A phase IIb, open-label, randomized controlled dose ranging multi-centre trial to evaluate the safety, tolerability, pharmacokinetics and exposure-response relationship of different doses of delpazolid in combination with bedaquiline delamanid moxifloxacin in adult subjects with newly diagnosed, uncomplicated, smear-positive, drug-sensitive pulmonary tuberculosis.

BACKGROUND: Linezolid is an effective, but toxic anti-tuberculosis drug that is currently recommended for the treatment of drug-resistant tuberculosis. Improved oxazolidinones should have a better safety profile, while preserving efficacy. Delpazolid is a novel oxazolidinone developed by LegoChem Biosciences Inc. that has been evaluated up to phase 2a clinical trials. Since oxazolidinone toxicity can occur late in treatment, LegoChem Biosciences Inc. and the PanACEA Consortium designed DECODE to be an innovative dose-ranging study with long-term follow-up for determining the exposure-response and exposure-toxicity relationship of delpazolid to support dose selection for later studies. Delpazolid is administered in combination with bedaquiline, delamanid and moxifloxacin. METHODS: Seventy-five participants with drug-sensitive, pulmonary tuberculosis will receive bedaquiline, delamanid and moxifloxacin, and will be randomized to delpazolid dosages of 0 mg, 400 mg, 800 mg, 1200 mg once daily, or 800 mg twice daily, for 16 weeks. The primary efficacy endpoint will be the rate of decline of bacterial load on treatment, measured by MGIT liquid culture time to detection from weekly sputum cultures. The primary safety endpoint will be the proportion of oxazolidinone class toxicities; neuropathy, myelosuppression, or tyramine pressor response. Participants who convert to negative liquid media culture by week 8 will stop treatment after the end of their 16-week course and will be observed for relapse until week 52. Participants who do not convert to negative culture will receive continuation phase treatment with rifampicin and isoniazid to complete a six-month treatment course. DISCUSSION: DECODE is an innovative dose-finding trial, designed to support exposure-response modelling for safe and effective dose selection. The trial design allows assessment of occurrence of late toxicities as observed with linezolid, which is necessary in clinical evaluation of novel oxazolidinones. The primary efficacy endpoint is the change in bacterial load, an endpoint conventionally used in shorter dose-finding trials. Long-term follow-up after shortened treatment is possible through a safety rule excluding slow-and non-responders from potentially poorly performing dosages. TRIAL REGISTRATION: DECODE was registered in ClinicalTrials.gov before recruitment start on 22 October 2021 (NCT04550832).

Laparoscopic large hiatus hernia repair with mesh reinforcement versus suture cruroplasty alone: a systematic review and meta-analysis.

BACKGROUND: To compare the difference in outcomes in laparoscopic large hiatus hernia (LHH) repair using suture-based and mesh-based repair techniques. METHODS: A systematic search of articles was conducted in PubMed, Medline and Embase using the PRISMA guidelines. Studies comparing recurrences and reoperations in those patients with large hiatal hernia repair (> 30% stomach in the chest, > 5 cm hiatal defect, hiatal surface area > 10 cm2) who had mesh vs no mesh were assessed quantitatively. The impact of mesh on significant intraoperative/postoperative surgical complications was qualitatively assessed. RESULTS: Pooled data included six randomized controlled trials and thirteen observational studies with 1670 patients (824 with no mesh, 846 with mesh). There was a significant reduction in the total recurrence rate with mesh (OR 0.44, 95% CI 0.25-0.80, p = 0.007). Mesh use did not cause significant reduction in recurrences > 2 cm (OR 0.94, 95% CI 0.52-1.67, p = 0.83) or in reoperation rates (OR 0.64, 95% CI 0.39-1.07, p = 0.09). None of the specific meshes assessed were found to be superior in the reduction of recurrence or reoperation rates. Cases of mesh erosion with eventual foregut resection were noted and were associated with synthetic meshes only. CONCLUSION: Mesh reinforcement seemed protective against total recurrence in LHH although this has to be interpreted with caution given the level of heterogeneity introduced by the inclusion of observational studies in the analysis. There was no significant reduction in large recurrences (> 2 cm) or reoperation rate. If the synthetic mesh is to be used patients need to be informed of the risk of mesh erosion.

Development and internal validation of clinical prediction models for outcomes of complicated intra-abdominal infection.

BACKGROUND: Complicated intra-abdominal infections (cIAIs) are associated with significant morbidity and mortality. The aim of this study was to describe the clinical characteristics of patients with cIAI in a multicentre study and to develop clinical prediction models (CPMs) to help identify patients at risk of mortality or relapse. METHODS: A multicentre observational study was conducted from August 2016 to February 2017 in the UK. Adult patients diagnosed with cIAI were included. Multivariable logistic regression was performed to develop CPMs for mortality and cIAI relapse. The c-statistic was used to test model discrimination. Model calibration was tested using calibration slopes and calibration in the large (CITL). The CPMs were then presented as point scoring systems and validated further. RESULTS: Overall, 417 patients from 31 surgical centres were included in the analysis. At 90 days after diagnosis, 17.3 per cent had a cIAI relapse and the mortality rate was 11.3 per cent. Predictors in the mortality model were age, cIAI aetiology, presence of a perforated viscus and source control procedure. Predictors of cIAI relapse included the presence of collections, outcome of initial management, and duration of antibiotic treatment. The c-statistic adjusted for model optimism was 0.79 (95 per cent c.i. 0.75 to 0.87) and 0.74 (0.73 to 0.85) for mortality and cIAI relapse CPMs. Adjusted calibration slopes were 0.88 (95 per cent c.i. 0.76 to 0.90) for the mortality model and 0.91 (0.88 to 0.94) for the relapse model; CITL was -0.19 (95 per cent c.i. -0.39 to -0.12) and - 0.01 (- 0.17 to -0.03) respectively. CONCLUSION: Relapse of infection and death after complicated intra-abdominal infections are common. Clinical prediction models were developed to identify patients at increased risk of relapse or death after treatment, these now require external validation.

Complications and functional outcomes after ileo-anal pouch excision-a systematic review of 14 retrospective observational studies.

PURPOSE: The ileo-anal pouch (IAP) has been the gold standard procedure for maintenance of bowel continuity after panproctocolectomy for ulcerative colitis, familial adenomatous polyposis or hereditary non-polyposis colorectal cancer. However, the IAP has an estimated failure rate of 13% at 10 years post-procedure (Tulchinsky et al., Ann Surg 238(2):229-34, 2003), which can result in pouch excision (P.E.). This systematic review aims to synthesise all the available studies reporting post-operative outcomes of P.E. and its impact on patient quality of life (QoL), when available, which have not previously been summarised. METHODS: PubMed, Embase, Medline and the Cochrane library databases were searched with terms 'Pouch AND excision' OR 'Pouch AND removal' OR 'Pouch AND remove' OR 'IAP AND excision'. All studies reporting post-operative morbidity, mortality or functional outcomes in patients who had P.E. were included. Studies with < 5 patients, non-English studies and conference abstracts were excluded. RESULTS: 14 studies comprising 1601 patients were included. Overall complications varied from 18 to 63% with the most common being persistent perineal sinus (9-40%) or surgical site infection (wound-2 to 30%; intra-abdominal collection-3 to 24%). The mortality rate was between 0.58 and 1.4%. QoL is generally lower in P.E. patients compared to the normal population across various QoL measures and P.E. patients often had urinary and sexual dysfunction post-operatively. CONCLUSIONS: There is a substantial incidence of complications after P.E.; however, there is no evidence describing QoL pre- and post-P.E. Further longitudinal research comparing QoL in patients undergoing P.E. and other treatment options such as indefinite diversion is required to definitively assess QoL post-procedure.

Malignant spinal cord compression.

Malignant spinal cord compression (MSCC) is a potentially devastating consequence of cancer. Early recognition of the signs and symptoms of MSCC can allow diagnosis prior to the development of irreversible complications. Information provision to patients and doctors regarding the risk of MSCC and a streamlined pathway for further investigation are both key to improving the outcome for patients developing this condition. Described in this paper is the development of such a pathway at Aberdeen Royal Infirmary.

Age at death and the effect of lead-time bias in patients with colorectal cancer: a 10-year follow-up.

AIM: Studies addressing the benefit of early intervention are prone to lead-time bias, which results in an artificial improvement in cancer-specific mortality. We have previously compared the age at death for patients with colorectal cancer presenting on an emergency or elective basis. In this study, we aimed to repeat the analysis with a minimum follow-up of 10 years. METHOD: A nonscreen-detected cohort of patients presenting with colorectal cancer to three Lanarkshire Hospitals between 2000 and 2006 were entered into a prospective database, with analysis performed on 28 November 2016. The following data were collected: age at death, presentation type (emergency/elective), operative intent (palliative/curative) and Dukes stage. Results are presented as [mean (95% confidence intervals)]. Statistical analysis was undertaken using Student's t-test and multivariate analysis performed using Cox proportional hazard models. RESULTS: One thousand six hundred and thirty-six patients were identified. Elective patients presented younger than emergency patients [67.9 (67.3-68.5) vs 70.9 (69.6-72.2) years; P < 0.0001]. Overall mortality was 71.1% at time of analysis; no difference was seen in the mean age at death between emergency and elective presentation [73.5 (72.4-74.8) vs 73.6 (72.3-74.9) years; P = 0.841]. CONCLUSION: Current early detection strategies to diagnose colorectal cancer may improve cancer-specific survival by increasing lead-time bias. However, in our cohort of symptomatic patients, treatment on an elective or emergency basis does not influence overall survival. These data suggest that in selected patients, particularly where there is comorbidity, it may be reasonable to adopt a more expectant approach to investigate and treat colorectal symptoms.

Cross sectional imaging of truncal and quadriceps muscles relates to different functional outcomes in cancer.

INTRODUCTION: Following the consensus definition of cancer cachexia, more studies are using CT scan analysis of truncal muscles as a marker of muscle wasting. However, how CT-derived body composition relates to function, strength and power in patients with cancer is largely unknown. AIMS: We aimed to describe the relationship between CT truncal (L3) skeletal muscle index (SMI) and MRI quadriceps cross sectional area with lower limb strength, power and measures of complex function. METHODS: Patients undergoing assessment for potentially curative surgery for oesophagogastric or pancreatic cancer were recruited from the regional upper gastrointestinal (UGI) or hepatopancreaticobiliary (HPB) multi-disciplinary team meetings. Maximum Isometric Knee Extensor Strength (IKES) and Maximum Leg Extensor Power (Nottingham Power Rig) (LEP) were used as measures of lower limb performance. Both Sit to Stand (STS) and Timed Up and Go (TUG) were used as measures of global complex muscle function. Muscle SMI was measured from routine CT scans at the level of the third lumbar vertebrae (L3) and MRI scan was used for the assessment of quadriceps muscles. Linear regression analysis was performed for CT SMI or MRI quadriceps as a predictor of each measure of performance. RESULTS: Forty-four patients underwent assessment. Height and weight were significantly related to function in terms of quadriceps power, while only weight was associated with strength (P < 0.001). CT SMI was not related to measures of quadriceps strength or power but had significant association with more complex functional measures (P = 0.006, R2 = 0.234 and 0.0019, R2 = 0.175 for STS and TUG respectively). In comparison, both gross and fat-subtracted measures of quadriceps muscle mass from MRI were significantly correlated with quadriceps strength and power (P < 0.001), but did not show any significant association with complex functional measures. CONCLUSION: CT SMI and MRI quadriceps have been shown to reflect different aspects of functional ability with CT SMI being a marker of global muscle function and MRI quadriceps being specific to quadriceps power and strength. This should therefore be considered when choosing outcome measures for trials or definitions of muscle mass and function.

A nonmyeloablative chimeric mouse model accurately defines microglia and macrophage contribution in glioma.

AIMS: Resident and peripherally derived glioma associated microglia/macrophages (GAMM) play a key role in driving tumour progression, angiogenesis, invasion and attenuating host immune responses. Differentiating these cells' origins is challenging and current preclinical models such as irradiation-based adoptive transfer, parabiosis and transgenic mice have limitations. We aimed to develop a novel nonmyeloablative transplantation (NMT) mouse model that permits high levels of peripheral chimerism without blood-brain barrier (BBB) damage or brain infiltration prior to tumour implantation. METHODS: NMT dosing was determined in C57BL/6J or Pep3/CD45.1 mice conditioned with concentrations of busulfan ranging from 25 mg/kg to 125 mg/kg. Donor haematopoietic cells labelled with eGFP or CD45.2 were injected via tail vein. Donor chimerism was measured in peripheral blood, bone marrow and spleen using flow cytometry. BBB integrity was assessed with anti-IgG and anti-fibrinogen antibodies. Immunocompetent chimerised animals were orthotopically implanted with murine glioma GL-261 cells. Central and peripheral cell contributions were assessed using immunohistochemistry and flow cytometry. GAMM subpopulation analysis of peripheral cells was performed using Ly6C/MHCII/MerTK/CD64. RESULTS: NMT achieves >80% haematopoietic chimerism by 12 weeks without BBB damage and normal life span. Bone marrow derived cells (BMDC) and peripheral macrophages accounted for approximately 45% of the GAMM population in GL-261 implanted tumours. Existing markers such as CD45 high/low proved inaccurate to determine central and peripheral populations while Ly6C/MHCII/MerTK/CD64 reliably differentiated GAMM subpopulations in chimerised and unchimerised mice. CONCLUSION: NMT is a powerful method for dissecting tumour microglia and macrophage subpopulations and can guide further investigation of BMDC subsets in glioma and neuro-inflammatory diseases.

Fulminant Anti-GAD antibody encephalitis presenting with status epilepticus requiring aggressive immunosuppression.

Antibodies against glutamic acid decarboxylase (GAD) are reported in association with numerous neurological conditions including temporal lobe epilepsy and limbic encephalitis. We report a case of Anti-GAD-Antibody associated encephalitis presenting with epilepsia partialis continua (EPC) progressing to a fulminant encephalopathy preferentially affecting the frontal lobes associated with coma and refractory status epilepticus. The abnormalities identified on MRI included marked bilateral frontal lobe involvement which has not been reported in other auto-immune encephalitides and may be specific for Anti-GAD-Antibody associated encephalitis. Similar to the majority of cases of Anti-GAD associated neurological disturbance no underlying malignancy was identified. Treatment with high dose corticosteriods, IVIG and plasmapheresis had minimal response, but escalation of treatment with rituximab and cyclophosphamide was associated with clinical improvement, reducing antibody titers and resolution of MRI changes.

Thrombalexin: Use of a Cytotopic Anticoagulant to Reduce Thrombotic Microangiopathy in a Highly Sensitized Model of Kidney Transplantation.

Early activation of coagulation is an important factor in the initiation of innate immunity, as characterized by thrombotic microangiopathy (TMA). In transplantation, systemic anticoagulation is difficult due to bleeding. A novel "cytotopic" agent, thrombalexin (TLN), combines a cell-membrane-bound (myristoyl tail) anti-thrombin (hirudin-like peptide [HLL]), which can be perfused directly to the donor organ or cells. Thromboelastography was used to measure time to clot formation (r-time) in both rhesus and human blood, comparing TLN versus HLL (without cytotopic tail) versus negative control. Both TLN- and HLL-treated rhesus or human whole blood result in significantly prolonged r-time compared to kaolin controls. Only TLN-treated human endothelial cells and neonatal porcine islets prolonged time to clot formation. Detection of membrane-bound TLN was confirmed by immunohistochemistry and fluorescence activated cell sorter. In vivo, perfusion of a nonhuman primate kidney TLN-supplemented preservation solution in a sensitized model of transplantation demonstrated no evidence of TLN systemically. Histologically, TLN was shown to be present up to 4 days after transplantation. There was no platelet deposition, and TMA severity, as well as microvascular injury scores (glomerulitis + peritubular capillaritis), were less in the TLN-treated animals. Despite promising evidence of localized efficacy, no survival benefit was demonstrated.

Adenomatous-Dominant Benign Prostatic Hyperplasia (AdBPH) as a Predictor for Clinical Success Following Prostate Artery Embolization: An Age-Matched Case-Control Study.

PURPOSE: To investigate the clinical impact of performing prostate artery embolization (PAE) on patients with adenomatous-dominant benign prostatic hyperplasia (AdBPH). MATERIALS AND METHODS: Twelve patients from the ongoing proSTatic aRtery EmbolizAtion for the treatMent of benign prostatic hyperplasia (STREAM) trial were identified as having AdBPH; defined as two or more adenomas within the central gland of ≥1 cm diameter on multi-parametric MRI (MP-MRI). These patients were age-matched with patients from the STREAM cohort, without AdBPH. Patients were followed up with repeat MP-MRI at 3 months and 1 year. International prostate symptom score (IPSS), international index for erectile function (IIEF), and quality of life assessment from the IPSS and EQ-5D-5S questionnaires were recorded pre-PAE and at 6 weeks, 3 months, and 1 year. RESULTS: The mean age of patients was 68 (61-76). All patients had PAE as a day-case procedure. The technical success in the cohort was 23/24 (96%). There was a significant reduction in prostate volume following embolization with a median reduction of 34% (30-55) in the AdBPH group, compared to a mean volume reduction of 22% (9-44) in the non-AdBPH group (p = 0.04). There was a significant reduction in IPSS in the AdBPH group following PAE when compared with the control group [AdBPH median IPSS 8 (3-15) vs. non-AdBPH median IPSS 13 (8-18), p = 0.01]. IPSS QOL scores significantly improved in the AdBPH group (p = 0.007). There was no deterioration in sexual function in either group post-PAE. CONCLUSIONS: This is the first time that AdBPH has been identified as being a predictor of clinical success following PAE.

Validating a robust double-quantum-filtered (1) H MRS lactate measurement method in high-grade brain tumours.

(1) H MRS measurements of lactate are often confounded by overlapping lipid signals. Double-quantum (DQ) filtering eliminates lipid signals and permits single-shot measurements, which avoid subtraction artefacts in moving tissues. This study evaluated a single-voxel-localized DQ filtering method qualitatively and quantitatively for measuring lactate concentrations in the presence of lipid, using high-grade brain tumours in which the results could be compared with standard acquisition as a reference. Paired standard acquisition and DQ-filtered (1) H MR spectra were acquired at 3T from patients receiving treatment for glioblastoma, using fLASER (localization by adiabatic selective refocusing using frequency offset corrected inversion pulses) single-voxel localization. Data were acquired from 2 × 2 × 2 cm(3) voxels, with a repetition time of 1 s and 128 averages (standard acquisition) or 256 averages (DQ-filtered acquisition), requiring 2.15 and 4.3 min respectively. Of 37 evaluated data pairs, 20 cases (54%) had measureable lactate (fitted Cramér-Rao lower bounds ≤ 20%) in either the DQ-filtered or the standard acquisition spectra. The measured DQ-filtered lactate signal was consistently downfield of lipid (1.33 ± 0.03 ppm vs 1.22 ± 0.08 ppm; p = 0.002), showing that it was not caused by lipid breakthrough, and that it matched the lactate signal seen in standard measurements (1.36 ± 0.02 ppm). In the absence of lipid, similar lactate concentrations were measured by the two methods (mean ratio DQ filtered/standard acquisition = 1.10 ± 0.21). In 7/20 cases with measurable lactate, signal was not measureable in the standard acquisition owing to lipid overlap but was quantified in the DQ-filtered acquisition. Conversely, lactate was undetected in seven DQ-filtered acquisitions but visible using the standard acquisition. In conclusion, the DQ filtering method has proven robust in eliminating lipid and permits uncontaminated measurement of lactate. This is important validation prior to use in tissues outside the brain, which contain large amounts of lipid and which are often susceptible to motion.

Evidence of In Vivo Existence of Borrelia Biofilm in Borrelial Lymphocytomas.

Lyme borreliosis, caused by the spirochete Borrelia burgdorferi sensu lato, has grown into a major public health problem. We recently identified a novel morphological form of B. burgdorferi, called biofilm, a structure that is well known to be highly resistant to antibiotics. However, there is no evidence of the existence of Borrelia biofilm in vivo; therefore, the main goal of this study was to determine the presence of Borrelia biofilm in infected human skin tissues. Archived skin biopsy tissues from borrelial lymphocytomas (BL) were reexamined for the presence of B. burgdorferi sensu lato using Borrelia-specific immunohistochemical staining (IHC), fluorescent in situ hybridization, combined fluorescent in situ hybridization (FISH)-IHC, polymerase chain reaction (PCR), and fluorescent and atomic force microscopy methods. Our morphological and histological analyses showed that significant amounts of Borrelia-positive spirochetes and aggregates exist in the BL tissues. Analyzing structures positive for Borrelia showed that aggregates, but not spirochetes, expressed biofilm markers such as protective layers of different mucopolysaccharides, especially alginate. Atomic force microscopy revealed additional hallmark biofilm features of the Borrelia/alginate-positive aggregates such as inside channels and surface protrusions. In summary, this is the first study that demonstrates the presence of Borrelia biofilm in human infected skin tissues.

Human Papillomavirus E2 Regulates SRSF3 (SRp20) To Promote Capsid Protein Expression in Infected Differentiated Keratinocytes.

UNLABELLED: The human papillomavirus (HPV) life cycle is tightly linked to differentiation of the infected epithelial cell, suggesting a sophisticated interplay between host cell metabolism and virus replication. Previously, we demonstrated in differentiated keratinocytes in vitro and in vivo that HPV type 16 (HPV16) infection caused increased levels of the cellular SR splicing factors (SRSFs) SRSF1 (ASF/SF2), SRSF2 (SC35), and SRSF3 (SRp20). Moreover, the viral E2 transcription and replication factor that is expressed at high levels in differentiating keratinocytes could bind and control activity of the SRSF1 gene promoter. Here, we show that the E2 proteins of HPV16 and HPV31 control the expression of SRSFs 1, 2, and 3 in a differentiation-dependent manner. E2 has the greatest transactivation effect on expression of SRSF3. Small interfering RNA depletion experiments in two different models of the HPV16 life cycle (W12E and NIKS16) and one model of the HPV31 life cycle (CIN612-9E) revealed that only SRSF3 contributed significantly to regulation of late events in the virus life cycle. Increased levels of SRSF3 are required for L1 mRNA and capsid protein expression. Capsid protein expression was regulated specifically by SRSF3 and appeared independent of other SRSFs. Taken together, these data suggest a significant role of the HPV E2 protein in regulating late events in the HPV life cycle through transcriptional regulation of SRSF3 expression. IMPORTANCE: Human papillomavirus replication is accomplished in concert with differentiation of the infected epithelium. Virus capsid protein expression is confined to the upper epithelial layers so as to avoid immune detection. In this study, we demonstrate that the viral E2 transcription factor activates the promoter of the cellular SRSF3 RNA processing factor. SRSF3 is required for expression of the E4(^)L1 mRNA and so controls expression of the HPV L1 capsid protein. Thus, we reveal a new dimension of virus-host interaction crucial for production of infectious virus. SRSF proteins are known drug targets. Therefore, this study provides an excellent basis for developing strategies to regulate capsid protein production in the infected epithelium and the production of new virions.

Emergency General Surgery: evolution of a subspecialty by stealth.

BACKGROUND: Emergency surgical patients account for around half of all NHS surgical workload and 80 % of surgical deaths. Few trainees opt to CCT in General Surgery, and there is no recognised subspecialty training program in Emergency General Surgery (EGS). Despite this lack of training and relevant assessment by examination, there appears to be an increasing number of EGS posts advertised. This study aims to provide information about potential future employment opportunities for surgical trainees. METHODS: All consultant surgeon posts, advertised in the British Medical Journal between January 2009 and December 2014 were included. Data collected included specialty, region and institute of advertised post. For the purposes of statistical analysis, data was divided into two separate year bands: 2009-2011 and 2012-2014. Statistical analysis was by Chi-squared test; p <0.01 was considered statistically significant. An online tool was also used to determine experience and attitudes towards EGS amongst Consultant members of the ASGBI and all UK trainees in national training number (NTN) posts. RESULTS: Over the six-year study period, there were 1240 consultant job adverts in a general surgical specialty. Nine hundred and 75 were substantive posts; the region with the most jobs was London and the South East (n = 278). There were 55 jobs advertised in EGS, either with (20) or without (35) another subspecialty. The number of EGS adverts increased significantly in 2012-14 compared to 2009-11 (p = 0.008). 229 (28 %) Consultants and 309 (22 %) trainees responded to the survey. 16 % of consultants work in NHS institutions with Emergency General Surgeons. Only 21 % of trainees believe EGS will be delivered by EGS consultants in the future whilst 8.2 % of trainees stated EGS as their career plan. Less than half of all UK consultant surgeons see EGS as a subspecialty. CONCLUSIONS: This data demonstrates increasing societal need for EGS consultants over the last six years and the emergence of Emergency Surgery as a new subspecialty. In order to meet the EGS needs of the NHS, general surgical training and the examination system need to be revised.

Comparison of optimised endovaginal vs external array coil T2-weighted and diffusion-weighted imaging techniques for detecting suspected early stage (IA/IB1) uterine cervical cancer.

OBJECTIVE: To compare sensitivity and specificity of endovaginal versus external-array coil T2-W and T2-W + DWI for detecting and staging small cervical tumours. METHODS: Optimised endovaginal and external array coil MRI at 3.0-T was done prospectively in 48 consecutive patients with stage Ia/Ib1 cervical cancer. Sensitivity/specificity for detecting tumour and parametrial extension against histopathology for a reading radiologist were determined on coronal T2-W and T2W + DW images. An independent radiologist also scored T2-W images without and with addition of DWI for the external-array and endovaginal coils on separate occasions >2 weeks apart. Cohen's kappa assessed inter- and intra-observer agreement. RESULTS: Median tumour volume in 19/38 cases positive on subsequent histology was 1.75 cm(3). Sensitivity, specificity, PPV, NPV were: reading radiologist 91.3 %, 89.5 %, 91.3 %, 89.5 %, respectively; independent radiologist T2-W 82.6 %, 73.7 %, 79.1 %, 77.8 % for endovaginal, 73.9 %, 89.5 %, 89.5 %, 73.9 % for external-array coil. Adding DWI improved sensitivity and specificity of endovaginal imaging (78.2 %, 89.5 %); adding DWI to external-array imaging improved specificity (94.7 %) but reduced sensitivity (66.7 %). Inter- and intra-observer agreement on T2-W + DWI was good (kappa = 0.67 and 0.62, respectively). CONCLUSION: Endovaginal coil T2-W MRI is more sensitive than external-array coil for detecting tumours <2 cm(3); adding DWI improves specificity of endovaginal imaging but reduces sensitivity of external-array imaging. KEY POINTS: • Endovaginal more accurate than external-array T2-W MRI for detecting small cervical cancers. • Addition of DWI improves sensitivity and specificity of endovaginal T2-W imaging. • Addition of DWI substantially reduces sensitivity of external-array T2-W imaging.

Bevacizumab and Combination Chemotherapy in rectal cancer Until Surgery (BACCHUS): a phase II, multicentre, open-label, randomised study of neoadjuvant chemotherapy alone in patients with high-risk cancer of the rectum.

BACKGROUND: In locally advanced rectal cancer (LARC) preoperative chemoradiation (CRT) is the standard of care, but the risk of local recurrence is low with good quality total mesorectal excision (TME), although many still develop metastatic disease. Current challenges in treating rectal cancer include the development of effective organ-preserving approaches and the prevention of subsequent metastatic disease. Neoadjuvant systemic chemotherapy (NACT) alone may reduce local and systemic recurrences, and may be more effective than postoperative treatments which often have poor compliance. Investigation of intensified NACT is warranted to improve outcomes for patients with LARC. The objective is to evaluate feasibility and efficacy of a four-drug regimen containing bevacizumab prior to surgical resection. METHODS/DESIGN: This is a multi-centre, randomized phase II trial. Eligible patients must have histologically confirmed LARC with distal part of the tumour 4-12 cm from anal verge, no metastases, and poor prognostic features on pelvic MRI. Sixty patients will be randomly assigned in a 1:1 ratio to receive folinic acid + flurourcil + oxaliplatin (FOLFOX) + bevacizumab (BVZ) or FOLFOX + irinotecan (FOLFOXIRI) + BVZ, given in 2 weekly cycles for up to 6 cycles prior to TME. Patients stop treatment if they fail to respond after 3 cycles (defined as ≥ 30 % decrease in Standardised Uptake Value (SUV) compared to baseline PET/CT). The primary endpoint is pathological complete response rate. Secondary endpoints include objective response rate, MRI tumour regression grade, involved circumferential resection margin rate, T and N stage downstaging, progression-free survival, disease-free survival, overall survival, local control, 1-year colostomy rate, acute toxicity, compliance to chemotherapy. DISCUSSION: In LARC, a neoadjuvant chemotherapy regimen - if feasible, effective and tolerable would be suitable for testing as the novel arm against the current standards of short course preoperative radiotherapy (SCPRT) and/or fluorouracil (5FU)-based CRT in a future randomised phase III trial. TRIAL REGISTRATION: Clinical trial identifier BACCHUS: NCT01650428.

The development of practice standards for radiation oncology in Australia: a tripartite approach.

In many areas of health care, practice standards have become an accepted method for professions to assess and improve the quality of care delivery. The aim of this work is to present the development of practice standards for radiation oncology in Australia, highlighting critical points and lessons learned. Following a review of radiotherapy services in Australia, a multidisciplinary group with support from the Australian Government developed practice standards for radiation oncology in Australia. The standards were produced in a multistep process including a nationwide survey of radiotherapy centres and piloting of the standards in a representative subset of all Australian radiotherapy centres. The standards are grouped into three sections: Facility management (covering staffing, data management, equipment and processes); Treatment planning and delivery (providing more detailed guidance on prescription, planning and delivery); Safety and quality management (including radiation safety, incident monitoring and clinical trials participation). Each of the 16 standards contains specific criteria, a commentary and suggestions for the evidence required to demonstrate compliance. The development of the standards was challenging and time consuming, but the collaborative efforts of the professions resulted in standards applicable throughout Australia and possibly further afield.

Suspected iatrogenic ureteric injury: an approach to diagnostic imaging.

Iatrogenic ureteric injury (IUI) is the leading cause of ureteric trauma and a complication of major abdominal and pelvic surgery. IUI carries significant morbidity and mortality, which can be further compounded by delayed diagnosis due to its non-specific clinical presentation. We review ureteric anatomy, types of IUI, and imaging strategies available for diagnosis. We propose an imaging protocol for prompt diagnosis and follow-up.