Clinicopathological and molecular characterisation of ‘multiple-classifier’ endometrial carcinomas

Endometrial carcinoma (EC) molecular classification based on four molecular subclasses identified in The Cancer Genome Atlas (TCGA) has gained relevance in recent years due to its prognostic utility and potential to predict benefit from adjuvant treatment. While most ECs can be classified based on a single classifier (POLE exonuclease domain mutations – POLEmut, MMR deficiency – MMRd, p53 abnormal – p53abn), a small but clinically relevant group of tumours harbour more than one molecular classifying feature and are referred to as ‘multiple-classifier’ ECs. We aimed to describe the clinicopathological and molecular features of multiple-classifier ECs with abnormal p53 (p53abn). Within a cohort of 3518 molecularly profiled ECs, 107 (3%) tumours displayed p53abn in addition to another classifier(s), including 64 with MMRd (MMRd–p53abn), 31 with POLEmut (POLEmut–p53abn), and 12 with all three aberrations (MMRd–POLEmut–p53abn). MMRd–p53abn ECs and POLEmut–p53abn ECs were mostly grade 3 endometrioid ECs, early stage, and frequently showed morphological features characteristic of MMRd or POLEmut ECs. 18/28 (60%) MMRd–p53abn ECs and 7/15 (46.7%) POLEmut–p53abn ECs showed subclonal p53 overexpression, suggesting that TP53 mutation was a secondary event acquired during tumour progression. Hierarchical clustering of TCGA ECs by single nucleotide variant (SNV) type and somatic copy number alterations (SCNAs) revealed that MMRd–p53abn tumours mostly clustered with single-classifier MMRd tumours (20/23) rather than single-classifier p53abn tumours (3/23), while POLEmut–p53abn tumours mostly clustered with single-classifier POLEmut tumours (12/13) and seldom with single-classifier p53abn tumours (1/13) (both p ≤ 0.001, chi-squared test). Finally, the clinical outcome of patients with MMRd–p53abn and POLEmut–p53abn ECs [stage I 5-year recurrence-free survival (RFS) of 92.2% and 94.1%, respectively] was significantly different from single-classifier p53abn EC (stage I RFS 70.8%, p = 0.024 and p = 0.050, respectively). Our results support the classification of MMRd–p53abn EC as MMRd and POLEmut–p53abn EC as POLEmut. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Auranofin and gold sodium thiomalate in the treatment of rheumatoid arthritis: A one-year,double-blind,comparative multicenter study

Summary In a 48-week, double-blind trial, 122 patients were randomly assigned to treatment with auranofin (60) and gold sodium thiomalate (GST) (62) at five centers. Both groups showed significant improvement (P<0.05) from baseline in parameters of disease activity. Results of the covariance analysis for all patients who completed the trial showed no significant differences (P<0.05) in efficacy between the two groups. The proportions of patients showing 50% or greater improvement in tender joints, swollen joints, activity index, severity of pain, general health rating, and erythrocyte sedimentation rate (ESR) were similar for both auranofin-treated and GST-treated patients who completed the 48-week trial. When all patients who entered the trial were evaluated, a slightly greater proportion of patients on auranofin had improved. Diarrhea occurred more frequently with auranofin (32%) compared to GST (19%), whereas rash and pruritus were twice as common in those patients treated with GST compared to those treated with auranofin. The withdrawal rate due to adverse reactions was 10% for auranofin vs 26% for GST. It was concluded that the efficacy of auranofin was comparable to that of injectable gold and was better tolerated, as evidenced by the lower withdrawal rate from adverse events for the auranofin patients.Abbreviations ARA American Rheumatism Association - ESR Erythrocyte sedimentation rate - GGT Gamma-glutamyl-transpeptidase - GST Gold sodium thiomalate - NSAID Nonsteroidal antiinflammatory drug - RA Rheumatoid arthritis - SGOT Serum-glutamate-oxalacetate transaminase - SGPT Serum-glutamate-pyruvate transaminase - WBC White blood count Dedicated to Prof. Dr. N. Zöllner on the occasion of his 65th birthday     

Diagnosis of schizophrenia by computer and clinicians: A pilot study

Investigations show significant disagreement among mental health professionals in diagnosing schizophrenia.^1–11 Recently, computer-based systems have been used in attempts to improve diagnostic consistency. Spitzer and Endicott, among others, have devised a computer program using the Mental Status Examination Report (MSER) as input data.^12–19 The MSER is a systematic, relatively objective inventory of observed behaviors used to obtain a mental status. The MSER was used at the Hillside Division during 1973 and 1974. It was filled out 1 week after admission by therapists who were specially trained for this task. It was noted that a nonschizophrenic computer diagnosis was given to a number of patients diagnosed schizophrenic by clinicians, but the reverse rarely occurred. Was this due to the computer program, the MSER, clinicians, or other factors? These questions have heightened relevance in light of the imminence of Professional Standards Review Organization (PSRO).²⁰ Hospitals may be required to establish definitive operational diagnostic criteria and correlated treatments in order to maintain accreditation and be reimbursed by third-party payers. This study investigated these diagnostic discrepancies in order to ascertain what specific criteria could be used in making a schizophrenic diagnosis in hospitalized patients. Secondarily, the study sought to shed further light on whether such a computer system could be useful as an adjunctive diagnostic modality to pinpoint difficult cases.     

Inter-cycle and inter-observer variability of the antral follicle count in routine clinical practice

Antral follicle count (AFC) is a reliable predictor of ovarian response to stimulation and its inter-cycle and inter-observer variability has been extensively studied on in vitro fertilization (IVF), mostly in highly selected populations within studies not originally designed for this purpose. In this retrospective cohort study, we assess the inter-cycle variation of AFC in a setting similar to that of the daily practice. We included only patients undergoing mild stimulation for intrauterine insemination (IUI). One hundred and forty-eight patients had two (62 patients, group A), three (49 patients, group B) or four (37 patients, group C) IUI cycles and AFC was measured on early follicular phase of each cycle by one of the members of the medical team within daily practice. Intra-class correlation coefficients were used to estimate variability. Inter-cycle variability rendered ICCs above 0.70 in all groups improving along with the number of cycles [Group A ICC 0.78 (95%CI 0.66–0.86), Group B ICC 0.87 (95%CI 0.80–0.92) and Group C ICC 0.91 (95%CI 0.85–0.95)]. Inter-observer variability showed a high degree of concordance with ICCs above 0.95. We provide the closest approximation to real inter-cycle and inter-observer AFC variability expected in routine clinical practice.     

Spontaneous pallidal neuronal activity in human dystonia: comparison with Parkinson's disease and normal macaque

Dystonia is a movement disorder defined by sustained muscle contractions, causing twisting and repetitive movements and abnormal postures. To understand the abnormalities in pallidal discharge in dystonia, we have analyzed the spontaneous activity of 453 neurons sampled from the internal or external pallidum (GPi or GPe) of 22 patients with dystonia, 140 neurons from 11 patients with Parkinson's disease (PD), and 157 neurons from two normal non-human primates (NHPs; Macacca mulatta). All recordings were performed without systemic sedation. Mean GPi discharge rate in dystonia was 55.3 +/- 1.3 (SE) Hz. This was significantly lower than in the normal NHPs (82.5 +/-2.5 Hz) and lower than in PD patients (95.2 +/- 2.3 Hz). Mean GPe discharge rate in dystonia (54.0 +/- 1.9 Hz) was lower than in the normal NHPs (69.7 +/- 3.3 Hz) and was indistinguishable from that in PD patients (56.6 +/- 3.5 Hz). Mean GPi discharge rate was inversely correlated with dystonia severity. GPi showed increased oscillatory activity in the 2- to 10-Hz range and increased bursting activity in both dystonia and PD as compared with the normal NHPs. Because the abnormalities in discharge patterns were similar in dystonia compared with PD, we suggest that bursting and oscillatory activity superimposed on a high background discharge rate are associated with parkinsonism, whereas similar bursting and oscillations superimposed on a lower discharge rate are associated with dystonia. Our findings are most consistent with a model of dystonia pathophysiology in which the two striatal cell populations contributing to the direct and indirect intrinsic pathways of the basal ganglia both have increased spontaneous activity.