LANGERHANS CELL HISTIOCYTOSIS IN A CHILD WITH MULTISYSTEMIC LESIONS ASSOCIATED WITH INFECTED POLIOMYELITIS AND SARS-COV-2, FEATURES OF DIAGNOSTICS. CLINICAL CASE.

Langerhans cell histiocytosis (LCH) is an abnormal clonal proliferation of Langerhans cells. The prognosis varies depending on the form of the disease and organ damage. Any organs and systems can be involved in the pathological process in various combinations. A poor response to standard therapy and an unfavorable prognosis are characteristic of patients with a multisystem form of LCH and involvement of organs at risk. Skin lesions are a classic sign of LCH. Purpose - to describe the complexity and duration of diagnosis of LCH with multisystem damage in a boy aged 2 years and 2 months, infected with poliomyelitis and coronavirus. Clinical case. The first clinical manifestations of LCH in the child debuted with an eczematous-seborrheic rash on the scalp with spread to the limbs and trunk. The child was treated for toxicoderma, hemorrhagic vasculitis at the place of residence for 6 months. The boy lost 1.5 kg of body weight in 1 month. At the time of hospitalization, seborrheic-eczematous rashes on the skin with a hemorrhagic component, trophic-inflammatory changes in the nails of the hands, signs of protein-energy deficiency, stomatitis, gingivitis, hepatosplenomegaly, polyserositis, diabetes insipidus, osteolytic foci of the frontal bones were found. Results of the tests: anemia, thrombocytopenia, hypoproteinemia and hypoalbuminemia, coagulation disorders. The patient had the onset of lower flaccid paraparesis, muscle hypotonia. The boy was diagnosed with a number of infectious complications, including poliomyelitis (a derivative of vaccine poliovirus type 2), COVID-19. The child received LCH-III cytostatic therapy with a positive effect. The research was carried out in accordance with the principles of the Helsinki Declaration. The informed consent of the patient was obtained for conducting the studies.Copyright © 2023 Institute of Physics of the Russian Academy of Sciences. All rights reserved.

Reactivation of Parvovirus B19 Infection: An Uncommon Trigger of Macrophage Activation Syndrome in Adult-Onset Still's Disease.

A 40-year-old woman presented with four weeks of intermittent high-grade fever, cough, and joint pain, and two weeks of a generalized rash. She was found to have adult-onset Still's disease (AOSD) and rapidly developed macrophage activation syndrome (MAS) on the second day of admission. Among infectious etiologies, Epstein-Barr virus and members of the herpes virus family are common triggers of MAS. However, our patient was found to have reactivation/recurrence of parvovirus B19 infection as the cause; this is an uncommon trigger reported infrequently in the medical literature. Despite intensive treatment, the patient passed away.

A rare case of Rosai-Dorfman disease presenting as a pulmonary artery mass in a 33-year-old female with hypoxia.

Rosai-Dorfman disease (RDD) is a rare form of non-Langerhans histiocytosis. It is often idiopathic in etiology, but has been associated with viral, autoimmune, and malignant disease. Adequate diagnosis of RDD requires a combination of clinical symptoms, radiography, and histology. Most commonly, patients with RDD present with cervical lymphadenopathy. We describe a case of a young female who was initially thought to have a pulmonary embolism at the time of a COVID-19 infection but was noted to have a rare occurrence of RDD presenting as a pulmonary artery mass upon further evaluation of radiology and histology. Though RDD is frequently benign, extranodal involvement can progress to end organ damage and must be recognized appropriately.

Modified Treatment for Pediatric Multisystemic Histiocytosis during Sars-Cov2 Lockdown. Series of Cases

Purpose: Backbone treatment ofmultisystemic histiocytosis (MS-LCH) is steroids in combination with chemotherapy (vinblastine/vincristine and/or cytarabine). This approach requires a central venous access (CVA) placement because of the possibility of citostatic extravasation and length of treatment. SARS-CoV2 lockdown forced us to adapt standard treatment in order to skip CVA placement, use of available cytostatics, reduce toxicity and hospital visits. We report here our experience using a modified treatment (MT) Methods:Series of 4 pediatric patients (pt) of MS-LCH treated during 2020 with a MT. Induction: Oral Methylprednisone 40 mg/m2 daily for 4weeks, tapering for 2weeks, and subcutaneous/intravenous cytarabine 100 mg/m2/day for 4 days, day 1-14. Evaluation at 6th week. If NAD or ADB, continuation treatment: Methylprednisone 40 mg/m2/day for 5 days every 15 days and subcutaneous/intravenous cytarabine 100 mg/m2/day for 4 days every 3 weeks. Clinical and hematologic evaluation every 3 weeks. We studied the presence of circulating CD207+/CD1a+ cells (cc) by flow cytometry Results:Female 3pt. Identical twins (pt#1,2). Age at diagnosis: 7, 7, 11 and 29 months. Involvement: skin, lymph nodes and hematopoietic (pt#1,2,3,4), ear (pt#2,3,4), bone (pt#3), hepatosplenomegaly (pt#4) All pt achieved ADB after 6 weeks of treatment. Reactivation: 1pt because of non-adherence to treatment. No grade 3/4 toxicity. COVID infection with mild symptoms (pt#1,2). Status: all alive with NAD at 2 years (pt#1,2) and 1 year (pt#3,4) of treatment. All pt started with a low score for cc and increased them with the treatment in negative trend to their clinical status Conclusion(s): This MT was feasible to treat pt with MS-LCH during the SAR-Cov2 lockdown, even those with risk organ involvement.We were able to skip CVA and reduce toxicity. Treatment could be restraining cc migration to the lesions.

Clinical Profile, Treatment and Outcome of Pediatric ''Coffee Bean'' Histiocytosis: A Single Center Experience

Introduction: Langerhans Cell Histiocytosis is a group of diseases with a myriad of clinical manifestations and biological behavior, characterized by proliferation and accumulation of Langerhans cells in different organs. Aims & Objectives: This study is to demonstrate the varied clinical presentations and the treatment outcome of the children in one of the few pediatriccenters in North India that cater to various benign and malignant blood disorders of children. Material(s) and Method(s): The study describes the 4-year experience of our center in managing children with LCH. The clinical presentations, relevant laboratory, and radiological findings, treatment, and outcome of all the 14 children presenting between December 2018 and August 2022 were retrieved from our Hospital Information system. The LCH IV protocol was taken as the backbone for classification, risk organ involvement, stratum allocation, for deciding on treatment strategy, treatment response, and outcome. Result(s): A total of 14 children were diagnosed with LCH during the study period. The mean age at diagnosis was 36 months(range: 10-110 months, median: 34 months). The male: female ratio was 9:5. 12 children had multisystem LCH while 2 children had single system LCH. Lymphadenopathy was the most common clinical presentation while the skeletal system was the most common system involved, affecting 64% of the children. There were a total of 8(57%) children who were in complete remission, of which 1 child expired and one relapsed, though went into the second remission. One child had a progressive disease. Three(21%) children left against medical advice while 1 child abandoned treatment 2 weeks into therapy. One of the children became covid positive after diagnosis and expired before the treatment could be initiated. Conclusion(s): The wide array of clinical manifestations warrants the need for a high index of suspicion for an earlier diagnosis of LCH. The morphological identification of Langerhan's cells and positive IHC for CD1a, S100, and/or CD207 are necessary for definitive diagnosis. All patients with LCH should undergo BRAF-V600E mutational testing to aid in diagnosis and treatment.

Case report: A rare case of Rosai-Dorfman-Destombes disease after the COVID-19 infection.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to cause immune dysregulation and, therefore, has varied and often rare presentations. Rosai-Dorfman-Destombes disease (RDD) is an unusual non-Langerhans cell (non-LC) histiocytosis presenting with massive lymphadenopathy and various systemic symptoms. A 55-year-old Asian-American woman with no significant medical history or recent use of new drugs initially presented with cervical lymphadenopathy and urticarial rash 1 week after receiving the COVID-19 messenger RNA (mRNA) vaccine (Moderna, mRNA-1273) against SARS-CoV-2. The biopsy of the skin rash was consistent with a drug reaction. Approximately 2 months later, she developed mild flu-like symptoms and was diagnosed with a COVID-19 infection. Her symptoms were mild and self-resolving. Approximately 3 months later, she developed a generalized patchy erythematous rash on the face and the body that gradually worsened; diffuse lymphadenopathy involving the bilateral cervical, axillary, and inguinal areas; and constitutional symptoms. Laboratory results were consistent with lymphopenia, anemia, and an elevated sedimentation rate. Supraclavicular lymph node biopsy showed Rosai-Dorfman disease with a marked polyclonal plasmacytosis. She was started on a tapering dose of corticosteroids and showed clinical improvements over the next few weeks. Herein, we present a rare case of a histiocytic disorder that developed after contracting the SARS-COV2 infection in the event of receiving a recent mRNA COVID vaccination.

HYPERSENSITIVITY PNEUMONITIS PRESENTING AS SEVERE CYSTIC LUNG DISEASE FOLLOWING COVID-19 INFECTION

SESSION TITLE: Dirty Jobs: Occupational Lung Diseases SESSION TYPE: Case Reports PRESENTED ON: 10/18/2022 11:15 am - 12:15 pm INTRODUCTION: Hypersensitivity Pneumonitis (HP) is a group of immunologically mediated lung diseases. It develops in susceptible individuals with exposure to provoking antigens along with influence from genetic and environmental factors. There remains no standardized approach for assessing the various forms of HP and the diverse nature of the disease makes it difficult and often underdiagnosed. Cystic disease is not uncommon in HP, but the advanced cystic disease seen in our young patient was unique and likely compounded by her pregnancy as well as a previous illness with COVID-19. CASE PRESENTATION: A 26-year-old female construction worker at 12 weeks gestation, with a past medical history of polysubstance abuse and previous COVID-19 infection ten months prior, presented with progressively worsening dyspnea of 9 months. She was admitted with acute hypoxic respiratory failure due to recurrent right pneumothorax requiring multiple thoracenteses and eventually chest tube placement. CT Chest demonstrated severe cystic interstitial fibrosis with emphysematous changes. Initial lung biopsy showed interstitial fibrosis as a possible sequela of COVID-19. Due to her pregnancy and medical complications, she was transferred to a transplant center where she continued to have recurrent pneumothoraces requiring video-assisted thoracoscopic surgery. Autoimmune workup, HP panel, and extended myositis panel were negative. However, a repeat lung biopsy pointed to subacute HP. Despite steroid and immunosuppressant initiation, her hospital course was complicated by cardiac arrest and brain death. She went on to become an organ donor. DISCUSSION: Diffuse cystic lung diseases are characterized by parenchymal destruction of the airway walls leading to expansion of the distal airspaces forming multi-lobular cysts. A broad differential diagnosis for this exists including infection, Langerhans histiocytosis, lymphangioleiomyomatosis, interstitial pneumonia, and HP. The first step to evaluate HP is a detailed history of potential exposures. Our patient worked in construction and was exposed to commonly demonstrated antigens used in paint, plastic, and wood manufacture. Pregnancy appears to trigger symptoms in some patients, seen in prior case reports. Our patient's symptoms began after her COVID infection. Though not clearly studied, some studies have proposed that dysregulation of COVID - 19 immune response triggers interstitial fibrosis as a long-term sequela. Early diagnosis and treatment with steroids are vital to the treatment and prevention of complications such as recurrent pneumothorax. CONCLUSIONS: Covid-19 is an emerging risk factor for the propagation of various immune-mediated diseases. Progression of disease may occur even after the infection has been cured and limited data is available regarding its relation. Early recognition and treatment can be effective life-saving measures in these patients. Reference #1: Baldi BG, Carvalho CRR, Dias OM, Marchiori E, Hochhegger B. Diffuse cystic lung diseases: differential diagnosis. J Bras Pneumol. 2017;43(2):140-149. Reference #2: Densem C, Niven R, Barber P, Bishop P. Development of cryptogenic fibrosing alveolitis during pregnancy. J R Soc Med. 1998;91(11):591-593. Reference #3: Ambardar SR, Hightower SL, Huprikar NA, Chung KK, Singhal A, Collen JF. Post-COVID-19 Pulmonary Fibrosis: Novel Sequelae of the Current Pandemic. J Clin Med. 2021;10(11):2452. Published 2021 Jun 1 DISCLOSURES: No relevant relationships by Anastasia Brit No relevant relationships by Steven Colby No relevant relationships by Patrick Koo No relevant relationships by Vishruth Vyata No relevant relationships by Harika Yadav

A CASE OF ROSAI-DORFMAN DISEASE PRESENTING AS A PULMONARY ARTERY MASS

SESSION TITLE: Pathology Under the Microscope SESSION TYPE: Case Reports PRESENTED ON: 10/19/2022 11:15 am - 12:15 pm INTRODUCTION: Rosai-Dorfman disease (RDD) is a rare, idiopathic, nonmalignant lymphohistiocytic proliferative disorder that presents with lymphadenopathy and less commonly with extranodal involvement (1). This is a case of a patient found to have a pulmonary artery mass and bone lesions consistent with RDD. CASE PRESENTATION: A 33-year-old female with COVID pneumonia presented with one week of dyspnea, myalgias, and chills. She developed hypoxia requiring 2L of supplemental oxygen. Physical exam was benign and without lymphadenopathy. CT angiography demonstrated a well circumscribed 2.3cm x 2.1cm eccentric filling defect concerning for a pulmonary embolism versus vascular mass. She had a normal troponin and brain natriuretic peptide. Echocardiogram showed normal left ventricular ejection fraction and right ventricular size and function. Lower extremity dopplers were negative for acute deep venous thrombosis. Cardiac MRI demonstrated a mass in the posterior aspect of the proximal main pulmonary artery superior to the pulmonic valve measuring 1.9cm x 1.6cm that was consistent with a benign cardiac tumor. Patient was discharged and underwent sternotomy and excision of the mass one week later. Pathology showed histiocytosis consistent with RDD. Post-operatively she developed recurrent fevers and imaging showed bony lesions in her lumbar spine, maxilla, and skull base. Pathology from an IR guided biopsy of the lumbar lesion was suggestive of RDD. DISCUSSION: RDD is a rare, nonmalignant lymphohistiocytic proliferative disorder that usually involves lymph nodes. Concurrent nodal and extranodal involvement has been reported in 43% of cases while isolated extranodal involvement has been reported in 23% of cases. Common extranodal sites include cutaneous, soft tissue, upper respiratory tract, bone, and central nervous system (1). There are only a few cases reported of pulmonary artery involvement. These cases include a patient with RDD invading the pulmonary trunk and aorta who required surgical resection and reconstruction due to impending right ventricular failure (2) and a young woman with RDD causing nearly complete obstruction of the main pulmonary artery resulting in severe pulmonary hypertension and heart failure who required debulking (3). This case demonstrates RDD involving the main pulmonary artery and bones which was incidentally discovered when the patient was hospitalized for COVID pneumonia. RDD has a benign course but when the pulmonary artery is involved, patients often require surgical excision. CONCLUSIONS: RDD is a benign proliferation of histiocytes that most commonly presents with cervical lymphadenopathy. Extranodal involvement has been reported but pulmonary artery involvement is rare. RDD has a benign course, but pulmonary arterial involvement often requires surgical excision. Reference #1: Gaitonde, S. (2007). Multifocal, extranodal sinus histiocytosis with massive lymphadenopathy: an overview. Archives of pathology & laboratory medicine, 131(7), 1117-1121. Reference #2: Prendes, B. L., Brinkman, W. T., Sengupta, A. L., & Bavaria, J. E. (2009). Atypical presentation of extranodal Rosai-Dorfman disease. The Annals of thoracic surgery, 87(2), 616-618. Reference #3: Walters, D. M., Dunnington, G. H., Dustin, S. M., Frierson, H. F., Peeler, B. B., Kozower, B. D., … & Lau, C. L. (2010). Rosai-Dorfman disease presenting as a pulmonary artery mass. The Annals of thoracic surgery, 89(1), 300-302. DISCLOSURES: No relevant relationships by Veena Dronamraju Advisory Committee Member relationship with Nabriva Please note: 1 day Added 03/14/2022 by Rohit Gupta, value=Consulting fee No relevant relationships by MARUTI KUMARAN no disclosure on file for Bilal Lashari;No relevant relationships by Parth Rali No relevant relationships by Stephanie Tittaferrante No relevant relationships by Yoshiya Toyoda

COVID-19 AS A CONFOUNDER IN A CASE OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS

SESSION TITLE: Pulmonary Involvement in Critical Care Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: Hemophagocytic Lymphohistiocytosis (HLH) is a condition in which the body's natural ability to end an immune or inflammatory response is defective1. COVID-19 also presents with severe inflammation, and like HLH, leads to significantly elevated ferritin2. We present a case that was initially thought to be COVID-19, but the patient was diagnosed with HLH in the setting of S. aureus endocarditis. CASE PRESENTATION: A 62-year-old male with a history of atrial fibrillation, mechanical mitral valve on warfarin, type II diabetes, chronic obstructive pulmonary disease, and recently diagnosed COVID-19 presented to the hospital with progressive dyspnea. In the emergency department, he was found to be hypoxemic and in atrial fibrillation with rapid ventricular response. He had a fever of 39.3°C and his initial laboratory workup revealed hemoglobin of 11.9 g/dL, leukocytes of 5,700, platelets of 83,000, AST 35 U/L, ALT 34 U/L, CRP of 31.89 mg/dL, and ferritin of 1994 ug/L. The patient was admitted and started on dexamethasone 6 mg daily. The following day, the patient's blood work revealed a significant worsening of AST and ALT to 7280 U/L and 3319 U/L, respectively. D-dimer increased to 11861 ng/mL (DDU) and ferritin to 36,470 ug/L. On the third day of admission, his clinical status declined acutely as he became significantly bradycardic, progressing to a cardiac arrest after which he required cardiopulmonary resuscitation, intubation, and was transferred to the intensive care unit. A CT scan obtained revealed hepatomegaly of 22 cm and blood cultures were positive for S. aureus requiring vancomycin treatment. The patient was kept on dexamethasone due to concerns for HLH. Ferritin continued to worsen, reaching 50,749 ug/L. His sCD25 came back positive. Unfortunately, the patient expired on his fifth day of hospitalization after discussing with his family their goals for his care and switching his care to comfort only. DISCUSSION: HLH is a challenging condition since diagnosis is difficult and mortality is high. There are a few methods used to diagnose HLH. Usually, 5 of 8 criteria must be met, which was achieved with this patient. However, often the patient only fulfills 4 of 8 since many criteria are difficult to obtain such as bone marrow biopsy, sCD25, and CXCL9. A useful tool is the H-calculator3. Our patient scored a 180 indicating a 50-75% likelihood of HLH. Assessing the likelihood of disease is important since sCD25 and CXCL9 take time and if the patient is clinically deteriorating treatment should not be delayed. CONCLUSIONS: HLH is catastrophic and rare. Physicians should always have it as a differential diagnosis in patients with severe inflammatory states and elevated ferritins to avoid anchoring bias. If suspicion is high based on clinical evaluation and scores, treatment should not be delayed. Reference #1: Filipovich A, McClain K, Grom A. Histiocytic disorders: recent insights into pathophysiology and practical guidelines. Biol Blood Marrow Transplant. 2010;16(1 Suppl):S82-S89. doi:10.1016/j.bbmt.2009.11.014 Reference #2: Cheng L, Li H, Li L, et al. Ferritin in the coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis. J Clin Lab Anal. 2020;34(10):e23618. doi:10.1002/jcla.23618 Reference #3: Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014;66(9):2613-2620. doi:10.1002/art.38690 DISCLOSURES: No relevant relationships by Areeka Memon No relevant relationships by Carissa Monterroso No relevant relationships by Carson Oprysko No relevant relationships by Eduardo Padrao No relevant relationships by Mouna Penmetsa

*CHILDREN WITH ACUTE SEVERE HEPATITIS OF UNDETERMINED ETIOLOGY HAVE A SYSTEMIC T CELL ACTIVATION AND INTERFERON GAMMA (IFN-gamma) ACTIVITY REMINISCENT OF HEMOPHAGOCYTIC HISTIOCYTOSIS: A POTENTIAL ROLE FOR T CELL AND IFN-gamma DIRECTED THERAPIES

Background: 30-50% of pediatric acute liver failure (PALF) is of unknown cause, or indeterminate PALF (iPALF), which frequently results in transplantation. A subset of iPALF is characterized by T-cell activation. Some children with acute severe hepatitis of unknown etiology (SH-u) can evolve to iPALF. Hemophagocytic Lymphohistiocytosis (HLH) is a well-defined hyper-inflammatory condition characterized by marked T-cell activation and frequent severe liver involvement. We postulated SH-u evolving to iPALF has hyper-inflammatory immune signatures that are identifiable before fulfilling PALF criteria, and might overlap with those seen in HLH. We compared the immune dysregulation signatures of children with HLH to children with SH-u, PALF cases with known etiologies, and healthy pediatric controls (HC). Method(s): Between 2019-2021, we prospectively enrolled 14 patients hospitalized with SH-u and 7 patients with PALF of known etiologies. Age dependent standard of care diagnostic studies were performed. SH-u was defined as ALT> 500, INR < 2, and no hepatic encephalopathy. HLH enrollees fulfilled the 2004 diagnostic criteria. High dimension T-cell immunophenotyping, cytokine and chemokine profiling (71-plex) was done for SH-u, HLH (n=5), and HC (n= 16) peripheral blood samples. T cell activation was prospectively identified by co-expression of surface activation markers HLA-DR and CD38. Based on immune studies in HC, CD8 effector memory (EM) activation of >9% distinguished patients with significant T cell activation from HC. This cutoff of >9% was therefore used to identify SH-u patients with T cell activation. Normally distributed data were compared by either a two-tailed t-test or an ordinary One-Way Anova test with Turkey's multiple comparison test. Non-normally distributed data were compared by either the Mann-Whitney test or Kruskal-Wallis test with Dunn's multiple comparisons test. P Values < 0.05 were deemed significant. Result(s): Subjects ranged in age from 4 days to 19 years old. There were no age or sex differences between the groups. One SH-u patient had prior COVID infection, but no subject met MIS-c criteria. Two SH-u patients ultimately evolved to PALF criteria with INR> 2. All patients with SH-u had higher CD8 EM T-cell activation (mean +/- SEM = 43.7+/-6.3%;range 9.2 to 81.3;p<0.0001), which was significantly higher than HC (2.9+/-0.5%) and PALF of known etiology (4.0+/-0.9%) . However, the amplitude of T-cell activation was lower in the SH-u group relative to the HLH group (90.3+/-2.7%;p<0.0001), as shown in Figure 1. A similar trend in T cell activation was noted in the CD4 compartment. Overall, the activation in the CD8 compartment was much greater than in CD4. SH-u patients had a decreased CD4/CD8 ratio compared to the PALF group. Despite higher T cell activation in patients with SH-u compared to PALF, ferritin, often used to screen for hyper-inflammation, was lower in the SH-u group when compared to PALF group (1240+/-609 vs. 39517+/-32149;p<0.05) and very significantly lower than HLH (32415 +/- 14845;p =0.002). 50% of patients with SH-u etiology had ferritin < 500 mg/L. Cytopenia (hemoglobin < 9 g/dL, ANC < 1000/mL, platelets < 100,000/mL) is characteristic of patients with HLH. Despite overlapping T cell activation with HLH, the SH-u cohort had only 2 patients with this feature: one with thrombocytopenia and one with neutropenia. Supportive of this higher T cell activation, we noted chemokines driven by IFN-gamma, CXCL9 and CXCL10, to be elevated in SH-u compared to HCs and comparable to HLH patients. As a proof of concept, 1 patient with SH-u and thrombocytopenia underwent treatment with Emapalumab (an IFN-gamma blocking antibody) along with other immune modulators both with complete liver, immune, and platelet count recovery. Conclusion(s): Our cohort of SH-u was associated with significant T-cell activation. In addition, our patients with HLH and SH-u with T cell activation had similar increased IFN-gamma activity. Despite this T cell activation, ferritin values were significantly lower in SH-u compared to PALF without T cell activation. Ferritin may not be a reliable screening test to identify SH-u patients with significant T cell activation. If validated in a larger well-defined population of SH-u, the results may suggest a role for IFN-gamma blocking agents in a subgroup of SH-u prior to PALF or before bone marrow failure development.

PET-derived parameters for response assessment in neoadjuvant atezolizumab: A secondary analysis of PRINCEPS phase II trial

Background: Immune Checkpoint Blockade (ICB) is moving from metastatic to curative setting in different diseases including NSCLC. While for metastatic disease radiological endpoints are currently the standard surrogate marker of benefit from ICBs, based on RECIST or PERCIST criteria, in neoadjuvant setting they often underestimate the response and then pathological response (PR) criteria were developed to evaluate Major PR (MPR), defined as ≤10% viable tumor cells after neoadjuvant treatment, and PR, defined as less than 50% residual tumor cells. Anyway, a non-invasive approach to determine the response to treatment is still an unmet need. Methods: PRINCEPS was a phase 2 clinical trial including limited-stage (IB-IIIA) NSCLC patients who received one administration of atezolizumab before surgery. 18-F FDG PET was performed within 28 days and after 15-22 days from atezolizumab. Surgery was performed at day 22-29 from atezolizumab. PET derived parameters including MTV and TLG was extracted by experienced nuclear physicians. Results: 30 patients were enrolled, all received A and underwent surgical resection after a median of 23 days. MPR was identified in 4, pPR in 8 tumors. Paired PET were available for 28 pts. Mean time from A to PET was 18 days (IQR 3.5). Total TLG and MTV reduction was not correlated with percentage of pPR (p=0.117 and p=0.843, respectively). Reduction of MTV (Pearson correlation 0.509, p=0.006) and TLG (Pearson correlation 0.562, p=0.002) in the primary tumor were strongly correlated with pPR, while no correlation was observed between percentage of pPR and variation in tumor diameters by RECIST criteria (-0.24, p=0.2) nor metabolic response (-0.12, p=0.55). The appearance of metabolically active hilar and mediastinal, non-pathological lymph nodes (LN) was noted in 12/28 patients, and specifically in. 2 out of 4 MPR and 5 out of 8 pPR. A trend toward an higher pPR was observed with LN appearance (mean 52% reduction in pts with LN appearance vs 29% without, p 0.061), probably reflecting immune activation. LN appearance was associated with hyperplasia and histiocytosis in resected, non-metastatic LNs. Conclusions: PET is able to early detect tumor response in localized NSCLC patients treated with ICBs in neoadjuvant setting. Clinical trial identification: NCT02994576. Legal entity responsible for the study: Institut Gustave Roussy. Funding: Roche. Disclosure: N. Chaput-Gras: Financial Interests, Personal, Advisory Board, Strong-Iopredi Scientific Advisory Board: AstraZeneca;Financial Interests, Institutional, Invited Speaker, Educational Session On Immune Cell Death: Servier;Financial Interests, Institutional, Expert Testimony, Expertise On Immune Cell Death Biomarkers: Servier;Financial Interests, Personal, Invited Speaker: Cytune Pharma;Financial Interests, Institutional, Research Grant, Research grant to identify immune biomarkers associated to clinical response in patients treated with agonistic mAbs: GSK;Financial Interests, Institutional, Research Grant, Preclinical studies in mice: GSK;Financial Interests, Institutional, Research Grant, Immune profiling of Head & Neck tumors: Sanofi. D. Planchard: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Samsung, Celgene, AbbVie, Daiichi Sankyo, Janssen;Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, Pfizer, priME Oncology, Peer CME, Samsung, AbbVie, Janssen;Non-Financial Interests, Principal Investigator, Institutional financial interests: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Daiichi Sankyo, Sanofi-Aventis, Pierre Fabre;Non-Financial Interests, Principal Investigator: AbbVie, Sanofi, Janssen. L. Mezquita: Financial Interests, Personal, Advisory Board: Takeda, AstraZeneca, Roche;Financial Interests, Personal, Invited Speaker: Roche, BMS, AstraZeneca, Takeda;Financial Interests, Personal, Research Grant, SEOM Beca Retorno 2019: BI;Financial Interests, Personal, Research Grant, ESMO TR Research Fellowship 2019: BMS;Financial Interests, Institutional, Resea ch Grant, COVID research Grant: Amgen;Financial Interests, Institutional, Invited Speaker: Inivata, Stilla. J. Remon Masip: Financial Interests, Personal, Invited Speaker: Roche, Pfizer, MSD, Boehringer-Ingelheim;Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Janssen, Takeda, Sanofi;Financial Interests, Personal, Expert Testimony: Ose Immunotherapeutics;Non-Financial Interests, Principal Investigator, PI of PECATI trial in Thymic malignancies endorsed by a grant by MSD: MSD;Non-Financial Interests, Other, Co-PI of APPLE trial (EORTC-1525): AstraZeneca. F. Barlesi: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, Mirati, MSD, Pierre Fabre, Pfizer, Sanofi Aventis, Seattle Genetics, Takeda;Non-Financial Interests, Principal Investigator: AstraZeneca, BMS, Merck, Pierre Fabre, F. Hoffmann-La Roche Ltd. B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Janssen, Onxeo, OSE Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals;Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, Eisai, Genzyme Corporation, Inivata, Ipsen, Turning Point Therapeutics. All other authors have declared no conflicts of interest.

Evaluation of Glycosylated Ferritin in Adult-Onset Still's Disease and Differential Diagnoses.

Glycosylated ferritin (GF) has been reported as a good diagnostic biomarker for adult-onset Still's disease (AOSD), but only a few studies have validated its performance. We performed a retrospective study of all adult patients with at least one GF measurement over a 2-year period in one hospital laboratory. The diagnosis of AOSD was based on the expert opinion of the treating physician and validated by two independent investigators. Patients' characteristics, disease activity, and outcome were recorded and compared. Twenty-eight AOSD and 203 controls were identified. Compared to controls, the mean GF was significantly lower (22.3% vs. 39.3, p < 0.001) in AOSD patients. GF had a high diagnostic accuracy for AOSD, independent of disease activity or total serum ferritin (AUC: 0.674 to 0.915). The GF optimal cut-off value for AOSD diagnosis was 16%, yielding a specificity of 89% and a sensitivity of 63%. We propose a modified diagnostic score for AOSD, based on Fautrel's criteria but with a GF threshold of 16% that provides greater specificity and increases the positive predictive value by nearly 5 points. GF is useful for ruling out differential diagnoses and as an appropriate classification criterion for use in AOSD clinical trials.

AN UNUSUAL CASE OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS ASSOCIATED WITH M.CHIMAERA OR LARGE CELL NEUROENDOCRINE CARCINOMA

CASE: 56-year-old Caucasian male presented to the hospital with worsening weakness, exertional dyspnea, dry and nonproductive cough, and a 5-pound weight loss in 2 weeks associated with loss of appetite. He has a significant medical history of mitral valve repair in July 2014, status post bioprosthetic mitral valve replacement in August 2019- culture-negative treated with ceftriaxone, vancomycin, and doxycycline for 6 weeks complicated with CVA, atrial flutter, tobacco abuse, alcohol abuse. His shortness of breath worsened quickly with O2 saturations dropping to 85% and had to be placed on BiPAP followed by high flow nasal cannula/ noninvasive ventilation and became febrile. He was then transferred to ICU for acute hypoxemic respiratory failure. Differentials could be very broad ranging from infections like visceral leishmaniasis, atypical/tuberculous mycobacteria, histoplasmosis, Ehrlichia, Bartonella, Brucella, adeno, disseminated HSV, hematological like Langerhans cell histiocytosis, multicentric Castleman disease. In this patient, differentials included hemophagocytic lymphohistiocytosis, COVID-19. Covid was negative x2. His lab abnormalities as well as diagnostic testing revealed hemophagocytic lymphohistiocytosis. He was empirically started on antibiotics and dexamethasone 20 mg to be continued for 2 weeks then taper if the patient has continued improvement. Dexamethasone was tapered over 8 weeks. On later admissions, Carious test was positive for M. chimaera, and core biopsy of the lung nodule showed large cell neuroendocrine carcinoma. IMPACT/DISCUSSION: Hemophagocytic lymphohistiocytosis (HLH) is a rare but very dangerous condition, characterized by abnormal activation of the immune system, causing hemophagocytosis, inflammation, and potentially widespread organ damage. The primary (genetic) form, caused by mutations affecting lymphocyte cytotoxicity, is most commonly seen in children. Secondary HLH is commonly associated with infections or malignancies. Most current information on diagnosis and treatment is based on pediatric populations. The HLH-2004 diagnostic criteria are the most commonly used diagnostic criteria and were developed for children;but used in adults as commonly as in children, although there is a gap in the knowledge. The HLH-2004 diagnosis criteria state that diagnosis of HLH can be established if either a molecular diagnosis is made consistent with HLH or diagnostic criteria for HLH is fulfilled, which includes meeting 5 of 8 criteria. These are lab and clinical findings including fever, splenomegaly, significant cytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis in bone marrow/spleen or lymph nodes, low or no NK cell activity, ferritin >500 ug/L or sCD25 >2400 U/mL. CONCLUSION: HLH is a disease that needs to be diagnosed and treated promptly, it is fatal otherwise. Treatment is mostly tailored to the patient's root cause, treat the cause, and symptomatic treatment with dexamethasone and etoposide.

When Hearing Hoofbeats Is Actually Zebras: A Common Presentation of Uncommon Pathology

Since the beginning of the SARS CoV-2 pandemic two years ago respiratory complaints have been one of the most common presenting symptoms to the emergency departments across the United States. At this time, over 45 million Americans have tested positive for the SARS CoV-2 virus and the vast majority of the patients who present to the hospital with this infection are due to the consequences of systemic inflammation, most significantly in the lungs. We would like to share a case of a 79 year old female with known cystic lung disease (suspected Pulmonary Langerhans Cell Histiocytosis) on 4L oxygen via nasal cannula (NC) at baseline who presented to a community hospital from her nursing facility for hypoxia. Upon presentation to the hospital she was found to test positive for the SARS CoV-2 virus. In the course of her work up she received a CTA of the chest which did show mild ground glass changes consistent with a mild viral pneumonia, more significantly, the scan revealed numerous pulmonary arterio-venous malformations (AVMs) in bilateral lower lobes that were not present on previous imaging of the chest. A detailed work up of the patient was unable to be performed due to the patient declining invasive testing and wishing to pursue hospice. The patient was found to have an estimated shunt fraction >30% with a cardiac echo that confirmed an intrapulmonary shunt and an acute drop in the patient's left ventricular ejection fraction (LVEF) due to an NSTEMI 3 months prior to admission. We believe that this patient had underlying hereditary hemorrhagic telangiectasia resulting in pulmonary AVMs that were minimally symptomatic until the patient's acute drop in her LVEF which led to a drastic increase in her intrapulmonary shunt fraction.

A diagnosis erupting from within

We report a case of eruptive xanthomas in a 31 year old Caucasian man with a background history of poorly controlled Type 2 diabetes mellitus, obstructive sleep apnoea and fatty liver disease. He developed a widespread pruritic rash which started on his left arm 9 h after his first dose of the Pfizer covid vaccination which progressed to involve bilateral upper limbs, lower limbs and abdomen. However, he presented a week later with acute abdominal pain and was later admitted to ICU with pancreatitis resulting in diabetic ketoacidosis. Dermatology were consulted for management of his pruritic eruption and possible covid vaccination adverse reaction. Physical examination revealed multiple excoriated yellow to pink papules. His bloods showed a total cholesterol of 31 and triglycerides of 157. A biopsy was taken which demonstrated perivascular and periadnexal foam cells in the superficial to mid dermis consistent with eruptive xanthoma. He was commenced on fenofibrate to manage his hypertriglyceridemia and insulin to manage his diabetes. This case highlights the rarity of eruptive xanthomas and that it can go unrecognised or misdiagnosed if not considered. Clinicians should consider a biopsy to confirm the diagnosis and consider differentials of Non-Langerhans cell and Langerhans cell histiocytosis, disseminated granuloma annulare and sarcoidosis. Eruptive xanthomas are lipid deposits in the skin in the context of high triglycerides >20 mmol/L. They are characterised by firm 2-5 mm papules that commonly involve the extensor surfaces. The papules can be pruritic or tender. The xanthomas usually resolve within two weeks of normalisation of triglyceride levels, as observed in this patient. Effective treatment options include dietary modification and lipid lowering medication such as fenofibrate. In refractory cases, surgical excisions, cryotherapy and ablative lasers such as Er-YAG and CO2 have been reported . Clinical photos and histology will be presented for discussion.

Progressive destruction of jaws caused by the delayed treatment of Langerhans cell histiocytosis in a 2-year-old boy: A case report.

Langerhans cell histiocytosis (LCH) is a disease with varied clinic manifestations. The oral symptoms and signs of LCH localized to the jaws are nonspecific, which may lead to misdiagnosis of this disease. The purpose of this paper was to present the case of a 2-year, 4-month-old LCH patient with progressive destruction of jaws caused by the delayed treatment due to the global outbreak of COVID-19. The cone beam CT analysis after an interval of 6 months reminded us the great significance of early diagnosis and treatment of LCH.

Langerhans cell histiocytosis presenting as post-COVID-19 multisystem inflammatory syndrome: A rare case report

Langerhans cell histiocytosis is a rare clonal disease of monocyte-macrophage system characterized with uncontrolled proliferation and accumulation of immature dendritic cells. Acute disseminated form of this disease known as Letterer-Siwe disease is life threatening. Here, we report such a case who presented as multisystem inflammatory syndrome following COVID-19 infection. [ FROM AUTHOR] Copyright of Indian Journal of Paediatric Dermatology is the property of Wolters Kluwer India Pvt Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Multisystem Langerhans cell histiocytosis: Literature review and case report.

Langerhans cell histiocytosis (LCH) refers to a group of diseases of unknown etiology, typically discovered in childhood, characterized by the accumulation of Langerhans cells (white blood cells with large cell nuclei that may contain cytoplasmic histiocytosis X bodies) involving one or more organ systems, including bones, lungs, pituitary gland, skin, lymph nodes, and liver. This disease is also known as histiocytosis X or eosinophilic granuloma. Pulmonary LCH is common (identified in 40% of LCH patients) and may be isolated to the lung or involve other organs. Although LCH is characterized by clonal cell proliferation, adult LCH is considered likely to represent the manifestation of an aberrant immune response to an unspecified antigenic stimulus rather than a manifestation of tumor proliferation. We report a very complicated clinical case of LCH, with multiple organ damage that received a variety of different diagnoses. An LCH diagnosis was confirmed based on postoperative spinal cord pathology results and immunohistochemistry examinations. This case report highlights the clinical, laboratory, and imaging signs observed in this case that should be noted to help doctors more quickly recognize, diagnose, and treat similar cases.