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The COVID-19 pandemic has reached direct and indirect medical and social consequences with a subset of patients who rapidly worsen and die from severe-critical manifestations. As a result, there is still an urgent need to identify prognostic biomarkers and effective therapeutic approaches. Severe-critical manifestations of COVID-19 are caused by a dysregulated immune response. Immune checkpoint molecules such as Programmed death-1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1) play an important role in regulating the host immune response and several lines of evidence underly the role of PD-1 modulation in COVID-19. Here, by analyzing blood sample collection from both hospitalized COVID-19 patients and healthy donors, as well as levels of PD-L1 RNA expression in a variety of model systems of SARS-CoV-2, including in vitro tissue cultures, ex-vivo infections of primary epithelial cells and biological samples obtained from tissue biopsies and blood sample collection of COVID-19 and healthy individuals, we demonstrate that serum levels of PD-L1 have a prognostic role in COVID-19 patients and that PD-L1 dysregulation is associated to COVID-19 pathogenesis. Specifically, PD-L1 upregulation is induced by SARS-CoV-2 in infected epithelial cells and is dysregulated in several types of immune cells of COVID-19 patients including monocytes, neutrophils, gamma delta T cells and CD4+ T cells. These results have clinical significance since highlighted the potential role of PD-1/PD-L1 axis in COVID-19, suggest a prognostic role of PD-L1 and provide a further rationale to implement novel clinical studies in COVID-19 patients with PD-1/PD-L1 inhibitors.

Efficient predictive biomarkers are needed for immune checkpoint inhibitor (ICI)-based immunotherapy in non-small cell lung cancer (NSCLC). Testing the predictive value of single nucleotide polymorphisms (SNPs) in programmed cell death 1 ( PD-1 ) or its ligand 1 ( PD-L1 ) has shown contrasting results. Here, we aim to validate the predictive value of PD-L1 SNPs in advanced NSCLC patients treated with ICIs as well as to define the molecular mechanisms underlying the role of the identified SNP candidate. rs822336 efficiently predicted response to anti-PD-1/PD-L1 immunotherapy in advanced non-oncogene addicted NSCLC patients as compared to rs2282055 and rs4143815. rs822336 mapped to the promoter/enhancer region of PD-L1 , differentially affecting the induction of PD-L1 expression in human NSCLC cell lines as well as their susceptibility to HLA class I antigen matched PBMCs incubated with anti-PD-1 monoclonal antibody nivolumab. The induction of PD-L1 expression by rs822336 was mediated by a competitive allele-specificity binding of two identified transcription factors: C/EBPβ and NFIC. As a result, silencing of C/EBPβ and NFIC differentially regulated the induction of PD-L1 expression in human NSCLC cell lines carrying different rs822336 genotypes. Analysis by binding microarray further validated the competitive allele-specificity binding of C/EBPβ and NFIC to PD-L1 promoter/enhancer region based on rs822336 genotype in human NSCLC cell lines. These findings have high clinical relevance since identify rs822336 and induction of PD-L1 expression as novel biomarkers for predicting anti-PD-1/PD-L1-based immunotherapy in advanced NSCLC patients.

Advancement in sequencing technologies allows for the identification of molecular pathways involved in tumor progression and treatment resistance. Implementation of novel agents targeting these pathways, defined as targeted therapy, significantly improves the prognosis of cancer patients. Targeted therapy also includes the use of monoclonal antibodies (mAbs). These drugs recognize specific oncogenic proteins expressed in cancer cells. However, as with many other types of targeting agents, mAb-based therapy usually fails in the long-term control of cancer progression due to the development of resistance. In many cases, resistance is caused by the activation of alternative pathways involved in cancer progression and the development of immune evasion mechanisms. To overcome this off-target resistance, bispecific antibodies (bsAbs) were developed to simultaneously target differential oncogenic pathway components, tumor-associated antigens (TAA) and immune regulatory molecules. As a result, in the last few years, several bsAbs have been tested or are being tested in cancer patients. A few of them are currently approved for the treatment of some hematologic malignancies but no bsAbs are approved in solid tumors. In this review, we will provide an overview of the state-of-the-art of bsAbs for the treatment of solid malignancies outlining their classification, design, main technologies utilized for production, mechanisms of action, updated clinical evidence and potential limitations.

Introduction Multiple myeloma (MM) with pulmonary extramedullary disease is rare and usually associated with poor prognosis, and no data on daratumumab‐based regimens have been reported yet. Case Presentation Here, a 64‐year‐old man with pulmonary plasmacytoma received daratumumab‐based regimens and has achieved a very good partial response with lung mass disappearance and overall survival of 16 months. He did not receive autologous stem cell transplantation because of several comorbidities, such as severe drug‐induced neuropathy and JAK2‐mutated myeloproliferative neoplasm with marked splenomegaly. Conclusions We showed the efficacy of daratumumab in combination with targeted therapies for the treatment of pulmonary MM.

Background/Objectives: Eosinophilic esophagitis (EoE) and achalasia are two chronic esophageal disorders, characterized by inflammatory and neuromotor dysfunction, respectively, that share overlapping immune-inflammatory features. Emerging evidence suggests that dysbiosis of the oral and esophageal microbiota may represent a common determinant in their pathophysiology. This review aims to provide a comparative and integrated overview of microbial and immune alterations in EoE and Achalasia, with potential diagnostic and therapeutic implications. Methods: A bibliographic search was conducted on PubMed and Scopus including clinical studies, experimental research, and review articles published between 2015 and 2025. The keywords Eosinophilic Esophagitis, Achalasia, Microbiota, and Dysbiosis were used for article selection. Results: In EoE, several studies demonstrated increased bacterial diversity with predominance of Prevotella and reduction of Streptococcus, findings associated with greater inflammatory severity and epithelial barrier dysfunction. Conversely, Achalasia is characterized by reduced microbial diversity and a shift from Gram-positive commensals to Gram-negative taxa capable of activating pro-inflammatory pathways (TLR4-MYD88-NF-κB), leading to neuronal loss and impaired peristalsis. Conclusions: Both EoE and Achalasia share the hallmark of dysbiosis, although with distinct immune profiles (Th2 vs. Th17). The identification of specific microbial “signatures” suggests promising perspectives for non-invasive biomarkers and microbiota-targeted therapies, including probiotics and glycan-modulating strategies. Further prospective studies are needed to clarify causal mechanisms and validate microbiota manipulation as a complementary therapeutic approach in esophageal diseases.

Thin melanomas are tumors less than 1 mm thick according to Breslow classification. Their prognosis is in most cases excellent. However, a small subset of these tumors relapses. These clinical findings emphasize the need of novel prognostic biomarkers to identify this subset of tumors. Characterization of tumor immune microenvironment (TIME) is currently investigated as a prognostic and predictive biomarker for cancer immunotherapy in several solid tumors including melanoma. Here, taking into account the limited availability of tumor tissues, by characterizing some of the characteristics of TIME such as number of infiltrating lymphocytes, HLA class I antigen and PD-L1 expression, we show that number of infiltrating CD8+ and FOXP3+ T cells as well as CD8+/FOXP3+ T cell ratio can represent a useful prognostic biomarker in thin melanoma. Although further investigations in a larger patient cohort are needed, these findings have potential clinical significance since they can be used to define subgroups of thin melanoma patients who have a worse prognosis and might need different treatment modalities.

Background: Approximately 25.0% of metastatic prostate cancer patients harbour DNA damage repair mutations, including BRCA1 and BRCA2, which are actionable targets for poly(ADP-ribose) polymerase (PARP) inhibitors. Accurate detection of BRCA1/2 mutations is critical for guiding targeted therapies, but crucial pre-analytical factors, such as tissue storage duration and DNA fragmentation, drastically affect the reliability of next-generation sequencing (NGS) using real-world diagnostic specimens. Methods: This multicentre study analysed 954 formalin-fixed paraffin-embedded tissue samples from 11 centres, including 559 biopsies and 395 surgical specimens. This study examined the impact of storage duration (<1 year, 1–2 years, and >2 years) and DNA parameters (concentration and fragmentation index) on NGS success rates. Logistic regression and Cox regression analyses were used to assess correlations between these factors and sequencing outcomes. Results: NGS success rates decreased significantly with longer storage, from 87.8% (<1 year) to 69.1% (>2 years). Samples with higher DNA concentrations and fragmentation indexes had higher success rates (p < 0.001). Surgical specimens had superior success rates (83.3%) compared with biopsies (72.8%) due to better DNA quality. The DNA degradation rate was more pronounced in older samples, underscoring the negative impact of extended storage. Conclusions: Timely testing of BRCA1/2 mutations is critical for optimizing the identification of prostate cancer patients eligible for PARP inhibitors. Surgical specimens provide more reliable results than biopsies and minimizing the storage duration significantly enhances testing outcomes. Standardizing pre-analytical and laboratory procedures across centres is essential to ensure personalized treatments and improve patient outcomes.

Fine-needle aspiration cytology (FNAC) is commonly used to obtain a pre-surgical pathological diagnosis in many organs, but its cost-effectiveness in lymphadenopathy has not been studied yet. We calculated the cost and diagnostic accuracy of a diagnostic algorithm that uses FNAC as a first-line procedure and compared it to a purely surgical approach in 545 consecutive lymphadenopathies. In 74% of the cases, FNAC alone can obtain a sufficiently detailed diagnosis, avoiding the surgical biopsy. In doing so, the average cost of diagnosis is cut to less than one-third, the patient avoids an invasive procedure and the diagnosis is reached earlier. In conclusion, the systematic use of lymph node-FNAC in the initial assessment of lymphadenopathy is clinically and economically advantageous as it avoids surgical biopsies in cases where cytology can suffice.

While the two-level structure of the Sydney System was intentionally conceived to be applicable even in settings where ancillary testing is unavailable, it is important to note that cytopathologists should strive to perform ancillary techniques whenever possible, for three reasons. [...]it helps to further subclassify the nosological process responsible for the lymphadenopathy (e.g., \"malignant, lymphoma\" can become \"malignant, follicular В-cell lymphoma\" after flow cytometry; \"malignant, metastasis\" can become \"malignant, breast cancer metastasis\" after immunocytochemistry; and \"benign, granulomatous\" can become \"benign, tuberculous lymphadenopathy\" after polymerase chain reaction). [...]the relatively high risk of malignancy (ROM) registered for the category atypical (atypical, undermined significance-atypical lymphoid uncertain significance, AUS-ALUS) by Gupta et al. Response to comment on \"A stepwise approach to fine needle aspiration cytology of lymph nodes\" Yosep Chong1, Gyeongsin Park1, Hee Jeong Cha2, Hyun-Jung Kim3, Chang Suk Kang4, Jamshid Abdul-Ghafar1, Seung-Sook Lee5 1 Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul; 2 Department of Pathology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan; 3 Department of Pathology, Inje University Sanggye Paik Hospital, Seoul; 4 Department of Pathology, Samkwang Medical Laboratories, Seoul; 5 Department of Pathology, Korea Institute of Radiological and Medical Sciences, Seoul, Korea To the Editor, We read Caputo et al.'s letter [1] regarding our recently published review, \"A Stepwise Approach to Fine Needle Aspiration Cytology of Lymph Nodes,\" with great interest and we really appreciate to their keen observation and critique to our review [2].

Background Thyroid disease is common in the elderly population. The incidence of hypothyroidism and multinodular goitre gradually increases with age. In view of a growth of aging population, we performed a literature review about the feasibility of thyroid surgery in the elderly. Methods We conducted a literature search in the PubMed database in September 2012 and all English-language publications on thyroidectomy in geriatric patients since 2002 were retrieved. The potential original articles mainly focusing on thyroidectomy in elderly patients were all identified and full texts were obtained and reviewed for further hand data retrieving. Results We retrieved five papers based on different primary end-point. Four were retrospective non randomized studies and one was prospective non randomized study. At last 65, 70, 75 and 80 years were used as an age cut-off. All studies evaluate the indications of thyroidectomy in geriatric patients, postoperative morbility and mortality. Only one study specifically assesses the rate of the rehospitalization after thyroidectomy among the elderly. Conclusions Thyroid nodules are particularly important in elderly patients, as the incidence of malignancy increases and they are usually more aggressive tumors. An age of at least 70 years is an independent risk factor for complications after general surgery procedures. Thyroid surgery in patients aged 70 years or older is safe and the relatively high rate of thyroid carcinoma and toxic goiter may justify an aggressive approach. A programmed operation with a careful pre-operative evaluation and a risk stratification should make the surgical procedures less hazardous, specially in 80 years old patients with an high ASA score.