BRAF V600E is associated with higher incidence of second cancers in adults with Langerhans cell histiocytosis.

In this retrospective study, BRAF mutation status did not correlate with disease extent or (event-free) survival in 156 adults with Langerhans cell histiocytosis. BRAFV600E was associated with an increased incidence of second malignancies, often comprising hematological cancers, which may be clonally related.

International expert consensus recommendations for the diagnosis and treatment of Langerhans cell histiocytosis in adults.

Langerhans cell histiocytosis (LCH) can affect children and adults with a wide variety of clinical manifestations, including unifocal, single-system multifocal, single-system pulmonary (smoking-associated), or multisystem disease. The existing paradigms in the management of LCH in adults are mostly derived from the pediatric literature. Over the last decade, the discovery of clonality and MAPK-ERK pathway mutations in most cases led to the recognition of LCH as a hematopoietic neoplasm, opening the doors for treatment with targeted therapies. These advances have necessitated an update of the existing recommendations for the diagnosis and treatment of LCH in adults. This document presents consensus recommendations that resulted from the discussions at the annual Histiocyte Society meeting in 2019, encompassing clinical features, classification, diagnostic criteria, treatment algorithm, and response assessment for adults with LCH. The recommendations favor the use of 18F-Fluorodeoxyglucose positron emission tomography-based imaging for staging and response assessment in the majority of cases. Most adults with unifocal disease may be cured by local therapies, while the first-line treatment for single-system pulmonary LCH remains smoking cessation. Among patients not amenable or unresponsive to these treatments and/or have multifocal and multisystem disease, systemic treatments are recommended. Preferred systemic treatments in adults with LCH include cladribine or cytarabine, with the emerging role of targeted (BRAF and MEK inhibitor) therapies. Despite documented responses to treatments, many patients struggle with a high symptom burden from pain, fatigue, and mood disorders that should be acknowledged and managed appropriately.

Clinical characteristics, molecular aberrations, treatments, and outcomes of malignant histiocytosis.

Malignant histiocytosis (MH) is an extremely rare neoplasm of the macrophage-dendritic cell lineage. We report the clinical characteristics, molecular aberrations, treatments, and outcomes of patients with MH seen at two referral centers from January 2000 to May 2023. We identified 43 patients with MH, of which 26 had histiocytic sarcoma (MH-H), 9 interdigitating dendritic cell sarcoma (MH-IDC), and 8 Langerhans cell sarcoma (MH-LC). The median age at diagnosis was 61 years (range, 3-83). Thirty-three patients (77%) had multifocal disease, while 10 had unifocal involvement. Tumor specimens from 22 patients (51%) underwent targeted next generation sequencing, and 19 of 22 (86%) had at least one pathogenic mutation, including mutations in MAPK pathway genes (73%). The median overall survival (OS) among the entire cohort was 16 months (95% CI: 8-50). The outcomes of those with multifocal disease were significantly shorter than their unifocal counterpart: median OS of 10 months versus 50 months (p = .07). Patients with risk organ involvement (bone marrow, spleen, or liver) had significantly inferior outcomes. Chemotherapy and surgery were the most common first-line treatments for multifocal and unifocal disease, respectively. While the outcome for patients with multifocal disease was poor, there was a subset of patients who had durable responses to treatment. Our study highlights that MH has heterogeneous clinical presentation, frequent oncogenic mutations, and prognosis, which is strongly tied to disease extent and type of organ involvement.

How Effective Is Phage Therapy for Prosthetic Joint Infections? A Preliminary Systematic Review and Proportional Meta-Analysis of Early Outcomes.

Background and Objectives: Despite the promise of phage therapy (PT), its efficacy in prosthetic joint infection (PJI) management is unknown. Much of the current literature is largely limited to case reports and series. Materials and Methods: In order to help inform power calculations for future clinical trials and comparative analyses, we performed a systematic review and proportional meta-analysis of early PT outcomes to provide a preliminary assessment of early phage therapy treatment outcomes for cases of PJI. Results: In a search of available literature across MEDLINE (Ovid, Wolters Kluwer, Alphen aan den Rijn, The Netherlands), Embase (Elsevier, Amsterdam, The Netherlands), the Web of Science Core Collection (Clarivate, London, UK), and Cochrane Central (Wiley, Hoboken, NJ, USA) up to 23 September 2023, we identified 37 patients with PJIs receiving adjunctive PT. Patients most frequently reported Staphylococcal species infection (95%) and intraarticular phage delivery (73%). Phage cocktail (65%) and antibiotic co-administration (97%) were common. A random-effects proportional meta-analysis suggested infection remission in 78% of patients (95% CI: 39%, 95%) (I2 = 55%, p = 0.08) and 83% with a minimum 12-month follow-up (95% CI: 53%, 95%) (I2 = 26%, p = 0.26). Conclusions: Our study provides a preliminary estimate of PT's efficacy in PJIs and informs future comparative studies.

Putative Protein Interactome of the Rhomboid Protease RHBDL4.

The physiological functions of the rhomboid-related protein 4 (RHBDL4) are emerging, but their molecular details remain unclear. Because increased expression of RHBDL4 has been clinically linked to poorer outcomes in cancer patients, this association urgently demands a better understanding of RHBDL4. To elucidate the molecular interactions and pathways that RHBDL4 may be involved in, we conducted proximity-dependent biotin identification (BioID) assays. Our analyses corroborated several of the expected protein interactors such as the transitional endoplasmic reticulum (ER) ATPase VCP/p97 (TERA), but they also described novel putative interactors including IRS4, PGAM5, and GORS2. Using proximity-ligation assays, we validated VCP/p97, COPB, and VRK2 as proteins that are in proximity to RHBDL4. Overall, our results support the emerging functions of RHBDL4 in ER quality control and also point toward putative RHBDL4 functions in protein membrane insertion and membrane organization and trafficking.

Malignant Histiocytosis Comprises a Phenotypic Spectrum That Parallels the Lineage Differentiation of Monocytes, Macrophages, Dendritic Cells, and Langerhans Cells.

Malignant histiocytoses (MHs), or the 'M group' of the Histiocyte Society classification, are characterized by neoplastic histiocytes with large pleomorphic nuclei. MH encompasses the diagnoses of histiocytic sarcoma, interdigitating dendritic cell sarcoma, and Langerhans cell sarcoma. We aimed to define the phenotypic spectrum of MH and examine the genotypic features across this spectrum. Using immunohistochemistry, we arranged the 22 cases into 4 subtypes that correspond to the lines of differentiation from monocytic and dendritic cell precursors as follows: (1) macrophage (n = 5): CD68+, CD163+, CD14+, and Factor 13a+; (2) monocyte-macrophage (n = 5): CD68+, CD163+, CD14+, S100+, and OCT2+; (3) dendritic cell (n = 6): CD68+, CD11c+, S100+, lysozyme+, ZBTB46+, and CD1a/langerin < 5%; and (4) Langerhans cell (n = 6): CD68+, CD11c+, S100+, ZBTB46+, CD1a+, and langerin+. The phenotypic subtypes align with those seen in low-grade histiocytic neoplasms as follows: MH-macrophage type correlates with Erdheim-Chester disease phenotype; MH-monocyte-macrophage type with Rosai-Dorfman disease phenotype, and MH-Langerhans cell type with Langerhans cell histiocytosis. Activating mutations in MAPK-pathway genes were identified in 80% of MH cases; 29% had mutations in the PI3k-AKT-mTOR pathway and 59% had mutations in epigenetic modulating genes. Strong expression of cyclin D1 was present in all cases, whereas p-ERK and p-AKT were not uniformly expressed. Eight of 22 (36%) MH cases were proven to be clonally related to a prior B-cell lymphoma. Defining the phenotypic spectrum of MH provides a guide to diagnosis and allows further exploration into the potential biological and clinical significance.

Ophthalmologic Involvement in Adults with Histiocytic Disorders: Clinical Presentation and Treatment Outcomes.

PURPOSE: To evaluate the clinical presentation, treatment, and outcomes in adult patients with histiocytic disorders with ocular, orbital, optic nerve, or cavernous sinus involvement. DESIGN: Observational, retrospective chart review. PARTICIPANTS: Adult patients (age ≥ 18 years) at Mayo Clinic from January 1, 1996, to July 1, 2021, with histiocytic disorders. Inclusion criteria were (1) histiocytic disorder by biopsy and appropriate clinical phenotype; (2) available medical records; and (3) ocular, orbital, optic nerve, or cavernous sinus involvement. METHODS: Retrospective chart review. MAIN OUTCOME MEASURES: Response to therapy, measured in clinical and radiographic impact. RESULTS: Thirty-two patients were identified: 7 with Langerhans cell histiocytosis (LCH); 15 with Erdheim-Chester disease (ECD); 1 with mixed LCH/ECD phenotype; 8 with Rosai-Dorfman disease (RDD); and 1 with mixed RDD/ECD phenotype. Ophthalmologic involvement was part of the initial presentation in 69% of patients (22/32). Eyelid edema (13/32, 41%) and proptosis (12/32, 38%) were the most frequent presentations. Isolated orbital or cavernous sinus involvement was present in 3 of 7 patients with LCH and 1 of 8 patients with RDD. Optic nerve sheath involvement was present in 2 of 7 LCH patients, 14 of 15 ECD patients, and 1 RDD/ECD patient. Diffuse (> 75%) orbital involvement was seen in 12 of 15 ECD patients and 1 of 7 LCH patients. Ocular involvement was seen in 1 of 15 ECD patients, 6 of 8 RDD patients, and 1 of 1 mixed RDD/ECD patient. The cavernous sinuses were involved in 1 of 7 LCH patients, 5 of 15 ECD patients, and both mixed phenotype patients. Visual acuity was affected in 14 patients (14/24, 58%) with a median logarithm of the minimum angle of resolution visual acuity of 0.1 (range, -0.12 to 3). BRAF V600E mutations were found in 75% (3/4) of LCH patients and 91% (10/11) of ECD patients. Patients received a variety of treatment, and response was variable across disease types. CONCLUSIONS: Orbital involvement was more commonly seen in LCH and ECD, whereas ocular involvement was more common in RDD. Visual acuity may be impacted from ocular involvement or compression of the optic nerve with diffuse orbital involvement.

Sorghum bicolor SbHSP110 has an elongated shape and is able of protecting against aggregation and replacing human HSPH1/HSP110 in refolding and disaggregation assays.

Perturbations in the native structure, often caused by stressing cellular conditions, not only impair protein function but also lead to the formation of aggregates, which can accumulate in the cell leading to harmful effects. Some organisms, such as plants, express the molecular chaperone HSP100 (homologous to HSP104 from yeast), which has the remarkable capacity to disaggregate and reactivate proteins. Recently, studies with animal cells, which lack a canonical HSP100, have identified the involvement of a distinct system composed of HSP70/HSP40 that needs the assistance of HSP110 to efficiently perform protein breakdown. As sessile plants experience stressful conditions more severe than those experienced by animals, we asked whether a plant HSP110 could also play a role in collaborating with HSP70/HSP40 in a system that increases the efficiency of disaggregation. Thus, the gene for a putative HSP110 from the cereal Sorghum bicolor was cloned and the protein, named SbHSP110, purified. For comparison purposes, human HsHSP110 (HSPH1/HSP105) was also purified and investigated in parallel. First, a combination of spectroscopic and hydrodynamic techniques was used for the characterization of the conformation and stability of recombinant SbHSP110, which was produced folded. Second, small-angle X-ray scattering and combined predictors of protein structure indicated that SbHSP110 and HsHSP110 have similar conformations. Then, the chaperone activities, which included protection against aggregation, refolding, and reactivation, were investigated, showing that SbHSP110 and HsHSP110 have similar functional activities. Altogether, the results add to the structure/function relationship study of HSP110s and support the hypothesis that plants have multiple strategies to act upon the reactivation of protein aggregates.

Safety and Efficacy of CT-Guided Percutaneous Biopsy of Suspicious Subcentimeter Pelvic and Retroperitoneal Lymph Nodes Detected by 11C-Choline PET in Patients With Prostate Cancer.

BACKGROUND. In patients with prostate cancer, PET using targeted radiotracers can identify increased activity in small morphologically normal lymph nodes, facilitating earlier detection of metastatic disease. OBJECTIVE. The purpose of this article was to assess the efficacy and safety of CT-guided biopsy of suspicious pelvic and retroperitoneal lymph nodes measuring smaller than 1 cm detected by 11C-choline PET in patients with prostate cancer, with comparison with nodes measuring 1 cm or larger. METHODS. This retrospective study included patients with prostate cancer who underwent CT-guided percutaneous biopsy of suspicious pelvic or retroperitoneal lymph nodes detected by 11C-choline PET/CT or PET/MRI (performed because of a rising or elevated PSA level or known recurrent or metastatic disease) between June 1, 2012, and March 20, 2020. Patient, lymph node, and procedural characteristics, as well as biopsy outcomes and complications, were recorded. Biopsies of lymph nodes measuring smaller than 1 cm and of lymph nodes measuring 1 cm and larger were compared. RESULTS. A total of 269 patients (mean age, 68.7 ± 6.8 [SD] years) were included. A total of 156 patients underwent biopsy of lymph nodes measuring smaller than 1 cm (range, 3-9 mm); 113 patients underwent biopsy of lymph nodes measuring 1 cm or larger (range, 10-35 mm). Lymph nodes smaller than 1 cm and lymph nodes 1 cm and larger showed no significant difference in diagnostic yield (89.7% vs 92.9%; p = .40). Diagnostic yield was not significantly different between nodes smaller than 1 cm and nodes 1 cm and larger for any individual anatomic location within the pelvis or retroperitoneum (all p > .05). Malignant yield was lower for nodes smaller than 1 cm than for nodes 1 cm and larger (44.9% vs 63.7%; p = .003). The single biopsied 3-mm node had a nondiagnostic specimen. Diagnostic yield and malignant yield were 100.0% and 40.0%, respectively, for 4-mm nodes, and 95.5% and 45.5%, respectively, for 5-mm nodes. Patients with nodes smaller than 1 cm and nodes 1 cm and larger showed no significant difference in minor (12.8% vs 7.1%; p = .16) or major (0.6% vs 2.7%; p = .31) complication rate. CONCLUSION. The findings support the safety and efficacy of CT-guided biopsy of suspicious subcentimeter pelvic and retroperitoneal lymph nodes detected on 11C-choline PET in patients with prostate cancer. CLINICAL IMPACT. Earlier diagnosis of metastatic lymphadenopathy will impact prognostic assessment and management decisions in patients with recurrent prostate cancer.

Neurological Manifestations of Histiocytic Disorders.

PURPOSE OF REVIEW: Histiocytic disorders, including Erdheim-Chester disease (ECD), Langerhans cell histiocytosis (LCH), and Rosai-Dorfman disease (RDD), are rare neoplasms that may present with a spectrum of neurologic involvement. Diagnostic delay is common due to heterogeneity in presentation and challenging pathology. RECENT FINDINGS: Recent advances in the treatment of these diseases targeted towards mutations in the MAP kinase pathway have led to an improved prognosis in these patients with neurologic involvement. It is critical for clinicians to have a high index of suspicion to allow for early targeted treatment and optimize neurologic outcomes. A systematic approach to diagnosis is presented in this article to allow for accurate diagnosis of these rare diseases.

Impact of premorbid oral anticoagulant use on survival in patients with traumatic intracranial hemorrhage.

OBJECTIVE: Although oral anticoagulant use has been implicated in worse outcomes for patients with a traumatic brain injury (TBI), prior studies have mostly examined the use of vitamin K antagonists (VKAs). In an era of increasing use of direct oral anticoagulants (DOACs) in lieu of VKAs, the authors compared the survival outcomes of TBI patients on different types of premorbid anticoagulation medications with those of patients not on anticoagulation. METHODS: The authors retrospectively reviewed the records of 1186 adult patients who presented at a level I trauma center with an intracranial hemorrhage after blunt trauma between 2016 and 2022. Patient demographics; comorbidities; and pre-, peri-, and postinjury characteristics were compared based on premorbid anticoagulation use. Multivariable Cox proportional hazards regression modeling of mortality was performed to adjust for risk factors that met a significance threshold of p < 0.1 on bivariate analysis. RESULTS: Of 1186 patients with a traumatic intracranial hemorrhage, 49 (4.1%) were taking DOACs and 53 (4.5%) used VKAs at the time of injury. Patients using oral anticoagulants were more likely to be older (p < 0.001), to have a higher Charlson Comorbidity Index (p < 0.001), and to present with a higher Glasgow Coma Scale (GCS) score (p < 0.001) and lower Injury Severity Score (ISS; p < 0.001) than those on no anticoagulation. Patients using VKAs were more likely to undergo reversal than patients using DOACs (53% vs 31%, p < 0.001). Cox proportional hazards regression demonstrated significantly increased hazard ratios (HRs) for VKA use (HR 2.204, p = 0.003) and DOAC use (HR 1.973, p = 0.007). Increasing age (HR 1.040, p < 0.001), ISS (HR 1.017, p = 0.01), and Marshall score (HR 1.186, p < 0.001) were associated with an increased risk of death. A higher GCS score on admission was associated with a decreased risk of death (HR 0.912, p < 0.001). CONCLUSIONS: Patients with a traumatic intracranial injury who were on oral anticoagulant therapy before injury demonstrated higher mortality rates than patients who were not on oral anticoagulation after adjusting for age, comorbid conditions, and injury presentation.

Outcomes of Adolescent T-condylar Fractures: Kids Do Not Always Make You Look Good.

BACKGROUND: Optimal treatment for pediatric and adolescent T-condylar fractures remains poorly understood. We sought to assess how functional outcomes and range of motion (ROM) after surgical fixation of T-condylar fractures are affected by patient and surgical factors. METHODS: This is a retrospective cohort study of 52 patients with operatively treated T-condylar fractures at a single tertiary pediatric referral center between 2003 and 2021. All patients younger than 18 at the time of injury with a radiographically confirmed diagnosis were included. RESULTS: Fifty-two T-condylar fractures were included, with a mean patient age of 12.9 years (SD, 2.8). The cohort was 65% male. Nine (19%) fractures were open, 46% (24/52) were AO type C2, and 33% (17/52) occurred in skeletally mature individuals. The surgical approach was through olecranon osteotomy in 29% (15/52) of patients, and fixation included anatomically specific plates and screws in 42% (22/52) of patients. In our cohort, 46% (24/52) achieved good outcomes based on Jarvis ROM criteria and 42% (22/52) achieved good to excellent results based on Roberts functional criteria. The median loss of ROM was 58 degrees at 6 weeks, 20 degrees at 3 and 6 months, and 8 degrees at 1 year postoperatively. We observed a complication rate of 54% (28/52). Patients undergoing adult-type plate fixation had better postoperative range of motion at 6 weeks (ROM loss 52 vs. 80 degrees, P =0.03) and 3 months (10 vs. 35 degrees P =0.004) compared with pediatric-type fixation and trended towards better functional outcomes. We did not identify significant differences in functional outcome scores or complication rates with respect to surgical approach or skeletal maturity. CONCLUSIONS: Surgical fixation of pediatric and adolescent T-condylar fractures achieved a good to excellent functional outcome in only a minority of patients (46% Jarvis / 42% Roberts) with a high rate of postoperative complications (54%). Future work is needed to elucidate optimal treatment to minimize complications and achieve the best functional outcomes in these challenging fractures. LEVEL OF EVIDENCE: Level-IV.

Mimics of Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm with frequent multiorgan involvement. An accurate diagnosis of ECD requires the correlation of clinical features, histopathologic and radiologic findings. We describe a case series of patients with a referral diagnosis of ECD, whereby the diagnosis was changed to non-histiocytic diseases after comprehensive review at a tertiary care center. This accurate revision of the referral diagnosis of ECD enabled initiation of proper disease-directed therapy in a timely manner for these patients and avoided unnecessary exposure to systemic cytotoxic chemotherapy or targeted agents. Our study highlights the value of a multidisciplinary team of histiocytosis experts in confirming the diagnosis of ECD and also brings attention to other conditions to consider that can mimic ECD, including osteopoikilosis, tenosynovial giant cell tumour, IgG4-related disease, fibrous dysplasia and chronic recurrent multifocal osteomyelitis.

Impact of a Multidisciplinary Tumor Board on the Care of Patients with Histiocytic Disorders: The Histiocytosis Working Group experience.

INTRODUCTION: Histiocytic disorders pose significant diagnostic and management challenges for the clinicians due to diverse clinical manifestations and often non-specific histopathologic findings. Herein, we report the tumor board experience from the first-of-its-kind Histiocytosis Working Group (HWG). MATERIALS AND METHODS: The HWG was established in June 2017 and consists of experts from 10 subspecialties that discuss cases in a multidisciplinary format. We present the outcome of tumor board case discussions during the first 2 years since its inception (June 2017-June 2019). RESULTS: Forty cases with a suspected histiocytic disorder were reviewed at HWG during this time period. Average number of subspecialties involved in HWG case discussion was 5 (range, 2-9). Histiocytosis Working Group tumor board recommendations led to significant changes in the care of 24 (60%) patients. These included change in diagnosis (n = 11, 27%) and change in treatment (n = 13, 33%). CONCLUSION: Our report highlights the feasibility of a multidisciplinary tumor board and its impact on outcomes of patients with histiocytic disorders.

Association of Incidental Positron Emission Tomography Uptake in the Esophagus to Gastroesophageal Reflux Disease.

The Los Angeles (LA) classification is the most accurate means of assessing esophageal injury from caustic gastric acid with focused and greater concentrations in areas of erosive disease.1 However, data from animal models and patients have proposed that an initial diffuse inflammatory pathway contributes to injury in gastroesophageal reflux disease (GERD) mediated by interleukin (IL) 8, IL1ß,2,3 and hypoxia-inducible factors.4,5 These observations demonstrate a lymphocyte predominant inflammatory process over course of 1-2 weeks associated with basal zone hyperplasia and dilation of intercellular spaces.6 In cultured human esophageal epithelial cells and patients, it is further suggested that acid causes this chronic inflammatory reaction.

Sustained, complete response to pexidartinib in a patient with CSF1R-mutated Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a histiocytic neoplasm that predominantly harbors mitogen-activated protein kinase (MAPK) pathway variants. MAPK inhibitors typically are effective treatments, but mutations outside the MAPK pathway, such as CSF1R variants, may cause refractory ECD. We describe a patient with a novel somatic mutation in CSF1R (CSF1RR549_E554delinsQ ) that resulted in refractory ECD affecting the central nervous system. Cell model studies, RNA sequencing analysis, and in silico protein modeling suggested that she had a gain-of-function mutation occurring in a region critical for autoinhibition. The patient was treated with pexidartinib, a CSF1R inhibitor, and has had a complete clinical and metabolic response lasting more than 1.5 years to date. To our knowledge, this is the first report to describe successful treatment of a patient with ECD by using an agent that specifically targets CSF1R. This case also highlights the critical role of individualized molecular profiling to identify novel therapeutic targets in ECD.

Organizational characteristics of Brain Injury Clubhouse Model programs.

OBJECTIVE: We provide an overview of the Clubhouse Model and the history and development of Brain Injury Clubhouses. We describe organizational-level characteristics associated with eight Brain Injury Clubhouses to address gaps in the literature and inform future studies or program development. METHODS: A electronic survey, the Clubhouse Profile Questionnaire (CPQ) was tailored for Brain Injury Clubhouses. The CPQ gathers program-level data that can be used to identify active ingredients of Clubhouses, understand best practices, examine, and evaluate program characteristics. The brain injury version of the CPQ was administered to a sample of eight Clubhouses affiliated with the International Brain Injury Clubhouse Association as part of a project designed to gather data on Clubhouse program characteristics and describe sociodemographic characteristics of people served by Brain Injury Clubhouses. RESULTS: CPQ data from eight Brain Injury Clubhouses was analyzed. Brain Injury Clubhouse programs in this sample served approximately 17 members per day. There was wide variability in the size, funding and funding mechanisms, and length of operation of Brain Injury Clubhouses in this study. CONCLUSIONS: Findings suggest that Brain Injury Clubhouses offer a wide range of services and supports. Additional research on the impact of Brain Injury Clubhouses is needed.

The J Domain of Sacsin Disrupts Intermediate Filament Assembly.

Autosomal Recessive Spastic Ataxia of the Charlevoix Saguenay (ARSACS) is caused by mutation in the SACS gene resulting in loss of function of the protein sacsin. A key feature is the formation of abnormal bundles of neurofilaments (NF) in neurons and vimentin intermediate filaments (IF) in cultured fibroblasts, suggesting a role of sacsin in IF homeostasis. Sacsin contains a J domain (SacsJ) homologous to Hsp40, that can interact with Hsp70 chaperones. The SacsJ domain resolved NF bundles in cultured Sacs-/- neurons. Having studied the mechanism using NF assembled in vitro from purified NF proteins, we report that the SacsJ domain interacts with NF proteins to disassemble NFL filaments, and to inhibit their initial assembly. A cell-penetrating peptide derived from this domain, SacsJ-myc-TAT was efficient in disassembling NF bundles in cultured Sacs-/- motor neurons, restoring the NF network; however, there was some loss of vimentin IF and NF in cultured Sacs+/+ fibroblasts and motor neurons, respectively. These results suggest that sacsin through its SacsJ domain is a key regulator of NF and vimentin IF networks in cells.

How We Do It: A Multidisciplinary Approach to 177Lu DOTATATE Peptide Receptor Radionuclide Therapy.

Lutetium 177 (177Lu) DOTA-0-Tyr3-Octreotate (DOTATATE) peptide receptor radionuclide therapy (PRRT) is an effective treatment for advanced gastroenteropancreatic neuroendocrine tumors. This review presents a clinical practice workflow that has been successful since 177Lu DOTATATE PRRT was approved by the U.S. Food and Drug Administration. The workflow relies heavily on the input of a multidisciplinary team and involves a nuclear medicine consultation service, tumor board, and specific preparations in advance of therapy and day-of-therapy procedures. A systematic checklist designed to ensure appropriate selection of treatment candidates and identification of any concerns to address to safely administer PRRT is provided. All patients were evaluated with gallium 68 DOTATATE PET/CT, and in cases of high-grade tumors, they were also evaluated with fluorine 18 fluorodeoxyglucose PET/CT, with imaging findings reviewed as part of the systematic checklist before PRRT. Adverse effects are discussed and imaging follow-up regimens are reviewed, including alternative diagnostic contrast materials. Approaches to multiple challenging patient scenarios are illustrated through case examples. Finally, alternative theranostic radionuclides and treatment strategies are discussed.

BAG3P215L/KO Mice as a Model of BAG3P209L Myofibrillar Myopathy.

BCL-2-associated athanogene 3 (BAG3) is a co-chaperone to heat shock proteins important in degrading misfolded proteins through chaperone-assisted selective autophagy. The recurrent dominant BAG3-P209L mutation results in a severe childhood-onset myofibrillar myopathy (MFM) associated with progressive muscle weakness, cardiomyopathy, and respiratory failure. Because a homozygous knock-in (KI) strain for the mP215L mutation homologous to the human P209L mutation did not have a gross phenotype, compound heterozygote knockout (KO) and KI mP215L mice were generated to establish whether further reduction in BAG3 expression would lead to a phenotype. The KI/KO mice have a significant decrease in voluntary movement compared with wild-type and KI/KI mice in the open field starting at 7 months. The KI/KI and KI/KO mice both have significantly smaller muscle fiber cross-sectional area. However, only the KI/KO mice have clear skeletal muscle histologic changes in MFM. As in patient muscle, there are increased levels of BAG3-interacting proteins, such as p62, heat shock protein B8, and αB-crystallin. The KI/KO mP215L strain is the first murine model of BAG3 myopathy that resembles the human skeletal muscle pathologic features. The results support the hypothesis that the pathologic development of MFM requires a significant decrease in BAG3 protein level and not only a gain of function caused by the dominant missense mutation.