Multidisciplinary clinical guidelines in proactive monitoring, early diagnosis, and effective management of trastuzumab deruxtecan (T-DXd)-induced interstitial lung disease (ILD) in breast cancer patients.

Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugate (ADC), has altered the treatment landscape in breast cancer (BC), irrespective of the HR-receptor status. The use of the agent is increasing, despite the finding that exposure to T-DXd increases the risk of interstitial lung disease (ILD), particularly in BC patients. Although T-DXd-related ILD can be potentially severe and life-threatening, most low-grade cases can be treated safely using a multidisciplinary approach comprising early and accurate diagnosis, effective management, close monitoring, and the prompt administration of steroids. Additionally, increasing patients' education on ILD symptoms ensures close attention and enables prompt reporting, enhancing patient outcomes. It is recommended that predictive biomarkers are assessed in patients with risk factors for developing ILD. Currently, diagnostic criteria comprise newly identified pulmonary opacities, the relation of symptom onset to medication initiation, and the exclusion of other causes of ILD. The general condition of patients is weakened during the management of ILD (BC progression and corticosteroid treatment). Consequently, BC chemotherapy might be attenuated. This highlights the importance of preventing (high-grade) ILD, especially since its use is expanded. Identifying high-risk patients, diagnosing, and customizing treatment is, however, challenging and additional information on patient selection is often not fully clarified. In this paper, we provide updated multidisciplinary clinical guidance for patient selection, proactive monitoring, early diagnosis, and effectively management of T-DXd-induced ILD in HER2-positive BC patients. We describe the risk factors for developing ILD, patients' characteristics of ILD, and the histopathological and radiographic characteristics of ILD, including real-world clinical practice reports. These recommendations provide a structured step-by-step approach for managing each suspected BC-related ILD grade.

Pulmonary transit time as a marker of diastolic dysfunction in Takotsubo syndrome.

AIM: To evaluate the pulmonary transit time (PTT) and its derived parameters using cardiac magnetic resonance imaging (CMRI) as markers of diastolic dysfunction in Takotsubo syndrome (TS) and its relationship with transthoracic echocardiography and CMRI parameters. MATERIALS AND METHODS: Twenty-two patients with TS, who exhibited diastolic dysfunction as assessed by transthoracic echocardiography, were enrolled retrospectively and the PTT, pulmonary transit time index (PTTI), and pulmonary blood volume index (PBVI) were evaluated using first-pass CMRI. PTT was calculated as the number of cardiac cycles required for a bolus of contrast agent to move from the right ventricle (RV) to the left ventricle (LV), whereas PTTI represents the PTT interval corrected for the heart rate. Finally, PBVI was calculated as the product of PTTI, and RV stroke volume indexed for body surface area. Normal references of PTT, PTTI, and PBVI were evaluated in a cohort of 20 age- and sex-matched healthy controls. RESULTS: Compared with healthy subjects, TS patients showed significantly higher PTT, PTTI, and PBVI (p=0.0001, p=0.0001, and p=0.002, respectively). Using multivariable logistic regression, PBVI provided the best differentiation between TS and controls (AUC 0.84). PBVI was significantly associated with the index of diastolic dysfunction and left atrial strain parameters. In addition, PBVI demonstrated a significant correlation with global T2 mapping (r=0,520, p=0,019). CONCLUSION: PTT and the derived parameters, as assessed using first-pass CMRI, are potential tools for assessing LV diastolic dysfunction in patients with TS.

Fetal programming of COVID-19: may the barker hypothesis explain the susceptibility of a subset of young adults to develop severe disease?

The risk stratification of young adults between subjects who will develop a mild form COVID-19 and subjects who will undergo a severe disease remains inaccurate. In this review, we propose that the Barker hypothesis might explain the increased susceptibility to severe forms of COVID-19 in subjects who underwent intrauterine growth restriction (IUGR). In this paper evidence indicating an association between a low birth weight and an adult phenotype which might favor a severe outcome of SARS-CoV-2 infection are presented: lower lung functional capacity; increased respiratory morbidity; changes in fibrinogen and Factor VII serum levels and dysregulation of the hemostasis and thrombosis system; acquisition of a pro-thrombotic phenotype; low nephron number, with decreased ability to sustain renal function and increased renal morbidity; heart remodeling, with a less efficient cardiac function; endothelial dysfunction, a risk factor for the insurgence of the multiple organ failure; remodeling of arteries, with changes in the elastic properties of the arterial wall, predisposing to the insurgence and progression of atherosclerosis; dysfunction of the innate immune system, a risk factor for immune diseases in adulthood. These data suggest that young and adult subjects born too small (IUGR) or too early (pre-terms) might represent a subgroup of "at risk subjects", more susceptible toward severe forms of COVID-19. Given that LBW may be considered a surrogate of IUGR, this phenotypic marker should be included among the indispensable clinical data collected in every patient presenting with SARS-COV-2 infection, irrespectively of his/her age.

Vaccine-induced severe thrombotic thrombocytopenia following COVID-19 vaccination: a report of an autoptic case and review of the literature.

OBJECTIVE: Vaccine-induced immune thrombocytopenia (VITT) is a new syndrome occurring primarily in healthy young adults, with a female predominance, after receiving the first dose of ChAdOx1 nCoV-19 vaccine. We describe VITT syndrome characterized by severe thrombosis and thrombocytopenia found in our patient, with fatal outcome. CASE REPORT: A 58-year-old man, after 13 days from the first administration of ChAdOx1 nCoV-19 vaccine (AstraZeneca), presented with abdominal pain, diarrhea and vomitus. Laboratory tests revealed a severe thrombocytopenia, low fibrinogen serum levels and marked increase of D-dimer serum levels. The patient quickly developed a multiple organ failure, till death, three days after the hospital admission. RESULTS: At histology, in the lungs, interalveolar septa appeared thickened with microthrombi in the capillaries and veins. Interalveolar septa appeared thickened and showed vascular proliferation. Thrombi were detected in the capillaries of glomerular tufts. In the hearth, thrombi were observed in veins and capillaries. In the liver, voluminous fibrin thrombi were diffusely observed in the branches of the portal vein. Microthrombi were also found in the vasa vasorum of the wall of abdominal aorta. In the brain, microthrombi were observed in the capillaries of the choroid plexuses. Diffuse hemorrhagic necrosis was observed in the intestinal wall with marked congestion of the venous vessels. CONCLUSIONS: In our patient, the majority of data necessary for a VITT final diagnosis were present: thrombocytopenia and thrombosis in pulmonary, portal, hepatic, renal and mesenteric veins, associated with a marked increase of D-dimer serum levels. The finding of cerebral thrombosis in choroid plexuses, is a new finding in VITT. These features are suggestive for a very aggressive form of VITT.

Perivascular Fat Density and Contrast Plaque Enhancement: Does a Correlation Exist?

BACKGROUND AND PURPOSE: Inflammatory changes in the fat tissue surrounding the coronary arteries have been associated with coronary artery disease and high-risk vulnerable plaques. Our aim was to investigate possible correlations between the presence and degree of perivascular fat density and a marker of vulnerable carotid plaque, namely contrast plaque enhancement on CTA. MATERIALS AND METHODS: One-hundred patients (76 men, 24 women; mean age, 69 years) who underwent CT angiography for investigation of carotid artery stenosis were retrospectively analyzed. Contrast plaque enhancement and perivascular fat density were measured in 100 carotid arteries, and values were stratified according to symptomatic (ipsilateral-to-cerebrovascular symptoms)/asymptomatic status (carotid artery with the most severe degree of stenosis). Correlation coefficients (Pearson ρ product moment) were calculated between the contrast plaque enhancement and perivascular fat density. The differences among the correlation ρ values were calculated using the Fisher r-to-z transformation. Mann-Whitney analysis was also calculated to test differences between the groups. RESULTS: There was a statistically significant positive correlation between contrast plaque enhancement and perivascular fat density (ρ value = 0.6582, P value = .001). The correlation was stronger for symptomatic rather than asymptomatic patients (ρ value = 0.7052, P value = .001 versus ρ value = 0.4092, P value = .001). CONCLUSIONS: There was a positive association between perivascular fat density and contrast plaque enhancement on CTA. This correlation was stronger for symptomatic rather than asymptomatic patients. Our results suggest that perivascular fat density could be used as an indirect marker of plaque instability.

Automated carotid intima-media thickness and its link for prediction of SYNTAX score in Japanese coronary artery disease patients.

AIM: The purpose of this study was to evaluate whether the automated carotid intima-media thickness (CIMT) identified by using automated software could predict the SYNTAX score for coronary artery disease (CAD) patients. METHODS: Three-hundred-seventy consecutive patients (males 218; median age 69±11 years) who underwent carotid-ultrasound and coronary angiography were analyzed. Two experienced interventional cardiologists calculated the SYNTAX score from the carotid angiograms. After ultrasonographic examinations were performed, the plaque score (PS) was calculated and automated carotid IMT analysis was obtained by a fully automated algorithm. Correlation and stepwise logistic regression analysis were calculated and also the receiver operating characteristics (ROC) curve analysis was computed. RESULTS: The mean SYNTAX score was 8.1±14.4; the PS was 7.1±14.4 and the mean CIMT was 0.86±0.23 mm (Normality rejected with a P-value of 0.001). A statistically significant correlation was found between the CIMT and SYNTAX score (r=0.323; P=0.0001) and between the PS and SYNTAX score (r=0.583; P=0.0001). The area under the ROC curve (Az) between CIMT and coronary artery disease was 0.648 (P=0.0001) and the CIMT of 1 mm or more was associated with the presence coronary artery disease with a specificity of 90.5%. Logistic regression analysis confirmed the association between CIMT and SYNTAX score (P=0.0002). CONCLUSIONS: Results of our study using an automated algorithm showed a statistical significant association between CIMT and SYNTAX score and indicated that CIMT may be considered a reliable parameter for prediction of SYNTAX score in coronary artery disease patient population from Japan.

[HFR-AEQUILIBRIUM and intradialytic cardiovascular stability: results of the first multicenter study in Lazio]. / HFR-AEQUILIBRIUM e stabilità cardiovascolare intradialitica: risultati del primo studio multi-centrico laziale.

Intradialytic hypotension (IDH) is a still-frequent and poorly-understood complication of haemodialysis. Haemofiltration has recently been shown to reduce the phenomenon of IDH. HFR-Aequilibrium adds to traditional HFR and is, in practice, a variant comprising endogenous re-infusion of haemodiafiltration with dialysate sodium concentration and ultrafiltration rate profiles elaborated by the 'Profiler' plasma sodium biofeedback system, and measurement of plasma sodium via the on-line Natrium sodium sensor.

Thirst distress and interdialytic weight gain: a study on a sample of haemodialysis patients.

Severe thirst distress is frequent in haemodialysis (HD) patients, and some studies have noted a positive relationship between thirst and an increased interdialytic weight gain (IDWG). The goal of this explorative study was to describe the perception of thirst and correlated symptoms in HD patients, and verify the correlation between thirst intensity and the IDWG. The study was performed on an opportunistic sample of patients treated in the dialysis unit of a city hospital in the North-East of Italy. Data were collected using a questionnaire containing a demographic and a clinical part, the Thirst Distress Scale, and a Visual Analogue Scale (VAS) 0-10 about thirst intensity. The sample of 107 patients was composed of 71 males (66%). The average age was 68 years (SD 12, median 70 years). Fluid restriction causes severe physical discomfort and xerostomy. 66% of the respondents declared a thirst level of more than 7 on the VAS scale. The average IDWG was 2.47 kg. The chi2 test did not show a significant difference when correlated with thirst intensity (p = 0.88).

[Diastolic heart failure]. / Lo scompenso cardiaco diastolico: aspetti clinici, fisiopatologici e terapeutici.

Until recently, the development of heart failure was related exclusively to the acute or chronic impairment in systolic function. Currently, the concept of heart failure not sustained primarily by a significant reduction in contractility has been clearly defined by several epidemiological and pathophysiological observations. This condition, defined as 'diastolic heart failure' or 'heart failure with preserved systolic function' can be related to different cardiac diseases with a higher prevalence in the elderly. Afterload mismatch situations, such as hypertension or aortic stenosis, as well as hypertrophic cardiomyopathy or pericardial diseases, determine this common clinical syndrome more frequently. Currently, the treatment of diastolic heart failure is still empirical, as there are few and inconclusive data coming from evidence-based medicine.

Cumulative effect of complete left bundle-branch block and chronic atrial fibrillation on 1-year mortality and hospitalization in patients with congestive heart failure. A report from the Italian network on congestive heart failure (in-CHF database).

BACKGROUND: Many clinical variables have been proposed as prognostic factors in patients with congestive heart failure. Among these, complete left bundle-branch block and atrial fibrillation are known to impair significantly left ventricular performance in patients with congestive heart failure. However, their combined effect on mortality has been poorly investigated. The aim of this study was to determine whether left bundle-branch block associated with atrial fibrillation had an independent, cumulative effect on mortality for congestive heart failure. METHODS AND RESULTS: We analysed the Italian Network on congestive heart failure (IN-CHF) Registry that was established by the Italian Association of Hospital Cardiologists in 1995. One-year follow-up data were available for 5517 patients. Complete left bundle-branch block and atrial fibrillation were associated in 185 (3.3%) patients. In this population the cause of congestive heart failure was dilated cardiomyopathy (38.4%), ischaemic heart disease (35.1%), hypertensive heart disease (17.3%), and other aetiologies (9.2%). This combination of electrical defects was associated with an increased 1-year mortality from any cause (hazard ratio, HR: 1.88; 95% CI 1.37-2.57) and sudden death (HR: 1.89; 95% CI 1.17-3.03) and 1-year hospitalization rate (HR: 1.83; 95% CI 1.26-2.67). CONCLUSIONS: In patients with congestive heart failure, the contemporary presence of left bundle-branch block and atrial fibrillation was associated with a significant increase in mortality. This synergistic effect remained significant after adjusting for clinical variables usually associated with advanced heart failure. We can conclude that this combination of electrical disturbances identifies a congestive heart failure specific population with a high risk of mortality.

Metoprolol-induced functional benefit in dilated cardiomyopathy is sustained over four years and favorably influences outcome.

BACKGROUND: Beta-blockers improve survival and ventricular function in patients with heart failure. We evaluated the long-term persistence of metoprolol-induced improvement and its impact on prognosis in idiopathic dilated cardiomyopathy. METHODS: Two hundred and four of 586 patients enrolled in a registry on the natural history of idiopathic dilated cardiomyopathy survived 4 years without transplantation; 98 of them were on standard heart failure treatment, whereas 106 took metoprolol in addition. We analyzed the effects of treatment using beta-blockers in terms of changes in left ventricular ejection fraction (LVEF), NYHA functional class and left ventricular end-diastolic diameter index (LVEDDI) after 1, 2 and 4 follow-up years in order to elaborate an improvement score that was related to the subsequent outcome over 60 months after the 4-year follow-up visit. RESULTS: Greater LVEF increases and NYHA functional class and LVEDDI decreases were observed in patients submitted to metoprolol vs standard treatment at all stages of follow-up. Changes (delta vs baseline) for LVEF (p = 0.02), NYHA functional class (p = 0.0001) and LVEDDI (p = 0.004) were maximal during the first year (10 +/- 11 vs 6 +/- 12 units, -0.72 +/- 0.77 vs -0.23 +/- 0.81, -3.5 +/- 5 vs -1.6 +/- 3.5 mm), persisted at 2 (12 +/- 12 vs 8 +/- 12 units, -0.80 +/- 0.70 vs -0.37 +/- 0.87, -4.2 +/- 5 vs -2.3 +/- 4 mm) but showed a trend to decline at 4 years (11 +/- 12 vs 8 +/- 13 units, -0.54 +/- 0.90 vs -0.24 +/- 0.91, -4.3 +/- 5 vs -2.3 +/- 5 mm) of follow-up. Improvement at 4 years was associated with a better transplant-free survival (81 vs 52%, p = 0.0005, odds ratio 0.36, 95% confidence interval 0.18 to 0.74). CONCLUSIONS: In idiopathic dilated cardiomyopathy, the more significant improvement in symptoms and left ventricular function and size, that is observed following treatment using metoprolol, translates into a better outcome. These benefits peak within the first 2 years of start of treatment but may begin to fade thereafter.

Correlation between chronic prostatitis syndrome and pelvic venous disease: a survey of 2,554 urologic outpatients.

OBJECTIVES: In this study we evaluated the association between chronic prostatitis syndrome (CPS), varicocele and hemorrhoids as manifestations of a pelvic venous disease. METHODS: Our retrospective study was based upon 2,554 patients treated in two general urology clinics over the past 10 years. We have assessed the incidence of CPS among urological patients. RESULTS: We found 483 patients with CPS, representing 18.9% of the total number of visits at the outpatient clinic. In this group the percentage of varicocele and hemorrhoids was 14.69 and 8.48%, whereas in a control group these figures were 5.02 and 5.84%, respectively (p<0.001 and 0.1054). Such a difference is statistically significant and suggests a higher prevalence of varicocele in the CPS group, but this may be due to a methodological error of the retrospective study. CONCLUSION: Only a prospective study, which is of importance due to the frequency of the disease, can give a precise answer to this question.

Alcohol abuse and dilated cardiomyopathy in men.

Excessive ethanol intake is reported in 3% to 40% of patients with idiopathic dilated cardiomyopathy (IDC). In the prevasodilator era, the prognosis was reportedly better in alcoholic than in IDC patients, an advantage limited to abstinent patients. No large series of patients systematically treated with angiotensin-converting enzyme inhibitors has since been described. We analyzed long-term outcome according to alcohol abuse in male patients with IDC. Among 338 men who had been prospectively enrolled in a multicenter registry, 79 (23%) were defined as alcohol abusers and further classified at follow-up as having stopped (AAS) or continued (AAC) abuse. AAC subjects at enrollment reported a higher daily alcohol intake than AAS subjects (178 +/- 113 vs 127 +/- 54 g/day, p = 0.012). During a mean of 59 +/- 35 months, 102 patients died and 45 underwent transplantation. Seven-year transplant-free survival was significantly lower in alcohol abusers (41%) than in patients with IDC (53%, p = 0.026), and significantly lower in AAC subjects (27%) than in either patients with IDC or AAS (45%) (p = 0. 018). Although IDC patients had beneficial changes in left ventricular function at follow-up, only AAS patients had significant improvement in ejection fraction. In this large series of patients treated with angiotensin-converting enzyme inhibitors and prospectively followed up, excessive alcohol intake was found in about one fourth of cases and persistent alcohol abuse correlated with a worse prognosis and function at follow-up.

Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease.

BACKGROUND: Inherited mutations cause approximately 35 percent of cases of dilated cardiomyopathy; however, few genes associated with this disease have been identified. Previously, we located a gene defect that was responsible for autosomal dominant dilated cardiomyopathy and conduction-system disease on chromosome 1p1-q21, where nuclear-envelope proteins lamin A and lamin C are encoded by the LMNA (lamin A/C) gene. Mutations in the head or tail domain of this gene cause Emery-Dreifuss muscular dystrophy, a childhood-onset disease characterized by joint contractures and in some cases by abnormalities of cardiac conduction during adulthood. METHODS: We evaluated 11 families with autosomal dominant dilated cardiomyopathy and conduction-system disease. Sequences of the lamin A/C exons were determined in probands from each family, and variants were confirmed by restriction-enzyme digestion. The genotypes of the family members were ascertained. RESULTS: Five novel missense mutations were identified: four in the alpha-helical-rod domain of the lamin A/C gene, and one in the lamin C tail domain. Each mutation caused heritable, progressive conduction-system disease (sinus bradycardia, atrioventricular conduction block, or atrial arrhythmias) and dilated cardiomyopathy. Heart failure and sudden death occurred frequently within these families. No family members with mutations had either joint contractures or skeletal myopathy. Serum creatine kinase levels were normal in family members with mutations of the lamin rod but mildly elevated in some family members with a defect in the tail domain of lamin C. CONCLUSIONS: Genetic defects in distinct domains of the nuclear-envelope proteins lamin A and lamin C selectively cause dilated cardiomyopathy with conduction-system disease or autosomal dominant Emery-Dreifuss muscular dystrophy. Missense mutations in the rod domain of the lamin A/C gene provide a genetic cause for dilated cardiomyopathy and indicate that this intermediate filament protein has an important role in cardiac conduction and contractility.

[Infections from extemporaneous catheters for hemodialysis. Experience in a center]. / Infezione dei cateteri estemporanei per emodialisi. Esperienza di un centro.

BACKGROUND AND AIMS: This study reports a retrospective evaluation of the predominance of infection in 67 dual lumen central venous catheters (CVC), 35 of which were positioned in the femoral vein by the nephrological team and 32 in the subclavian vein by anesthetists. METHODS: The microorganisms responsible for infection, the prevalence of clinically symptomatic infections, the relationship between CVC-correlated infection and the time the catheter remained inserted were evaluated, together with a comparison between the two different insertion sites. RESULTS: Culture tests, performed using Maki's semiquantitative technique, gave positive results in 16/67 (23.8%) cases. The main pathogenic agents found were Staphylococcus epidermidis (37.5%) and Staphylococcus aureus (31.2%). In 3/16 cases (18.78%) infections were clinically symptomatic. The mean permanence of CVC with positive cultures was not statistically different to the mean permanence of CVC with negative cultures (22.44 +/- 13.48 vs 18.38 +/- 17.76). The microorganisms isolated on femoral and subclavian catheters showed a comparable distribution and the prevalence of infection was not statistically different in the two insertion sites. CONCLUSIONS: In conclusion, in the absence of infection, the authors tend to keep working catheters in the site, thus avoiding repeated invasive manoeuvres for replacement and/or repositioning, whereas in the presence of suspected systemic infection they feel it is more prudent to remove the CVC without waiting for the results of the hemoculture, starting first empiric and then specific antibiotic treatment on the basis of the antibiogram.

Dystrophin gene abnormalities in two patients with idiopathic dilated cardiomyopathy.

Two new cases of dilated cardiomyopathy (DC) caused by dystrophinopathy are reported. One patient, a 24 year old man, had a family history of X linked DC, while the other, a 52 year old man, had sporadic disease. Each had abnormal dystrophin immunostaining in muscle or cardiac biopsy specimens, but neither had muscle weakness. Serum creatine kinase activity was raised only in the patient with familial disease. Analysis of dystrophin gene mutations showed a deletion of exons 48-49 in the patient with familial DC and of exons 49-51 in the other. Dystrophin transcription in cardiac tissue from the patient with sporadic disease showed abundant expression, predominantly of the muscle isoform. This study, together with previous reports, suggests that some patients with DC have a dystrophinopathy that can be diagnosed using a combination of biochemical and genetic analyses.