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Histopathological evaluation of lymph nodes in Merkel cell carcinoma has become crucial in progression estimation and treatment modification. This study was undertaken to determine the most sensitive immunohistochemical panel for detecting MCC nodal metastases. We included 56 patients with 102 metastatic MCC lymph nodes, which were tested with seven antibodies: cytokeratin (CKAE1/AE3), CK20, chromogranin A, synaptophysin, INSM1, SATB2, and neurofilament (NF). Tissue microarrays (TMA) composed of 2-mm tissue cores from each nodal metastasis were constructed. A semiquantitative 5-tier scoring system (0%, < 25%, 25-74%, 75-99%, 100% positive MCC cells with moderate to strong reactivity) was implemented. In the statistical assessment, we included Merkel cell polyomavirus (MCPyV) status and expression heterogeneity between lymph nodes from one patient. A cumulative percentage of moderate to strong expression ≥ 75% of tumoral cells was observed for single cell markers as follows: 91/102 (89.2%) SATB2, 85/102 (83%) CKAE1/AE3, 80/102 (78.4%) synaptophysin, 75/102 (75.5%) INSM1, 68/102 (66.7%) chromogranin A, 60/102 cases (58.8%) CK20, and 0/102 (0%) NF. Three markers presented a complete lack of immunoreactivity: 8/102 (7.8%) CK20, 7/102 (6.9%) chromogranin A, and 6/102 (5.9%) NF. All markers showed expression heterogeneity in lymph nodes from one patient; however, the most homogenous was INSM1. The probability of detecting nodal MCC metastases was the highest while using SATB2 as a first-line marker (89.2%) with subsequential adding CKAE1/AE3 (99%); these results were independent of MCPyV status. Synaptophysin showed a superior significance in confirming the neuroendocrine origin of metastatic cells. This comprehensive analysis allows us to recommend simultaneous evaluation of SATB2, CKAE1/AE3, and synaptophysin in the routine pathologic MCC lymph node protocol., (© 2023. The Author(s).)

Background: Impaired neutrophil activity is an important issue in chronic lymphocytic leukemia (CLL), as it contributes to a dysfunctional immune response leading to life-threatening infections in patients. Some features typical of CLL neutrophils, e.g., the B-cell-supportive secretion profile, have already been described. However, most of these studies were performed on cells isolated from peripheral blood. It is still unclear which molecular factors and cell types are involved in shaping neutrophil function and phenotype in the CLL microenvironment. Since regulatory T cells (Treg) play an important role in CLL progression and influence the activity of neutrophils, we investigated the crosstalk between Treg and neutrophils in the spleen using a murine model of CLL., Methods: In this work, we used an Eµ-TCL1 mouse model of human CLL. For our in vivo and ex vivo experiments, we inoculated wild-type mice with TCL1 leukemic cells isolated from Eµ-TCL1 transgenic mice and then monitored disease progression by detecting leukemic cells in peripheral blood. We analyzed both the phenotype and activity of neutrophils isolated from the spleens of TCL1 leukemia-bearing mice. To investigate the interrelation between Treg and neutrophils in the leukemia microenvironment, we performed experiments using TCL1-injected DEREG mice with Treg depletion or RAG2KO mice with adoptively transferred TCL1 cells alone or together with Treg., Results: The obtained results underline the plasticity of the neutrophil phenotype, observed under the influence of leukemic cells alone and depending on the presence of Treg. In particular, Treg affect the expression of CD62L and IL-4 receptor in neutrophils, both of which are crucial for the function of these cells. Additionally, we show that Treg depletion and IL-10 neutralization induce changes in the leukemia microenvironment, partially restoring the "healthy" phenotype of neutrophils., Conclusions: Altogether, the results indicate that the crosstalk between Treg and neutrophils in CLL may play an important role in CLL progression by interfering with the immune response., (© 2023. YUMED Inc. and BioMed Central Ltd.)

Regulatory T cells (Tregs) are capable of inhibiting the proliferation, activation and function of T cells and play an important role in impeding the immune response to cancer. In chronic lymphocytic leukemia (CLL) a dysfunctional immune response and elevated percentage of effector-like phenotype Tregs have been described. In this study, using the Eµ-TCL1 mouse model of CLL, we evaluated the changes in the Tregs phenotype and their expansion at different stages of leukemia progression. Importantly, we show that Tregs depletion in DEREG mice triggered the expansion of new anti-leukemic cytotoxic T cell clones leading to leukemia eradication. In TCL1 leukemia-bearing mice we identified and characterized a specific Tregs subpopulation, the phenotype of which suggests its role in the formation of an immunosuppressive microenvironment, supportive for leukemia survival and proliferation. This observation was also confirmed by the gene expression profile analysis of these TCL1-specific Tregs. The obtained data on Tregs are consistent with those described so far, however, above all show that the changes in the Tregs phenotype described in CLL result from the formation of a specific, described in this study Tregs subpopulation. In addition, functional tests revealed the ability of Tregs to inhibit T cells that recognize model antigens expressed by leukemic cells. Moreover, inhibition of Tregs with a MALT1 inhibitor provided a therapeutic benefit, both as monotherapy and also when combined with an immune checkpoint inhibitor. Altogether, activation of Tregs appears to be crucial for CLL progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Goral, Firczuk, Fidyt, Sledz, Simoncello, Siudakowska, Pagano, Moussay, Paggetti, Nowakowska, Gobessi, Barankiewicz, Salomon-Perzynski, Benvenuti, Efremov, Juszczynski, Lech-Maranda and Muchowicz.)

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with a high risk of recurrence and poor prognosis. The treatment of locally advanced disease involves surgery and radiotherapy. To analyze real-life treatment patterns and clinical outcomes, we conducted a retrospective analysis of data from 161 MCC patients treated with curative intent in four oncological centers in Poland. The median age at diagnosis was 72 years (30-94); 49.7% were male. Lymph node (LN) involvement at diagnosis was found in 26.9% of patients. Sentinel lymph node biopsy (SLNB) was performed in 36.5% of patients (positive in 10.5%), and 51.9% of patients received perioperative treatment. The relapse rate was 38.3%. With the median follow-up of 2.3 years, the median disease-free survival (DFS) was not reached, and the 1-year rate was 65%. The negative independent risk factors for DFS were male gender, metastases in LN at diagnosis, no SLNB in patients without clinical nodal metastases, and no perioperative radiotherapy. The estimated median overall survival (OS) was 6.9 years (95% CI 4.64-9.15). The negative independent risk factors for OS were male gender, age above 70, metastases in LN at diagnosis, and no SLNB in patients without clinical nodal metastases. Our results confirm that the MCC treatment should be conducted in an experienced multidisciplinary team; however, the outcomes are still unsatisfactory.

Background: Although BRAF/MEK inhibitors are generally considered to be equally effective whether given before or after immunotherapy, no prospective trial has confirmed this hypothesis and contradictory data have been published in the melanoma field., Objective: We aimed to investigate the outcomes of patients with metastatic melanoma depending on the first-line treatment., Patients and Methods: In this ambidirectional cohort, single-center study, we included 253 consecutive melanoma patients treated in our institution with an anti-PD1 antibody or BRAF/MEK inhibitors, who started first-line treatment between December 2015 and March 2018. Kaplan-Meier estimator, log-rank test, and Cox proportional hazard model were used in this analysis., Results: First-line median progression-free survival (PFS) for all patients was 5.7 months (m), 6.9 m on anti-PD-1 therapy and 5.6 m for combination targeted therapy. Patients with BRAF mutated melanoma had 6.0 m median PFS on immunotherapy. At a median follow-up of 23.2 m with 149 events, in BRAF wild-type patients treated with anti-PD1, median overall survival (OS) was 18.1 m. BRAF mutated patients treated with first-line BRAF/MEK inhibitors had 11.7 m median OS. High neutrophil to lymphocyte ratio, high LDH level, ECOG > 0, and the presence of brain metastases negatively impacted PFS and OS., Conclusions: In BRAF mutated patients with normal LDH, first-line immunotherapy seems a more effective approach. We have demonstrated that although BRAF mutation is a negative prognostic factor in stage IV melanoma, the use of two different systemic treatment modalities allows achievement of comparable survival in BRAF mutated and BRAF wild-type patients.

Introduction: Gastric lymphoma takes 70% of lymphomas in gastric tract. Lack of characteristic symptoms and histological changes makes these disease difficult to recognize. The aim of the study was to search for specific constellation of the symptoms due to validation of diagnostic standards., Material and Methods: Retrospective analysis of clinical data for the group of 64 patients treated during 10 years in Hematology Department of Pomeranian Medical University in Szczecin., Results: Recognition of gastric lymphoma in 80% was based on gastrocopy and histopatology examination. Gastrectomy was useful in 14 cases. Classic Ultrasound Abdomen Examination confirmed changes in 40%. Epigastic pain was raported as the most common symptom (54 from 64 patients). Systemic symptom appears in 34/64 patients (usually the loss of the body mass)., Conclusions: 1. Clinical symptoms of non-Hodgkin's lymphoma in gastric localization are not specific. Epigastric pain, nausea and body mass lost are the symptoms the most often reported and physical symptoms do not reflect in systemic disease. 2. The standard of examination should consist of the transesophageal sonography (EUS) completed with multiple biopsy of gastric membrane and Hp tests.

Objective: : Surgical pulmonary vein isolation (PVI) for paroxysmal atrial fibrillation (PAF) blocks trigger stimulation from PVs and partially disconnects the atria from sympathetic and parasympathetic neural stimulation. This study describes long-term changes in heart rate variability (HRV) and autonomic activity (AA) after successful bipolar radiofrequency PVI., Methods: : Twenty-seven patients who underwent coronary artery bypass grafting and successful (defined as stable sinus rhythm for 1 year) off-pump bipolar radiofrequency PVI for PAF were prospectively followed 3, 6, and 12 months after surgery including 24 hours Holter electrocardiogram. The following HRV and AA parameters were calculated: mean NN-interval, SD of NN-intervals, SD of averaged NN-intervals, root mean square of successive differences, low frequency (LF) power (0.04-0.15 Hz; a parameter specific for sympathetic activity), high frequency (HF) power (0.15-0.4 Hz; a parameter specific for parasympathetic activity), and the LF:HF ratio., Results: : Preoperatively, high HRV and AA parameters were recorded. In 3-, 6-, and 12-month time, a progressive reduction of HRV and AA was observed, reaching significance after 12 months. Respective rates before surgery and 12 months after it were: for SD of averaged NN-intervals (122.4 ± 113; 80.5 ± 42 milliseconds; P = 0.046), for root mean square of successive differences (79.2 ± 93; 45 ± 20 milliseconds; P = 0.04). The LF:HF ratios were 1.22 and 0.73 before and 12 months after surgery, respectively. The statistically significant continuous reduction in LF:HF ratio (P = 0.02) is suggestive of a progressive parasympathetic dominance 12 months after surgery., Conclusions: : Successful PVI for PAF results in HRV and sympathetic activity reduction with preoperative sympathetic dominance and oncoming vagal dominance after 1 year from surgery. Despite preoperative sympathetic dominance, successful PVI for PAF results in HRV and a reduction in sympathetic activity with emerging parasympathetic dominance 12 months after surgery.