVI; 25 (19%) had TNT. Rates of grades 1-2 mrTRG with SIM vs no SIM were 38.5% and 29.7% (X 2 = 1.09, p = 0.30), respectively. There was no significant difference in rates of > grade 2 GI and non-GI AE. Four serious AE were recorded, none related to study treatment. Median follow-up was 3.2 years. 3-year local recurrence rates (LRR) were low: 1 (2.2%) and 3 (5.5%) with SIM vs no SIM, respectively (HR: 0.29, 95% CI: 0.03 to 2.67, p = 0.26). 3-year disease-free survival (DFS) with SIM vs no SIM was 84% and 72%, respectively (HR 0.48; 95% CI: 0.21–1.08, p = 0.07). Conclusions: The rates of favorable mrTRG, 3-year LRR and DFS were numerically better with the addition of SIM to pCRT, though the differences were not statistically significant. SIM was well tolerated. Interpretation is limited by reduced sample size and statistical power. PathTRG and other key outcomes will be presented at the meeting. Clinical trial information: ACTRN12617001087347 .

Background:Health care system-wide outcomes from routine treatment with erlotinib and gefitinib are incompletely understood. Objective:The aim of the study is to describe the effectiveness of erlotinib and gefitinib during the first decade of their routine use for treating advanced epidermal growth factor receptor (EGFR) mutation-positive nonsquamous non-small cell lung cancer in the entire cohort of patients treated in Aotearoa New Zealand. Methods:Patients were identified, and data collated from national pharmaceutical dispensing, cancer registration, and mortality registration electronic databases by deterministic data linkage using National Health Index numbers. Time-to-treatment discontinuation and overall survival were measured from the date of first dispensing of erlotinib or gefitinib and analyzed by Kaplan-Meier curves. Associations of treatment outcomes with baseline factors were evaluated using univariable and multivariable Cox regressions. Results:Overall, 752 patients were included who started treatment with erlotinib (n=418) or gefitinib (n=334) before October 2020. Median time-to-treatment discontinuation was 11.6 (95% CI 10.8-12.4) months, and median overall survival was 20.1 (95% CI 18.1-21.6) months. Shorter time-to-treatment discontinuation was independently associated with high socioeconomic deprivation (hazard ratio [HR] 1.3, 95% CI 1.1-1.5 compared to the New Zealand Index of Deprivation 1-4 group), EGFR L858R mutations (HR 1.3, 95% CI 1.1-1.6 compared to exon 19 deletion), and distant disease at cancer diagnosis (HR 1.4, 95% CI 1.2-1.7 compared to localized or regional disease). The same factors were independently associated with shorter overall survival. Outcome estimates and predictors remained unchanged in sensitivity analyses. Conclusions:Outcomes from routine treatment with erlotinib and gefitinib in New Zealand patients with advanced EGFR-mutant nonsquamous non-small cell lung cancer are comparable with those reported in randomized trials and other health care system-wide retrospective cohort studies. Socioeconomic status, EGFR mutation subtype, and disease extent at cancer diagnosis were independent predictors of treatment outcomes in that setting.

BackgroundStarting in 2010, the epidermal growth factor receptor (EGFR) kinase inhibitors erlotinib and gefitinib were introduced into routine use in Aotearoa New Zealand (NZ) for treating advanced lung cancer, but their impact in this setting is unknown. ObjectiveThe study described in this protocol aims to understand the effectiveness and safety of these new personalized lung cancer treatments and the contributions made by concomitant medicines and other factors to adverse outcomes in the general NZ patient population. A substudy aimed to validate national electronic health databases as the data source and the methods for determining patient eligibility and identifying outcomes and variables. MethodsThis study will include all NZ patients with advanced EGFR mutation–positive lung cancer who were first dispensed erlotinib or gefitinib before October 1, 2020, and followed until death or for at least 1 year. Routinely collected health administrative and clinical data will be collated from national electronic cancer registration, hospital discharge, mortality registration, and pharmaceutical dispensing databases by deterministic data linkage using National Health Index numbers. The primary effectiveness and safety outcomes will be time to treatment discontinuation and serious adverse events, respectively. The primary variable will be high-risk concomitant medicines use with erlotinib or gefitinib. For the validation substudy (n=100), data from clinical records were compared to those from national electronic health databases and analyzed by agreement analysis for categorical data and by paired 2-tailed t tests for numerical data. ResultsIn the validation substudy, national electronic health databases and clinical records agreed in determining patient eligibility and for identifying serious adverse events, high-risk concomitant medicines use, and other categorical data with overall agreement and κ statistic of >90% and >0.8000, respectively; for example, for the determination of patient eligibility, the comparison of proxy and standard eligibility criteria applied to national electronic health databases and clinical records, respectively, showed overall agreement and κ statistic of 96% and 0.8936, respectively. Dates for estimating time to treatment discontinuation and other numerical variables and outcomes showed small differences, mostly with nonsignificant P values and 95% CIs overlapping with zero difference; for example, for the dates of the first dispensing of erlotinib or gefitinib, national electronic health databases and clinical records differed on average by approximately 4 days with a nonsignificant P value of .33 and 95% CIs overlapping with zero difference. As of May 2024, the main study is ongoing. ConclusionsA protocol is presented for a national whole-of-patient-population retrospective cohort study designed to describe the safety and effectiveness of erlotinib and gefitinib during their first decade of routine use in NZ for treating EGFR mutation–positive lung cancer. The validation substudy demonstrated the feasibility and validity of using national electronic health databases and the methods for determining patient eligibility and identifying the study outcomes and variables proposed in the study protocol. Trial RegistrationAustralian New Zealand Clinical Trials Registry ACTRN12615000998549; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368928 International Registered Report Identifier (IRRID)DERR1-10.2196/51381

Diminished insulin and insulin-like growth factor-1 signaling extends the lifespan of invertebrates1-4; however, whether it is a feasible longevity target in mammals is less clear5-12. Clinically utilized therapeutics that target this pathway, such as small-molecule inhibitors of phosphoinositide 3-kinase p110α (PI3Ki), provide a translatable approach to studying the impact of these pathways on aging. Here, we provide evidence that dietary supplementation with the PI3Ki alpelisib from middle age extends the median and maximal lifespan of mice, an effect that was more pronounced in females. While long-term PI3Ki treatment was well tolerated and led to greater strength and balance, negative impacts on common human aging markers, including reductions in bone mass and mild hyperglycemia, were also evident. These results suggest that while pharmacological suppression of insulin receptor (IR)/insulin-like growth factor receptor (IGFR) targets could represent a promising approach to delaying some aspects of aging, caution should be taken in translation to humans.

Cholangiocarcinoma has a poor prognosis because of the poor early detection rate and limited treatment options. Therefore, it is important to understand the symptoms of paraneoplastic syndromes in order to detect occult malignancy early, when it is still at a highly treatable stage. Here, we report an extremely rare case of cholangiocarcinoma with paraneoplastic syndrome related to a clinical diagnosis of dermatomyositis (DM) sine dermatitis. A 74-year-old Caucasian man experienced 3 weeks of painless jaundice, progressive proximal muscle weakness and renal failure with rhabdomyolysis. Based on the results of laboratory tests and imaging (magnetic resonance cholangiopancreatography, endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography) and histological examination, the diagnosis was cholangiocarcinoma. The diagnosis was consistent with cholangiocarcinoma with paraneoplastic syndrome provoked by DM sine dermatitis. He was successfully treated with biliary stent insertion and supportive management. Eventually, Whipple surgery was successfully performed. Paraneoplastic syndrome is very rare in patients with cholangiocarcinoma, and it is extremely uncommon in the setting of DM. This is the first case in New Zealand.

Background Retrospective studies show improved outcomes in colorectal cancer patients if taking statins, including overall survival, pathological response of rectal cancer to preoperative chemoradiotherapy (pCRT), and reduced acute and late toxicities of pelvic radiation. Major tumour regression following pCRT has strong prognostic significance and can be assessed in vivo using MRI-based tumour regression grading (mrTRG) or after surgery using pathological TRG (pathTRG). Methods A double-blind phase 2 trial will randomise 222 patients planned to receive long-course fluoropyrimidine-based pCRT for rectal adenocarcinoma at 18+ sites in New Zealand and Australia. Patients will receive simvastatin 40 mg or placebo daily for 90 days starting 1 week prior to standard pCRT. Pelvic MRI 6 weeks after pCRT will assess mrTRG grading prior to surgery. The primary objective is rates of favourable (grades 1–2) mrTRG following pCRT with simvastatin compared to placebo, considering mrTRG in 4 ordered categories (1, 2, 3, 4–5). Secondary objectives include comparison of: rates of favourable pathTRG in resected tumours; incidence of toxicity; compliance with intended pCRT and trial medication; proportion of patients undergoing surgical resection; cancer outcomes and pathological scores for radiation colitis. Tertiary objectives include: association between mrTRG and pathTRG grouping; inter-observer agreement on mrTRG scoring and pathTRG scoring; studies of T-cell infiltrates in diagnostic biopsies and irradiated resected normal and malignant tissue; and the effect of simvastatin on markers of systemic inflammation (modified Glasgow prognostic score and the neutrophil-lymphocyte ratio). Trial recruitment commenced April 2018. Discussion When completed this study will be able to observe meaningful differences in measurable tumour outcome parameters and/or toxicity from simvastatin. A positive result will require a larger RCT to confirm and validate the merit of statins in the preoperative management of rectal cancer. Such a finding could also lead to studies of statins in conjunction with chemoradiation in a range of other malignancies, as well as further exploration of possible mechanisms of action and interaction of statins with both radiation and chemotherapy. The translational substudies undertaken with this trial will provisionally explore some of these possible mechanisms, and the tissue and data can be made available for further investigations. Trial registration ANZ Clinical Trials Register ACTRN12617001087347 . ( www.anzctr.org.au , registered 26/7/2017) Protocol Version: 1.1 (June 2017).

509 Background: A Cochrane meta-analysis of randomised trials using histamine-type 2 receptor antagonists with surgery for colorectal cancer (CRC) demonstrated a hazard ratio of 0.53 for mortality if patients used cimetidine. The benefit is likely to be specific to patients whose tumours express the antigens that allow circulating cells to bind to endothelial selectin (E-selectin), the expression of which is induced by inflammatory cytokines perioperatively and inhibited by cimetidine. This trial sought to evaluate several key issues critical to informing the conduct of a phase 3 trial. Methods: Patients with non-metastatic CRC planned for curative-intent surgery were randomised to receive cimetidine 800mg BID or placebo orally for 5 weeks, starting 2-7 days preoperatively. A subset of patients had serial blood sampling for inflammatory cytokines. In addition to DFS and OS, endpoints assessed include treatment compliance and toxicity, recruitment issues, post-operative stay and complications, and tumour characteristics including expression of sialyl Lewis antigens and COX-2. Results: 123 patients (36% female) have been recruited in 4 centres over 3.5 years; another 4 are required to complete the planned 120 treated patients. The primary tumour was rectal in 45% and pathological postoperative tumour stage was 0-I, II, III, and IV in 29%, 33%, 35%, and 2% respectively. About 50% of CRC patients were eligible and fewer than half of those were recruited. Patient compliance was excellent with 89% of patients taking their medication orally in the first 2 days postoperatively. Inflammatory cytokines were commonly elevated postoperatively for up to 2 weeks but normalised by 4 weeks. Immunostaining for tumour antigens is in progress and will be presented. DFS and OS data are immature. Conclusions: Oral administration of cimetidine for 5 weeks is well-tolerated and feasible over the perioperative period, and covers the duration of elevated inflammatory cytokines. Correlative immunostaining studies will be presented. Clinical trial information: 12609000769280.

OBJECTIVE:The survival rate for head and neck squamous cell carcinoma (HNSCC) is among the lowest of the major cancers and has not substantially improved in the past two decades. Tumours with similar histological features may have widely differing clinical outcomes and thus identification of prognostic and predictive biomarkers may be valuable for determining appropriate clinical management strategies. The objective of this study was to establish the prognostic significance of six molecular markers in HNSCC in a New Zealand population: matrix metalloproteinases 2 and 9 (MMP-2, MMP-9), tissue inhibitor of matrix metalloproteinase-1, sialyl Lewis antigens a and x (sLe(a) , sLe(x) ) and alpha B-crystallin.METHODS:Retrospective review of 145 sequential HNSCC patients from a tertiary centre with minimum 3 years surveillance. Sections from formalin-fixed paraffin-embedded tumour blocks were immunostained for the molecular markers and scored. Cox regression modelling was used to adjust for potential confounding variables impacting on cancer survival.RESULTS:Multivariate analysis for individual biomarkers, controlling for age, sex, tumour grade, N-stage, T-stage, tumour site, smoking history and alcohol use, revealed poorer survival with tumour expression of MMP-2 (hazard ratio = 1.98, 95% confidence interval: 1.11-3.52, P = 0.021) and sLe(x) (hazard ratio = 3.22, 95% confidence interval: 1.33-7.80, P = 0.010). A stepwise analysis showed that MMP-2 and sLe(x) were independently prognostic after covariate adjustment.CONCLUSIONS:MMP-2 and sLe(x) were negative prognostic markers for survival in these HNSCC patients. This offers opportunities for clinical trials to reduce the risk of nodal and distant metastases through blocking tumour cell adhesion to endothelium.

Intravascular large B-cell lymphoma (IVLBCL), a subtype of diffuse large B-cell lymphoma, is a rare entity characterised by proliferation of malignant lymphocytes within the intravascular compartment usually without involvement of lymph nodes. It has a heterogeneous clinical presentation and aggressive, often fatal, clinical course. As such the diagnosis is often made at autopsy. This case report presents a 46-year-old male in whom the diagnosis of IVLBCL affecting multiple organs was established at autopsy. The variable presenting and clinical features of this entity are discussed with the aim of heightening the awareness of this aggressive disease. Intravascular large B-cell lymphoma (IVLBCL), a subtype of diffuse large B-cell lymphoma, is a rare entity characterised by proliferation of malignant lymphocytes within the intravascular compartment usually without involvement of lymph nodes. It has a heterogeneous clinical presentation and aggressive, often fatal, clinical course. As such the diagnosis is often made at autopsy. This case report presents a 46-year-old male in whom the diagnosis of IVLBCL affecting multiple organs was established at autopsy. The variable presenting and clinical features of this entity are discussed with the aim of heightening the awareness of this aggressive disease.

Kaposi's sarcoma (KS) of the gastro-intestinal tract is a common disease in the AIDS setting, although it is often asymptomatic. In this paper we wish to highlight the occurrence of gastro-intestinal KS with appendiceal involvement. Two of the patients presented with features of acute appendicitis, and KS of the appendix was not suspected at the time of surgery. In the remaining patient KS of the appendix was part of generalised gastro-intestinal involvement. It is important to remember that KS can cause appendicitis by producing a submucosal nodule that abuts into the lumen and thereby causes obstruction. KS of the gastro-intestinal tract may therefore masquerade as 'simple' appendicitis, or indeed remain asymptomatic.

Background/Aims: In hepatitis C, iron depletion may improve serum aminotransferases and the response to interferon, but it is not known whether inflammation and fibrosis correlate with hepatic iron content, Our aim was to establish whether hepatic iron content correlates with histological and serum indices of hepatic inflammation and fibrosis in hepatitis B and C.Methods: Total hepatic iron was measured using computerized histomorphometry, inflammation and fibrosis using Knodell score, on histological slides from 31 patients with chronic hepatitis B and 38 with hepatitis C.Results: Total hepatic iron was similar in the hepatitis B and C groups (0.82+/-1.72 % and 0.56+/-1.12%; mean+/-SD). No iron was detectable in 11 patients with hepatitis B and 13 with hepatitis C. Alanine aminotransferase (85.96+/-67.1 vs 44.2+/-39.7 p<0.05), aspartate aminotransferase (93.8+/-75.6 vs 47+/-33.5 IU/ml p<0.05) and histological inflammatory score (9.33+/-3.51 vs 7.79+/-3.3 p=0.07) mere increased in those with stainable hepatic iron compared to those without. However where iron was present, no association was found between the amount of hepatic iron and inflammatory or fibrosis scores, In hepatitis C, fibrosis was minimal in 77% of patients if iron was absent vs 24% with iron present, while marked fibrosis was present in 56% with iron vs 15% without iron (p<0.01, Fisher's exact test).Conclusion: Hepatic iron is associated with increased hepatic inflammation in chronic hepatitis B and hepatitis C and with high fibrosis scores in hepatitis C, There is a threshold effect, and once present, increasing iron does not correlate with increasing inflammation or fibrosis.

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Vascular ectasia of the duodenum as an unusual source of upper gastro-intestinal bleeding in a patient with cirrhotic portal hypertension and oesophageal varices is reported. Morphological structure and situation of ectatic duodenal vessels indicate the possible coexistence of variceal distension and angiodysplasia.

Mild acid treatment of sarcoplasmic reticulum membranes results in a first order decline in calcium transport activity while calcium stimulated ATPase activity remains unimpaired (Berman, M.C., McIntosh, D.B. and Kench, K.E. (1977) J. Biol. Chem. 252 994–1001). This uncoupling is apparently irreversible. Acid inactivated sarcoplasmic reticulum membranes, solubilized with Triton X-100 and reconstituted by passage through a Bio-Bead column, reactivated 80% of the calcium transport activity when compared with untreated, control reconstituted SR vesicles. It is suggested that the inactivated conformation of the (Ca2+, Mg2+-)ATPase is constrained by lipid-protein interactions.