Artificial intelligence-based reticulin proportionate area - a novel histological outcome predictor in hepatocellular carcinoma.

AIMS: Reticulin stain is used routinely in the histological evaluation of hepatocellular carcinoma (HCC). The goal of this study was to assess whether the histological reticulin proportionate area (RPA) in HCCs predicts tumour-related outcomes. METHODS AND RESULTS: We developed and validated a supervised artificial intelligence (AI) model that utilises a cloud-based, deep-learning AI platform (Aiforia Technologies, Helsinki, Finland) to specifically recognise and quantify the reticulin framework in normal livers and HCCs using routine reticulin staining. We applied this reticulin AI model to a cohort of consecutive HCC cases from patients undergoing curative resection between 2005 and 2015. A total of 101 HCC resections were included (median age = 68 years, 64 males, median follow-up time = 49.9 months). AI model RPA reduction of > 50% (compared to normal liver tissue) was predictive of metastasis [hazard ratio (HR) = 3.76, P = 0.004, disease-free survival (DFS, HR = 2.48, P < 0.001) and overall survival (OS), HR = 2.80, P = 0.001]. In a Cox regression model, which included clinical and pathological variables, RPA decrease was an independent predictor of DFS and OS and the only independent predictor of metastasis. Similar results were found in the moderately differentiated HCC subgroup (WHO grade 2), in which reticulin quantitative analysis was an independent predictor of metastasis, DFS and OS. CONCLUSION: Our data indicate that decreased RPA is a strong predictor of various HCC-related outcomes, including within the moderately differentiated subgroup. Reticulin, therefore, may represent a novel and important prognostic HCC marker, to be further explored and validated.

Bone marrow fibrosis is associated with non-response to CD19 CAR T-cell therapy in B-acute lymphoblastic leukemia.

CD19 directed CAR T-cell therapy is used to treat relapsed/refractory B-cell acute lymphoblastic leukemia. The role of the pre-CAR bone marrow (BM) stromal microenvironment in determining response to CAR T-cell therapy has been understudied. We performed whole transcriptome analysis, reticulin fibrosis assessment and CD3 T-cell infiltration on BM core biopsies from pre- and post-CAR timepoints for 61 patients, as well as on a cohort of 54 primary B-ALL samples. Pathways of fibrosis, extracellular matrix development, and associated transcription factors AP1 and TGF-ß3, were enriched and upregulated in nonresponders (NR) even prior to CAR T cell therapy. NR showed significantly higher levels of BM fibrosis compared to complete responders by both clinical reticulin assessment and AI-assisted digital image scoring. CD3+ T cells showed a trend toward lower infiltration in NR. NR had significantly higher levels of pre-CAR fibrosis compared to primary B-ALL. High levels of fibrosis were associated with lower overall survival after CAR T-cell therapy. In conclusion, BM fibrosis is a novel mechanism mediating nonresponse to CD19-directed CAR T-cell therapy in B-ALL. A widely used clinically assay for quantitating myelofibrosis can be repurposed to determine patients at high risk of non-response. Genes and pathways associated with BM fibrosis are a potential target to improve response.

Utility of texture analysis for objective quantitative ex vivo assessment of meningioma consistency: method proposal and validation.

BACKGROUND: Tumor consistency is considered to be a critical factor for the surgical removal of meningiomas and its preoperative assessment is intensively studied. A significant drawback in the research of predictive methods is the lack of a clear shared definition of tumor consistency, with most authors resorting to subjective binary classification labeling the samples as "soft" and "hard." This classification is highly observer-dependent and its discrete nature fails to capture the fine nuances in tumor consistency. To compensate for these shortcomings, we examined the utility of texture analysis to provide an objective observer-independent continuous measure of meningioma consistency. METHODS: A total of 169 texturometric measurements were conducted using the Brookfield CT3 Texture Analyzer on meningioma samples from five patients immediately after the removal and on the first, second, and seventh postoperative day. The relationship between measured stiffness and time from sample extraction, subjectively assessed consistency grade and histopathological features (amount of collagen and reticulin fibers, presence of psammoma bodies, predominant microscopic morphology) was analyzed. RESULTS: The stiffness measurements exhibited significantly lower variance within a sample than among samples (p = 0.0225) and significant increase with a higher objectively assessed consistency grade (p = 0.0161, p = 0.0055). A significant negative correlation was found between the measured stiffness and the time from sample extraction (p < 0.01). A significant monotonic relationship was revealed between stiffness values and amount of collagen I and reticulin fibers; there were no statistically significant differences between histological phenotypes in regard to presence of psammoma bodies and predominant microscopic morphology. CONCLUSIONS: We conclude that the values yielded by texture analysis are highly representative of an intrinsic consistency-related quality of the sample despite the influence of intra-sample heterogeneity and that our proposed method can be used to conduct quantitative studies on the role of meningioma consistency.

TAFRO syndrome with a fatal clinical course following BNT162b2 mRNA (Pfizer-BioNTech) COVID-19 vaccination: A case report.

TAFRO syndrome is a rare disorder that manifests as thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly. Although this disease often follows a severe clinical course, the cause remains unknown. The coronavirus disease 2019 (COVID-19) pandemic is a major global problem. Vaccination against COVID-19 has been successful; however, there are concerns about severe adverse events. Herein, we report a rare presentation of TAFRO syndrome triggered by the COVID-19 vaccine with a fatal clinical course. A 42-year-old Japanese man presented to our hospital complaining of fever lasting for 2 weeks that occurred a day after receiving the BNT162b2 mRNA (Pfizer-BioNTech) COVID-19 vaccine. The patient had a low platelet count, ascites, reticulin myelofibrosis, renal failure, and lymphadenopathy and was diagnosed with TAFRO syndrome. Despite administering several immunosuppressive drugs, the condition did not improve. The patient repetitively developed and eventually died of bacteremia caused by multidrug-resistant Klebsiella pneumoniae. We highlight the first reported case of TAFRO syndrome after COVID-19 vaccination.

Therapeutic Intervention with Dietary Chitosan Nanoparticles Alleviates Fish Pathological and Molecular Systemic Inflammatory Responses against Infections.

Marine bio-sourced chitosan nanoparticles (CSNP) are antimicrobial and immunomodulatory agents beneficial for fish medicine. Herein, dietary CSNP was investigated for the amelioration of the systemic inflammatory responses of an induced fish model. One hundred and forty-four rainbow trout were assigned to one pathogen-free and non-supplemented group (negative control), and three challenged groups: non-supplemented (positive control), CSNP-preventive, and CSNP-therapeutic. After a feeding experiment extended for 21 days, the organosomatic indices (OSI) and molecular aspects were assessed. After a challenge experiment extended for further 28 days, CSNP-therapeutic intervention was assessed on fish survival and systemic inflammatory responses on pathology, histo-morphology, and molecular aspects. With CSNP administration, OSI nonsignificantly decreased and the relative expression of targeted inflammatory-mediator genes was significantly increased. The CSNP-therapeutic fish showed an RPS of 80% as compared to the positive control group, and CSNP-therapeutic administration retained the highest gene expression augmentation up to 28 days after the challenge. Notably, the splenic reticulin fibers framework of the CSNP-therapeutic group retained the highest integrity among the groups during the infection. After recovery, reticulin fibers density in the CSNP-therapeutic samples was significantly higher than in the negative control group, which indicates high innate immunity. Thus, CSNP showed promising biotherapeutic features enhancing fish resistance against infections.

Idiopathic Plasmacytic Lymphadenopathy Forms an Independent Subtype of Idiopathic Multicentric Castleman Disease.

Idiopathic multicentric Castleman disease (iMCD) is a type of Castleman disease that is not related to KSHV/HHV8 infection. Currently, iMCD is classified into iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly) and iMCD-NOS (not otherwise specified). The former has been established as a relatively homogeneous disease unit that has been recently re-defined, while the latter is considered to be a heterogeneous disease that could be further divided into several subtypes. In 1980, Mori et al. proposed the concept of idiopathic plasmacytic lymphadenopathy (IPL), a disease presenting with polyclonal hypergammaglobulinemia and a sheet-like proliferation of mature plasma cells in the lymph nodes. Some researchers consider IPL to be a part of iMCD-NOS, although it has not been clearly defined to date. This is the first paper to analyze iMCD-NOS clinicopathologically, to examine whether IPL forms a uniform disease unit in iMCD. Histologically, the IPL group showed prominent plasmacytosis and the hyperplasia of germinal centers, while the non-IPL group showed prominent vascularity. Clinically, the IPL group showed significant thrombocytosis and elevated serum IgG levels compared to the non-IPL group (p = 0.007, p < 0.001, respectively). Pleural effusion and ascites were less common in the IPL group (p < 0.001). The IPL group was more likely to have an indolent clinical course and a good response to the anti-IL-6 receptor antibody, while the non-IPL counterpart frequently required more aggressive medical interventions. Thus, the IPL group is a clinicopathologically uniform entity that forms an independent subtype of iMCD.

Advanced extramedullary hematopoiesis with a marked increase in reticulin fibers and hemorrhage on various organs: the first autopsy case report.

Myelofibrosis is characterized by stem cell-derived clonal proliferation potentially resulting in bone marrow fibrosis. As the disease progresses, extramedullary hematopoiesis is frequently detected in the spleen and the liver but rarely in other organs. We report a case of a 68-year-old woman with myelofibrosis with a JAK2 mutation, showing extramedullary hematopoiesis (EMH) in various organs with a marked increase in reticulin fibers, and myeloproliferative neoplasm (MPN)-related necrotizing crescent glomerulonephritis. She was admitted to our hospital owing to respiratory discomfort. Computed tomography revealed a mass in the anterior mediastinum. Ten days later, the patient died owing to respiratory distress. At autopsy, EMH were detected in the anterior mediastinum, heart, lung, spleen, and the kidney with a marked increase in reticulin fibers. We considered that respiratory distress was partially caused by EMH. In the kidney, necrotizing crescent glomerulonephritis was observed. Immunohistochemically, the glomerular basement and mesangial area were IgA- and C3d-positive. Ultrastructural examination revealed the presence of dense deposits in the subendothelial space and the mesangial and paramesangial areas. Thus, we suspected that MPN-related necrotizing crescentic glomerulonephritis harbored a pathogenesis similar to that of IgA-dominant post-infectious glomerulonephritis or IgA nephropathy. This case report could widen the spectrum of MPN- or EMH-related lesions.

Association of mast cells and bone marrow reticulin fibrosis in patients with bcr-abl negative chronic myeloproliferative neoplasms.

BACKGROUND: We aimed to investigate the association of bone marrow mast cell numbers (MCN) and the degree of reticulin fibrosis in patients with chronic myeloproliferative neoplasms (MPN). METHODS: This was a case-control study that recruited 47 patients who were diagnosed with bcr-abl negative MPN. Thirty patients with lymphoma served as controls. JAK2 mutation was studied and all subjects underwent bone marrow biopsy at the time of diagnosis. Mast and CD34+ cells were counted. Marrow reticulin fiber was graded. RESULTS: Thirty-four patients had essential thrombocythemia (ET), 8 patients had primary myelofibrosis (PMF) and 5 patients had polycythemia vera (PV). Fourteen MPN patients had JAK2, whereas the controls had not. MCN was higher in patients than controls (p = 0.001). There was no significant difference regarding CD34. Reticulin fibrosis was present in 57.4% of MPN patients, whereas there was any in controls. PMF patients had more CD34 + cells than PV and ET. PMF patients had more reticulin fibers compared with other subgroups (p < 0.001). MCN, but not CD34+ cell counts, was significantly higher in JAK2(+) patients than JAK2(-) patients. CONCLUSION: MCN and reticulin fibrosis were significantly increased in MPN patients. JAK2 positivity had significantly increased MCN compared to patients without JAK2. JAK2 was associated with increased reticulin fibrosis.

Reticulin staining pattern in the differential diagnosis of benign parathyroid lesions.

AIM: A reticulin staining pattern (RSP) can be used for the differential diagnosis of endocrine gland lesions, as in the adrenal and hypophysis glands. We aimed to use RSP for the differential diagnosis of parathyroid gland lesions. MATERIALS AND METHODS: In this study, we evaluated 97 parathyroid lesions in 85 patients, as well as 29 normal parathyroid glands. All sections were stained with a silver impregnation-based kit for the reticulin stain. The RSPs were classified as short thick fiber-, anastomosing- and nodular/alveolar-pattern. The dominant pattern was accepted as being greater than 50% in each section. RESULTS: Short thick fibers and anastomosing and nodular RSPs were seen in adenomas, but there was no alveolar pattern. Although nodular/alveolar patterns were seen in focal areas in hyperplasia, they never became the dominant pattern. Nodular dominant RSPs were seen in adenomas; however, nodular RSPs were not seen in hyperplasia in a dominant pattern (p = 0.049). While short thick fibers were not seen in normal glands, they could be seen in adenomas (p < 0.001) and in hyperplasia (p < 0.001). CONCLUSION: RSPs can be used in the differential diagnosis of parathyroid lesions. While short thick reticular fibers support adenomas and hyperplasia rather than normal tissue, a nodular dominant pattern supports adenomas rather than hyperplasia.

Comparison of the clinical characteristics of TAFRO syndrome and idiopathic multicentric Castleman disease in general internal medicine: a 6-year retrospective study.

BACKGROUND: Although thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly (TAFRO) syndrome was first described as a variant of idiopathic multicentric Castleman disease (CD), patients with TAFRO syndrome demonstrate more aggressive clinical features. Because these patients may present with fever of unknown origin, general physicians need to recognise its characteristic laboratory data and clinical features during hospitalisation. AIMS: to describe the features, symptoms and characteristics of TAFRO syndrome and to compare them to those of idiopathic CD. METHODS: This was a retrospective study of patients with histopathologically confirmed TAFRO syndrome and idiopathic multicentric CD who were diagnosed and managed between April 2012 and June 2018 in a Japanese university hospital's General Medicine Department. RESULTS: We found that the hospitalisations were significantly longer among patients with TAFRO syndrome compared to those with idiopathic CD (median: 87 days; range: 34-236 days vs median: 30 days; range: 13-59 days; P < 0.01). Patients with TAFRO syndrome were more likely to present with fever, abdominal pain and elevated inflammatory markers and be misdiagnosed with an infectious disease during the first hospital visit. Approximately 40% of patients with TAFRO syndrome had no radiographically enlarged lymph nodes. CONCLUSIONS: TAFRO syndrome may present as an infectious disease with an aggressive clinical course. Our study highlights the importance of giving significance to chief complaints and laboratory data. Physicians need to recognise the clinical and laboratory features of this disease to avoid missing this potentially fatal disorder.

Fibrillar force generation by fibroblasts depends on formin.

Fibroblasts in the extra-cellular matrix (ECM) often adopt a predominantly one-dimensional fibrillar geometry by virtue of their adhesion to the fibrils in the ECM. How much forces such fibrillar fibroblasts exert and how they respond to the extended stiffness of their micro-environment comprising of other ECM components and cells are not clear. We use fibroblasts adherent on fibronectin lines micropatterned onto soft polyacrylamide gels as an in vitro experimental model that maintains fibrillar cell morphology while still letting the cell mechanically interact with a continuous micro-environment of specified stiffness. We find that the exerted traction, quantified as the strain energy or the maximum exerted traction stress, is not a function of cell length. Both the strain energy and the maximum traction stress exerted by fibrillar cells are similar for low (13 kPa) or high (45 kPa) micro-environmental stiffness. Furthermore, we find that fibrillar fibroblasts exhibit prominent linear actin structures. Accordingly, inhibition of the formin family of nucleators strongly decreases the exerted traction forces. Interestingly, fibrillar cell migration is, however, not affected under formin inhibition. Our results suggest that fibrillar cell migration in such soft microenvironments is not dependent on high cellular force exertion in the absence of other topological constraints.

The sympathomimetic agonist mirabegron did not lower JAK2-V617F allele burden, but restored nestin-positive cells and reduced reticulin fibrosis in patients with myeloproliferative neoplasms: results of phase II study SAKK 33/14.

The ß-3 sympathomimetic agonist BRL37344 restored nestin-positive cells within the stem cell niche, and thereby normalized blood counts and improved myelofibrosis in a mouse model of JAK2-V617F-positive myeloproliferative neoplasms. We therefore tested the effectiveness of mirabegron, a ß-3 sympathomimetic agonist, in a phase II trial including 39 JAK2-V617F-positive patients with myeloproliferative neoplasms and a mutant allele burden more than 20%. Treatment consisted of mirabegron 50 mg daily for 24 weeks. The primary end point was reduction of JAK2-V617F allele burden of 50% or over, but this was not reached in any of the patients. One patient achieved a 25% reduction in JAK2-V617F allele burden by 24 weeks. A small subgroup of patients showed hematologic improvement. As a side study, bone marrow biopsies were evaluated in 20 patients. We found an increase in the nestin+ cells from a median of 1.09 (interquartile range 0.38-3.27)/mm2 to 3.95 (interquartile range 1.98-8.79)/mm2 (P<0.0001) and a slight decrease of reticulin fibrosis from a median grade of 1.0 (interquartile range 0-3) to 0.5 (interquartile range 0-2) (P=0.01) between start and end of mirabegron treatment. Despite the fact that the primary end point of reducing JAK2-V617F allele burden was not reached, the observed effects on nestin+ mesenchymal stem cells and reticulin fibrosis is encouraging, and shows that mirabegron can modify the microenvironment where the JAK2-mutant stem cells are maintained. (Registered at clinicaltrials.gov identifier: 02311569).

Integrating clinical, morphological, and molecular data to assess prognosis in patients with primary myelofibrosis at diagnosis: A practical approach.

Currently available prognostic scoring systems in primary myelofibrosis (PMF) do not integrate clinical, histological, and molecular data, or they also required information on "other" mutations that are available in the clinical practice only in a very limited number of laboratories. In the present multicenter study, including 401 PMF patients, an integrated International Prognostic Scoring System (I-IPSS) was developed by combining IPSS, grade of bone marrow fibrosis (GBMF), and driver mutations molecular status (MS) to define PMF prognosis at diagnosis. Four prognostic categories were identified: I-IPSS-low risk (113 patients), I-IPSS-intermediate-1 risk (56 patients), I-IPSS-intermediate-2 risk (154 patients), and I-IPSS-high risk (78 patients). Median overall survival was 26.7 years in I-IPSS-intermediate-1, 10.8 in I-IPSS-intermediate-2, and 6.4 in I-IPSS-high-risk patients (log-rank test <0.0001); instead, it was not reached in the I-IPSS-low-risk cohort because of the extremely low number of registered deaths. The addition of GBMF and MS to IPSS improved the efficacy for predicting the risk of death. Indeed, the sensitivity of I-IPSS was significantly higher (P < .05) than that of IPSS, considering both total deaths and 5- and 10-year mortality. This comprehensive approach allows clinicians to evaluate mutual interactions between IPSS, GBMF, and MS and identify high-risk patients with poor prognosis who may benefit from aggressive treatments. More importantly, this integrated score can be easily applicable worldwide as it only required information that represent the good clinical practice in the management of PMF patients.

Immobilized chemokine fields and soluble chemokine gradients cooperatively shape migration patterns of dendritic cells.

Chemokines orchestrate immune cell trafficking by eliciting either directed or random migration and by activating integrins in order to induce cell adhesion. Analyzing dendritic cell (DC) migration, we showed that these distinct cellular responses depended on the mode of chemokine presentation within tissues. The surface-immobilized form of the chemokine CCL21, the heparan sulfate-anchoring ligand of the CC-chemokine receptor 7 (CCR7), caused random movement of DCs that was confined to the chemokine-presenting surface because it triggered integrin-mediated adhesion. Upon direct contact with CCL21, DCs truncated the anchoring residues of CCL21, thereby releasing it from the solid phase. Soluble CCL21 functionally resembles the second CCR7 ligand, CCL19, which lacks anchoring residues and forms soluble gradients. Both soluble CCR7 ligands triggered chemotactic movement, but not surface adhesion. Adhesive random migration and directional steering cooperate to produce dynamic but spatially restricted locomotion patterns closely resembling the cellular dynamics observed in secondary lymphoid organs.

Histological dating of subdural hematoma in infants.

BACKGROUND: After infant deaths due to non-accidental head injury (NAHI) with subdural hematoma (SDH), the magistrates ask experts to date the traumatic event. To do so, the expert only has tools based on adult series of NAHI. We aimed to develop an SDH dating system applicable to infants aged under 3 years. METHODS AND RESULTS: We studied a retrospective multicenter collection of 235 infants who died between the ages of 0 and 36 months, diagnosed with SDH by forensic pathological examination and with known posttraumatic interval (PTI). Two pathologists assessed blindly and independently 12 histomorphological criteria relating to the clot and 14 relating to the dura mater in 73 victims (31 girls, 42 boys) whose median age was 3.8 months. Histopathological changes were significantly correlated with PTI for the appearance of red blood cells (RBCs) and the presence or absence of siderophages, and regarding the dura mater, the quantity of lymphocytes, macrophages, and siderophages; presence or absence of hematoidin deposits; collagen and fibroblast formation; neomembrane thickness; and presence or absence of neovascularization. Dating systems for SDH in adults are not applicable to infants. Notably, neomembrane of organized connective tissue is formed earlier in infants than in adults. CONCLUSION: Our dating system improves the precision and reliability of forensic pathological expert examination of NAHI, particularly for age estimation of SDH in infants. However, the expert can only define a time interval. Histopathology is indispensable to detect repetitive trauma.

Granulosa Cell Tumors of the Ovary With Prominent Thecoma-like Foci: A Report of 16 Cases Emphasizing the Ongoing Utility of the Reticulin Stain in the Modern Era.

Sixteen adult granulosa cell tumors which had conspicuous zones of cells with pale cytoplasm imparting a resemblance to thecoma are reported. The neoplasms occurred in patients from 38 to 86 yr of age, the majority being over 55 yr of age. Ten tumors were incidental findings, the remainder being associated with symptoms or signs related to an adnexal mass. All the tumors were unilateral, typically small, usually under 5 cm, with only 3 being larger. With 1 exception they were uniformly solid and were typically entirely or focally yellow on sectioning. Microscopic examination typically showed a nodular pattern of growth constituted by cells with moderate to abundant pale cytoplasm; the cells resembled those seen in most thecomas. The nodules occasionally became confluent and focally a diffuse pattern was seen. Typical foci of adult granulosa cell neoplasia in the form of foci of conspicuous epithelial differentiation were absent or rare in most cases but were seen in subtle form in 6 cases and overtly in 3. A few tumors had other features seen in some thecomas, hyaline plaques, sclerosis, and calcification. Reticulin stains were examined in 13 cases and showed that the thecoma-like foci exhibited a dearth of reticulum indicating that those areas were predominantly of granulosa cell nature. Most adult granulosa cell tumors have cells with scant cytoplasm; occasional tumors have abundant eosinophilic cytoplasm, so-called luteinized adult granulosa cell tumors. That some granulosa cell tumors have the cytoplasmic features described herein has occasionally been noted but the resemblance to thecoma has not been emphasized to the best of our knowledge and in the past such tumors may have been misdiagnosed as thecoma, the referral diagnosis in 6 of our cases. A reticulin stain is of crucial aid in indicating the epithelial nature of the thecoma-like foci in these cases. Given the small size of the majority of the tumors the distinction between a small adult granulosa cell tumor and thecoma does not have significant prognostic or therapeutic implications in most cases but awareness of this feature of a small subset of adult granulosa cell tumors is warranted. Our findings have import to the diagnosis of thecoma which is uncommon if strict criteria, including exclusion of granulosa tumors of the type described, are used.

Celiac Disease and Celiac Antibodies in DM1 Patients: When Are Screening and Biopsy Recommended?

INTRODUCTION: The prevalence of celiac disease (CD) is increased in diabetes mellitus type 1 (DM1) patients. In most cases, CD is diagnosed in asymptomatic patients and hence periodic screening tests are recommended, but the timing, frequency of tests and indication for duodenal biopsy is unclear. The purpose of this study was to investigate the dynamics of CD serology in DM1 and identify risk factors for CD. METHODS: Celiac serology and duodenal biopsy results from 1990 until 2015 were collected from patients with DM1. The outcome of positive celiac serology, the incidence and risk factors for CD in DM1 patients were investigated. RESULTS: A total of 314 DM1 patients who had celiac serology were identified, with follow-up period up to 23 years. Of 31 patients (9.9%) with positive celiac serology, 11(35.4%) had spontaneous normalization after various time periods. Eighteen patients were diagnosed with CD (58.1% of positive celiac serology, 5.73% of the study cohort). Age under 4.5 years was a risk factor for CD, but not family background of autoimmune diseases or gender. All patients with CD diagnosis were diagnosed during the first 6 years following DM1 diagnosis. CONCLUSION: Screening asymptomatic DM1 patients for CD beyond 6 years after diagnosis is not recommended. Spontaneous normalization of CD serology occurs, and hence, serologic follow-up may be performed. In children with DM1 diagnosis under the age of 4.5 years or with positive CD serology at DM1 diagnosis, there is an increased risk for CD and therefore positive serology should lead to biopsy.

Hepatic Campylobacter jejuni infection in patients with Castleman-Kojima disease (idiopathic multicentric Castleman disease with thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome).

Castleman-Kojima disease, also known as idiopathic multicentric Castleman disease with TAFRO syndrome (iMCD-TAFRO), is a recently recognized systemic inflammatory disorder with a characteristic series of clinical symptoms, including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O). Patients with iMCD-TAFRO often develop severe abdominal pain, elevated alkaline phosphatase levels, and systemic inflammation, but the etiological factors are unknown. To investigate the potential role of bacterial infection in the pathogenesis of iMCD-TAFRO, we performed polymerase chain reaction (PCR) for the bacterial 16S rRNA gene with DNA extracted from liver specimens of three patients with iMCD-TAFRO, four patients with amyotrophic lateral sclerosis, and seven patients with inflammatory conditions. Sequencing of the PCR product showed 99% DNA sequence identity with Campylobacter jejuni in all three patients with iMCD-TAFRO and in two patients with inflammatory conditions. Immunohistochemical and electron microscopy analyses could not identify C. jejuni in patients with iMCD-TAFRO. The findings indicated that C. jejuni infection is not the pathological cause of iMCD-TAFRO; however, this ubiquitous bacterium may play a role in uncontrolled systemic hypercytokinemia, possibly through the development of cross-reactive autoantibodies.

Captopril mitigates splenomegaly and myelofibrosis in the Gata1low murine model of myelofibrosis.

Allogeneic stem cell transplantation is currently the only curative therapy for primary myelofibrosis (MF), while the JAK2 inhibitor, ruxolitinib. Has been approved only for palliation. Other therapies are desperately needed to reverse life-threatening MF. However, the cell(s) and cytokine(s) that promote MF remain unclear. Several reports have demonstrated that captopril, an inhibitor of angiotensin-converting enzyme that blocks the production of angiotensin II (Ang II), mitigates fibrosis in heart, lung, skin and kidney. Here, we show that captopril can mitigate the development of MF in the Gata1low mouse model of primary MF. Gata1low mice were treated with 79 mg/kg/d captopril in the drinking water from 10 to 12 months of age. At 13 months of age, bone marrows were examined for fibrosis, megakaryocytosis and collagen expression; spleens were examined for megakaryocytosis, splenomegaly and collagen expression. Treatment of Gata1low mice with captopril in the drinking water was associated with normalization of the bone marrow cellularity; reduced reticulin fibres, splenomegaly and megakaryocytosis; and decreased collagen expression. Our findings suggest that treating with the ACE inhibitors captopril has a significant benefit in overcoming pathological changes associated with MF.

Defective WNT signaling associates with bone marrow fibrosis-a cross-sectional cohort study in a family with WNT1 osteoporosis.

This study explores bone marrow function in patients with defective WNT1 signaling. Bone marrow samples showed increased reticulin and altered granulopoiesis while overall hematopoiesis was normal. Findings did not associate with severity of osteoporosis. These observations provide new insight into the role of WNT signaling in bone marrow homeostasis. INTRODUCTION: WNT signaling regulates bone homeostasis and survival and self-renewal of hematopoietic stem cells. Aberrant activation may lead to osteoporosis and bone marrow pathology. We aimed to explore bone marrow findings in a large family with early-onset osteoporosis due to a heterozygous WNT1 mutation. METHODS: We analyzed peripheral blood samples, and bone marrow aspirates and biopsies from 10 subjects with WNT1 mutation p.C218G. One subject was previously diagnosed with idiopathic myelofibrosis and others had no previously diagnosed hematologic disorders. The findings were correlated with the skeletal phenotype, as evaluated by number of peripheral and spinal fractures and bone mineral density. RESULTS: Peripheral blood samples showed no abnormalities in cell counts, morphology or distributions but mild increase in platelet count. Bone marrow aspirates (from 8/10 subjects) showed mild decrease in bone marrow iron storages in 6 and variation in cell distributions in 5 subjects. Bone marrow biopsies (from 6/10 subjects) showed increased bone marrow reticulin (grade MF-2 in the myelofibrosis subject and grade MF-1 in 4 others), and an increase in overall, and a shift towards early-phase, granulopoiesis. The bone marrow findings did not associate with the severity of skeletal phenotype. CONCLUSIONS: Defective WNT signaling associates with a mild increase in bone marrow reticulin and may predispose to myelofibrosis, while overall hematopoiesis and peripheral blood values are unaltered in individuals with a WNT1 mutation. In this family with WNT1 osteoporosis, bone marrow findings were not related to the severity of osteoporosis.