Permanent his bundle pacing: Description and comparison of four implantation techniques.

INTRODUCTION: Permanent His bundle pacing (HBP) is the most physiological pacing modality, and new implantation systems are now available. The aim of the present study was to describe and compare four different techniques to perform HBP. METHODS AND RESULTS: We included all consecutive patients who underwent a HBP attempt in our initial experience between June 2020 and May 2022. The success and characteristics of the procedure were compared among four implantation techniques: the Biotronik Selectra 3D sheath with Solia S60 lead (Selectra 3D), the Boston Scientific Site Selective Pacing Catheter with Ingevity lead (SSPC), the Abbott steerable stylet locator with Tendril lead (Locator), and the use of a standard stylet manually pre-shaped with a conventional pacing lead (Curved stylet). Ninety-eight patients (median age 79 years [interquartile range, 73-83], 83% men) were identified. The Selectra 3D technique was used in 43 procedures, SSPC in 26, Locator in 18 and Curved stylet in 11. The groups had similar clinical characteristics. Overall, procedural success was achieved in 91 patients (93%) with similar proportions among groups (p = .986). Fluoroscopy and procedural times were 6.0 (4.4-8.5) and 60 (45-75) min, respectively, without significant differences (p = .333 and p = .790). The rate of selective capture, the pacing threshold, and the paced QRS duration were also comparable. There was one pre-discharge HBP lead dislodgment (1%) that required implant revision. CONCLUSION: In our experience, four techniques for HBP achieved comparable results in terms of safety and effectiveness. The availability of different systems may lead to widespread use of physiological pacing.

Leadless pacemaker implantation in dextrocardia with situs viscerum inversus: A case report and literature review.

Leadless pacemaker implantation (LPI) has fewer device complications and reduced chance of infection compared to conventional pacemakers. Dextrocardia with situs viscerum inversus (DC+SVI) is a rare condition, which seldom leads to cardiac complications. However, its presence poses a challenge to operators in cardiac procedures. LPI reports in DC patients are scarce. We report a case of LPI in a DC+SVI patient, followed by a brief but comprehensive literature review.

Glucocorticoids and natural killer cells: A suppressive relationship.

Glucocorticoids exert their pharmacological actions by mimicking and amplifying the function of the endogenous glucocorticoid system's canonical physiological stress response. They affect the immune system at the levels of inflammation and adaptive and innate immunity. These effects are the basis for therapeutic use of glucocorticoids. Innate immunity is the body's first line of defense against disease conditions. It is relatively nonspecific and, among its mediators, natural killer (NK) cells link innate and acquired immunity. NK cell numbers are altered in patients with auto immune diseases, and research suggests that interactions between glucocorticoids and natural killer cells are critical for successful glucocorticoid therapy. The aim of this review is to summarize these interactions while highlighting the latest and most important developments in this field. Production and release in the blood of endogenous glucocorticoids are strictly regulated by the hypothalamus-pituitary adrenal axis. A self-regulatory mechanism prevents excessive plasma levels of these hormones. However, exogenous stimuli such as stress, inflammation, infections, cancer, and autoimmune disease can trigger the hypothalamus-pituitary-adrenal axis response and lead to excessive systemic release of glucocorticoids. Thus, stress stimuli, such as sleep deprivation, intense exercise, depression, viral infections, and cancer, can result in release of glucocorticoids and associated immunosuppressant effects. Among these effects are decreases in the numbers and activities of NK cells in inflammatory and autoimmune diseases (e.g., giant cell arteritis, polymyalgia rheumatica, and familial hypogammaglobulinemia).

Brentuximab Vedotin and Bendamustine Produce Long-Term Clinical Benefit in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma: A Multicenter Real-Life Experience.

BACKGROUND: Patients with relapsed or refractory classical Hodgkin lymphoma (R/R cHL) have limited opportunities for curative therapy. High-dose therapy followed by autologous stem cell transplantation (HDT-ASCT) produces cure rates of 50% to 60%. Patients relapsing after, or ineligible for HDT-ASCT have limited therapeutic options and long-term remission is uncommon. Furthermore, few patients are candidate to allogeneic stem cell transplantation (AlSCT), a potentially curative approach. The combination of brentuximab vedotin and bendamustine (BVB) is a promising treatment for patients with R/R cHL, regardless of SCT eligibility. PATIENTS AND METHODS: We conducted a real-life study of BVB in 41 patients with R/R cHL after failure of ≥ 1 therapy including ASCT, AlSCT, or BV. RESULTS: Among 40 patients evaluable for efficacy, the overall response rate and complete response (CR) rate were 75% and 50%, respectively. No significant differences were observed between patients with primary refractory and relapsed disease, previously treated with ≤ 2 and ≥ 3 lines of therapy, or BV-exposed and BV-naïve. After a median follow-up of 38 months, the median progression free survival (PFS) for the entire population is 26 months; PFS is not reached, 10.5 months, and 4 months for patients achieving CR, partial response and no response, respectively (P < .0001). BVB was well tolerated and no grade 4 toxicity or new safety signals were observed. The most common treatment-emergent adverse events were infections. CONCLUSION: Our experience supports the efficacy and tolerability of the BVB combination in R/R cHL as a bridge to SCT, or as a definitive therapy for SCT-ineligible patients. Larger comparative studies testing BVB against standards of care are warranted in both settings.

EBV-Driven Lymphoproliferative Disorders and Lymphomas of the Gastrointestinal Tract: A Spectrum of Entities with a Common Denominator (Part 3).

EBV is the first known oncogenic virus involved in the development of several tumors. The majority of the global population are infected with the virus early in life and the virus persists throughout life, in a latent stage, and usually within B lymphocytes. Despite the worldwide diffusion of EBV infection, EBV-associated diseases develop in only in a small subset of individuals often when conditions of immunosuppression disrupt the balance between the infection and host immune system. EBV-driven lymphoid proliferations are either of B-cell or T/NK-cell origin, and range from disorders with an indolent behavior to aggressive lymphomas. In this review, which is divided in three parts, we provide an update of EBV-associated lymphoid disorders developing in the gastrointestinal tract, often representing a challenging diagnostic and therapeutic issue. Our aim is to provide a practical diagnostic approach to clinicians and pathologists who face this complex spectrum of disorders in their daily practice. In this part of the review, the chronic active EBV infection of T-cell and NK-cell type, its systemic form; extranodal NK/T-cell lymphoma, nasal type and post-transplant lymphoproliferative disorders are discussed.

IGFBP-6/sonic hedgehog/TLR4 signalling axis drives bone marrow fibrotic transformation in primary myelofibrosis.

Primary myelofibrosis is a Ph-negative chronic myeloproliferative neoplasm characterized by bone marrow fibrosis and associated with the involvement of several pathways, in addition to bone marrow microenvironment alterations, mostly driven by the activation of the cytokine receptor/JAK2 pathway. Identification of driver mutations has led to the development of targeted therapy for myelofibrosis, contributing to reducing inflammation, although this currently does not translate into bone marrow fibrosis remission. Therefore, understanding the clear molecular cut underlying this pathology is now necessary to improve the clinical outcome of patients. The present study aims to investigate the involvement of IGFBP-6/sonic hedgehog /Toll-like receptor 4 axis in the microenvironment alterations of primary myelofibrosis. We observed a significant increase in IGFBP-6 expression levels in primary myelofibrosis patients, coupled with a reduction to near-normal levels in primary myelofibrosis patients with JAK2V617F mutation. We also found that both IGFBP-6 and purmorphamine, a SHH activator, were able to induce mesenchymal stromal cells differentiation with an up-regulation of cancer-associated fibroblasts markers. Furthermore, TLR4 signaling was also activated after IGFBP-6 and purmorphamine exposure and reverted by cyclopamine exposure, an inhibitor of the SHH pathway, confirming that SHH is involved in TLR4 activation and microenvironment alterations. In conclusion, our results suggest that the IGFBP-6/SHH/TLR4 axis is implicated in alterations of the primary myelofibrosis microenvironment and that IGFBP-6 may play a central role in activating SHH pathway during the fibrotic process.

Gastrointestinal Manifestations in Systemic Mastocytosis: The Need of a Multidisciplinary Approach.

Mastocytosis represents a heterogeneous group of neoplastic mast cell disorders. The basic classification into a skin-limited disease and a systemic form with multi-organ involvement remains valid. Systemic mastocytosis is a disease often hard to diagnose, characterized by different symptoms originating from either the release of mast cell mediators or organ damage due to mast cell infiltration. Gastrointestinal symptoms represent one of the major causes of morbidity, being present in 60-80% of patients. A high index of suspicion by clinicians and pathologists is required to reach the diagnosis. Gastrointestinal mastocytosis can be a challenging diagnosis, as symptoms simulate other more common gastrointestinal diseases. The endoscopic appearance is generally unremarkable or nonspecific and gastrointestinal mast cell infiltration can be focal and subtle, requiring an adequate sampling with multiple biopsies by the endoscopists. Special stains, such as CD117, tryptase, and CD25, should be performed in order not to miss the gastrointestinal mast cell infiltrate. A proper patient's workup requires a multidisciplinary approach including gastroenterologists, endoscopists, hematologists, oncologists, and pathologists. The aim of this review is to analyze the clinicopathological features of gastrointestinal involvement in systemic mastocytosis, focusing on the relevance of a multidisciplinary approach.

Alpha-fetoprotein elevation in NUT midline carcinoma: a case report.

BACKGROUND: Nuclear protein in testis (NUT) midline carcinoma is a rarely diagnosed and potentially under-recognized type of squamous carcinoma that is considered one of the most aggressive human solid tumors. Alpha-fetoprotein elevation has been associated with chronic liver diseases and a limited number of cancers. In particular, in presence of a mediastinal mass in a young man, alpha-fetoprotein elevation is considered nearly pathognomonic of a non-seminoma germ-cell tumor. CASE PRESENTATION: A 22-year old man without any comorbidity was diagnosed with a large mediastinal mass with skeletal and lymph node metastases. The clinical picture was dominated by a life-threatening superior vena cava syndrome with elevated alpha-fetoprotein and lactate dehydrogenase that supported the diagnostic suspicion of mediastinal germ-cell tumor. However, a biopsy showed a poorly-differentiated and diffusely necrotic carcinoma. We eventually reached the diagnosis of the peculiar entity of NUT midline carcinoma, but the differential diagnosis was quite challenging also because alpha-fetoprotein is not reported as a marker of NUT midline carcinoma. Notably, alpha-fetoprotein levels correlated with disease course. CONCLUSIONS: The life-threatening aggressiveness of NUT midline carcinoma mandates to reach the right diagnosis in the shortest possible time. In this regard, poorly differentiated carcinomas lacking glandular differentiation mandate testing for NUT expression by immunohistochemistry. Awareness of a potentially misleading tumor marker elevation can help to broaden the differential diagnosis and establish the most appropriate treatment.