Combination of Imaging Features and Clinical Biomarkers Predicts Positive Pathology and Microbiology Findings Suggestive of Spondylodiscitis in Patients Undergoing Image-Guided Percutaneous Biopsy.

BACKGROUND AND PURPOSE: Pathology and microbiology results for suspected spondylodiscitis on MR imaging are often negative in up to 70% of cases. We aimed to predict whether MR imaging features will add diagnostic value when combined with clinical biomarkers to predict positive findings of spondylodiscitis on pathology and/or microbiology from percutaneous biopsy. MATERIALS AND METHODS: In this retrospective single-center institutional review board-approved study, patients with radiologically suspected spondylodiscitis and having undergone percutaneous biopsies were assessed. Demographic characteristics, laboratory values, and tissue and blood cultures were collected. Pathology and microbiology results were used as end points. Three independent observers provided MR imaging-based scoring for typical MR imaging features for spondylodiscitis. Multivariate logistic regression and receiver operating characteristic analysis were performed to determine an optimal combination of imaging and clinical biomarkers in predicting positive findings on pathology and/or microbiology from percutaneous biopsy suggestive of spondylodiscitis. RESULTS: Our patient cohort consisted of 72 patients, of whom 33.3% (24/72) had spondylodiscitis. The mean age was 63 ± 16 years with a male/female ratio of 41:31. Logistic regression revealed a combination with an area under the curve of 0.72 for pathology and 0.68 for pathology and/or microbiology. Epidural enhancement on MR imaging improved predictive performance to 0.87 for pathology and 0.78 for pathology and/or microbiology. CONCLUSIONS: Our findings demonstrate that epidural enhancement on MR imaging added diagnostic value when combined with clinical biomarkers to help predict which patients undergoing percutaneous biopsy will have positive findings for spondylodiscitis on pathology and/or microbiology.

Essential medicine selection during the COVID-19 pandemic: Enabling access in uncharted territory.

The COVID-19 pandemic requires urgent decisions regarding treatment policy in the face of rapidly evolving evidence. In response, the South African Essential Medicines List Committee established a subcommittee to systematically review and appraise emerging evidence, within very short timelines, in order to inform the National Department of Health COVID-19 treatment guidelines. To date, the subcommittee has reviewed 14 potential treatments, and made recommendations based on local context, feasibility, resource requirements and equity. Here we describe the rapid review and evidence-to-decision process, using remdesivir and dexamethasone as examples. Our experience is that conducting rapid reviews is a practical and efficient way to address medicine policy questions under pandemic conditions.

Thrombotic thrombocytopenic purpura-like syndrome associated with arcanobacterium pyogenes endocarditis in a post-transplant patient: A case report.

Systemic Arcanobacterium pyogenes is a rare bacterial infection in humans.1The diagnosis of thrombotic thrombocytopenic purpura (TTP)-like syndrome and infective endocarditis (IE) is often elusive. We report a case of TTP-like syndrome associated with A. pyogenes endocarditis in a post-allogenic transplant patient.

FOLFOX and intensified split-course chemoradiation as initial treatment for rectal cancer with synchronous metastases.

BACKGROUND: Optimal initial management of rectal carcinoma with synchronous metastases (RCSM) is controversial - both for patients being treated with curative and palliative intent. This study aims to evaluate the use of an upfront treatment strategy combining FOLFOX chemotherapy with split-course pelvic chemoradiation (FOLFOX + CRT) for patients with RCSM. MATERIAL AND METHODS: An analysis of all patients who commenced treatment with FOLFOX + CRT at our institutions between January 2009 and June 2014 was performed. The regimen consisted of a total of 12 weeks of treatment with split-course pelvic chemoradiation (50.4Gy with concurrent oxaliplatin and 5-FU) alternating with FOLFOX chemotherapy. Restaging imaging was performed following treatment, with subsequent management as per local standard of care. RESULTS: 78 patients (15 with resectable liver-only metastases) were identified. 77 (99%) completed at least 45Gy of radiation and 87% completed ≥75% of planned dose intensity of both oxaliplatin and 5FU. Two (2.6%) patients died within 30 days of treatment. Rates of radiological complete or partial response for local and metastatic disease were 90% and 66%, respectively. 24% patients had radiological disease progression of metastatic disease. Median overall survival for patients with unresectable metastatic disease at baseline was 23 months (95%CI: 19-28). 12 patients underwent radical surgery to both the rectum and liver and had an estimated 3-year overall survival rate of 62% (95%CI: 37-100). For those patients who did not proceed to rectal surgery, only 7% required palliative re-irradiation or surgery at a later date and all >20months from initial treatment. CONCLUSIONS: In patients with unresectable metastatic disease, FOLFOX + CRT provides durable pelvic control for the majority without the need for additional local treatment. For patients with an advanced primary tumor and synchronous resectable liver-only metastases, FOLFOX + CRT can be considered a feasible and tolerable upfront treatment option.

Phase II trial evaluating the feasibility of interdigitating folfox with chemoradiotherapy in locally advanced and metastatic rectal cancer.

BACKGROUND: Patients (pts) with metastatic rectal cancer and symptomatic primary, require local and systemic control. Chemotherapy used during chemoradiotherapy (CRT) is adequate for radiosensitisation, but suboptimal for systemic control. The aim of this phase II study was to assess tolerability, local/systemic benefits, of a novel regimen delivering interdigitating intensive chemotherapy with radical CRT. METHODS: Eligible pts had untreated synchronous symptomatic primary/metastatic rectal cancer. A total of 12 weeks of treatment with split-course pelvic CRT (total 50.4 Gy with concurrent oxaliplatin and 5-FU infusion) alternating with FOLFOX chemotherapy. All pts staged with CT, MRI and FDG-PET pre and post treatment. RESULTS: Twenty-six pts were treated. Rectal primary MRI stage: T3 81% and T4 15%. Liver metastases in 81%. Twenty-four pts (92%) completed the 12-week regimen. All patients received planned RT dose, and for both agents over 88% of patients achieved a relative dose intensity of >75%. Grade 3 toxicities: neutropenia 23%, diarrhoea 15%, and radiation skin reaction 12%. Grade 4 toxicity: neutropenia 15%. FDG-PET metabolic response rate for rectal primary 96%, and for metastatic disease 60%. CONCLUSIONS: Delivery of interdigitating chemotherapy with radical CRT was feasible to treat both primary and metastatic rectal cancer. High completion and response rates were encouraging.

Role of (chemo)-radiotherapy in resectable gastric cancer.

The prognosis of patients with locally advanced gastric cancer remains poor, despite radical surgical resection. Adjuvant therapy has been shown to improve survival and, in Western countries, is delivered either postoperatively (chemoradiotherapy) or perioperatively (chemotherapy). Debate continues as to which of these represents the optimal strategy. High-dose gastric irradiation comes at the expense of significant toxicity, and increasing efforts have focused on attempts to reduce toxicity and normal tissue doses. The development of advancing radiotherapy technologies now allows improved target delineation and coverage. However, gastric irradiation remains technically challenging and requires an understanding of postoperative surgical anatomy, patterns of failure and lymph node drainage, as well as an appreciation of the uncertainties around organ motion and filling. Ongoing trials are examining the optimal strategy in which to incorporate (chemo)-radiotherapy, as well as the addition of targeted therapies, in gastric cancer. This overview discusses the current role and evidence for (chemo)-radiotherapy, as well as the technical challenges encountered in the radiotherapeutic management of resectable gastric cancer.

Definitive chemoradiotherapy for oesophageal cancer -- a promising start on an exciting journey.

Despite many advances in the management of oesophageal cancer, survival rates remain poor. Currently there is no clear consensus on the optimum management modality for localised disease. Surgery alone or combined with neoadjuvant chemotherapy or chemoradiotherapy and definitive chemoradiotherapy are all treatment options used for treating selected patient groups throughout the world. This overview discusses the evidence for definitive chemoradiotherapy, its role for certain patient groups and compared with other treatment options and how it has evolved with emerging technologies over recent decades. It highlights some key areas of research for future trials, including more precise treatment delivery, treatment intensification and a possible randomised controlled trial comparing radiation and surgical-based treatment.

The Victorian Lung Cancer Registry pilot: improving the quality of lung cancer care through the use of a disease quality registry.

BACKGROUND: Lung cancer remains a major disease burden in Victoria (Australia) and requires a complex and multidisciplinary approach to ensure optimal care and outcomes. To date, no uniform mechanism is available to capture standardized population-based outcomes and thereby provide benchmarking. The establishment of such a data platform is, therefore, a primary requisite to enable description of process and outcome in lung cancer care and to drive improvement in the quality of care provided to individuals with lung cancer. MATERIALS AND METHODS: A disease quality registry pilot has been established to capture prospective data on all adult patients with clinical or tissue diagnoses of small cell and non-small cell lung cancer. Steering and management committees provide clinical governance and supervise quality indicator selection. Quality indicators were selected following extensive literature review and evaluation of established clinical practice guidelines. A minimum dataset has been established and training and data capture by data collectors is facilitated using a web-based portal. Case ascertainment is established by regular institutional reporting of ICD-10 discharge coding. Recruitment is optimized by provision of opt-out consent. RESULTS: The collection of a standardized minimum data set optimizes capacity for harmonized population-based data capture. Data collection has commenced in a variety of settings reflecting metropolitan and rural, and public, and private health care institutions. The data set provides scope for the construction of a risk-adjusted model for outcomes. A data access policy and a mechanism for escalation policy for outcome outliers has been established. CONCLUSIONS: The Victorian Lung Cancer Registry provides a unique capacity to provide and confirm quality assessment in lung cancer and to drive improvement in quality of care across multidisciplinary stakeholders.

Augmentation of thrombin generation in neonates undergoing cardiopulmonary bypass.

INTRODUCTION: Factor concentrates are currently available and becoming increasingly used off-label for treatment of bleeding. We compared recombinant activated factor VII (rFVIIa) with three-factor prothrombin complex concentrate (3F-PCC) for the ability to augment thrombin generation (TG) in neonatal plasma after cardiopulmonary bypass (CPB). First, we used a computer-simulated coagulation model to assess the impact of rFVIIa and 3F-PCC, and then performed similar measurements ex vivo using plasma from neonates undergoing CPB. METHODS: Simulated TG was computed according to the coagulation factor levels from umbilical cord plasma and the therapeutic levels of rFVIIa, 3F-PCC, or both. Subsequently, 11 neonates undergoing cardiac surgery were enrolled. Two blood samples were obtained from each neonate: pre-CPB and post-CPB after platelet and cryoprecipitate transfusion. The post-CPB products sample was divided into control (no treatment), control plus rFVIIa (60 nM), and control plus 3F-PCC (0.3 IU ml(-1)) aliquots. Three parameters of TG were measured ex vivo. RESULTS: The computer-simulated post-CPB model demonstrated that rFVIIa failed to substantially improve lag time, TG rate and peak thrombin without supplementing prothrombin. Ex vivo data showed that addition of rFVIIa post-CPB significantly shortened lag time; however, rate and peak were not statistically significantly improved. Conversely, 3F-PCC improved all TG parameters in parallel with increased prothrombin levels in both simulated and ex vivo post-CPB samples. CONCLUSIONS: Our data highlight the importance of prothrombin replacement in restoring TG. Despite a low content of FVII, 3F-PCC exerts potent procoagulant activity compared with rFVIIa ex vivo. Further clinical evaluation regarding the efficacy and safety of 3F-PCC is warranted.

Early caffeine therapy and clinical outcomes in extremely preterm infants.

OBJECTIVE: To determine if early caffeine (EC) therapy is associated with decreased bronchopulmonary dysplasia (BPD) or death, decreased treatment of patent ductus arteriosus (PDA), or shortened duration of ventilation. STUDY DESIGN: In a retrospective cohort of 140 neonates ≤1250 g at birth, infants receiving EC (initiation <3 days of life) were compared with those receiving late caffeine (LC, initiation ≥3 days of life) using logistic regression. RESULT: Of infants receiving EC, 25% (21/83) died or developed BPD compared with 53% (30/57) of infants receiving LC (adjusted odds ratio (aOR) 0.26, 95% confidence interval (CI) 0.09 to 0.70; P<0.01). PDA required treatment in 10% of EC infants versus 36% of LC infants (aOR 0.28, 95%CI 0.10 to 0.73; P=0.01). Duration of mechanical ventilation was shorter in infants receiving EC (EC, 6 days; LC, 22 days; P<0.01). CONCLUSION: Infants receiving EC therapy had improved neonatal outcomes. Further studies are needed to determine if caffeine prophylaxis should be recommended for preterm infants.

Effects of in utero antiretroviral exposure on mitochondrial DNA levels, mitochondrial function and oxidative stress.

OBJECTIVES: HIV and antiretroviral (ART) exposure in utero may have deleterious effects on the infant, but uncertainty still exists. The objective of this study was to evaluate aspects of mitochondrial DNA (mtDNA) content, mitochondrial function and oxidative stress simultaneously in placenta, umbilical cord blood and infant blood in HIV/ART-exposed infants compared with uninfected controls. METHODS: HIV-1-infected pregnant women and HIV-1-uninfected healthy pregnant controls were enrolled in the study prospectively. Placenta and umbilical cord blood were obtained at delivery and infant blood was obtained within 48 h of delivery. mtDNA content was determined for each specimen. Nuclear [subunit IV of cytochrome c-oxidase (COX IV)]- and mitochondrial (COX II)-encoded polypeptides of the oxidative phosphorylation enzyme cytochrome c-oxidase were quantified in cord and infant blood. Placental mitochondria malondialdehyde (MDA) concentrations were measured as a marker of oxidative stress. RESULTS: Twenty HIV-positive/HIV-exposed and 26 control mother-infant pairs were enrolled in the study. All HIV-infected women and their infants received ART. Placental MDA concentration and mtDNA content in placenta and cord blood were similar between groups. The cord blood COX II:IV ratio was lower in the HIV-positive group than in the controls, whereas the infant peripheral blood mtDNA content was higher in the HIV-exposed infants, but the infant peripheral blood COX II:IV ratio was similar. No infant had clinical evidence of mitochondrial disease or acquired HIV infection. In multivariable regression analyses, the significant findings in cord and infant blood were both most associated with HIV/ART exposure. CONCLUSIONS: HIV-exposed infants showed reduced umbilical cord blood mitochondrial enzyme expression with increased infant peripheral blood mitochondrial DNA levels, the latter possibly reflecting a compensatory mechanism to overcome HIV/ART-associated mitochondrial toxicity.

FDG-PET metabolic response predicts outcomes in anal cancer managed with chemoradiotherapy.

BACKGROUND: The aim was to investigate the correlation between (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) metabolic response to chemoradiotherapy and clinical outcomes in squamous cell carcinoma (SCC) of the anus. METHODS: A total of 48 patients with biopsy-proven anal SCC underwent FDG-PET scans at baseline and post chemoradiotherapy (54 Gy, concurrent 5-FU/mitomycin). Kaplan-Meier analysis was used to determine survival outcomes according to FDG-PET metabolic response. RESULTS: In all, 79% patients (n=38) had a complete metabolic response (CMR) at all sites of disease, 15% (n=7) had a CMR in regional nodes but only partial response in the primary tumour (overall partial metabolic response (PMR)) and 6% (n=3) had progressive distant disease despite CMR locoregionally (overall no response (NR)). The 2-year progression-free survival (PFS) was 95% for patients with a CMR, 71% for PMR and 0% for NR (P<0.0001). The 5-year overall survival (OS) was 88% in CMR, 69% in PMR and 0% in NR (P<0.0001). Cox proportional hazards regression analyses for PFS and OS found significant associations for incomplete (PMR+NR) vs complete FDG-PET response to treatment only, (HR 4.1 (95% CI: 1.5-11.5, P=0.013) and 6.7 (95% CI: 2.1-21.6, P=0.002), respectively). CONCLUSION: FDG-PET metabolic response to chemoradiotherapy in anal cancer is significantly associated with PFS and OS, and in this cohort incomplete FDG-PET response was a stronger predictor than T or N stage.

Chemoradiotherapy in the management of primary squamous-cell carcinoma of the rectum.

AIM: To assess the efficacy of chemoradiotherapy in the management of primary squamous-cell carcinoma of the rectum. METHOD: Nine patients with primary squamous-cell carcinoma of the rectum were treated with chemoradiotherapy from 1985 to 2007. All patients were female, with a mean age of 54 years (range 41-72 years). The mean distance of the tumour from the anal verge was 6 cm (range 4-10 cm). Seven patients were treated with curative intent (two postoperative, three preoperative, two chemoradiotherapy alone). Clinical stages for the curative group were T1N0M0 (1), T3N0M0 (3), T3N1M0 (1) and T4N0M0 (2). Chemoradiotherapy consisted of pelvic radiation 45-54 Gy in 1.8 Gy/fraction and concurrent 5-fluorouracil and mitomycin C. The mean follow-up duration for the curative group was 39 months (range 15-120 months). RESULTS: All seven patients treated with curative intent achieved local control. A complete pathological response was seen in all patients after preoperative chemoradiotherapy. Two patients did not have surgery and remained free of disease. One patient with gross residual disease after surgery achieved local control. 18-Fluorodeoxyglucose (FDG) avidity was detected in all patients who had FDG-PET scans. Both primary and metastatic tumours demonstrated FDG-avidity. CONCLUSION: Primary squamous-cell carcinoma of the rectum appears to be very sensitive to chemoradiotherapy. The high complete response rate suggests that chemoradiotherapy alone with salvage surgery for local failure should be further explored. FDG-PET scan may have a role to play in the management of this disease.

Homocysteine status and cardiovascular risk factors in patients with psoriasis: a case-control study.

BACKGROUND: Psoriasis is a hyperproliferative, cutaneous disorder with the potential to lower levels of folate. This may result in raised levels of homocysteine, an independent risk factor for the development of cardiovascular disease. OBJECTIVE: A study was conducted to compare levels of red-cell folate (RCF) and homocysteine in patients with psoriasis and in healthy controls. Levels of homocysteine were also examined in the context of other major cardiovascular risk factors. METHODS: In total, 20 patients with psoriasis and 20 controls had their RCF, homo-cysteine and other conventional cardiovascular risk factors assessed. RESULTS: Patients with psoriasis had a trend towards lower levels of RCF. Significantly raised levels of homocysteine were found in patients with psoriasis compared with controls (P = 0.007). There was no correlation between homocysteine levels, RCF levels or disease activity as measured by the Psoriasis Area and Severity Index. Patients with psoriasis had higher body mass index (P < 0.004) and higher systolic blood pressure (P < 0.001) than controls. This may contribute to the excess cardiovascular mortality observed in patients with psoriasis.

Phase I trial of docetaxel, cisplatin and concurrent radical radiotherapy in locally advanced oesophageal cancer.

BACKGROUND: Locally advanced oesophageal cancer (LAEC) is associated with poor survival and more effective treatments are needed. The aim of this phase I trial was to assess the maximum tolerated dose (MTD) of a novel weekly docetaxel and cisplatin regimen concurrent with radical radiotherapy. METHODS: Patients with unresectable, non-metastatic LAEC were eligible. Treatment comprised docetaxel 15-30 mg m(-2) per week and cisplatin 15-30 mg m(-2) per week in six planned dose levels (DLs) in 3-6 patient cohorts with 50 Gy radiotherapy in 25 fractions. Maximum tolerated dose was based on defined dose-limiting toxicities (DLTs) during therapy and 2 weeks post therapy. RESULTS: A total of 24 patients were enrolled. There were two DLTs: grade 3 fever in DL1 (docetaxel 15 mg m(-2), cisplatin 15 mg m(-2)) and grade 3 nausea in DL2 (20 mg m(-2), 15 mg m(-2)). These DLs were each expanded to six patients without further DLTs. The most common acute toxicity was grade 3 radiation oesophagitis (37.5%). There were no grade 4 toxicities, and haematologic toxicity was minimal. Cisplatin and docetaxel dose intensity was 100% at the highest dose level (DL6). A MTD was not reached in this trial. Tumour overall response rate was 50% (33% complete, 17% partial). CONCLUSION: Cisplatin and docetaxel each 30 mg m(-2) per week concurrent with 50 Gy radiotherapy is recommended for use in phase II clinical trials in oesophageal cancer.