Serum phosphorylated neurofilament-heavy chain levels in multiple sclerosis patients.

OBJECTIVES: We evaluated whether the measurement of serum phosphorylated neurofilament heavy chain (pNF-H) titre is likely to be a valid biomarker of axonal injury in multiple sclerosis (MS). METHODS: Serum pNF-H concentrations were measured by ELISA in cases with relapsing-remitting (RR)-MS (n=81), secondary progressive (SP) MS (n=13) and primary progressive (PP)-MS; n=6) MS; first demyelinating event (FDE; n=82); and unaffected controls (n=135). A subset of MS cases (n=45) were re-sampled on one or multiple occasions. The Multiple Sclerosis Severity Score (MSSS) and MRI measures were used to evaluate associations between serum pNF-H status, disease severity and cerebral lesion load and activity. RESULTS: We confirmed the presence of pNF-H peptides in serum by ELISA. We showed that a high serum pNF-H titre was detectable in 9% of RR-MS and FDE cases, and 38.5% of SP-MS cases. Patients with a high serum pNF-H titre had higher average MSSS scores and T2 lesion volumes than patients with a low serum pNF-H titre. Repeated sampling of a subset of MS cases showed that pNF-H levels can fluctuate over time, likely reflecting temporal dynamics of axonal injury in MS. CONCLUSIONS: A subset of FDE/MS cases was found to have a high serum pNF-H titre, and this was associated with changes in clinical outcome measures. We propose that routine measurement of serum pNF-H should be further investigated for monitoring axonal injury in MS.

NHS Health Check programme: a rapid review update.

OBJECTIVE: To update a rapid review published in 2017, which evaluated the NHS Health Check programme. METHODS: An enlarged body of evidence was used to readdress six research objectives from a rapid review published in 2017, relating to the uptake, patient experiences and effectiveness of the NHS Health Check programme. Data sources included MEDLINE, PubMed, Embase, Health Management Information Consortium (HMIC), Cumulative Index of Nursing and Allied Health Literature (CINAHL), Global Health, PsycINFO, the Cochrane Library, NHS Evidence, Google Scholar, Google, ClinicalTrials.gov and the ISRCTN registry, Web of Science, Science Citation Index, The Cochrane Library, NHS Evidence, OpenGrey and hand searching article reference lists. These searches identified records from between January 1996 and December 2019. Screening, data extraction and quality appraisal using the Critical Appraisals Skills Programme checklists were performed in duplicate. Grading of Recommendations Assessment, Development and Evaluations was implemented. Data were synthesised narratively. RESULTS: 697 studies were identified, and 29 new studies included in the review update. The number of published studies on the uptake, patient experiences and effectiveness of the NHS Health Check programme has increased by 43% since the rapid review published in 2017. However, findings from the original review remain largely unchanged. NHS Health Checks led to an overall increase in the detection of raised risk factors and morbidities including diabetes mellitus, hypertension, raised blood pressure, cholesterol and chronic kidney disease. Individuals most likely to attend the NHS Health Check programme included women, persons aged ≥60 years and those from more socioeconomically advantaged backgrounds. Opportunistic invitations increased uptake among men, younger persons and those with a higher deprivation level. CONCLUSIONS: Although results are inconsistent between studies, the NHS Health Check programme is associated with increased detection of heightened cardiovascular disease risk factors and diagnoses. Uptake varied between population subgroups. Opportunistic invitations may increase uptake.

Local anaesthetic toxicity during an awake tracheal intubation course.

We report a case of local anaesthetic toxicity in an anaesthetic trainee participating as a subject for an awake tracheal intubation training course. The trainee experienced symptoms of toxicity despite the dose of lidocaine administered being less than the maximum safe dose recommended for airway topicalisation. We argue this highlights the variability in absorption of local anaesthetic and the importance of safety during awake tracheal intubation training courses. It is essential to use the minimum safe dose of local anaesthetic required during topicalisation for awake tracheal intubation. We have now made it our course policy that participants cannot undergo awake tracheal intubation less than 2 weeks before a period of coryzal illness. We recommend that operators remain vigilant for signs of local anaesthetic toxicity when undertaking this procedure and adhere to newly published Difficult Airway Society awake tracheal intubation guidelines.

The effects of diabetes on tuberculosis treatment outcomes: an updated systematic review and meta-analysis.

BACKGROUND: Previous evidence synthesis has suggested diabetes mellitus (DM) worsens tuberculosis (TB) treatment outcomes. However, these reviews are limited by the number, robustness and conflicting results among the studies included. We conducted a systematic review to update earlier analyses and explore heterogeneity among studies.METHODS: MEDLINE, EMBASE, AIM, LILACS, IMEMR, IMSEAR and WPRIM were searched between 1 January 1980 and 23 July 2018 unrestricted by language or region. All cohort and case-control studies investigating the difference in TB treatment outcomes amongst TB-DM patients compared to those with TB alone were included. Two reviewers independently assessed titles, abstracts, and extracted data. Culture conversion at two/three months, all-cause mortality, treatment failure, relapse and multidrug-resistant TB (MDR-TB) were evaluated using random effects meta-analysis with generic inverse variance. Heterogeneity was explored using subgroup analyses and meta-regression.RESULTS: One hundred and four publications were identified. Sixty-four studies including 56 122 individuals with TB-DM and 243 035 with TB, reported on death. Some outcomes showed substantial heterogeneity between studies, which we could not fully explain, though confounding adjustment and country income level accounted for some of the differences. TB-DM patients had higher odds of death (OR 1.88, 95%CI 1.59-2.21) and relapse (OR 1.64, 95%CI 1.29-2.08) compared to TB patients. More limited evidence suggested TB-DM patients had double the risk of developing MDR-TB (OR 1.98, 95%CI 1.51-2.60).CONCLUSION: DM is associated with increased risks of poor TB treatment outcomes, particularly mortality, and may increase risk of developing primary MDR-TB. Cost-effectiveness of interventions to enhance TB-DM treatment should be assessed.

Point of care HbA1c level for diabetes mellitus management and its accuracy among tuberculosis patients: a study in four countries.

BACKGROUND: Diabetes mellitus (DM) is common among tuberculosis (TB) patients and often undiagnosed or poorly controlled. We compared point of care (POC) with laboratory glycated haemoglobin (HbA1c) testing among newly diagnosed TB patients to assess POC test accuracy, safety and acceptability in settings in which immediate access to DM services may be difficult. METHODS: We measured POC and accredited laboratory HbA1c (using high-performance liquid chromatography) in 1942 TB patients aged 18 years recruited from Peru, Romania, Indonesia and South Africa. We calculated overall agreement and individual variation (mean ± 2 standard deviations) stratified by country, age, sex, body mass index (BMI), HbA1c level and comorbidities (anaemia, human immunodeficiency virus [HIV]). We used an error grid approach to identify disagreement that could raise significant concerns. RESULTS: Overall mean POC HbA1c values were modestly higher than laboratory HbA1c levels by 0.1% units (95%CI 0.1-0.2); however, there was a substantial discrepancy for those with severe anaemia (1.1% HbA1c, 95%CI 0.7-1.5). For 89.6% of 1942 patients, both values indicated the same DM status (no DM, HbA1c <6.5%) or had acceptable deviation (relative difference <6%). Individual agreement was variable, with POC values up to 1.8% units higher or 1.6% lower. For a minority, use of POC HbA1c alone could result in error leading to potential overtreatment (n = 40, 2.1%) or undertreatment (n = 1, 0.1%). The remainder had moderate disagreement, which was less likely to influence clinical decisions. CONCLUSION: POC HbA1c is pragmatic and sufficiently accurate to screen for hyperglycaemia and DM risk among TB patients.

Historical perspectives of thoracic anatomy.

The simultaneous fascination and revulsion that has existed over the ages regarding dissection of the human body continues to the present day. This article discusses the historical aspects of thoracic anatomy and focuses on several major themes, culminating with the work (contributions) of Vesalius.

Diabetes and poor tuberculosis treatment outcomes: issues and implications in data interpretation and analysis.

Tuberculosis (TB) remains one of the 10 leading causes of death worldwide, especially in low- and middle-income countries. We conducted a systematic review and meta-analysis including 88 studies examining the association between diabetes mellitus (DM) and TB treatment outcomes. However, we found several common methodological problems among them, including inappropriate adjustments for confounding factors, not using optimal statistical methods for 'time to event' data, misclassification in exposure (DM) and outcomes (TB treatment outcomes) due to study design and non-standardisation of definitions, misunderstanding of basic study design concept, standardisation of TB treatment outcomes and quality control of publications. Many of these problems would apply more broadly to other 'risk factors' for poor TB treatment outcomes. These issues need to be addressed and resolved to improve the quality of the studies and provide more accurate results for policy makers in the future to tackle the burden of TB.

Effect of prior cancer chemotherapy on human tumor-specific cytotoxicity in vitro in response to immunopotentiating biologic response modifiers.

Tumor-specific cytotoxicity was measured in fresh human biopsy specimens by a modification of the differential staining cytotoxicity assay. ImuVert, a cytokine inducer derived from Serratia marcescens, which produces broad-spectrum activation of both macrophages and lymphocytes, was dramatically more effective when it was tested in tumors obtained from patients with previously treated, chemotherapy-responsive adenocarcinomas (breast and ovary) than when it was tested in tumors obtained from either previously untreated patients or previously treated patients with chemotherapy-refractory adenocarcinomas (colon, lung, pancreas, stomach, kidney, gallbladder, uterus, and prostate). Similar findings, relating to prior chemotherapy treatment status, were obtained for tumor necrosis factor and interferon gamma, but not for interleukin-2 or interferon alpha. On the basis of these findings and on other evidence in the literature, we speculate that response to chemotherapy produces massive release and processing of tumor antigens. We further speculate that this response leads to a state in which the human immune system is primed (via in situ vaccination) to respond to exogenous macrophage-activation signals with potent, specific antitumor effects.

Induction chemotherapy with mitomycin, vindesine, and cisplatin for stage III unresectable non-small-cell lung cancer: results of the Toronto Phase II Trial.

PURPOSE: The 5-year survival rates with surgical resection for preoperatively identified stage IIIA N2 non-small-cell lung cancer (NSCLC) are less than 10%. A pilot study of mitomycin, vindesine, and cisplatin (MVP) induction chemotherapy was undertaken in an attempt to improve the curative potential of surgery in this group of patients. PATIENTS AND METHODS: Thirty-nine patients with mediastinoscopy stage IIIA N2 NSCLC received two cycles of MVP. Responding patients underwent thoracotomy for resection and two further courses of MVP. RESULTS: The overall response rate was 64% (25 of 39) with three complete and 22 partial responses. Twenty-two patients were resected, which included a radical mediastinal node dissection. Eighteen resections were complete and four were incomplete. Pathologically, three patients (7.7%) had no tumor remaining. Toxicity included two postoperative deaths secondary to a bronchopleural (BP) fistula, mitomycin pulmonary toxicity in two patients, and septic deaths in four patients. Twenty-eight patients have died; 20 have recurrent or progressive disease. Eight of the 18 patients completely resected have recurred, with a median time to recurrence of 20.6 months. Sites of recurrence include two locoregional, five distant (two in brain), and one in both. Median survival of all 39 patients is 18.6 months, with a 3-year survival of 26%. The median survival for those patients completely resected was 29.7 months with a 3-year survival of 40%. CONCLUSIONS: We conclude (1) that MVP is an effective but toxic chemotherapeutic regimen for limited NSCLC; (2) the median survival seems to be prolonged; and (3) the role of induction chemotherapy followed by surgery in stage IIIA N2 NSCLC requires a phase III randomized trial to compare it with other treatment modalities.

Induction chemotherapy with mitomycin, vindesine, and cisplatin for stage IIIA (T1-3, N2) unresectable non-small-cell lung cancer: final results of the Toronto phase II trial.

PURPOSE: This is a phase II study to assess the role of induction chemotherapy in the management of stage IIIA non-small-cell lung cancer (NSCLC). We are now reporting the long-term follow-up of the Toronto phase II trial. METHODS: Sixty five patients with mediastinoscopy proven stage IIIA NSCLC received two cycles of preoperative MVP or VLB/P followed by thoracotomy followed by two further courses of chemotherapy. RESULTS: The overall response rate was 67.7% with three complete and 41 partial responders. Forty seven patients went on to thoracotomy with 35 complete resections. Pathologically 4.6% of patients had no tumour remaining. There were three postop deaths as well as five chemotherapy related deaths. Of the 35 patients completely resected 19 have recurred including eight in brain. The median survival for the entire 65 patients is 18.6 months with a 1 year survival of 66%, 5 year survival of 29% and a 10 year survival of 22%. CONCLUSIONS: The long-term survival of induction chemotherapy is maintained. The high incidence of brain recurrences warrants assessment of the role of prophylactic cranial radiation. The role of surgery for stage IIIA NSCLC following induction chemotherapy awaits further study.

Evolution of thoracic surgery in Canada.

BACKGROUND: Canada's contributions toward the 21st century's practice of thoracic surgery have been both unique and multilayered. Scattered throughout are tales of pioneers where none had gone before, where opportunities were greeted by creativity and where iconic figures followed one another. OBJECTIVE: To describe the numerous and important achievements of Canadian thoracic surgeons in the areas of surgery for pulmonary tuberculosis, thoracic oncology, airway surgery and lung transplantation. METHOD: Information was collected through reading of the numerous publications written by Canadian thoracic surgeons over the past 100 years, interviews with interested people from all thoracic surgery divisions across Canada and review of pertinent material form the archives of several Canadian hospitals and universities. RESULTS: Many of the developments occurred by chance. It was the early and specific focus on thoracic surgery, to the exclusion of cardiac and general surgery, that distinguishes the Canadian experience, a model that is now emerging everywhere. From lung transplantation in chimera twin calves to ex vivo organ preservation, from the removal of airways to tissue regeneration, and from intensive care research to complex science, Canadians have excelled in their commitment to research. Over the years, the influence of Canadian thoracic surgery on international practice has been significant. CONCLUSIONS: Canada spearheaded the development of thoracic surgery over the past 100 years to a greater degree than any other country. From research to education, from national infrastructures to the regionalization of local practices, it happened in Canada.

Current status of surgical resection for lung cancer.

There have been no major breakthroughs in surgical management for primary lung cancer during the past 40 years. Improved 5-year survival relates primarily to improved preoperative staging and appropriate selection of patients for resection. Perioperative morbidity and mortality, however, has been significantly reduced. Certain principles pertain to current surgical management: resection remains the best treatment for patients with localized, non-small cell primary lung cancer. Accurate preoperative diagnosis and staging: whenever possible, it is desirable to establish the diagnosis and cell type before operation. Accurate evaluation of the N status warrants wide application of invasive staging with mediastinoscopy or a variant. Indications for resection: only patients in whom a complete resection is anticipated should be selected for surgery. Such cases included T1 to T4 stages, N0 and N1 tumors, and selected N2 cases. The indication for resection in patients with hematogenous metastases are anecdotal. Intraoperative staging: accurate and deliberate intraoperative staging with evaluation of nodes using the American Thoracic Society map is highly desirable. The nature of nodal metastases exerts a critical influence on prognosis and in the selection of patients for surgical resection. At present, there is no clear indication for adjuvant therapy in surgically resected cases other than for evaluation and clinical trials.

Lung cancer. The past twenty-five years.

On the occasion of this Fourth World Conference on Lung Cancer, I am privileged to present the opening keynote address. This presentation has been sponsored by the Ontario Cancer Treatment and Research Foundation. In 1952, the Foundation established an annual lectureship in memory of one of their prominent physicians. Dr. Gordon Earle Richards was one of Canada's pioneer radiologists and radiotherapists who was appointed Director of the Institute of Radiotherapy at Toronto General Hospital at a time when radium and high-voltage x-rays were just coming into common use for the treatment of malignant disease. He established an international reputation for his contributions to clinical radiotherapy, and was subsequently appointed Professor of Radiology at the University of Toronto. He was Managing Director of the Ontario Cancer Treatment and Research Foundation between 1945 and 1949. I wish to thank the Foundation for the privilege of presenting the 33rd Gordon Richards Memorial Lecture.

Staging of the mediastinum. Role of mediastinoscopy and computed tomography.

During the 1940s and 1950s, as many as 50% of thoracotomies identified nonresectable tumors. At present, better than 90% of patients undergoing thoracotomy for presumably resectable lung cancer are found to have operable tumors. This improvement is the result of major advances in the preoperative staging of this disease. Mediastinoscopy and computed tomography (CT) are the most valuable techniques for evaluating the mediastinum in patients with primary cancer of the lung. For each modality, the primary objective is to define the presence or absence of spread to mediastinal lymph nodes. In patients with non-small-cell lung cancer, surgical resection remains the treatment of choice so long as all recognizable tumor can be removed at operation. Both mediastinoscopy and CT provide critical information concerning the potential for a complete resection. Computed tomography remains the most effective noninvasive technique for the evaluation of mediastinal nodes.

Non-small cell lung cancer: role of surgery for stages I-III.

Survival following surgical resection of non-small cell lung cancer (NSCLC) has improved since the 1960s, although the 5-year survival rate remains low. This article provides an overview of the role of surgery for NSCLC stages I-III, with a focus on optimizing long-term survival in those patients with resectable disease. Topics explored include diagnosis and staging, indications for resection, types of resection, and indications for adjuvant therapy. A review of the literature indicates a clear survival advantage for complete resection, and is suggestive of an advantage for mediastinal lymph node dissection (vs lymph node sampling) and neoadjuvant therapy (vs adjuvant therapy).

Preoperative assessment of esophageal pathology.

Panmural esophagitis results in esophageal thickening and shortening and prevents adequate reduction of a hernia. Twenty patients with panmural esophagitis, treated by Belsey repair, have been followed up for more than 5 years; 9 of them remain asymptomatic and 11 have symptomatic reflux, 7 of whom have required further surgery. Belsey also has reported a 45 per cent recurrence rate in patients with this type of disease. Preoperative recognition of panmural esophagitis allows a planned surgical approach and the use of a surgical technique designed for the management of an irreducible hernia. The ability to predict these changes was studied in 124 patients, who were evaluated by history, radiology, endoscopy, and manometry prior to transthoracic hernia repair. The esophagus was inspected at operation to determine the presence of panmural changes. History was of no value in assessment. Radiologically, a large and irreducible hernia was associated with panmural changes, but these changes also occurred in the absence of ulceration. Manometric studies allowed accurate prediction of mural changes. Over 90 per cent of patients with panmural esophagitis have more than 40 per cent disordered motor activity (DMA) in the distal part of the esophagus, and 75 per cent of such patients have more than 60 per cent DMA. Combining these investigative data allowed the accurate prediction of panmural changes in 90 per cent of the 124 patients.