TPO-RAs in pITP: description of a case series and analysis of predictive factors for response.

OBJECTIVE: To report our experience concerning sustained response (SR) after TPO-RA discontinuation in adult pITP patients and to identify possible predictive factors for outcome. METHODS: Thirty-nine pITP patients who received a TPO-RA were evaluated. Response (R) was defined as a platelet count ≥30 × 109 /L and at least a twofold increase in the baseline count and complete response (CR) as a platelet count ≥100 × 109 /L, in the absence of bleeding. Durable response (DR) was defined as a R/CR persisting ≥4 wk with a stable dose of TPO-RA, and SR as the first assessed platelet count ≥30 × 109 /L, available at more than 4 wk after discontinuation of TPO-RA, in the absence of other concomitant or rescue therapies. RESULTS: Twenty-nine/39 (74%) were responders: 18 (46%) reached a CR and 11 (28%) a R. A DR was observed in 16/29 (55%) responders. Seven SR (18%) were reached: five of seven patients achieved a SR from a prior DR. CR was statistically associated with the achievement of a subsequent DR: 13/18 (72%) CR patients obtained a DR, while only three of 11 (27%) R ones did (P = 0.027). CONCLUSIONS: CR was a significant prognostic factor for the achievement of a DR. Moreover, we observed a trend for DR patients to obtain a subsequent SR.

Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype.

RAS signaling plays a key role in controlling appropriate cell responses to extracellular stimuli and participates in early and late developmental processes. Although enhanced flow through this pathway has been established as a major contributor to oncogenesis, recent discoveries have revealed that aberrant RAS activation causes a group of clinically related developmental disorders characterized by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, ectodermal and musculoskeletal anomalies, and increased risk for certain malignancies. Here, we report that heterozygous germline mutations in CBL, a tumor-suppressor gene that is mutated in myeloid malignancies and encodes a multivalent adaptor protein with E3 ubiquitin ligase activity, can underlie a phenotype with clinical features fitting or partially overlapping Noonan syndrome (NS), the most common condition of this disease family. Independent CBL mutations were identified in two sporadic cases and two families from among 365 unrelated subjects who had NS or suggestive features and were negative for mutations in previously identified disease genes. Phenotypic heterogeneity and variable expressivity were documented. Mutations were missense changes altering evolutionarily conserved residues located in the RING finger domain or the linker connecting this domain to the N-terminal tyrosine kinase binding domain, a known mutational hot spot in myeloid malignancies. Mutations were shown to affect CBL-mediated receptor ubiquitylation and dysregulate signal flow through RAS. These findings document that germline mutations in CBL alter development to cause a clinically variable condition that resembles NS and that possibly predisposes to malignancies.

Application of Bayes' Theorem in Valuating Depression Tests Performance.

The validity of clinical diagnoses is a fundamental topic in clinical psychology, because now there are some political administrations, as the IOM or the U.K. government, which are focusing on best evidence-based practice in clinical psychology. The most problematic issue in clinical psychology is to avoid wrong diagnoses which can have negative consequences on individual life and on the utility of clinical treatments. In the case of diagnoses based on self-report tests, the diagnostic decision about individual health is based on the comparison between its score and the cutoff, according to the frequentist approach to probability. However, the frequentist approach underestimates the possible risks of incorrect diagnoses based on cutoffs only. The Bayesian approach is a valid alternative to make diagnoses on the basis of the scores from psychological tests. The Bayes' theorem estimates the posterior probability of the presence of a pathology on the basis of the knowledge about the diffusion of this pathology (prior probability) and of the knowledge of sensitivity and specificity values of the test. With all this information, it is possible to estimate the diagnostic accuracy of some self-report tests used for assessing depression. We analyzed the diagnostic accuracy of the most used psychological tests of depression (Zung's Self-Rating Depression Scale, Hamilton Rating Scale for Depression, Center for Epidemiological Studies for Depression and the Beck Depression Inventory), together with a new scale (Teate Depression Inventory) developed with the IRT procedure, by analyzing the published works in which data about sensitivity and specificity of these scales are reported. Except the TDI, none of these scales can reach a satisfactory level of diagnostic accuracy, probably for the absence of an optimal procedure to select test items and subjects with clearly defined pathological symptoms which could allow the reduction of false positives in test scoring.

Repeated successful use of eltrombopag in chronic primary immune thrombocytopenia: description of an intriguing case.

Thrombopoietin receptor agonists (TPO-RAs) are used as effective alternative treatments in ITP patients unresponsive to first-/second-line therapies. TPO-RAs can also be used to normalize platelet count to safely perform invasive procedures and chemotherapy, in case of malignancies. In few responsive patients, TPO-RAs can be suspended maintaining a sustained response.