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Endometrial cancer (EC) is the most common gynecological cancer in developed countries. The ESGO/ESTRO/ESP updated evidence-based guidelines in 2020, introducing molecular classification to guide EC treatment. The genomic-based approach has identified four prognostic subgroups of EC. Each of these may benefit from a tailored treatment depending on the molecular profile, the histotype, and stage of disease for the adjuvant and the metastatic/recurrent setting. Several clinical trials are now ongoing to identify the best treatment according to the molecular profile of EC.This review analyzes tailored treatment for EC according to the molecular profile, both in the adjuvant and in the metastatic/recurrent setting. The authors review the results of clinical studies and highlight ongoing trials.Several new agents are under evaluation in order to personalize EC treatment according to specific molecular profiles in the adjuvant, advanced, and recurrent settings. Clinical trials investigating the impact of molecular classification have yielded encouraging results. EC can no longer be considered a single tumor entity susceptible to a single treatment modality but rather be split into four distinct types, requiring tailored treatments.

The prognosis of patients with advanced endometrial cancer is poor with limited therapeutic options. Nevertheless, the integration of molecular features in the clinico-pathological classification of endometrial cancer has significantly refined prognostic risk groups, representing a major breakthrough not only in the management of the disease but also in treatment perspectives. New therapeutic compounds such as target therapies, immunotherapy, and hormonal therapies have emerged for this clinical setting. Furthermore, molecular-driven clinical trials may improve significantly the efficacy of new treatments selecting those patients who are highly likely to respond. This review aims at describing the state of the art of advanced stage III-IVa endometrial cancer management, providing also the most interesting clinical perspectives.

Lurbinectedin is an antitumor agent belonging to the natural marine-based tetrahydroisoquinoline family which has shown very promising clinical activity with a favorable safety profile in many types of cancer. Preclinical evidence showed that lurbinectedin inhibits active transcription and binds to GC-rich sequences, leading to irreversible degradation of RNA polymerase II and generation of single- and double-strand DNA breaks and, as a consequence, apoptosis of tumor cells. In addition, lurbinectedin has demonstrated modulation of the tumor microenvironment and activity against cancer cells harboring homologous recombination DNA repair deficiency. Although considerable improvements have been made in the treatment of epithelial ovarian cancer, most patients with advanced disease experience recurrence with a dismal prognosis due to chemotherapy (mainly platinum) resistance. Platinum-resistant/refractory ovarian cancer remains a difficult-to-treat setting of disease, and currently, the exploration of new therapeutic approaches represents a main field of interest. Although the CORAIL phase III study did not meet its primary endpoint, the results suggest that lurbinectedin might be a valid alternative for patients that have exhausted therapeutic options. This article will focus on the clinical evidence, the most recent investigations, and the future perspective regarding the use of lurbinectedin in ovarian cancer.

In the huge spectrum of lung neuroendocrine neoplasms, typical and atypical carcinoids should be considered as a separate biological entity from poorly differentiated forms, harboring peculiar molecular alterations. Despite their indolent behavior, lung carcinoids correlate with a worse survival. To date, only limited therapeutic options are available and novel drugs are strongly needed. In this work, we extensively reviewed scientific literature exploring available therapeutic options, new molecular targets and future perspectives in the management of well differentiated neoplasms of bronchopulmonary tree. Systemic therapy represents the main option in advanced and unresectable disease; accepted choices are somatostatin analogs, peptide receptor radionuclide therapy, everolimus and chemotherapy. To date, an univocal treatment strategy has not been identified yet, thus tailored therapeutic algorithms should consider treatment efficacy as well as safety profiles. Several molecular alterations found in carcinoid tumors might act as molecular targets leading to development of new therapeutic options. Further studies are necessary to identify new potential “druggable” molecular targets in the selected subset of low-grade lung carcinoids. Furthermore, evaluating the available therapies in more homogeneous population might improve their efficacy through a perfect tailoring of treatment options.

Fungal compounds have long been used for centuries as food supplements. β-glucans have been identified as the most interesting molecules with beneficial effects in several chronic diseases. In vitro studies have shown that they are able to elicit the immune cells maturation and activation with the result of an increased release of proinflammatory cytokines and chemokines and a stimulation of anti-bacterial activity of macrophages and neutrophils. As β-glucans enhance pathogen elimination through non-self antigens identification, they can also direct immune response against tumor cells. These compounds also stimulate the activity on adaptive immune cells and they have been regarded as biological response modifiers. In this way, β-glucans can be exploited as adjuvant cancer therapy, in particular by a synergic action with chemotherapy or immunotherapy. In the immuno-oncology era, the need is to identify innovative drugs that can simultaneously target and inhibit different biological processes relevant for cancer cells survivors. Recent clinical studies showed promising results about the combination of β-glucans and immune checkpoint inhibitors for patients affected by different solid tumors. This review aims to investigate molecular mechanisms of action of β-glucans and is focused on their application in clinical practice as immune-adjuvants for treatment of cancer patients.

Chronic heart failure is one of the most important geriatric syndromes, associated with disability, increased hospital admissions, and high mortality. The aim of this study was to evaluate the existence of age-related differences in clinical effectiveness and outcomes of cardiac resynchronization therapy (CRT), alone or in combination with an implantable cardioverter-defibrillator (CRT-D), in a large, real-world registry. A total of 1,787 patients admitted for CRT or CRT-D to the 117 centers participating in the InSync/InSync ICD Italian Registry from 1999 to 2005 were evaluated. Patients were divided into 3 age groups:65 years (n = 571), 65 to 74 years (n = 740), and ≥75 years (n = 476). The left ventricular ejection fraction did not differ in the 3 groups (26 ± 8% vs 26 ± 7% vs 27 ± 8%, p = 0.123). Atrial fibrillation prevalence demonstrated an age-related increase. The use of recommended medical therapy for chronic heart failure decreased with age, as well as CRT-D implantation (p0.001). The percentage of echocardiographic responders to CRT was similar in the 3 groups, and New York Heart Association class significantly improved independent of age. During the follow-up period (19 ± 13 months), all-cause mortality was higher in patients aged ≥75 years than in those aged65 years (p = 0.005). In the whole population, mortality was associated with the nonresponder condition, the presence of atrial fibrillation and the lack of prescription of recommended medical therapy. In conclusion, CRT improved left ventricular performance and functional capacity independent of age. The proportion of the responder condition to CRT was the same in all groups. Pharmacologic undertreatment is an important issue in a "real-world" geriatric population.

Simultaneous stimulation of 2 left ventricular (LV) sites could enhance the effectiveness of cardiac resynchronization therapy (CRT). The aim of this study was to evaluate the acute hemodynamic response to dual-site LV CRT. Two LV pacing leads were successfully implanted in 12 CRT candidates (New York Heart Association classes III to IV, QRSor=120 ms). Target positions were the lateral or posterolateral vein (site A) and anterior or anterolateral vein (site B). A conductance catheter was placed in the left ventricle for pressure-volume measurements. Tested CRT configurations were alternated by atrial overdrive pacing at a fixed rate and included site A and B single-site CRT and dual-site LV CRT (2 LV sites plus right ventricular apex) at 4 atrioventricular intervals. Overall, single-site LV CRT significantly enhanced stroke volume, stroke work, maximum pressure derivative, and conductance-derived indexes of LV synchrony when delivered in site A, whereas no significant changes were noticed with pacing in site B. Specifically, site-A pacing resulted in a higher stroke volume increase (LV pacing site associated with the best hemodynamic response [best-LV]) in 8 patients, and site-B pacing, in 4 patients. At intermediate atrioventricular intervals, dual-site LV CRT resulted in improved stroke volume, stroke work, maximum pressure derivative, and LV synchrony with respect to single-site CRT when delivered at the best-LV (all p0.05). However, single-site CRT at best-LV produced results similar to dual-site LV CRT when the atrioventricular interval was optimized in each patient. In conclusion, adding a second LV lead does not result in further improvement in acute hemodynamic response with respect to standard CRT when the single LV pacing site and atrioventricular interval are optimal.

Automatic mode switching, enabling the pacemaker to pace at an independent ventricular rate when atrial fibrillation occurs, was introduced to provide protection against rapid ventricular pacing during atrial arrhythmia. This study proposes a technique to test automatic mode switching performance. It is based on a programmable system (Arrhythmia Simulator) generating pulse trains that, when applied to the patient's skin, may interfere with the implanted device simulating supraventricular arrhythmias. The amplitude of the output signals is 5 V and they are delivered through an output resistance of 50 kΩ limiting the current to 100 μA that guarantees no risk of muscle stimulation during the test and meanwhile low noise signals on the surface ECG. The duration of pulses is 20 ms. Pulses delivered by the Arrhythmia Simulator were correctly sensed by the pacemaker's atrial channel, and the detected amplitude was 2 ± 0.8 mV, ranging from 1 to 3 mV. The performance of the system was reliable and safe in every patient despite the use of different pacemaker leads. Automatic mode switching was induced in every patient at every attempt. The pulses delivered by Arrhythmia Simulator didn't alter the quality of ECG tracings making easy and reliable the analysis.

Recently, two-dimensional (2D) speckle-tracking echocardiography has enabled assessment of a particular behaviour of left ventricular (LV) motion defined as twisting/untwisting. The aim of our study is to evaluate whether in early stage of hypertension and systemic amyloidosis, subclinical alteration of LV twist and untwist is already present even if no LV hypertrophy is evidenced. Forty-seven patients with light chain immunoglobulin amyloidosis (AL) entered the study and were classified having cardiac amyloidosis (CA) or not (NCA) if the mean value of LV wall thickness was ≥12 mm or not. Twenty-two consecutive patients with history of arterial essential hypertension (Hyp Group) and no sign of LV hypertrophy were enrolled. A total of 26 asymptomatic healthy subjects, age-matched, were analysed as control group. All three groups of patients and healthy subjects underwent traditional and 2D speckle-tracking echocardiography evaluation. LV diameters, volumes, wall thickness, mass, ejection fraction, E/A and E/E' ratio were evaluated. Twisting and untwisting rates were significantly increased in NCA and Hyp group when compared with CA and control group. Moreover, despite similar LV mass and diastolic dysfunction degree, untwisting rate peak was significantly delayed in NCA when compared with Hyp group. In patients with CA, untwisting rate delay was similar to patients with NCA. Our results show that amyloidosis and systemic hypertension produce both LV twist and untwist rate enhancement before LV hypertrophy is developed. In patients with amyloidosis irrespectively of LV infiltration degree, a significant LV untwisting rate peak delay occurs suggesting that different aetiology of cardiac involvement could differently affect LV untwisting rate.

Summary Introduction: Recently, two-dimensional (2D) speckle-tracking echocardiography has enabled assessment of a particular behaviour of left ventricular (LV) motion defined as twisting/untwisting. The aim of our study is to evaluate whether in early stage of hypertension and systemic amyloidosis, subclinical alteration of LV twist and untwist is already present even if no LV hypertrophy is evidenced. Methods: Forty-seven patients with light chain immunoglobulin amyloidosis (AL) entered the study and were classified having cardiac amyloidosis (CA) or not (NCA) if the mean value of LV wall thickness was ≥12 mm or not. Twenty-two consecutive patients with history of arterial essential hypertension (Hyp Group) and no sign of LV hypertrophy were enrolled. A total of 26 asymptomatic healthy subjects, age-matched, were analysed as control group. All three groups of patients and healthy subjects underwent traditional and 2D speckle-tracking echocardiography evaluation. LV diameters, volumes, wall thickness, mass, ejection fraction, E/A and E/E′ ratio were evaluated. Results: Twisting and untwisting rates were significantly increased in NCA and Hyp group when compared with CA and control group. Moreover, despite similar LV mass and diastolic dysfunction degree, untwisting rate peak was significantly delayed in NCA when compared with Hyp group. In patients with CA, untwisting rate delay was similar to patients with NCA. Conclusion: Our results show that amyloidosis and systemic hypertension produce both LV twist and untwist rate enhancement before LV hypertrophy is developed. In patients with amyloidosis irrespectively of LV infiltration degree, a significant LV untwisting rate peak delay occurs suggesting that different aetiology of cardiac involvement could differently affect LV untwisting rate.