Complete genomic characterization in patients with cancer of unknown primary origin in routine diagnostics.

BACKGROUND: In ∼3%-5% of patients with metastatic disease, tumor origin remains unknown despite modern imaging techniques and extensive pathology work-up. With long diagnostic delays and limited and ineffective therapy options, the clinical outcome of patients with cancer of unknown primary (CUP) remains poor. Large-scale genome sequencing studies have revealed that tumor types can be predicted based on distinct patterns of somatic variants and other genomic characteristics. Moreover, actionable genomic events are present in almost half of CUP patients. This study investigated the clinical value of whole genome sequencing (WGS) in terms of primary tumor identification and detection of actionable events, in the routine diagnostic work-up of CUP patients. PATIENTS AND METHODS: A WGS-based tumor type 'cancer of unknown primary prediction algorithm' (CUPPA) was developed based on previously described principles and validated on a large pan-cancer WGS database of metastatic cancer patients (>4000 samples) and 254 independent patients, respectively. We assessed the clinical value of this prediction algorithm as part of routine WGS-based diagnostic work-up for 72 CUP patients. RESULTS: CUPPA correctly predicted the primary tumor type in 78% of samples in the independent validation cohort (194/254 patients). High-confidence predictions (>95% precision) were obtained for 162/254 patients (64%). When integrated in the diagnostic work-up of CUP patients, CUPPA could identify a primary tumor type for 49/72 patients (68%). Most common diagnoses included non-small-cell lung (n = 7), gastroesophageal (n = 4), pancreatic (n = 4), and colorectal cancer (n = 3). Actionable events with matched therapy options in clinical trials were identified in 47% of patients. CONCLUSIONS: Genome-based tumor type prediction can predict cancer diagnoses with high accuracy when integrated in the routine diagnostic work-up of patients with metastatic cancer. With identification of the primary tumor type in the majority of patients and detection of actionable events, WGS is a valuable diagnostic tool for patients with CUP.

Gut microbiome of treatment-naïve MS patients of different ethnicities early in disease course.

Although the intestinal microbiome has been increasingly implicated in autoimmune diseases, much is unknown about its roles in Multiple Sclerosis (MS). Our aim was to compare the microbiome between treatment-naïve MS subjects early in their disease course and controls, and between Caucasian (CA), Hispanic (HA), and African American (AA) MS subjects. From fecal samples, we performed 16S rRNA V4 sequencing and analysis from 45 MS subjects (15 CA, 16 HA, 14 AA) and 44 matched healthy controls, and whole metagenomic shotgun sequencing from 24 MS subjects (all newly diagnosed, treatment-naïve, and steroid-free) and 24 controls. In all three ethnic groups, there was an increased relative abundance of the same single genus, Clostridium, compared to ethnicity-matched controls. Analysis of microbiota networks showed significant changes in the network characteristics between combined MS cohorts and controls, suggesting global differences not restricted to individual taxa. Metagenomic analysis revealed significant enrichment of individual species within Clostridia as well as particular functional pathways in the MS subjects. The increased relative abundance of Clostridia in all three early MS cohorts compared to controls provides candidate taxa for further study as biomarkers or as etiologic agents in MS.

Liver Transplantation and Abuse of Drugs and Alcohol: A Correlation Between Scales of the MMPI-2.

BACKGROUND: Clinical practice requires an accurate psychological assessment of subjects with clinical history of alcohol abuse and/or substance abuse (abuse history [AH]) for therapeutic choice. This study aims to identify significant correlations between the Minnesota Multiphasic Personality Inventory (MMPI)-2 scales in patients awaiting liver transplantation. METHODS: We evaluated a personality questionnaire containing MMPI-2 scales in the sample of 308 patients (81.8% males and 18.2% females) awaiting liver transplantation. The AH group composed 44.49% of patients and in the abuse free (AF) group, 55.51%. Scales were compared using Shapiro-Wilk test and Mann-Whitney U test. Interrelationships were examined using Spearman's correlation. RESULTS: This analysis found 27 scales of the MMPI-2 that were statistically different between 2 groups (AF and AH). In the AH group, we found a significant correlation between the following pairs of scales: Schizophrenia Scale (Sc) with the Addictions Potential Scale, Social Introversion scale (Si) with the Psychopathic Deviate scale (Pd), and Social Discomfort scale with Pd; the ES scale was negatively correlated with the Sc and Si scales. This interim study showed that the understanding of these indicators is crucial both for the assessment accuracy and for a prediction of the degree of therapy compliance after the transplantation. CONCLUSIONS: The scales of the MMPI-2 indicated a marked tendency to emotional rigidity, a lack of self-esteem and susceptibility judgment. Social introversion and social discomfort trends lead to impulsive behavior and deviant actions that combine poorly with good compliance with treatment.

A project for the evaluation of awareness of under-aged patients involved in clinical trials. Development of the IGG- Awareness Scale.

AIM: Most very sick, under-aged children express a desire or need for information about their illness and therapy. Most of them are being treated with experimental trials, and their parents/ tutors have been requested to provide informed consent. The need to understand, mostly by the older patients, may differ depending on age and gender, but it always involves psychology. Although the literature is full of guidelines and papers about assent of under-aged patients, there is a lack of data about their awareness. METHODS: The authors report a project for the evaluation of awareness of under-aged patients in their involvement in clinical trials; a simple investigative instrument that consists of a short, simple, semistructured interview which includes a questionnaire of 11 items is presented. A preliminary investigation was performed with a convenience sample of 15 school-aged children with cancer. The interview project was accomplished after this evaluation. The main aim was to evaluate the degree of awareness of sick youngsters between 11 and 18 years of age with regards to the experimental trial they are undergoing. RESULTS AND CONCLUSIONS: The study is a monocentric, transversal and descriptive survey, approved by the Research Ethics Committee of our institution. A complete analysis of the total scores of awareness will be performed.

Geometric and material contributions to whole bone structural behavior in GDF-7-deficient mice.

The growth/differentiation factors (GDFs) are a subfamily of bone morphogenetic proteins (BMPs) known to play a role in a variety of skeletal processes. Previous work using the brachypod mouse demonstrated that mice deficient in GDF-5 have long bones with diminished material properties and ash content compared with control littermates. Our aim was to examine the role of a related GDF family member, GDF-7 (BMP-12), in cortical bone by examining the geometric and material contributions to whole bone structural behavior in GDF-7-deficient mice. Femora from 16-week-old GDF-7 -/- animals had significantly smaller bone cross-sectional geometric parameters (e.g., -20% medial/lateral and anterior/posterior moments of inertia). Despite having smaller bone cross-sections, all structural parameters obtained from four-point bending tests were comparable to those of wild-type bones due to elevated cortical bone material properties (+18% modulus of elasticity, +28% yield strength, and +18% ultimate strength). No significant differences in ash content or collagen content were detected, however. These data suggest that GDF-7 deficiency is associated with elevated cortical bone material properties that compensate for decreased geometric properties, thereby preserving bone structural integrity. The compositional and/or microstructural bases for these altered material properties remain to be determined, however.

Altered hypertrophic chondrocyte kinetics in GDF-5 deficient murine tibial growth plates.

The growth/differentiation factors (GDFs) are a subgroup of the bone morphogenetic proteins best known for their role in joint formation and chondrogenesis. Mice deficient in one of these signaling proteins, GDF-5, exhibit numerous skeletal abnormalities, including shortened limb bones. The primary aim of this study was determine whether GDF-5 deficiency would alter the growth rate in growth plates from the long bones in mice and, if so, how this is achieved. Stereologic and cell kinetic parameters in proximal tibial growth plates from 5-week-old female GDF-5 -/- mice and control littermates were examined. GDF-5 deficiency resulted in a statistically significant reduction in growth rate (-14%, p=0.03). The effect of genotype on growth rate was associated with an altered hypertrophic phase duration, with hypertrophic cells from GDF-5 deficient mice exhibiting a significantly longer phase duration compared to control littermates (+25%, p=0.006). These data suggest that one way in which GDF-5 might modulate the rate of endochondral bone growth could be by affecting the duration of the hypertrophic phase in growth plate chondrocytes.

[Microcalcification and breast pathology: differential diagnosis and oncogenic risk assessment]. / Le microcalcificazioni nella patologia mammaria: diagnosi differenziale e valutazione del rischio oncogeno.

Breast cancer is one of the first cause of death in women. The investigation and the study of microcalcifications can discover about half of hidden breast carcinomas and this is an excellent help for the diagnosis. The aim of this study is to give some guidelines for a correct interpretation of these microcalcifications.

[Periodontal pathology during pregnancy]. / Patologia del parodonto in corso di gestazione.

There is emerging evidence from the dental literature that periodontal disease may be a risk factor for systemic disease; in addition, several investigators report a link between periodontal infections and pregnancy complications. In the past few decades, major advances have been made in the elucidation of the etiology, pathogenesis and treatment of periodontal disease. These developments will be of importance to the obstetrician as periodontal disease may become a potential modifiable risk factor for pregnancy complications.

The effect of growth/differentiation factor-5 deficiency on femoral composition and mechanical behavior in mice.

A subclass of the bone morphogenetic proteins (BMPs), known as growth/differentiation factors (GDFs) 5, 6, and 7, have been shown to affect several skeletal processes, including endochondral ossification, synovial joint formation, and tendon and ligament repair. Mice deficient in GDF-5 have also been shown to exhibit biomechanical abnormalities in tendon that may be associated with altered type I collagen. The purpose of this study was to investigate the effect of GDF-5 deficiency on another type I collagen-rich tissue: cortical bone. Analyses were performed on femora from 8-week-old GDF-5-deficient male brachypodism mice. We hypothesized that GDF-5-deficient bones would exhibit altered geometric, structural, and material properties compared with control littermates. Mutant animals were significantly smaller in body mass than controls (-21%). Geometrically, mutant long bones were significantly shorter (-25%), had a lower polar moment of inertia (-34%), and a lower geometric strength indicator (analogous to the section modulus of a circular section) (-30%). When normalized by body mass, however, geometric differences were no longer significant. Structurally, GDF-5-deficient femora were weaker (-31%) and more compliant (-57%) than controls when tested to failure in torsion. Lower bone structural stiffness in the mutants was not completely explained by the smaller bone geometry, because mutant bones exhibited a significantly lower effective shear modulus (-36%). Although body mass did not fully explain the reduced structural strength in mutant bones, strength differences were adequately explained by bone cross-sectional geometry; maximum effective shear stress was not significantly different between mutants and controls, despite a statistically significant 6% lower ash fraction in mutant femora. No significant difference was detected in collagen content, as indicated by hydroxyproline per dry mass.

Hypertension and menopausal syndrome: effects of hormone replacement therapy and antihypertensive drugs.

Arterial hypertension is a common finding in climacteric women even though the role of reduced estrogen levels in promoting this condition remains unclear. The purpose of the present survey was to evaluate the effects of hormone replacement therapy in hypertensive postmenopausal women. 180 patients were studied; they had been postmenopausal for 12-18 months and afflicted with mild or moderate essential arterial hypertension for less than 2 years. Patients were randomly divided into two groups and treated with progestin-estrogen therapy (group I, 96 patients) or with antihypertensive drugs (group II, 84 patients). Fourty-one cases in group I (42.7%) responded adequately to hormone therapy with persistent normalization of blood pressure levels; antihypertensive drugs were effective in 61 patients in group II (72.5%). The 23 unresponsive patients in group II were subsequently treated with progestin-estrogen therapy and a normalization of pressure values was achieved in 10 of these (43.5%). These results suggest that hormonal treatment determines, in at least one third of the cases, a significant reduction in blood pressure values. Moreover, hormone replacement may be effective even in patients that have not responded to antihypertensive drugs.

[Supraventricular tachycardia in children]. / Le tachicardie sopraventricolari nell'infanzia.

Supraventricular tachycardia is one of the most frequent arrhythmias in childhood. It may accompany congenital heart disease. W.P. W. syndrome, or a normal state of health. A re-entry circuit is the most commonly observed electrophysiological mechanism. Persistence is followed by decompensation. Drug management is based on digitalis, ATP, amiodarone, and verapamil. Atrial and ventricular pacing and surgery are alternatives when other means fail. Persistent tachycardia (i.e. its presence over long periods) is much less frequent that the paroxysmal form, and its aetiology is generally unknown. Even here, the clinical picture is substantially related to decompensation. Digitalis + amiodarone is the best treatment, though the arrhythmia may resolve spontaneously.

[Atrial fibrillation and flutter in children]. / Fibrillazione e flutter atriale nell'infanzia.

Flutter and atrial fibrillation are extremely rare in children. Their aetiology and pathogenesis vary from one case to another. The clinical picture may be influenced by a number of factors (age, duration of the arrhythmia, ventricular frequency), while the natural history is often related to the presence or otherwise of associated cardiopathies. There is no standard treatment. Digitalis with or without other antiarrhythmic drugs is often employed as the drug of choice, though its place may be taken by ayodarone or verapamil.