Reflex Xpert MTB/XDR Testing of Residual Rifampicin-Resistant Specimens: A Clinical Laboratory-Based Diagnostic Accuracy and Feasibility Study in South Africa.

Background: The World Health Organization-approved Xpert MTB/XDR test detects Mycobacterium tuberculosis and resistance to isoniazid, fluoroquinolones, ethionamide, and injectable drugs directly in specimens. This pragmatic, laboratory-based study assessed the diagnostic accuracy and feasibility of a reflex testing approach, where Xpert MTB/XDR was performed on residual specimens previously processed for Xpert MTB/RIF Ultra. Methods: Routine respiratory specimens, processed for Xpert MTB/RIF Ultra, were stored in sample reagent buffer at 2°C-8°C. If rifampicin resistant, the residual specimen was assessed for adequate volume (≥2 mL) and tested with Xpert MTB/XDR, with storage time recorded. A second specimen was used for routine and reference standard testing (culture and sequencing). Results: Specimens (99% sputum) from 763 participants submitted to 2 large routine laboratories were included. Xpert MTB/XDR yielded valid resistance detection results in 639 (84%), compared with 507 (66%) for routine testing (difference [95% CI], 18% [13%-22%]). The median turnaround time for results was 23 hours for Xpert MTB/XDR and 15 days for routine testing. While 748 specimens (98%) were ≥2 mL, only 102 (13%) were stored for ≤4 hours. By the reference standard, 284 of 394 (72%) were isoniazid resistant, and 57 of 380 (15%) were fluroquinolone resistant. The sensitivities of Xpert MTB/XDR were 94% (95% CI, 91%-97%) for isoniazid and 91% (81%-97%) for fluoroquinolone resistance detection. The specificities were 98% (94%-100%) and 100% (98%-100%), respectively. Conclusions: Xpert MTB/XDR performed favorably compared with the reference, and the reflex testing approach increased results availability over routine testing, while dramatically decreasing turnaround time from weeks to hours. Laboratory workflow precluded testing within the manufacturer-recommended 4-hour storage time, but longer storage did not appear detrimental.

Asymmetric synthesis of trans-4,5-disubstituted γ-butyrolactones involving a key allylboration step. First access to (-)-nicotlactone B and (-)-galbacin.

An efficient asymmetric synthesis of trans-4,5-disubstituted γ-butyrolactones from aldehydes and enantioenriched γ-carbamate alkenylboronates is reported. The cornerstone of this strategy is the implementation of sequential [3,3]-allyl cyanate rearrangement/allylboration/nucleophilic addition/cyclisation reactions. Diverse γ-butyrolactones such as the flavouring compounds, (+)-trans-whiskey lactone and (+)-trans-cognac lactone, as well as an advanced intermediate towards the first synthesis of natural products, (-)-nicotlactone B and (-)-galbacin, have thus been obtained.

Buprenorphine/Naloxone Maintenance Therapy: an Observational Retrospective Report on the Effect of Dose on 18 months Retention in an Office-Based Treatment Program.

CONTEXT AND OBJECTIVE: Buprenorphine has been available with few reports of the dose range necessary to adequately maintain patients. We report on the effect of 8 mg/d versus 16 mg/d of buprenorphine on long-term patient retention in office-based opioid maintenance (OBOMT). DESIGN SETTING AND PARTICIPANTS: Case series, at an urban hospital-based primary care clinic providing OBOMT to 157 opiate-dependent, low socioeconomic status, uninsured, nonhomeless patients. INTERVENTION: The OBOMT program operated by a comprehensive sobriety treatment program experienced State funding cuts. Thus, after 2 years, the program was required by the State funder to decrease the buprenorphine maintenance dose from 16 to 8 mg/d for all new admissions. We report on patient retention before and after dose reduction. MAIN OUTCOME MEASURES: The primary outcomes of this study were to measure and compare patient retention in the 2 cohorts at each point of treatment transition over the 18 months following OBOMT initiation. RESULTS: No significant differences in patient retention were observed between the 16 and 8 mg/d patient cohorts. Lower dose buprenorphine maintenance (8 mg/d) in uninsured patients enrolled in publicly funded long-term OBOMT combined with comprehensive sobriety counseling was as effective as higher dose therapy (16 mg/d) in promoting patient retention throughout the study period. This lower dose resulted in a substantial saving to the public funding agency. CONCLUSIONS: In an observational retrospective report, retention in treatment of opiate-addicted patients was the same at 8 and 16 mg/d buprenorphine doses after 18 months. These data have implications for public and managed care funding of OBOMT, for the general prescribing of buprenorphine in outpatient care, and may be instructive in the ongoing debate about the relationship between buprenorphine dose.

A stratified analysis of the perioperative outcome of 17623 patients undergoing major head and neck cancer surgery in England over 10 years: Towards an Informatics-based Outcomes Surveillance Framework.

OBJECTIVES: To perform a national analysis of the perioperative outcome of major head and neck cancer surgery to develop a stratification strategy and outcomes assessment framework using hospital administrative data. DESIGN: A Hospital Episode Statistics N = near-all analysis. SETTINGS: The English National Health Service. MAIN OUTCOME MEASURES: Local audit data were used to assess and triangulate the quality of the administrative dataset. Within the national dataset, cancer sites, morbidities, social deprivation, treatment, complications, and in-hospital mortality were recorded. RESULTS: Within local audit datasets, the accuracy of assigning newly-derived Cancer Site Strata and Resection Strata were 92.3% and 94.2%, respectively. Accuracy of morbidities assignment was 97%. Within the national dataset, we identified 17 623 major head and neck cancer resections between 2002 and 2012. There were 12 413 males and mean age at surgery was 63 ± 12 years. The commonest cancer site strata were oral cavity (42%) and larynx-hypopharynx (32%). The commonest resection site was the larynx (n = 4217), and 13 211 and 11 841 patients had neck dissection and flap-based reconstruction, respectively. There were prognostically significant baseline differences between patients with oromandibular and pharyngolaryngeal malignancy. Patients with pharyngolaryngeal malignancies had a greater burden of morbidities, lower socio-economic status, fewer primary resections, and a sixfold increased risk of undergoing their major resection during an emergency hospital admission. Mean length of stay was 25 days and each complication linearly increased it by 9.6 days. There were 609 (3.5%) in-hospital deaths and a basket of seven medical and three surgical complications significantly increased the risk of in-hospital death. At least one potentially lethal complication occurred in 26% of patients. The risk of in-hospital death in a patient with no potentially lethal complication was 1.1% and this increased to 6% with one potentially lethal complication, and to 15.1% if two potentially lethal complications occurred in one patient. Complex oral-pharyngeal resections and pharyngolaryngectomies had the highest risks of complications and mortality. CONCLUSION: Mortality following head and neck cancer surgery shows variation across different resection strata. We propose an Informatics-based Framework for Outcomes Surveillance (IFOS) in Head and Neck Surgery for perpetual quality assurance, using the local hospital coding data or its collated destination, the national administrative dataset.

A national analysis of trends, outcomes and volume-outcome relationships in thyroid surgery.

OBJECTIVES: Thyroid conditions are common, and their incidence is increasing. Surgery is the mainstay treatment for many thyroid conditions, and understanding its utilisation trends and morbidity is central to improving patient care. DESIGN: An N = near-all analysis of the English administrative dataset to identify trends in thyroid surgery specialisation, volume-outcome relationships, and the incidence and risk factors for short- and long-term morbidity. MAIN OUTCOME MEASURES: Between 2004 and 2012, 72 594 patients underwent elective thyroidectomy in England. Information about age, sex, morbidities, nature of thyroid disease and surgery, adjuvant treatments and complications including hypocalcaemia and vocal palsy was recorded. RESULTS: Mean age at surgery was 49 ± 30, and a female predominance (82%) was observed. Most patients underwent hemithyroidectomy (51%) or total thyroidectomy (32%). Patients underwent surgery for benign (52.5%), benign inflammatory (21%) and malignant (17%) thyroid diseases. Thyroid surgery grew by 2.9% a year and increased in specialisation. Increased surgeon volume significantly reduced lengths of stay: the proportion of length of stay outliers fell from 11.8% for patients of occasional thyroidectomists (<5 per year) to 2.8% for patients of high-volume surgeons (>50 thyroidectomies a year). Post-discharge vocal palsy and hypocalcaemia occurred in 1.87% and 1.58% of cases, respectively. High-volume surgeons had a reduced incidence of vocal palsy, and volumes >30 were consistently protective. CONCLUSIONS: Thyroid surgery is increasingly specialised. High-volume surgeons, that is patients who perform 50 or more thyroidectomies per year, achieve lower complications and shorter lengths of stay.

New quality measure for SNP array based CNV detection.

MOTIVATION: Only a few large systematic studies have evaluated the impact of copy number variants (CNVs) on common diseases. Several million individuals have been genotyped on single nucleotide variation arrays, which could be used for genome-wide CNVs association studies. However, CNV calls remain prone to false positives and only empirical filtering strategies exist in the literature. To overcome this issue, we defined a new quality score (QS) estimating the probability of a CNV called by PennCNV to be confirmed by other software. RESULTS: Out-of-sample comparison showed that the correlation between the consensus CNV status and the QS is twice as high as it is for any previously proposed CNV filters. ROC curves displayed an AUC higher than 0.8 and simulations showed an increase up to 20% in statistical power when using QS in comparison to other filtering strategies. Superior performance was confirmed also for alternative consensus CNV definition and through improving known CNV-trait associations. AVAILABILITY AND IMPLEMENTATION: http://goo.gl/T6yuFM CONTACT: zoltan.kutalik@unil.ch or aurelien@mace@unil.chSupplementary information: Supplementary data are available at Bioinformatics online.

Factors associated with delays in head and neck cancer treatment: case-control study.

BACKGROUND: Delays in head and neck cancer treatment lead to increased mortality, more extensive treatment and patient anxiety. We aim to treat all patients with cancer within 62 days of receipt of a referral. An analysis was conducted of those patients whose treatment had been delayed in order to identify factors associated with treatment delay. METHODS: In this retrospective case-control study, 50 patients whose treatment was delayed were identified and compared with 50 patients whose treatment was not delayed. Individual factors assessed included patient age, co-morbidity, tumour location and stage, the treatment agreed, the hospitals to which the patients were referred, and the clinicians they saw. RESULTS: There was a significant association between referral to a non-head and neck cancer centre, or review by a non-head and neck multidisciplinary team member, and treatment delay. CONCLUSION: In the context of centralisation of head and neck cancer services, it is important to consider delays that may be associated with a 'hub and spoke' model of service provision.

Assessment of a novel, full-thickness incisional biopsy model to restage rectal tumours after neoadjuvant chemoradiotherapy: results of an ex vivo pilot study.

BACKGROUND: There is currently no reliable means to restage rectal cancers after neoadjuvant chemoradiation. Recent histological evidence shows that the epicentre for residual cancer cells is focussed directly underneath any residual mucosal abnormality (RMA). This proof-of-concept study aimed to determine the utility of a novel, minimally invasive method of incisional biopsy as a restaging tool. A secondary aim was to compare its performance to clinical response assessment. METHODS: After surgical resection, 0.5 × 0.5 cm, full-thickness incisional biopsy was performed in 15 rectal cancers. Of these, 13 had RMA and 2 had mucosal cCR but a palpable intramural abnormality. In all patients, a full-thickness incisional biopsy was taken through the centre of these areas. The ypT stage of the incisional biopsy and the final total specimen were compared. Complete mucosal clinical response was deemed to have occurred when either no residual tumour or only a flat mucosal scar remained. RESULTS: Incisional biopsy correctly identified all patients that had been downstaged to ypT0; however, it also falsely identified 5 of 10 patients (50%) with yp residual disease as ypT0. Overall performance of incisional biopsy to detect residual cancer was 50% sensitivity, 100 % specificity, 100% PPV, and 50% NPV with an accuracy of 66%. A complete mucosal clinical response occurred in only one of five patients downstaged to ypT0 (20% sensitive). It also occurred in one patient, which was ultimately staged as ypT3. CONCLUSION: This prospective data demonstrates that incisional biopsy is not suitable as a stand-alone method to restage rectal cancer after CRT. Alternate or complementary means of restaging are needed.

Role of reconstructive surgery in the management of head and neck cancer: a national outcomes analysis of 11,841 reconstructions.

BACKGROUND: The quality of head and neck cancer reconstruction in England is not known. Hospital administrative data provides details of treatment within the English National Health Service and may be used for national outcomes analysis. METHODS: An algorithm for identifying head and neck surgery with flap-based reconstruction from administrative data was constructed and validated against information from three cancer units. The validated algorithm was applied to 2003-2013 national activity. RESULTS: The algorithm was 91% sensitive and over 99% specific. Its application to administrative data identified 11,841 patients and demonstrated an increase of 52% in reconstruction-containing head and neck cancer surgery in the past decade. There were 7776 males and mean treatment age was 62 years. Oral cavity was the commonest primary site (n = 7567; 64%) and 7575 patients (64%) underwent primary surgery. The commonest procedure was floor-of-mouth excision (n = 3614) and 9749 patients had a neck dissection. The most commonly used flap was the radial forearm (n = 4429). Flap failure occurred in 496 (4.2%) patients. It increased the mean length of stay from 22 to 41 days (P < 0.00001), and the odds ratio of in-hospital death to 2.37 [95% confidence interval 1.66-3.38; P < 0.0001]. Lethality of reconstructive failure was not uniform and was highest when a pharyngolaryngeal flap failed. CONCLUSIONS: Reconstructive surgery is central to the multidisciplinary management of head and neck cancer. Its quality directly influences patient morbidity and survival. We recommend that analysis of hospital administrative data should be periodically carried out as part of an over-arching quality assurance programme and, particularly for pharyngolaryngeal reconstructions, surgery should be undertaken in units with the best reconstructive outcomes.

Depth and lateral spread of microscopic residual rectal cancer after neoadjuvant chemoradiation: implications for treatment decisions.

AIM: The aim of this study was to determine the distribution of residual tumour within the bowel wall in relation to residual mucosal abnormalities (RMAs) and surrounding normal mucosa in patients with rectal cancer who underwent neoadjuvant chemoradiation followed by curative surgery. METHOD: Archived pathological slides from a cohort of 60 patients with residual tumour were retrieved. The incidence, distance and depth of tumour spread (ypT) under RMAs and adjacent normal mucosa were reviewed and recorded. RESULTS: Histological sections containing both RMA and adjacent normal mucosa were available for 45 of 60 patients with ypT1 (n = 6), ypT2 (n = 18) and ypT3 (n = 21) disease. The maximal depth of invasion, as measured by ypT stage, was found underneath the RMA in 44 of 45 (98%) patients. Microscopic tumour spread lateral to the RMA and under adjacent normal mucosa was found in 32 of 45 (71%) patients. The median and maximum distances of lateral spread for ypT1 tumours were 0 and 4 mm; for ypT2 were 2.5 and 9 mm; and for ypT3 were 4 and 9 mm respectively. CONCLUSION: Lateral tumour spread under normal mucosa adjacent to RMAs is a common finding and extended up to 9 mm in this study. The epicentre for maximum depth of invasion was directly underneath the RMAs in nearly all cases. These data have clinical and technical implications if local excision is to be considered.

Gene expression profile is associated with chemoradiation resistance in rectal cancer.

AIM: Patients with rectal cancer who achieve a complete pathological response after preoperative chemoradiation (CRT) have an improved oncological outcome. Identifying factors associated with a lack of response could help our understanding of the underlying biology of treatment resistance. This study aimed to develop a gene expression signature for CRT-resistant rectal cancer using high-throughput nucleotide microarrays. METHOD: Pretreatment biopsies of rectal adenocarcinomas were prospectively collected and freshly frozen according to an institutional review board-approved protocol. Total tumour mRNA was extracted and gene expression levels were measured using microarrays. Patients underwent proctectomy after completing standard long-course CRT and the resected specimens were graded for treatment response. Gene expression profiles for nonresponders were compared with those of responders. Differentially expressed genes were analyzed for functional significance using the Ingenuity Pathway Analysis (IPA) software. RESULTS: Thirty-three patients treated between 2006 and 2009 were included. We derived 812-gene and 183-gene signatures separating nonresponders from responders. The classifiers were able to identify nonresponders with a sensitivity and specificity of 100% using the 812-gene signature, and sensitivity and specificity of 33% and 100% using the 183-gene signature. IPA canonical pathway analysis revealed a significant ratio of differentially expressed genes in the 'DNA double-strand break repair by homologous recombination' pathway. CONCLUSION: Certain rectal cancer gene profiles are associated with poor response to CRT. Alterations in the DNA double-strand break repair pathway could contribute to treatment resistance and provides an opportunity for further studies.

Ectopic sequestered thyroid tissue: an unusual cause of a mediastinal mass.

An 80-year-old female presented with an incidental finding of a retrosternal mass on magnetic resonance imaging. Ultrasound demonstrated a mediastinal lesion adjacent to but separate from the inferior pole of the right thyroid lobe. Fine needle aspiration cytology demonstrated colloid and follicular cells. At surgery, the right thyroid lobe was found to be normal. A discrete 5 cm nodule was found in the anterior mediastinum separate from the thyroid and just anterior and to the right of the trachea and thymus. The nodule had a vascular pedicle arising from the mediastinum. The differential diagnosis included metastatic thyroid carcinoma. Histology was consistent with a benign ectopic sequestered thyroid nodule. Extensive investigations demonstrated no sign of a thyroid malignancy.

Predictive value of sperm-FISH analysis on the outcome of preimplantation genetic diagnosis (PGD) for a pericentric inversion inv5(p15.3q11.2) carrier.

BACKGROUND: Pericentric inversions (PIs) are structural chromosomal abnormalities, potentially associated with infertility or multiple miscarriages. More rarely, at meiosis, odd numbers of genetic recombinations within the inversion loop produce recombinant gametes which may lead to aneusomy of recombination in the offspring. METHODS: We report a FISH segregation analysis of an inv5(p15.3q11.2) carrier, both in sperm and blastomeres. In sperm, we directly evaluated the proportion of recombinant gametes and compared the results with chromosomal abnormalities found in blastomeres collected from embryos obtained following a preimplantation genetic diagnosis (PGD) procedure. RESULTS: A total of 7006 sperm nuclei were analyzed. The size of the inverted segment represented 27% of the total length of chromosome 5. The frequencies of balanced chromosomes (normal or inverted), recombinant chromosomes and unbalanced combinations were 97.1, 0.17 and 2.73%, respectively. Of six embryos, PGD FISH analysis revealed that one was a balanced embryo, whereas five were unbalanced and there were no recombinants. CONCLUSIONS: This study demonstrated the value of sperm-FISH analysis in providing reproductive genetic counseling for PI carriers. Our study also highlights the clinical relevance of performing PGD instead of prenatal diagnosis.