Long-Term Tolerance and Efficacy of Siltuximab (Anti-IL-6) in a Young Adult with Idiopathic Multicentric Castleman Disease During COVID-19.

Background: Castleman disease (CD) is a rare lymphoproliferative disorder with various subtypes, including the HHV-8-negative/idiopathic multicentric CD (iMCD). The diagnosis of iMCD remains challenging due to its non-specific presentation, in the form of generalised lymphadenopathies and inflammation. Two clinical presentations have been recently defined: a severe form iMCD-TAFRO and a milder form of iMCD not otherwise specified (iMCD-NOS). identification of interleukin-6 (IL-6) as a major culprit of inflammatory symptoms led to the development of anti-IL-6 therapies, with siltuximab being the approved first-line treatment. Case description: A 16-year-old male presented with recurrent fever, night sweats and several other non-specific symptoms. After extensive evaluations, an excisional lymph node biopsy confirmed the iMCD-NOS diagnosis. The patient received high-dose steroid therapy followed by siltuximab for four years. This treatment was well tolerated with only mild neutropenia not leading to dose adjustment. On siltuximab, the patient developed two mild COVID-19 episodes. His response to siltuximab remained effective throughout four years. Discussion: The absence of biomarker or causal agent identification poses a diagnostic challenge requiring lymph node histopathology for a definitive diagnosis of iMCD. Anti-IL 6 (siltuximab) is the recommended frontline therapy, suppressing inflammation and halting disease progression. Intravenous administration every 3 to 6 weeks can impact patient quality of life, prompting further research for alternative treatments. High-dose steroids, rituximab, cyclosporine, tacrolimus, lenalidomide or combined chemotherapy such as rituximab-bortezomib-dexamethasone are among the considered options according to disease severity. Conclusion: Overall, long-term siltuximab effectively controlled iMCD symptoms and was well tolerated by this young adult, who endured two mild COVID-19 episodes. LEARNING POINTS: Lymph node biopsy rather than bone marrow biopsy is needed for the diagnosis of iMCD.We were able to control the patient's condition in the absence of cumulative toxicity during four years of siltuximab anti-IL6 therapy.Immunosuppressive anti-IL6 therapy did not worsen two episodes of COVID-19.

A Deep Learning-Based Approach to Estimate Paneth Cell Granule Area in Celiac Disease.

CONTEXT.­: Changes in Paneth cell numbers can be associated with chronic inflammatory diseases of the gastrointestinal tract. So far, no consensus has been achieved on the number of Paneth cells and their relevance to celiac disease (CD). OBJECTIVES.­: To compare crypt and Paneth cell granule areas between patients with CD and without CD (non-CD) using an artificial intelligence-based solution. DESIGN.­: Hematoxylin-eosin-stained sections of duodenal biopsies from 349 patients at the McGill University Health Centre were analyzed. Of these, 185 had a history of CD and 164 were controls. Slides were digitized and NoCodeSeg, a code-free workflow using open-source software (QuPath, DeepMIB), was implemented to train deep learning models to segment crypts and Paneth cell granules. The total area of the entire analyzed tissue, epithelium, crypts, and Paneth cell granules was documented for all slides, and comparisons were performed. RESULTS.­: A mean intersection-over-union score of 88.76% and 91.30% was achieved for crypt areas and Paneth cell granule segmentations, respectively. On normalization to total tissue area, the crypt to total tissue area in CD was increased and Paneth cell granule area to total tissue area decreased when compared to non-CD controls. CONCLUSIONS.­: Crypt hyperplasia was confirmed in CD compared to non-CD controls. The area of Paneth cell granules, an indirect measure of Paneth cell function, decreased with increasing severity of CD. More importantly, our study analyzed complete hematoxylin-eosin slide sections using an efficient and easy to use coding-free artificial intelligence workflow.

A Blast From the Past: Abdominal Wall Amyloidosis Due to Enfuvirtide Injections.

Enfuvirtide was the first marketed fusion inhibitor that worked by binding to glycoprotein 41 of the HIV envelope, preventing the conformational changes required for HIV fusion with CD4+ T cells. Due to its novel mechanisms of action, it was frequently used in the past as part of regimens for the indication of multi-class-resistant HIV until newer oral agents emerged. Here, we describe the case of a 40-year-old man who used enfuvirtide injections from 2012 to 2017 inclusive for multi-class-resistant HIV until he presented in 2021 with an abscess overlying a right lower quadrant mass requiring drainage via pigtail. Congo red stain of the tissue showed positive apple green birefringence on amorphous material after polarization, enabling the diagnosis of enfuvirtide-induced amyloidosis. The patient experienced significant improvement following surgical excision of the cysts and nodules. This case demonstrates that sequelae of injection site reactions can persist for many years following the cessation of enfuvirtide injections.

An integrated virtual pathology education platform developed using Microsoft Power Apps and Microsoft Teams.

The transition towards digital pathology and an extensive selection of video conferencing platforms have helped provide continuity to education even during the COVID-19 pandemic. Innovative approaches for pathology education, will likely persist beyond the pandemic, as they have powerful didactic potential. While there is a wide selection of software for use as educational tools, an environment to access all resources with ease is clearly lacking. In this technical note, we highlight our customized educational applications built using a low-code approach. Our applications, developed with Microsoft Power Apps, serve both educational and examination purposes and are launched using Microsoft Teams. Building applications using a low-code approach has made our applications very specific to our use and enabled daily distanced education. Combined with existing features on Teams, such as file sharing, meeting scheduling, and messaging, the applications serve as a unique and customizable pathology educational platform.

Pulmonary lymphangiectasia in myotubular myopathy: a novel unrecognized association?

Chylothorax has been reported in rare cases of X-linked myotubular myopathy, but the pathophysiology of this association is not fully understood. We report a case of a neonate presenting prenatally with hydrops and chylothorax. The patient died at 17 days of life due to respiratory failure secondary to severe pulmonary hypertension. Comprehensive genetic testing identified a de novo hemizygous frameshift mutation in the MTM1 gene (c.142-143del, p.Glu48Serfs*12) with subsequent autopsy confirming the diagnosis of X-linked myotubular myopathy. Lung microscopy demonstrated primary pulmonary lymphangiectasia as the cause for the massive chylothorax. To the best of our knowledge, this is the first reported case of molecularly confirmed X-linked myotubular myopathy with pulmonary lymphangiectasia with prenatal findings of hydrops, chylothorax and postnatal severe pulmonary hypertension.

A novel mouse model of PMS2 founder mutation that causes mismatch repair defect due to aberrant splicing.

Hereditary non-polyposis colorectal cancer, now known as Lynch syndrome (LS) is one of the most common cancer predisposition syndromes and is caused by germline pathogenic variants (GPVs) in DNA mismatch repair (MMR) genes. A common founder GPV in PMS2 in the Canadian Inuit population, NM_000535.5: c.2002A>G, leads to a benign missense (p.I668V) but also acts as a de novo splice site that creates a 5 bp deletion resulting in a truncated protein (p.I668*). Individuals homozygous for this GPV are predisposed to atypical constitutional MMR deficiency with a delayed onset of first primary malignancy. We have generated mice with an equivalent germline mutation (Pms2c.1993A>G) and demonstrate that it results in a splicing defect similar to those observed in humans. Homozygous mutant mice are viable like the Pms2 null mice. However, unlike the Pms2 null mice, these mutant mice are fertile, like humans homozygous for this variant. Furthermore, these mice exhibit a significant increase in microsatellite instability and intestinal adenomas on an Apc mutant background. Rectification of the splicing defect in human and murine fibroblasts using antisense morpholinos suggests that this novel mouse model can be valuable in evaluating the efficacy aimed at targeting the splicing defect in PMS2 that is highly prevalent among the Canadian Inuits.

Erythema multiforme-like eruption associated with plant-induced allergic contact dermatitis in a pediatric patient: A case report.

An 11-year-old boy presented to the emergency department 5 days after playing in the forest. His initial eruption, consistent with allergic contact dermatitis to poison ivy, progressed into target lesions involving his extremities, palms, upper trunk, and face, consistent with an erythema multiforme-like eruption. This report details the case and reviews the literature concerning this atypical and potentially underreported complication of plant-induced allergic contact dermatitis.

Routine Surveillance Catheterization is Useful in Guiding Management of Stable Fontan Patients.

We developed a Fontan surveillance catheterization protocol as part of routine assessment of stable patients 10 years after Fontan completion. The surveillance catherization includes hemodynamic assessment with inhaled nitric oxide, angiography, liver biopsy, and transcatheter intervention if indicated. We aimed to describe hemodynamic and liver biopsy findings, response to pulmonary vasoreactivity testing, rates of transcatheter intervention, and changes in medical therapy following surveillance catheterization in stable Fontan patients. A single-center retrospective review of Fontan patients undergoing surveillance catheterization between November 2014 and May 2019 was performed. Liver biopsies were independently scored by two pathologists. Sixty-three patients underwent surveillance catheterization (mean age 14.6 ± 3.0 years). The mean Fontan pressure was 11.8 ± 2.1 mmHg. The mean cardiac index was 2.9 ± 0.6 L/min/m2. In the 51 patients who underwent pulmonary vasoreactivity testing, there was a significant decrease in median pulmonary vascular resistance (1.8 [range 0.8-4.1] vs 1.4 [range 0.7-3.0] Wood units × m2; p < 0.001). The mean cardiac index increased (3.0 ± 0.6 vs 3.2 ± 0.7 L/min/m2, p = 0.009). The Fontan pressure did not change significantly. Fifty-seven patients underwent liver biopsy, and all but one showed fibrosis. Nineteen patients (33.3%) demonstrated bridging fibrosis or cirrhosis. Twenty-five patients underwent 34 transcatheter interventions. Pulmonary artery or Fontan stent placement was performed in 19 patients. Phosphodiesterase type 5 inhibitors were initiated in nine patients following surveillance catheterization. Routine surveillance catheterization with liver biopsy in adolescent Fontan patients reveals information that can guide interventional and medical management. Further long-term follow-up and assessment are indicated to assess the benefit of these interventions.

Crystallization and preliminary X-ray diffraction analysis of the middle domain of Paip1.

The poly(A)-binding protein (PABP) simultaneously interacts with the poly(A) tail of mRNAs and the scaffolding protein eIF4G to mediate mRNA circularization, resulting in stimulation of protein translation. PABP is regulated by the PABP-interacting protein Paip1. Paip1 is thought to act as a translational activator in 5' cap-dependent translation by interacting with PABP and the initiation factors eIF4A and eIF3. Here, the crystallization and preliminary diffraction analysis of the middle domain of Paip1 (Paip1M), which produces crystals that diffract to a resolution of 2.2 A, are presented.