Germinal BRCA1-2 pathogenic variants (gBRCA1-2pv) and pancreatic cancer: epidemiology of an Italian patient cohort.

OBJECTIVE: Germline BRCA1-2 pathogenic variants (gBRCApv) increase the risk of pancreatic cancer and predict for response to platinating agents and poly(ADP-ribose) polymerase inhibitors. Data on worldwide gBRCApv incidence among pancreatic ductal adenocarcinoma (PDAC) patients are sparse and describe a remarkable geographic heterogeneity. The aim of this study is to analyze the epidemiology of gBRCApv in Italian patients. MATERIALS AND METHODS: Patients of any age with pancreatic adenocarcinoma, screened within 3 months from diagnosis for gBRCApv in Italian oncologic centers systematically performing tests without any selection. For the purposes of our analysis, breast, ovarian, pancreas, and prostate cancer in a patient's family history was considered as potentially BRCA-associated. Patients or disease characteristics were examined using the χ2 test or Fisher's exact test for qualitative variables and the Student's t-test or Mann-Whitney test for continuous variables, as appropriate. RESULTS: Between June 2015 and May 2020, 939 patients were tested by 14 Italian centers; 492 (52%) males, median age 62 years (range 28-87), 569 (61%) metastatic, 273 (29%) with a family history of potentially BRCA-associated cancers. gBRCA1-2pv were found in 76 patients (8.1%; 9.1% in metastatic; 6.4% in non-metastatic). The gBRCA2/gBRCA1 ratio was 5.4 : 1. Patients with gBRCApv were younger compared with wild-type (59 versus 62 years, P = 0.01). The gBRCApv rate was 17.1% among patients <40 years old, 10.4% among patients 41-50 years old, 9.2% among patients 51-60 years old, 6.7% among patients aged 61-70 years, and 6.2% among patients >70 years old (none out of 94 patients >73 years old). gBRCApv frequency in 845 patients <74 years old was 9%. Patients with/without a family history of potentially BRCA-associated tumors had 14%/6% mutations. CONCLUSION: Based on our findings of a gBRCApv incidence higher than expected in a real-life series of Italian patients with incident PDAC, we recommend screening all PDAC patients <74 years old, regardless of family history and stage, due to the therapeutic implications and cancer risk prevention in patients' relatives.

Molecular cloning and expression of ovarian cathepsin D in seabream, Sparus aurata.

In marine fish producing pelagic eggs, the acquirement of buoyancy by the eggs through the hydration process is a key event of reproduction; moreover, the yolk proteolysis, which leads to buoyancy, seems to affect the fertility and survival of the spawned eggs. Recently we demonstrated that cathepsin D is the aspartic protease responsible for this intraoocytic processing of vitellogenin into yolk proteins. In the present study, we isolated, cloned, and sequenced the cDNA encoding cathepsin D and studied expression of the message by Northern blotting and whole-mount in situ hybridization. The full-length seabream cathepsin D cDNA is 1837 base pairs long, encoding a protein of 400 amino acids (aa) consisting of a signal peptide of 19 aa, a prosequence of 44 aa, and a mature peptide of 336 aa. An absolute sequence conservation at the aspartyl residues (+33 and +221) was found, and there are three potential N-glycosylation sites at +70, aa +189, and aa +274. The aa sequence of seabream cathepsin D reveals a high degree of sequence similarity with cathepsin D mRNAs from other organisms (73% sequence homology to mouse and rat, 72% to human and trout, 69% to chicken, 66% to pig, and 65% to Xenopus). The cathepsin D mRNA in floating eggs was present as a single band that was approximately 1.9 kilobases (kb) in size, while in the sinking eggs there were several fast-migrating bands (size range 1.3-0.2 kb). Whole-mount hybridization was used to investigate transcription of cathepsin D in the developing embryo; during the hatching period, cathepsin D mRNA-positive cells were distributed in a wide region between the trunk and the tail, and in the ventral region over the yolk ball. The highest levels of cathepsin D enzymatic activity were found in the sinking eggs and during the hatching period of embryonic development. These data suggest that cathepsin D can be considered a possible marker for egg quality.

Prevalence and prognostic significance of right-sided cardiac mobile thrombi in acute massive pulmonary embolism.

The prevalence of right-sided cardiac mobile thrombi, "in transit" from the systemic venous system, was 18% in a series of 130 patients with massive pulmonary embolism referred to early echocardiography and receiving thrombolytic drugs (56%) or intravenous heparin (40%). The mortality rate was lower than previously reported and seemed to be related more to clinical and hemodynamic impairment than to presence of thromboembolus.

[The early echocardiographic diagnosis of a massive pulmonary embolism]. / Diagnosi ecocardiografica precoce di embolia polmonare massiva.

BACKGROUND: In several cases of clinically suspected massive pulmonary embolism (MPE), a lung perfusion scanning and/or a pulmonary angiography are not quickly available or feasible. METHODS: Fifty patients admitted to our ICU with a clinically suspected MPE underwent an echocardiographic (Echo) investigation very shortly after onset (within 2 hours in 38 cases, and within 6 hours in 12). An Echo-Doppler study was also performed in 18 patients. RESULTS: Highly significant differences (p < 0.001) emerged between patients with PE and healthy age-mates for each type of Echo measurement and in all views. The RVDD/LVDD ratio turned out to be the most frequently affected parameter, being altered in 96% of cases. An abnormal diastolic leftward shift of the interventricular septum was detected in 81% of cases. Only one of our 50 patients failed to show any evidence of RV pressure overload; however, this was a patient with a severe dilated cardiomyopathy. In 22 cases in whom hemodynamic monitoring was performed, no significant correlation emerged between RVDD and LVDD, on one hand, mean PAP and cardiac index on the other. All 18 patients examined by Echo-Doppler had mild to moderate tricuspid regurgitation with a peak RV-RA gradient of 38 +/- 7 mm Hg (range 31-53 mm Hg). Seven patients (14%) were found to harbor right heart thrombi when first examined. Overall mortality in this uncommonly high risk population was as high as 28%. CONCLUSIONS: In a clinical setting suggesting a MPE, an Echo study conducted very shortly after onset may corroborate a tentative diagnosis of PE, thereby permitting timely fibrinolytic therapy pending a lung scan and/or angiography, or in situations where such imaging facilities are not available or readily usable.

[Heart arrest in acute pulmonary embolism. An anatomo-clinical study]. / L'arresto cardiaco nell'embolia polmonare acuta. Studio anatomo-clinico.

The Authors describe the modalities and mechanisms of cardiac arrest (CA) in the course of acute pulmonary embolism (PE). Clinical data refer to 39 CA episodes occurred in 28 patients with massive or submassive PE; autopsy data are from 26 of 28 patients of the same series. One-third of 39 CAs proved at least momentarily reversible; two-thirds were irreversible. Data analysis showed that most CA episodes, reversible or otherwise, seen in the course of PE were due to electromechanical dissociation (EMD). In fact, EMD was responsible for 12 of 13 reversible CAs and 22 of 26 irreversible arrests. EMD usually follows shock, but may occur unheralded. When EMD-induced CA is at least temporarily reversible, the heart rate is often normal or high and QRS complexes are narrow. In most cases the sudden rise of right ventricular afterload came on top of a pre-existing myocardial damage, for the most part of ischemic, sometimes necrotic, origin. In this series, therefore, it seems quite difficult to tell "primary" from "secondary" forms of EMD. External cardiac massage continued for as long as 40 minutes was associated in some cases with a bolus fibrinolytic infusion within minutes from occurrence of CA. Five of 7 patients so treated made a temporary recovery and two survived; at autopsy, none of the 5 patients who died showed any evidence of bleeding attributable to local injury.