3D Specimen Scanning and Mapping in Musculoskeletal Oncology: A Feasibility Study.

BACKGROUND: Surgical resection is the primary treatment for bone and soft tissue tumors. Negative margin status is a key factor in prognosis. Given the three-dimensional (3D) anatomic complexity of musculoskeletal tumor specimens, communication of margin results between surgeons and pathologists is challenging. We sought to perform ex vivo 3D scanning of musculoskeletal oncology specimens to enhance communication between surgeons and pathologists. METHODS: Immediately after surgical resection, 3D scanning of the fresh specimen is performed prior to frozen section analysis. During pathologic grossing, whether frozen or permanent, margin sampling sites are annotated on the virtual 3D model using computer-aided design (CAD) software. RESULTS: 3D scanning was performed in seven cases (six soft tissue, one bone), with specimen mapping on six cases. Intraoperative 3D scanning and mapping was performed in one case in which the location of margin sampling was shown virtually in real-time to the operating surgeon to help achieve a negative margin. In six cases, the 3D model was used to communicate final permanent section analysis. Soft tissue, cartilage, and bone (including lytic lesions within bone) showed acceptable resolution. CONCLUSIONS: Virtual 3D scanning and specimen mapping is feasible and may allow for enhanced documentation and communication. This protocol provides useful information for anatomically complex musculoskeletal tumor specimens. Future studies will evaluate the effect of the protocol on positive margin rates, likelihood that a re-resection contains additional malignancy, and exploration of targeted adjuvant radiation protocols using a patient-specific 3D specimen map.

Augmented-Reality Surgery to Guide Head and Neck Cancer Re-resection: A Feasibility and Accuracy Study.

BACKGROUND: Given the complex three-dimensional (3D) anatomy of head and neck cancer specimens, head and neck surgeons often have difficulty relocating the site of an initial positive margin to perform re-resection. This cadaveric study aimed to determine the feasibility and accuracy of augmented reality surgery to guide head and neck cancer re-resections. METHODS: This study investigated three cadaveric specimens. The head and neck resection specimen was 3D scanned and exported to the HoloLens augmented reality environment. The surgeon manually aligned the 3D specimen hologram into the resection bed. Accuracy of manual alignment and time intervals throughout the protocol were recorded. RESULTS: The 20 head and neck cancer resections performed in this study included 13 cutaneous and 7 oral cavity resections. The mean relocation error was 4 mm (range, 1-15 mm) with a standard deviation of 3.9 mm. The mean overall protocol time, from the start of 3D scanning to alignment into the resection bed, was 25.3 ± 8.9 min (range, 13.2-43.2 min). Relocation error did not differ significantly when stratified by greatest dimension of the specimen. The mean relocation error of complex oral cavity composite specimens (maxillectomy and mandibulectomy) differed significantly from that of all the other specimen types (10.7 vs 2.8; p < 0.01). CONCLUSIONS: This cadaveric study demonstrated the feasibility and accuracy of augmented reality to guide re-resection of initial positive margins in head and neck cancer surgery.

Impact of implantation time on early function of cardiac transplant.

BACKGROUND: Data on out-of-ice implantation ischemia in heart transplant are scarce. We examined implantation time's impact on allograft dysfunction. METHODS: We conducted a single-site retrospective review of all primary adult heart transplants from June 2012 to August 2019 for implantation warm ischemic time (WIT), defined as first atrial stitch to aortic crossclamp removal. Univariate regression was used to assess the relationship of perioperative variables to primary graft dysfunction (PGD) and to pulmonary artery pulsatility index (PAPi) at postoperative hour 24. A threshold of p < .10 was set for the inclusion of covariates in multivariate regression. Secondary analyses evaluated for consistency among alternative criteria for allograft dysfunction. A post hoc subgroup analysis examined WIT effect in prolonged total ischemia of 240 min or longer. RESULTS: Complete data were available for 201 patients. Baseline characteristics were similar between patients who did and did not have WIT documented. In univariate analysis, female gender, longer total ischemic time (TIT), longer bypass time, greater blood transfusions, and pretransplant intensive care unit (ICU) care were associated with PGD, whereas longer bypass time was associated with worse PAPi and pretransplant ICU care was associated with better PAPi. In multivariate analysis, longer bypass time predicted PGD, and worse PAPi and preoperative ICU admission predicted PGD and better PAPi. Results did not differ in secondary or subgroup analyses. CONCLUSIONS: This study is one of few examining the functional impact of cardiac implantation ischemia. Results suggest allograft implantation time alone may not impact postoperative graft function, which was driven by intraoperative bypass duration and by preoperative ICU care, instead.

Engineering approaches for RNA-based and cell-based osteoarthritis therapies.

Osteoarthritis (OA) is a chronic, debilitating disease that substantially impairs the quality of life of affected individuals. The underlying mechanisms of OA are diverse and are becoming increasingly understood at the systemic, tissue, cellular and gene levels. However, the pharmacological therapies available remain limited, owing to drug delivery barriers, and consist mainly of broadly immunosuppressive regimens, such as corticosteroids, that provide only short-term palliative benefits and do not alter disease progression. Engineered RNA-based and cell-based therapies developed with synthetic chemistry and biology tools provide promise for future OA treatments with durable, efficacious mechanisms of action that can specifically target the underlying drivers of pathology. This Review highlights emerging classes of RNA-based technologies that hold potential for OA therapies, including small interfering RNA for gene silencing, microRNA and anti-microRNA for multi-gene regulation, mRNA for gene supplementation, and RNA-guided gene-editing platforms such as CRISPR-Cas9. Various cell-engineering strategies are also examined that potentiate disease-dependent, spatiotemporally regulated production of therapeutic molecules, and a conceptual framework is presented for their application as OA treatments. In summary, this Review highlights modern genetic medicines that have been clinically approved for other diseases, in addition to emerging genome and cellular engineering approaches, with the goal of emphasizing their potential as transformative OA treatments.

A programmable arthritis-specific receptor for guided articular cartilage regenerative medicine.

Objective: Investigational cell therapies have been developed as disease-modifying agents for the treatment of osteoarthritis (OA), including those that inducibly respond to inflammatory factors driving OA progression. However, dysregulated inflammatory cascades do not specifically signify the presence of OA. Here, we deploy a synthetic receptor platform that regulates cell behaviors in an arthritis-specific fashion to confine transgene expression to sites characterized by cartilage degeneration. Methods: An scFv specific for type II collagen (CII) was used to produce a synthetic Notch (synNotch) receptor that enables "CII-synNotch" mesenchymal stromal cells (MSCs) to recognize CII fibers exposed in damaged cartilage. Engineered cell activation by both CII-treated culture surfaces and on primary tissue samples was measured via inducible reporter transgene expression. TGFß3-expressing cells were assessed for cartilage anabolic gene expression via qRT-PCR. In a co-culture with CII-synNotch MSCs engineered to express IL-1Ra, ATDC5 chondrocytes were stimulated with IL-1α, and inflammatory responses of ATDC5s were profiled via qRT-PCR and an NF-κB reporter assay. Results: CII-synNotch MSCs are highly responsive to CII, displaying activation ranges over 40-fold in response to physiologic CII inputs. CII-synNotch cells exhibit the capacity to distinguish between healthy and damaged cartilage tissue and constrain transgene expression to regions of exposed CII fibers. Receptor-regulated TGFß3 expression resulted in upregulation of Acan and Col2a1 in MSCs, and inducible IL-1Ra expression by engineered CII-synNotch MSCs reduced pro-inflammatory gene expression in chondrocytes. Conclusion: This work demonstrates proof-of-concept that the synNotch platform guides MSCs for spatially regulated, disease-dependent delivery of OA-relevant biologic drugs.

Structural optimization of siRNA conjugates for albumin binding achieves effective MCL1-directed cancer therapy.

The high potential of siRNAs to silence oncogenic drivers remains largely untapped due to the challenges of tumor cell delivery. Here, divalent lipid-conjugated siRNAs are optimized for in situ binding to albumin to improve pharmacokinetics and tumor delivery. Systematic variation of the siRNA conjugate structure reveals that the location of the linker branching site dictates tendency toward albumin association versus self-assembly, while the lipid hydrophobicity and reversibility of albumin binding also contribute to siRNA intracellular delivery. The lead structure increases tumor siRNA accumulation 12-fold in orthotopic triple negative breast cancer (TNBC) tumors over the parent siRNA. This structure achieves approximately 80% silencing of the anti-apoptotic oncogene MCL1 and yields better survival outcomes in three TNBC models than an MCL-1 small molecule inhibitor. These studies provide new structure-function insights on siRNA-lipid conjugate structures that are intravenously injected, associate in situ with serum albumin, and improve pharmacokinetics and tumor treatment efficacy.

Utility of iliac crest tetracycline-labelled bone biopsy in osteoporosis and metabolic bone disease: An evaluation of 95 cases over a period of 25 years.

Background: Metabolic bone diseases (MBD) are typically diagnosed by non-invasive imaging and clinical biomarkers. However, imaging does not provide structural information, and biomarkers can be transiently affected by many systemic factors. Bone biopsy and pathologic evaluation is the gold standard for diagnosis of MBD, however, it is rarely utilized. We describe our technique for iliac crest tetracycline-labelled bone using a cannulated drill and assess the utility of bone biopsies to provide diagnostic and therapeutic guidance. Methods: In the 25-year period between March 1998 and January 2023, a total of 95 bone biopsies were performed on 94 patients for an osteological indication at Vanderbilt University Medical Center (VUMC). Patient demographics, bone biopsy indications, complications, diagnostic utility, and subsequent therapeutic guidance were retrospectively reviewed and analyzed. Results: The procedure had minimal complications and was well tolerated by patients. This technique provided good quality specimens for pathology, which helped establish a diagnosis and treatment change in most patients. Patients that had biopsy-guided treatment alterations showed significant increases in Dual-Energy X-ray Absorptiometry (DEXA) bone mineral density (BMD) scores post-biopsy and subsequent treatment. Conclusion: Despite scientific and technological progress in non-invasive diagnostic imaging, clinical biomarkers, and procedures for MBD, there remains a small but significant subset of patients who may benefit from inclusion of tetracycline-labelled bone biopsy into the diagnostic and therapeutic picture. Future prospective comparison studies are warranted. Mini abstract: Tetracycline-labelled bone biopsies are under-utilized. Biopsy led to a histological diagnosis and ensuing treatment alteration in most patients with significant increases in bone mineral density. The biopsy procedure used herein provided good specimens with low pain/adverse events. Bone biopsy remains a valuable tool in a small, though significant, subset of patients.

Nonviral In Vivo Delivery of CRISPR-Cas9 Using Protein-Agnostic, High-Loading Porous Silicon and Polymer Nanoparticles.

The complexity of CRISPR machinery is a challenge to its application for nonviral in vivo therapeutic gene editing. Here, we demonstrate that proteins, regardless of size or charge, efficiently load into porous silicon nanoparticles (PSiNPs). Optimizing the loading strategy yields formulations that are ultrahigh loading─>40% cargo by volume─and highly active. Further tuning of a polymeric coating on the loaded PSiNPs yields nanocomposites that achieve colloidal stability under cryopreservation, endosome escape, and gene editing efficiencies twice that of the commercial standard Lipofectamine CRISPRMAX. In a mouse model of arthritis, PSiNPs edit cells in both the cartilage and synovium of knee joints, and achieve 60% reduction in expression of the therapeutically relevant MMP13 gene. Administered intramuscularly, they are active over a broad dose range, with the highest tested dose yielding nearly 100% muscle fiber editing at the injection site. The nanocomposite PSiNPs are also amenable to systemic delivery. Administered intravenously in a model that mimics muscular dystrophy, they edit sites of inflamed muscle. Collectively, the results demonstrate that the PSiNP nanocomposites are a versatile system that can achieve high loading of diverse cargoes and can be applied for gene editing in both local and systemic delivery applications.

Structural Optimization of siRNA Conjugates for Albumin Binding Achieves Effective MCL1-Targeted Cancer Therapy.

The high potential for therapeutic application of siRNAs to silence traditionally undruggable oncogenic drivers remains largely untapped due to the challenges of tumor cell delivery. Here, siRNAs were optimized for in situ binding to albumin through C18 lipid modifications to improve pharmacokinetics and tumor delivery. Systematic variation of siRNA conjugates revealed a lead structure with divalent C18 lipids each linked through three repeats of hexaethylene glycol connected by phosphorothioate bonds. Importantly, we discovered that locating the branch site of the divalent lipid structure proximally (adjacent to the RNA) rather than at a more distal site (after the linker segment) promotes association with albumin, while minimizing self-assembly and lipoprotein association. Comparison to higher albumin affinity (diacid) lipid variants and siRNA directly conjugated to albumin underscored the importance of conjugate hydrophobicity and reversibility of albumin binding for siRNA delivery and bioactivity in tumors. The lead conjugate increased tumor siRNA accumulation 12-fold in orthotopic mouse models of triple negative breast cancer over the parent siRNA. When applied for silencing of the anti-apoptotic oncogene MCL-1, this structure achieved approximately 80% MCL1 silencing in orthotopic breast tumors. Furthermore, application of the lead conjugate structure to target MCL1 yielded better survival outcomes in three independent, orthotopic, triple negative breast cancer models than an MCL1 small molecule inhibitor. These studies provide new structure-function insights on optimally leveraging siRNA-lipid conjugate structures that associate in situ with plasma albumin for molecular-targeted cancer therapy.

Suppression of local inflammation via galectin-anchored indoleamine 2,3-dioxygenase.

The treatment of chronic inflammation with systemically administered anti-inflammatory treatments is associated with moderate-to-severe side effects, and the efficacy of locally administered drugs is short-lived. Here we show that inflammation can be locally suppressed by a fusion protein of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO) and galectin-3 (Gal3). Gal3 anchors IDO to tissue, limiting the diffusion of IDO-Gal3 away from the injection site. In rodent models of endotoxin-induced inflammation, psoriasis, periodontal disease and osteoarthritis, the fusion protein remained in the inflamed tissues and joints for about 1 week after injection, and the amelioration of local inflammation, disease progression and inflammatory pain in the animals were concomitant with homoeostatic preservation of the tissues and with the absence of global immune suppression. IDO-Gal3 may serve as an immunomodulatory enzyme for the control of focal inflammation in other inflammatory conditions.

Albumin-binding RNAi Conjugate for Carrier Free Treatment of Arthritis.

Osteoarthritis (OA) and rheumatoid arthritis (RA) are joint diseases that are associated with pain and lost quality of life. No disease modifying OA drugs are currently available. RA treatments are better established but are not always effective and can cause immune suppression. Here, an MMP13-selective siRNA conjugate was developed that, when delivered intravenously, docks onto endogenous albumin and promotes preferential accumulation in articular cartilage and synovia of OA and RA joints. MMP13 expression was diminished upon intravenous delivery of MMP13 siRNA conjugates, consequently decreasing multiple histological and molecular markers of disease severity, while also reducing clinical manifestations such as swelling (RA) and joint pressure sensitivity (RA and OA). Importantly, MMP13 silencing provided more comprehensive OA treatment efficacy than standard of care (steroids) or experimental MMP inhibitors. These data demonstrate the utility of albumin 'hitchhiking' for drug delivery to arthritic joints, and establish the therapeutic utility of systemically delivered anti-MMP13 siRNA conjugates in OA and RA. Editorial summary: Lipophilic siRNA conjugates optimized for albumin binding and "hitchhiking" can be leveraged to achieve preferential delivery to and gene silencing activity within arthritic joints. Chemical stabilization of the lipophilic siRNA enables intravenous siRNA delivery without lipid or polymer encapsulation. Using siRNA sequences targeting MMP13, a key driver of arthritis-related inflammation, albumin hitchhiking siRNA diminished MMP13, inflammation, and manifestations of osteoarthritis and rheumatoid arthritis at molecular, histological, and clinical levels, consistently outperforming clinical standards of care and small molecule MMP antagonists.

Beyond the Scalpel: Attracting and Nurturing Surgeon-Scientists in Plastic Surgery.

SUMMARY: With plastic surgery being at the forefront of innovation and discovery in multiple research disciplines, plastic surgery is poised for M.D./Ph.D. and research-focused M.D. trainees to be attracted to this field. Surprisingly, recent reports have shown that the number of surgeon-scientists pursuing research is on the decline, with these declines being even more pronounced within plastic surgery. It is essential that plastic surgery remains a leader in translational research by cultivating a group of individuals who have been trained in basic research and are thereby competitive to obtain extramural grant funding. To address this need, the authors review data elucidating why the research-oriented trainee may forego pursuing a career in plastic surgery. Although much of the existing literature is speculative, the authors identified the current number of M.D./Ph.D.s in plastic surgery using data obtained from the American Society of Plastic Surgeons and investigated number of grants in plastic surgery compared to other medical and surgical fields using the National Institutes of Health Research Portfolio Online Reporting Tools Expenditures and Results. The authors hypothesize that economic constraints and difficulty securing protected research time may be contributing to fewer trainees pursuing plastic surgery. The purpose of this article is (1) to discuss potential reasons deterring research-oriented trainees from pursuing careers as surgeon-scientists within plastic surgery; (2) to propose solutions that may attract more trainees interested in careers as surgeon-scientists to the field of plastic surgery; (3) to highlight the lack of quantitative data regarding surgeon-scientist training in plastic surgery; and (4) to propose and encourage future research avenues to help attract and nurture surgeon-scientists in plastic surgery.

The Paramedian Forehead Flap: A Retrospective Clinical Model for Understanding the Connection Between Supraorbital and Supratrochlear Nerve Pathology and Headaches.

Background: In the later stages of a paramedian forehead flap (PMFF) surgery, the supratrochlear (STN) and branches of the supraorbital nerve (SON) are transected during flap inset above the supraorbital rim. This can lead to either a nerve release if the compression point was previously distal to the transection point or a new nerve compression through neuroma or scar tissue formation. We inferred that PMFF could be a model for understanding the correlation between STN/SON pathology and migraines headaches (MH). We hypothesized that patients undergoing PMFF would experience either a change in severity or an onset of a new headache (HA) or MH. Methods: One hundred ninety-nine patients who underwent a PMFF at a tertiary medical centre were identified and contacted by phone. Patients were asked about the presence of MH or HA before and after the procedure. If a patient reported a perioperative history of MH/HA, their pre- and postoperative MH/HA characteristics were recorded. Results: Of the 199 patients contacted, 74 reported no perioperative HA/MH history and 14 reported a perioperative history of HA/MH. Of these 14 patients, 5 had stable HA/MH pre- and post-surgery, and 9 reported a change in HA/MH post-surgery. In this subset of 9 patients, 3 reported change in HA/MH quality post-surgery, 1 reported HA/MH resolution post-surgery, and 5 reported new onset HA/MH post-surgery. Conclusion: Sixty-four percent of patients with perioperative HA/MH experienced a change in headache quality following surgery. These results suggest a potential connection between SON and STN pathology and HA/MH pathophysiology; further work is warranted.

Historique: Dans les dernières phases de l'opération du lambeau frontal paramédian (LFPM), le nerf supratrochléaire (NST) et les rameaux du nerf supraorbital (NSO) sont sectionnés pour installer le lambeau au-dessus de l'arcade sourcilière. Cette intervention peut libérer le nerf si le point de compression se trouvait auparavant dans la partie distale de l'incision ou provoquer une nouvelle compression nerveuse par la formation d'un névrome ou de tissu cicatriciel. Les chercheurs ont présumé que le LFPM pouvait servir de modèle pour comprendre la corrélation entre la pathologie du NST ou du NSO et les migraines. Les chercheurs ont postulé que les patients qui se font greffer un LFPM présenteraient soit un changement de la gravité de leurs migraines ou de leurs céphalées ou de nouvelles migraines ou céphalées. Méthodologie: Les chercheurs ont communiqué par téléphone avec 191 patients qui se sont fait greffer un LFPM dans un centre de soins tertiaires. Ils leur ont demandé s'ils souffraient de migraines ou de céphalées avant et après l'intervention. Si le patient déclarait des antécédents périopératoires de migraines ou de céphalées, les chercheurs en consignaient les caractéristiques. Résultats: Des 199 patients, 74 n'ont déclaré aucun antécédent de migraines ou de céphalées, mais 14 ont signalé une histoire périopératoire de ces symptômes. De ces 14 patients, cinq présentaient une migraine ou une céphalée avant et après l'opération et neuf, un changement à ces manifestations. Dans ce sous-groupe de neuf patients, trois ont déclaré un changement de la qualité des migraines et des céphalées après l'opération, un en a signalé la résolution après l'opération et cinq, l'apparition après l'opération. Conclusion: Au total, 64% des patients ayant des migraines et des céphalées ont ressenti un changement à la qualité de leurs symptômes après l'opération. Ces résultats laissent croire à un lien potentiel entre la pathologie du NSO et du NST et la physiopathologie des migraines et des céphalées. D'autres travaux s'imposent sur le sujet.

Benign Neurofibroma/Schwannoma Hybrid Peripheral Nerve Sheath Tumor of the Ulnar Nerve Harboring a Metastatic Papillary Thyroid Carcinoma Deposit: A Case Report of Tumor-to-Tumor Metastasis.

A 74-year-old man with a medical history significant for papillary thyroid cancer (PTC) presented with a rapidly enlarging grape-sized mass in his right medial arm with paresthesia in the ulnar nerve distribution. Imaging was suspicious for a peripheral nerve sheath tumor (PNST), but an ultrasound-guided biopsy was equivocal. The mass was excised with final histopathology demonstrating a benign neurofibroma/schwannoma hybrid nerve sheath tumor (N/S HNST) harboring a metastatic PTC deposit, ultimately mimicking the rare glandular schwannoma subtype. Next-generation sequencing (NGS) of the lesion demonstrated somatic variants in BRAF and TERT (common in PTC) and NF2 (common in PNSTs). After excision, the patient's nerve symptoms improved. A postsurgical PET/CT scan also showed progression in the lungs/mediastinum. Due to the metastatic nature of his PTC, he was treated with 14 mg of Lenvima (lenvatinib) daily, and his PET/CT surveillance was performed at more frequent intervals. Tumor-to-tumor metastasis (TTM) is a rare occurrence. To our knowledge, this is the first case reported on PTC metastasizing into a benign (hybrid) PNST, which mimicked glandular schwannoma. Symptomatology, imaging characteristics, NGS, and histopathological characteristics that can decipher between different benign PNST subtypes (schwannoma, neurofibroma, glandular, hybrid, etc.), malignant PNSTs (MPNSTs), and TTM are described.

Reactive oxygen species-degradable polythioketal urethane foam dressings to promote porcine skin wound repair.

Porous, resorbable biomaterials can serve as temporary scaffolds that support cell infiltration, tissue formation, and remodeling of nonhealing skin wounds. Synthetic biomaterials are less expensive to manufacture than biologic dressings and can achieve a broader range of physiochemical properties, but opportunities remain to tailor these materials for ideal host immune and regenerative responses. Polyesters are a well-established class of synthetic biomaterials; however, acidic degradation products released by their hydrolysis can cause poorly controlled autocatalytic degradation. Here, we systemically explored reactive oxygen species (ROS)-degradable polythioketal (PTK) urethane (UR) foams with varied hydrophilicity for skin wound healing. The most hydrophilic PTK-UR variant, with seven ethylene glycol (EG7) repeats flanking each side of a thioketal bond, exhibited the highest ROS reactivity and promoted optimal tissue infiltration, extracellular matrix (ECM) deposition, and reepithelialization in porcine skin wounds. EG7 induced lower foreign body response, greater recruitment of regenerative immune cell populations, and resolution of type 1 inflammation compared to more hydrophobic PTK-UR scaffolds. Porcine wounds treated with EG7 PTK-UR foams had greater ECM production, vascularization, and resolution of proinflammatory immune cells compared to polyester UR foam-based NovoSorb Biodegradable Temporizing Matrix (BTM)-treated wounds and greater early vascular perfusion and similar wound resurfacing relative to clinical gold standard Integra Bilayer Wound Matrix (BWM). In a porcine ischemic flap excisional wound model, EG7 PTK-UR treatment led to higher wound healing scores driven by lower inflammation and higher reepithelialization compared to NovoSorb BTM. PTK-UR foams warrant further investigation as synthetic biomaterials for wound healing applications.

Hiding in plain sight: Gene panel and genetic markers reveal 26-year undiagnosed tumor-induced osteomalacia of the rib concurrently misdiagnosed as X-linked hypophosphatemia.

Tumor-induced osteomalacia (TIO), caused by phosphaturic mesenchymal tumors (PMTs), is a rare paraneoplastic syndrome characterized by frequent bone fractures, bone pain, muscle weakness, and affected gait. These tumors typically secrete high levels of Fibroblastic Growth Factor 23 (FGF23), a hormone which acts on the kidney to cause hypophosphatemia, ultimately impairing bone mineralization. In this case report, we present a 41-year-old female with FGF23-mediated hypophosphatemia with a 26-year delay in TIO diagnosis and a concurrent misdiagnosis of X-linked hypophosphatemic rickets (XLH). Given an absence of family history of hypophosphatemia, a 13-gene hypophosphatemia panel including XLH (PHEX gene) was performed and came back negative prompting a diagnostic search for a PMT causing TIO. A 68Ga-DOTATATE PET/CT scan revealed the presence of a 9th right rib lesion, for which she underwent rib resection. The patient's laboratory values (notably serum phosphorus, calcium, and vitamin D) normalized, with FGF23 decreasing immediately after surgery, and symptoms resolving over the next three months. Chromogenic in situ hybridization (CISH) and RNA-sequencing of the tumor were positive for FGF23 (CISH) and the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1), previously determined to be present in the majority of TIO-associated tumors. This case demonstrates the notion that rare and diagnostically challenging disorders like TIO can be undiagnosed and/or misdiagnosed for many years, even by experienced clinicians and routine lab testing. It also underscores the power of novel tools available to clinicians such as gene panels, CISH, and RNA sequencing, and their ability to characterize TIO and its related tumors in the context of several phenotypically similar diseases.

Characterization of physical, functional, and cognitive performance in 15 adults with hypophosphatasia.

OBJECTIVE: Given the small but growing body of literature related to physical functioning and the scarce data related to fine motor and cognitive functioning in adults with hypophosphatasia (HPP), our objective was to characterize physical, functional, and cognitive performance in adults with HPP. A future objective is to utilize this characterization to develop guidelines for evaluation by physical therapists (PT), occupational therapists (OT), and speech-language pathologists (SLP). METHOD: We evaluated physical, functional, and cognitive performance in 15 adults with HPP through standardized assessments of mobility, balance, fine motor control, activities of daily living, cognition, and self-reported measures of health-related quality of life, fatigue, depression, and anxiety. The median age at enrollment was 44 years (range 26-79 years). Among the participants, 11 (73%) were women. Five participants (33%) were on enzyme replacement therapy. RESULTS: Compared with the general population, HPP participants traveled shorter distances on the Six-Minute Walk Test (420 m (m) [SD: 132] vs 620 m [SD: 49], p < 0.00005), had slower gait on the 10-Meter Walk Test [HPP men (3.71 ft/s (f/s) [SD: 0.77] vs 4.70 f/s [SD: 0.14], p < 0.00005) and HPP women (3.39 f/s [SD: 0.67] vs 4.56 f/s [SD: 0.09], p < 0.00005)]. HPP participants had decreased upper extremity (UE) dexterity by Nine Hole Peg Test [right UE in HPP men (22.7 s (s) [SD: 2.3] vs 19.0 s [SD: 3.9], p = 0.03), left UE in HPP men (23.3 s [SD: 0.7] vs 19.8 s [SD: 3.7], p = 0.03), right UE in HPP women (19.8 s [SD: 2.0] vs 17.7 s [SD: 3.2], p = 0.01), and left UE in HPP women (21.1 s [SD: 2.5] vs 18.9 s[SD: 3.4], p = 0.02)], and some had abnormally slow bilateral UE reaction times via Dynavision (0.9 s [0.85,0.96], functional speed <1.15 s). On the Short Form-36 (SF36), HPP patients reported worse energy/fatigue (30.4 [SD 22.7] vs 52.2 [SD: 22.4], p = 0.0001), social functioning (54.5 [SD: 34.2] vs 78.8 [SD: 25.5], p = 0.0002), pain (46.1 [SD: 27.3] vs 70.8 [SD: 25.5], p = 0.0001), general health (36.8 [SD: 24.0] vs 57.0 [SD: 21.1], p = 0.0002), and health change i.e. perception of health improvement (32.1 [SD: 15.3] vs 59.1 [SD: 23.1], p < 0.00005) than the general population. Fatigue Severity Scale scores were well above the median for a healthy population (5.21 [SD: 1.8] vs 2.3 [SD: 1.21], p < 0.00005), indicating significant fatigue. HPP participants had significantly higher DASS scores for depression (8.5 [SD: 6.5] vs 5.0 [SD: 7.5], p = 0.02), anxiety (7.9 [SD: 6.7] vs 3.4 [SD: 5.1], p = 0.00009), and stress (14.7 [SD: 12.4] vs 8.1 [SD: 8.4], p = 0.0003) compared to the general population. CONCLUSION: Objective functional assessments demonstrated defects in physical functioning, including decreased ability to walk distances, slow gait speed, and diminished ability to repeatedly rise from a sitting position. In addition, participants self-reported significant limitations due to physical dysfunction. Decreased upper extremity dexterity may indicate problems with activities of daily living and delayed reaction times can have safety implications. Some patients with HPP have increased difficulties with depression, anxiety, and stress. PT, OT, and SLP specialists can aid in establishing baseline assessment of impairment and objective metrics for assessing efficacy of treatment.

Shape-Defined microPlates for the Sustained Intra-articular Release of Dexamethasone in the Management of Overload-Induced Osteoarthritis.

Osteoarthritis (OA) is treated with the intra-articular injection of steroids such as dexamethasone (DEX) to provide short-term pain management. However, DEX treatment suffers from rapid joint clearance. Here, 20 × 10 µm, shape-defined poly(d,l-lactide-co-glycolide)acid microPlates (µPLs) are created and intra-articularly deposited for the sustained release of DEX. Under confined conditions, DEX release is projected to persist for several months, with only ∼20% released in the first month. In a highly rigorous murine knee overload injury model (post-traumatic osteoarthritis), a single intra-articular injection of Cy5-µPLs is detected in the cartilage surface, infrapatellar fat pad/synovium, joint capsule, and posterior joint space up to 30 days. One intra-articular injection of DEX-µPL (1 mg kg-1) decreased the expression of interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, IL-6, and matrix metalloproteinase (MMP)-13 by approximately half compared to free DEX at 4 weeks post-treatment. DEX-µPL also reduced load-induced histological changes in the articular cartilage and synovial tissues relative to saline or free DEX. In sum, the µPLs provide sustained drug release along with the capability to precisely control particle geometry and mechanical properties, yielding long-lasting benefits in overload-induced OA. This work motivates further study and development of particles that provide combined pharmacological and mechanical benefits.