Estimation of the incidence for non-terminal events in presence of a terminal event and evaluation of covariate effects: Sub-distribution and marginal distributions based on copulas. An application to disease progression on a breast cancer trial dataset

In clinical studies, during follow-up several kinds of events related to disease progression may be observed. In the semi-competing risks setting, some events, such as death, may prevent the observation of disease progression, thus acting as competitor for the event of interest. Methods of analysis specific for semi-competing risks data referring to marginal distribution of the non-competing events constitute a recent area of methodological research which has received a great impulse in latest years. However in clinical applications the analysis is traditionally based on crude cumulative incidences, and inference on marginal distributions is seldom considered, even when the principal aim concerns the probability of observing disease progression and death occurred without progression is a \u201cnuisance\u201d. Aim of this work is making a comparative review of semi-parametric marginal and sub-distribution methods of analysis, with particular reference to marginal regression models based on copulas. More specifically, two structures were considered for marginal models: in the first one all parameters are time-dependent, while in the second one parameters vary with covariates but does not depend on time. Applications to breast cancer clinical trial data and to a simulated dataset are reported, to show the differences and the similarities among marginal and sub-distribution approaches. Results highlight that, when the competing event acts during the whole follow-up, the marginal approach became essential for the correct estimation of marginal incidences and covariate effects. Regression methods based on copulas are promising, however there is a need of refinements concerning model building strategies, and, of standardised software routine for the practical application of these methods

Multimodal Batch-Wise Change Detection

We address the problem of detecting distribution changes in a novel batch-wise and multimodal setup. This setup is characterized by a stationary condition where batches are drawn from potentially different modalities among a set of distributions in Rd represented in the training set. Existing change detection (CD) algorithms assume that there is a unique-possibly multipeaked-distribution characterizing stationary conditions, and in batch-wise multimodal context exhibit either low detection power or poor control of false positives. We present MultiModal QuantTree (MMQT), a novel CD algorithm that uses a single histogram to model the batch-wise multimodal stationary conditions. During testing, MMQT automatically identifies which modality has generated the incoming batch and detects changes by means of a modality-specific statistic. We leverage the theoretical properties of QuantTree to: 1) automatically estimate the number of modalities in a training set and 2) derive a principled calibration procedure that guarantees false-positive control. Our experiments show that MMQT achieves high detection power and accurate control over false positives in synthetic and real-world multimodal CD problems. Moreover, we show the potential of MMQT in Stream Learning applications, where it proves effective at detecting concept drifts and the emergence of novel classes by solely monitoring the input distribution

Long-term follow-up of elderly patients with operable breast cancer treated with surgery without axillary dissection plus adjuvant tamoxifen.

Between 1982 and 1990, 321 elderly patients (range 70-92 years, median age 77) with operable breast cancer (T1 in 219, T2 in 77, T3 in one and T4b in 24 patients) and clinically uninvolved axillary nodes underwent surgery without axillary dissection and received adjuvant tamoxifen. All patients had surgery performed under local anaesthesia. Tamoxifen was given after surgery at the dose of 20 mg daily, indefinitely. With a median follow-up of 67 months (range 42-141), 17 patients developed local relapse, 14 ipsilateral axillary recurrence, five ipsilateral breast cancer, five contralateral breast cancer, 13 second primary and 23 developed distant metastases. The cumulative probability of developing a local, axillary and distant recurrence at 72 months was estimated to be 5.4%, 4.3% and 6.2%, respectively. Out of 244 patients who did not develop any relapse, 83 (25.8%) died from intercurrent disease. The 72 month relapse-free survival rate was 76%. This experience suggests that elderly patients with small tumours without clinical axillary involvement may be satisfactorily treated with conservative surgery and tamoxifen. The importance of axillary dissection is controversial owing to a high response rate to hormonal therapy and an increased death rate due to concomitant diseases

Fungal aneurism of the right posterior inferior cerebellar artery (PICA)

In this case-report, the Authors show the case of a sudden death occurred in a 38-year-old woman submitted to surgical excision of a right acoustic neurinoma. At the autopsy, was detected a cerebral hemorrhage with multifocal localization by a ruptured rare fungal aneurysm of the Posterior Inferior Cerebellar Arthery (PICA). The PCR analysis, carried out on formalin-fixed paraffin-embedded tissue, identified the Aspergillus Penicillioides as the involved pathogen. We discuss the main points of infectious aneurysms, being a potential neurosurgical complication

Contribution of 3H-thymidine labelling index and flow cytometric S-phase in predicting survival of patients with non-Hodgkin's lymphoma.

The 3H-thymidine labelling index (3H-dT LI) of cell suspensions from fresh material and the flow cytometric S-phase (FCM-S) of nuclei recovered from paraffin blocks were determined on the same pathologic lymph node specimen for 190 non-Hodgkin's lymphomas (NHLs). FCM-S was defined by a planimetric method and by an optimization procedure. Poor correlation coefficients were observed among the three cell kinetic variables. All three cell kinetic variables were significant indicators of 8-year survival and median survival time. The life-regression procedure evidenced a significant relative contribution of 3H-dT LI and FCM-S, thus suggesting a different biologic meaning of the two cell kinetic variables. This finding was further supported by evidence that simultaneous use of 3H-dT LI and FCM-S can identify groups of patients with different survival better than when either modality is used alone. Multivariate analysis indicated that the risk groups as defined by cell kinetic variables are predictors of survival even in the presence of established factors such as histology and stage

Estimation of the Piecewise Exponential Model by Bayesian P-Splines via Gibbs Sampling: Robustness and Reliability of Posterior Estimates

In the investigation of disease dynamics, the effect of covariates on the hazard function is a major topic. Some recent smoothed estimation methods have been proposed, both frequentist and Bayesian, based on the relationship between penalized splines and mixed models theory. These approaches are also motivated by the possibility of using automatic procedures for determining the optimal amount of smoothing. However, estimation algorithms involve an analytically intractable hazard function, and thus require ad-hoc software routines. We propose a more user-friendly alternative, consisting in regularized estimation of piecewise exponential models by Bayesian P-splines. A further facilitation is that widespread Bayesian software, such as WinBUGS, can be used. The aim is assessing the robustness of this approach with respect to different prior functions and penalties. A large dataset from breast cancer patients, where results from validated clinical studies are available, is used as a benchmark to evaluate the reliability of the estimates. A second dataset from a small case series of sarcoma patients is used for evaluating the performances of the PE model as a tool for exploratory analysis. Concerning breast cancer data, the estimates are robust with respect to priors and penalties, and consistent with clinical knowledge. Concerning soft tissue sarcoma data, the estimates of the hazard function are sensitive with respect to the prior for the smoothing parameter, whereas the estimates of regression coefficients are robust. In conclusion, Gibbs sampling results an efficient computational strategy. The issue of the sensitivity with respect to the priors concerns only the estimates of the hazard function, and seems more likely to occur when non-large case series are investigated, calling for tailored solutions

Thallium toxicity due to audultered infusion with thallium sulfate in eight members belonging to the same family nucleus: Autopsy findings and ICP-MS analysis (inductively coupled plasma mass spectrometry) in a triple homicide

The banning of the heavy metal thallium (Tl) in many Countries, because of its toxicity, led to a remarkable reduction of the number of cases of poisoning both accidental and homicidal forcing us to better study the pharmacokinetics of this poison using new technologies. The Authors, in this work, are reporting the case of a collective thallium toxicosis caused by voluntary adulteration of an infusion with thallium sulfate, occurred in 8 members of the same familial nucleus; the administration of Prussian Blu resulted to be ineffective for 3 of these members that died at a later time. The most peculiar aspects of this rare manner of poisoning are discussed; the analytical procedures used, Inductively Coupled Plasma Mass Spectrometry (ICP-MS) in particular, resulted to be fundamental in the forensic diagnosis process of acute poisoning cause by thallium

Technical note: Preparation improvement of charred cadaveric viscera using sandison’s rehydrating solution for histological analysis

In forensic evaluation of charred corpses, internal detrimental signs may result as more significant of those observed during external examination and is often arduous to state if a victim was exposed to fire before or after death. When the histological analysis of the remaining internal viscera is necessary, the massive destruction caused by the lesion, the charring and the coarctation of the samples don't allow to give further information or to determine the remaining organic components of the viscera. This limit is determined by the intrinsic characteristics of this thermal lesivity of self-maintenance even after the exitus of the subject, worsening the initial detrimental framework. The Authors, with the purpose of improving the microscopic visualization of the samples collected from cadavers with peculiar deterioration, as in case of carbonization, suggest the use of a specific technical protocol based on the use of Sandison's rehydrating solution since the samples treated with this solution showed, at microscopic examination, a substantial histological-morphological improvement