Public health impact of herpes zoster vaccination on older adults in Singapore: a modeling study.

In Singapore, population aging and rising life expectancy are increasing herpes zoster (HZ) burden, which may be reduced by vaccination. The present study modeled the public health impact of HZ vaccination in Singapore using ZOster ecoNomic Analysis (ZONA) model adapted with Singapore-specific key model inputs, where available. Base case analysis was conducted in adults ≥ 50 years of age (YOA), exploring three vaccination strategies (no vaccination, recombinant zoster vaccine [RZV], zoster vaccine live [ZVL]) under mass vaccination setting (30% coverage). Scenario and sensitivity analyses were performed. Out of 1.51 million adults in 2021 (base case population), 406,513 (27.0%) cases of HZ, 68,264 (4.5%) cases of post-herpetic neuralgia (PHN), and 54,949 (3.6%) cases of other complications were projected without vaccination. RZV was estimated to avoid 73,129 cases of HZ, 11,094 cases of PHN, and 9,205 cases of other complications over the subjects' remaining lifetime; ZVL would avoid 17,565 cases of HZ, 2,781 cases of PHN, and 1,834 cases of other complications. The number needed to vaccinate to prevent one case of HZ/PHN was lower for RZV (7/41) than ZVL (26/163). Among all five age-stratified cohorts (50-59/60-64/65-69/70-79/≥80 YOA), RZV (versus no vaccination/ZVL) avoided the largest number of cases in the youngest cohort, 50-59 YOA. Results were robust under scenario and sensitivity analyses. Mass vaccination with RZV is expected to greatly reduce the public health burden of HZ among Singapore individuals ≥ 50 YOA. Findings support value assessment and decision-making regarding public health vaccination strategies for HZ prevention in Singapore.

Risk of shingles (herpes zoster) increases with age, especially from 50 years. Shingles is a major public health concern in Singapore, given its rapidly aging population. Vaccination can prevent shingles and reduce its public health burden. Two shingles vaccines are available in Singapore: recombinant zoster vaccine (RZV) since 2021, zoster vaccine live (ZVL) since 2008. To understand the value of preventing shingles via vaccination, this study assessed the public health impact of shingles vaccination. Three vaccination strategies (no vaccination, vaccination with RZV, vaccination with ZVL) were compared in 1.51 million Singapore adults aged 50 years and above. Without vaccination, public health burden of shingles would be high; an estimated 406,513 (27.0%) would have shingles, 68,264 (4.5%) would have shingles-related long-term nerve pain, 54,949 (3.6%) would have other shingles-related complications, and 17,762 (1.2%) would be hospitalized due to shingles. Shingles vaccination could reduce this public health burden: RZV avoided 73,129 cases of shingles, 11,094 cases of shingles-related long-term nerve pain, 9,205 cases of other shingles-related complications, and 2,827 hospitalizations due to shingles, which was 4­6 times that avoided with ZVL (shingles: 17,565; shingles-related long-term nerve pain: 2,781; other shingles-related complications: 1,834; hospitalizations due to shingles: 484). Shingles vaccination for adults aged 50 years and above, especially early vaccination from 50­59 years, could reduce its public health burden more than vaccination at later ages and contribute toward healthy aging, preventive care, and the Healthier SG initiative. Results support local public health value assessments and decision-making for shingles prevention.

The Evolving Landscape of Lung Cancer Surgical Resection: An Update for Radiologists With Focus on Key Chest CT Findings.

Evolution of the multimodality management of early lung cancer, including progress in surgical techniques, has introduced the possibility of resection for lung cancer cases that historically were considered unresectable (e.g., select cases of T4 disease and oligometastatic disease). However, the TNM classification does not uniformly correlate with lung cancer operability and resectability. Radiologic evaluation is therefore critical in identifying patients' suitability to undergo lung cancer resection and in guiding the selection of a surgical approach from among a range of such approaches, including wedge resection, segmentectomy, lobectomy, bilobectomy, and pneumonectomy. The radiologist must understand the available surgical options, along with their advantages and disadvantages, and provide a report that includes critical information on tumor size, location, and extension and anatomic relations that may influence the surgical technique. Preoperative CT findings may also help predict expected postoperative lung function and the associated impact on the postoperative course of the patient. This article reviews the role of chest CT in the preoperative evaluation of lung cancer, focusing on the key CT findings that help direct surgical decision making in the context of an expanding range of patients who may be considered candidates for resection.

Maintaining safe lung cancer surgery during the COVID-19 pandemic in a global city.

BACKGROUND: SARS-CoV-2 has challenged health service provision worldwide. This work evaluates safe surgical pathways and standard operating procedures implemented in the high volume, global city of London during the first wave of SARS-CoV-2 infection. We also assess the safety of minimally invasive surgery(MIS) for anatomical lung resection. METHODS: This multicentre cohort study was conducted across all London thoracic surgical units, covering a catchment area of approximately 14.8 Million. A Pan-London Collaborative was created for data sharing and dissemination of protocols. All patients undergoing anatomical lung resection 1st March-1st June 2020 were included. Primary outcomes were SARS-CoV-2 infection, access to minimally invasive surgery, post-operative complication, length of intensive care and hospital stay (LOS), and death during follow up. FINDINGS: 352 patients underwent anatomical lung resection with a median age of 69 (IQR: 35-86) years. Self-isolation and pre-operative screening were implemented following the UK national lockdown. Pre-operative SARS-CoV-2 swabs were performed in 63.1% and CT imaging in 54.8%. 61.7% of cases were performed minimally invasively (MIS), compared to 59.9% pre pandemic. Median LOS was 6 days with a 30-day survival of 98.3% (comparable to a median LOS of 6 days and 30-day survival of 98.4% pre-pandemic). Significant complications developed in 7.3% of patients (Clavien-Dindo Grade 3-4) and 12 there were re-admissions(3.4%). Seven patients(2.0%) were diagnosed with SARS-CoV-2 infection, two of whom died (28.5%). INTERPRETATION: SARS-CoV-2 infection significantly increases morbidity and mortality in patients undergoing elective anatomical pulmonary resection. However, surgery can be safely undertaken via open and MIS approaches at the peak of a viral pandemic if precautionary measures are implemented. High volume surgery should continue during further viral peaks to minimise health service burden and potential harm to cancer patients. FUNDING: This work did not receive funding.

Vortioxetine improves cognition in mild cognitive impairment.

This study investigated the effects of vortioxetine on cognitive function in adults with mild cognitive impairment (MCI). This single-arm, open-label, phase II study enrolled 111 adults with MCI without depressive symptoms to receive 5-10 mg/day vortioxetine for 6 months. Main outcomes assessed: cognitive function [Montreal Cognitive Assessment (MoCA); Digit Symbol Substitution Test (DSST)], disease severity [Clinical Dementia Rating (CDR)], clinician-assessed improvement and safety. Mean MoCA score increased from 24.2 points (baseline) to 29.7 points (month 6), placing most subjects within the cognitively normal range (≥26 points). Compared with baseline, MoCA and DSST scores were significantly improved at months 1, 3 and 6 (P < 0.001 for all). Global CDR scores significantly improved from baseline to month 6 (mean change -0.37 points; P < 0.001), representing an improvement from very mild impairment (0.50 points) to cognitively normal status (0.13 points), mainly in CDR memory scores. At month 6, 89.6% of subjects had improved disease severity. Adverse events and adverse drug reactions were reported in 9.9% (n = 11) and 2.7% (n = 3) of subjects, respectively. Vortioxetine treatment was associated with significant improvement in cognitive function and a favorable safety profile in community-dwelling older adults with MCI. Given the lack of evidence for efficacious pharmacologic interventions for MCI, our results are encouraging and warrant further investigation.

Comparing conventional and high sensitivity troponin T measurements in identifying adverse cardiac events in patients admitted to an Asian emergency department chest pain observation unit.

BACKGROUND: High sensitive cardiac troponin assays can be used for prediction of major adverse cardiac events (MACE) in patients with chest pain. METHODS: We included patients with symptoms suggestive of acute coronary syndrome in the emergency department observation unit. We compared the accuracy of conventional troponin T (cTnT) with high sensitive troponin T (hsTnT) at various ranges, as well as the utility of hsTnT and cTnT in prediction of 30-day and 1-year MACE. RESULTS: 1023 patients were included (68.1% male, median age 56 years). There were 2712 hsTnT and cTnT values compared. hsTnT had a higher AUC than cTnT for 30-day and 1-year MACE. The optimal cut-off of 0-hour hsTnT for 30-day (PPV 34%, NPV 96.6%) and 1-year MACE (PPV 40.2%, NPV 94.2%) was 16 ng/L.For 844 patients who had values for both 0 and 2 h hsTnT, we proposed a rule-out cut-off of 0 and 2 h hsTnT < 16 ng/L (NPV 97.0%, 95%CI 95.5-98.1%) and a rule-in cut-off of 0 and 2 h hsTnT ≥ 26 ng/L (PPV 58.8%, 95%CI 40.7%-75.4%) for 30-day MACE. Negative 0-2 h delta-hsTnT had poor predictive discriminant capabilities on 30-day (PPV 8.2%) and 1-year MACE (PPV 12.3%). CONCLUSION: The cut off values of hsTnT used in the 0 and 2-hour algorithm to rule-out (16 ng/L) and rule-in MACE (26 ng/L) are in the range that previous cTnT assays are unable to measure accurately. Risk scores can be used to further improve NPV of the rule-out group. A fall in hsTnT level acutely is not predictive of MACE.

Elective Lung Resections in the Elderly: Where Do We Draw the Line?

INTRODUCTION: The increasing longevity of the Western population means patients with a more advanced age are being diagnosed with resectable disease. With improvements in imaging and diagnostic capabilities, this trend is likely to develop further. As a unit operating on a higher proportion of older patients and with limited literature regarding the population of older than 85 years, we retrospectively compared the outcomes of patients older than 85 years in our unit treated with elective lung resection for non-small cell lung cancer (NSCLC) with those between the age of 80 and 84 years inclusive. METHODS: All patients who underwent elective lung cancer resection between the years 2012 and 2015 were identified from the National Thoracic Surgical Database. RESULTS: A total of 701 elective lung resections were performed during this time frame; 76 patients between the ages of 80 and 84 years and 18 patients older than 85 years. The follow-up period was 3 to 7 years. There was a significant increase in the Thoracic Surgery Scoring System (2.04; 2.96%, p = 0.0015) and a significant reduction in the transfer factor (94.7; 69.5%, p = 0.0001) between the younger and older groups. There were three (3.9%) in-hospital deaths in the 80 to 84 years age group and no in-hospital deaths in the 85 years and older age group. CONCLUSION: This study demonstrates that surgery for early NSCLC can be safely performed in 85 years and older population. This is a higher risk population and parenchymal-sparing procedures should be considered.

Loneliness in adolescence: a Rasch analysis of the Perth A-loneness scale.

PURPOSE: The psychometric properties of the Perth A-loneness Scale (PALs) have been extensively validated using classical test theory, but to date no studies have applied a Rasch analysis. The purpose of this study was to validate the PALs four subscales, using Rasch analysis. METHODS: Responses from 1484 adolescents (58% female, mean age = 12.8 years), 131 of whom had a diagnosed neurodevelopmental disorder, from 10 Western Australian secondary schools were included in the Rasch analysis. Overall fit, individual item fit, local response dependence, dimensionality, operation of response categories, and differential item functioning (DIF) were examined. RESULTS: The Rasch analysis supported the factor structure of the PALs. A reasonable to high reliability was obtained for each of the subscales. Participants did not distinguish consistently between the higher categories 'very often' and 'always' on three of the subscales. No item showed Differential Item Functioning (DIF) for neurodevelopmental disorder status and age. One item on each of the Positive and Negative Attitude to Aloneness subscales showed DIF for gender. CONCLUSION: The results support the interval scale measurement properties of the PALs and provide clinicians and researchers with a measure to assess adolescent loneliness, a construct strongly associated with a constellation of mental health problems.

Thoracic Surgery during Coronavirus Disease 2019 (COVID-19): The Experience of a Level 1 Trauma Center.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus primarily affecting the respiratory system, was initially diagnosed in Wuhan, China, in late 2019. Identified as coronavirus disease 2019 (COVID-19) by the World Health Organization, the virus rapidly became a global pandemic. The effects on health care worldwide were unprecedented as countries adapted services to treat masses of critically ill patients.The aim of this study is to analyze the effect that the COVID-19 pandemic had on thoracic surgery at a major trauma center during peak prevalence. METHODS: Prospective unit data were collected for all patients who underwent thoracic surgery during March 2020 until May 2020 inclusive. Retrospective data were collected from an earlier comparable time period as a comparison. RESULTS: In the aforementioned time frame, 117 thoracic surgical operations were performed under the care of four thoracic surgeons. Six operations were performed on three patients who were being treated for SARS-CoV-2. One operation was performed on a patient who had recovered from SARS-CoV-2. There were no deaths due to SARS-CoV-2 in any patient undergoing thoracic surgery. CONCLUSION: This study demonstrates that during the first surge of SARS-CoV-2, it was possible to adapt a thoracic oncology and trauma service without increase in mortality due to COVID-19. This was only possible due to a significant reduction in trauma referrals, cessation of benign and elective work, and the more stringent reprioritization of cancer surgery. This information is vital to learn from our experience and prepare for the predicted second surge and any similar future pandemics we might face.

Spatial and Temporal Heterogeneity of PD-L1 Expression and Tumor Mutational Burden in Gastroesophageal Adenocarcinoma at Baseline Diagnosis and after Chemotherapy.

PURPOSE: Intrapatient heterogeneity of programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) in gastroesophageal adenocarcinoma (GEA) could influence their roles as predictive biomarkers for response to immune checkpoint inhibitors (ICI). In this retrospective analysis, we evaluated the spatiotemporal heterogeneity and prognostic relevance of PD-L1 expression and TMB in GEA. EXPERIMENTAL DESIGN: A cohort of 211 patients with stage II-IV GEA was retrospectively reviewed for a total of 407 tumor samples with PD-L1 expression data and 319 tumor samples with TMB data. PD-L1 status was defined as positive if combined positive score (CPS) ≥1 using the 22C3 pharmDx assay. TMB levels were categorized as low, intermediate, or high (≤5, 5-15, or >15 mutations/Mb), or using a single threshold (<10 or ≥10 mutation/Mb), determined by next-generation sequencing using a targeted gene panel. RESULTS: Of 407 tumors, 56% were PD-L1 negative and 44% PD-L1 positive. Of 319 tumors, 50% were TMB-low, 45% TMB-intermediate, and 5% TMB-high; 86% had <10 and 14% ≥10 mutations/Mb. TMB level was significantly associated with MSI-status. PD-L1 expression and TMB exhibited marked spatial heterogeneity between baseline primary and metastatic tumors (61% and 69% concordance), and temporal heterogeneity between tumors before and after chemotherapy (57%-63% and 73%-75% concordance). PD-L1 expression and TMB were not significantly associated with overall survival. CONCLUSIONS: PD-L1 expression and TMB exhibit marked spatial and temporal heterogeneity in GEA. This heterogeneity should be considered when obtaining tumor samples for molecular testing and when deciding whether ICI therapy is appropriate.See related commentary by Klempner et al., p. 6401.

ANGPTL4 T266M variant is associated with reduced cancer invasiveness.

Angiopoietin-like 4 (ANGPTL4) is a secretory protein that can be cleaved to form an N-terminal and a C-terminal protein. Studies performed thus far have linked ANGPTL4 to several cancer-related and metabolic processes. Notably, several point mutations in the C-terminal ANGPTL4 (cANGPTL4) have been reported, although no studies have been performed that ascribed these mutations to cancer-related and metabolic processes. In this study, we compared the characteristics of tumors with and without wild-type (wt) cANGPTL4 and tumors with cANGPTL4 bearing the T266M mutation (T266M cANGPTL4). We found that T266M cANGPTL4 bound to integrin α5ß1 with a reduced affinity compared to wt, leading to weaker activation of downstream signaling molecules. The mutant tumors exhibited impaired proliferation, anoikis resistance, and migratory capability and had reduced adenylate energy charge. Further investigations also revealed that cANGPTL4 regulated the expression of Glut2. These findings may explain the differences in the tumor characteristics and energy metabolism observed with the cANGPTL4 T266M mutation compared to tumors without the mutation.

Treating Comorbid Anxiety in Adolescents With ADHD Using a Cognitive Behavior Therapy Program Approach.

OBJECTIVE: To evaluate an 8-week cognitive behavior therapy (CBT) treatment specifically designed for adolescents with ADHD and comorbid anxiety. METHOD: Using a multiple baseline design, nine adolescents (13 years to 16 years 9 months) received a weekly CBT, which focused on four identified anxiety-arousing times. Participants self-recorded their levels of anxiety for each of the four times during baseline, intervention, and a maintenance phase. Anxiety was also assessed using the Multidimensional Anxiety Scale for Children (MASC). RESULTS: Paired samples t tests supported the success of the intervention. Interrupted time-series data for each participant revealed varying rates of success across the four times, however. The MASC data revealed significant reductions in Physical Symptoms of Anxiety, Social Anxiety, Separation Anxiety, Harm Avoidance, and Total Anxiety. CONCLUSION: The data demonstrate the efficacy of a CBT program for the treatment of comorbid anxiety in adolescents with ADHD.

Role of pneumococcal vaccination in prevention of pneumococcal disease among adults in Singapore.

The burden of disease associated with Streptococcus pneumoniae infection in adults can be considerable but is largely preventable through routine vaccination. Although substantial progress has been made with the recent licensure of the new vaccines for prevention of pneumonia in adults, vaccine uptake rates need to be improved significantly to tackle adult pneumococcal disease effectively. Increased education regarding pneumococcal disease and improved vaccine availability may contribute to a reduction in pneumococcal disease through increased vaccination rates. The increase in the elderly population in Singapore as well as globally makes intervention in reducing pneumococcal disease an important priority. Globally, all adult vaccines remain underused and family physicians give little priority to pneumococcal vaccination for adults in daily practice. Family physicians are specialists in preventive care and can be leaders in ensuring that adult patients get the full benefit of protection against vaccine-preventable diseases. They can play a key role in the immunization delivery of new and routine vaccines by educating the public on the risks and benefits associated with vaccines. Local recommendations by advisory groups on vaccination in adults will also help to tackle vaccine preventable diseases in adults.

Might digital drains speed up the time to thoracic drain removal?

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was: might digital drains speed up the time to thoracic drain removal in terms of time till chest drain removal, hospital stay and overall cost? A total of 296 papers were identified as a result of the search as described below. Of these, five papers provided the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of the papers are tabulated. A literature search revealed that several single-centre prospective randomized studies have shown significantly earlier removal of chest drains with digital drains ranging between 0.8 and 2.1 days sooner. However, there was heterogeneity in studies in the management protocol of chest drains in terms of the use of suction, number of drains and assessment for drain removal. Some protocols such as routinely keeping drains irrespective of the presence of air leak or drain output may have skewed results. Differences in exclusion criteria and protocols for discharging home with portable devices may have biased results. Due to heterogeneity in the management protocol of chest drains, there is conflicting evidence regarding hospital stay. The limited data on cost suggest that there may be significantly lower postoperative costs in the digital drain group. All the studies were single-centre series generally including patients with good preoperative lung function tests. Further larger studies with more robust chest drain management protocols are required especially to assess length of hospital stay, cost and whether the results are applicable to a larger patient population.

Conceptualising loneliness in adolescents: development and validation of a self-report instrument.

This paper reports the development and psychometric evaluations of a multidimensional model of loneliness in Australian adolescents. In the first study a new instrument was designed and administered to 1,074 adolescents (ages 10-18 years, M = 13.01). An exploratory factor analysis from data supplied by 694 of these participants yielded a 4-factor structure (friendship, isolation, negative attitude to solitude, and positive attitude to solitude). Competing measurement models were then evaluated using confirmatory factor analysis with data from the remaining 380 participants; strong support was demonstrated for the conceptual model. Significant main effects were evident for geographical location (rural remote/urban), age and sex. In a second study, involving 235 Australian adolescents (ages 10.0-16 years, M = 13.8) the superiority of the first-order model represented by four correlated factors was confirmed. The findings have clinical and practical implications for professional groups represented by child and adolescent psychiatry, pediatric and clinical psychology services, researchers, and educators. Specifically, the new self-report instrument identifies adolescents who are at risk of loneliness and its associated adverse outcomes and in doing has the potential to offer new insights into prevention and intervention.

Is sublobar resection equivalent to lobectomy for surgical management of peripheral carcinoid?

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was: Is sub-lobar resection equivalent to lobectomy in terms of operative morbidity and mortality, long-term survival and disease recurrence in patients with peripheral carcinoid lung cancer? A total of 342 papers were identified using the search as described below. Of these, 10 papers presented the best evidence to answer the clinical question as they presented sufficient data to reach conclusions regarding the issues of interest for this review. Long-term survival, disease recurrence and operative morbidity were included in the assessment. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of the papers are tabulated. A literature search showed that there is a good prognosis after resection of lung carcinoid with the 10-year disease-free survival rate ranging between 77 and 94%, and suggested that sub-lobar resection of a typical carcinoid did not compromise the long-term survival. The proportion of peripheral tumours ranged between 22.6 and 100% and the proportion of patients with a preoperative diagnosis of carcinoid ranged between 51.9 and 86.7%, with many series not providing either or both of these data. As a result, a lobectomy or greater resection was necessary on anatomical or diagnostic grounds and led to a low number of sub-lobar resections. Owing to the high heterogeneity within and between series and small numbers of cases included, it is difficult to draw conclusions on disease recurrence and postoperative morbidity. All studies available retrospectively compared heterogeneous groups of non-matched group of patients, which can bias the outcomes reported. There is a lack of comprehensive randomized studies to compare a lobectomy or greater resection and sub-lobar resection. We conclude that there is little objective evidence to show the equivalence or superiority of lobectomy over sub-lobar resection.

Interpersonal and affective dimensions of psychopathic traits in adolescents: development and validation of a self-report instrument.

We report the development and psychometric evaluations of a self-report instrument designed to screen for psychopathic traits among mainstream community adolescents. Tests of item functioning were initially conducted with 26 adolescents. In a second study the new instrument was administered to 150 high school adolescents, 73 of who had school records of suspension for antisocial behavior. Exploratory factor analysis yielded a 4-factor structure (Impulsivity α = 0.73, Self-Centredness α = 0.70, Callous-Unemotional α = 0.69, and Manipulativeness α = 0.83). In a third study involving 328 high school adolescents, 130 with records of suspension for antisocial behavior, competing measurement models were evaluated using confirmatory factor analysis. The superiority of a measurement model represented by four correlated factors was supported, and this model was invariant across gender and age. The findings provide researchers and clinicians with a psychometrically strong, self-report instrument and a greater understanding of psychopathic traits in mainstream adolescents.

Is video mediastinoscopy a safer and more effective procedure than conventional mediastinoscopy?

A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was whether video-assisted mediastinoscopy (VAM) is a more effective procedure than conventional mediastinoscopy (CM). A total of 108 papers were identified using the search as discussed below. Of which, eight papers presented the best evidence to answer the clinical question as they included a sufficient number of patients to reach conclusions regarding the issues of interest for this review. Complications, complication rates, number of lymph nodes biopsies, number of stations sampled and training opportunities were included in the assessment. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of the papers are tabulated. Literature search revealed that CM is a safe procedure associated with low mortality (0-0.05%) and morbidity (0-5.3%). CM has high levels of accuracy (83.8-97.2%) and negative predictive value (81-95.7%). Training in CM can be difficult as the limited vision means that the trainer cannot monitor directly the dissection and the areas biopsied by the trainee as one operator and effectively see at any time. VAM is also a safe procedure with comparable results to that of CM in term of mortality (0%), morbidity (0.83-2.9%), accuracy (87.9-98.9%) and negative predictive values (83-98.6%). The main advantage is higher number of biospsies taken (VAM, 6-8.5; CM, 5-7.13) and number of mediastinal lymph node stations sampled (VAM, 1.9-3.6; CM, 2.6-2.98). VAM can be associated with more aggressive dissecting and that can lead to more complications. The use of VAM can provide a better and safer training opportunity since both trainer and trainee can share the magnified image on the monitor. All studies available are comparing heterogeneous groups of non-matched group of patients which can bias the outcomes reported. There is a lack of comprehensive randomized studies to compare both procedures and to support any preference towards VAM over CM. We conclude that there is actually very little objective evidence of VAM superiority over CM.

Molecular mechanisms for synchronized transcription of three complement C1q subunit genes in dendritic cells and macrophages.

Hereditary homozygous C1q deficiency is rare, but it almost certainly causes systemic lupus erythematosus. On the other hand, C1q levels can decline in systemic lupus erythematosus patients without apparent C1q gene defects and the versatility in C1q production is a likely cause. As an 18-subunit protein, C1q is assembled in a 1:1:1 ratio from three different subunits. The three human C1q genes are closely bundled on chromosome 1 (C1qA-C1qC-C1qB) and their basal and IFNγ-stimulated expression, largely restricted to macrophages and dendritic cells, is apparently synchronized. We cloned the three gene promoters and observed that although the C1qB promoter exhibited basal and IFNγ-stimulated activities consistent with the endogenous C1qB gene, the activities of the cloned C1qA and C1qC promoters were suppressed by IFNγ. To certain extents, these were corrected when the C1qB promoter was cloned at the 3' end across the luciferase reporter gene. A 53-bp element is essential to the activities of the C1qB promoter and the transcription factors PU.1 and IRF8 bound to this region. By chromatin immunoprecipitation, the C1qB promoter was co-precipitated with PU.1 and IRF8. shRNA knockdown of PU.1 and IRF8 diminished C1qB promoter response to IFNγ. STAT1 instead regulated C1qB promoter through IRF8 induction. Collectively, our results reveal a novel transcriptional mechanism by which the expression of the three C1q genes is synchronized.

Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study.

BACKGROUND: The effects of extra-pleural pneumonectomy (EPP) on survival and quality of life in patients with malignant pleural mesothelioma have, to our knowledge, not been assessed in a randomised trial. We aimed to assess the clinical outcomes of patients who were randomly assigned to EPP or no EPP in the context of trimodal therapy in the Mesothelioma and Radical Surgery (MARS) feasibility study. METHODS: MARS was a multicentre randomised controlled trial in 12 UK hospitals. Patients aged 18 years or older who had pathologically confirmed mesothelioma and were deemed fit enough to undergo trimodal therapy were included. In a prerandomisation registration phase, all patients underwent induction platinum-based chemotherapy followed by clinical review. After further consent, patients were randomly assigned (1:1) to EPP followed by postoperative hemithorax irradiation or to no EPP. Randomisation was done centrally with computer-generated permuted blocks stratified by surgical centre. The main endpoints were feasibility of randomly assigning 50 patients in 1 year (results detailed in another report), proportion randomised who received treatment, proportion eligible (registered) who proceeded to randomisation, perioperative mortality, and quality of life. Patients and investigators were not masked to treatment allocation. This is the principal report of the MARS study; all patients have been recruited. Analyses were by intention to treat. This trial is registered, number ISRCTN95583524. FINDINGS: Between Oct 1, 2005, and Nov 3, 2008, 112 patients were registered and 50 were subsequently randomly assigned: 24 to EPP and 26 to no EPP. The main reasons for not proceeding to randomisation were disease progression (33 patients), inoperability (five patients), and patient choice (19 patients). EPP was completed satisfactorily in 16 of 24 patients assigned to EPP; in five patients EPP was not started and in three patients it was abandoned. Two patients in the EPP group died within 30 days and a further patient died without leaving hospital. One patient in the no EPP group died perioperatively after receiving EPP off trial in a non-MARS centre. The hazard ratio [HR] for overall survival between the EPP and no EPP groups was 1·90 (95% CI 0·92-3·93; exact p=0·082), and after adjustment for sex, histological subtype, stage, and age at randomisation the HR was 2·75 (1·21-6·26; p=0·016). Median survival was 14·4 months (5·3-18·7) for the EPP group and 19·5 months (13·4 to time not yet reached) for the no EPP group. Of the 49 randomly assigned patients who consented to quality of life assessment (EPP n=23; no EPP n=26), 12 patients in the EPP group and 19 in the no EPP group completed the quality of life questionnaires. Although median quality of life scores were lower in the EPP group than the no EPP group, no significant differences between groups were reported in the quality of life analyses. There were ten serious adverse events reported in the EPP group and two in the no EPP group. INTERPRETATION: In view of the high morbidity associated with EPP in this trial and in other non-randomised studies a larger study is not feasible. These data, although limited, suggest that radical surgery in the form of EPP within trimodal therapy offers no benefit and possibly harms patients. FUNDING: Cancer Research UK (CRUK/04/003), the June Hancock Mesothelioma Research Fund, and Guy's and St Thomas' NHS Foundation Trust.

A systematic review of lung-sparing extirpative surgery for pleural mesothelioma.

OBJECTIVES: There is a resurgence of interest in lung-sparing extirpative surgery for malignant pleural mesothelioma with recent reports of better survival and fewer adverse consequences than with extrapleural pneumonectomy. However, these operations are not well-characterized and to offer evidence-based clinical recommendations and to plan future trials a summary of what is already known is required. DESIGN: A formal literature search was performed and all recovered titles were sequentially sifted by title, abstract and full-text reading according to prespecified criteria. Papers were selected if they contained data relevant to the area of enquiry. Quantitative synthesis and textual analysis, appropriate to the material, were performed. SETTING: Follow-up studies of patients undergoing surgery for malignant pleural mesothelioma in specialist thoracic or cardiothoracic units. PARTICIPANTS: Among the operated patients described in these papers, a total of 1270 patients had undergone lung-sparing surgery for mesothelioma. RESULTS: There were no randomized trials or other forms of controlled studies. From 464 titles, 26 papers contained sufficient data on 1270 patients to be included in the systematic review. Operative descriptions for all series were extracted and tabulated and variation was found in the nature of surgery within and between series, and the degree of detail with which it was described. There was more operative detail in recent papers. All available numerical data were extracted, tabulated and summarized using quantitative methods. The average survival at 1, 2, 3, 4 and 5 years was 51%, 26%, 16%, 11% and 9%, respectively. There were no data on patients' performance status, symptomatic change, or other patient reported outcomes. CONCLUSIONS: In the absence of any form of control data, no conclusions can be drawn concerning survival differences or symptomatic benefits attributable to surgery. As mesothelioma surgery is restricted to a selected minority of patients who often have multiple therapies, future research will require controlled studies with explicit definitions of the clinical and surgical intent.