Extended pleurectomy decortication and chemotherapy versus chemotherapy alone for pleural mesothelioma (MARS 2): a phase 3 randomised controlled trial.

BACKGROUND: Extended pleurectomy decortication for complete macroscopic resection for pleural mesothelioma has never been evaluated in a randomised trial. The aim of this study was to compare outcomes after extended pleurectomy decortication plus chemotherapy versus chemotherapy alone. METHODS: MARS 2 was a phase 3, national, multicentre, open-label, parallel two-group, pragmatic, superiority randomised controlled trial conducted in the UK. The trial took place across 26 hospitals (21 recruiting only, one surgical only, and four recruiting and surgical). Following two cycles of chemotherapy, eligible participants with pleural mesothelioma were randomly assigned (1:1) to surgery and chemotherapy or chemotherapy alone using a secure web-based system. Individuals aged 16 years or older with resectable pleural mesothelioma and adequate organ and lung function were eligible for inclusion. Participants in the chemotherapy only group received two to four further cycles of chemotherapy, and participants in the surgery and chemotherapy group received pleurectomy decortication or extended pleurectomy decortication, followed by two to four further cycles of chemotherapy. It was not possible to mask allocation because the intervention was a major surgical procedure. The primary outcome was overall survival, defined as time from randomisation to death from any cause. Analyses were done on the intention-to-treat population for all outcomes, unless specified. This study is registered with ClinicalTrials.gov, NCT02040272, and is closed to new participants. FINDINGS: Between June 19, 2015, and Jan 21, 2021, of 1030 assessed for eligibility, 335 participants were randomly assigned (169 to surgery and chemotherapy, and 166 to chemotherapy alone). 291 (87%) participants were men and 44 (13%) women, and 288 (86%) were diagnosed with epithelioid mesothelioma. At a median follow-up of 22·4 months (IQR 11·3-30·8), median survival was shorter in the surgery and chemotherapy group (19·3 months [IQR 10·0-33·7]) than in the chemotherapy alone group (24·8 months [IQR 12·6-37·4]), and the difference in restricted mean survival time at 2 years was -1·9 months (95% CI -3·4 to -0·3, p=0·019). There were 318 serious adverse events (grade ≥3) in the surgery group and 169 in the chemotherapy group (incidence rate ratio 3·6 [95% CI 2·3 to 5·5], p<0·0001), with increased incidence of cardiac (30 vs 12; 3·01 [1·13 to 8·02]) and respiratory (84 vs 34; 2·62 [1·58 to 4·33]) disorders, infection (124 vs 53; 2·13 [1·36 to 3·33]), and additional surgical or medical procedures (15 vs eight; 2·41 [1·04 to 5·57]) in the surgery group. INTERPRETATION: Extended pleurectomy decortication was associated with worse survival to 2 years, and more serious adverse events for individuals with resectable pleural mesothelioma, compared with chemotherapy alone. FUNDING: National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (15/188/31), Cancer Research UK Feasibility Studies Project Grant (A15895).

A comprehensive investigation of industrial plastic pellets on beaches across the Laurentian Great Lakes and the factors governing their distribution.

Industrial, pre-consumer pellets are a major type of plastics pollution found on shorelines worldwide. This study investigates the distribution and characteristics of plastic pellets accumulated on beaches of the Laurentian Great Lakes of North America and provides a "snapshot" of pellet distribution in a lake system that accounts for 21% of the world's freshwater reserves. We sampled pellets simultaneously from 10m2 quadrats on 66 beaches and characterized the 12,595 pellets collected (average of 19.1 pellets/m2). Forty-two beaches contained pellets and 86% of the pellets were found on three beaches: Rossport (Lake Superior), Baxter (Lake Huron), and Bronte (Lake Ontario). The number of pellets on each beach was compared with factors hypothesized to control their accumulation. In general, positive correlations were found between pellet abundance and watershed population, number of plastic-related industries, and proximity to a river mouth, although for Lake Superior, abundance was related to a train spill that took place over 10 years ago. Beach grain size appears to be related to pellet abundance, with very fine sand, fine sand and medium sand containing the greatest number of pellets. All pellets were visually characterized based on size, color, shape, weathering, and distinguishing traits. The predominant color was white, oblate shapes were most common, and the main distinguishing trait was a dimple. Most pellets showed little evidence of weathering, with the weathered samples mainly from Lakes Erie and Ontario. Lake Ontario pellets were the most varied, with 6/7 shapes, 35/40 colors, and 21/25 distinguishing traits, indicating a wider range of pellet sources compared to the other lakes. Polymer compositions were mainly polyethylene (PE) and polypropylene (PP). Our results will lead to increased recognition of regional pellet pollution in the Great Lakes watershed, thereby motivating change during their production, transport and use.

Retrospective analysis of the diagnostic yield of newborn drug testing.

BACKGROUND: The objective of this study was to identify high-yield screening risk factors for detecting maternal non-medical drug use during pregnancy. METHODS: A four year retrospective analysis was conducted at an academic medical center. Detailed chart review of both the newborn and mother's medical record was performed on all cases for which one or more drug(s) or metabolite(s) were identified and confirmed in meconium or urine. RESULTS: 229 (9.2%) of 2,497 meconium samples out of 7,749 live births confirmed positive for one or more non-medical drugs. History of maternal non-medical drug and/or tobacco use in pregnancy was present in 90.8% of non-medical drug use cases. Addition of social risk factors and inadequate prenatal care increased the yield to 96.9%. CONCLUSIONS: Use of focused screening criteria based on specific maternal and social risk factors may detect many prenatal non-medical drug exposures.

McKusick Kaufman syndrome, complications arising at puberty.

BACKGROUND: McKusick Kaufman Syndrome (MKS), a rare genetic condition, presents in the neonatal period with a classic triad of postaxial polydactyly, congenital heart disease, and hydrometrocolpos. The diagnosis is typically clinical, based on the presence of polydactyly and hydrometrocolpos. CASE: We report the case of a 13-year-old female, who was diagnosed with MKS in infancy and underwent vaginal reconstructive surgery for a urogenital sinus. She was lost to follow-up thereafter. She presented to our institution at age 13 with pyometra, pyosalpinx, and tubo-ovarian abscess due to a stenotic cervix obstructing menstrual outflow. SUMMARY AND CONCLUSION: Gynecologic follow-up is imperative in patients with history of vaginal reconstruction to monitor for hematometra from outflow obstruction to prevent life threatening secondary bacterial infections.

Pheochromocytoma causing cardiomyopathy, ischemic stroke and acute arterial thrombosis: a case report and review of the literature.

Pheochromocytoma is a rare catecholamine secreting neuroendocrine tumor with an estimated annual incidence of one to four per million and prevalence among hypertensive patients of 0.1 to 0.6%. The symptoms and signs of pheochromocytoma include the classic triad of episodic headache, increased sweating, and palpitations. These are as a result of an uncontrolled release of catecholamines. There exist only a small number of reports of pheochromocytoma simulating hypertrophic obstructive cardiomyopathy, few reports of pheochromocytoma-induced ischemic stroke and only two reported cases with pheochromocytoma-induced arterial thrombosis. We present a case of multiple, rare clinical complications of pheochromocytoma occurring in the same patient and the review of literature of these complications.

Screening for parathyroid hormone resistance in patients with nonphenotypically evident pseudohypoparathyroidism.

OBJECTIVE: Hypocalcemia and hyperphosphatemia in the setting of elevated parathyroid hormone (PTH) and normal vitamin D metabolites, raises the possibility of PTH resistance. The idiopathic and inherited forms of PTH resistance are referred to as pseudohypoparathyroidism. Nonphenotypically evident pseudohypoparathyroidism can go undiagnosed for decades. We have designed a new test to diagnose PTH resistance and confirmed its clinical utility in the diagnosis of pseudohypoparathyroidism. METHODS: Our test consists of a subcutaneous injection of commercially available recombinant PTH and concomitant measurement of cyclic adenosine monophosphate in urine. We implemented the test in 2 patients with recalcitrant hypocalcemia and a healthy control subject. RESULTS: Our test unequivocally demonstrated PTH resistance in both patients. One of the patients had phenotypically evident pseudohypoparathyroidism type-1a hence, PTH resistance was suspected. The other patient with nonphenotypically evident disease, also showed PTH resistance and was later demonstrated to have pseudohypoparathyroidism type-1b at the genomic level and confirmed to be of familial type. CONCLUSION: Our results show for the first time the implementation of a simple new diagnostic tool designed to check for PTH resistance. This new test has already proven to be useful in few occasions at our institution. Larger populations, however, should be tested before implementation of such a test is considered a standard of care.

Diarrhea etiology in a pediatric emergency department: a case control study.

BACKGROUND: The etiology of childhood diarrhea is frequently unknown. METHODS: We sought Aeromonas, Campylobacter, Escherichia coli O157:H7, Pleisiomonas shigelloides, Salmonella, Shigella, Vibrio, and Yersinia (by culture), adenoviruses, astroviruses, noroviruses, rotavirus, and Shiga toxin-producing E. coli (STEC; by enzyme immunoassay), Clostridium difficile (by cytotoxicity), parasites (by microscopy), and enteroaggregative E. coli (EAEC; by polymerase chain reaction [PCR] analysis) in the stools of 254 children with diarrhea presenting to a pediatric emergency facility. Age- and geographic-matched community controls without diarrhea (n = 452) were similarly studied, except bacterial cultures of the stool were limited only to cases. RESULTS: Twenty-nine (11.4%) case stools contained 13 Salmonella, 10 STEC (6 O157:H7 and 4 non-O157:H7 serotypes), 5 Campylobacter, and 2 Shigella. PCR-defined EAEC were present more often in case (3.2%) specimens than in control (0.9%) specimens (adjusted odds ratio [OR], 3.9; 95% confidence interval [CI], 1.1-13.7), and their adherence phenotypes were variable. Rotavirus, astrovirus, and adenovirus were more common among cases than controls, but both groups contained noroviruses and C. difficile at similar rates. PCR evidence of hypervirulent C. difficile was found in case and control stools; parasites were much more common in control specimens. CONCLUSIONS: EAEC are associated with childhood diarrhea in Seattle, but the optimal way to identify these agents warrants determination. Children without diarrhea harbor diarrheagenic pathogens, including hypervirulent C. difficile. Our data support the importance of taking into account host susceptibility, microbial density, and organism virulence traits in future case-control studies, not merely categorizing candidate pathogens as being present or absent.

What is the utility of distal forearm DXA in primary hyperparathyroidism?

BACKGROUND: Primary hyperparathyroidism (PHPT) leads to increased bone turnover, low bone mineral density, and increased fracture risk. These effects are, however, preferentially seen in the distal forearm, which is rich in cortical bone. This study aimed to determine how frequently the distal forearm T score was the worst T score and if this T score alone led to higher rate of diagnosis of osteopenia or osteoporosis. MATERIALS AND METHODS: We retrospectively reviewed a prospective database of 300 patients undergoing parathyroidectomy at our institution between November 2000 and January 2009. The bone mineral density of the lumbar spine, total proximal femurs, and distal third of the nondominant radius was measured by dual x-ray absorptiometry. Data on bone density are reported as T scores. RESULTS: The mean T scores were -1.30 ± 0.2 in the distal forearm, -1.0 ± 0.1 in the total proximal femurs, and -0.9 ± 0.1 in the spine. The distal forearm T score was the worst bone mineral density T score in 39% of patients. This T score alone led to an upstaging in diagnosis to osteopenia or osteoporosis in 9.4% of patients. CONCLUSION: In patients with PHPT, the worst T score is commonly found in the distal forearm. This T score can identify additional patients with a diagnosis of osteopenia or osteoporosis. Distal forearm bone mineral density should, therefore, be assessed in all patients who have a diagnosis of PHPT.

Infarction of an extralobar pulmonary sequestration in a young child: diagnosis and excision by video-assisted thoracoscopy.

A 4-year-old male presented with abdominal pain. A computed tomography scan of the abdomen was negative, but a pleural effusion and mass was noted in the lower left thorax. Video-assisted thoracoscopic surgery revealed the mass to be a rare case of extralobar pulmonary sequestration that had undergone infarction.

Antibody capture of soluble Abeta does not reduce cortical Abeta amyloidosis in the PDAPP mouse.

BACKGROUND: In vivo administration of antibodies against the amyloid-beta (Abeta) peptide has been shown to reduce and reverse the progressive amyloidosis that develops in a variety of mouse models of Alzheimer's disease (AD). This work has been extended to clinical trials where subsequent autopsy cases of AD subjects immunized against Abeta showed similar reductions in parenchymal amyloid plaques, suggesting this approach to reduce neuropathology in man is feasible. OBJECTIVE: Multiple hypotheses have been advanced to explain how anti-Abeta antibodies may lower amyloid burden. In this report, we compare approaches utilizing either plaque-binding or peptide-capturing anti-Abeta antibodies for effectiveness in reducing amyloidosis in a mouse model of AD. METHODS: A plaque-binding monoclonal antibody (3D6) and an Abeta peptide-capturing monoclonal antibody (266) were compared in chronic treatment and prevention paradigms using a transgenic mouse model of AD. The effects of antibody therapy on plaque burden and plasma clearance of Abeta were investigated by quantitative imaging and clearance studies of intravenously injected (125)I-Abeta. RESULTS: The plaque-binding antibody 3D6 was highly effective in either treatment or prevention of amyloidosis. In these studies, the peptide-capture antibody 266 showed no reduction in amyloidosis in either paradigm and showed trends towards increasing amyloidosis. Antibody 266 was also found to greatly prolong (>180-fold) the normally rapid peripheral clearance of Abeta, in contrast to that found with 3D6 (>24-fold). CONCLUSION: Reversing and preventing Alzheimer's type amyloidosis is most effectively accomplished with anti-amyloid antibodies that avidly bind plaque.

Beta-amyloid immunotherapy prevents synaptic degeneration in a mouse model of Alzheimer's disease.

Alzheimer's disease neuropathology is characterized by key features that include the deposition of the amyloid beta peptide (Abeta) into plaques, the formation of neurofibrillary tangles, and the loss of neurons and synapses in specific brain regions. The loss of synapses, and particularly the associated presynaptic vesicle protein synaptophysin in the hippocampus and association cortices, has been widely reported to be one of the most robust correlates of Alzheimer's disease-associated cognitive decline. The beta-amyloid hypothesis supports the idea that Abeta is the cause of these pathologies. However, the hypothesis is still controversial, in part because the direct role of Abeta in synaptic degeneration awaits confirmation. In this study, we show that Abeta reduction by active or passive Abeta immunization protects against the progressive loss of synaptophysin in the hippocampal molecular layer and frontal neocortex of a transgenic mouse model of Alzheimer's disease. These results, substantiated by quantitative electron microscopic analysis of synaptic densities, strongly support a direct causative role of Abeta in the synaptic degeneration seen in Alzheimer's disease and strengthen the potential of Abeta immunotherapy as a treatment approach for this disease.