The Role of Immunotherapy in a Tolerogenic Environment: Current and Future Perspectives for Hepatocellular Carcinoma

In contrast to several tumors whose prognoses are radically affected by novel immunotherapeutic approaches and/or targeted therapies, the outcomes of advanced hepatocellular carcinoma (HCC) remain poor. The underlying cirrhosis that is frequently associated with it complicates medical treatment and often determines survival. The landscape of HCC treatment had included sorafenib as the only drug available for ten years, until 2018, when lenvatinib was approved for treatment. The second-line systemic treatments available for hepatocellular carcinoma include regorafenib, cabozantinib, ramucirumab, and, more recently, immune checkpoint inhibitors. However, the median survival remains below 15 months. The results obtained in clinics should be interpreted whilst considering the peculiar role of the liver as an immune organ. A healthy liver microenvironment ordinarily experiences stimulation by gut-derived antigens. This setup elucidates the response to chronic inflammation and the altered balance between tolerance and immune response in HCC development. This paper provides an overview of the mechanisms involved in HCC pathogenesis, with a special focus on the immune implications, along with current and future clinical perspectives

The Brief Strategic Treatment of Cardiophobia: A Clinical Case Study

AbstractMany individuals presenting to medical settings with heart-related symptoms for which no medical explanation is found might suffer from cardiophobia, but this condition is still poorly identified and addressed. This article presents a case of cardiophobia treated in an outpatient cardiac rehabilitation unit and, for the first time, describes the application of brief strategic therapy for the treatment of this condition. In the case reported, the first therapeutic encounter and the key elements of the strategic approach are described in detail with the aim to explain how brief strategic therapy works and how it can be used to identify and address cardiophobia-related behaviors. A 64-year-old male presented to cardiac rehabilitation reporting intense anxiety-provoking heart palpitations, and believing he was at risk of dying from a heart attack. After 3 sessions, an overall improvement in heart-related bodily sensations followed a decrease in the patient's continuous checking of his heartbeat and seeking reassurance—factors that were largely responsible for the persistence of the problem. Moreover, quantitative evaluation showed increased scores of mood state at the end of treatment. This improvement persisted at the 18-month follow-up. This case is an interesting example of how brief strategic therapy can contribute to the development of a new conceptual model for the diagnosis and treatment of cardiophobia. Still, more systematic research in the field is needed to prove the efficacy and effectiveness of this therapeutic approach on symptoms of heart-focused anxiety

Cabozantinib After a Previous Immune Checkpoint Inhibitor in Metastatic Renal Cell Carcinoma: A Retrospective Multi-Institutional Analysis

Background: Angiogenesis has been recognized as the most important factor for tumor invasion, proliferation, and progression in metastatic renal cell carcinoma (mRCC). However, few clinical data are available regarding the efficacy of cabozantinib following immunotherapy. Objective: To describe the outcome of cabozantinib in patients previously treated with immunotherapy. Patients and methods: Patients with mRCC who received cabozantinib immediately after nivolumab were included. The primary endpoint was to assess the outcome in terms of efficacy and activity. Results: Eighty-four mRCC patients met the criteria to be included in the final analysis. After a median follow-up of 9.4 months, median overall survival was 17.3 months. According to the IMDC criteria, the rates of patients alive at 12 months in the good, intermediate, and poor prognostic groups were 100%, 74%, and 33%, respectively (p < 0.001). The median progression-free survival (PFS) was 11.5 months (95% CI 8.3-14.7); no difference was found based on duration of previous first-line therapy or nivolumab PFS. The overall response rate was 52%, stable disease was found as the best response in 25.3% and progressive disease in 22.7% of patients. Among the 35 patients with progressive disease on nivolumab, 26 (74.3%) patients showed complete/partial response or stable disease with cabozantinib as best response after nivolumab. The major limitations of this study are the retrospective nature and the short follow-up. Conclusions: Cabozantinib was shown to be effective and active in patients previously receiving immune checkpoint inhibitors. Therefore, cabozantinib can be considered a valid therapeutic option for previously treated mRCC patients, irrespective of the type and duration of prior therapies

Acute contractile recovery extent during biventricular pacing is not associated with follow-up in patients undergoing resynchronization

It has been reported that contractility, as assessed using dobutamine infusion, is independently associated with reverse remodeling after CRT. Controversy, however, exists about the capacity of this approach to predict a long-term clinical response. This studys purpose was to assess whether long-term CRT clinical effects can be predicted according to acute inotropic response induced by biventricular stimulation (CRT on), as compared with AAI–VVI right stimulation pacing mode (CRT off), quantified at the time of implantation. In 98 patients (ejection fraction 29 ± 10%), acute changes in left ventricular (LV) elastance (Ees), arterial elastance (Ea), and Ees/Ea, as assessed from slope changes of the force–frequency relation obtained when the heart rate increased, and also assessed while measuring triplane LV volumes and continuous noninvasive blood pressure, were related to death or rehospitalization during a 3-year follow-up. Other covariances tested were age, gender, disease etiology, QRS duration, amount of mitral regurgitation, LV diastolic volume, ejection fraction, and the degree of asynchrony and longitudinal strain at baseline. There was a marked increment in the Ees slope with CRT (interaction P = 0.004), no Ea change, and modest Ees/Ea increase (interaction P < 0.05). In Cox analysis, however, neither slope changes nor baseline values of Ees, Ea, and Ees/Ea were associated with long-term follow-up. Only ventricular diastolic volume (direct relation P = 0.002) and QRS duration (inverse relation P = 0.009) predicted death/rehospitalization. Acute contractile recovery in CRT patients is not associated with 3 years prognosis. Instead, death or rehospitalization can be predicted from QRS duration and LV diastolic volume at baseline

A Root in Synapsis and the Other One in the Gut Microbiome-Brain Axis: Are the Two Poles of Ketogenic Diet Enough to Challenge Glioblastoma?

: Glioblastoma is the most frequent and aggressive brain cancer in adults. While precision medicine in oncology has produced remarkable progress in several malignancies, treatment of glioblastoma has still limited available options and a dismal prognosis. After first-line treatment with surgery followed by radiochemotherapy based on the 2005 STUPP trial, no significant therapeutic advancements have been registered. While waiting that genomic characterization moves from a prognostic/predictive value into therapeutic applications, practical and easy-to-use approaches are eagerly awaited. Medical reports on the role of the ketogenic diet in adult neurological disorders and in glioblastoma suggest that nutritional interventions may condition outcomes and be associated with standard therapies. The acceptable macronutrient distribution of daily calories in a regular diet are 45-65% of daily calories from carbohydrates, 20-35% from fats, and 10-35% from protein. Basically, the ketogenic diet follows an approach based on low carbohydrates/high fat intake. In carbohydrates starvation, body energy derives from fat storage which is used to produce ketones and act as glucose surrogates. The ketogenic diet has several effects: metabolic interference with glucose and insulin and IGF-1 pathways, influence on neurotransmission, reduction of oxidative stress and inflammation, direct effect on gene expression through epigenetic mechanisms. Apart from these central effects working at the synapsis level, recent evidence also suggests a role for microbiome and gut-brain axis induced by a ketogenic diet. This review focuses on rationales supporting the ketogenic diet and clinical studies will be reported, looking at future possible perspectives

Guidewire replacement of valved tunneled-cuffed silicone catheters with power injectable polyurethane tunneled-cuffed catheters or with ports

Background: Silicone Cuffed Centrally Inserted Central venous catheters (CICCs) were a type of catheters that have been used for a long time especially in cancer patients. Recently, thanks to biomedic research progresses, polyurethane catheters have resulted in higher surgical performances compared to classical silicone ones. Indeed, the inferior calibers of these new catheters lead to an extremely faster infusion rate. The presence of a valve at the tip of the catheter could suggest an impossible replacement procedure over a Seldinger guidewire. Method: The aim of this article is to explain our replacement technique over guidewire of silicone cuffed and valved tunneled CICCs with a power injectable polyurethane cuffed tunneled CICC. The casistic presented was evaluated at the Vascular Access Unit of ASST Spedali Civili in Brescia, Italy. The study involved 35 successful catheter replacement over guidewire, meanwhile cases where patients presented sepsis, exit site infection, or catheter damage were premeditatedly excluded. Results:The maneuver was always conducted following the same procedure without noticing particular complications associated with CICC insertion. Indeed, the operation was quick, feasible, and safe. Septic, thromboembolic, or hemorrhagic complications also related to patients presenting dysfunctional coagulation cascade were not encountered. Conclusions: Our experience regarding the replacement technique of silicone cuffed and valved catheters over guidewire was considered feasible, accurate, and efficient for all patients treated, even in those presenting thrombocytopenia or a dysfunctional coagulation cascade

Extragonadal germ cell tumors: Not just a matter of location. A review about clinical, molecular and pathological features

Abstract Extragonadal germ cell tumors (EGGCTs) are uncommon neoplasms, which arise in anatomical locations other than gonads. The pathogenesis of these neoplasms is still poorly understood and it is a matter of debate if they really represent extragondal primary neoplasms or rather extragondal metastasis from occult gonadal neoplasms. The actual observations suggest that EGGCTs represent a unique entity, so their biology and behavior are substantially different from gonadal counterparts. The diagnosis of EGGCTs is often challenging, and differential diagnosis is particularly wide. Nevertheless, a correct diagnosis is essential for the correct management of the patient. We summarize the state of art about EGGCTs, with particular emphasis on diagnosis and prognosis