Validation of histomolecular classification utilizing histological subtype, MUC1, and CDX2 for prognostication of resected ampullary adenocarcinoma.

BACKGROUND: Outcomes for ampullary adenocarcinomas are heterogeneous, and numerous methods of categorisation exist. A histomolecular phenotype based on histology, caudal-type homeodomain transcription factor 2 (CDX2) staining and Mucin 1 (MUC1) staining has recently been tested and validated in two cohorts. We attempt to validate this classification in a large patient population. METHODS: Tissue samples from 163 patients with resected ampullary adenocarcinoma were classified based on histology and immunohistochemical expression of CDX2 and MUC1. A pancreaticobiliary histomolecular classification (PB) was defined as a sample with pancreaticobiliary histology, positive MUC1 and negative CDX2 expression. RESULTS: There were 82 deaths; median follow-up of 32.4 months; and median overall survival of 87.7 (95% CI 42.9-109.5) months. PB comprised 28.2% of the cases. Factors associated with overall survival were histological subtype (P=0.0340); T1/2 vs T3/4 (P=0.001); perineural (P<0.0001) and lymphovascular (P=0.0203) invasion; and histomolecular intestinal histomolecular phenotype (INT) vs PB phenotype (106.4 vs 21.2 months, P<0.0001). Neither MUC1 nor CDX2 was statistically significant, although MUC1 positivity defined as ⩾10% staining was significant (P=0.0023). In multivariate analysis, age (HR 1.03), PB phenotype (HR 2.26) and perineural invasion (PNI; HR 2.26) were associated with poor survival. CONCLUSIONS: The prognostic ability of histomolecular phenotype has been validated in an independent cohort of ampullary adenocarcinoma patients.

Cloning and expression of human HBP1, a high mobility group protein that enhances myeloperoxidase (MPO) promoter activity.

Factors which regulate transcription in immature myeloid cells are of great current interest for the light they may shed upon myeloid differentiation. In the course of screening for transcription factors which interact with the human myeloperoxidase (MPO) promoter we, for the first time, identified and cloned the cDNA and genomic DNA for human HBP1 (HMG-Box containing protein 1), a member of the high mobility group of non-histone chromosomal proteins. HBP1 cDNA was initially cloned from rat brain in 1994, but its presence in human cells or in myeloid tissue had not been described previously. The sequence of human HBP1 cDNA shows 84% overall homology with the rat HBP1 cDNA sequence. We have subsequently cloned the gene, which is present as a single copy, 25 kbp in length. Northern blotting reveals a single 2.6 kb mRNA transcript which is expressed at higher levels in human myeloid and B lymphoid cell lines than in T cell lines tested and is present in several non-myeloid human cell lines. Comparison of the mRNA and genomic sequences reveals the gene to contain 10 exons and 9 introns. The sequence of human HBP1 mRNA contains a single open reading frame, which codes for a protein 514 amino acids in length. The amino acid sequence specified by the coding region shows 95% homology with the rat HBP1 protein. The human protein sequence exhibits a putative DNA-binding domain similar to that seen in rat HBP1 and shows homology with the activation and repressor domains previously demonstrated in the rat protein. We have expressed human HBP1 protein both in vitro and in prokaryotic and eukaryotic cells. The expressed fusion protein binds to a sequence in a functionally important region within the basal human MPO promoter. In transient co-transfection experiments HBP1 enhances MPO promoter activity. Human HBP1 appears to be a novel transcription factor which is likely to play an important role in regulating transcription in developing myeloid cells.

Sleep deprivation and resident performance.

Cognitive and complex motor performance may be impaired by extended sleep deprivation, but objective data concerning the effects in residents of the sleep deprivation engendered by usual hospital on-call schedules are scant and conflicting. We studied three cohorts of surgical residents (N = 26) who were on call every other night. Each resident kept a sleep diary, gave a self-assessment of motivation and fatigue, and underwent a battery of psychometric tests each morning for 18 or 19 days. The psychometric tests measured cognition, discernment, visual and auditory vigilance, and rapid eye-hand coordination. Sleep deprivation was defined as the lack of four hours of continuous sleep during the preceding 24 hours, and it occurred during 89% of the on-call nights. Daily testing in a repeated-measures design allowed each participant to serve as his or her own control. Sleep deprivation did not affect overall cognitive or motor performance. Further analysis of the correlation between sleep parameters (total sleep and longest uninterrupted sleep interval) and performance on each component of the psychometric test battery identified changes in performance on some tests but only trivial effects due to sleep. The assumption that sleep deprivation associated with usual on-call schedules impairs cognitive and motor performance of residents such that clinical care of patients may be compromised is not supported by our observations.

Age, gender, lateral dominance, and prediction of operative skill among general surgery residents.

Ability patterns and surgical proficiency were examined in matched groups of general surgery residents selected on the basis of age, gender, or hand preference from a population of 141 residents who had completed neuropsychologic tests of visuospatial, psychomotor, and stress tolerance abilities and had been rated on 12 aspects of technical skill exhibited during 1480 operative procedures. Older residents (ages 28 to 42 years) exhibited less motor speed (p less than 0.05) and coordination (p less than 0.005) and more caution in avoiding psychomotor errors (p less than 0.05) than did their younger counterparts. No differences were found for visuospatial abilities, stress tolerance, or rated surgical skill. These findings indicate that although age does appear to adversely affect pure motor skills, these are not important components of operative proficiency. Female residents exhibited superior (p less than 0.05) academic achievement (MCAT, Verbal and National Boards Part II) as compared with their male counterparts. They also excelled on a signal detection task requiring identification of visual patterns. However, the women scored less well (p less than 0.05) than men on a visuomotor task demonstrated to be a significant predictor of operative skill. Greater cautiousness in avoiding errors may be a contributing factor to their reduced efficiency on this task. In comparison to male controls, female residents received consistently lower surgical skills ratings, particularly on items measuring confidence and task organization. Left-handed residents were more reactive to stress (p less than 0.03), more cautious (p less than 0.04), and more proficient on a neuropsychologic test of tactile-spatial abilities (p less than 0.03) than right-handed counterparts. Although these traits correlated positively (p less than 0.05) with rated operative skill within the left-handed group, the group received consistently lower ratings than did right-handed residents. The inconvenience of assisting left-handed residents may overshadow attending surgeons' perceptions of their innate abilities. These findings demonstrate significant, neuropsychologically based differences among surgery residents that pose unique challenges to persons responsible for their selection and training.

Neuropsychologic predictors of operative skill among general surgery residents.

The present study develops a rating scale method for evaluating operative skills, assesses the predictive utility of neuropsychologic tests of nonverbal cognitive and psychomotor abilities in accounting for individual differences in surgical skills, and compares the efficiency of these measures with those of traditional residency selection criteria. According to a multifactorial design, 120 general surgery residents were tested with a neuropsychologic test battery and then rated by attending surgeons on surgical skills exhibited during the course of 1445 surgical procedures. Analysis of the neuropsychologic battery resulted in three factors (complex visuo-spatial organization, stress tolerance, psychomotor abilities) that were statistically unrelated to traditional measures such as Medical College Admission Test and National Board scores. Multiple regression analyses indicated that academic predictors, taken alone, either do not correlate (National Board scores) or correlate negatively (Medical College Admission Test scores) with the surgery ratings. Conversely, neuropsychologic test scores show significant positive correlation (r = 0.68) with the ratings. When both sets of predictor variables are combined, a multiple regression coefficient of 0.80 is found with the ratings, with more than two thirds of the predictive power attributable to the neuropsychologic test scores. These tests may provide a useful addition to traditional methods of predicting operative skills.