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PolyADP-ribose polymerase (PARP) inhibitors (PARPis) represent the first clinically approved drugs able to provoke “synthetic lethality” in patients with homologous recombination-deficient (HRD) tumors. Four PARPis have just received approval for the treatment of several types of cancer. Besides, another three additional PARPis underlying the same mechanism of action are currently under investigation. Despite the success of these targeted agents, the increasing use of PARPis in clinical practice for the treatment of different tumors raised the issue of PARPis resistance, and the consequent disease relapse and dismal prognosis for patients. Several mechanisms of resistance have been investigated, and ongoing studies are currently focusing on strategies to address this challenge and overcome PARPis resistance. This review aims to analyze the mechanisms underlying PARPis resistance known today and discuss potential therapeutic strategies to overcome these processes of resistance in the future.

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.

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.

Background Specific components of lipid profile seem to differently impact on immune activity against cancer and unraveling their prognostic role in patients with solid cancer treated with immune checkpoint inhibitors (ICIs) is needed. Materials and Methods We retrospectively collected baseline clinicopathological characteristics including circulating lipid profile (total cholesterol [TC], triglycerides [TG], low-density lipoproteins [LDL], high-density lipoproteins [HDL]) of patients with consecutive solid cancer treated with ICIs, and we investigated their role in predicting clinical outcomes. Results At a median follow-up of 32.9 months, among 430 enrolled patients, those with TC ≥ 200 mg/dl showed longer median progression-free survival (mPFS; 6.6 vs. 4.7 months, P = .4), although not reaching statistical significance, and significantly longer median overall survival (mOS; 19.4 vs. 10.8 months, P = .02) compared to those with TC < 200 mg/dl. Conversely, patients with TG ≥150 mg/dl displayed shorter PFS (3.4 vs. 5.1 months, P = .02) and OS (7.1 vs. 12.9 months, P = .009) compared to those with TG <150 mg/dl. TC and TG were then combined in a “LIPID score” identifying three subgroups: good-risk (GR) (TC ≥200 mg/dl and TG <150 mg/dl), intermediate-risk (IR) (TC <200 mg/dl and TG <150 mg/dl or TC ≥200 mg/dl and TG ≥150 mg/dl) and poor-risk (PR) (TC <200 mg/dl and TG ≥150 mg/dl). The mPFS of GR, IR, and PR groups was 7.8, 4.3, and 2.5 months, respectively (P = .005); mOS of GR, IR, and PR was 20.4, 12.4, and 5.3 months, respectively (P < .001). At multivariable analysis, the PR profile represented an independent poor prognostic factor for both PFS and OS. Conclusions We developed a lipid score that defined subgroups of patients with cancer who differently benefit from ICIs. Further mechanistic insights are warranted to clarify the prognostic and predictive role of lipid profile components in patients treated with ICIs. Specific components of lipid profile have different effects on immune activity against cancer. This study aimed to unravel their prognostic role in solid tumors treated with immune checkpoint inhibitors.

This review provides a comprehensive update on recent evidence regarding gynecologic tumors associated with Lynch Syndrome (LS). Endometrial cancer (EC) and ovarian cancer (OC) are the first and second most common gynecologic malignancies in developed countries, respectively, and LS is estimated to be the hereditary cause in 3% of both EC and OC. Despite the increasing evidence on LS-related tumors, few studies have analyzed the outcomes of LS-related EC and OC stratified by mutational variant. This review aims to provide a comprehensive overview of the literature and comparison between updated international guidelines, to help outline a shared pathway for the diagnosis, prevention, and management of LS. Through the widespread adoption of the immunohistochemistry-based Universal Screening, LS diagnosis and identification of mutational variants could be standardized and recognized by international guidelines as a feasible, reproducible, and cost-effective method. Furthermore, the development of a better understanding of LS and its mutational variants will support our ability to better tailor EC and OC management in terms of prophylactic surgery and systemic treatment in the light of the promising results shown by immunotherapy.

In recent years, BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi), together with immune checkpoint inhibitors (ICIs), have changed the therapeutic strategy of cutaneous melanoma, both in adjuvant and metastatic settings. These inhibitors have significantly improved the clinical outcome for patients with melanoma, including in both BRAF-mutated and BRAF-wild type disease. Some preclinical and clinical studies have revealed that BRAFi and MEKi are able to influence T- and B-cell activation, and to modulate immune system activation within the tumor microenvironment. Dabrafenib and trametinib have been shown to enhance the expression of melanoma antigens on BRAF-mutated cells, and to favor both a cytotoxic and immune response against melanoma cells. Thereby, the present study described a case series of five women treated with BRAFi and MEKi, in both adjuvant and metastatic settings, that experienced potential immune-related adverse events. In particular, these patients exhibited sarcoidosis, mesenteric panniculitis, lymphocytic colitis and neuropathy of phrenic nerve. Considering that T and B cells are responsible for immune-related adverse events, as observed in patients treated with ICIs, the present study suggested a possible role of BRAFi and MEKi as triggers of immune system activation and subsequent immune-related toxicities.

ObjectivesPARP inhibitors alone and in combination with Bevacizumab have shown significant clinical benefit as maintenance therapy in ovarian cancer (OC) patients regardless BRCA mutations and in homologous-recombination deficiency (HRD) positive women, respectively. However, despite the improvements in the therapeutic algorithm of OC over the years, the best treatment in HRD positive patients and the preferred treatment in HRD negative tumors have not been well defined. MITO 25.1 aims to evaluate the best first line treatment in the different molecular subgroups, evaluated with Foundation Medicine LOH test.MethodsMITO 25.1 is a multicenter, randomized, phase II study that will evaluate the effect of Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib vs Carboplatin-Paclitaxel-Rucaparib on progression-free survival (PFS) in OC patients treated according to HRD status. HRD negative patients will be randomized in ARM A to receive Carboplatin + Paclitaxel + Bevacizumab q21 followed by Bevacizumab q 21 or in ARM B to receive Carboplatin + Paclitaxel q 21 followed by Rucaparib as maintenance. HRD positive patients will be randomized in ARM B or in ARM C to receive Carboplatin + Paclitaxel + Bevacizumab q21 followed by Bevacizumab + Rucaparib as maintenance. The primary endpoint will be PFS.ResultsTrial in progress.there are no available results at the time of submission.ConclusionsTrial in progress:there are no available conclusions at the time of submission

Introduction/BackgroundPoly (ADP-ribose) polymerase (PARP) inhibitors alone and in combination with Bevacizumab have shown significant clinical benefit as maintenance therapy in women with newly diagnosed ovarian cancer (OC) regardless BRCA mutational status and in homologous-recombination deficiency (HRD) positive patients, respectively. However, despite the remarkable improvements in the therapeutic algorithm of OC disease over the years, the best first line treatment is still controversial.MethodologyMITO 25.1 is a multicenter, randomized open-label, phase II study comparing Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib vs Carboplatin-Paclitaxel-Rucaparib.Eligible patients, with histological confirmed high grade serous or endometrioid advanced OC, will be randomized in a 1:1 ratio according to HRD status.Results HRD negative patients: ARM A: Carboplatin AUC 5 + Paclitaxel 175 mg/m2 q 21 + Bevacizumab 15 mg/kg for 5 cycles (starting from cycle 2) followed by Bevacizumab 15 mg/kg q 21 for 17 cycles, ARM B: Carboplatin AUC 5 + Paclitaxel 175 mg/m2 q 21 for 6 cycles followed by Rucaparib 600 mg BID q 28 for 24 cycles as maintenance HRD positive patients: ARM B: Carboplatin AUC 5 + Paclitaxel 175 mg/m2 q 21 for 6 cycles followed by Rucaparib 600 mg BID q 28 for 24 cycles as maintenance: ARM C: Carboplatin AUC 5+ Paclitaxel 175 mg/m2 q 21 + Bevacizumab 15 mg/kg for 5 cycles (starting from cycle 2) followed by Bevacizumab 15 mg/kg q 21 days for 16 cycles + Rucaparib 500 mg part BID q 28 for 24 cycles as maintenanceConclusionThe primary endpoint will be PFS. The secondary endpoints will be overall survival (OS), PFS2, adverse events according to CTCAE 5.0 and patient-reported outcome. Patients recruiting started in March 2021. To date, 159 of the 300 patients planned have been enrolled.

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 k[Omega] limiting the current to 100 [mu]A 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.

On November 30, 1998, the historic centre of Urbino was inscribed on the UNESCO World Heritage List, and the municipality developed the Management Plan for the UNESCO site in the years 2012-2013. The proposed work is part of the University of Urbino's research project for a Plan for the Conservation, Enhance- ment, and Management of its Architectural Heritage (35 buildings, eleven of which are historic buildings owned in the historic center) and the artworks contained therein. The contribution is focused on the pilot project of Palazzo Albani, a historic building recognized of great value by the community as a non-renewable, irreproducible, and irreplaceable resource. The work experiments with an operational flow that starts from the analysis of historical archival sources, with special attention to technical-constructive aspects, and direct investigation, to the identification of the best interventions and the application of new documentary protocols for the communication of the heritage in its different aspects palace and contained works.