Mark Tacey

Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer

Detection of circulating tumor DNA in patients with resected stage II colon cancer provides evidence of residual disease. Footprints of persistent cancer Stage II colon cancer, which has spread through the wall of the colon but has not metastasized to the lymph nodes, can present a therapeutic dilemma. On one hand, these tumors can usually be completely removed by surgery, and the majority does not recur even without chemotherapy. On the other hand, it is difficult to determine which of these tumors will recur and to identify patients who would benefit from adjuvant chemotherapy after surgery. Tie et al. show that the presence of circulating tumor DNA in a patient’s blood after surgery is a sign of persistent tumor and a greatly increased risk of relapse, suggesting that this group of patients may require chemotherapy to prevent recurrence. Detection of circulating tumor DNA (ctDNA) after resection of stage II colon cancer may identify patients at the highest risk of recurrence and help inform adjuvant treatment decisions. We used massively parallel sequencing–based assays to evaluate the ability of ctDNA to detect minimal residual disease in 1046 plasma samples from a prospective cohort of 230 patients with resected stage II colon cancer. In patients not treated with adjuvant chemotherapy, ctDNA was detected postoperatively in 14 of 178 (7.9%) patients, 11 (79%) of whom had recurred at a median follow-up of 27 months; recurrence occurred in only 16 (9.8 %) of 164 patients with negative ctDNA [hazard ratio (HR), 18; 95% confidence interval (CI), 7.9 to 40; P < 0.001]. In patients treated with chemotherapy, the presence of ctDNA after completion of chemotherapy was also associated with an inferior recurrence-free survival (HR, 11; 95% CI, 1.8 to 68; P = 0.001). ctDNA detection after stage II colon cancer resection provides direct evidence of residual disease and identifies patients at very high risk of recurrence.

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.

A Systematic Review of the Definitions, Determinants, and Clinical Outcomes of Antimicrobial De-escalation in the Intensive Care Unit

Antimicrobial de-escalation (ADE) is a strategy to reduce the spectrum of antimicrobials and aims to prevent the emergence of bacterial resistance. We present a systematic review describing the definitions, determinants and outcomes associated with ADE. We included 2 randomized controlled trials and 12 cohort studies. There was considerable variability in the definition of ADE. It was more frequently performed in patients with broad-spectrum and/or appropriate antimicrobial therapy (P= .05 to .002), when more agents were used (P= .002), and in the absence of multidrug-resistant pathogens (P< .05). Where investigated, lower or improving severity scores were consistently associated with ADE (P= .04 to <.001). The pooled effect of ADE on mortality is protective (relative risk, 0.68; 95% confidence interval, .52-.88). Because the determinants of ADE are markers of clinical improvement and/or of lower risk of treatment failure this effect on mortality cannot be retained as evidence. None of the studies were designed to investigate the effect of ADE on antimicrobial resistance.

Validation of Conventional Fluoroscopic and ECG Criteria for Right Ventricular Pacemaker Lead Position Using Cardiac Computed Tomography

It is hypothesized that pacing the right ventricular (RV) septum is associated with less deleterious outcomes than RV apical pacing. Our aim was to validate fluoroscopic and electrocardiography (ECG) criteria for describing pacemaker and implantable cardioverter defibrillator RV “septal” lead position against the proposed gold standard: cardiac computed tomography (CT).

Telemedicine interventions for gestational diabetes mellitus: A systematic review and meta-analysis

OBJECTIVE To evaluate the effect of telemedicine on GDM service and maternal, and foetal outcomes. METHODS A systematic review and meta-analysis of randomised controlled trials (RCT) of telemedicine interventions for GDM was conducted. We searched English publications from 01/01/1990 to 31/08/2013, with further new publication tracking to June 2015 on MEDLINE, EMBASE, PUBMED, CINAHL, the Cochrane Central Register of Controlled Trials and the World Health Organization International Clinical Trials Registry electronic databases. Findings are presented as standardised mean difference (SMD) and odds ratios (OR) or narrative and quantitative description of findings where meta-analysis was not possible. RESULTS Our search yielded 721 abstracts. Four met the inclusion criteria; two publications arose from the same study, resulting in three studies for review. All studies compared telemedicine to usual care. Telemedicine was associated with significantly fewer unscheduled GDM clinic visits, SMD. Quality of life, glycaemic control (HbA1c, pre and postprandial blood glucose level (BGL)), and caesarean section rate were similar between the telemedicine and usual care groups. None of the studies evaluated costs. CONCLUSIONS Telemedicine has the potential to streamline GDM service utilisation without compromising maternal and foetal outcomes. Its advantage may lie in the convenience of reducing face-to-face and unscheduled consultations. Studies are limited and more trials that include cost evaluation are required.

Clinical trial participation and outcome for patients with glioblastoma: Multivariate analysis from a comprehensive dataset

Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. Although multiple clinical and tumor-related variables affect survival outcomes, the effect of clinical trial participation has not been explored. The aim of this study was to determine whether clinical trial participation improves outcome for patients with GBM. Data from patients with GBM were accessed from a dataset collected over 12 years (1998-2010) at two institutions. Univariable and multivariate logistic regression analyses were performed to look for relationships between clinical trial participation, other baseline clinical and sociodemographic variables and overall survival (OS). In total, 542 patients were identified and included in the analysis; median age was 62 years. Sixty-one patients (11%) were enrolled in a clinical trial. Clinical trial enrollment was associated with improved median survival (14.5 months compared to 6.3 months, p < 0.001) and this difference remained significant in multivariate analysis (hazard ratio 0.67, p = 0.046). Age, poor performance status and operation type were also independent predictors for OS in multivariate analysis. Disease site, socioeconomic status and co-morbidity did not affect survival outcome. This is the first study in patients with GBM to suggest a survival benefit from clinical trial participation, independent of age and performance status; while also confirming the importance of other previously reported prognostic factors. This should encourage clinicians to offer trial therapies to patients with GBM and encourage patients to participate in available studies.

Comparison between poor and long‐term survivors with glioblastoma: Review of an Australian dataset

Despite the largely poor prognosis for patients with glioblastoma, 5‐year survival approaches 10%. In many circumstances the reasons for discrepant outcomes remain unknown. This retrospective cohort study compared clinical and socio‐demographic variables between long‐term and poor survivors with glioblastoma.

MRI Grading versus Histology: Predicting Survival of World Health Organization Grade II–IV Astrocytomas

BACKGROUND AND PURPOSE: Histologic grading of intracranial astrocytomas is affected by sampling error and substantial inter- and intraobserver variability. We proposed that incorporating MR imaging into grading will predict patient survival more accurately than histopathology alone. MATERIALS AND METHODS: Patients with a new diagnosis of World Health Organization grades II–IV astrocytoma or mixed oligoastrocytoma diagnosed between September 2007 and December 2010 were identified. Two hundred forty-five patients met the inclusion criteria. Preoperative MRIs were independently reviewed by 2 readers blinded to the histologic grade, and an MR imaging grade was given. The MR imaging and histopathologic grades were compared with patient survival. RESULTS: Patients with grade II or III astrocytomas on histology but evidence of necrosis on MR imaging (consistent with a grade IV tumor) had significantly worse survival than patients with the same histology but no evidence of necrosis on MR imaging (P = .002 for grade II histology and P = .029 for grade III). Their survival was not significantly different from that in patients with grade IV tumors on histology (P = .164 and P = .385, respectively); this outcome suggests that all or most are likely to have truly been grade IV tumors. MR imaging evidence of necrosis was less frequent in grade II and III oligoastrocytomas, preventing adequate subgroup analysis. CONCLUSIONS: MR imaging can improve grading of intracranial astrocytomas by identifying patients suspected of being undergraded by histology, with high interobserver agreement. This finding has the potential to optimize patient management, for example, by encouraging more aggressive treatment earlier in the patients course.

Health Care Cost Analysis in a Population-based Inception Cohort of Inflammatory Bowel Disease Patients in the First Year of Diagnosis

BACKGROUND There are limited prospective population-based data on the health care cost of IBD in the post-biologicals era. A prospective registry that included all incident cases of inflammatory bowel disease [IBD] was established to study disease progress and health cost. AIM To prospectively assess health care costs in the first year of diagnosis among a well-characterised cohort of newly diagnosed IBD patients. METHOD Incident cases of IBD were prospectively identified in 2007-2008 and 2010-2013 from multiple health care providers, and enrolled into the population-based registry. Health care resource utilisation for each patient was collected through active surveillance of case notes and investigations including specialist visits, diagnostic tests, medications, medical hospitalisation, and surgery. RESULTS Off 276 incident cases of IBD, 252 [91%] were recruited to the registry, and health care cost was calculated for 242 (146 Crohns disease [CD] and 96 ulcerative colitis [UC] patients). The median cost in CD was higher at A

Surgery for the correction of hallux valgus: Minimum five-year results with a validated patient-reported outcome tool and regression analysis

5905 per patient (interquartile range [IQR]: A