Conflicts of interest in clinical guidelines, advisory committee reports, opinion pieces, and narrative reviews: associations with recommendations.

BACKGROUND: Treatment and diagnostic recommendations are often made in clinical guidelines, reports from advisory committee meetings, opinion pieces such as editorials, and narrative reviews. Quite often, the authors or members of advisory committees have industry ties or particular specialty interests which may impact on which interventions are recommended. Similarly, clinical guidelines and narrative reviews may be funded by industry sources resulting in conflicts of interest. OBJECTIVES: To investigate to what degree financial and non-financial conflicts of interest are associated with favourable recommendations in clinical guidelines, advisory committee reports, opinion pieces, and narrative reviews. SEARCH METHODS: We searched PubMed, Embase, and the Cochrane Methodology Register for studies published up to February 2020. We also searched reference lists of included studies, Web of Science for studies citing the included studies, and grey literature sources. SELECTION CRITERIA: We included studies comparing the association between conflicts of interest and favourable recommendations of drugs or devices (e.g. recommending a particular drug) in clinical guidelines, advisory committee reports, opinion pieces, or narrative reviews. DATA COLLECTION AND ANALYSIS: Two review authors independently included studies, extracted data, and assessed risk of bias. When a meta-analysis was considered meaningful to synthesise our findings, we used random-effects models to estimate risk ratios (RRs) with 95% confidence intervals (CIs), with RR > 1 indicating that documents (e.g. clinical guidelines) with conflicts of interest more often had favourable recommendations. We analysed associations for financial and non-financial conflicts of interest separately, and analysed the four types of documents both separately (pre-planned analyses) and combined (post hoc analysis). MAIN RESULTS: We included 21 studies analysing 106 clinical guidelines, 1809 advisory committee reports, 340 opinion pieces, and 497 narrative reviews. We received unpublished data from 11 studies; eight full data sets and three summary data sets. Fifteen studies had a risk of confounding, as they compared documents that may differ in other aspects than conflicts of interest (e.g. documents on different drugs used for different populations). The associations between financial conflicts of interest and favourable recommendations were: clinical guidelines, RR: 1.26, 95% CI: 0.93 to 1.69 (four studies of 86 clinical guidelines); advisory committee reports, RR: 1.20, 95% CI: 0.99 to 1.45 (four studies of 629 advisory committee reports); opinion pieces, RR: 2.62, 95% CI: 0.91 to 7.55 (four studies of 284 opinion pieces); and narrative reviews, RR: 1.20, 95% CI: 0.97 to 1.49 (four studies of 457 narrative reviews). An analysis combining all four document types supported these findings (RR: 1.26, 95% CI: 1.09 to 1.44). One study investigating specialty interests found that the association between including radiologist guideline authors and recommending routine breast cancer screening was RR: 2.10, 95% CI: 0.92 to 4.77 (12 clinical guidelines). AUTHORS' CONCLUSIONS: We interpret our findings to indicate that financial conflicts of interest are associated with favourable recommendations of drugs and devices in clinical guidelines, advisory committee reports, opinion pieces, and narrative reviews. However, we also stress risk of confounding in the included studies and the statistical imprecision of individual analyses of each document type. It is not certain whether non-financial conflicts of interest impact on recommendations.

A Rare Case of CK20/CK7 Double Negative Merkel Cell Carcinoma.

The authors present a case of Merkel cell carcinoma (MCC) with unique immunohistochemical staining characteristics. A 57-year-old woman presented with a firm 0.3 cm tan papule on her left nasal-labial fold that was reportedly increasing in size and bleeding. She had a history of multiple head and neck actinic keratoses, papillary thyroid carcinoma, and a family history of an uncle with melanoma. The clinical differential diagnosis was "non-melanoma skin cancer." Histological examination showed a markedly atypical-appearing basaloid neoplasm, present mostly in the dermis, with focal pagetoid spread into the epidermis. The cells showed hyperchromatic-staining nuclei, crowding, nuclear molding, and scant cytoplasm with atypical mitoses. The findings were consistent with a malignant tumor, highly suspicious for MCC. A pancytokeratin stain was strongly positive and showed perinuclear dot-like positivity. CK20 and CK7 stains were both negative. Synaptophysin was strongly positive, chromogranin was focally positive, CD56 was weakly positive, and neurofilament was positive in a perinuclear dot-like pattern. TTF-1, PAX5, S100, and Melan-A were negative, arguing against metastatic small cell carcinoma of lung or thyroid, B-cell lymphoma, or melanoma, respectively. Although the CK20/CK7 double negativity is very unusual, the staining characteristics of this case are most consistent with a primary cutaneous MCC. Up to 10%-15% of MCCs can be CK20 negative, and those cases are typically CK7 positive. This case is unique, as a CK20/CK7 double negative case has not been previously reported; however, the diagnosis can still be rendered based on the clinical, histological, and other immunohistochemical findings.

Biphasic Sarcomatoid Porocarcinoma.

Sarcomatoid carcinomas are rare malignant tumors, which usually demonstrate a well-differentiated epithelial component in association with a poorly differentiated spindle-cell component. Several different subtypes have been reported and categorized primarily under the differentiated epithelial component, with the majority of cutaneous sarcomatoid carcinomas arising in the setting of a basal cell or squamous cell carcinoma. To date, only 4 cases of sarcomatoid porocarcinoma have been reported in the literature. The authors present a case of an 84-year-old woman with an ulcerated papule on her scalp for several months. Histopathology revealed an exophytic and endophytic epidermal proliferation with multiple mitoses and ductal differentiation overlying a poorly differentiated, infiltrative spindle-cell proliferation in the dermis. Ductal and cystic structures were scattered throughout the malignancy. Immunohistochemistry was notable for strong and diffuse pancytokeratin positivity, p63 positivity, focally positive carcinoembryonic antigen within the ductal lumina, and periodic acid-schiff-positive, diastase-resistant intracellular deposits. They present the findings of this rare case of primary cutaneous sarcomatoid porocarcinoma.

Do mast cells play a pathogenetic role in neurofibromatosis type 1 and ulcerative colitis?

Concurrent association of neurofibromatosis type I and ulcerative colitis has been reported in one clinical case (Tavakkoli et al., 2009). Although this association may represent a casual finding, a common pathophysiology is postulated. Mast cells have been implicated in the pathogenesis of both neurofibromatosis type 1 and ulcerative colitis (He, 2004; Yoshida et al., 2010). Mast cells are typically present in neurofibromas microenvironment where they appear to contribute to tumor initiation, progression and angiogenesis (Staser et al., 2010, 2013). Moreover, interaction of mast cells with nerves throughout the gastrointestinal tract has been correlated with progression and maintenance of ulcerative colitis (Stoyanova and Gulubova, 2002). We describe a 14 year-old male with history of neurofibromatosis type 1 and new onset of ulcerative colitis diagnosed on clinical and histological findings. On gross examination the entire colonic mucosa appeared edematous showing a peculiar granular pattern, with focal erythema, shallow ulcers and multiple sessile polyps. Hematoxylin and eosin stained tissue biopsies from the colonic mucosa showed chronic inflammatory bowel disease, severe activity, consistent with chronic ulcerative colitis. Immunohistochemistry stain of the intestinal lesions revealed high expression of Neuron Specific Enolase (NSE) and S100 highlighting the presence of a Schwann cell component. In addition, c-kit/CD117 positive stain indicated a marked increase of mast cells in the lamina propria. This pattern of cellularity in the lamina propria showing increased mast cells and augmented Schwann cell component was absent in the colonic mucosa of a normal control or a patient with ulcerative colitis alone. Our observation supports the evidence of a pathogenetic role of the mast cell in ulcerative colitis associated with neurofibromatosis type 1. Further investigations are warranted to confirm the significance of this correlation as it may impact therapeutic approaches of these pathologies.

Mechanism of hepatotoxicity due to black cohosh (Cimicifuga racemosa): histological, immunohistochemical and electron microscopy analysis of two liver biopsies with clinical correlation.

BACKGROUND: Consumption of herbal supplements in the developed world remains high. Cimicifuga racemosa (C. racemosa) extract, or black cohosh, is widely used as a hormone replacing and an anti-inflammatory agent, and has been shown to cause idiosyncratic hepatitis. The mechanism of acute liver injury in those cases is unclear. To date, hepatotoxic effects of C. racemosa have been studied mostly in vitro and in animal models. Data on human tissue is extremely limited, and mostly confined to histological findings of explanted livers. METHODS: We evaluated clinical data and examined surgical diagnostic liver biopsy specimens obtained from two female patients, who developed acute submassive liver necrosis, following consumption of C. racemosa. Both patients presented with acute elevation of liver enzymes, cholestasis, absence of reactivity to hepatitis A, B and C antibodies, and weak non-specific positivity for autoimmune serological markers. Initial histological interpretation of the biopsies, with focus on hepatic parenchyma and portal tracts, was done by light microscopy, followed by special stain series and immunohistochemical studies, including Cam 5.2, AE1/AE3, reticulin, α-actin, sirius red, and PAS with diastase. Areas of prominent lymphocytic infiltration of the periportal liver plate, observed microscopically, were further evaluated by electron microscopy (EM). 4HNE adduction study, an immunofluorescent assay, was performed to detect products of the oxidative damage and their localization in the liver parenchyma. RESULTS: Oxidative damage was evident by accumulation of 4HNE protein adducts in the cytoplasm of hepatocytes, secondary lysosomes and macrophages. We hypothesize that the adducted proteins, accumulated in the liver parenchyma, serve as autoantigens, which provoke an autoimmune response, and cause migration of lymphocytes to the affected regions. The formation of immunological synapses between hepatocytes and lymphocytes, predominantly T-lymphocytes, is demonstrated by electron microscopy. The autoimmune response induces piecemeal, or troxis necrosis of hepatocytes, a well described biological phenomenon, where lymphocytes gradually remove hepatocytes in a piecemeal fashion, slowly consuming them and leaving fragments of liver cells, or nubbins of anuclear cytoplasm of liver cell, at the interface between lymphocytes and hepatocytes. CONCLUSION: The pattern of pathological injury of liver cells in both patients, following consumption of black cohosh, is identical to troxis necrosis, seen during autoimmune hepatitis. Recognition of the possibility of the acute hepatic injury by the herbal supplement black cohosh is essential for early accurate diagnosis, and timely patient management.

Alcoholic liver disease patients treated with S-adenosyl-L-methionine: an in-depth look at liver morphologic data comparing pre and post treatment liver biopsies.

BACKGROUND: The objective of this study is to assess if there were any changes in liver biopsies after treatment with S-adenosyl-L-methionine(SAMe) in alcoholic liver disease patients. METHODS: Liver biopsies of 14 patients were randomized for SAMe treatment at week 0 (biopsy #1) and at 24 weeks (biopsy #2). Patients received 1.2g of SAMe or placebo by mouth daily and stopped alcohol intake. Biopsies were semi-quantitatively scored for: steatosis, inflammation, necrosis, fibrosis, apoptosis by TUNEL stain, percent fibrosis per square field, smooth muscle actin stain, Kupffer cells, polymorphonuclear leukocytes, lipogranules, lymphocytes, balloon cell formation, Mallory-Denk bodies, and duct metaplasia. RESULTS: Comparing treatment arm to placebo arm, no significant difference was found between biopsy #1 and biopsy #2. However, when both study arms were grouped together, there was decrease in smooth muscle actin stain, where the P-value=0.027. CONCLUSION: Treatment with SAMe did not show a statistically significant difference in the characteristics studied. However, when both the treatment and placebo arm data were grouped together to increase the n and power, there was a decrease in the smooth muscle actin stain, reflecting a decrease in stellate cells activation, likely due to the alcohol abstinence. This study suggests that it may not be beneficial to wait for more definitive treatment, like liver transplant in alcoholic liver disease patients, since the liver tissue remained largely with the same degree of pathology six months out, regardless of treatment.

Case Report: Primary Duodenal Melanoma with Brain Metastasis.

Malignant duodenal tumors can be primary or secondary. Although the most common primary tumor involving the duodenum is an adenocarcinoma, primary malignant melanomas arising in the small intestine are exceedingly rare and remain a controversial clinical entity. In this report, we present a unique case of primary duodenal melanoma with brain metastasis managed successfully by surgical excision, stereotactic radiation, and adjuvant immunotherapy.

Synchronous Bilateral Primary Testicular Tumors With Discordant Histopathology.

Concomitant presentation of histologically distinct bilateral testicular tumors is exceedingly rare. Here we report the case of a 20-year-old male who presented with a left testicular mass. He was found to have bilateral testicular masses on ultrasound and underwent bilateral orchiectomy. Left testicular pathology revealed a mixed germ cell tumor consisting of teratoma, seminoma, and germ cell neoplasia in situ; right testicular pathology revealed two foci of pure seminomas. He is currently on active surveillance and remains in remission at 18-month follow-up. Our case demonstrates the rare occurrence of bilateral primary synchronous testicular tumors with different histopathology in each testis. Despite the rarity of this condition, its treatment is based on standard management of unilateral testicular carcinoma, with the added element of prioritization of one tumor over the other. It is important for clinicians to tailor management for bilateral testicular germ cell tumors according to the most aggressive component.

Association between conflicts of interest and favourable recommendations in clinical guidelines, advisory committee reports, opinion pieces, and narrative reviews: systematic review.

OBJECTIVE: To investigate the association between conflicts of interest and favourable recommendations in clinical guidelines, advisory committee reports, opinion pieces, and narrative reviews. DESIGN: Systematic review. ELIGIBILITY CRITERIA: Studies that compared the association between conflicts of interest and favourable recommendations of drugs or devices (eg, recommending a drug) in clinical guidelines, advisory committee reports, opinion pieces (eg, editorials), or narrative reviews. DATA SOURCES: PubMed, Embase, Cochrane Methodology Register (from inception to February 2020), reference lists, Web of Science, and grey literature. DATA EXTRACTION AND ANALYSIS: Two authors independently extracted data and assessed the methodological quality of the studies. Pooled relative risks and 95% confidence intervals were estimated using random effects models (relative risk >1 indicates that documents with conflicts of interest more often had favourable recommendations than documents with no conflicts of interest). Financial and non-financial conflicts of interest were analysed separately, and the four types of documents were analysed separately (preplanned) and combined (post hoc). RESULTS: 21 studies that analysed 106 clinical guidelines, 1809 advisory committee reports, 340 opinion pieces, and 497 narrative reviews were included. Unpublished data were received for 11 studies (eight full datasets and three summary datasets). 15 studies showed risk of confounding because the compared documents could differ in factors other than conflicts of interest (eg, different drugs used for different populations). The relative risk for associations between financial conflicts of interest and favourable recommendations for clinical guidelines was 1.26 (95% confidence interval 0.93 to 1.69; four studies of 86 clinical guidelines), for advisory committee reports was 1.20 (0.99 to 1.45; four studies of 629 advisory committee reports), for opinion pieces was 2.62 (0.91 to 7.55; four studies of 284 opinion pieces), and for narrative reviews was 1.20 (0.97 to 1.49; four studies of 457 narrative reviews). An analysis of all four types of documents combined supported these findings (1.26, 1.09 to 1.44). In one study that investigated specialty interests, the association between including radiologists as authors of guidelines and recommending routine breast cancer was: relative risk 2.10, 95% confidence interval 0.92 to 4.77; 12 clinical guidelines). CONCLUSIONS: We interpret our findings to indicate that financial conflicts of interest are associated with favourable recommendations of drugs and devices in clinical guidelines, advisory committee reports, opinion pieces, and narrative reviews. Limitations of this review were risk of confounding in the included studies and the statistical imprecision of individual analyses of each document type. It is not certain whether non-financial conflicts of interest influence recommendations. SYSTEMATIC REVIEW REGISTRATION: Cochrane Methodology Review Protocol MR000040.

Hg2+ and Cd2+ interact differently with biomimetic erythrocyte membranes.

In order to characterize the potentially deleterious effects of toxic Hg(2+) and Cd(2+) on lipid membranes, we have studied their binding to liposomes whose composition mimicked erythrocyte membranes. Fluorescence spectroscopy utilizing the concentration dependent quenching of Phen Green SK by Hg(2+) and Cd(2+) was found to be a sensitive tool to probe these interactions at metal concentrations < or =1 microM. We have systematically developed a metal binding affinity assay to screen for the interactions of Hg(2+) or Cd(2+) with certain lipid classes. A biomimetic liposome system was developed that contained four major lipid classes of erythrocyte membranes (zwitterionic lipids: phosphatidylcholine and phosphatidylethanolamine; negatively charged: phosphatidylserine and neutral: cholesterol). In contrast to Hg(2+), which preferentially bound to the negatively charged phosphatidylserine compared to the zwitterionic components, Cd(2+) bound stronger to the two zwitterionic lipids. Thus, the observed distinct differences in the binding affinity of Hg(2+) and Cd(2+) for certain lipid classes together with their known effects on membrane properties represent an important first step toward a better understanding the role of these interactions in the chronic toxicity of these metals.

Retrospective review of pediatric oral lesions from a dental school biopsy service.

UNLABELLED: This report presents a review of the results from 5457 biopsies of patients, 0-16 years of age, received over 15 years at the University of the Pacific School of Dentistry (Pacific Oral and Maxillofacial Pathology Laboratory). PURPOSE: To carry out the largest and most up to date U.S. survey of oral specimens from children. METHOD: The computerized data was retrieved and compiled for age and diagnoses. The lesions were divided by the MIND classification system into 1) Metabolic 2) Inflammatory 3) Neoplastic and 4) Developmental. RESULTS: Inflammatory lesions formed the largest group of biopsies (2758, 51%) followed by Developmental conditions (1928, 35%) and Neoplasms (734, 13%). Dentigerous cysts were the most common lesions, followed by the mucous retention phenomenon (mucocele). The 15 most frequently occurring lesions accounted for 80% of all biopsies. Eight malignancies and 22 benign aggressive tumors were also included. CONCLUSIONS: 1. Pathoses increase with age. 2. Results from our study are similar to most of the other studies. 3. More serious pathoses occur in some countries where there is limited access to care, resulting in patients seeking care only when symptomatic. 4. Oral malignancies are rare, but as with any malignancy, early diagnosis renders a more favorable prognosis.

Large cystic mass in the right atrium: multimodality imaging and pathologic features of a giant interatrial septal aneurysm.

The case demonstrates the use of echocardiography, cardiac computed tomography (CCT) and cardiac magnetic resonance imaging (CMRI) to determine the size, location, anatomic connection, perfusion and hemodynamic significance of a large tumor in the right atrium. The mass was surgically excised and pathology confirmed an ultimate diagnosis of an interatrial septal aneurysm (ISA). Transesophageal echocardiography enhances the sensitivity of detecting ISA and is the initial test of choice when an ISA is suspected on transthoracic echocardiography. In addition, the use of CCT and CMRI helps further define the anatomy, perfusion and tissue characteristics of the mass. Our case demonstrates the utility of multimodality non-invasive imaging to characterize an unusual tumor leading to a successful surgical treatment and a corresponding pathologic diagnosis of a large, cystic aneurysm of the interatrial septum.

Excited state photoreaction between the indole side chain of tryptophan and halocompounds generates new fluorophores and unique modifications.

Photoreaction of indole containing compounds with chloroform and other trichlorocompounds generates products with redshifted fluorescence. In proteins, this reaction can be used for the fluorescent detection of proteins. Little characterization of products generated through the photochemical reaction of indoles with halocompounds has been done, yet is fundamental for the development of other fluorophores, protein labeling agents, and bioactive indole derivatives. Here, we have characterized which isomers form in the photoreaction between tryptophan and chloroform using (1)H-NMR of tryptophan and methylated derivatives to reveal that the two major products that are formed result from modification at the 4- and 6-carbon positions of the indole ring. Reaction at position 6 generates 6-formyl tryptophan and the reaction at position 4 generates an imine because the formyl derivative that is initially formed reacts further with the tryptophan amine group. The spectroscopic properties and product molecular weights of photoproducts formed from photoreaction of tryptophan with other trihalo and monohalocompounds are also determined. The indole ring of tryptophan can be modified with various additions from halocompounds, including the addition of labels to the indole ring via methylene groups. This opens possibilities for generating novel tryptophan based fluorophores and protein labeling strategies using this photochemistry.

Hg- and Cd-induced modulation of lipid packing and monolayer fluidity in biomimetic erythrocyte model systems.

The public health consequences that are associated with the low level exposure of various human populations to Cd(2+) and Hg(2+) are incompletely understood. In order to assess if interactions between these inorganic pollutants and erythrocyte biomembranes may contribute to their chronic toxicity, we have used a Langmuir trough to probe the effect of HgCl2 and CdCl2 on the packing and elasticity properties of biomimetic lipid monolayers using different lipid mixtures. These lipid films were deposited at room temperature on a biologically relevant subphase (1mM phosphate, 100mM NaCl at pH 7.4) in the absence and presence of 100µM HgCl2, CdCl2 and 1:1 mixtures thereof. The interactions of heavy metals with the lipids were monitored as changes in the surface pressure (π)-area (A) isotherms. In addition, metal induced changes to the elastic properties of the model systems were analyzed by area and compressibility data of phosphatidylcholine (PC) systems containing 0, 15, 30, 45 and 100% phosphatidylethanolamine (PE) and phosphatidylserine (PS). These mixtures revealed changes in lateral lipid packing as indicated by area expansion as well as enhanced film rigidity. The results demonstrate that both heavy metals affected the various lipid matrices, but metal mixtures showed the strongest impact. Based on these data, the adverse interaction of Hg(2+) and Cd(2+) with lipid bilayer membranes is identified as a feasible mechanism by which these toxic metals exert toxicity in mammalian cells. Interestingly, these metal interactions were found to depend on the lipid composition.