Plain Radiography: A Unique Component of Spinal Assessment and Predictive Health.

While some research supports utilizing plain radiography for measuring biomechanical alignment of the spine for prognosis and treatment, there are contrasting viewpoints regarding both the value and utilization of these procedures in conservative care. Evaluation of both conservative and non-conservative approaches to spinal care revealed vast differences in radiographic utilization and interpretation between orthopedic surgeons, primary care physicians, chiropractic physicians, and physical therapists, which may account for the different viewpoints and rationales in the literature. A research summary is provided to explore any unique biomechanical parameters identified with plain radiography of the spine (PROTS) and how these measurements may relate to patient health. Understanding any unique value provided through biomechanical assessment utilizing PROTS may help chiropractic physicians determine the appropriate use of radiographic procedures in clinical practice and how to coordinate efforts with other conservative and non-conservative spinal healthcare professions to improve patient health.

An unappreciated cell survival-independent role for BAFF initiating chronic lymphocytic leukemia.

Background: Chronic Lymphocytic Leukemia (CLL) is characterized by the expansion of CD19+ CD5+ B cells but its origin remains debated. Mutated CLL may originate from post-germinal center B cells and unmutated CLL from CD5+ mature B cell precursors. Irrespective of precursor types, events initiating CLL remain unknown. The cytokines BAFF and APRIL each play a significant role in CLL cell survival and accumulation, but their involvement in disease initiation remains unclear. Methods: We generated novel CLL models lacking BAFF or APRIL. In vivo experiments were conducted to explore the impact of BAFF or APRIL loss on leukemia initiation, progression, and dissemination. Additionally, RNA-seq and quantitative real-time PCR were performed to unveil the transcriptomic signature influenced by BAFF in CLL. The direct role of BAFF in controlling the expression of tumor-promoting genes was further assessed in patient-derived primary CLL cells ex-vivo. Results: Our findings demonstrate a crucial role for BAFF, but not APRIL, in the initiation and dissemination of CLL cells. In the absence of BAFF or its receptor BAFF-R, the TCL1 transgene only increases CLL cell numbers in the peritoneal cavity, without dissemination into the periphery. While BAFF binding to BAFF-R is dispensable for peritoneal CLL cell survival, it is necessary to activate a tumor-promoting gene program, potentially linked to CLL initiation and progression. This direct role of BAFF in controlling the expression of tumor-promoting genes was confirmed in patient-derived primary CLL cells ex-vivo. Conclusions: Our study, involving both mouse and human CLL cells, suggests that BAFF might initiate CLL through mechanisms independent of cell survival. Combining current CLL therapies with BAFF inhibition could offer a dual benefit by reducing peripheral tumor burden and suppressing transformed CLL cell output.

Proactive enteral nutrition for patients undergoing allogeneic stem cell transplantation- implementation and clinical outcomes.

BACKGROUND/ OBJECTIVES: Nutrition support is frequently required post allogeneic haematopoietic progenitor cell transplantation (HPCT) however the tolerance of enteral nutrition (EN) can vary. This mixed methods study aimed to explore staff perceptions, barriers and enablers to the use of EN post HPCT and report the implementation and outcomes of a nutrition protocol. SUBJECT/ METHODS: A survey on barriers and enablers to the use of EN was developed and distributed to medical and nursing staff. Data on nutrition and clinical outcomes was collected for 12 months post implementation of a new nutrition protocol. RESULTS: Thirty staff completed the survey, key barriers identified included uncertain EN tolerance, lack of confidence in nasogastric tube placement and insufficient training and resources. Eighty-four patients commenced EN, 23 changed to PN (27%) and 61 received EN only (73%). In total 36 patients received PN and eight patients oral nutrition support only. There was a difference in type of conditioning (p = 0.025) and nutritional status (p = 0.016) between patients who received PN vs EN only, with a higher proportion of malnourished patients receiving PN (23% vs 5%). Patients who received PN had a longer length of hospital stay (median 22 vs 19 days, p = 0.012) and lower rate of survival to day 100 (81% vs 95%, p = 0.036) than patients who received EN. CONCLUSION: The use of EN may lead to improved clinical outcomes compared to PN therefore should be implemented as first line nutrition support.

Safety, Feasibility, and Acceptability of a Multisite Individualized Exercise Intervention for People with Multiple Myeloma.

INTRODUCTION: High rates of disease- and treatment-related symptoms, such as bone lesions, in people with multiple myeloma (MM) create uncertainty on the safety and feasibility of exercise. This study determined the safety, feasibility, and acceptability of an individualized exercise medicine program for people with MM at any disease stage. METHODS: A multisite, randomized waitlist-controlled trial was conducted of an individualized, high-intensity aerobic, resistance, and impact-loading exercise program. The exercise sessions were supervised twice weekly by accredited exercise physiologists, with one additional unsupervised session per week, for 12 wk. Safety was determined by number of adverse and serious adverse events. Feasibility outcome measures were study eligibility, recruitment, adherence, and attrition. Acceptability was determined by qualitative interviews and subjective levels of enjoyment. RESULTS: Of 203 people with MM screened, 88% were eligible, with 34% accepting participation (60 people) and 20% attrition for the between-group analysis, meeting a priori criteria (≥25% and <25%, respectively). No adverse or serious adverse events attributed to testing and/or exercise training were reported. Attendance at supervised exercise sessions was 98%, with 45% completion of the home-based exercise sessions. Adherence rates were 35%, 63%, and 34% for the aerobic, resistance, and impact-loading protocols, with 55%, 80%, and 37% of participants meeting a priori criteria (75% of protocol). Acceptability of the exercise program was high (mean, 82%; 95% confidence interval, 78%-87%) and highly supported by qualitative responses. CONCLUSIONS: An individualized, high-intensity aerobic, resistance, and impact-loading exercise medicine program is safe and acceptable, and feasible by some measures for people with MM. Adherence to the prescribed exercise protocols was limited by comorbidities and disease symptoms. Strategies to improve unsupervised exercise completion are warranted in this population.

Relapsed nodular lymphocyte-predominant Hodgkin lymphoma presenting as severe paraneoplastic hepatitis: a case report.

BACKGROUND: Hematological malignancies are an infrequent but important cause of liver dysfunction. There are several mechanisms by which this can occur, including direct malignant infiltration of the hepatic parenchyma and/or vasculature, vanishing bile duct syndrome, and paraneoplastic hepatitis. Paraneoplastic hepatitis is an extremely rare mechanism by which a hematological malignancy can cause liver dysfunction, and we present the first case, to our knowledge, of paraneoplastic hepatitis caused by nodular lymphocyte-predominant Hodgkin lymphoma in the literature. CASE PRESENTATION: A 28-year-old Caucasian male presented with 3 weeks of fatigue, epigastric pain, and jaundice. His medical history was significant for early stage nodular lymphocyte-predominant Hodgkin lymphoma in the cervical region in remission for 5 years after primary treatment with involved-field radiotherapy. Liver biochemistry was normal at the time of treatment for lymphoma and there was no known liver disease before the current presentation. On physical examination, there was scleral icterus and ecchymoses, but no evidence of hepatic encephalopathy, other stigmata of chronic liver disease, or lymphadenopathy. A computed tomography scan of his neck, chest, abdomen, and pelvis showed heterogeneous enhancement of the liver, multiple enlarged upper abdominal lymph nodes, and an enlarged spleen with multiple rounded lesions. Portal and hepatic veins were patent. Initial workup for viral, autoimmune-, toxin-, and medication-related hepatitis was negative. A transjugular liver biopsy was performed with histology showing a predominantly T-cell mediated hepatitis with very extensive multiacinar hepatic necrosis, but no evidence of lymphoma within the liver. Retroperitoneal lymph node biopsy revealed nodular lymphocyte-predominant Hodgkin lymphoma. The patient's symptoms, bilirubin, and transaminases improved significantly after treatment with oral prednisolone and a staged introduction of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy. CONCLUSIONS: Nodular lymphocyte-predominant Hodgkin lymphoma may cause paraneoplastic hepatitis. Physicians should be aware of the possibility of this life-threatening presentation and the importance of early liver biopsy and treatment before acute liver failure occurs. Interestingly, paraneoplastic hepatitis did not occur when nodular lymphocyte-predominant Hodgkin lymphoma was first diagnosed and confined to the cervical region, but was the presenting feature of the recurrence below the diaphragm.

Rescue of infant progressive familial intrahepatic cholestasis type 3 mice by repeated dosing of AAV gene therapy.

Background & Aims: Gene therapy using recombinant adeno-associated virus (rAAV) vector carrying multidrug resistance protein 3 (MDR3) coding sequence (AAV8-MDR3) represents a potential curative treatment for progressive familial intrahepatic cholestasis type 3 (PFIC3), which presents in early childhood. However, patients with the severest form of PFIC3 should receive treatment early after detection to prevent irreversible hepatic fibrosis leading ultimately to liver transplantation or death. This represents a challenge for rAAV-based gene therapy because therapeutic efficacy is expected to wane as rAAV genomes are lost owing to hepatocyte division, and the formation of AAV-specific neutralising antibodies precludes re-administration. Here, we tested a strategy of vector re-administration in infant PFIC3 mice with careful evaluation of its oncogenicity - a particular concern surrounding rAAV treatment. Methods: AAV8-MDR3 was re-administered to infant Abcb4 -/- mice 2 weeks after a first dose co-administered with tolerogenic nanoparticles carrying rapamycin (ImmTOR) given at 2 weeks of age. Eight months later, long-term therapeutic efficacy and safety were assessed with special attention paid to the potential oncogenicity of rAAV treatment. Results: Co-administration with ImmTOR mitigated the formation of rAAV-specific neutralising antibodies and enabled an efficacious second administration of AAV8-MDR3, resulting in stable correction of the disease phenotype, including a restoration of bile phospholipid content and healthy liver function, as well as the prevention of liver fibrosis, hepatosplenomegaly, and gallstones. Furthermore, efficacious repeat rAAV administration prevented the appearance of liver malignancies in an animal model highly prone to developing hepatocellular carcinoma. Conclusions: These outcomes provide strong evidence for rAAV redosing through co-administration with ImmTOR, as it resulted in a long-term therapeutic effect in a paediatric liver metabolic disorder, including the prevention of oncogenesis. Impact and implications: Redosing of gene therapy for inborn hepatobiliary disorders may be essential as effect wanes during hepatocyte division and renewal, particularly in paediatric patients, but the approach may carry long-term risks of liver cancer. Viral vectors carrying a therapeutic gene exerted a durable cure of progressive familial intrahepatic cholestasis type 3 in infant mice and reduced the risk of liver cancer only following a second administration.

The importance of frailty assessment in multiple myeloma: a position statement from the Myeloma Scientific Advisory Group to Myeloma Australia.

Multiple myeloma (MM) is a disease of older people, yet factors relating to comorbidity and frailty may threaten treatment tolerability for many of this heterogenous group. There has been increasing interest in defining specific and clinically relevant frailty assessment tools within the MM population, with the goal of using these frailty scores, not just as a prognostic instrument, but also as a predictive tool to allow for a frailty-adapted treatment approach. This paper reviews the various frailty assessment frameworks used in the evaluation of patients with MM, including the International Myeloma Working Group Frailty Index (IMWG-FI), the Mayo Frailty Index and the simplified frailty scale. While the IMWG-FI remains the most widely accepted tool, the simplified frailty scale is the most user-friendly in busy day-to-day clinics based on its ease of use. This paper summarises the recommendations from the Myeloma Scientific Advisory Group (MSAG) of Myeloma Australia, on the use of frailty assessment tools in clinical practice and proposes a frailty-stratified treatment algorithm to aid clinicians in tailoring therapy for this highly heterogeneous patient population.

Gene therapy for liver diseases - progress and challenges.

Gene therapy is poised to revolutionize modern medicine, with seemingly unlimited potential for treating and curing genetic disorders. For otherwise incurable indications, including most inherited metabolic liver disorders, gene therapy provides a realistic therapeutic option. In this Review, we discuss gene supplementation and gene editing involving the use of recombinant adeno-associated virus (rAAV) vectors for the treatment of inherited liver diseases, including updates on several ongoing clinical trials that are producing promising results. Clinical testing has been essential in highlighting many key translational challenges associated with this transformative therapy. In particular, the interaction of a patient's immune system with the vector raises issues of safety and the duration of treatment efficacy. Furthermore, several serious adverse events after the administration of high doses of rAAVs suggest greater involvement of innate immune responses and pre-existing hepatic conditions than initially anticipated. Finally, permanent modification of the host genome associated with rAAV genome integration and gene editing raises concerns about the risk of oncogenicity that require careful evaluation. We summarize the main progress, challenges and pathways forward for gene therapy for liver diseases.

Gene Therapy for Acquired and Genetic Cholestasis.

Cholestatic diseases can be caused by the dysfunction of transporters involved in hepatobiliary circulation. Although pharmacological treatments constitute the current standard of care for these diseases, none are curative, with liver transplantation being the only long-term solution for severe cholestasis, albeit with many disadvantages. Liver-directed gene therapy has shown promising results in clinical trials for genetic diseases, and it could constitute a potential new therapeutic approach for cholestatic diseases. Many preclinical gene therapy studies have shown positive results in animal models of both acquired and genetic cholestasis. The delivery of genes that reduce apoptosis or fibrosis or improve bile flow has shown therapeutic effects in rodents in which cholestasis was induced by drugs or bile duct ligation. Most studies targeting inherited cholestasis, such as progressive familial intrahepatic cholestasis (PFIC), have focused on supplementing a correct version of a mutated gene to the liver using viral or non-viral vectors in order to achieve expression of the therapeutic protein. These strategies have generated promising results in treating PFIC3 in mouse models of the disease. However, important challenges remain in translating this therapy to the clinic, as well as in developing gene therapy strategies for other types of acquired and genetic cholestasis.

A minimal bile salt excretory pump promoter allows bile acid-driven physiological regulation of transgene expression from a gene therapy vector.

BACKGROUND: Bile acid (BA) homeostasis is mainly regulated by bile salt excretory pump (BSEP), a hepatocyte transporter that transfers BAs to the bile. BSEP expression is regulated by BA levels through activation of farnesoid X receptor transcription factor, which binds to the inverted repeat (IR-1) element in the BSEP promoter. Gene therapy of cholestatic diseases could benefit from using vectors carrying endogenous promoters physiologically regulated by BAs, however their large size limits this approach, especially when using adeno-associated viral vector (AAV) vectors. RESULTS: We evaluated the functionality and BA-mediated regulation of minimal versions of human and mouse BSEP promoters containing IR-1 using AAV vectors expressing luciferase. Unexpectedly, a minimal mouse BSEP promoter (imPr) showed higher BA-mediated expression and inducibility than a minimal human promoter (ihPr) or than full-length BSEP promoters in human hepatic cells. In addition, in mice receiving an AAV8 vector carrying imPr promoter-driven luciferase expression was efficiently regulated by administration of a BA-enriched diet. Interestingly, this vector also expressed significantly higher luciferase levels in Abcb4-/- mice, which have high levels of BAs, compared to wild type mice, or to mice receiving a vector containing the luciferase gene downstream of the constitutive alpha-1 antitrypsin promoter. In contrast, the AAV vector containing ihPr showed very low luciferase expression with no inducibility. Finally, we optimized imPr by adding three IR-1 repeats at its 5' end. This new promoter provided higher levels of luciferase than imPr both in vitro and in vivo. CONCLUSIONS: The imPr could represent a useful tool for gene therapy approaches in which physiological BA regulation is desired.

mRNA and gene editing: Late breaking therapies in liver diseases.

The efficient delivery of RNA molecules to restore the expression of a missing or inadequately functioning protein in a target cell and the intentional specific modification of the host genome using engineered nucleases represent therapeutic concepts that are revolutionizing modern medicine. The initiation of several clinical trials using these approaches to treat metabolic liver disorders as well as the recently reported remarkable results obtained by patients with transthyretin amyloidosis highlight the advances in this field and show the potential of these therapies to treat these diseases safely and efficaciously. These advances have been possible due, firstly, to significant improvements made in RNA chemistry that increase its stability and prevent activation of the innate immune response and, secondly, to the development of very efficient liver-targeted RNA delivery systems. In parallel, the breakout of CRISPR/CRISPR-associated 9-based technology in the gene editing field has marked a turning point in in vivo modification of the cellular genome with therapeutic purposes, which can be based on gene supplementation, correction, or silencing. In the coming years we are likely to witness the therapeutic potential of these two strategies both separately and in combination. In this review we summarize the preclinical data obtained in animal models treated with mRNA as a therapeutic agent and discuss the different gene editing strategies applied to the treatment of liver diseases, highlighting both their therapeutic efficacy as well as safety concerns.

An Individualized Exercise Intervention for People with Multiple Myeloma-Study Protocol of a Randomized Waitlist-Controlled Trial.

People with multiple myeloma (MM) are second only to people with lung cancer for the poorest reported health-related quality of life (HRQoL) of all cancer types. Whether exercise can improve HRQoL in MM, where bone pain and lesions are common, requires investigation. This trial aims to evaluate the efficacy of an exercise intervention compared with control on HRQoL in people with MM. Following baseline testing, people with MM (n = 60) will be randomized to an exercise (EX) or waitlist control (WT) group. EX will complete 12-weeks of supervised (24 sessions) and unsupervised (12 sessions) individualized, modular multimodal exercise training. From weeks 12-52, EX continue unsupervised training thrice weekly, with one optional supervised group-based session weekly from weeks 12-24. The WT will be asked to maintain their current activity levels for the first 12-weeks, before completing the same protocol as EX for the following 52 weeks. Primary (patient-reported HRQoL) and secondary (bone health and pain, fatigue, cardiorespiratory fitness, muscle strength, body composition, disease response, and blood biomarkers) outcomes will be assessed at baseline, 12-, 24- and 52-weeks. Adverse events, attendance, and adherence will be recorded and cost-effectiveness analysis performed. The findings will inform whether exercise should be included as part of standard myeloma care to improve the health of this unique population.

Imaging of patients with multiple myeloma and associated plasma cell disorders: consensus practice statement by the Medical Scientific Advisory Group to Myeloma Australia.

Imaging modalities for multiple myeloma (MM) have evolved to enable earlier detection of disease. Furthermore, the diagnosis of MM requiring therapy has recently changed to include disease prior to bone destruction, specifically the detection of focal bone lesions. Focal lesions are early, abnormal areas in the bone marrow, which may signal the development of subsequent lytic lesions that typically occur within the next 18-24 months. Cross-sectional imaging modalities are more sensitive for the detection and monitoring of bone and bone marrow disease and are now included in the International Myeloma Working Group current consensus criteria for initial diagnosis and treatment response assessment. The aim of this consensus practice statement is to review the evidence supporting these modalities. A more detailed Position Statement can be found on the Myeloma Australia website.

Novel vectors and approaches for gene therapy in liver diseases.

Gene therapy is becoming an increasingly valuable tool to treat many genetic diseases with no or limited treatment options. This is the case for hundreds of monogenic metabolic disorders of hepatic origin, for which liver transplantation remains the only cure. Furthermore, the liver contains 10-15% of the body's total blood volume, making it ideal for use as a factory to secrete proteins into the circulation. In recent decades, an expanding toolbox has become available for liver-directed gene delivery. Although viral vectors have long been the preferred approach to target hepatocytes, an increasing number of non-viral vectors are emerging as highly efficient vehicles for the delivery of genetic material. Herein, we review advances in gene delivery vectors targeting the liver and more specifically hepatocytes, covering strategies based on gene addition and gene editing, as well as the exciting results obtained with the use of RNA as a therapeutic molecule. Moreover, we will briefly summarise some of the limitations of current liver-directed gene therapy approaches and potential ways of overcoming them.

Use of an adeno-associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model.

Phenylketonuria (PKU) is the most common inborn error of metabolism of the liver, and results from mutations of both alleles of the phenylalanine hydroxylase gene (PAH). As such, it is a suitable target for gene therapy via gene delivery with a recombinant adeno-associated virus (AAV) vector. Here we use the synthetic AAV vector Anc80 via systemic administration to deliver a functional copy of a codon-optimized human PAH gene, with or without an intron spacer, to the Pahenu2 mouse model of PKU. Dose-dependent transduction of the liver and expression of PAH mRNA were present with both vectors, resulting in significant and durable reduction of circulating phenylalanine, reaching near control levels in males. Coat color of treated Pahenu2 mice reflected an increase in pigmentation from brown to the black color of control animals, further indicating functional restoration of phenylalanine metabolism and its byproduct melanin. There were no adverse effects associated with administration of AAV up to 5 × 1012 VG/kg, the highest dose tested. Only minor and/or transient variations in some liver enzymes were observed in some of the AAV-dosed animals which were not associated with pathology findings in the liver. Finally, there was no impact on cell turnover or apoptosis as evaluated by Ki-67 and TUNEL staining, further supporting the safety of this approach. This study demonstrates the therapeutic potential of AAV Anc80 to safely and durably cure PKU in a mouse model, supporting development for clinical consideration.

CRISPR-Cas9 gene editing of hepatitis B virus in chronically infected humanized mice.

Chronic hepatitis B virus (HBV) infection is a major public health problem. New treatment approaches are needed because current treatments do not target covalently closed circular DNA (cccDNA), the template for HBV replication, and rarely clear the virus. We harnessed adeno-associated virus (AAV) vectors and CRISPR-Staphylococcus aureus (Sa)Cas9 to edit the HBV genome in liver-humanized FRG mice chronically infected with HBV and receiving entecavir. Gene editing was detected in livers of five of eight HBV-specific AAV-SaCas9-treated mice, but not control mice, and mice with detectable HBV gene editing showed higher levels of SaCas9 delivery to HBV+ human hepatocytes than those without gene editing. HBV-specific AAV-SaCas9 therapy significantly improved survival of human hepatocytes, showed a trend toward decreasing total liver HBV DNA and cccDNA, and was well tolerated. This work provides evidence for the feasibility and safety of in vivo gene editing for chronic HBV infections, and it suggests that with further optimization, this approach may offer a plausible way to treat or even cure chronic HBV infections.

Nutrition support during allogeneic stem cell transplantation: evidence versus practice.

PURPOSE: Enteral (EN) or parenteral nutrition (PN) is frequently required during allogeneic haematopoietic progenitor cell transplantation (HPCT), however there is limited consensus on the appropriate mode and timing of nutrition support commencement. This study aimed to investigate current nutrition support practices in Australian allogeneic transplant units and explore barriers and enablers to the use of EN and PN. METHODS: All Australian adult allogeneic HPCT units were eligible to participate. A survey tool was developed, and phone interview with each unit dietitian was completed to explore current nutrition support and perceived barriers and enablers to provision of nutrition care. RESULTS: A total of 12 (100%) units agreed to participate. Six (50%) units reported using PN as standard care and six use EN routinely for one or more conditioning regimens. All units using EN place feeding tubes proactively with tolerance of EN reported at 50-95%. The most frequently reported barriers to the use of EN include perception of poor EN tolerance, medical team preference for PN, gastrointestinal symptoms and thrombocytopenia. Reported barriers to the use of PN include fluid overload, elevated liver enzymes, patient apprehension about PN commencement, medical team uncertainty if PN is required and patients approaching engraftment. CONCLUSION: There is wide variation in the mode and timing of nutrition support provided to patients undergoing allogeneic HPCT. Clinical guidelines should be updated to reflect recent findings on EN use and incorporate strategies to optimise EN tolerance. This will assist in standardising practice and facilitate evidence-based nutrition care.