Anatomic Reversal of Shoulder Joint After Neck of Humerus Fracture.

We report on a singular case of a unique form of post-traumatic reversal of the humeral head after humeral neck fracture, in which the pattern of collapse resulted in the formation of a native reverse polarity shoulder. In essence, the humeral head became a socket, and the glenoid rounded to become a head with well-preserved shoulder function. To our knowledge, this is the first case of an acquired shoulder deformity that bears a remarkable functional similarity to a prosthetic reverse polarity shoulder replacement.

Orthogeriatric Care Following Hip Fracture: Improving Post-Operative Outcomes in an Aged Population.

INTRODUCTION: Hip fractures globally are associated with high levels of morbidity, mortality, and significant financial burden. This audit aimed to assess the impact of orthogeriatric liaison care on post-operative outcomes following surgical management of neck or femur fractures. METHODS: Here, 258 patients who underwent hip fracture surgery over 1-year were included. Data were collected as an audit following the transition to an orthogeriatric liaison care model, involving regular orthogeriatric review (thrice weekly ward rounds, daily board rounds), superseding orthogeriatric review as requested. The audit is meant to assess the development of post-operative non-surgical site infection (NSSI) and mortality and duration of inpatient stay. Outcomes were compared to previous data from our hospital site in 2015/2016. RESULTS: Patients with severe cognitive impairment and systemic disease (Abbreviated Mental Test Score (AMTS) < 7 and American Society of Anesthesiologists (ASA) grade ≥ 3) showed significantly elevated NSSI risk, consistent across the study periods. Both periods demonstrated an increased risk of NSSI associated with admission from nursing homes. Despite the 2021/2022 cohort being notably older, NSSI risk decreased from 40.6% to 37.2% after implementing the orthogeriatric care model. NSSI risk was notably reduced for severe cognitive impairment (51.6% vs. 71%), and the p-value was 0.025. Average hospital stay decreased post-intervention (2.4 days shorter), with a notable reduction for NSSI patients (3.4 days shorter). Overall mortality rates were similar, although mortality due to infection was significantly reduced in 2021/2022 (44.4% vs. 93.3%), and the p-value was 0.003. CONCLUSION: The orthogeriatric liaison care model significantly decreased NSSI only in individuals with severe cognitive impairment and infection-associated mortality. This highlights the integral role of orthogeriatricians in the care of elderly hip fracture patients.

A Self-Assembled 3D Model Demonstrates How Stiffness Educates Tumor Cell Phenotypes and Therapy Resistance in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense and stiff extracellular matrix (ECM) associated with tumor progression and therapy resistance. To further the understanding of how stiffening of the tumor microenvironment (TME) contributes to aggressiveness, a three-dimensional (3D) self-assembling hydrogel disease model is developed based on peptide amphiphiles (PAs, PA-E3Y) designed to tailor stiffness. The model displays nanofibrous architectures reminiscent of native TME and enables the study of the invasive behavior of PDAC cells. Enhanced tuneability of stiffness is demonstrated by interacting thermally annealed aqueous solutions of PA-E3Y (PA-E3Yh) with divalent cations to create hydrogels with mechanical properties and ultrastructure similar to native tumor ECM. It is shown that stiffening of PA-E3Yh hydrogels to levels found in PDAC induces ECM deposition, promotes epithelial-to-mesenchymal transition (EMT), enriches CD133+/CXCR4+ cancer stem cells (CSCs), and subsequently enhances drug resistance. The findings reveal how a stiff 3D environment renders PDAC cells more aggressive and therefore more faithfully recapitulates in vivo tumors.

Versican Associates with Tumor Immune Phenotype and Limits T-cell Trafficking via Chondroitin Sulfate.

Immunotherapies for cancers of epithelial origin have limited efficacy, and a growing body of evidence links the composition of extracellular matrix (ECM) with the likelihood of a favorable response to treatment. The ECM may be considered an immunologic barrier, restricting the localization of cytotoxic immune cells to stromal areas and inhibiting their contact with tumor cells. Identifying ECM components of this immunologic barrier could provide targets that whether degraded in situ may support antitumor immunity and improve immunotherapy response. Using a library of primary triple-negative breast cancer tissues, we correlated CD8+ T-cell tumor contact with ECM composition and identified a proteoglycan, versican (VCAN), as a putative member of the immunologic barrier. Our analysis reveals that CD8+ T-cell contact with tumor associates with the location of VCAN expression, the specific glycovariant of VCAN [defined through the pattern of posttranslational attachments of glycosaminoglycans (GAG)], and the cell types that produce the variant. In functional studies, the isomers of chondroitin sulfate presented on VCAN have opposing roles being either supportive or inhibiting of T-cell trafficking, and removal of the GAGs ameliorates these effects on T-cell trafficking. Overall, we conclude that VCAN can either support or inhibit T-cell trafficking within the tumor microenvironment depending on the pattern of GAGs present, and that VCAN is a major component of the ECM immunologic barrier that defines the type of response to immunotherapy. SIGNIFICANCE: The response to immunotherapy has been poor toward solid tumors despite immune cells infiltrating into the tumor. The ECM has been associated with impacting T-cell infiltration toward the tumor and in this article we have identified VCAN and its structural modification, chondroitin sulfate as having a key role in T-cell invasion.

Hip Dysplasia in a Patient in Late Adolescence With Charcot-Marie-Tooth and Multiple Acyl-CoA Dehydrogenase Deficiency.

This case report explores a unique presentation of hip dysplasia in a female patient aged 21 years old diagnosed with Charcot-Marie-Tooth disease (CMT) type 1A and multiple acyl-CoA dehydrogenase deficiency (MADD). The coexistence of these neuromuscular and metabolic disorders in a patient with hip dysplasia provides an opportunity to investigate their potential interactions and impact on diagnosis, treatment, and prognosis. The patient underwent labral repair with shelf osteotomy and later a total hip replacement. This case highlights the need for further research to better understand the relationships between CMT, MADD, neuromuscular dysplasia, and hip dysplasia. A deeper understanding of these interactions may lead to improved diagnostic techniques, earlier intervention, and personalized treatment approaches for patients with co-morbid conditions, ultimately improving patient outcomes and reducing complications later in life.

A Novel Primary Cilium-Mediated Mechanism Through which Osteocytes Regulate Metastatic Behavior of Both Breast and Prostate Cancer Cells.

Bone metastases are a common cause of suffering in breast and prostate cancer patients, however, the interaction between bone cells and cancer cells is poorly understood. Using a series of co-culture, conditioned media, human cancer spheroid, and organ-on-a-chip experiments, this study reveals that osteocytes suppress cancer cell proliferation and increase migration via tumor necrosis factor alpha (TNF-α) secretion. This action is regulated by osteocyte primary cilia and associated intraflagellar transport protein 88 (IFT88). Furthermore, it shows that cancer cells block this mechanism by secreting transforming growth factor beta (TGF-ß), which disrupts osteocyte cilia and IFT88 gene expression. This bi-directional crosstalk signaling between osteocytes and cancer cells is common to both breast and prostate cancer. This study also proposes that osteocyte inhibition of cancer cell proliferation decreases as cancer cells increase, producing more TGF-ß. Hence, a positive feedback loop develops accelerating metastatic tumor growth. These findings demonstrate the importance of cancer cell-osteocyte signaling in regulating breast and prostate bone metastases and support the development of therapies targeting this pathway.

Opposing roles for ADAMTS2 and ADAMTS14 in myofibroblast differentiation and function.

Crosstalk between cancer and stellate cells is pivotal in pancreatic cancer, resulting in differentiation of stellate cells into myofibroblasts that drives tumour progression. To assess cooperative mechanisms in a 3D context, we generated chimeric spheroids using human and mouse cancer and stellate cells. Species-specific deconvolution of bulk-RNA sequencing data revealed cell type-specific transcriptomes underpinning invasion. This dataset highlighted stellate-specific expression of transcripts encoding the collagen-processing enzymes ADAMTS2 and ADAMTS14. Strikingly, loss of ADAMTS2 reduced, while loss of ADAMTS14 promoted, myofibroblast differentiation and invasion independently of their primary role in collagen-processing. Functional and proteomic analysis demonstrated that these two enzymes regulate myofibroblast differentiation through opposing roles in the regulation of transforming growth factor ß availability, acting on the protease-specific substrates, Serpin E2 and fibulin 2, for ADAMTS2 and ADAMTS14, respectively. Showcasing a broader complexity for these enzymes, we uncovered a novel regulatory axis governing malignant behaviour of the pancreatic cancer stroma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Excision of trochanteric bursa during total hip replacement: Does it reduce the incidence of post-operative trochanteric bursitis?

BACKGROUND: Trochanteric bursitis is a common complication following total hip replacement (THR), and it is associated with high level of disability and poor quality of life. Excision of the trochanteric bursa prophylactically during THR could reduce the occurrence of post-operative trochanteric bursitis. AIM: To evaluate whether synchronous trochanteric bursectomy at the time of THR affects the incidence of post-operative trochanteric bursitis. METHODS: This retrospective cohort study was conducted in the secondary care setting at a large district general hospital. Between January 2010 and December 2020, 954 patients underwent elective primary THR by two contemporary arthroplasty surgeons, one excising the bursa and the other not (at the time of THR). All patients received the same post-operative rehabilitation and were followed up for 1 year. We reviewed all cases of trochanteric bursitis over this 11-year period to determine the incidence of post-THR bursitis. Two proportion Z-test was used to compare incidences of trochanteric bursitis between groups. RESULTS: 554 patients underwent synchronous trochanteric bursectomy at the time of THR whereas 400 patients did not. A total of 5 patients (incidence 0.5%) developed trochanteric bursitis following THR; 4 of whom had undergone bursectomy as part of their surgical approach, 1 who had not. There was no statistically significant difference between the two groups (Z value 1.00, 95%CI: -0.4% to 1.3%, P = 0.32). There were also 8 other patients who had both trochanteric bursitis and hip osteoarthritis prior to their THR; all of whom were treated with THR and synchronous trochanteric bursectomy, and 7 had resolution of their lateral buttock pains but 1 did not. CONCLUSION: Synchronous trochanteric bursectomy during THR does not materially affect the incidence of post-operative bursitis. However, it is successful at treating patients with known trochanteric bursitis and osteoarthritis requiring THR.

Fracture Neck of the Femur: A Case of Two Pathologies.

We report a case of a 65-year-old woman who sustained a left neck of femur (NOF) fracture following low-energy trauma. Computed tomography (CT) scan for the neck, chest, abdomen and pelvis was normal apart from enlargement of the right lobe of the thyroid. Interestingly, thyroid function was normal. While waiting for the result of thyroid cytology and bone histology, the patient recovered well from the operation and started to engage well with physiotherapy. The result of the investigation showed presence of diffuse large B-cell lymphoma in the left NOF and right lobe of the thyroid. As the presence of lymphoma only in these two organs is extremely rare, it is not yet clear what is underlying mechanism for such association. Therefore, such observations may raise many future research questions as detailed in the discussion of this case report. This case also illustrates the importance of a multidisciplinary approach in identifying, evaluating, and treating unique and complex presentations of NOF fracture, with a focus on the patient's history, clinical examination and applying diagnostic tools.

Organ-on-a-Chip and Microfluidic Platforms for Oncology in the UK.

Organ-on-chip systems are capable of replicating complex tissue structures and physiological phenomena. The fine control of biochemical and biomechanical cues within these microphysiological systems provides opportunities for cancer researchers to build complex models of the tumour microenvironment. Interest in applying organ chips to investigate mechanisms such as metastatsis and to test therapeutics has grown rapidly, and this review draws together the published research using these microfluidic platforms to study cancer. We focus on both in-house systems and commercial platforms being used in the UK for fundamental discovery science and therapeutics testing. We cover the wide variety of cancers being investigated, ranging from common carcinomas to rare sarcomas, as well as secondary cancers. We also cover the broad sweep of different matrix microenvironments, physiological mechanical stimuli and immunological effects being replicated in these models. We examine microfluidic models specifically, rather than organoids or complex tissue or cell co-cultures, which have been reviewed elsewhere. However, there is increasing interest in incorporating organoids, spheroids and other tissue cultures into microfluidic organ chips and this overlap is included. Our review includes a commentary on cancer organ-chip models being developed and used in the UK, including work conducted by members of the UK Organ-on-a-Chip Technologies Network. We conclude with a reflection on the likely future of this rapidly expanding field of oncological research.

Targeting cancer glycosylation repolarizes tumor-associated macrophages allowing effective immune checkpoint blockade.

Immune checkpoint blockade (ICB) has substantially improved the prognosis of patients with cancer, but the majority experiences limited benefit, supporting the need for new therapeutic approaches. Up-regulation of sialic acid-containing glycans, termed hypersialylation, is a common feature of cancer-associated glycosylation, driving disease progression and immune escape through the engagement of Siglec receptors on tumor-infiltrating immune cells. Here, we show that tumor sialylation correlates with distinct immune states and reduced survival in human cancers. The targeted removal of Siglec ligands in the tumor microenvironment, using an antibody-sialidase conjugate, enhanced antitumor immunity and halted tumor progression in several murine models. Using single-cell RNA sequencing, we revealed that desialylation repolarized tumor-associated macrophages (TAMs). We also identified Siglec-E as the main receptor for hypersialylation on TAMs. Last, we found that genetic and therapeutic desialylation, as well as loss of Siglec-E, enhanced the efficacy of ICB. Thus, therapeutic desialylation represents an immunotherapeutic approach to reshape macrophage phenotypes and augment the adaptive antitumor immune response.

Multi-Scale Analysis of the Composition, Structure, and Function of Decellularized Extracellular Matrix for Human Skin and Wound Healing Models.

The extracellular matrix (ECM) is a complex mixture of structural proteins, proteoglycans, and signaling molecules that are essential for tissue integrity and homeostasis. While a number of recent studies have explored the use of decellularized ECM (dECM) as a biomaterial for tissue engineering, the complete composition, structure, and mechanics of these materials remain incompletely understood. In this study, we performed an in-depth characterization of skin-derived dECM biomaterials for human skin equivalent (HSE) models. The dECM materials were purified from porcine skin, and through mass spectrometry profiling, we quantified the presence of major ECM molecules, including types I, III, and VI collagen, fibrillin, and lumican. Rheological analysis demonstrated the sol-gel and shear-thinning properties of dECM materials, indicating their physical suitability as a tissue scaffold, while electron microscopy revealed a complex, hierarchical structure of nanofibers in dECM hydrogels. The dECM materials were compatible with advanced biofabrication techniques, including 3D printing within a gelatin microparticle support bath, printing with a sacrificial material, or blending with other ECM molecules to achieve more complex compositions and structures. As a proof of concept, we also demonstrate how dECM materials can be fabricated into a 3D skin wound healing model using 3D printing. Skin-derived dECM therefore represents a complex and versatile biomaterial with advantageous properties for the fabrication of next-generation HSEs.

Orthoplastic Reconstruction of Type IIIB Open Tibial Shaft Fractures Using Debrided, Devitalized Cortical Segments: Health-Related Quality-of-Life Outcomes.

OBJECTIVE: To determine health-related quality of life (HRQoL) in patients who sustained type IIIB open tibial diaphyseal (OTA/AO-42) fractures and underwent orthoplastic reconstruction using mechanically relevant devitalized bone (ORDB) versus those who did not require the use of devitalized bone as part of their orthoplastic reconstruction. DESIGN: Consecutive cohort study. PATIENTS/PARTICIPANTS: The study included 74 patients who sustained a type IIIB open tibial diaphyseal fracture requiring orthoplastic reconstruction over a 4-year period in a major trauma center. All patients underwent a two-stage orthoplastic reconstruction protocol, with the second stage consisting of definitive fixation and flap coverage (free fascial anterolateral thigh flap) in a single sitting. Patients were contacted at a minimum of 30 months to measure HRQoL. INTERVENTION: Patients requiring ORDB versus those who did not require the use of devitalized bone as part of their orthoplastic reconstruction. MAIN OUTCOME MEASUREMENTS: The primary outcome measure was HRQoL ascertained using Euro-Qol (EQ)-5D and Short-Form (SF)-36 scores. RESULTS: Thirty (n = 30) patients underwent ORDB with the remaining 44 not requiring devitalized bone as part of their reconstruction. The median age was 46.5 years [interquartile range (IQR) 29.0], with a median follow-up of 3.8 years (IQR 1.5). The median cohort EQ-5D was 0.743 (IQR 0.222), ORDB 0.743 (IQR 0.195) versus non-ORDB 0.748 (IQR 0.285), P = 0.71. The median physical component SF-36 score was 80 (IQR 50), ORDB 80 (IQR 34.5) versus non-ORDB 77.5 (IQR 58.75), P = 0.72. The median mental component SF-36 score was 80 (IQR 28), ORDB 80 (IQR 21) versus non-ORDB 80 (IQR 36), P = 0.29. CONCLUSIONS: In patients who sustained a type IIIB open tibial shaft fracture and who underwent a 2-stage orthoplastic reconstruction, ORDB does not seem to be associated with inferior health-related quality of life based on EQ-5D or SF-36 scores. The results of this approach should be considered within the strict combined orthoplastic approach in the study unit. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Open lower limb fractures in the elderly.

OBJECTIVE: The aim of this study was to assess the outcomes of open lower limb fractures in patients aged 65 and over. The primary outcome was mortality at 30 days, and the secondary outcome was reoperation. METHODS: This study retrospectively identified patients aged 65 and over, presenting with an open tibia or ankle fracture, over a two-year period. Patient demographics, injury characteristics and surgical interventions were documented. The 30-day and one-year mortality was recorded, as well as any complications encountered. RESULTS: There were 88 patients included in the study, with a mean age of 78 years and 66% of patients were female. Of this cohort, 67 patients (76%) had low energy injuries and 64 patients (73%) had Gustillo-Anderson type IIIB injuries. Treatment consisted of a one-stage surgical procedure in 49 patients (56%) and a two-stage procedure in 37 patients (42%), with two patients dying before definitive treatment. Primary wound closure was performed in 23 patients (26%), four patients (5%) had a split skin graft alone, 35 patients (40%) had local flaps, 21 patients (24%) were managed with free flaps and three patients (3%) had primary below knee amputations. The 30-day mortality rate was 10%, the one-year mortality rate was 19% and the reoperation rate was 8%. CONCLUSION: Open lower limb fractures in the elderly are a life and limb threatening injury, with a similar demographic and mortality profile to hip fracture. This study demonstrates that limb salvage can be achieved in 93% of cases, with treatment performed as a one-stage procedure in 56% of cases.

Building invitro 3D human multicellular models of high-grade serous ovarian cancer.

Three-dimensional (3D), multicellular invitro models provide a useful platform for studying human cancer biology, particularly through deconvolution of the tumor microenvironment, or where animal models do not recapitulate the human condition. Here, we detail a protocol for building human multicellular models made of patient-derived primary cells and malignant cell lines, which recapitulate features of the tumor microenvironment. This protocol is optimized for building 3D models of high-grade serous ovarian cancer omental metastasis but can be adapted for modeling other cancers. For complete details on the use and execution of this profile, please refer to Delaine-Smith et al. (2021) and Malacrida et al. (2021).

Disruption of pancreatic stellate cell myofibroblast phenotype promotes pancreatic tumor invasion.

In pancreatic ductal adenocarcinoma (PDAC), differentiation of pancreatic stellate cells (PSCs) into myofibroblast-like cancer-associated fibroblasts (CAFs) can both promote and suppress tumor progression. Here, we show that the Rho effector protein kinase N2 (PKN2) is critical for PSC myofibroblast differentiation. Loss of PKN2 is associated with reduced PSC proliferation, contractility, and alpha-smooth muscle actin (α-SMA) stress fibers. In spheroid co-cultures with PDAC cells, loss of PKN2 prevents PSC invasion but, counter-intuitively, promotes invasive cancer cell outgrowth. PKN2 deletion induces a myofibroblast to inflammatory CAF switch in the PSC matrisome signature both in vitro and in vivo. Further, deletion of PKN2 in the pancreatic stroma induces more locally invasive, orthotopic pancreatic tumors. Finally, we demonstrate that a PKN2KO matrisome signature predicts poor outcome in pancreatic and other solid human cancers. Our data indicate that suppressing PSC myofibroblast function can limit important stromal tumor-suppressive mechanisms, while promoting a switch to a cancer-supporting CAF phenotype.

TGFBI Production by Macrophages Contributes to an Immunosuppressive Microenvironment in Ovarian Cancer.

The tumor microenvironment evolves during malignant progression, with major changes in nonmalignant cells, cytokine networks, and the extracellular matrix (ECM). In this study, we aimed to understand how the ECM changes during neoplastic transformation of serous tubal intraepithelial carcinoma lesions (STIC) into high-grade serous ovarian cancers (HGSOC). Analysis of the mechanical properties of human fallopian tubes (FT) and ovaries revealed that normal FT and fimbria had a lower tissue modulus, a measure of stiffness, than normal or diseased ovaries. Proteomic analysis of the matrisome fraction between FT, fimbria, and ovaries showed significant differences in the ECM protein TGF beta induced (TGFBI, also known as ßig-h3). STIC lesions in the fimbria expressed high levels of TGFBI, which was predominantly produced by CD163-positive macrophages proximal to STIC epithelial cells. In vitro stimulation of macrophages with TGFß and IL4 induced secretion of TGFBI, whereas IFNγ/LPS downregulated macrophage TGFBI expression. Immortalized FT secretory epithelial cells carrying clinically relevant TP53 mutations stimulated macrophages to secrete TGFBI and upregulated integrin αvß3, a putative TGFBI receptor. Transcriptomic HGSOC datasets showed a significant correlation between TGFBI expression and alternatively activated macrophage signatures. Fibroblasts in HGSOC metastases expressed TGFBI and stimulated macrophage TGFBI production in vitro. Treatment of orthotopic mouse HGSOC tumors with an anti-TGFBI antibody reduced peritoneal tumor size, increased tumor monocytes, and activated ß3-expressing unconventional T cells. In conclusion, TGFBI may favor an immunosuppressive microenvironment in STICs that persists in advanced HGSOC. Furthermore, TGFBI may be an effector of the tumor-promoting actions of TGFß and a potential therapeutic target. SIGNIFICANCE: Analysis of ECM changes during neoplastic transformation reveals a role for TGFBI secreted by macrophages in immunosuppression in early ovarian cancer.

Targeting Versican as a Potential Immunotherapeutic Strategy in the Treatment of Cancer.

A growing body of literature links events associated with the progression and severity of immunity and inflammatory disease with the composition of the tissue extracellular matrix as defined by the matrisome. One protein in the matrisome that is common to many inflammatory diseases is the large proteoglycan versican, whose varied function is achieved through multiple isoforms and post-translational modifications of glycosaminoglycan structures. In cancer, increased levels of versican are associated with immune cell phenotype, disease prognosis and failure to respond to treatment. Whether these associations between versican expression and tumour immunity are the result of a direct role in the pathogenesis of tumours is not clear. In this review, we have focused on the role of versican in the immune response as it relates to tumour progression, with the aim of determining whether our current understanding of the immunobiology of versican warrants further study as a cancer immunotherapy target.

Flexor tendon injuries: Repair & Rehabilitation.

Flexor tendon injuries are common and occur mostly by penetrating trauma. Suspected flexor tendon injuries require a thorough clinical assessment and often are not isolated injuries. A detailed understanding of flexor tendon anatomy and spatial relationships is essential, especially when repairing multi-tendon injuries. Principles of flexor tendon repair include a strong suture construct, minimising gap formation between tendon ends, preserving tendon blood supply and providing a smooth repair interface. Moreover, adequate exposure of the zone of injury using full-thickness skin flaps and preservation of neurovascular and pulley structures is essential. In this article an overview of contemporary management strategies is presented. Today's hand surgeons and therapists can choose from a variety of treatment options when managing these important and potentially life-changing injuries.