Sialic acid blockade inhibits the metastatic spread of prostate cancer to bone.

BACKGROUND: Bone metastasis is a common consequence of advanced prostate cancer. Bisphosphonates can be used to manage symptoms, but there are currently no curative treatments available. Altered tumour cell glycosylation is a hallmark of cancer and is an important driver of a malignant phenotype. In prostate cancer, the sialyltransferase ST6GAL1 is upregulated, and studies show ST6GAL1-mediated aberrant sialylation of N-glycans promotes prostate tumour growth and disease progression. METHODS: Here, we monitor ST6GAL1 in tumour and serum samples from men with aggressive prostate cancer and using in vitro and in vivo models we investigate the role of ST6GAL1 in prostate cancer bone metastasis. FINDINGS: ST6GAL1 is upregulated in patients with prostate cancer with tumours that have spread to the bone and can promote prostate cancer bone metastasis in vivo. The mechanisms involved are multi-faceted and involve modification of the pre-metastatic niche towards bone resorption to promote the vicious cycle, promoting the development of M2 like macrophages, and the regulation of immunosuppressive sialoglycans. Furthermore, using syngeneic mouse models, we show that inhibiting sialylation can block the spread of prostate tumours to bone. INTERPRETATION: Our study identifies an important role for ST6GAL1 and α2-6 sialylated N-glycans in prostate cancer bone metastasis, provides proof-of-concept data to show that inhibiting sialylation can suppress the spread of prostate tumours to bone, and highlights sialic acid blockade as an exciting new strategy to develop new therapies for patients with advanced prostate cancer. FUNDING: Prostate Cancer Research and the Mark Foundation For Cancer Research, the Medical Research Council and Prostate Cancer UK.

Impact of the COVID-19 pandemic on care for anorexia and bulimia nervosa in US military-connected adolescents and young adults.

OBJECTIVE: This study examined the impact of the COVID-19 pandemic on healthcare engagement for anorexia nervosa (AN) and bulimia nervosa (BN) in a large, geographically diverse population. METHOD: This repeated monthly, cross-sectional study queried Military Health System records of individuals aged 10-21 before and during the pandemic (February 2019-January 2022). ICD-10 codes identified encounters for AN and BN. Monthly rates of care were modeled as the number of unique individuals with an ICD-10-identified eating disorder-related encounter per month divided by the enrolled population. Poisson regression analysis evaluated rates of care stratified by eating disorder, clinical setting, and sex. RESULTS: In a population of 1.76 million adolescents and young adults, 1629 individuals with AN or BN received care during the pre-pandemic period; 3256 received care during the pandemic. The monthly rate of care for females with AN during the pandemic increased in inpatient settings (adjusted relative risk [aRR]: 1.31 [1.16-1.49]) and outpatient settings (aRR: 1.42 [1.37-1.47]); monthly care rates in males with AN increased in the outpatient setting (aRR: 1.46 [1.28-1.67]). Females with BN had increased engagement in outpatient settings (aRR: 1.09 [1.03-1.16]); BN care for males showed no significant monthly changes during the pandemic period in either healthcare setting. DISCUSSION: With increased rates of AN and BN disorder-related care during the pandemic, screening for eating disorder symptomatology may allow for timely diagnosis and intervention in periods of heightened stress. Pandemic-related increases in healthcare engagement may strain limited resources, emphasizing a need to expand accessibility of clinical expertise. PUBLIC SIGNIFICANCE: This study indicates that monthly rates of healthcare engagement during the COVID-19 pandemic for AN and BN varied based on clinical setting and sex in an adolescent and young adult population. The increased number of individuals seeking eating disorder-related care, especially outpatient care, attributed to heightened stressors necessitates accessible professionals with eating disorder clinical expertise.

Radiographic bladder shift is a harbinger of intraoperative blood loss in acetabular surgical fixation.

PURPOSE: The purpose of this study was to characterize the relationship between a novel radiographic measurement on initial AP pelvis radiograph (termed "bladder shift," BS) to intraoperative blood loss (IBL) during acetabular surgical fixation. METHODS: All adult patients receiving unilateral acetabular fixation (Level 1 academic trauma; 2008-18) were reviewed. AP pelvis radiographs were reviewed for visible bladder outlines and then measured to determine the percentage deformation toward the midline. Hemoglobin & hematocrit data were then used to calculate quantitative blood loss between pre- and post- operative blood counts for data analysis. RESULTS: 371 patients with unilateral traumatic acetabular fractures requiring fixation were reviewed; 99 of these had visible bladder outlines, complete blood count and transfusion data (2008-2018; 66% associated patterns). Median bladder shift (BS) was 13.3%. Every 10% of bladder shift was associated with 123 mL greater IBL. Patients with full bladder shift to midline sustained a median 1.5L IBL (interquartile range [IQR] 0.8 to 1.6). Associated patterns had a threefold greater median BS (associated: 16.5% [15.4 to 45.9] vs. elementary: 5.6% [1.1 to 15.4], p < 0.05) and received intraoperative pRBC twice as frequently (57% vs. 24%, p < 0.01). CONCLUSIONS: Radiographic bladder shift is an easily available visual marker, in patients sustaining acetabular fractures, that may predict intraoperative hemorrhage and need for transfusions.

Post Post-Mobilization Films for LC1 Pelvic Ring Injuries: Follow up Stress Imaging Demonstrates Minimal Utility.

OBJECTIVE: To assess the utility of outpatient postmobilization radiographs in the nonoperative treatment of lateral compression type I (LC1) (OTA/AO 61-B1) pelvic ring injuries. DESIGN: Retrospective series. SETTING: Academic, Level 1 trauma center, 2008-2018. PATIENTS/PARTICIPANTS: A series of 173 patients with nonoperatively treated LC1 pelvic ring injuries was identified. Of these, 139 received a complete set of outpatient pelvic radiographs with which to assess displacement. INTERVENTION: Outpatient pelvic radiographs to assess additional fracture displacement and potential need for surgical intervention. MAIN OUTCOME MEASUREMENTS: Rate of conversion to late operative intervention based on radiographic displacement. RESULTS: No patient in this cohort received late operative intervention. A majority of the patients sustained incomplete sacral fractures (82.6%) and unilateral rami fractures (75.1%), and 92.8% demonstrated less than 10 mm of displacement on their final radiographs. CONCLUSIONS: There is a low utility of repeat outpatient radiographs of stable, nonoperative LC1 pelvic ring injuries as they do not undergo late displacement. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Delay of fixation increases 30-day complications and mortality in traumatic pelvic ring injuries.

PURPOSE: While decreased time to fixation in femur fractures improves mortality, it remains unclear if the same relationship exists for pelvic fractures. The National Trauma Data Bank (NTDB) is a data repository for trauma hospitals in the United States (injury characteristics, perioperative data, procedures, 30-day complications), and we used this to investigate early, significant complications after pelvic-ring injuries. METHODS: The NTDB (2015-2016) was queried to capture operative pelvic ring injuries in adult patients with injury severity score (ISS) ≥ 15. Complications included medical and surgical complications, as well as 30-day mortality. Multivariable logistic regression was used to investigate the association between days to procedure and complications after adjusting for demographic characteristics and comorbidities. RESULTS: 2325 patients met inclusion criteria. 532 (23.0%) sustained complications, and 72 (3.2%) died within the first 30 days. The most common complications were deep vein thrombosis (DVT) (5.7%), acute kidney injury (AKI) (4.6%), and unplanned intensive care unit (ICU) admission (4.4%). In a multivariate analysis, days to procedure was independently significantly associated with complications, with an adjusted odds ratio (95% confidence interval) of 1.06 (1.03-1.09, P < 0.001), best interpreted as a 6% increase in the odds of complication or death for each additional day. CONCLUSION: Time to pelvic fixation is a significant and modifiable risk factor for major complications and death. This suggests we should prioritize time to pelvic fixation on trauma patients to minimize mortality and major complications.

Outcomes of Fracture Surgery in Patients With Escalating Hemoglobin A1C in the Setting of Unmanaged Diabetes.

OBJECTIVE: To determine whether there is a threshold of elevated hemoglobin A1C (HbA1c) above which the complication risk is so high that fracture fixation should be avoided. DESIGN: Retrospective cohort study. SETTING: Academic Level I trauma center. PATIENTS/PARTICIPANTS: A cohort of 187 patients with HbA1c values >7 and operatively treated extremity fractures. INTERVENTION: Surgical fixation of extremity fractures. MAIN OUTCOME MEASUREMENTS: Rate of major orthopaedic complication (loss of reduction, nonunion, infection, and need for salvage procedure). RESULTS: 34.8% demonstrated HbA1c > 9% and 12.3% with HbA1c > 11. Major complications occurred in 31.4%; HbA1c values were not predictive. We found no evidence of a clinically or statistically significant relationship between HbA1c and risk of major complication. The odds ratio for a one-point increase in HbA1c was 1.006 ( P = 0.9439), and the area under the receiver operating characteristic curve, which reflects the average probability that someone with a major complication will have a higher HbA1c than someone without, was 0.51 (95% confidence interval 0.42-0.61), equivalent to random chance. CONCLUSION: Diabetic patients with fracture demonstrated an extremely high overall rate of complications, with 30.5% experiencing a major complication. However, patients with extreme diabetic neglect did not have higher complication rates after extremity fracture fixation when compared with patients with controlled and uncontrolled diabetes. There was no correlation between rate of complication and level of HbA1c. In addition, there was no difference in complication rate between upper and lower extremity fractures or between fractures treated with open or percutaneous fixation. This suggests that fracture treatment decision-making should not be altered for patients with poor diabetic control, and that surgery is not contraindicated in patients with an extremely high HbA1c. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Metastatic Infiltration of Nervous Tissue and Periosteal Nerve Sprouting in Multiple Myeloma-Induced Bone Pain in Mice and Human.

Multiple myeloma (MM) is a neoplasia of B plasma cells that often induces bone pain. However, the mechanisms underlying myeloma-induced bone pain (MIBP) are mostly unknown. Using a syngeneic MM mouse model, we show that periosteal nerve sprouting of calcitonin gene-related peptide (CGRP+) and growth associated protein 43 (GAP43+) fibers occurs concurrent to the onset of nociception and its blockade provides transient pain relief. MM patient samples also showed increased periosteal innervation. Mechanistically, we investigated MM induced gene expression changes in the dorsal root ganglia (DRG) innervating the MM-bearing bone of male mice and found alterations in pathways associated with cell cycle, immune response and neuronal signaling. The MM transcriptional signature was consistent with metastatic MM infiltration to the DRG, a never-before described feature of the disease that we further demonstrated histologically. In the DRG, MM cells caused loss of vascularization and neuronal injury, which may contribute to late-stage MIBP. Interestingly, the transcriptional signature of a MM patient was consistent with MM cell infiltration to the DRG. Overall, our results suggest that MM induces a plethora of peripheral nervous system alterations that may contribute to the failure of current analgesics and suggest neuroprotective drugs as appropriate strategies to treat early onset MIBP.SIGNIFICANCE STATEMENT Multiple myeloma (MM) is a painful bone marrow cancer that significantly impairs the quality of life of the patients. Analgesic therapies for myeloma-induced bone pain (MIBP) are limited and often ineffective, and the mechanisms of MIBP remain unknown. In this manuscript, we describe cancer-induced periosteal nerve sprouting in a mouse model of MIBP, where we also encounter metastasis to the dorsal root ganglia (DRG), a never-before described feature of the disease. Concomitant to myeloma infiltration, the lumbar DRGs presented blood vessel damage and transcriptional alterations, which may mediate MIBP. Explorative studies on human tissue support our preclinical findings. Understanding the mechanisms of MIBP is crucial to develop targeted analgesic with better efficacy and fewer side effects for this patient population.

Heterologous effect of influenza vaccination on molluscum contagiosum infection; a case report of siblings.

BACKGROUND: Molluscum contagiosum virus (MCV) is a benign, common cutaneous infection predominantly affecting the younger pediatric population. Traditional treatments may be time consuming with variable efficacy. Time to spontaneous resolution is variable and treatment is often sought to shorten duration of infection, prevent further autoinoculation, prevent infectious spread to others and treat cosmetic intolerability. CASE PRESENTATION: We present the case of two patients with complete, simultaneous clearance of their molluscum contagiosum infections after receiving a routine 2018 quadrivalent influenza vaccination. Neither patient has had recurrence of molluscum contagiosum or permanent scarring. We review trials of intralesional immunotherapy in treatment of cutaneous infections to theorize the mechanism of MCV infection clearance post influenza vaccination. CONCLUSION: We propose a delayed-type hypersensitivity reaction was induced as a heterologous effect of the influenza vaccination, similar to that seen in current immunotherapy treatments. This is the first reported case of MCV-directed immune reaction with infection clearance after influenza vaccination.

HSV1716 Prevents Myeloma Cell Regrowth When Combined with Bortezomib In Vitro and Significantly Reduces Systemic Tumor Growth in Mouse Models.

Multiple myeloma remains largely incurable due to refractory disease; therefore, novel treatment strategies that are safe and well-tolerated are required. Here, we studied the modified herpes simplex virus HSV1716 (SEPREHVIR®), which only replicates in transformed cells. Myeloma cell lines and primary patient cells were infected with HSV1716 and assessed for cell death using propidium iodide (PI) and Annexin-V staining and markers of apoptosis and autophagy by qPCR. Myeloma cell death was associated with dual PI and Annexin-V positivity and increased expression of apoptotic genes, including CASP1, CASP8, CASP9, BAX, BID, and FASL. The combination of HSV1716 and bortezomib treatments prevented myeloma cell regrowth for up to 25 days compared to only transient cell growth suppression with bortezomib treatment. The viral efficacy was tested in a xenograft (JJN-3 cells in NSG mice) and syngeneic (murine 5TGM1 cells in C57BL/KaLwRijHsd mice) systemic models of myeloma. After 6 or 7 days, the post-tumor implantation mice were treated intravenously with the vehicle or HSV1716 (1 × 107 plaque forming units/1 or 2 times per week). Both murine models treated with HSV1716 had significantly lower tumor burden rates compared to the controls. In conclusion, HSV1716 has potent anti-myeloma effects and may represent a novel therapy for multiple myeloma.

Distribution of Bacterial Species and Resistance Patterns in Surgical Site Infection after Prior Administration of Vancomycin and Tobramycin Intrawound Powdered Antibiotic Prophylaxis.

OBJECTIVE: Evaluate the species distribution and resistance patterns of bacterial pathogens causing surgical site infection (SSI) after operative fracture repair, with and without the use of intrawound powdered antibiotic (IPA) prophylaxis during the index surgery. DESIGN: Retrospective cohort study. SETTING: Academic, level 1 trauma center, 2018-2020. PATIENTS/PARTICIPANTS: Fifty-nine deep SSIs were identified in a sample of 734 patients with 846 fractures (IPA [n = 320], control [n = 526]; open [n = 157], closed fractures [n = 689]) who underwent orthopaedic fracture care. Among SSIs, 28 (48%) patients received IPA prophylaxis and 25 (42%) of the fractures were open. INTERVENTION: Intrawound powdered vancomycin and tobramycin. MAIN OUTCOME MEASUREMENTS: Distribution of bacterial species and resistance patterns causing deep surgical site infections requiring operative debridement. RESULTS: Zero patients developed infections caused by resistant strains of streptococci, enterococci, gram-negative enterics, Pseudomonas , or Cutibacterium species. The only resistant strains isolated were methicillin resistance (19%) and oxacillin-resistant coagulase-negative staphylococci (16%). There was no associated statistical difference in the proportion of bacterial species isolated, their resistance profiles, or rate of polymicrobial infections between the IPA and control group. Most (93%) cases using IPAs included vancomycin and tobramycin powders. There were 59 SSIs; 28 (9%) in the IPA cohort and 31 (6%) in the control cohort ( P = 0.13). CONCLUSION: The use of local antibiotic prophylaxis resulted in no measurable increase in the proportion of infections caused by resistant bacterial pathogens after operative treatment of fractures. However, the small sample size and limited time frame of these preliminary data require continued investigation into their role as an adjunct to SSI prophylaxis. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

The strategy and clinical relevance of in vitro models of MAP resistance in osteosarcoma: a systematic review.

Over the last 40 years osteosarcoma (OS) survival has stagnated with patients commonly resistant to neoadjuvant MAP chemotherapy involving high dose methotrexate, adriamycin (doxorubicin) and platinum (cisplatin). Due to the rarity of OS, the generation of relevant cell models as tools for drug discovery is paramount to tackling this issue. Four literature databases were systematically searched using pre-determined search terms to identify MAP resistant OS cell lines and patients. Drug exposure strategies used to develop cell models of resistance and the impact of these on the differential expression of resistance associated genes, proteins and non-coding RNAs are reported. A comparison to clinical studies in relation to chemotherapy response, relapse and metastasis was then made. The search retrieved 1891 papers of which 52 were relevant. Commonly, cell lines were derived from Caucasian patients with epithelial or fibroblastic subtypes. The strategy for model development varied with most opting for continuous over pulsed chemotherapy exposure. A diverse resistance level was observed between models (2.2-338 fold) with 63% of models exceeding clinically reported resistance levels which may affect the expression of chemoresistance factors. In vitro p-glycoprotein overexpression is a key resistance mechanism; however, from the available literature to date this does not translate to innate resistance in patients. The selection of models with a lower fold resistance may better reflect the clinical situation. A comparison of standardised strategies in models and variants should be performed to determine their impact on resistance markers. Clinical studies are required to determine the impact of resistance markers identified in vitro in poor responders to MAP treatment, specifically with respect to innate and acquired resistance. A shift from seeking disputed and undruggable mechanisms to clinically relevant resistance mechanisms may identify key resistance markers that can be targeted for patient benefit after a 40-year wait.

The Effect of COVID-19 on the Mental Health of Military Connected Children and Adolescents.

With a growing body of literature describing the coronavirus disease 2019 (COVID-19) pandemic's effect on children and adolescents, there remain few official reports regarding mental health in military connected youth. With sparse literature available specifically in youth associated with the Armed Forces, published studies on global child and adolescent mental health during the COVID-19 pandemic are first reviewed. Military connected youth have unique needs and experiences. Implications of pandemic-related stressors on their mental health are suggested based on analysis of disaster and deployment literature. Military members have continued to move and deploy throughout the pandemic. Uniformed families have high risk factors for mental health concerns. Managing the mental health of military connected youth will fall heavily on civilian providers, both in primary and subspecialty practices. As such, vigilance for psychological health concerns and familiarity with military resources are vital for the mental wellness of our military pediatric patients. [Pediatr Ann. 2022;51(4):e138-e143.].

Collagen X Longitudinal Fracture Biomarker Suggests Staged Fixation in Tibial Plateau Fractures Delays Rate of Endochondral Repair.

OBJECTIVES: To use a novel, validated bioassay to monitor serum concentrations of a breakdown product of collagen X in a prospective longitudinal study of patients sustaining isolated tibial plateau fractures. Collagen X is the hallmark extracellular matrix protein present during conversion of soft, cartilaginous callus to bone during endochondral repair. Previous preclinical and clinical studies demonstrated a distinct peak in collagen X biomarker (CXM) bioassay levels after long bone fractures. SETTING: Level 1 academic trauma facility. PATIENTS/PARTICIPANTS: Thirty-six patients; isolated tibial plateau fractures. INTERVENTION: (3) Closed treatment, ex-fix (temporizing/definitive), and open reduction internal fixation. MAIN OUTCOME MEASUREMENTS: Collagen X serum biomarker levels (CXM bioassay). RESULTS: Twenty-two men and 14 women (average age: 46.3 y; 22.6-73.4, SD 13.3) enrolled (16 unicondylar and 20 bicondylar fractures). Twenty-five patients (72.2%) were treated operatively, including 12 (33.3%) provisionally or definitively treated by ex-fix. No difference was found in peak CXM values between sexes or age. Patients demonstrated peak expression near 1000 pg/mL (average: male-986.5 pg/mL, SD 369; female-953.2 pg/mL, SD 576). There was no difference in peak CXM by treatment protocol, external fixator use, or fracture severity (Schatzker). Patients treated with external fixation (P = 0.05) or staged open reduction internal fixation (P = 0.046) critically demonstrated delayed peaks. CONCLUSIONS: Pilot analysis demonstrates a strong CXM peak after fractures commensurate with previous preclinical and clinical studies, which was delayed with staged fixation. This may represent the consequence of delayed construct loading. Further validation requires larger cohorts and long-term follow-up. Collagen X may provide an opportunity to support prospective interventional studies testing novel orthobiologics or fixation techniques. LEVEL OF EVIDENCE: Level II, prospective clinical observational study.

The Use of Oncolytic Viruses in the Treatment of Multiple Myeloma.

Multiple myeloma accounts for 1% of all new cancers worldwide. It is the second most common haematological malignancy and has a low five-year survival rate (53.2%). Myeloma remains an incurable disease and is caused by the growth of malignant plasma cells in the bone marrow. Current anti-myeloma therapies (conventional chemotherapies, immunomodulatory drugs i.e., thalidomide and its' analogues, proteasome inhibitors, monoclonal antibodies, and radiotherapy) initially substantially debulk tumour burden, but after a period of remission 'plateau phase' disease invariably relapses due to tumour recrudescence from foci of minimal residual disease (MRD) and accumulating drug resistance. Therefore, there is a compelling clinical need for the development of novel treatment regimens to target MRD and effectively eliminate all remaining tumour cells. This review will discuss the potential use of oncolytic virus (OV) therapies in the treatment of myeloma. Specifically, it will focus on preclinical studies using DNA viruses (adenovirus (Ad), vaccinia virus (VV), myxoma virus (MYXV), and herpes simplex virus (HSV)), RNA viruses (reovirus (reo), coxsackie virus, measles virus (MV) and bovine viral diarrhoea virus (BVDV), and vesicular stomatitis virus (VSV)), and on four types of viruses (VV, reo, MV-NIS and VSV-IFNß-NIS) that have been assessed clinically in a small number of myeloma patients.

Myeloma Bone Disease: The Osteoblast in the Spotlight.

Lytic bone disease remains a life-altering complication of multiple myeloma, with up to 90% of sufferers experiencing skeletal events at some point in their cancer journey. This tumour-induced bone disease is driven by an upregulation of bone resorption (via increased osteoclast (OC) activity) and a downregulation of bone formation (via reduced osteoblast (OB) activity), leading to phenotypic osteolysis. Treatments are limited, and currently exclusively target OCs. Despite existing bone targeting therapies, patients successfully achieving remission from their cancer can still be left with chronic pain, poor mobility, and reduced quality of life as a result of bone disease. As such, the field is desperately in need of new and improved bone-modulating therapeutic agents. One such option is the use of bone anabolics, drugs that are gaining traction in the osteoporosis field following successful clinical trials. The prospect of using these therapies in relation to myeloma is an attractive option, as they aim to stimulate OBs, as opposed to existing therapeutics that do little to orchestrate new bone formation. The preclinical application of bone anabolics in myeloma mouse models has demonstrated positive outcomes for bone repair and fracture resistance. Here, we review the role of the OB in the pathophysiology of myeloma-induced bone disease and explore whether novel OB targeted therapies could improve outcomes for patients.

Reovirus-induced cell-mediated immunity for the treatment of multiple myeloma within the resistant bone marrow niche.

BACKGROUND: Multiple myeloma (MM) remains an incurable disease and oncolytic viruses offer a well-tolerated addition to the therapeutic arsenal. Oncolytic reovirus has progressed to phase I clinical trials and its direct lytic potential has been extensively studied. However, to date, the role for reovirus-induced immunotherapy against MM, and the impact of the bone marrow (BM) niche, have not been reported. METHODS: This study used human peripheral blood mononuclear cells from healthy donors and in vitro co-culture of MM cells and BM stromal cells to recapitulate the resistant BM niche. Additionally, the 5TGM1-Kalw/RijHSD immunocompetent in vivo model was used to examine reovirus efficacy and characterize reovirus-induced immune responses in the BM and spleen following intravenous administration. Collectively, these in vitro and in vivo models were used to characterize the development of innate and adaptive antimyeloma immunity following reovirus treatment. RESULTS: Using the 5TGM1-Kalw/RijHSD immunocompetent in vivo model we have demonstrated that reovirus reduces both MM tumor burden and myeloma-induced bone disease. Furthermore, detailed immune characterization revealed that reovirus: (i) increased natural killer (NK) cell and CD8+ T cell numbers; (ii) activated NK cells and CD8+ T cells and (iii) upregulated effector-memory CD8+ T cells. Moreover, increased effector-memory CD8+ T cells correlated with decreased tumor burden. Next, we explored the potential for reovirus-induced immunotherapy using human co-culture models to mimic the myeloma-supportive BM niche. MM cells co-cultured with BM stromal cells displayed resistance to reovirus-induced oncolysis and bystander cytokine-killing but remained susceptible to killing by reovirus-activated NK cells and MM-specific cytotoxic T lymphocytes. CONCLUSION: These data highlight the importance of reovirus-induced immunotherapy for targeting MM cells within the BM niche and suggest that combination with agents which boost antitumor immune responses should be a priority.

Orthopaedic Care of the Transgender Patient.

¼: A transgender person is defined as one whose gender identity is incongruent with their biological sex assigned at birth. This highly marginalized population numbers over 1.4 million individuals in the U.S.; this prevalence skews more heavily toward younger generations and is expected to increase considerably in the future. ¼: Gender-affirming hormone therapy (GAHT) has physiologic effects on numerous aspects of the patient's health that are pertinent to the orthopaedic surgeon, including bone health, fracture risk, and perioperative risks such as venous thromboembolism and infection. ¼: Language and accurate pronoun usage toward transgender patients can have a profound effect on a patient's experience and on both objective and subjective outcomes. ¼: Gaps in research concerning orthopaedic care of the transgender patient are substantial. Specific areas for further study include the effects of GAHT on fracture risk and healing, outcome disparities and care access across multiple subspecialties, and establishment of perioperative management guidelines.

The P2RX7B splice variant modulates osteosarcoma cell behaviour and metastatic properties.

Background: Osteosarcoma (OS) is the most common type of primary bone cancer affecting children and adolescents. OS has a high propensity to spread meaning the disease is often incurable and fatal. There have been no improvements in survival rates for decades. This highlights an urgent need for the development of novel therapeutic strategies. Here, we report in vitro and in vivo data that demonstrates the role of purinergic signalling, specifically, the B isoform of the purinergic receptor P2RX7 (P2RX7B), in OS progression and metastasis. Methods: TE85 and MNNG-HOS OS cells were transfected with P2RX7B. These cell lines were then characterised and assessed for proliferation, cell adhesion, migration and invasion in vitro. We used these cells to perform both paratibial and tail vein injected mouse studies where the primary tumour, bone and lungs were analysed. We used RNA-seq to identify responsive pathways relating to P2RX7B. Results: Our data shows that P2RX7B expression confers a survival advantage in TE85 + P2RX7B and MNNG-HOS + P2RX7B human OS cell lines in vitro that is minimised following treatment with A740003, a specific P2RX7 antagonist. P2RX7B expression reduced cell adhesion and P2RX7B activation promoted invasion and migration in vitro, demonstrating a metastatic phenotype. Using an in vivo OS xenograft model, MNNG-HOS + P2RX7B tumours exhibited cancer-associated ectopic bone formation that was abrogated with A740003 treatment. A pro-metastatic phenotype was further demonstrated in vivo as expression of P2RX7B in primary tumour cells increased the propensity of tumour cells to metastasise to the lungs. RNA-seq identified a novel gene axis, FN1/LOX/PDGFB/IGFBP3/BMP4, downregulated in response to A740003 treatment. Conclusion: Our data illustrates a role for P2RX7B in OS tumour growth, progression and metastasis. We show that P2RX7B is a future therapeutic target in human OS.

Multiple myeloma-A painful disease of the bone marrow.

Multiple myeloma is a bone marrow neoplasia with an incidence of 6/100,000/year in Europe. While the disease remains incurable, the development of novel treatments such as autologous stem cell transplantation, proteasome inhibitors and monoclonal antibodies has led to an increasing subset of patients living with long-term myeloma. However, more than two thirds of patients suffer from bone pain, often described as severe, and knowledge on the pain mechanisms and its effect on their health-related quality of life (HRQoL) is limited. In this review, we discuss the mechanisms of myeloma bone disease, the currently available anti-myeloma treatments and the lessons learnt from clinical studies regarding HRQoL in myeloma patients. Moreover, we discuss the mechanisms of cancer-induced bone pain and the knowledge that animal models of myeloma-induced bone pain can provide to identify novel analgesic targets. To date, information regarding bone pain and HRQoL in myeloma patients is still scarce and an effort should be made to use standardised questionnaires to assess patient-reported outcomes that allow inter-study comparisons of the available clinical data.