Interobserver agreement of a probabilistic approach to reporting breast fine-needle aspirations on ThinPrep

We have previously demonstrated the accuracy and reproducibility of a probabilistic/categorical approach for reporting breast fine-needle aspiration (FNA). However, the interobserver agreement in the application of this approach has not been assessed. Twenty breast FNA cases (each on one ThinPrep slide) were pulled from the cytology files of Beth Israel Deaconess Medical Center. The cases included benign epithelial proliferative lesions (6), DCIS (4), and infiltrating carcinoma (10), as shown by subsequent histology. Six pathologists with 14-25 yr of experience in interpreting breast FNA and 0-8 yr of experience with ThinPrep preparations rendered diagnoses according to the probabilistic approach. The kappa statistic for the unremarkable/proliferative, atypical, suspicious, and positive categories were 0.64, 0.08, 0.43, and 0.75, respectively (P < 0.001 for all except for the atypical category [P = 0.09]). Spearman's rho correlating the individual pathologist's diagnosis and the histologic diagnosis ranged from 0.51 (P = 0.02) to 0.78 (P < 0.0001). This was not correlated with the pathologists' years of experience interpreting breast FNA (P = 1.0) or with their years using ThinPrep preparations for breast FNA (P = 0.96). In conclusion, the interobserver agreement was excellent for the positive category in the probabilistic approach, poor for the atypical category, and fair to good for the other categories. The specific level of experience interpreting breast FNA or using ThinPrep among experienced pathologists did not seem to influence their accuracy in reporting the cases in our study.     

ThinPrep vs. conventional smear cytologic preparations in analyzing fine-needle aspiration specimens from palpable breast masses.

Limited data exist concerning the cellular features of the ThinPrep (Cytyc Corp., Boxborough, MA) technique in the analysis of breast fine-needle aspiration specimens. Therefore, we analyzed a series of 75 surgically excised palpable breast masses and compared ThinPrep and conventional smear fine-needle aspiration preparations. Each mass was aspirated twice. The first sample was used for two alcohol-fixed conventional smears, and the second sample was rinsed into CytoLyt (Cytyc Corp., Boxborough, MA) solution for processing into a ThinPrep slide. The paired slides were separated and independently analyzed for adequacy, overall cellularity, single epithelial cells (absent, rare, moderate, or numerous), epithelial architecture (sheets or three-dimensional clusters), myoepithelial cells and stripped bipolar nuclei (present or absent), and nuclear detail (poor, satisfactory, or excellent). Each sample was classified as negative, negative consistent with fibroadenoma, atypical favoring benign, atypical favoring malignant, or positive for malignant cells. The 75 breast masses included 32 carcinomas and 43 benign lesions. Four conventional smears and one ThinPrep were unsatisfactory. Significantly, more conventional smears were limited by drying artifact (9 vs. 0). ThinPrep aspirates of carcinomas had better nuclear detail (P = 0.03) and greater cellularity (P = 0.05). ThinPrep aspirates of benign masses had greater epithelial cellularity (P = 0.007) and better nuclear detail (P < 0.001), and more specimens had myoepithelial cells (P = 0.007). The ThinPrep interpretation classified 29 of 32 carcinomas (91%) as positive and three as atypical favoring malignant (sensitivity = 100%). The conventional smear interpretation classified 28 of 31 carcinomas (90%) as positive and three as atypical favoring malignant (sensitivity = 100%). The ThinPrep interpretation classified 42 benign lesions as negative (23 cases), negative consistent with fibroadenoma (8 cases), atypical favoring benign (10 cases), and atypical favoring malignant (1 case) (specificity = 74%). The conventional smear interpretation classified 40 benign lesions as negative (25 cases), negative consistent with fibroadenoma (12 cases), and atypical favoring benign (3 cases) (specificity = 93%). ThinPrep was less specific, but the difference was not statistically significant (P = 0.065). In summary, ThinPrep aspirates had greater cellularity and better nuclear detail than conventional smears, and were just as sensitive in identifying the carcinomas. The difference in specificity between the two techniques was not statistically significant (P = 0.065). Diagn. Cytopathol. 1999;21:137-141.     

Comparative analysis of Shwachman‐Diamond syndrome to other inherited bone marrow failure syndromes and genotype–phenotype correlation

Hashmi SK, Allen C, Klaassen R, Fernandez CV, Yanofsky R, Shereck E, Champagne J, Silva M, Lipton JH, Brossard J, Samson Y, Abish S, Steele M, Ali K, Dower N, Athale U, Jardine L, Hand JP, Beyene J, Dror Y. Comparative analysis of Shwachman‐Diamond syndrome to other inherited bone marrow failure syndromes and genotype–phenotype correlation. Our knowledge of the phenotypes of inherited bone marrow failure syndromes (IBMFSs) derives from case reports or case series in which only one IBMFS was studied. However, the substantial phenotypic overlap necessitates comparative analysis between the IBMFSs. Shwachman–Diamond syndrome (SDS) is an IBMFS that the appreciation of what comprises its clinical phenotype is still evolving. In this analysis we used data on 125 patients from the Canadian Inherited Marrow Failure Study (CIMFS), which is a prospective multicenter population‐based study. Thirty‐four cases of SDS patients were analyzed and compared to other patients with the four most common IBMFSs on the CIMFS: Diamond Blackfan anemia, Fanconi anemia (FA), Kostmann/severe congenital neutropenia and dyskeratosis congenita (DC). The diagnosis of SDS, FA and DC was often delayed relative to symptoms onset; indicating a major need for improving tools to establish a rapid diagnosis. We identified multiple phenotypic differences between SDS and other IBMFSs, including several novel differences. SBDS biallelic mutations were less frequent than in previous reports (81%). Importantly, compared to patients with biallelic mutations, patients with wild type SBDS had more severe hematological disease but milder pancreatic disease. In conclusion, comprehensive study of the IBMFSs can provide useful comparative data between the disorders. SBDS‐negative SDS patients may have more severe hematological failure and milder pancreatic disease.     

Initial combination therapy with saxagliptin and metformin provides sustained glycaemic control and is well tolerated for up to 76 weeks

Aim: To assess the efficacy and safety of saxagliptin + metformin initial combination therapy compared with saxagliptin or metformin alone over 76 weeks (24‐week short‐term + 52‐week long‐term extension) in treatment‐naÏve type 2 diabetes mellitus patients with inadequate glycaemic control. Methods: In this phase 3, parallel‐group, double‐blind, active‐controlled study, 1306 patients 18–77 years of age (HbA1c 8.0–12.0%) were randomized to saxagliptin 5 mg + 500 mg metformin, saxagliptin 10 mg + 500 mg metformin, saxagliptin 10 mg + placebo or 500 mg metformin + placebo. Blinded metformin was titrated during weeks 1–5 of the short‐term treatment period in 500 mg/day increments to 2000 mg/day maximum in the metformin‐based treatment groups. No titration of metformin was permitted during the long‐term treatment period. A total of 888 patients completed the study (76 weeks), 613 without being rescued. Changes in HbA1c, fasting plasma glucose, 120‐min postprandial glucose (PPG) and PPG‐area under the curve (AUC) from baseline to week 76 were analysed using a repeated‐measures model. Results: At 76 weeks, adjusted mean changes from baseline HbA1c (95% CI) for saxagliptin 5 mg + metformin, saxagliptin 10 mg + metformin, saxagliptin 10 mg and metformin were ?2.31 (?2.44, ?2.18), ?2.33 (?2.46, ?2.20), ?1.55 (?1.70, ?1.40) and ?1.79% (?1.93, ?1.65), respectively (post hoc and nominal p < 0.0001 vs. metformin and saxagliptin monotherapies for saxagliptin 5 mg + metformin and saxagliptin 10 mg + metformin). The proportions of patients requiring rescue or discontinuation for insufficient glycaemic control were lower for saxagliptin + metformin than for either monotherapy. Little or no attenuation in PPG‐AUC or 120‐min PPG was observed between weeks 24 and 76 for saxagliptin + metformin, indicating persistent efficacy. Adverse event rates were similar across groups; hypoglycaemic events occurred at a low frequency. Conclusion: Saxagliptin + metformin initial combination therapy was well tolerated and produced sustained glycaemic control for up to 76 weeks, with greater improvements in glycaemic parameters compared with either drug alone.     

Carney Complex: case report and review

Carney complex is a very rare multiple neoplasia syndrome with cardiac, cutaneous, and neural tumours with a variety of pigmented lesion of skin. We are reporting a rare case of carney complex in which left atrial myxoma with superficial angiomyxoma, giant cell tumour of bone and lentigines showed a unique association. This patient underwent successful surgical excision of left atrial myxoma under cardiopulmonary bypass.     

Failure of collateral blood flow is associated with infarct growth in ischemic stroke

Changes in collateral blood flow, which sustains brain viability distal to arterial occlusion, may impact infarct evolution but have not previously been demonstrated in humans. We correlated leptomeningeal collateral flow, assessed using novel perfusion magnetic resonance imaging (MRI) processing at baseline and 3 to 5 days, with simultaneous assessment of perfusion parameters. Perfusion raw data were averaged across three consecutive slices to increase leptomeningeal collateral vessel continuity after subtraction of baseline signal analogous to digital subtraction angiography. Changes in collateral quality, Tmax hypoperfusion severity, and infarct growth were assessed between baseline and days 3 to 5 perfusion–diffusion MRI. Acute MRI was analysed for 88 patients imaged 3 to 6 hours after ischemic stroke onset. Better collateral flow at baseline was associated with larger perfusion–diffusion mismatch (Spearman''s Rho 0.51, P<0.001) and smaller baseline diffusion lesion volume (Rho −0.70, P<0.001). In 30 patients without reperfusion at day 3 to 5, deterioration in collateral quality between baseline and subacute imaging was strongly associated with absolute (P=0.02) and relative (P<0.001) infarct growth. The deterioration in collateral grade correlated with increased mean Tmax hypoperfusion severity (Rho −0.68, P<0.001). Deterioration in Tmax hypoperfusion severity was also significantly associated with absolute (P=0.003) and relative (P=0.002) infarct growth. Collateral flow is dynamic and failure is associated with infarct growth.     

Photochemical inactivation of pathogenic bacteria in human platelet concentrates

Platelet concentrates (PC) may be infrequently contaminated with low levels of bacteria that can cause septicemia and death in patients receiving transfusion therapy. We evaluated the efficacy of a photochemical decontamination (PCD) technique using 8-methoxypsoralen (8-MOP) and long wavelength UV light (UVA) to inactivate bacteria in standard therapeutic PC. Twelve phylogenetically distinct pathogenic bacteria, 5 gram-positive and 7 gram-negative organisms, were seeded into PC to a final challenge dose ranging from 10(5) to 10(7) colony- forming units (CFU)/mL. Contaminated PC were treated with 8-MOP (5 micrograms/mL) and 5 J/cm2 of UVA, a PCD treatment regimen found to adequately preserve in vitro platelet function. Greater than 10(5) CFU/mL of all 5 gram-positive (Staphylococcus aureus, Streptococcus epidermidis, Streptococcus pyogenes, Listeria monocytogenes, and Corynebacterium minutissimum) and 2 of the gram-negative (Escherichia coli and Yersinia enterocolitica) organisms were inactivated. The remaining 5 gram-negative organisms were more resistant, with less than 10(1) to 10(3.7) CFU/mL inactivated under these conditions. The inactivation efficiency for this resistant group of gram-negative organisms was improved when PC were resuspended in a synthetic storage medium with reduced plasma protein concentration (15%) and an increased 8-MOP concentration (23.4 micrograms/mL). Illumination with 3 J/cm2 of UVA in this system inactivated greater than 10(5) CFU/mL of 4 resistant gram-negative organisms (Salmonella choleraesuis, Enterobacter cloacae, Serratia marcescens, and Klebsiella pneumoniae) and 10(4.1) CFU/mL of the most resistant gram-negative organism (Pseudomonas aeruginosa). This level of PCD treatment did not adversely affect in vitro platelet function. These results demonstrate that PCD using 8-MOP (5 to 23.4 micrograms/mL) effectively inactivated high levels of pathogenic bacteria in PC with adequate preservation of in vitro platelet properties.