Observer agreement in pediatric semiquantitative vertebral fracture diagnosis

Background

The Genant semiquantitative (GSQ) method has been a standard procedure for diagnosis of vertebral fractures in adults but has only recently been shown to be of clinical utility in children. Observer agreement using the GSQ method in this age group has not been described.

Objective

To evaluate observer agreement on vertebral readability and vertebral fracture diagnosis using the GSQ method in pediatric vertebral morphometry.

Materials and methods

Spine radiographs of 186 children with acute lymphoblastic leukemia were evaluated independently by three radiologists using the same GSQ methodology as in adults. A subset of 100 radiographs was evaluated on two occasions.

Results

An average of 4.7% of vertebrae were unreadable for the three radiologists. Intraobserver Cohen’s kappa (κ) on readability ranged from 0.434 to 0.648 at the vertebral level and from 0.416 to 0.611 at the patient level, while interobserver κ for readability had a range of 0.330 to 0.504 at the vertebral level and 0.295 to 0.467 at the patient level. Intraobserver κ for the presence of vertebral fracture had a range of 0.529 to 0.726 at the vertebral level and was 0.528 to 0.767 at the patient level. Interobserver κ for fracture at the vertebral level ranged from 0.455 to 0.548 and from 0.433 to 0.486 at the patient level.

Conclusion

Most κ values for both intra- and interobserver agreement in applying the GSQ method to pediatric spine radiographs were in the moderate to substantial range, comparable to the performance of the technique in adult studies. The GSQ method should be considered for use in pediatric research and clinical practice.     

Follicular lesion of undetermined significance in thyroid FNA revisited

Controversy exists regarding the validity of follicular lesion of undetermined significance (FLUS), an indeterminate diagnostic category of The Bethesda System for Reporting Thyroid Cytopathology (BSRTC). According to BSRTC, FLUS carries a 5–15% risk of cancer. This study was designed to determine if cytomorphology could stratify FLUS into subgroups with different risks of malignancy. Reports of 127 consecutive FNAs reported as FLUS with subsequent tissue diagnoses were evaluated for the presence of various cytologic features and the results were correlated with histological diagnoses. FLUS cases with focal nuclear atypia (nuclear overlap/crowding, nuclear grooves/membrane irregularities, nuclear enlargement, and/or nuclear pseudoinclusions) were more frequently malignant on excision whereas those with architectural atypia (microfollicles) were more often benign on excision (P < 0.05). The presence of any one or more of these nuclear features increased the risk of carcinoma in subsequent thyroid resection. Papillary carcinomas predominated in excised FLUS cases with focal nuclear atypia whereas most FLUS with architectural atypia were adenomas or hyperplastic nodules on histological evaluation. BSRTC recommends that thyroid aspirates containing follicular cell nuclear and/or architectural atypia insufficient for a diagnosis of suspicious for follicular neoplasm, suspicious for malignancy or malignant be classified as FLUS. Our findings indicate that FLUS cases with focal nuclear atypia carry a risk for malignancy that is substantially higher than that assigned to FLUS and are best classified as suspicious. FLUS cases lacking these atypical nuclear features have a risk for malignancy that approximates the risk BSRTC has assigned to FLUS. Diagn. Cytopathol. 2014;42:18–22. © 2013 Wiley Periodicals, Inc.     

The influence of drug-exposure conditions on the development of resistance to methotrexate or ZD1694 in cultured human leukaemia cells

The influence of drug-exposure conditions on the development of resistance to methotrexate (MTX) or ZD1694 was studied by treating MOLT-3 human lymphoblastic-leukaemia cells in a continuous or a pulsatile (high-dose, short-term) drug-exposure schedule. Continuous exposure of the cells to MTX with stepwise escalation of the drug concentrations resulted in a MTX-resistant sub-line (MOLT-3/MTX_10,000) with impaired reduced-folate carrier (RFC) and increased dihydrofolate-reductase (DHFR) activity. Conversely, a MTX-resistant clone (MOLT-3/MTX·P-9) with unaltered RFC and DHFR activity, but with decreased cellular accumulation of antifolates, was selected by high-dose short-term treatment of the cells with MTX. MTX resistance in the latter cells was pronounced after short-term rather than continuous-exposure incubation with MTX, suggesting defective polyglutamation of the drug. On the other hand, 2 ZD1694-resistant sub-lines which were established by continuous (MOLT-3/ZD1694·C) or by pulsatile drug-exposure schedule (MOLT-3/ZD1694·P-9) demonstrated extremely low accumulation and poor retention of [³H]ZD1694, with no change of initial drug uptake and little or no increase of thymidylate-synthase (TS) activity, irrespective of drug-exposure conditions for their establishment. HPLC analysis displayed a virtual absence of ZD1694 polyglutamates in both ZD1694-resistant sub-lines and low accumulation in MOLT-3/MTX·P-9 as compared with the parent line. However, folylpolyglutamate-synthetase (FPGS) mRNA was only moderately decreased in the 2 ZD1694-resistant sub-lines and to an even lesser extent in MOLT-3/MTX·P-9. In addition, γ-glutamyl-hydrolase (GGH) activity was not increased, but was slightly down-regulated in the polyglutamation-defective sublines. These results indicate that the mechanism(s) of the resistance developed may depend not only on drug-exposure conditions while raising resistance but also on the biochemical properties of the drug. © 1996 Wiley-Liss, Inc.     

Clinical correlates among 49 families with hemophilia A and factor VIII gene inversions

Inversions between a gene A copy within intron 22 of the factor VIII gene and additional copies outside the factor VIII gene were found in 49 families with hemophilia A. Inversion patterns were that of recombination with a distal gene A copy in 34, a proximal copy in 14, and a third (variant) copy in one. Baseline factor VIII clotting activity levels were <1% of normal in 43 and 1% in 6. No inversion was detected in 61 other families whose affected members had ≤1% activity levels nor in 42 families with moderately severe hemophilia A and 2–5% baseline levels. Both high titer and low level alloantibody inhibitors were found in patients with or without an inversion. Of 13 high titer inhibitors, 8 were persistent and 1 of these patients had an inversion. Of 5 that responded to daily factor VIII infusions, 4 were in patients with gene inversions. Of the 49 families with an inversion, the occurrence of hemophilia was isolated in 30 and the mother was a carrier in the 25 in which additional family members were informative. In three of these families with isolated occurrence, the maternal grandmother was a carrier whereas in three others a de novo mutation occurred in the maternal grandfather's factor VIII gene. Screening for gene inversions in patients with severe (or “borderline” severe) hemophilia A provides a direct marker of the mutation in 45% of families. It is useful even if there is no living affected member and in predicting the likely severity of an infant in which there are no reliable baseline clotting activities, including 70% of families with isolated occurrences of hemophilia A. © 1996 Wiley-Liss, Inc.