Early derangement of INR predicts liver failure after liver resection for hepatocellular carcinoma.

BACKGROUND: Surgical resection, where appropriate, remains one of the best treatment options for hepatocellular carcinoma (HCC), however outcomes can be compromised by the development of liver failure. We reviewed our experience of liver resection for HCC patients to identify factors that may predict the development of post-hepatectomy liver failure (PHLF) and survival. METHODS: A single centre retrospective cohort study. Data was collected between 1999 and 2017 from all patients undergoing HCC resection in a tertiary university hospital from electronic medical records. PHLF was defined as per the International Study Group for Liver Surgery criteria. Variables with p < 0.15 on univariate analysis were included in a multivariate binary logistic regression model. Kaplan-Meier analyses were used to determine correlations with overall survival (OS) and disease-free survival (DFS), and variables with p < 0.15 on univariate analysis selected for a step-down Cox proportional hazard regression model. RESULTS: Overall, 120 patients underwent liver resection within the study period, of which 22 (18%) developed PHLF. Patients with normal INR ≤1.20 at day 2 did not develop PHLF whereas patients with INR >1.60 were at significant risk. Resection of multiple tumours (odds ratio 21.63, p = 0.002) and deranged postoperative day 2 INR>1.6 (odds ratio 21.05, p < 0.0001) were identified as independent prognostic markers of PHLF. CONCLUSION: The use of INR measurement at day 2 predicts PHLF and may enable us to objectively identify and stratify patients who may be eligible for enhanced recovery programs from those who will merit close monitoring in high dependency areas.

Initial experience of TAS-102 chemotherapy in Australian patients with Chemo-refractory metastatic colorectal cancer.

For patients with refractory metastatic colorectal cancer (mCRC) treatment with Trifluridine/Tipiracil, also known as TAS-102, improves overall survival. This study aims to investigate the efficacy and safety of TAS-102 in a real-world population from Victoria, Australia. A retrospective analysis of prospectively collected data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry was undertaken. The characteristics and outcomes of patients receiving TAS-102 were assessed and compared to those enrolled in the registration study (RECOURSE). Across 13 sites, 107 patients were treated with TAS-102. The median age was 60 years (range: 31-83), compared to 63 for RECOURSE. Comparing registry TAS-102-treated and RECOURSE patients, 75% vs 100% were ECOG performance status 0-1, 74% vs 79% had initiated treatment more than 18 months from diagnosis of metastatic disease and 36% vs 49% were RAS wild-type. Median time on treatment was 10.4 weeks (range: 1.7-32). Median progression-free survival (PFS) was 3.3 months compared to 2 months in RECOURSE, while median overall survival was the same at 7.1 months. Two patients (2.3%) had febrile neutropenia and there were no treatment-related deaths, where TAS-102 dose at treatment initiation was at clinician discretion.TRACC registry patients treated with TAS-102 were younger than those from the RECOURSE trial, with similar overall survival observed. Less strict application of RECIST criteria and less frequent imaging may have contributed to an apparently longer PFS.

AI-enhanced simultaneous multiparametric 18F-FDG PET/MRI for accurate breast cancer diagnosis.

PURPOSE: To assess whether a radiomics and machine learning (ML) model combining quantitative parameters and radiomics features extracted from simultaneous multiparametric 18F-FDG PET/MRI can discriminate between benign and malignant breast lesions. METHODS: A population of 102 patients with 120 breast lesions (101 malignant and 19 benign) detected on ultrasound and/or mammography was prospectively enrolled. All patients underwent hybrid 18F-FDG PET/MRI for diagnostic purposes. Quantitative parameters were extracted from DCE (MTT, VD, PF), DW (mean ADC of breast lesions and contralateral breast parenchyma), PET (SUVmax, SUVmean, and SUVminimum of breast lesions, as well as SUVmean of the contralateral breast parenchyma), and T2-weighted images. Radiomics features were extracted from DCE, T2-weighted, ADC, and PET images. Different diagnostic models were developed using a fine Gaussian support vector machine algorithm which explored different combinations of quantitative parameters and radiomics features to obtain the highest accuracy in discriminating between benign and malignant breast lesions using fivefold cross-validation. The performance of the best radiomics and ML model was compared with that of expert reader review using McNemar's test. RESULTS: Eight radiomics models were developed. The integrated model combining MTT and ADC with radiomics features extracted from PET and ADC images obtained the highest accuracy for breast cancer diagnosis (AUC 0.983), although its accuracy was not significantly higher than that of expert reader review (AUC 0.868) (p = 0.508). CONCLUSION: A radiomics and ML model combining quantitative parameters and radiomics features extracted from simultaneous multiparametric 18F-FDG PET/MRI images can accurately discriminate between benign and malignant breast lesions.

Real-world impact of anti-HER2 therapy-related cardiotoxicity in patients with advanced HER2-positive breast cancer.

BACKGROUND: Anti-HER2 therapy-related cardiotoxicity is well described in the context of clinical trials, particularly in the setting of early stage disease, but there is more limited data in advanced breast cancer and in the real world setting. MATERIAL AND METHODS: A prospectively-maintained registry database with 312 consecutive patients diagnosed with HER2 positive advanced breast cancer in Australia was analysed. RESULTS: 287 patients (92%) received anti-HER2 therapy, 17 (6%) experienced anti-HER2 therapy-related cardiotoxicity. Patients who experienced cardiotoxicity were more likely to have ≥2 risk factors for cardiotoxicity (OR 3.9 95% CI 1.4-11.3 p = 0.01). A prior diagnosis of cardiovascular disease was significantly associated with cardiotoxicity (OR 7.1 95% CI 1.3-39.5). Cardiotoxicity resolved on imaging in 65% of patients; there was no association between severity and resolution. 11 patients (65%) received cardiologist input. Of the patients who developed cardiotoxicity, 12 patients (71%) received further anti-HER2 therapy in the first- or second-line setting without recurrent cardiotoxicity. DISCUSSION AND CONCLUSION: Therapy-related cardiotoxicity is an uncommon complication of anti-HER2 therapy in the real world setting. Cardiac toxicity resolved in the majority of affected patients, and further anti-HER2 therapy was administered without recurrence of cardiac issues. Our data suggests anti-HER2 therapy can be safely given in routine care, even in patients with risk factors for toxicity.

Fluoride doped γ-Fe2O3 nanoparticles with increased MRI relaxivity.

Iron oxide nanoparticles (IONs) are being actively researched and experimented with as contrast agents for Magnetic Resonance Imaging (MRI), as well as image-directed delivery of therapeutics. The efficiency of an MRI contrast agent can be described by its longitudinal and transverse relaxivities, r1 and r2. γ-Fe2O3 nanoparticles - doped with fluoride in a controlled manner and functionalised with citric acid - showed a 3-fold increase in r1 and a 17-fold increase in r2 in a magnetic field of 3 T and almost 6-fold increase in r1 and a 14-fold increase in r2 at 11 T. Following fluorination, PXRD shows that the crystal structure of γ-Fe2O3 is maintained, Mössbauer spectroscopy shows that the oxidation state of the Fe cation is unchanged and HREM shows that the particle size does not vary. However, magnetisation curves show a large increase in the coercive field, pointing towards a large increase in the magnetic anisotropy for the fluorinated nanoparticles compared to the un-doped γ-Fe2O3 nanoparticles. Therefore, a chemically induced increase in magnetic anisotropy appears to be the most relevant parameter responsible for the large increase in relaxivity for γ-Fe2O3 nanoparticles.

Secondary technical resectability of colorectal cancer liver metastases after chemotherapy with or without selective internal radiotherapy in the randomized SIRFLOX trial.

BACKGROUND: Secondary resection of initially unresectable colorectal cancer liver metastases (CRLM) can prolong survival. The added value of selective internal radiotherapy (SIRT) to downsize lesions for resection is not known. This study evaluated the change in technical resectability of CRLM with the addition of SIRT to FOLFOX-based chemotherapy. METHODS: Baseline and follow-up hepatic imaging of patients who received modified FOLFOX (mFOLFOX6: fluorouracil, leucovorin, oxaliplatin) chemotherapy with or without bevacizumab (control arm) versus mFOLFOX6 (with or without bevacizumab) plus SIRT using yttrium-90 resin microspheres (SIRT arm) in the phase III SIRFLOX trial were reviewed by three or five (of 14) expert hepatopancreatobiliary surgeons for resectability. Reviewers were blinded to one another, treatment assignment, extrahepatic disease status, and information on clinical and scanning time points. Technical resectability was defined as at least 60 per cent of reviewers (3 of 5, or 2 of 3) assessing a patient's liver metastases as surgically removable. RESULTS: Some 472 patients were evaluable (SIRT, 244; control, 228). There was no significant baseline difference in the proportion of technically resectable liver metastases between SIRT (29, 11·9 per cent) and control (25, 11·0 per cent) arms (P = 0·775). At follow-up, significantly more patients in both arms were deemed technically resectable compared with baseline: 159 of 472 (33·7 per cent) versus 54 of 472 (11·4 per cent) respectively (P = 0·001). More patients were resectable in the SIRT than in the control arm: 93 of 244 (38·1 per cent) versus 66 of 228 (28·9 per cent) respectively (P < 0·001). CONCLUSION: Adding SIRT to chemotherapy may improve the resectability of unresectable CRLM.

ANTECEDENTES: La resección secundaria de metástasis hepáticas de cáncer colorrectal (colorectal cancer liver metastases, CRLM) inicialmente irresecables puede prolongar la supervivencia. Se desconoce el valor añadido de la radioterapia interna selectiva (selective internal radiation therapy, SIRT). Este estudio evaluó el cambio en la resecabilidad técnica de las CRLM secundario a la adición de SIRT a una quimioterapia tipo FOLFOX. MÉTODOS: Las pruebas de radioimagen basales y durante el seguimiento de pacientes tratados con un régimen FOLFOX modificado (mFOLFOX6: fluorouracilo, leucovorina, oxaliplatino) ± bevacizumab (grupo control) versus mFOLFOX6 (± bevacizumab) más SIRT usando microesferas de resina de yttrium-90, en el ensayo de fase III SIRFLOX, fueron revisadas por 3-5 (de 14) cirujanos expertos hepatobiliares para determinar la resecabilidad. Los expertos efectuaron la revisión de forma ciega unos respecto a otros en relación con la asignación al tratamiento, estado de la enfermedad extra-hepática y situación clínica en el momento del estudio radiológico. La resecabilidad técnica se definió como ≥ 60% de revisores evaluando las metástasis del paciente como quirúrgicamente resecables. RESULTADOS: Fueron evaluables un total de 472 pacientes (control, n = 228; SIRT, n = 244). No hubo diferencias significativas basales en la proporción de metástasis hepáticas técnicamente resecables entre SIRT (29/244; 11,9%) y el grupo control (25/228; 11,0%: P = 0,775). Durante el seguimiento y en ambos brazos de tratamiento, un número significativamente mayor de pacientes se consideraron técnicamente resecables en comparación con la situación basal (54/472 (11,4%) basal y 159/472 (33,7%) al seguimiento). Hubo más pacientes resecables en el grupo SIRT que en el control (93/244 (38,1%) y 66/228 (28,9%); P < 0,001, respectivamente). CONCLUSIÓN: La adición de SIRT a la quimioterapia puede mejorar la resecabilidad de las CRLM irresecables.

Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer.

BACKGROUND: In early-stage pancreatic cancer, there are currently no biomarkers to guide selection of therapeutic options. This prospective biomarker trial evaluated the feasibility and potential clinical utility of circulating tumor DNA (ctDNA) analysis to inform adjuvant therapy decision making. MATERIALS AND METHODS: Patients considered by the multidisciplinary team to have resectable pancreatic adenocarcinoma were enrolled. Pre- and post-operative samples for ctDNA analysis were collected. PCR-based-SafeSeqS assays were used to identify mutations at codon 12, 13 and 61 of KRAS in the primary pancreatic tumor and to detect ctDNA. Results of ctDNA analysis were correlated with CA19-9, recurrence-free and overall survival (OS). Patient management was per standard of care, blinded to ctDNA data. RESULTS: Of 112 patients consented pre-operatively, 81 (72%) underwent resection. KRAS mutations were identified in 91% (38/42) of available tumor samples. Of available plasma samples (N = 42), KRAS mutated ctDNA was detected in 62% (23/37) pre-operative and 37% (13/35) post-operative cases. At a median follow-up of 38.4 months, ctDNA detection in the pre-operative setting was associated with inferior recurrence-free survival (RFS) [hazard ratio (HR) 4.1; P = 0.002)] and OS (HR 4.1; P = 0.015). Detectable ctDNA following curative intent resection was associated with inferior RFS (HR 5.4; P < 0.0001) and OS (HR 4.0; P = 0.003). Recurrence occurred in 13/13 (100%) patients with detectable ctDNA post-operatively, including in seven that received gemcitabine-based adjuvant chemotherapy. CONCLUSION: ctDNA studies in localized pancreatic cancer are challenging, with a substantial number of patients not able to undergo resection, not having sufficient tumor tissue for analysis or not completing per protocol sample collection. ctDNA analysis, pre- and/or post-surgery, is a promising prognostic marker. Studies of ctDNA guided therapy are justified, including of treatment intensification strategies for patients with detectable ctDNA post-operatively who appear at very high risk of recurrence despite gemcitabine-based adjuvant therapy.

Hypertension as a predictor of advanced colorectal cancer outcome and cetuximab treatment response.

Background: Adrenergic receptor stimulation is involved in the development of hypertension (htn) and has been implicated in cancer progression and dissemination of metastases in various tumours, including colon cancer. Adrenergic antagonists such as beta-blockers (bbs) demonstrate inhibition of invasion and migration in colon cancer cell lines and have been associated with decreased mortality in colorectal cancer (crc). We examined the association of baseline htn and bb use with overall (os) and progression-free survival (pfs) in patients with pretreated, chemotherapy refractory, metastatic crc (mcrc). We also examined baseline htn as a predictor of cetuximab efficacy. Methods: Using data from the Canadian Cancer Trials Group co.17 study [cetuximab vs. best supportive care (bsc)], we coded baseline htn and use of anti-htn medications, including bbs, for 572 patients. The chi-square test was used to assess the associations between those variables and baseline characteristics. Cox regression models were used for univariate and multivariate analyses of os and pfs by htn diagnosis and bb use. Results: Baseline htn, bb use, and anti-htn medication use were not found to be prognostic for improved os. Baseline htn and bb use were not significant predictors of cetuximab benefit. Conclusions: In chemorefractory mcrc, neither baseline htn nor bb use is a significant prognostic factor. Baseline htn and bb use are not predictive of cetuximab benefit. Further investigation to determine whether baseline htn or bb use have a similarly insignificant impact on prognosis in patients receiving earlier lines of treatment remains warranted.

Prognostic value of MACC1 and proficient mismatch repair status for recurrence risk prediction in stage II colon cancer patients: the BIOGRID studies.

BACKGROUND: We assessed the novel MACC1 gene to further stratify stage II colon cancer patients with proficient mismatch repair (pMMR). PATIENTS AND METHODS: Four cohorts with 596 patients were analyzed: Charité 1 discovery cohort was assayed for MACC1 mRNA expression and MMR in cryo-preserved tumors. Charité 2 comparison cohort was used to translate MACC1 qRT-PCR analyses to FFPE samples. In the BIOGRID 1 training cohort MACC1 mRNA levels were related to MACC1 protein levels from immunohistochemistry in FFPE sections; also analyzed for MMR. Chemotherapy-naïve pMMR patients were stratified by MACC1 mRNA and protein expression to establish risk groups based on recurrence-free survival (RFS). Risk stratification from BIOGRID 1 was confirmed in the BIOGRID 2 validation cohort. Pooled BIOGRID datasets produced a best effect-size estimate. RESULTS: In BIOGRID 1, using qRT-PCR and immunohistochemistry for MACC1 detection, pMMR/MACC1-low patients had a lower recurrence probability versus pMMR/MACC1-high patients (5-year RFS of 92% and 67% versus 100% and 68%, respectively). In BIOGRID 2, longer RFS was confirmed for pMMR/MACC1-low versus pMMR/MACC1-high patients (5-year RFS of 100% versus 90%, respectively). In the pooled dataset, 6.5% of patients were pMMR/MACC1-low with no disease recurrence, resulting in a 17% higher 5-year RFS [95% confidence interval (CI) (12.6%-21.3%)] versus pMMR/MACC1-high patients (P = 0.037). Outcomes were similar for pMMR/MACC1-low and deficient MMR (dMMR) patients (5-year RFS of 100% and 96%, respectively). CONCLUSIONS: MACC1 expression stratifies colon cancer patients with unfavorable pMMR status. Stage II colon cancer patients with pMMR/MACC1-low tumors have a similar favorable prognosis to those with dMMR with potential implications for the role of adjuvant therapy.

Benefit from cytoreductive nephrectomy and the prognostic role of neutrophil-to-lymphocyte ratio in patients with metastatic renal cell carcinoma.

BACKGROUND: The role of cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) in the era of targeted therapies is currently undefined. In recent years, neutrophil-to-lymphocyte ratio (NLR) has emerged as a prognostic marker in several cancers, including mRCC. In this multicentre retrospective study, we aim to assess the impact of CN in mRCC and the value of NLR in risk stratification and patient selection. METHODS: Retrospective data from patients with de novo mRCC from four large Australian hospitals were collected. Survival analyses were performed using the Kaplan-Meier method and compared using the log-rank test. Multivariate analyses were performed using the Cox proportional hazards method. RESULTS: Our study identified 91 de novo mRCC patients. Patients who underwent CN (n = 46, 51%) were more likely to be younger (59.0 years vs 64.6 years, P = 0.019) and to have received systemic therapy (91% vs 76%, P = 0.043). Median overall survival (mOS) was significantly improved in patients who underwent CN (23.0 months vs 10.9 months, hazard ratios (HR) 0.33, 95% confidence interval (CI) 0.20-0.55, P < 0.0001). Patients with NLR ≥ 5 also had inferior mOS (6.2 months vs 16.7 months, HR 1.94, 95% CI 1.14-3.29, P = 0.014). CN was associated with substantially improved survival in patients with both NLR < 5 (mOS 31.1 months vs 7.0 months, HR 0.41, 95% CI, 0.18-0.64, P = 0.0009) and NLR ≥ 5 (mOS 10.9 months vs 2.3 months, HR 0.33, 95% CI, 0.11-0.69, P = 0.009). Significant survival benefits associated with CN were maintained in multivariate analyses (HR 0.39, 95% CI 0.22-0.70, P = 0.0014). CONCLUSIONS: CN is associated with significantly improved overall survival in de novo mRCC. The incremental survival benefit associated with CN was seen irrespective of NLR.

Survival impact of the Australian National Bowel Cancer Screening Programme.

BACKGROUND: The Australian National Bowel Cancer Screening Program (NBCSP) has been offering age-based faecal occult blood testing since 2006. With the rapid expansion of this programme, the NBCSP will ultimately offer biennial screening to all 50-74 years old by 2020. Participation rates remain low. Previous reports have described an increased proportion of earlier stage cancers in patients with NBCSP-detected tumours. METHODS: Data on consecutive patients enrolled into a prospective, comprehensive, multidisciplinary database at six Victorian hospitals were examined. Clinicopathologic and outcome data were compared for NBCSP and symptomatic presentation patients. RESULTS: We identified 3743 patients that presented with colorectal cancer (CRC) at participating hospitals since May 2006. Of 1930 patients aged between 50 and 70 years, 141 (7.3%) had a NBCSP detected cancer, 1441 (74.7%) presented with symptoms and 266 (13.8%) were diagnosed through screening outside of the NBCSP. Based on the American Society of Anaesthesiology score, the NBCSP patients were fitter. They had an earlier stage of diagnosis and were more likely to be female and less likely to have lymphovascular invasion or to present as an emergency. NBCSP detected patients had a lower rate of recurrence (HR 0.17, P = 0.0001) and fewer deaths (HR 0.19, P = 0.005). CONCLUSIONS: Patients with NBCSP-detected CRC have a markedly reduced risk of CRC recurrence and death compared with patients with a symptomatic presentation. The dominant driver of this appears to be earlier stage at diagnosis. Increased promotion of the impact of the NBCSP, including data related to the survival impact, should be undertaken to increase participation rates and achieve further survival gains.

Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer.

BACKGROUND: Early indicators of treatment response in metastatic colorectal cancer (mCRC) could conceivably be used to optimize treatment. We explored early changes in circulating tumor DNA (ctDNA) levels as a marker of therapeutic efficacy. PATIENTS AND METHODS: This prospective study involved 53 mCRC patients receiving standard first-line chemotherapy. Both ctDNA and CEA were assessed in plasma collected before treatment, 3 days after treatment and before cycle 2. Computed tomography (CT) scans were carried out at baseline and 8-10 weeks and were centrally assessed using RECIST v1.1 criteria. Tumors were sequenced using a panel of 15 genes frequently mutated in mCRC to identify candidate mutations for ctDNA analysis. For each patient, one tumor mutation was selected to assess the presence and the level of ctDNA in plasma samples using a digital genomic assay termed Safe-SeqS. RESULTS: Candidate mutations for ctDNA analysis were identified in 52 (98.1%) of the tumors. These patient-specific candidate tissue mutations were detectable in the cell-free DNA from the plasma of 48 of these 52 patients (concordance 92.3%). Significant reductions in ctDNA (median 5.7-fold; P < 0.001) levels were observed before cycle 2, which correlated with CT responses at 8-10 weeks (odds ratio = 5.25 with a 10-fold ctDNA reduction; P = 0.016). Major reductions (≥10-fold) versus lesser reductions in ctDNA precycle 2 were associated with a trend for increased progression-free survival (median 14.7 versus 8.1 months; HR = 1.87; P = 0.266). CONCLUSIONS: ctDNA is detectable in a high proportion of treatment naïve mCRC patients. Early changes in ctDNA during first-line chemotherapy predict the later radiologic response.

Recovery from TBT pollution in English Channel environments: A problem solved?

Following recognition of effects in the 1980s, tributyltin (TBT) has been monitored at sites in the English Channel to evaluate the prognosis for biota - spanning the introduction of restrictions on TBT use on small boats and the recent phase-out on the global fleet. We describe how persistence and impact of TBT in clams Scrobicularia plana has changed during this period in Southampton Water and Poole Harbour. TBT contamination (and loss) in water, sediment and clams reflects the abundance and type of vessel activity: half-times in sediment (up to 8y in Poole, 33y in Southampton) are longest near commercial shipping. Recovery of clam populations - slowest in TBT-contaminated deposits - provides a useful biological measure of legislative efficacy in estuaries. On rocky shores, recovery from imposex in Nucella lapillus is evident at many sites but, near ports, is prolonged by shipping impacts, including sediment legacy, for example, in the Fal.

Comparing oncological outcomes of laparoscopic versus open surgery for colon cancer: Analysis of a large prospective clinical database.

BACKGROUND: Oncological outcomes of laparoscopic colon cancer surgery have been shown to be equivalent to those of open surgery, but only in the setting of randomized controlled trials on highly selected patients. The aim of this study is to investigate whether this finding is generalizable to real world practice. METHODS: Analysis of prospectively collected data from the BioGrid Australia database was undertaken. Overall and cancer specific survival rates were compared with cox regression analysis controlling for the confounders of age, sex, BMI, ASA score, hospital site, year surgery performed, procedure, tumor stage, and adjuvant chemotherapy. RESULTS: Between 2003 and 2009, 1,106 patients underwent elective colon cancer resection. There were differences between the laparoscopic and open cohorts in BMI, procedure, post-operative complication rate, and tumor stage. When baseline confounders were accounted for using cox regression analysis, there was no difference in 5 year overall survival (χ(2) test 1.302, P = 0.254), or cancer specific survival (χ(2) test 0.028, P = 0.866). CONCLUSION: This large prospective clinical study validates previous trial results, and confirms that there is no difference in oncological outcome between laparoscopic and open surgery for colon cancer.

A retrospective 15-year review: survival advantage after switching to sirolimus in hepatitis C virus infected liver graft recipients.

BACKGROUND: The use of sirolimus-based immune suppression in liver transplantation, particularly in hepatitis C virus (HCV)-infected recipients, remains contentious. There is some evidence that sirolimus retards hepatic fibrosis, is renal sparing and may be of benefit in preventing hepatocellular carcinoma (HCC) recurrence. Sirolimus has not been adopted by many transplant centres because of persistent concerns regarding an increased risk of hepatic artery thrombosis, graft loss and death with de novo sirolimus. AIM: To review the impact of switching to sirolimus monotherapy in HCV-infected liver recipients with respect to survival, graft loss and hepatic fibrosis. METHODS: A retrospective review of 190 patients from a single centre undergoing first liver transplantation for HCV over 15 years. 113 patients were switched from calcineurin inhibitor (CNI)-based therapy to low-dose sirolimus monotherapy at a median of 15 months after transplantation for HCV-related fibrosis (72%), renal impairment (14%) or high-risk HCC (5%). RESULTS: Patients switched to sirolimus had improved survival (P < 0.001) and slower progression to cirrhosis (P = 0.001). In patients with HCC (n = 91), sirolimus duration rather than strategy was an independent predictor of survival (P = 0.001) and extended time to HCC recurrence (33 vs. 16 months). Patients switched for renal dysfunction showed improvement in serum creatinine (140-108 µmol/L, P = 0.001). Those remaining on CNI-therapy were more likely to develop post-transplant diabetes (P = 0.03). CONCLUSION: These data suggest selective switching to low-dose sirolimus monotherapy in HCV-positive liver recipients improves clinical outcome.

Treatment and outcomes of metastatic colorectal cancer in Australia: defining differences between public and private practice.

BACKGROUND: Prior studies have suggested improved outcomes for cancer patients managed in private centres, despite universal healthcare within Australia. AIMS: To compare patient, disease, treatment and survival data for metastatic colorectal cancer (mCRC) managed in private versus public centres. METHODS: Analysis of prospectively collected registry data for consecutive patients with mCRC managed at 16 participating centres from July 2009. RESULTS: Data for 1065 patients were examined. Age, gender and Charlson comorbidity score were similar for public and private patients. Private patients were more commonly Eastern Cooperative Oncology Group performance score 0-1 (85% vs 78%, P = 0.008), in the highest Index of Relative Socioeconomic Advantage and Disadvantage quintile (57% vs 18%, P < 0.001) or had a single metastatic site (62% vs 54%, P = 0.009). Patients treated in private were more likely to receive chemotherapy (84% vs 70%, P < 0.001), bevacizumab (59% vs 50%, P = 0.008), be treated with curative intent (37% vs 26%, P < 0.001) and undergo metastasectomy (30% vs 22%, P = 0.001). These management differences remained statistically significant after adjusting for baseline characteristics. Management in the private setting was associated with superior overall survival (median 27.9 vs 20 months, hazard ratio 0.7, 95% confidence interval: 0.57 to 0.86, P = 0.001), significant in multivariate analysis adjusting for all baseline covariates. CONCLUSIONS: Significant differences in baseline characteristics were noted for private versus public patients. However, these do not explain the higher rates of treatment delivery in the private setting, which likely contributed towards the observed survival difference. Further studies are required to determine if the increased likelihood of intervention in the private setting is driven by patient, clinician and/or institutional factors.

The role of tissue diagnosis prior to neoadjuvant chemoradiotherapy for locally advanced rectal cancer.

AIM: Neoadjuvant chemoradiotherapy is the standard of care for locally advanced rectal cancer, with diagnostic work-up routinely including a biopsy confirming invasive carcinoma. For the occasional patient where initial biopsies reveal only dysplasia, or even normal epithelium, repeat biopsy is currently advised, but this may delay therapy and repeat biopsy has potential adverse effects. The study aimed to determine, in the setting of clinical findings and imaging demonstrating locally advanced rectal cancer, whether the absence of a tissue diagnosis prior to commencing chemoradiation compromises patient outcome. METHOD: A review was conducted of our database, including comprehensive treatment and outcome details, in which consecutive patients with colorectal cancer have been enrolled since 1997 at a single institution. All records for patients who received neoadjuvant chemoradiotherapy for locally advanced rectal cancer were reviewed to identify patients for whom treatment was initiated before a tissue diagnosis was obtained, and to assess any consequences of this. RESULTS: Of 254 patients who had received neoadjuvant treatment for rectal cancer, 16 (6.3%) were found to have had neoadjuvant therapy without a tissue diagnosis of invasive cancer. Compared with cases where a tissue diagnosis had been obtained, median age (59 vs 63 years, P = 0.497), sex (75% vs 71.3% male, P = 0.955) and tumour location (56.3% vs 73.5% < 8 cm, P = 0.230) were similar. Of these, 14 (87.5%) had adenocarcinoma identified on histopathology review of the surgical specimen. Three patients were considered to have had complete pathological responses with mucin lakes within the muscularis propria (n = 2) or lymph nodes (n = 1) or fibrosis (n = 3). One of these had no mucin evident and only fibrosis; thus final pathological proof of invasive cancer was present in 15 (93.5%) patients. There were no local recurrences, but three of the 16 (18.8%) cases developed distant recurrence. CONCLUSION: For the small number of cases without a confirmatory tissue diagnosis before chemoradiation, no adverse consequences were identified. In particular the initial diagnosis was confirmed in 15 out of 16 cases following pathological examination of the operative specimen. We would suggest that, where clinical and radiological features support a diagnosis of locally advanced rectal cancer, proceeding directly to neoadjuvant chemoradiotherapy in the absence of a biopsy demonstrating invasive cancer may not be unreasonable, particularly where repeat biopsy would delay the commencement of treatment.

Multicenter retrospective analysis of metastatic colorectal cancer (CRC) with high-level microsatellite instability (MSI-H).

BACKGROUND: The microsatellite instability-high (MSI-H) phenotype, present in 15% of early colorectal cancer (CRC), confers good prognosis. MSI-H metastatic CRC is rare and its impact on outcomes is unknown. We describe survival outcomes and the impact of chemotherapy, metastatectomy, and BRAF V600E mutation status in the largest reported cohort of MSI-H metastatic colorectal cancer (CRC). PATIENTS AND METHODS: A retrospective review of 55 MSI-H metastatic CRC patients from two institutions, Royal Melbourne Hospital (Australia) and The University of Texas MD Anderson Cancer Center (United States), was conducted. Statistical analyses utilized Kaplan-Meier method, Log-rank test, and Cox proportional hazards models. RESULTS: Median age was 67 years (20-90), 58% had poor differentiation, and 45% had stage IV disease at presentation. Median overall survival (OS) from metastatic disease was 15.4 months. Thirteen patients underwent R0/R1 metastatectomies, with median OS from metastatectomy 33.8 months. Thirty-one patients received first-line systemic chemotherapy for metastatic disease with median OS from the start of chemotherapy 11.5 months. No statistically significant difference in progression-free survival or OS was seen between fluoropyrimidine, oxaliplatin, or irinotecan based chemotherapy. BRAF V600E mutation was present in 14 of 47 patients (30%). BRAF V600E patients demonstrated significantly worse median OS; 10.1 versus 17.3 months, P = 0.03. In multivariate analyses, BRAF V600E mutants had worse OS (HR 4.04; P = 0.005), while patients undergoing metastatectomy (HR 0.11; P = <0.001) and patients who initially presented as stage IV disease had improved OS (HR 0.27; P = 0.003). CONCLUSIONS: Patients with MSI-H metastatic CRC do not appear to have improved outcomes. BRAF V600E mutation is a poor prognostic factor in MSI-H metastatic CRC.

Regulation of the distribution of excitation energy in Ochromonas danica, an organism containing a chlorophyll-A/C/carotenoid light harvesting antenna.

A chlorophyll a, c-fucoxanthin pigment-protein complex8 functions as the major light harvesting antenna in the Chrysophyte Ochromonas danica. The regulated distribution of excitation energy between the two photosystems was investigated in these organisms and was shown to be strongly wavelength dependent. A light state transition was induced by pre-illumination of cells using light 2 (640 nm) and light 1 (700 nm) of equal absorbed intensity, and detected by reversible changes in the 77 K chlorophyll fluorescence emission spectra. Peaks at ∼ 690 nm and ∼ 720 nm in the low temperature spectra are most likely associated with PS2 and PS1 respectively. A room temperature fluorescence emission at 680 nm induced by modulated light 2 (500 nm) was strongly quenched in the presence of background light 1 (720 nm). Removal of light 1 led to an increase in fluorescence followed by a slow quenching. The room temperature fluorescence changes were directly correlated with changes in the 77 K emission spectra that indicated a change in the distribution of excitation energy between the two photosystems. It was established that DCMU (1 µmol) prevented the state 2. The conversion to state 1 followed a simple photochemical dose dependence and had a half-time of 20 s-1.5 min at 6 W m(-2). In contrast, the conversion to state 2 was independent of light intensity. These data indicate that O. danica undergoes a light state transition in response to the preferential excitation of PS2 or PS1.