Efficacy and safety of tildrakizumab in elderly patients: real-world multicenter study (ESTER - study).

Purpose of the article: Interleukin-23 inhibitors, such as tildrakizumab, have emerged as safe and effective options for the management of psoriasis. Yet their efficacy in elderly patients (aged 65 years or more), particularly in those with difficult-to-treat areas involvement, remains insufficiently explored. We conducted this real-life retrospective multicentric observational study to assess the effectiveness of tildrakizumab in elderly patients with moderate-to-severe psoriasis, with involvement of difficult-to-treat areas.Materials and methods: We enrolled forty-nine patients aged 65 years old or more (mean age 73.1 ± 6.0), all treated with tildrakizumab for at least 28 weeks. The effectiveness of tildrakizumab was assessed by Static Physician's Global Assessment of Genitalia (sPGA-G), fingernail-PGA (f-PGA), palmoplantar PGA (pp-PGA), scalp-specific PGA (sc-PGA), and Psoriasis Area and Severity Index (PASI) scores.Results: Significant improvements in PASI scores were observed within 28 weeks of treatment, with 77.5%, 60%, and 45.2% of patients achieving PASI75, PASI90, and PASI100, respectively. The mean PASI decreased significantly from baseline (13.6 ± 9.9) to 1.3 ± 1.7 at week 28. More than 90% of patients had clear sPGA-G and pp-PGA scores and over 70% had clear f-PGA and sc-PGA scores after 28 weeks.Conclusions: Our findings suggest that tildrakizumab could be a valuable option for the treatment of elderly patients, including those with difficult-to-treat areas involvement.

Improving outcomes of childhood and young adult non-Hodgkin lymphoma: 25 years of research and collaboration within the framework of the European Intergroup for Childhood Non-Hodgkin Lymphoma.

The European Intergroup for Childhood Non-Hodgkin Lymphoma (EICNHL) was established 25 years ago with the goal to facilitate clinical trials and research collaborations in the field both within Europe and worldwide. Since its inception, much progress has been made whereby major improvements in outcomes have been achieved. In this Review, we describe the different diagnostic entities of non-Hodgkin lymphoma in children and young adults describing key features of each entity and outlining clinical achievements made in the context of the EICNHL framework. Furthermore, we provide an overview of advances in biopathology with an emphasis on the role of biological studies and how they have shaped available treatments. Finally, for each entity, we describe future goals, upcoming clinical trials, and highlight areas of research that require our focus going forward.

Preliminary Study of the Relationship between Osteopontin and Relapsed Hodgkin's Lymphoma.

The primary objective of this study was to investigate the potential role of tissue osteopontin, also known as secreted phosphoprotein 1 (SPP1), as a contributing factor to an unfavorable prognosis in classical Hodgkin's lymphoma (HL) patients who received the same treatment protocol. The study involved 44 patients aged 4-22 years, with a median follow-up period of 3 years. Patients with higher levels of SPP1 were associated with tissue necrosis and inflammation, and there was a trend toward a poorer prognosis in this group. Before therapy, we found a correlation between positron emission tomography (PET) scans and logarithmic SPP1 levels (p = 0.035). However, the addition of SPP1 levels did not significantly enhance the predictive capacity of PET scans for recurrence or progression. Elevated SPP levels were associated with tissue mRNA counts of chemotactic and inflammatory chemokines, as well as specific monocyte/dendritic cell subtypes, defined by IL-17RB, PLAUR, CXCL8, CD1A, CCL13, TREM1, and CCL24 markers. These findings contribute to a better understanding of the potential factors influencing the prognosis of HL patients and the potential role of SPP1 in the disease. While the predictive accuracy of PET scans did not substantially improve during the study, the results underscore the complexity of HL and highlight the relationships between SPP1 and other factors in the context of HL relapse.

Relapsing subcutaneous nodules of the penis in a pediatric patient.

A 14-year-old boy presented with a history of non-tender, subcutaneous coalescing nodules located on the ventral-lateral aspects of the penis shaft for one year. Laboratory investigations for blood count and autoimmunity were within normal limits. Complete excision was performed, and on histology, the dermis showed necrobiotic material composed of altered collagen bundles, surrounded by a palisade of histiocytes and scattered lymphocytes, thus allowing a diagnosis of subcutaneous granuloma annulare. Only 18 published cases reported penile granuloma annulare. Medical management was advocated in 7/18 cases, either as a first-line or adjuvant therapy where surgery was not radical. Three patients received high-potency local steroids: two cases underwent adjuvant sessions of intralesional triamcinolone, and one patient received pentoxifylline orally. Surgery should be considered a second-line option since 5/8 of treated cases eventually recurred. The pentoxifylline-treated case witnessed a relapse after drug discontinuation, while topical steroids lead to complete recovery without relapses.

Promising drugs and treatment options for pediatric and adolescent patients with Hodgkin lymphoma.

Currently-available therapies for newly-diagnosed pediatric and adolescent patients with Hodgkin lymphoma result in >95% survival at 5 years. Long-term survivors may suffer from long-term treatment-related side effects, however, so the past 20 years have seen clinical trials for children and adolescents with HL gradually abandon the regimens used in adults in an effort to improve this situation. Narrower-field radiotherapy can reduce long-term toxicity while maintaining good tumor control. Various risk-adapted chemo-radiotherapy strategies have been used. Early assessment of tumor response with interim positron emission tomography and/or measuring metabolic tumor volume has been used both to limit RT in patients with favorable characteristics and to adopt more aggressive therapies in patients with a poor response. Most classical Hodgkin's lymphoma relapses occur within 3 years of initial treatment, while relapses occurring 5 years or more after diagnosis are rare. As the outcome for patients with relapsed/refractory classical Hodgkin lymphoma remains unsatisfactory, new drugs have been proposed for its prevention or treatment. This review summarizes the important advances made in recent years in the management of pediatric and adolescent with classical Hodgkin lymphoma, and the novel targeted treatments for relapsed and refractory classical Hodgkin lymphoma.

Extranodal Biphenotypic Non-Hodgkin Lymphoma of the Popliteal Cavity: A Case Report and Review of Literature.

Primary soft-tissue lymphoma (PSTL) is a rare extranodal non-Hodgkin lymphoma, characterized by a mass growing within soft-tissue, which is connective tissue, adipose tissue, and skeletal muscle. Here, we describe a case of biphenotypic lymphoblastic lymphoma arising from soft tissue of the popliteal fossa in an 11-year-old boy. A pediatric review about PSTL revealed that anaplastic large cell lymphoma is the most common histological type and a biphenotypic lymphoblastic lymphoma has not yet been reported in childhood. Lymphoma should always be considered in patients presenting with a soft-tissue mass, and a comprehensive immunohistochemical evaluation, including B-cell, T-cell, and myeloid markers, is needed to make a correct diagnosis and establish the most suitable treatment.

Thrombopoietin receptor agonists increase splenic regulatory T-cell numbers in immune thrombocytopenia.

Thrombopoietin receptor agonists (TPO-RA) are a valid therapy for immune thrombocytopenia (ITP), due to megakaryocyte stimulation and (poorly characterised) immune-modulatory effects. The spleen is pivotal in the pathogenesis of ITP, yet little is known on its immune microenvironment and on effects of TPO-RA on this organ. To address these topics, we analysed 35 spleens removed for primary refractory ITP. Pre-splenectomy TPO-RA administration correlated with increased splenic regulatory T cells (Tregs), type 2 T-helper cells and histiocyte density and with reduced red pulp sinusoids. Surgical outcome was not associated with TPO-RA administration, other pre-splenectomy therapies and/or Treg density. In conclusion, TPO-RA affect the splenic microenvironment, but this has no impact on splenectomy outcome.

Epstein-Barr virus associated gastric dysplasia: a new rare entity?

Epstein-Barr virus (EBV) infection characterizes a portion of gastric adenocarcinomas. However, since there is lack of evidence of EBV presence in pre-neoplastic lesions of gastric mucosa, the etiologic role of EBV in gastric carcinogenesis is still debated. We report an unusual case of an EBV-associated foveolar gastric dysplasia associated with a focus of EBV-positive low-grade tubular adenocarcinoma, arisen in the context of a lymphocytic-like (EBV-positive) gastritis. The present case offers the unique opportunity to determine whether EBV is an early or late event in gastric cancer development and to evaluate its prevalence in patients with gastric dysplasia. To properly address this question, we investigated EBER expression in a large mono-institutional series of gastric and gastro-esophageal cancers (n = 594) and associated precursor lesions (n = 84). All the selected gastric dysplastic lesions (n = 43) resulted EBV negative. In most cases, EBV is present only in gastric and gastroesophageal junction adenocarcinomas, but not in their precursor lesions. However, the reported case indicates that non-conventional EBV-associated dysplasia may represent a novel histopathological entity in the gastric dysplasia scenario and that EBV could play an early direct role in gastric carcinogenesis.

Primary breast lymphoma of childhood: a case report and review of literature.

BACKGROUND: Primary breast lymphoma (PBL) is an extremely rare neoplasm in children; by definition, it manifests in the breast without evidence of lymphoma elsewhere, except ipsilateral axillary nodes. CASE PRESENTATION: We report a case of a 15-year-old girl diagnosed with diffuse large B-cell lymphoma (DLBCL) of the right breast: the patient received chemotherapy and rituximab, achieving complete remission. A literature review revealed other 11 cases of pediatric PBL; it mainly affects female adolescents and can involve right and left breast equally. Different histologic subtypes have been described, arising from both B-cell and T-cell. Therapeutic approaches were very different, from chemotherapy to local treatment with surgery and/or radiotherapy. CONCLUSIONS: Our case is the first in which rituximab was administered, suggesting to be a promising therapy in B-cell PBL, as already demonstrated in pediatric B-cell lymphoma from other sites. Further investigations are needed to identify prognostic factors and establish the most effective treatment.

Hormonal therapies in migraine management: current perspectives on patient selection and risk management.

INTRODUCTION: The link between sex hormones and migraines has long been investigated but the mechanisms underlying this altered interaction are not yet fully understood. Herein, we retrace the knowledge on this association in relationship with risk of stroke. AREAS COVERED: Estrogens fluctuations could trigger migraine attacks and exogenous estrogens intake could be a risk factor for venous thromboembolism (VTE) and stroke. At the same time, ischemic heart diseases and stroke share a common substrate with migraine and other mood disorders, depression, and anxiety. EXPERT OPINION: The use of hormonal therapies in the context of contraception or replacement therapy must be closely evaluated in a careful risk assessment. We highlight the complex interaction of hormone/neuroinflammation pathways underlying the pathophysiology of migraine glimpsing in mood disorders a possible common denominator of link between hormonal and neuronal systems.

Prognostic Role of Minimal Disseminated Disease and NOTCH1/FBXW7 Mutational Status in Children with Lymphoblastic Lymphoma: The AIEOP Experience.

NOTCH1/FBXW7 (N/F) mutational status at diagnosis is employed for T-cell lymphoblastic lymphoma (T-LBL) patients' stratification in the international protocol LBL 2018. Our aim was to validate the prognostic role of Minimal Disseminated Disease (MDD) alone and in combination with N/F mutational status in a large retrospective series of LBL pediatric patients. MDD was analyzed in 132 bone marrow and/or peripheral blood samples by flow cytometry. Mutations in N/F genes were analyzed on 58 T-LBL tumor biopsies. Using the previously established cut-off of 3%, the four-year progression-free survival (PFS) was 57% for stage I-III patients with MDD ≥ 3% versus 80% for patients with MDD inferior to cut-off (p = 0.068). We found a significant worsening in the four-year PFS for nonmutated (51 ± 12%) compared to mutated patients (100%, p = 0.0013). Combining MDD and N/F mutational status in a subgroup of available cases, we found a statistically significant difference in the four-year PFS for different risk groups (p = 0.0012). Overall, our results demonstrate that N/F mutational status has a more relevant prognostic value than MDD at diagnosis. However, the combination of N/F mutations with MDD analysis could identify patients with very aggressive disease, which might benefit from a more intensive treatment.

Molecular features of non-anaplastic peripheral T-cell lymphoma in children and adolescents.

Non-anaplasticperipheral T-cell lymphomas (PTCL) are rare tumors in children, adolescents, and young adults (CAYA) with poor prognosis and scarce genetic data. We analyzed lymphoma tissue from 36 patients up to 18 years old with PTCL, not otherwise specified (PTCL-NOS), hepatosplenic T-cell lymphoma, Epstein-Barr virus (EBV)-positive T-lymphoproliferative diseases, subcutaneous panniculitis-like T-cell lymphoma, and other PTCL types. Twenty-three patients (64%) had at least one genetic variant detectable, including TET2, KMT2C, PIK3D, and DMNT3A. TP53 and RHOA variants, commonly found in adults, were not identified. Eight of 20 (40%) CAYA PTCL-NOS had no detectable mutations. The genetic findings suggest that CAYA PTCL differ from adult cases.

Genetic lesions in MYC and STAT3 drive oncogenic transcription factor overexpression in plasmablastic lymphoma.

Plasmablastic lymphoma mutational profile is undescribed. Here we performed a targeted exonic NGS analysis of 30 plasmablastic lymphoma cases with a B cell lymphoma dedicated panel and FISH for the detection of MYC rearrangements. A complete phenotyping of the neoplastic and microenvironment cell populations was also performed. We have identified an enrichment in recurrent genetic events in MYC (69% with MYC translocation or amplification and 3 cases with missense point mutations), PRDM1/Blimp1 and STAT3 mutations. These gene mutations were more frequent in EBV positive disease. Other genetic events included mutations in BRAF, EP300, BCR (CD79A and CD79B), NOTCH pathway (NOTCH2, NOTCH1 and SGK1) and MYD88pL265P. Immunohistochemical analysis showed consistent MYC expression, higher in cases with MYC rearrangements together with phospho-STAT3 (Tyr705) overexpression in cases with STAT3 SH2 domain mutations. Microenvironment populations were heterogeneous and unrelated with EBV, with an enrichment of Tumor Associated Macrophages (TAM) and PD1 positive T cells. PD-L1 was expressed in all cases in the TAM population but only in 5 cases in the neoplastic cells (4 out of 14 EBV positive cases). HLA expression was absent in the majority of PBL cases. In summary, Plasmablastic lymphoma mutational profile is heterogeneous and related with EBV infection. Genetic events in MYC, STAT3 and PRDM1/Blimp1 are more frequent in EBV positive disease. An enrichment in TAM and PD1 reactive T lymphocytes is found in the microenvironment of PBL cases, that express PD-L1 in the neoplastic cells in a fraction of cases.

Prognostic Factors in Childhood Anaplastic Large Cell Lymphoma: Long Term Results of the International ALCL99 Trial.

With the aim of describing the long-term follow-up and to define the prognostic role of the clinical/pathological/molecular characteristics at diagnosis for childhood, adolescent and young adults affected by anaplastic large cell lymphoma (ALCL), we analyzed 420 patients aged up to 22 years homogeneously treated within the international ALCL99 trial. The 10-year progression free survival (PFS) was 70% and overall survival was 90%, rare late relapses occurred but no secondary malignancies were reported. Among clinical/pathological characteristics, only patients presenting a small cell/lymphohistiocytic (SC/LH) pattern were independently associated with risk of failure (hazard ratio = 2.49). Analysis of minimal disseminated disease (MDD), available for 162 patients, showed that both SC/LH pattern (hazard ratio = 2.4) and MDD positivity (hazard ratio = 2.15) were significantly associated with risk of failure in multivariate analysis. Considering MDD and SC/LH results, patients were separated into three biological/pathological (bp) risk groups: a high-risk group (bpHR) including MDD-positive patients with SC/LH pattern; a low-risk group (bpLR) including MDD-negative patients without SC/LH pattern; and an intermediate-risk group (bpIR) including remaining patients. The 10-year PFS was 40%, 75% and 86% for bpHR, bpIR and bpLR, respectively (p < 0.0001). These results should be considered in the design of future ALCL trials to tailor individual treatments.

Comparison of Hodgkin's Lymphoma in Children and Adolescents. A Twenty Year Experience with MH'96 and LH2004 AIEOP (Italian Association of Pediatric Hematology and Oncology) Protocols.

Adolescents and young adults (AYAs) represent a distinct group of patients. The objectives of this study were: To compare adolescent prognosis to that of younger children; to compare the results achieved with the two consecutive protocols in both age groups; to analyze clinical characteristics of children and adolescents. Between 1996 and 2017, 1759 patients aged <18 years were evaluable for the study. Five hundred and sixty patients were treated with the MH'96 protocol and 1199 with the LH2004 protocol. Four hundred and eighty-two were adolescents aged ≥15 years. Patients in both age groups showed very favorable prognoses. In particular, OS improved with the LH2004 protocol, especially in the adolescent group and in the low risk group, where radiation therapy was spared. Adolescent characteristics differed significantly from the children's according to sex, histology, and the presence of symptoms. Remarkable is the decrease both in mixed cellularity in the children and in low stages in both age groups in the LH2004 protocol with respect to MH'96 protocol. Based on our experience, adopting pediatric protocols for AYA does not compromise patient outcomes.