Role of CDK4 as prognostic biomarker in Soft Tissue Sarcoma and synergistic effect of its inhibition in dedifferentiated liposarcoma sequential treatment.

Soft tissue sarcomas represent an heterogeneous group of rare mesenchymal tumors comprising 1% of all solid malignancies. Among them, liposarcoma is one of the most common histotypes with atypical lipomatous tumor/well differentiated liposarcoma and dedifferentiated liposarcoma (ALT/WDLPS and DDLPS) as the major sub-entities. The unavailability of predictive, prognostic and druggable biomarkers makes the management of these lesions challenging. In recent years CDK4 and its inhibitors have emerged as potential agents for these lesions especially for ALT/WDLPS and DDLPS but the results are not conclusive and need to be elucidated. This study involved 21 ALT/WDLPS and DDLPS patients. Histological analyses of MDM2 and CDK4 were carried out. Moreover, a DDLPS patient-derived cancer model was established in vitro and in vivo assessing the efficacy of palbociclib in combination and sequential treatment. Finally, in silico analyses on CDK4 expression were carried out. The results showed a higher expression of CDK4 and MDM2 in DDLPS compared to ALT/WDLPS. Moreover, no correlation between MDM2 expression and CDK4 was observed. Next, in vitro analysis of CDK4 inhibitor palbociclib showed an antagonistic effect when combined to other chemotherapeutics, while it exhibited a significant synergy when administered in sequential schedule with lenvatinib. Next, in vivo analysis on DDLPS xenotransplanted embryos assessing the efficacy and safety profile of the in vitro tested schedules confirmed the observed data. This proof-of-concept study sheds light on the natural history of ALT/WDLPS and DDLPS and provides the rationale for the clinical applicability of sequential treatment with palbociclib in the management of DDLPS.

Cardio-oncology rehabilitation: are we ready?

Cardio-oncology rehabilitation (CORE) is not only an essential component of cancer rehabilitation but also a pillar of preventive cardio-oncology. Cardio-oncology rehabilitation is a comprehensive model based on a multitargeted approach and its efficacy has been widely documented; when compared with an 'exercise only' programme, comprehensive CORE demonstrates a better outcome. It involves nutritional counselling, psychological support, and cardiovascular (CV) risk assessment, and it is directed to a very demanding population with a heavy burden of CV diseases driven by physical inactivity, cancer therapy-induced metabolic derangements, and cancer therapy-related CV toxicities. Despite its usefulness, CORE is still underused in cancer patients and we are still at the dawning of remote models of rehabilitation (tele-rehabilitation). Not all CORE is created equally: a careful screening procedure to identify patients who will benefit the most from CORE and a multidisciplinary customized approach are mandatory to achieve a better outcome for cancer survivors throughout their cancer journey. The aim of this paper is to provide an updated review of CORE not only for cardiologists dealing with this peculiar population of patients but also for oncologists, primary care providers, patients, and caregivers. This multidisciplinary team should help cancer patients to maintain a healthy and active life before, during, and after cancer treatment, in order to improve quality of life and to fight health inequities.

[ANMCO Position paper in collaboration with ITACARE-P: Cardio-oncology rehabilitation. Are we ready?] / Position paper ANMCO in collaborazione con ITACARE-P: Riabilitazione cardio-oncologica. "Are we ready?".

Cardio-oncology rehabilitation (CORE) is not only an essential component of cancer rehabilitation, but also a pillar of preventive cardio-oncology. CORE is a comprehensive model based on a multitargeted approach and its efficacy has been widely documented; when compared to an "exercise only" program, comprehensive CORE demonstrates a better outcome. It involves nutritional counseling, psychological support and cardiovascular risk assessment, and it is directed to a very demanding population with a heavy burden of cardiovascular diseases driven by physical inactivity, cancer therapy-induced metabolic derangements and cancer therapy-related cardiovascular toxicities. Despite its usefulness, CORE is still underused in cancer patients and we are still at the dawning of remote models of rehabilitation (telerehabilitation). Not all cardio-oncology rehabilitation is created equal: a careful screening procedure to identify patients who will benefit the most from CORE and a multidisciplinary customized approach are mandatory to achieve a better outcome for cancer survivors throughout their cancer journey.The aim of this position paper is to provide an updated review of CORE not only for cardiologists dealing with this peculiar patient population, but also for oncologists, primary care providers, patients and caregivers. This multidisciplinary team should help cancer patients to maintain a healthy and active life before, during and after cancer treatment, in order to improve quality of life and to fight health inequities.

High-grade transformation of a polymorphous adenocarcinoma of the salivary gland: a case report and review of the literature.

Background: Polymorphous adenocarcinoma (PAC) represents the second most widespread neoplasm of the minor salivary glands. These tumors rarely develop a histological progression from low-grade to high-grade malignancy, named "high-grade transformation" (HGT). Only nine cases are described in literature. Case description: Here, we describe the case of a 76-year-old male patient with a PAC recurrence of the oral floor displaying HGT, and we explore the tumor cytomorphological features, genomic profiling, and the patient's clinical management. The tumor mass was characterized by poorly atypical cellular elements with vesicular nuclei and comedonecrosis foci. The growth pattern was predominantly solid, tubular, and cribriform. The lesion did not show microsatellite instability or targeted molecular alterations. The case was successfully treated with radical surgery followed by radiotherapy. Conclusion: We report for the first time the recurrence of a PAC with HGT arising in the oral floor after 20 years from the primary lesion. These preliminary data and the literature analysis enhance the knowledge of this extremely rare disease.

Parastomal hernia: an overview.

Parastomal hernia (PH) is one of the most frequent ostomy complications, and the reported incidence in the literature is highly variable. As highlighted by the Association of Stoma Care Nurses UK, this complication develops mainly in children and older men over 70, but many predisposing factors are related to the individual patient and surgery. There is no standardised system for assessing PH. The main assessment techniques include objective examination, ultrasound scan and computed tomography. Prevention is based on various interventions by surgeons and stoma care nurses (SCNs). The SCN's primary interventions include accurate patient evaluation, pre-operative ostomy siting, education about body weight management and advice on appropriate exercises. The treatment of PH can be conservative or surgical, and the choice is based on the patient's clinical condition. Ostomy can significantly impact on a patient's quality of life (QoL), and the presence of PH can further aggravate the situation. This overview of PH considers the incidence, aetiology, prevention, treatment and impact on QoL.

Precision Medicine in Head and Neck Cancers: Genomic and Preclinical Approaches.

Head and neck cancers (HNCs) represent the sixth most widespread malignancy worldwide. Surgery, radiotherapy, chemotherapeutic and immunotherapeutic drugs represent the main clinical approaches for HNC patients. Moreover, HNCs are characterised by an elevated mutational load; however, specific genetic mutations or biomarkers have not yet been found. In this scenario, personalised medicine is showing its efficacy. To study the reliability and the effects of personalised treatments, preclinical research can take advantage of next-generation sequencing and innovative technologies that have been developed to obtain genomic and multi-omic profiles to drive personalised treatments. The crosstalk between malignant and healthy components, as well as interactions with extracellular matrices, are important features which are responsible for treatment failure. Preclinical research has constantly implemented in vitro and in vivo models to mimic the natural tumour microenvironment. Among them, 3D systems have been developed to reproduce the tumour mass architecture, such as biomimetic scaffolds and organoids. In addition, in vivo models have been changed over the last decades to overcome problems such as animal management complexity and time-consuming experiments. In this review, we will explore the new approaches aimed to improve preclinical tools to study and apply precision medicine as a therapeutic option for patients affected by HNCs.

The role of next-generation sequencing in detecting gene fusions with known and unknown partners: a single-center experience with methodologies' integration.

AIMS: Next-generation sequencing (NGS) is becoming a new gold standard for determining molecular predictive biomarkers. This study aimed to evaluate the reliability of NGS in detecting gene fusions, focusing on comparing gene fusions with known and unknown partners. METHODS: We collected all gene fusions from a consecutive case series using an amplicon-based DNA/RNA NGS platform and subdivided them into two groups: gene fusions with known partners and gene fusions with unknown partners. Gene fusions involving ALK, ROS1 and RET were also examined by immunohistochemistry (IHC) and/or fluorescent in situ hybridization (FISH). RESULTS: Overall, 1174 malignancies underwent NGS analysis. NGS detected gene fusions in 67 cases (5.7%), further subdivided into 43 (64.2%) with known partners and 24 (35.8%) with unknown partners. Gene fusions were predominantly found in non-small cell lung carcinomas (52/67, 77.6%). Gene fusions with known partners frequently involved ALK (20/43, 46.5%) and MET (9/43, 20.9%), while gene fusions with unknown partners mostly involved RET (18/24, 75.0%). FISH/IHC confirmed rearrangement status in most (89.3%) of the gene fusions with known partners, but in only one (4.8%) of the gene fusions with unknown partners, with a significant difference (p < 0.001). In 17 patients undergoing targeted therapy, the log-rank test revealed that the overall survival was higher in the known partner group than in the unknown partner group (p = 0.002). CONCLUSIONS: NGS is a reliable method for detecting gene fusions with known partners, but it is less accurate in identifying gene fusions with unknown partners, for which further analyses (such as FISH) are required.

Targeted management of evolving and established chronic lung disease of prematurity assisted by cardiopulmonary ultrasound: A case report of four patients.

Bronchopulmonary dysplasia (BPD) is one of the most common complications of premature birth. The current definition of BPD is based on the duration of oxygen therapy and/or respiratory support. Among the pitfalls of all the diagnostic definitions, the lack of a proper pathophysiologic classification makes it difficult to choose an appropriate drug strategy for BPD. In this case report, we describe the clinical course of four premature infants, admitted to the neonatal intensive care unit, for whom the use of lung and cardiac ultrasound was an integral part of the diagnostic and therapeutic process. We describe, for the first time to our knowledge, four different cardiopulmonary ultrasound patterns of evolving and established chronic lung disease of prematurity and the consequent therapeutic choices. This approach, if confirmed in prospective studies, may guide the personalized management of infants suffering from evolving and established BPD, optimizing the chances of success of the therapies and at the same time reducing the risk of exposure to inadequate and potentially harmful drugs.

Deciphering the Genomic Landscape and Pharmacological Profile of Uncommon Entities of Adult Rhabdomyosarcomas.

Adult rhabdomyosarcoma (RMS) represents an uncommon entity with an incidence of less than 3% of all soft tissue sarcomas (STS). Consequently, the natural history and the clinical management of this disease are infrequently reported. In order to fill this gap, we investigated the molecular biology of an adult RMS case series. The expression of epithelial mesenchymal transition-related gene and chemoresistance-related gene panels were evaluated. Moreover, taking advantage of our STS translational model combining patient-derived primary culture and 3D-scaffold, the pharmacological profile of an adult head and neck sclerosing RMS was assessed. Furthermore, NGS, microsatellite instability, and in silico analyses were carried out. RT-PCR identified the upregulation of CDH1, SLUG, MMP9, RAB22a, S100P, and LAPTM4b, representing promising biomarkers for this disease. Pharmacological profiling showed the highest sensitivity with anthracycline-based regimen in both 2D and 3D culture systems. NGS analysis detected RAB3IP-HMGA2 in frame gene rearrangement and FGFR4 mutation; microsatellite instability analysis did not detect any alteration. In silico analysis confirmed the mutation of FGFR4 as a promising marker for poor prognosis and a potential therapeutic target. We report for the first time the molecular and pharmacological characterization of rare entities of adult head and neck and posterior trunk RMS. These preliminary data could shed light on this poorly understood disease.

Three-dimensional collagen-based scaffold model to study the microenvironment and drug-resistance mechanisms of oropharyngeal squamous cell carcinomas.

OBJECTIVE: Squamous cell carcinoma (SCC) represents the most common histotype of all head and neck malignancies and includes oropharyngeal squamous cell carcinoma (OSCC), a tumor associated with different clinical outcomes and linked to human papilloma virus (HPV) status. Translational research has few available in vitro models with which to study the different pathophysiological behavior of OSCCs. The present study proposes a 3-dimensional (3D) biomimetic collagen-based scaffold to mimic the tumor microenvironment and the crosstalk between the extracellular matrix (ECM) and cancer cells. METHODS: We compared the phenotypic and genetic features of HPV-positive and HPV-negative OSCC cell lines cultured on common monolayer supports and on scaffolds. We also explored cancer cell adaptation to the 3D microenvironment and its impact on the efficacy of drugs tested on cell lines and primary cultures. RESULTS: HPV-positive and HPV-negative cell lines were successfully grown in the 3D model and displayed different collagen fiber organization. The 3D cultures induced an increased expression of markers related to epithelial-mesenchymal transition (EMT) and to matrix interactions and showed different migration behavior, as confirmed by zebrafish embryo xenografts. The expression of hypoxia-inducible factor 1α (1α) and glycolysis markers were indicative of the development of a hypoxic microenvironment inside the scaffold area. Furthermore, the 3D cultures activated drug-resistance signaling pathways in both cell lines and primary cultures. CONCLUSIONS: Our results suggest that collagen-based scaffolds could be a suitable model for the reproduction of the pathophysiological features of OSCCs. Moreover, 3D architecture appears capable of inducing drug-resistance processes that can be studied to better our understanding of the different clinical outcomes of HPV-positive and HPV-negative patients with OSCCs.

Role of Subclinical Iatrogenic Hyperthyroidism in the Setting of Heart Disease and Arrhythmic Burden.

BACKGROUND: Subclinical hyperthyroidism is defined by a subnormal serum thyroidstimulating hormone (TSH) level with normal free thyroxine (FT4) and free triiodothyronine (FT3) levels. Its prevalence varies from 0.6% to 16% in the elderly and can increase to 20% in patients receiving thyroid hormone replacement therapy. Thyroid disease and/or replacement therapy are frequently associated with cardiovascular involvement. CASES PRESENTATION: We report three clinical cases of patients with initial subclinical hyperthyroidism and cardiological manifestations, including supraventricular and ventricular extrasystoles, prolapse of the mitral valve with severe regurgitation, higher mean heart rate and deterioration of the arrhythmias on arrhythmogenic dysplasia substrate. CONCLUSION: We discuss the role of appropriate and early correction of thyroid dysfunction in improving cardiological manifestations.

Electrical Remodeling of Ventricular Repolarization Abnormality after Treatment in Pheochromocytoma: U Wave Finding in a Retrospective Analysis.

Background: Pheochromocytoma is a rare neuroendocrine tumor, clinically characterized by high blood pressure, palpitations, and headache. It is often associated with abnormalities of the ventricular repolarization phase; the dispersion of ventricular repolarization is the basis for ventricular arrhythmias (torsion de point, ventricular tachycardia or ventricular fibrillation). Objectives: Analysis of abnormal ventricular repolarization focused on the presence and amount of U wave in patients affected by pheochromocytoma and its modification after surgery. Materials and Methods: We reviewed pathology records of 722 patients admitted for adrenal nodule or suspected chromaffin-cell tumor and identified 39 patients affected by pheochromocytoma. Metanephrine, normetanephrine, and 3-methoxytyramine have been assessed by determining concentrations in 24-hour urine collection. Standard 12-lead electrocardiogram records have been reviewed with analysis of heart rate, P wave, PR interval, QRS duration, QTc, and U wave. Then we selected and compared 22 patients of 39 affected by pheochromocytoma, with both clinical and electrocardiographic data before and after surgery. Results: In our cohort of 39 patients affected by pheochromocytoma, we found U wave in ECG, before treatment, in 82.8 percent of patients, while only 37.0 percent after treatment (p<0.001) and we observed a statistically significant correlation between this wave and the urinary metanephrine. After surgery, in the selected 22 patients, we observed a clear significant reduction in systemic blood pressure, fasting glucose, metanephrine, normetanephrine, and 3-methoxytyramine. We found a significant reduction of U wave presence and leads involved in these patients after surgery (90.9% versus 9%). We observed a linear correlation between the amount of U waves in 12-lead electrocardiogram and metanephrine (r2=0.333, p=0.015), 3-methoxytyramine levels (r2=0.458, p=0.006), and tumor size (r2=0.429, p=0.003). Conclusions: In our retrospective analysis, patients affected by pheochromocytoma presented U wave in electrocardiogram. The presence and amount of U wave were associated with the metanephrine levels and the tumor size with significant reduction after surgical removal.

The use of an acellular matrix derived from human dermis for the treatment of full-thickness skin wounds.

Full-thickness skin wounds occur in many different clinical cases and the use of biological acellular dermal matrices (ADMs) to reconstruct the damaged area is increasing in the field of plastic and reconstructive surgery. In particular, the ability of ADMs to maintain the structural properties of extracellular matrix as well as to provide a suitable environment for cell growth makes their use suitable for the improvement of wound healing and the reduction of side effects deriving from contracture and scar tissue formation. In this study, we describe the clinical use of a recently developed human dermal matrix (HDM) in combination with graft skin as an alternative reconstructive solution for the treatment of full-thickness skin wounds. The HDM was applied in combination with autologous graft skin on three different clinical cases in which full-thickness skin wounds occurred. The clinical outcomes were evaluated in the patients during their follow-up. Histological as well as ultra-structural analysis were also performed on skin biopsy of the clinical case 3 one year after the treatment with HDM. The use of HDM stimulates the wound healing process in all clinical cases of full-thickness skin wounds here described with a functional and aesthetic rescue of the damaged area. Histological and ultra-structural analysis show a regenerative healing of the wound area with well-organized/oriented connective tissue in which cellular infiltration as well as blood vessels are evident. Our results support the clinical use of HDM as a permanent dermal replacement for the treatment of full-thickness skin wounds.

Simulador de dreno de tórax: desenvolvimento de modelo de baixo custo para capacitação de médicos e estudantes de medicina / Chest tube simulator: development of low-cost model for training of physicians and medical students

RESUMO Objetivo: criar, em impressora 3D, um simulador de baixo custo de caixa torácica humana que permita a reprodução da técnica de drenagem fechada de tórax (DFT) comparando sua eficácia com a do modelo animal. Métodos: foi realizada impressão 3D do arcabouço ósseo de um tórax humano a partir de uma tomografia de tórax. Após a impressão das costelas, foram realizados testes com diversos materiais que contribuíram para formar a simulação da caixa torácica e da pleura. Foi, então, realizado um estudo experimental, randomizado e controlado comparando sua eficácia ao modelo animal no ensino da DFT para estudantes de medicina, que foram divididos em dois grupos: Grupo Modelo Animal e Grupo Modelo Simulador, que treinaram DFT em animais e no modelo simulador, respectivamente. Resultados: a reconstrução do tórax exigiu o conhecimento anatômico para análise da tomografia e para edição fiel da superfície 3D. Não houve diferença significativa quanto à segurança de realizar o procedimento entre os grupos (7,61 vs. 7,73; p=0,398). Foi observada maior pontuação no grupo modelo simulador para uso como material didático e aprendizado da técnica de drenagem torácica quando comparado ao grupo modelo animal (p<0,05). Conclusão: o custo final para a confecção do modelo foi inferior ao de um simulador comercial, o que demonstra a viabilidade do uso da impressão 3D para esse fim. Além disso, o simulador desenvolvido se mostrou equivalente ao modelo animal quanto à simulação da técnica de drenagem para aprendizado prático e houve preferência pelo modelo simulador como material didático.

ABSTRACT Objective: by using a 3D printer, to create a low-cost human chest cavity simulator that allows the reproduction of the closed chest drainage technique (CCD), comparing its effectiveness with that of the animal model. Methods: it was made a 3D printing of the bony framework of a human thorax from a chest computerized tomography scan. After printing the ribs, we performed tests with several materials that contributed to form the simulation of the thoracic cavity and pleura. An experimental, randomized, and controlled study, comparing the efficacy of the simulator to the efficacy of the animal model, was then carried out in the teaching of CCD technique for medical students, who were divided into two groups: animal model group and simulator model group, that trained CCD technique in animals and in the simulator model, respectively. Results: the chest reconstruction required anatomical knowledge for tomography analysis and for faithful 3D surface editing. There was no significant difference in the safety of performing the procedure in both groups (7.61 vs. 7.73; p=0.398). A higher score was observed in the simulator model group for "use as didactic material" and "learning of the chest drainage technique", when compared to the animal model group (p<0.05). Conclusion: the final cost for producing the model was lower than that of a commercial simulator, what demonstrates the feasibility of using 3D printing for this purpose. In addition, the developed simulator was shown to be equivalent to the animal model in relation to the simulation of the drainage technique for practical learning, and there was preference for the simulator model as didactic material.

Serum uric acid as a prognostic marker in the setting of advanced vascular disease: a prospective study in the elderly.

BACKGROUND: Many epidemiological studies analyze the relationship between hyperuricemia and cardiovascular outcomes. This observational prospective study investigates the association of serum uric acid (SUA) levels with adverse cardiovascular events and deaths in an elderly population affected by advanced atherosclerosis. METHODS: Two hundred and seventy six elderly patients affected by advanced atherosclerosis (217 males and 59 females; aged 71.2 ± 7.8 years) were included. All patients were assessed for history of cardiovascular disease, cancer, obesity and traditional risk factors. Patients were followed for approximately 31 ± 11 months. Major events were recorded during follow-up, defined as myocardial infarction, cerebral ischemia, myocardial and/or peripheral revascularization and death. RESULTS: Mean SUA level was 5.47 ± 1.43 mg/dL; then we further divided the population in two groups, according to the median value (5.36 mg/dL). During a median follow up of 31 months (5 to 49 months), 66 cardiovascular events, 9 fatal cardiovascular events and 14 cancer-related deaths have occurred. The patients with increased SUA level presented a higher significant incidence of total cardiovascular events (HR: 1.867, P = 0.014, 95% CI: 1.134-3.074). The same patients showed a significant increased risk of cancer-related death (HR: 4.335, P = 0.025, 95% CI: 1.204-15.606). CONCLUSIONS: Increased SUA levels are independently and significantly associated with risk of cardiovascular events and cancer related death in a population of mainly elderly patients affected by peripheral vasculopathy.

Asymptomatic pulmonary embolism in lung cancer: prevalence and analysis of clinical and radiological characteristics in 141 outpatients.

Aims and background. The incidence of asymptomatic pulmonary embolism in cancer patients is unknown and strictly related to the imaging used for tumor assessment. Recent findings suggest a similar clinical outcome of asymptomatic pulmonary embolism events compared to symptomatic events with a significant impact on survival. The aim of the present study was to determine the prevalence of asymptomatic pulmonary embolism in a population of lung cancer outpatients and to investigate its clinical features. Methods. Outpatients with a diagnosis of lung carcinoma undergoing chemotherapy were selected from October 2006 to June 2009. Disease and patient characteristics, risk factors and treatment modalities were collected. All the computed tomography images performed for each patient during the study period were retrospectively reviewed to identify pulmonary embolism. Results. A total of 141 consecutive patients were included and 657 computed tomography scans were completely reviewed (from two to six consecutive scans for each patient). Asymptomatic pulmonary embolism in the study population had a prevalence of 14.9% (21 patients). Most of the events occurred in patients with adenocarcinoma, advanced stage and poor performance status, during the early phases of first-line chemotherapy or at the same time of the cancer diagnosis. Compared with the symptomatic pulmonary embolism events (5 patients), asymptomatic events occurred earlier (time from cancer diagnosis to pulmonary embolism of 3.5 [95% CI, 2.0-4.9] versus 12.1 months [95% CI, 6.3-17.9; P = 0.02]) and had a better prognosis (survival from PE of 7.5 [95% CI, 3.4-11.6] versus 1.9 months [95% CI, 0-3.9; P = 0.04]). Conclusions. Our findings indicate an underestimation of embolic events among lung cancer outpatients due to their frequent asymptomatic natur. Such a high prevalence suggests the importance to pay more attention to pulmonary embolism prevention in this population.

Primary diffuse large B-cell lymphoma of the testis: a case-report.

We report a case of a primary non-Hodgkin lymphoma of the testis in a 74-year-old man presented with a 1-month history of testicular swelling. The patient was submitted to right inguinal orchidectomy for the definitive diagnosis. Light microscopy demonstrated sheets of lymphoma cells involving epididymis and rete testis, but mainly extended into testicular parenchyma. The malignant cells were large with scant cytoplasm and large vesicular nuclei, the classic appearance of a diffuse large B-cell lymphoma. The immunohistochemical study was carried out, with the tumour cells being intensively positive for CD45, CD20 and Ki67 nuclear proliferative antigen. Clinical and pathological features of this non-Hodgkin lymphoma are described and discussed.