Mediastinal Nodes Research Articles

Case report: The effect of induction targeted therapies in stage III driver mutants non-small cell lung cancer

BackgroundOver the past decade, progress in the diagnosis and treatment of Non-Small Cell Lung Cancer (NSCLC) has led to the identification of many targeted mutations. This has enhanced PFS and OS in both advanced and early-stage NSCLC. The current standard of care for stage III NSCLC varies, and it may combine chemotherapy with either immunotherapy or radiotherapy. This study evaluated the role of induction targeted therapies in patients with driver mutations and inoperable NSCLC.MethodsThis is a single-center, retrospective study assessing the efficacy of targeted therapy in resectable stage III NSCLC patients who are EGFR or ALK-positive, using patient records, PET-CT, brain MRI staging, and mediastinal lymph node evaluation.ResultsBetween January 2020 and February 2024, we identified four patients with either EML4-ALK fusions (2/4) or EGFR mutations (2/4) who underwent treatment with brigatinib or osimertinib before surgery. All patients experienced clinical benefits. Of the two patients with ALK fusion, one responded almost completely, while the other exhibited a notable partial response. Among the patients with EGFR mutations, one had a complete response and the other displayed a significant partial response. All four patients subsequently underwent lobectomy surgical resection.ConclusionsThis case series highlights the potential of targeted therapies for resectable NSCLC in the neoadjuvant setting. Further research is required to confirm their benefits, assess their safety and efficacy, and determine optimal timing and sequencing.

Prognostic significance and risk factors of mediastinal lymph node metastasis in esophagogastric junction cancer: a single-center, retrospective study

Prognostic significance and risk factors of mediastinal lymph node metastasis in esophagogastric junction cancer: a single-center, retrospective study

Abstract 4136566: Primary Pericardial Mesothelioma: Diagnostic dilemma and rapid decline

Description of case: A 33-year-old man with no medical history or environment exposures, presented with dyspnea, nausea, and vomiting. He was tachycardic, with jugular venous distension, pulsus paradoxus, low voltage QRS and echocardiogram (TTE) showed a large pericardial effusion with ventricular interdependence. He underwent pericardiocentesis with negative fluid studies, including cytology. Two months later he represented with dyspnea and pleuritic chest pain, was diagnosed with pericarditis, and found to have recurrent pericardial effusion without tamponade. He was treated with aspirin and colchicine and discharged, with surveillance TTE showing a stable pericardial effusion but with significant adhesions and constrictive physiology (confirmed on right heart catheterization). Negative QuantiFERON was obtained and Anakinra started. Two months later he remained symptomatic with new pleural effusions and was sent for positron emission tomography scan which revealed diffuse intensely hypermetabolic pericardial thickening/fluid, up to 3.8 cm in maximal thickness and increased uptake in mediastinal nodes. Next, a cardiac MRI showed extensive circumferential thickening of the pericardial space approximately 2.5 cm in thickness. Both the visceral and parietal pericardium exhibited extensive scattered delayed hyperenhancement. Subsequent pericardial biopsy showed markedly fibrotic pericardium and pathology showed biphasic malignant pericardial mesothelioma. Immunosuppressive medications were stopped, and he underwent thoracentesis. After multidisciplinary discussions, he was started on nivolumab every two weeks and ipilimumab with a plan for surgery based on response to therapy. However, progressive symptoms and worsening constriction physiology led to palliative consultation and comfort care transition, with him dying shortly after. Discussion: Recurrent pericarditis and pericardial effusion, along with negative typical pericardial fluid studies, raised suspicion for a non-benign etiology. Multimodality imaging was employed and led to a pericardial biopsy. Constrictive pericarditis is an uncommon presentation of primary pericardial mesothelioma. Biphasic mesotheliomas from pleural or peritoneal origins are normally treated with systemic therapy with preference for combined immunotherapy. Primary pericardial mesothelioma is associated with a late presentation and high mortality rate, with surgery, if able to be done early appearing to be the recommended approach.

Abstract 4136539: Management of Malignant SVC Syndrome and Acute SVC Thrombosis with Complex Endovascular Intervention

Superior vena cava (SVC) syndrome occurs when there is SVC occlusion or obstruction. SVC obstruction can cause an increase in venous return pressure up to 40 mm Hg, producing edema of the face, neck and chest wall. Blood flow can be diverted to the right atrium through collateral venous networks in cases of gradual SVC compression. The most common cause of SVC syndrome is malignancy, as seen in 70% of cases. Traditionally, treatment is with radiation therapy but advances have now allowed for an endovascular approach. We present a case of malignant SVC syndrome with a complex percutaneous treatment approach that provided palliation with near immediate symptom improvement. A 64 year-old-female with history of cerebrovascular accident on Eliquis, right upper lobe squamous cell carcinoma of the lung in remission, and a mediastinal nodule under surveillance presented with facial and bilateral upper extremity edema. CT revealed bilateral pulmonary embolism and a large SVC thrombus causing impaired venous return. Invasive angiogram confirmed a 95% thrombotic tubular stenosis for which she underwent aspiration thrombectomy with alpha VAC F-18, then angioplasty with an Armada (Abbott) 10 x 40 mm compliant balloon and stenting with the Express (Boston Scientific) 10 x 37 mm stent. There was 0% residual stenosis and immediate clinical improvement. Oncological workup confirmed the right mediastinal mass to be a recurrence of squamous cell carcinoma. SVC syndrome occurred due to mediastinal mass compression and a near occlusive SVC thrombus. Aspiration thrombectomy was effective in treating the SVC thrombosis and was performed alongside pulmonary embolism thrombectomy. The Armada balloon is intended for lesion dilation in the peripheral arteries, but was safely used here for venous dilation. The Express stent is intended for palliation of malignant biliary neoplasms but has versatility and was utilized here for malignant neoplasm surrounding the SVC. Peripheral endovascular stenting is an advantageous treatment option for malignant SVC syndrome given the challenges due to recurrence from mass effect. This provides additional support to maintain vessel patency and is a safe palliation option for improvement in quality of life.

Abstract 4134298: Dipeptidyl Peptidase 4 Promotes Pressure Overload-Induced Heart Failure through enhancing Antigen Presentation

Background: Antigen presentation to CD4+ T cells plays a critical role in heart failure (HF). Dipeptidyl peptidase 4 (DPP4) has been shown to promote the activation of T lymphocytes. This study aims to investigate the role of DPP4 in antigen presentation in pressure overload-induced HF. Methods: To examine the role of DPP4 in antigen presentation during HF, we tested the recruitment and function of dendritic cells (DCs) in transverse aortic constriction (TAC)-induced HF mice. To further investigate, we generated DPP4 knockout mice and induced bone marrow-derived dendritic cells (BMDCs) in vitro. BMDCs were then adoptively transferred into OT-II mice, whose DCs require specific exogenous ovalbumin loading to activate CD4+ T cells. RNA-Seq analysis was performed to elucidate the mechanisms by which DPP4 affects the function of DCs. Results: We observed an increased quantity of DCs in the hearts and mediastinal lymph nodes of TAC mice, accompanied by elevated expression of DPP4. These DCs exhibited enhanced antigen-presenting abilities, resulting in increased activation of CD4+ T cells. DPP4 knockout suppressed DC maturation and attenuated their antigen-presenting capabilities. We found that OT-II mice subjected to TAC showed preserved cardiac function compared to wild-type (WT) mice. However, OT-II mice that received adoptive transfer of DPP4+/+ BMDCs exhibited worse cardiac function compared to those receiving DPP4-/- BMDCs, indicating that DPP4 in DCs contributes to HF progression. RNA-Seq analysis indicated that DPP4 in DCs influenced the T cell receptor signaling pathway and T cell differentiation. Mechanistically, DPP4 was found to inhibit the E3 ubiquitin ligase MARCH1 from binding to MHCII, thereby stabilizing MHCII through preventing its ubiquitin-dependent degradation in DCs. Conclusion: This study elucidates the significance of DPP4 in enhancing antigen presentation during heart failure. We propose that DPP4 represents a potential therapeutic target for heart failure.

NIMG-86. DISSEMINATEDCRYPTOCOCCUS NEOFORMANS MIMICKING CENTRAL NERVOUS SYSTEM PROGRESSION OF DIFFUSE LARGE B-CELL LYMPHOMA

Abstract A 57-year-old male with stage IV diffuse large B-cell lymphoma (DLBCL), non-germinal center subtype, underwent 6 cycles of polatuzumab, rituximab, cyclophosphamide, doxorubicin, prednisone, and pegfilgrastim (Pola-R-CHP) then presented to the hospital with progressive confusion, double vision, hearing loss, and lower extremity weakness. MRI of the brain and spinal cord with and without IV contrast revealed extensive leptomeningeal enhancement along the brain, several cranial nerves, cervical and thoracic spinal cord with enhancement of the cauda equina. Cerebrospinal fluid (CSF) analysis studies revealed 41 nucleated cells/mm3, protein to 264 mg/dL, and an initial cryptococcal antigen titer of 1:1280; serial lumbar punctures peaked at an opening pressure of 39.5 cm H2O before improvement. Flow cytometry was negative on two CSF studies. Multiple cultures grew Cryptococcus neoformans before sterilization of CSF culture on day 13. He received induction therapy for 4 weeks with amphotericin B and flucytosine. Flucytosine treatment was limited due to cytopenias on day 9 and continued induction with amphotericin B and fluconazole. Fluconazole was switched for voriconazole based on minimal inhibitory concentrations by broth dilution, however, the drug was undetectable on therapeutic drug monitoring 2 weeks later and switched back to fluconazole. Subsequent positron emission tomography revealed ongoing hypermetabolic thoracic, mediastinal, and hilar lymph nodes compared to PET scans prior to chemotherapy for which he underwent transbronchial fine needle aspiration concerning for Cryptococcus involvement. He remained on fluconazole 800mg/day and MRI 11 months after the initial presentation demonstrated ongoing but slightly improved leptomeningeal enhancement. Due to persistent symptoms despite sterile CSF cultures, he underwent a three-day course of IV methylprednisolone 1000mg with some incomplete improvement in symptoms. The opening pressure normalized and the cryptococcal antigen titer decreased to 1:20 about 11 months after initial treatment. This case highlights the risk of opportunistic infections like cryptococcal meningitis in patients undergoing chemotherapy.

Resection of Mediastinal Lymph Node Metastasis From HCC Using ICG Fluorescence Imaging and Repeat Resection of Its Solitary Recurrence

Resection of Mediastinal Lymph Node Metastasis From HCC Using ICG Fluorescence Imaging and Repeat Resection of Its Solitary Recurrence

Mycophenolate Mofetil, an Inhibitor of Inosine Monophosphate Dehydrogenase, and Tofacitinib, a Janus Kinase Inhibitor, Attenuate Airway Inflammation and Hyperresponsiveness in a Mouse Model of Allergic Asthma

Treatment-resistant asthma remains an unresolved clinical problem and a challenge for current medical science. Consequently, there is a growing and urgent need to develop novel or alternative therapeutic options for the treatment of asthma. The research problem raised in this study was to assess and compare mycophenolate mofetil (MMF), an inhibitor of inosine monophosphate dehydrogenase, and tofacitinib (TFB), a Janus kinase inhibitor, for anti-asthmatic properties, and consequently to determine whether these agents may have potential as alternative options for treatment of allergic asthma. For this purpose, we assessed the effect of administration of MMF and TFB on the development of a mouse model of allergic airway inflammation (AAI) and accompanying CD4+ (cluster of differentiation 4) T-cell immune response in the lung-draining mediastinal lymph nodes (MLNs) and lungs, i.e., in the inductive and effector sites, respectively, of the immune response underlying the development of allergic asthma. The results from a histopathological scoring system demonstrated that the administration of MMF and TFB did not prevent or abolish ovalbumin-induced AAI, but strongly attenuated its severity. The pulmonary function tests revealed that the treatment with MMF and TFB significantly reduced methacholine-induced bronchoconstriction. These results indicate that the treatment with TFB and MMF attenuated the development of ovalbumin-induced AAI. The magnitude of the anti-asthmatic effect was comparable between both agents. The study revealed that the impairment of the clonal expansion of effector CD4+ T cells in the MLNs is a critical event in the mechanism underlying the anti-asthmatic effect of MMF and TFB. Apart from this, the findings of the study strongly suggest that the suppression of the interleukin-33/suppression of tumorigenicity-2 signaling pathway may constitute an additional mechanism responsible for producing this effect. In turn, the results indicate that the anti-asthmatic action induced by the studied agents is not mediated by the generation of forkhead box protein 3-expressing CD4+ regulatory T cells. Clinical implication of the results: the results suggest that MMF and TFB may exert anti-asthmatic action, and thus they may be considered therapeutic options for the treatment of allergic asthma cases resistant to conventional/existing treatment.

A descriptive analysis of 21 patients with pulmonary amyloidosis: An observational study

Pulmonary amyloidosis is an extremely rare disease, often detected incidentally because of its asymptomatic nature and potential to result in fatal outcomes. In this study, we aimed to present the clinical and radiological features of patients diagnosed with pulmonary amyloidosis by biopsy. This descriptive study included 21 patients with pathologically diagnosed pulmonary amyloidosis. Pulmonary amyloidosis was classified as diffuse alveolar-septal amyloidosis (DASA), cystic amyloidosis (CPA), tracheobronchial amyloidosis (TBA), nodular amyloidosis (NPA), and extraparenchymal pulmonary amyloidosis (pleural and mediastinal lymph node). Clinical, bronchoscopic, and radiological specific characteristics were presented in detail to be used for differential diagnosis. The median age of the patients was 63 (40–83) years, and 14 (66.7%) were male. Twenty patients (95.2%) presented with at least 1 comorbidity. All patients diagnosed with tracheobronchial amyloidosis were symptomatic at presentation, whereas those diagnosed with NPA/extraparenchymal amyloidosis were often asymptomatic. The patients included 1 case of DASA, 1 case of CPA, 10 cases of NPA, 6 cases of TBA, and 3 cases of extraparenchymal amyloidosis involving the mediastinal lymph node and pleura. Sixteen patients (76.2%) were classified as localized amyloidosis, while 5 patients (23.8%) were classified as systemic amyloidosis following the diagnosis of multiple myeloma, monoclonal gammopathy of undetermined significance, systemic lupus erythematosus, Sjogren’s syndrome, and B-cell lymphoma. Bronchoscopic biopsies were sufficient for diagnosis, and notably, even transbronchial needle aspiration could be a useful diagnostic method. During the follow-up, we observed that the disease remained stable without progression. However, it is important to note that patients with concurrent malignancies experience fatal outcomes. In conclusion, it is crucial to distinguish pulmonary amyloidosis from other pulmonary diseases such as malignancies, infectious diseases, and interstitial lung diseases, which may have similar clinical and radiological findings. Bronchoscopic diagnostic methods are usually sufficient for the diagnosis. Although patients with pulmonary involvement mostly remain stable during long-term follow-up without progression, it is important to consider the risk of malignancy.

The value of a PET scan in selecting the best lymph node to biopsy, and confirming the diagnosis of idiopathic multicentric Castleman disease with HLH and EBV viremia in a previously healthy adult

Introduction: Castleman disease (CD) is a rare lymphoproliferative disorder having a variegated clinical presentation. Diagnosis of the idiopathic HIV- and HHV8-negative multicentric CD (iMCD) subtype poses a challenge given its non-specific clinical manifestations. iMCD presents as diffuse lymphadenopathy with inflammatory manifestations, primarily driven by interleukin-6 (IL-6). Treatment includes suppressing the inflammation by targeting IL-6 with monoclonal antibodies such as siltuximab and, in severe cases, immuno-chemotherapy to control B- and plasma-cell activation. Case description: A previously healthy 43-year-old male presented to the emergency department with fever, night sweats, anasarca, anaemia, thrombocytopenia and acute renal insufficiency. Extensive blood and imaging workup was initiated. Several diagnoses were entertained including viral infections (comprising COVID-19), haemophagocytic lymphohistiocytosis, lymphoma and autoimmune conditions. Initial axillary lymph node biopsy was not diagnostics. A positron emission tomography (PET) scan showed diffuse and symmetrical cervical and hilar/mediastinal lymphadenopathies. A mediastinal lymph node biopsy was then performed and indicated iMCD. The patient was treated with high-dose steroids and siltuximab. An Epstein-Barr virus (EBV) PCR was positive, and rituximab was added to the treatment. The patient recovered and felt well after two months. Conclusions: Non-specific symptoms, non-diagnostic first biopsy and iMCD resemblance to haemophagocytic lymphohistiocytosis further complicated the diagnosis. A PET scan allowed the best selection of a lymph node to be biopsied. Anti-IL6 is the recommended treatment; however, we are lacking information on the duration of siltuximab, and the long-term toxicity and immunosuppressive effect of this treatment. The contribution of EBV reactivation in the development and treatment of iMCD needs further investigation.

Exploring the left behind: unheard complication of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA)

Endobronchial ultrasound (EBUS) guided transbronchial needle aspiration (TBNA) is a widely used procedure in interventional pulmonology, known for its diagnostic accuracy and low complication rates. We report a rare complication of EBUS-TBNA involving the damage of the TBNA needle during sampling of a mediastinal lymph node, resulting in an impacted needle spring in the airway. Despite its rarity, awareness of such potential issues is crucial for all practitioners performing EBUS-TBNA to ensure patient safety and optimal outcomes.

Diagnosis of Respiratory Sarcopenia for Stratifying Postoperative Risk in Non–Small Cell Lung Cancer

Physical biomarkers for stratifying patients with lung cancer into subtypes suggestive of outcomes are underexplored. To investigate the clinical utility of respiratory sarcopenia for optimizing postoperative risk stratification in patients with non-small cell lung cancer (NSCLC). This retrospective cohort study reviewed consecutive patients undergoing lobectomy and mediastinal lymph node dissection for NSCLC at 2 institutions in Tokyo, Japan, between 2009 and 2018. Eligible patients underwent electronic computed tomography image analysis. Follow-up began at the date of surgery and continued until death, the last contact, or March 2022. Data analysis was performed from April 2022 to March 2023. Respiratory sarcopenia was identified by poor respiratory strength (peak expiratory flow rate) and was confirmed by a low pectoralis muscle index (PMI; pectoralis muscle area/body mass index). Patients with poor peak expiratory flow rate but normal PMI received a diagnosis of pre-respiratory sarcopenia. Short-term and long-term postoperative outcomes were compared among patients with a normal status, pre-respiratory sarcopenia, and respiratory sarcopenia. Group differences were analyzed using the Kruskal-Wallis test and Pearson χ2 test for continuous and categorical data, respectively. Survival differences were compared using the log-rank test. Univariable and multivariable analyses were conducted using the Cox proportional hazards model. Of a total of 1016 patients, 806 (497 men [61.7%]; median [IQR] age, 69 [64-76] years) were eligible for electronic computed tomography image analysis. The median (IQR) duration of follow-up for survival was 5.2 (3.6-6.4) years. Respiratory strength was more closely correlated with PMI than pectoralis muscle radiodensity (Pearson r2, 0.58 vs 0.29). Respiratory strength and PMI declined with aging simultaneously (both P for trend < .001). Pre-respiratory sarcopenia was present in 177 patients (22.0%), and respiratory sarcopenia was present in 130 patients (16.1%). The risk of postoperative complications escalated from 82 patients (16.4%) with normal status to 39 patients (22.0%) with pre-respiratory sarcopenia to 39 patients (30.0%) with respiratory sarcopenia (P for trend < .001), as did the risk of delayed recovery after surgery (P for trend < .001). Compared with patients with normal status or pre-respiratory sarcopenia, patients with respiratory sarcopenia exhibited worse 5-year overall survival (438 patients [87.2%] vs 133 patients [72.9%] vs 85 patients [62.5%]; P for trend < .001). Multivariable analysis identified respiratory sarcopenia as a factor independently associated with increased risk of mortality (hazard ratio, 1.83; 95% CI, 1.15-2.89; P = .01) after adjustment for sex, age, smoking status, performance status, chronic heart disease, forced expiratory volume in 1 second, diffusing capacity for carbon monoxide, C-reactive protein, albumin, carcinoembryonic antigen, histology, and pathologic stage. This study identified individuals at higher risk of poor outcomes by screening and staging respiratory sarcopenia. The early diagnosis of respiratory sarcopenia could optimize management strategies and facilitate longitudinal care in patients with NSCLC.

Inhibition of B cell activation by Ibrutinib improves cardiac function in experimental myocardial infarction in mice

Abstract Background Bruton's tyrosine kinase (BTK) is a key downstream mediator of B cell receptor (BCR) signaling. Upon BCR cross-linking, phosphorylated BTK modulates B cell activation, proliferation, and differentiation. Ibrutinib, which is clinically used in B-cell malignancies, irreversibly binds to the BTK kinase domain and blunts downstream BTK signaling. Purpose Here, we aimed to monitor B cell dynamics and activation in experimental myocardial infarction (MI) in mice, and evaluate the effect of B cell inhibition by Ibrutinib in cardiac function. Methods MI was induced in male 10-week-old C57BL/6 mice by permanent LAD ligation and Ibrutinib (25 mg/kg/day) was given in the drinking water. After 3, 7, 14, and 28 days, single cell suspensions were prepared for flow cytometry from peripheral blood, spleen, mediastinal lymph nodes (MLNs), and the bone marrow, as well as from the remote and infarcted myocardium. Total B cells and B cell subsets were quantified in the different locations by flow cytometry and B cell activation was monitored by BTK551 phosphorylation. After 28 days, cardiac function was evaluated by echocardiography. Results We found that total B cell numbers decrease in blood and spleen, and increase in MLNs, while plasma cells and plasmablasts increased in the infarcted heart on day 7 and 14 after MI. In the bone marrow, hematopoietic stem cells (HSC) increase after MI, while common lymphoid progenitors (CLP) and early-stage B cell progenitors (pre-pro and pro B cells) peak at day 7 after MI. The later-stage B cell progenitors (pre and immature B cells) showed a biphasic response, with an early decrease after 7 days and a later increase on day 14. Compared to the control group (vehicle), Ibrutinib treatment decreased B cell numbers in MLN and spleen by 27% and 14%, respectively, as well as decreased mature B cells by 28% in the bone marrow on day 28 after MI. Both BTK expression and phosphorylation in pro-B cells were inhibited by Ibrutinib by 8% and 15%, respectively. The inhibition of BTK phosphorylation was also evident in MLNs and spleen. Notably, Ibrutinib-treated mice showed an improved cardiac function on day 28 after MI, with stroke volume (SV) elevated by 41%, left ventricular ejection fraction (LVEF) elevated from 20% to 36% (p &amp;lt; 0.05), and fractional shortening (FS) elevated from 8.8% to 17.59% (p &amp;lt; 0.05). Conclusion Experimental MI leads to B cell lymphopoiesis in the bone marrow, mobilization into the infarcted myocardium, and activation in peripheral lymphoid organs. Ibrutinib treatment inhibits B cell development in the bone marrow, as well as B cell activation in peripheral lymphoid organs, and improves cardiac function post MI. Our data provides a meaningful insight for targeting B cells for the clinical treatment of patients with MI.Figure

Lymphatic-macrophage crosstalk during neonatal mouse heart regeneration and transition to fibrotic repair

Abstract Background In adult mice, myocardial infarction (MI) activates the cardiac lymphatics, which undergo sprouting angiogenesis (lymphangiogenesis) and function to drain interstitial fluid and traffic macrophages to mediastinal lymph nodes (MLNs). This prevents oedema and reduces inflammatory immune cell content to improve cardiac function. Purpose Given the importance of the adult cardiac lymphatics in macrophage clearance after injury, we investigated their role across the neonatal "regenerative window". At post-natal day 1 (P1) neonatal mice fully regenerate their heart following MI, in a macrophage-dependent manner, whereas equivalent injury at day 7 (P7) leads to scarring driven by pro-fibrotic macrophages. We hypothesised that lymphatics respond and function differently during this "window," to clear macrophage-specific subtypes depending upon their requirement for regeneration versus fibrotic repair. Methods &amp; Results Extensive lymphatic growth and sprouting was evident in intact neonatal hearts until P16, with strain-dependent developmental differences. The response to injury revealed limited lymphangiogenesis and minimal clearance of macrophages from P1 compared to P7 infarcted hearts, as determined by adoptive transfer experiments and monitoring of cleared macrophages to MLNs. This is coincident with maturation of lymphatic endothelial cell junctions across the neonatal period via transition from "zipper" (impermeable) to "button" (permeable) -type junctions. To gain molecular insight into the mechanisms underpinning lymphatic endothelium macrophage interactions at P1 versus P7, we generated unbiased single cell RNA sequencing datasets from neonatal heart samples after MI and observed altered signalling between lymphatic endothelial cells and macrophages across the neonatal period, including altered expression of the lymphangiocrine factor Reelin (RELN). Finally, in mice lacking the lymphatic endothelial receptor-1 (LYVE1), that exhibit impaired transmigration of interstitial macrophages to lymphatic vessels, magnetic resonance imaging (MRI) revealed a surprising impaired functional outcome in P1 mice 28 days post-MI. Given our observations that pro-regenerative macrophages at P1 are not trafficked, this suggested a distinct role for LYVE1 in tissue-resident (TR) macrophages, consistent with its expression in developing and post-natal hearts. Macrophage-specific deletion of Lyve1 during neonatal heart injury revealed impaired heart regeneration, characterised by reduced neovascular response and function, suggesting a hitherto unappreciated role for LYVE1 in regulating the pro-regenerative function of TR macrophages. Conclusions Collectively, we reveal that cardiac lymphatics are developmentally compromised for immune cell clearance in early neonates, which enables retention of pro-regenerative TR macrophages, and that LYVE1 plays an essential role in TR macrophages enabling heart regeneration via the induction of coronary angiogenesis.

Sarcoidosis of mediastinal and abdominal (visceral) lymph nodes, lungs, liver, goldbladder, spleen, complicated by phlegmonous cholecystitis

The article contains a description of generalized sarcoidosis diagnosed morphologically after cholecystectomy for phlegmonous cholecystitis.

Differences of in vitro immune responses between patent and pre-patent Litomosoides sigmodontis-infected mice are independent of the filarial antigenic stimulus used.

Lymphatic filariasis and onchocerciasis are neglected tropical diseases and cause significant public health problems in endemic countries, especially in sub-Saharan Africa. Since the human parasites are not viable in immune-competent mice, animal models have been developed, among them Litomosoides sigmodontis which permits a complete life cycle in BALB/c mice, including the development of patent infections with circulating microfilariae (Mf, the worm's offspring). To investigate the immunomodulatory properties of helminths in vitro, antigenic extracts can be prepared from different life cycle stages of the L. sigmodontis model, including adult worms, but the methods to prepare these antigens differ between research groups. This study analyzed whether different centrifugation methods during the preparation of an antigenic extract, the gender of used worms, or the different fractions (soluble or pellet) altered filarial-specific CD4+ Tcell responses. These cells were isolated from pre-patent or patent/chronic infected mice, hence those without and those with Mf, respectively. Ex vivo immune responses were compared at these two different time points of the infection as well as the parasitic parameters. Worm burden and cell infiltration were elevated in the thoracic cavity (TC) and draining mediastinal lymph nodes at the pre-patent stage. Within the TC, eosinophils were significantly up-regulated at the earlier time point of infection which was further reflected by the eosinophil-related eotaxin-1 levels. Regarding the production of cytokines by re-stimulated CD4+ T cells in the presence of different antigen preparations, cytokine levels were comparable for all used extracts. Our data show that immune responses differ between pre-patent and patent filarial infection, but not in response to the different antigenic extracts themselves.

Cryoprobe biopsy versus mechanical biopsies in pulmonary diagnostics.

Biopsy tools have been essential in improving the diagnostic accuracy of bronchoscopic procedures. Of these tools, cryobiopsy has emerged as a promising technique for diagnosing thoracic diseases. This review summarizes the existing data comparing cryobiopsies to other mechanical biopsy methods for sampling endobronchial, parenchymal, and mediastinal targets. Initially adopted for managing airway stenoses, the use of cryoprobes has expanded to diagnosing endobronchial lesions, parenchymal opacities, and mediastinal lymph node pathologies. Studies have demonstrated that cryobiopsy offers a higher diagnostic yield than forceps biopsy alone. By leveraging the Joule-Thomson effect to freeze and collect larger tissue samples compared to traditional methods, cryobiopsy improves diagnostic accuracy and helps in better characterizing the nature of the lesions. While the risk of complications, such as pneumothorax and hemorrhage are comparable to, or higher than traditional biopsy methods, cryobiopsy's enhanced diagnostic capabilities make it a valuable tool in the assessment of pulmonary disease. Compared with other mechanical biopsy techniques, cryoprobe biopsies significantly enhance the diagnostic yield for endobronchial lesions, interstitial lung disease, pulmonary nodules, and mediastinal lymph nodes.

Neurosarcoidosis Masquerading as Spinal Stenosis.

A 65-year-old woman was admitted to the neurology department with a suspected demyelinating disease due to complaints of progressive pain and weakness in both upper and lower limbs, as well as urinary incontinence. MRI of the spine revealed complex disc osteophyte with compression of the spinal cord in the cervical and lumbar spine at several vertebral levels, and localized enhancement in the cervical spine at the site of maximal spinal canal stenosis. During her hospitalization, the patient underwent extensive evaluation to rule out any systematic inflammatory diseases, infections, and malignancy. Chest CT revealed bilateral mediastinal lymphadenopathy. Transbronchial mediastinal lymph node biopsy showed numerous non-necrotizing granulomas without evidence of malignancy. After a thorough and careful exclusion of a demyelinating, infectious, and paraneoplastic myelopathies, and based on clinical, radiographic, and pathological findings, the patient was diagnosed with both neurosarcoidosis and spondylotic myelopathy. She was then treated for neurosarcoidosis, including glucocorticosteroids, azathioprine, and a biosimilar of the anti-TNF alpha agent infliximab, resulting in both clinical and radiographic improvement. Intramedullary spinal neurosarcoidosis is very rare and may present with clinical features of spondylotic myelopathy, with typical imaging findings occurring only in areas of spinal canal stenosis.

ALK-positive Anaplastic Large Cell Lymphoma Involving the Spinal Cord

Abstract Introduction/Objective ALK-positive anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that accounts for approximately 3% of non-Hodgkin lymphoma cases in the adult population. Lymph node involvement is most commonly seen, followed by extra-nodal involvement of the skin, soft tissue, and bone. Central nervous system involvement is rare at the time of diagnosis. This case study features a patient with systemic ALK-positive ALCL involving multiple nodal and extra-nodal sites, most notably the spinal cord. Methods/Case Report A 22-year-old female presented to the hospital with worsening back pain accompanied by neurological symptoms. MRI scans of her spine revealed extensive patchy abnormal marrow signal with enhancement of the thoracolumbar vertebrae (T1-L2) and adjacent extension into the spinal canal (T3-T7, T10-L1, L3-S1) and paraspinal soft tissues. A laminectomy of the T5-T7 and T11-T12 levels was performed for surgical decompression, and epidural and paraspinal resection specimens were submitted. These specimens, along with an excisional axillary lymph node biopsy, demonstrated ALK-positive ALCL after comprehensive immunohistochemical studies. In-situ hybridization for EBV was negative. CHOP therapy was initiated, but treatment was complicated by Candidemia and disseminated intravascular coagulation. The patient rapidly declined and passed away less than a month after hospital admission. At autopsy, enlargement of lymph nodes, the left ovary (17.8 g), and spleen (383.6 g) were noted on gross examination. A solid, white-tan lesion (2.1 x 0.9 x 0.8 cm) was found in the left ovary. Necrosis and infiltrates of large, pleomorphic lymphoid cells with irregular nuclear contours and prominent nucleoli were seen on microscopic examination of the spinal cord and leptomeninges, vertebral bone marrow, mediastinal lymph nodes, spleen, and left ovary. Consistent with previously submitted surgical specimens, the viable neoplastic cells stained strongly positive for ALK-1, CD4, and CD30. Results (if a Case Study enter NA) NA Conclusion This case study highlights an atypical presentation of ALCL with a fatal outcome. Given the availability of effective treatment options, prompt diagnosis is crucial to improving survival outcomes. Additional research is necessary to elucidate the clinical and pathological features of ALCL. The differential for back pain is broad, but including this entity for patients with similarly insidious clinical presentations can prevent a delay in diagnosis that allows for rapid progression of disease.

Synchronous endometrial and minor salivary gland carcinomas – role of molecular diagnostics amid lack of clinical suspicion

Abstract Introduction/Objective Synchronous malignancies account for 3-5% of all tumor diagnoses but can be challenging to detect if one or both tumors are rare histologic subtypes and clinical suspicion is lacking. Molecular diagnostics are critical for accurate diagnosis in these difficult cases to guide appropriate patient care. Methods/Case Report We report the case of a 49-year-old female who was diagnosed with a high-grade, mixed- histology endometrial adenocarcinoma a few years back. She was found to have hilar and mediastinal nodal carcinoma of uncertain differentiation a couple of months after her initial diagnosis, clinically labelled as metastatic endometrial carcinoma. Following neoadjuvant chemotherapy, her hysterectomy showed complete pathologic response, and was found to be POLE ultramutated on NGS. Follow-up PET scan in 2023 showed progression of hilar/endobronchial thickening, as well as interval increase in size of mediastinal nodes, again presumed to be endometrial metastases, despite the POLE mutant status. Repeat sampling was performed from both the sites, along with comprehensive molecular profiling. Cytology from the nodes and surgical pathology from the endobronchial lesion showed similar morphology consisting of hyperchromatic basaloid cells in cribriform arrangement with tubular structures containing myxoid stromal material, negative for PAX-8, ER, p40, and TTF1 immunostains, inconsistent with endometrial metastasis. Molecular studies including FISH and NGS showed MYB1::NFIB fusion characteristic of adenoid cystic carcinoma and absence of POLE mutation, definitively refuting the clinically suspected progression of endometrial metastasis. Molecular testing confirmed that the endobronchial tumor and mediastinal nodal involvement were caused by a second primary, distinct from her POLE-ultramutated endometrial carcinoma which disappeared with chemotherapy. Her extended molecular workup also revealed a pathogenic mutation in BRIP1, suggesting a genetic cancer predisposition syndrome requiring referral for genetic counseling. Results (if a Case Study enter NA) NA Conclusion Molecular pathology is an invaluable tool for unravelling diagnostic complexity. Pathologists must integrate cytomorphology, molecular genetics and knowledge of cancer biology to steer the clinical teams towards the best patient care.