Is Vancomycin MIC “Creep” Method Dependent? Analysis of Methicillin-Resistant Staphylococcus aureus Susceptibility Trends in Blood Isolates from North East Scotland from 2006 to 2010

This study investigated "creep" in vancomycin and daptomycin MICs among methicillin-resistant Staphylococcus aureus (MRSA) isolates from blood cultures over a 5-year period in a hospital in the United Kingdom, using different susceptibility testing methods. Trends in vancomycin and daptomycin susceptibility were evaluated by using Etest performed prospectively on isolates in routine clinical practice from December 2007 to December 2010 (n = 102). Comparison was made to results from prospective testing of subcultures at the Scottish MRSA Reference Laboratory, using an automated system (Vitek 2) and retrospective testing (Etest and CLSI reference broth microdilution [BMD] method) of stored isolates from 2006 to 2010 (n = 208). Spearman's rank correlations revealed a significant increase in vancomycin MIC (P = 0.012) and a significant decrease in daptomycin MIC (P = 0.03) by year of study for Etest results from the time of isolation. However, neither trend was replicated in MICs from automated or retrospective testing. The Friedman test revealed a significant difference between vancomycin MICs obtained from the same samples by different testing methods (χ(2) [3 degrees of freedom] = 97; P < 0.001). MICs from automated testing and Etest analysis of stored isolates were significantly lower than those from Etest analysis at the time of isolation for both antibiotics (P < 0.001). Effects of storage on the MIC appeared within the first 6 months of storage. Inconsistent evidence on vancomycin MIC creep and the relevance of the MIC to clinical outcome may arise from differences in susceptibility testing methods, including storage of isolates. There is a need to standardize and streamline susceptibility testing of vancomycin against MRSA.     

Antibiotic Susceptibility and Phage Typing of Methicillin-Resistant and -Sensitive Staphylococcus aureus Clinical Isolates at Three Periods During 1991–1997

 The aim of the study presented here was to evaluate the antibiotic susceptibility of Staphylococcus aureus over a 7-year period. A total of 2,122 clinical isolates of Staphylococcus aureus were collected from hospitalized patients at 3-year intervals during the period 1991–1997. The prevalence of methicillin-resistant isolates was 41.6%, 38.2% and 36% in 1991, 1994 and 1997, respectively; all of these isolates were sensitive to vancomycin. Over the study period, resistance to pristinamycin and fusidic acid increased slightly and resistance to imipenem, rifampicin and amikacin increased greatly, while resistance to trimethoprim/sulfamethoxazole decreased. For methicillin-sensitive Staphylococcus aureus isolates, significantly increased resistance was observed against amikacin only. Phage typing was conducted using the international set of phages. All of the isolates that were sensitive to group I, group II, or group V phages were sensitive to methicillin. Of the isolates that were sensitive to group III phages, 96% were methicillin resistant, and 70.5% of them were sensitive to phages 75 and 85.     

Analysis of the Clinical Characteristics and Antibiotics Resistance of Community-acquired Methicillin-resistant Staphylococcus aureus

Methicillin resistant Staphylococcus aureus (MRSA) is animportant nosocomial pathogen, and its infections withhospital based outbreak occur worldwide [1]. The princi pal risk factors identified for the acquisition of MRSA ininpatients of hospitals in…     

Analysis of the Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrum of Staphylococcus aureus Identifies Mutations That Allow Differentiation of the Main Clonal Lineages

Nosocomial infections involving epidemic methicillin-resistant Staphylococcus aureus (MRSA) strains are a serious problem in many countries. In order to analyze outbreaks, the infectious isolates have to be typed; however, most molecular methods are expensive or labor-intensive. Here, we evaluated matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) of cell extracts for the molecular characterization of S. aureus strains. The peak patterns of 401 MRSA and methicillin-susceptible S. aureus (MSSA) strains, including clinical and laboratory strains, were analyzed. Database searches indicated the peptides that were represented by the corresponding peaks in the spectra. The identities of the peptides were confirmed by the sequencing of mutants, the expression of antisense RNA fragments that resulted in the knockdown of the peptide of interest and the concomitant loss of the signal, or tandem MALDI-TOF MS (MALDI-TOF/TOF MS). It was shown that the signals derive mainly from stress proteins and ribosomal proteins. Peak shifts that differentiate the main S. aureus clonal complexes CC5, CC22, CC8, CC45, CC30, and CC1 correlate to point mutations in the respective genes. Retrospective typing of an MRSA outbreak showed that it is possible to differentiate unrelated MSSA, MRSA, and borderline resistant S. aureus (BORSA) strains isolated from health care workers. In conclusion, this method allows for the detection of the epidemic lineages of S. aureus during species identification by MALDI-TOF MS analysis.     

Antimicrobial Susceptibility of Respiratory Isolates of Enterobacteriaceae and Staphylococcus aureus in Italy: Incidence and Trends Over the Period 1997–1999

The antibiotic susceptibility of members of the family Enterobacteriaceae and of Staphylococcus aureus strains isolated from the respiratory tract was assessed over the period 1997–1999 as part of the Italian Epidemiological Observatory survey sponsored by the SmithKline Foundation. A standardised method was used to determine the MICs of 22 antibiotics against isolates of Klebsiella pneumoniae (n=870), Escherichia coli (n=684), Enterobacter cloacae (n=342), Enterobacter aerogenes (n=187) and Serratia marcescens (n=135) as well as the MICs of 11 antibiotics against isolates of Staphylococcus aureus (n=1,606). Overall, the susceptibility rate of Enterobacteriaceae isolates was ≥90% to 5 agents (meropenem, imipenem, amikacin, cefepime and gentamicin); 89–80% to 2 agents (ciprofloxacin and tobramycin); and <80% to 11 agents (cefotaxime, piperacillin-tazobactam, trimethoprim-sulfamethoxazole, cefetamet, ceftriaxone, ceftazidime, aztreonam, ticarcillin-clavulanate, tetracycline, piperacillin, cefuroxime, chloramphenicol, ticarcillin, amoxicillin-clavulanate and amoxicillin). During the 3-year monitoring period, antibiotic susceptibility increased in Klebsiella pneumoniae against amoxicillin-clavulanate, in Escherichia coli against third-generation cephalosporins and aztreonam, in Enterobacter aerogenes against amoxicillin and piperacillin-tazobactam and in Serratia marcescens against most of the antibiotics. In contrast, Enterobacter cloacae showed a tendency to develop resistance to cefetamet, amikacin and ciprofloxacin. Of the total number of Staphylococcus aureus strains, 38% were methicillin resistant. Nearly 80% of the methicillin-resistant strains displayed a multiresistance pattern (additional resistance to 2 or more non-beta-lactam antibiotics). Rates of susceptibility of particular species (Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus) were compared using strains from different geographical areas of Italy (northern, central and southern) and from different nosocomial areas (outpatients, intensive care unit [ICU] inpatients, non-ICU inpatients). Susceptibility of Klebsiella pneumoniae to several antibiotics was lower in southern Italy, whereas the incidence of methicillin-resistant strains was higher in northern and central Italy. The susceptibility of Escherichia coli was similar in all three areas. No significant differences in susceptibility of Klebsiella pneumoniae or Escherichia coli were found between strains from inpatients and outpatients or from inpatients admitted to ICU and non-ICU units. The incidence of methicillin-resistant Staphylococcus aureus was higher in ICU inpatients (52%) than in non-ICU inpatients (38%) and lower in outpatients (19%) than in inpatients. Electronic Publication     

What Is the mechanism of SIDS? Clues from epidemiology

The cause of sudden infant death syndrome (SIDS) is unknown. Many mechanisms have been postulated, although thermal stress, rebreathing of expired gases and infection/inflammation seem the most viable hypotheses for the causation of SIDS. Deaths from SIDS have reduced dramatically following the recommendation not to place infants to sleep prone. Epidemiological data have shown that prone sleeping position is more risky in winter, colder latitudes, higher altitudes, if the infant is unwell or has excessive bedding or clothing. This suggests prone sleeping position involves either directly or indirectly a thermal mechanism. SIDS caused by an infective/inflammatory mechanism might be associated with deaths occurring during the night. Rebreathing of expired gases, airway obstruction, long QT syndrome and other genetic conditions may explain a small number of sudden unexpected deaths in infancy. © 2009 Wiley Periodicals, Inc. Dev Psychobiol 51: 215–222, 2009     

Genetic Covariation Between the Author Recognition Test and Reading and Verbal Abilities: What Can We Learn from the Analysis of High Performance?

The Author Recognition Test (ART) measures print exposure and is a unique predictor of phonological and orthographic processes in reading. In a sample of adolescent and young adult twins and siblings (216 MZ/430 DZ pairs, 307 singletons; aged 11–29 years) ART scores were moderately heritable (67%) and correlated with reading and verbal abilities, with genes largely accounting for the covariance. We also examine whether high (and low) (i.e. 1SD above the mean) represents a quantitative extreme of the normal distribution. Heritability for high ART was of similar magnitude to the full sample, but, a specific genetic factor, independent from both low ART performance and high reading ability, accounted for 53–58% of the variance. This suggests a distinct genetic etiology for high ART ability and we speculate that the specific genetic influence is on orthographical processing, a critical factor in developing word recognition skills. Edited by Robert Plomin.     

Population Analysis and Epidemiological Features of Inhibitor-Resistant-TEM-β-Lactamase-Producing Escherichia coli Isolates from both Community and Hospital Settings in Madrid,Spain

Punctual mutations in the TEM-1 or TEM-2 gene may lead to inhibitor-resistant-TEM (IRT) β-lactamases with resistance to β-lactam-β-lactamase inhibitor combinations and susceptibility to cephalosporins. The aim of this work was to analyze the current epidemiology of IRT β-lactamases in contemporary clinical Escherichia coli. Isolates were prospectively collected in our hospital (2007 and 2008) from both outpatients (59.8%) and hospitalized patients (40.2%). The genetic relationships of the isolates were determined by XbaI pulsed-field gel electrophoresis, multilocus sequence typing, and phylogenetic group analysis. IRT genes were sequenced and located by hybridization, and the incompatibility group of the plasmids was determined. From a total of 3,556 E. coli isolates recovered during the study period, 152 (4.3%) showed reduced susceptibility to amoxicillin-clavulanate, with 18 of them producing IRT enzymes (0.5%). These were mostly recovered from urine (77.8%). A high degree of IRT diversity was detected (TEM-30, -32, -33, -34, -36, -37, -40, and -54), and the isolates were clonally unrelated but were mostly associated with phylogenetic group B2 (55.5%). In 12 out of 16 (75%) isolates, the bla_IRT gene was plasmid located and transferred by conjugation in 9 of them, whereas chromosomal localization was demonstrated in 4 isolates (25%). The sizes of the plasmids ranged from 40 kb (IncN) to 100 kb (IncFII, IncFI/FIIA), and they showed different restriction patterns by restriction fragment length polymorphism analysis. Unlike extended-spectrum β-lactamase producers, the frequency of IRT producers remains low in both community and hospital settings, with most of them causing urinary tract infections. Although bla_IRT genes are mainly associated with plasmids, they can be also located in the chromosome. Despite this situation, clonal expansion and/or gene dispersion was not observed, denoting the independent emergence of these enzymes.Resistance to β-lactam-β-lactamase inhibitor combinations in Escherichia coli may be due to different mechanisms, including TEM-1 penicillinase hyperproduction, constitutive AmpC overproduction or plasmid AmpC production, OXA-type β-lactamase production, permeability deficiencies involving OmpF and/or OmpC porins, inhibitor-resistant TEM (IRT)- and complex mutant TEM (CMT)-like ß-lactamase production, and more recently, carbapenemase production (4).IRT enzymes comprise a group of plasmid-encoding variants of TEM-1 and TEM-2 with decreased affinities for amino-, carboxy-, and ureidopenicillins and altered interaction with class A ß-lactamase inhibitors (6). IRT-producing isolates remain susceptible to cephalosporins, cephamycins, carbapenems, and in most cases, piperacillin-tazobactam. They are usually resistant to ampicillin-sulbactam and intermediate or resistant to amoxicillin-clavulanate combinations. IRT enzymes have previously been reported in different organisms, such as E. coli, Klebsiella spp., Enterobacter cloacae, Proteus mirabilis, Citrobacter freundii, and Shigella sonnei (4); but there are only a few recent epidemiological studies concerning these enzymes. Moreover, the population structure of IRT-producing E. coli isolates has not been addressed using a multilocus sequence typing (MLST) technique.The aim of the present work was to analyze the current epidemiology of IRT β-lactamases in contemporary E. coli isolates with reduced susceptibility to amoxicillin-clavulanate recovered in our hospital in 2007 and 2008.     

Is nasal carriage of Staphylococcus aureus the main acquisition pathway for surgical-site infection in orthopaedic surgery?

The endogenous or exogenous origin of Staphylococcus aureus, responsible for orthopaedic surgical-site infections (SSI), remains debated. We conducted a multicentre prospective cohort study to analyse the respective part of exogenous contamination and endogenous self-inoculation by S. aureus during elective orthopaedic surgery. The nose of each consecutive patient was sampled before surgery. Strains of S. aureus isolated from the nose and the wound, in the case of SSI, were compared by antibiotypes or pulsed-field gel electrophoresis (PFGE). A total of 3,908 consecutive patients undergoing orthopaedic surgery were included. Seventy-seven patients developed an SSI (2%), including 22 related to S. aureus (0.6%). S. aureus was isolated from the nose of 790 patients (20.2%) at the time of surgery. In the multivariate analysis, S. aureus nasal carriage was found to be a risk factor for S. aureus SSI in orthopaedic surgery. However, only nine subjects exhibiting S. aureus SSI had been found to be carriers before surgery: when compared, three pairs of strains were considered to be different and six similar. In most cases of S. aureus SSI, either an endogenous origin could not be demonstrated or pre-operative nasal colonisation retrieved a strain that was different from the one recovered from the surgical site     

Characterization of tetracycline and methicillin resistant Staphylococcus aureus strains in a Spanish hospital: Is livestock-contact a risk factor in infections caused by MRSA CC398?

Tetracycline-resistance (Tet^R) has been postulated as a marker of the livestock-associated methicillin-resistant Staphylococcus aureus (MRSA) lineage CC398. Objectives of the study: to determine the spa-types and assigned MLST clonal complexes (CCs) among all 98 MRSA-Tet^R strains recovered during 2011–2012 (from different patients) in a Spanish Hospital, analyzing the possible correlation with livestock-contact of the patients. All 98 strains were assigned to 9 CCs: CC398 (60.2%), CC1 (19.4%), CC5 (12.2%), and other CCs (8.2%). The 98 patients were classified into three groups: (A) contact with livestock-animals (n = 25); (B) no-contact with livestock-animals (n = 42); (C) no information about animal contact (n = 31). A significant higher percentage of CC398 strains was obtained in group A (76%) than in group B (50%) (p < 0.05), being the percentage in group C of 61.3%. Most of MRSA-Tet^R-CC398 strains presented a multi-resistance phenotype, including erythromycin, clindamycin, and ciprofloxacin, and the most prevalent detected genes were tet(M) and erm(C). Three strains presented the phenotype macrolide-susceptibility/lincosamide-resistance and contained the vga(A) gene. MRSA-CC1 strains showed higher percentages of erythromycin/clindamycin resistance (95%/89%) than MRSA-CC398 strains (58%/63%), and this resistance was usually mediated by erm(C) gene. Most of MRSA-CC5 strains showed resistance to ciprofloxacin, tobramycin/kanamycin and erythromycin. None of the strains presented the genes lukF/lukS-PV, tsst-1, eta, etb or etd. All MRSA-CC398 strains lacked the genes of the immune-evasion-cluster, but MRSA-CC1 strains carried these genes (type E). In conclusion, although MRSA CC398 is detected in a significant higher proportion in patients with livestock-contact; its detection in people without this type of contact also indicates its capacity for human-to-human transmission.     

Genetic causes of rare and common epilepsies: What should the epileptologist know?

In past decades, the identification of genes involved in epileptic disorders has grown exponentially. The pace of gene identification in epileptic disorders began to accelerate in the late 2000s, driven by new technologies such as molecular cytogenetics and next-generation sequencing (NGS). These technologies have also been applied to genetic diagnostics, with different configurations, such as gene panels, whole-exome sequencing and whole-genome sequencing. The clinician must be aware that any technology has its limitations and complementary techniques must still be used to establish a diagnosis for specific diseases. In addition, increasing the amount of genetic information available in a larger patient sample also increases the need for rigorous interpretation steps, when taking into account the clinical, electroclinical, and when available, functional data. Local, multidisciplinary discussions have proven valuable in difficult diagnostic situations, especially in cases where precision medicine is being considered. They also serve to improve genetic counseling in complex situations.In this article, we will briefly review the genetic basis of rare and common epilepsies, the current strategies used for molecular diagnosis, including their limitations, and some pitfalls for data interpretation, in the context of etiological diagnosis and genetic counseling.     

What is the optimal medical management of infertility and minor endometriosis? Analysis and future prospects

By asking the question 'What is the optimal medical management of infertility and minor endometriosis?', it is assumed that endometriosis has a detrimental effect on fertility. The published data suggest that oocyte dysfunction may contribute to infertility associated with endometriosis. This is expressed as a reduction in fertilization and implantation rates; implantation rates to a lesser extent, though still significant. Other evidence for oocyte dysfunction exists, not all of which is consistent. Suppression of ovulation and menstruation to treat endometriosis-associated infertility is not effective. However, ovulation induction, perhaps with intrauterine insemination, does result in pregnancy rates higher than in control cycles, while stimulated IVF success rates are equivalent to those of other diagnostic groups. For the future, angiogenesis is critical to the support of endometriotic deposits and targeted therapies are promised; their role in improving fertility has not yet been explored.     

Using a 48-hour delay from admission to the first positive culture without any other consideration: an accurate method to differentiate acquired and imported methicillin-resistant Staphylococcus aureus?

To differentiate imported and acquired strains of methicillin-resistant Staphylococcus aureus (MRSA), a 48-hour delay from hospital admission to the first MRSA-positive culture is usually considered. To assess if taking into account this delay without any other consideration is an accurate method, we defined 3 situations for whom we considered the MRSA acquisition status as questionable. The other situations were defined as either acquired MRSA or imported MRSA. We determined the acquisition status of MRSA (acquired, imported, or questionable) isolated during a 20-month period by considering or not considering screening samples performed on admission. The ratio "imported MRSA/acquired MRSA" (I/A) was calculated according to (1) the consideration of MRSA with questionable status as imported or acquired, and (2) the consideration of screening samples or not in the calculation of the ratio. The acquisition status in our hospital was questionable in 3.6% of patients when all samples were considered and in 12,0% when only clinical samples were taken into account (p = 0,01). The ratio I/A was 4-fold higher by considering both clinical and screening cultures and questionable status as imported than by considering only clinical samples and questionable status as acquired. Using a 48-hour delay without any other consideration is probably an accurate method to differentiate acquired and imported MRSA when a selective screening programme at admission in operational. Conversely, this definition seems to be more hazardous in the absence of screening.     

Multilocus Sequence Typing of Candida tropicalis Shows the Presence of Different Clonal Clusters and Fluconazole Susceptibility Profiles in Sequential Isolates from Candidemia Patients in S?o Paulo,Brazil

The profiles of 61 Candida tropicalis isolates from 43 patients (28 adults and 15 children) diagnosed with candidemia at two teaching hospitals in São Paulo, Brazil, were characterized by multilocus sequence typing (MLST). For the 14 patients who had bloodstream infections, 32 isolates were serially collected from their blood and/or catheters. Thirty-nine diploid sequence types (DSTs) were differentiated. According to the C. tropicalis MLST database (http://pubmlst.org/ctropicalis/), 36 DSTs and 23 genotypes identified from the 61 isolates had not previously been described. This report represents the first study to characterize sequential isolates of C. tropicalis from candidemia cases in South America. Microvariation in a single gene was found in the sequential isolates from 7 patients. The main polymorphisms occurred in the alleles of the XYR1 gene, specifically at nucleotide positions 215, 242, and 344. Macrovariation in six gene fragments was detected in the isolates from 3 patients. eBURST analysis added two new groups to this study (groups 6 and 18). Additionally, susceptibility tests indicate that 3 isolates were resistant to fluconazole. No correlation was found between the DSTs and susceptibility to fluconazole and/or selective antifungal pressure. Two patients were sequentially infected with resistant and susceptible strains. MLST is an important tool for studying the genetic diversity of multiple/sequential isolates of patients with candidemia, allowing the comparison of our data with those from other regions of the world, as well as allowing an analysis of the genetic relationship among several clones in sequential isolates from the same or different candidemia patient sites (blood or catheter).     

Emergence of SCCmec Type IV and SCCmec Type V Methicillin-Resistant Staphylococcus aureus Containing the Panton-Valentine Leukocidin Genes in a Large Academic Teaching Hospital in Central Switzerland: External Invaders or Persisting Circulators?

The hospital epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) has changed in the past few years due to the encroachment of community-associated MRSA (CA-MRSA) strains into health care settings. MRSA strains that were isolated during a 2-year period from patients of the Luzerner Kantonsspital were analyzed to elucidate their epidemiology. Moreover, extended surveillance of individuals who were contacts of those patients was carried out for 6 months to identify the routes of spread and to assess the quality of the infection control measures used in our setting. Patient data were collected to distinguish CA-MRSA strains from health care-associated MRSA (HA-MRSA) strains by epidemiological criteria, as defined by the Centers for Disease Control and Prevention (CDC). On the basis of the CDC definition, the majority of the strains were considered to be HA-MRSA. However, 87% of them belonged to staphylococcal cassette chromosome mec (SCCmec) types IV and V, which are traditionally associated with CA-MRSA. Surprisingly, classical nosocomial SCCmec types I and II represented a minority, whereas SCCmec type III was completely absent. By PFGE analysis, four predominant clonal lineages and 21 highly variable sporadic genotypes were detected. Twenty-eight percent of the MRSA strains studied carried the genes encoding the Panton-Valentine leukocidin (PVL), of which 21% and 83% were associated with SCCmec types IV and V, respectively. Among 289 contact individuals screened for MRSA carriage throughout the extended surveillance, a single secondary patient was discovered. The possibility of nosocomial transmission could be excluded. The high proportions of SCCmec type IV and V strains as well as PVL-positive strains suggest strong infiltration of CA-MRSA into our institution. Moreover, the low endemic prevalence of MRSA demonstrates that current infection control measures are sufficient to limit its spreading and the emergence of large epidemic outbreaks.Methicillin-resistant Staphylococcus aureus (MRSA), one of the most common nosocomial pathogens, usually carries genetic elements that confer resistance to a broad range of antibiotics (2, 25). Methicillin resistance in staphylococci is based on the expression of a modified penicillin-binding protein (PBP), PBP 2a, which is encoded by the mecA gene. This gene is located on the staphylococcal cassette chromosome mec (SCCmec), a mobile genetic element integrated in the chromosome (6, 23) which also carries the genes for specific recombinases (ccr) necessary for its excision and integration (24). On the basis of the mec and ccr complex sequences, SCCmec is classified into types I to VII (1, 25). Previous studies showed that health care-associated (HA) MRSA (HA-MRSA) infections are generally caused by multidrug-resistant strains harboring SCCmec types I, II, and III but rarely SCCmec type IV (26, 38, 47, 52). On the other hand, community-associated (CA) MRSA (CA-MRSA) strains carry SCCmec type IV, V, or VII; are commonly susceptible to the majority of non-β-lactam antibiotics; frequently produce the Panton-Valentine leukocidin (PVL); and differ in their pulsed-field gel electrophoresis (PFGE) patterns (38). Recent studies have reported that CA-MRSA strains are spreading in hospital settings and are replacing traditional HA-MRSA strains (44, 46, 47, 52).Although the average prevalence of MRSA strains in Switzerland has been lower than that in the surrounding countries—between 0 and 6% of the first isolates of S. aureus recovered, except in Geneva, where the rate is 20% (2, 17, 19)—the incidence of MRSA infections is increasing. Even though there are epidemiological data for MRSA in Switzerland (2, 17, 20, 44, 47), the extent of the problem in the central part of Switzerland is unknown. In this study, we aimed at assessing the frequency, diversity, and clonal distribution of MRSA strains that were isolated at the Luzerner Kantonsspital (LUKS) between January 2007 and December 2008, in order to elucidate their origin and ways of circulation within our institution. Moreover, in a 6-month prospective study, we evaluated the effects of extended health care-associated hygienic measures on nosocomial MRSA transmission.     

What can we learn from the errors in the frozen section diagnosis of pulmonary carcinoid tumors? An evidence-based approach

The intraoperative diagnosis of pulmonary neuroendocrine tumors can be difficult. Frozen section diagnosis was requested on 87 neuroendocrine tumors including 58 typical carcinoids, 8 atypical carcinoids, 18 large cell neuroendocrine carcinomas, and 3 small cell carcinomas from 2405 patients that underwent frozen section diagnosis at Cedars-Sinai Medical Center from 2002 to 2007. The deferral and error rate for carcinoid tumors was 4.13% and 7.5%, respectively, and resulted in 4 unnecessary lobectomies and 2 second thoracotomies. The most common errors included misdiagnoses as lymphoma, squamous carcinoma or metastasis from breast carcinoma. Thirty one pathologic features were evaluated in the 66 carcinoid tumors and 10 frozen sections each of lymphoma, squamous cell carcinoma, and metastatic breast carcinoma. Seven pathologic features were significant by chi square test at P > .05. Positive likelihood ratios identified 11 pathologic features that were useful for the diagnosis of carcinoid tumor from other neoplasms. The applicability of the 11 pathologic features was tested with a group of pathologists, resulting in significant improvement in diagnostic accuracy as measured by pre and posttests. The value of evidence-based pathology and Bayesian statistics to evaluate complex differential diagnoses in pathology is discussed.