ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group.

Circulating tumour DNA (ctDNA) assays conducted on plasma are rapidly developing a strong evidence base for use in patients with cancer. The European Society for Medical Oncology convened an expert working group to review the analytical and clinical validity and utility of ctDNA assays. For patients with advanced cancer, validated and adequately sensitive ctDNA assays have utility in identifying actionable mutations to direct targeted therapy, and may be used in routine clinical practice, provided the limitations of the assays are taken into account. Tissue-based testing remains the preferred test for many cancer patients, due to limitations of ctDNA assays detecting fusion events and copy number changes, although ctDNA assays may be routinely used when faster results will be clinically important, or when tissue biopsies are not possible or inappropriate. Reflex tumour testing should be considered following a non-informative ctDNA result, due to false-negative results with ctDNA testing. In patients treated for early-stage cancers, detection of molecular residual disease or molecular relapse, has high evidence of clinical validity in anticipating future relapse in many cancers. Molecular residual disease/molecular relapse detection cannot be recommended in routine clinical practice, as currently there is no evidence for clinical utility in directing treatment. Additional potential applications of ctDNA assays, under research development and not recommended for routine practice, include identifying patients not responding to therapy with early dynamic changes in ctDNA levels, monitoring therapy for the development of resistance mutations before clinical progression, and in screening asymptomatic people for cancer. Recommendations for reporting of results, future development of ctDNA assays and future clinical research are made.

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.

[Preliminary research on long non-coding RNA related signaling pathways regulated by SIRT1 in human trabecular meshwork cells].

Objective: To explore the possible mechanism of silent information regulator 1 (SIRT1) in regulating the function of human trabecular meshwork cells (HTMCs). Methods: Experimental study. HTMCs were transfected with SIRT1-overexpressed lentivirus and control lentivirus at the optimal multiplicity of infection, respectively. The total RNA was extracted, and the long non-coding RNA (lncRNA) microarray was used to detect the expression of lncRNAs. The differentially expressed lncRNAs were analyzed by bioinformatics. Real-time PCR was used to verify the microarray results. Student's t-test was used for comparison between groups. Results: Compared with the control group, there were 636 up-regulated lncRNAs and 2 246 down-regulated lncRNAs in the SIRT1 overexpressed group (all P<0.05). Gene ontology analysis showed that SIRT1 regulated extracellular matrix, cell metabolism, proliferation and apoptosis of HTMCs. Kyoto encyclopedia of genes and genomics pathway analysis indicated that differential lncRNAs induced by SIRT1 were involved in 19 signal pathways, including Notch signaling pathway, mitogen-activated protein kinase signaling pathway, inflammatory mediator regulation of tyrosinase-associated protein channels and extracellular matrix-receptor interaction. Conclusion: SIRT1 could have effects on the function of HTMCs through regulating lncRNAs in multiple signaling pathways, including Notch signaling pathway, mitogen-activated protein kinase signaling pathway, etc. (Chin J Ophthalmol, 2021, 57: 215-222).

Refinements in the design and division of the thenar flap to achieve better functional results.

Though the thenar flap has been described since 1926, its use has not been widespread. The main criticisms are donor site morbidity and proximal interphalangeal joint (PIPJ) stiffness. In this paper, we describe a standard design technique for flap design and division to address these two issues. From July 2018 to April 2019, a total of ten patients underwent thenar flap reconstruction of the fingertip. The flap dimensions ranged from 10 mm × 10 mm to 25 mm × 15 mm. All the flaps survived. One patient developed wound infection post division. All donor sites were closed primarily without skin graft. We are using mirror image technique to elevate the flap to ensure that it is inset in the position as we planned without displacement. It largely reduced the chance of rotation and extensive tension when fix the finger to the thenar region. Our technique allows for the flap design to be individually customized based on the orientation of the defect, making it simpler and more replicable. We have also emphasized how care during division of the thenar flap can help prevent complications.

[Safety and short-term efficacy analysis of breast-conserving surgery combined with intraoperative radiotherapy for early-stage breast cancer].

Objective: To analyze the safety and short-term efficacy of breast-conserving surgery combined with intraoperative radiotherapy for early-stage breast cancer. Methods: A total of 101 consecutive patients who received breast-conserving surgery plus intraoperative radiotherapy were recruited to summarize the recent follow-up results and clinicopathological data. Univariate analysis and Logistic regression model were used to evaluate the factors affecting the postoperative adverse reactions and cosmetic effects. Results: Among 101 patients, 4 patients had recurrence or metastasis. The 3-years disease free survival rate was 94.9%, and the 3-years cumulative recurrence rate was 5.1%. Univariate analysis showed that the menstrual status and postoperative whole breast radiotherapy were associated with the postoperative adverse reactions (P<0.05). The T stage and applicator diameter were associated with the cosmetic effect (P<0.05). Multivariate analysis indicated that the diameter of the applicator (OR=3.701, P=0.026) and postoperative whole breast radiotherapy (OR=5.962, P=0.005) were independent factors for the postoperative adverse reactions, and the diameter of the applicator (OR=2.522, P=0.037) was an independent factor for the cosmetic effect. Conclusion: Breast-conserving surgery combined with intraoperative radiotherapy shows safety and good short-term efficacy in low-risk early-stage breast cancer.

Serum Procalcitonin, White Blood Cell and Hypersensitive C-reactive Protein Combined with Age Established a New Prediction Model in Predicting ICU Admission in Adult Community-Acquired Pneumonia (CAP) Patients.

BACKGROUND: CAP is the most common cause of death in infectious diseases in developing countries, while also an important cause of death and morbidity in developed countries. In recent years, CURB-65 (or CRB-65) and pneumonia severity index (PSI) scoring systems have been widely used in the prognosis scoring system of CAP. However, each of them has some shortcomings in predicting ICU admission in CAP patients. The aim of this study is to analyze serum inflammatory biomarkers combined age to established a new prediction model in predicting ICU admission in CAP patients. METHODS: This is a retrospective study. The enrolled CAP patients received serum inflammatory biomarker tests, including procalcitonin (PCT), white blood cell count (WBC), hypersensitive C-reactive protein (hs-CRP), and erythrocyte sedimentation rate (ESR). Body temperature and age were also recorded. The main outcome measures were ICU admission. Univariate analysis and binary logistic regression analysis were used to explore the in-dependent risk factors which could be components of a new predicting model for ICU admission in CAP patients. Receiver operating characteristic curves (ROC) were used to evaluate the sensitivity and specificity of the new model, which consisted of the combination of all independent risk factors in predicting the main outcomes. RESULTS: Initially, 246 CAP patients were admitted to general wards, 61 of whom were subsequently transferred to ICU (61/246). Age, PCT, WBC, and hs-CRP were independent risk factors for subsequent admission to ICU for CAP patients in general wards. The AUC of the ROC curve of new prediction model (the joint model consists of age, PCT, WBC, and hs-CRP) was 0.93 (95% CI 0.85 - 0.96), the sensitivity and specificity were 85.2% and 88.1%, respectively. CONCLUSIONS: Serum inflammatory biomarkers combined age have high specificity and sensitivity in predicting ICU admission in adult CAP patients.

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.

MiR-340-5p is a potential prognostic indicator of colorectal cancer and modulates ANXA3.

OBJECTIVE: MicroRNAs (miRNAs) are increasingly recognized as oncogenes or tumor suppressors in colorectal cancer (CRC). The aim of this study was to explore the expression and functions of miR-340-5p in CRC. PATIENTS AND METHODS: The expression of miR-340-5p in CRC tissues and cell lines was detected by quantitative RT-PCR. Associations of miR-340-5p expression with clinicopathological factors and overall survival (OS) and progression-free survival (PFS) were statistically evaluated. Luciferase assay, RT-PCR, and Western blot were performed to verify the precise target of miR-340-5p. MTT assay, colony formation and transwell assay were performed to determine the proliferation, migration and invasion, respectively. RESULTS: Our results showed that miR-340-5p was significantly down-regulated in CRC tissues and cell lines, and was associated with histological grade (p=0.020), lymph nodes metastasis (p=0.003) and TNM stage (p=0.007). Furthermore, Kaplan-Meier and log-rank tests revealed that patients with low expression of miR-340-5p had a shorter OS (p=0.0110) and PFS (p=0.0032) than those with high expression of miR-340-5p. We further validated Annexin A3 (ANXA3) was a direct target of miR-340-5p in CRC. The functional assay showed that up-regulation of miR-340-5p or down-regulation of ANXA3 can both inhibit CRC cell proliferation, migration, and invasion. Besides, the re-expression of ANXA3 reversed the miR-340-5p induced suppression of cell proliferation, migration and invasion. CONCLUSIONS: Our data demonstrated that miR-340-5p exerted its tumor-suppressive function by directly targeting ANXA3 in CRC, suggesting that miR-340-5p might represent a novel prognostic biomarker and therapeutic target for CRC.

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.

Functional Study of the Vitamin K Cycle Enzymes in Live Cells.

Vitamin K-dependent carboxylation, an essential posttranslational modification catalyzed by gamma-glutamyl carboxylase, is required for the biological functions of proteins that control blood coagulation, vascular calcification, bone metabolism, and other important physiological processes. Concomitant with carboxylation, reduced vitamin K (KH2) is oxidized to vitamin K epoxide (KO). KO must be recycled back to KH2 by the enzymes vitamin K epoxide reductase and vitamin K reductase in a pathway known as the vitamin K cycle. Our current knowledge about the enzymes of the vitamin K cycle is mainly based on in vitro studies of each individual enzymes under artificial conditions, which are of limited usefulness in understanding how the complex carboxylation process is carried out in the physiological environment. In this chapter, we review the current in vitro activity assays for vitamin K cycle enzymes. We describe the rationale, establishment, and application of cell-based assays for the functional study of these enzymes in the native cellular milieu. In these cell-based assays, different vitamin K-dependent proteins were designed and stably expressed in mammalian cells as reporter proteins to accommodate the readily used enzyme-linked immunosorbent assay for carboxylation efficiency evaluation. Additionally, recently emerged genome-editing techniques TALENs and CRISPR-Cas9 were used to knock out the endogenous enzymes in the reporter cell lines to eliminate the background. These cell-based assays are easy to scale up for high-throughput screening of inhibitors of vitamin K cycle enzymes and have been successfully used to clarify the genotypes and their clinical phenotypes of enzymes of the vitamin K cycle.

Structural and functional insights into enzymes of the vitamin K cycle.

Vitamin K-dependent proteins require carboxylation of certain glutamates for their biological functions. The enzymes involved in the vitamin K-dependent carboxylation include: gamma-glutamyl carboxylase (GGCX), vitamin K epoxide reductase (VKOR) and an as-yet-unidentified vitamin K reductase (VKR). Due to the hydrophobicity of vitamin K, these enzymes are likely to be integral membrane proteins that reside in the endoplasmic reticulum. Therefore, structure-function studies on these enzymes have been challenging, and some of the results are notably controversial. Patients with naturally occurring mutations in these enzymes, who mainly exhibit bleeding disorders or are resistant to oral anticoagulant treatment, provide valuable information for the functional study of the vitamin K cycle enzymes. In this review, we discuss: (i) the discovery of the enzymatic activities and gene identifications of the vitamin K cycle enzymes; (ii) the identification of their functionally important regions and their active site residues; (iii) the membrane topology studies of GGCX and VKOR; and (iv) the controversial issues regarding the structure and function studies of these enzymes, particularly, the membrane topology, the role of the conserved cysteines and the mechanism of active site regeneration of VKOR. We also discuss the possibility that a paralogous protein of VKOR, VKOR-like 1 (VKORL1), is involved in the vitamin K cycle, and the importance of and possible approaches for identifying the unknown VKR. Overall, we describe the accomplishments and the remaining questions in regard to the structure and function studies of the enzymes in the vitamin K cycle.

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.

Randomised clinical trial: L-ornithine-L-aspartate reduces significantly the increase of venous ammonia concentration after TIPSS.

BACKGROUND: Use of TIPSS is associated with increases in ammonia concentration and hepatic encephalopathy (HE) risk. L-ornithine-L-aspartate (LOLA) is effective in reducing ammonia concentration. AIM: To evaluate the effects of LOLA on venous ammonia concentration after TIPSS. METHODS: The included patients were randomised to receive LOLA or no-LOLA treatment for 7 days. Fasting and post-prandial venous ammonia levels were the primary outcomes. Psychometric performance, post-TIPSS HE, and liver and renal function were assessed as secondary outcomes. RESULTS: Of 133 cirrhotic patients who received successful TIPSS between November 2011 and June 2012, 40 met the inclusion criteria and were randomised to the LOLA (n = 21) or control (n = 19) groups. Change in fasting ammonia significantly favoured the LOLA group at days 4 (P = 0.001) and 7 (P = 0.003). Changes in post-prandial ammonia concentration significantly favoured the LOLA group at days 1, 4 and 7 as well. During the study period, patients in the LOLA group had better improvement in psychometric tests than those in the control group. Overt HE during treatment was observed in one patient in the LOLA group and three patients in the control group (P = 0.331). There were no differences in complications, adverse events or mortality between the two groups. CONCLUSIONS: Prophylactic use of LOLA infusion after TIPSS is safe and effective in significantly reducing the increase of venous ammonia concentration, and can benefit the patient's mental status as well.

Synergistic sporicidal effect of ethanol on a combination of orthophthalaldehyde and didecyldimethylammonium chloride.

UNLABELLED: The objective of this study was to evaluate the potential synergistic effect of ethanol on a combination of orthophthalaldehyde (OPA) and didecyldimethylammonium chloride (DDAC) against the spores of Bacillus subtilis var. Niger. The quantitative carrier test for sporicidal testing of high-level disinfectants according to the guideline of China (Technical Standard for Disinfection 2002) was used as method. Considerable synergistic effect was observed after a 30-min treatment at 20°C. There was an augment in mean log reduction as the concentration of DDAC was increased ranging from 0·2 to 3 g l(-1) in combination with 6 g l(-1) OPA. Ten and 20% ethanol in combination with 6 g l(-1) OPA and 2 g l(-1) DDAC caused more than a 3-log reduction while either 6 g l(-1) OPA, 2 g l(-1) DDAC and 20% ethanol alone or a combination of two of the three agents produced less than a 1-log reduction. Further, 40-min exposure time of combination of OPA, DDAC and 20% ethanol led to greater than a 5-log reduction in spores, and no spore growth was observed following 60- and 90-min exposures. SIGNIFICANCE AND IMPACT OF THE STUDY: Orthophthalaldehyde (OPA) is very effective at concentrations far lower than its recommended in-use concentration of 0·5% (w/v) and is equally effective against both the gram-negative and gram-positive bacteria. However, it shows lower activity against spores. The synergistic sporicidal effect exhibited by ethanol on a combination of OPA and DDAC can be considered to enhance sporicidal activity for using in situations of sterilization, to reduce in-use concentration of OPA used alone, which may minimize its side effect. OPA may be a more satisfactory and the first-choice agent to replace glutaraldehyde (GTA) as a high-level disinfectant for medical devices.

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.

Developing a national database for metastatic colorectal cancer management: perspectives and challenges.

BACKGROUND: The changing treatment landscape for metastatic colorectal cancer creates multiple potential treatment strategies. An Australian-centric database capturing comprehensive information across a range of treatment locations would create a valuable resource enabling multiple important research questions to be addressed. AIMS: To establish a collection of a consensus dataset capturing treatment and outcomes at multiple public and private hospitals across Australia. METHODS: An electronic database was developed by a panel of clinicians, to capture an agreed dataset for patients with newly diagnosed metastatic colorectal cancer. Of particular interest were clinician decision-making, the impact of comorbidities and the frequency of major adverse events. RESULTS: Since July 2009, data collection has been established at six public and eight private hospitals across three Australian states and territories. Successful linkage and analysis, with support from BioGrid Australia, of selected data on the initial 864 patients demonstrates that data can be captured from diverse sites, including public and private practice, that multiple factors impact on treatment delivered and outcomes achieved and that comprehensive data on rare but important adverse events can be captured. As a clinical research tool, the project has been highly successful, generating multiple presentations at national and international conferences related to a diverse range of research questions. CONCLUSIONS: Multistate, project-specific data collection involving large numbers of patients is achievable. Providing invaluable insight into the routine clinical management of metastatic colorectal cancer in the era of targeted therapies, this also creates a significant resource for research, including many questions not being addressed by clinical trials.