Development of ISB 1442, a CD38 and CD47 bispecific biparatopic antibody innate cell modulator for the treatment of multiple myeloma.

Antibody engineering can tailor the design and activities of therapeutic antibodies for better efficiency or other advantageous clinical properties. Here we report the development of ISB 1442, a fully human bispecific antibody designed to re-establish synthetic immunity in CD38+ hematological malignancies. ISB 1442 consists of two anti-CD38 arms targeting two distinct epitopes that preferentially drive binding to tumor cells and enable avidity-induced blocking of proximal CD47 receptors on the same cell while preventing on-target off-tumor binding on healthy cells. The Fc portion of ISB 1442 is engineered to enhance complement dependent cytotoxicity, antibody dependent cell cytotoxicity and antibody dependent cell phagocytosis. ISB 1442 thus represents a CD47-BsAb combining biparatopic targeting of a tumor associated antigen with engineered enhancement of antibody effector function to overcome potential resistance mechanisms that hamper treatment of myeloma with monospecific anti-CD38 antibodies. ISB 1442 is currently in a Phase I clinical trial in relapsed refractory multiple myeloma.

Common Peroneal Nerve Compression Neuropathy Due to a Large Synovial Cyst From the Proximal Tibiofibular Joint in a Teenager.

Ganglion cysts are very rare in the lower limb and when present, ganglion cysts rarely cause compression neuropathy at any site. Peripheral nerve sheath tumors as a whole, are also very rare and mostly presented as a painful lump along the nerve path. Ganglion cysts are non-neoplastic gelatinous cysts, which lack true synovial lining. They can be divided into intraneural cysts which can be found within the epineurium of a peripheral nerve and lead to signs and symptoms of peripheral neuropathy or extraneural cysts which can develop from surrounding joints or tendon sheaths causing gradual nerve compression. Intraneural tumors of common peroneal nerve (CPN) are widely reported in the literature with varying degrees of symptoms; however, there are only a few case reports describing CPN palsy due to extraneural cysts. We are reporting a rare case of atraumatic CPN palsy, which resulted in irreversible foot drop in a teenage boy who presented with right leg radiating calf and foot pain. We recommend prompt investigation and excision of the cyst to decompress the nerve to increase the chances of early recovery and favorable outcomes.

First MTP joint injuries: MR imaging findings in surgically managed patients.

OBJECTIVES: Determine whether MR imaging findings or demographics predict surgical management in patients with first MTP joint injuries. MATERIALS AND METHODS: Retrospective study of 161 forefoot MRs for traumatic first MTP injury (M:F 92:69, mean age 33 ± 13 yrs.). Two radiologists reviewed imaging for ligamentous, osseous, and tendinous injuries. Ligaments and tendons were graded as 0:normal, 1:sprain or strain, 2:partial tear, 3:complete tear. Osseous injuries were classified as edema, fracture, or cartilage injury. Clinical data obtained included sex, age, injury acuity, sport participation, level of sport, and treatment. Imaging findings and demographic data were assessed to determine predictive factors for surgical management. Statistics included kappa, chi-squared, Fisher's exact, and logistic regression. RESULTS: Logistic regression (odds ratio [95% CI], p-value) showed that grade 2 or 3 injuries of the plantar ligamentous complex (2.87, [1.10, 7.48], p = 0.031), grade 2 or 3 injuries of the medial collateral ligament (3.24, [1.16, 9.08], p = 0.025), and participation in collegiate or professional sports (4.34 [1.64, 11.52], p = 0.003) were associated with an increased rate of surgical intervention. k = ligamentous injury (0.71-0.83), osseous trauma (0.88-0.95), and tendon injury (0.78). All other imaging findings and demographic factors were not significant predictors of surgery (p > 0.05). CONCLUSION: Participation in collegiate or professional sports and tears of the plantar ligamentous complex or medial collateral ligament predicted surgical management in patients with first MTP trauma.

Management of bone metastasis and cancer treatment-induced bone loss during the COVID-19 pandemic: An international perspective and recommendations.

Optimum management of patients with cancer during the COVID-19 pandemic has proved extremely challenging. Patients, clinicians and hospital authorities have had to balance the risks to patients of attending hospital, many of whom are especially vulnerable, with the risks of delaying or modifying cancer treatment. Those whose care has been significantly impacted include patients suffering from the effects of cancer on bone, where delivering the usual standard of care for bone support has often not been possible and clinicians have been forced to seek alternative options for adequate management. At a virtual meeting of the Cancer and Bone Society in July 2020, an expert group shared experiences and solutions to this challenge, following which a questionnaire was sent internationally to the symposium's participants, to explore the issues faced and solutions offered. 70 respondents, from 9 countries (majority USA, 39%, followed by UK, 19%) included 50 clinicians, spread across a diverse range of specialties (but with a high proportion, 64%, of medical oncologists) and 20 who classified themselves as non-clinical (solely lab-based). Spread of clinician specialty across tumour types was breast (65%), prostate (27%), followed by renal, myeloma and melanoma. Analysis showed that management of metastatic bone disease in all solid tumour types and myeloma, adjuvant bisphosphonate breast cancer therapy and cancer treatment induced bone loss, was substantially impacted. Respondents reported delays to routine CT scans (58%), standard bone scans (48%) and MRI scans (46%), though emergency scans were less affected. Delays in palliative radiotherapy for bone pain were reported by 31% of respondents with treatments often involving only a single dose without fractionation. Delays to, or cancellation of, prophylactic surgery for bone pain were reported by 35% of respondents. Access to treatments with intravenous bisphosphonates and subcutaneous denosumab was a major problem, mitigated by provision of drug administration at home or in a local clinic, reduced frequency of administration or switching to oral bisphosphonates taken at home. The questionnaire also revealed damaging delays or complete stopping of both clinical and laboratory research. In addition to an analysis of the questionnaire, this paper presents a rationale and recommendations for adaptation of the normal guidelines for protection of bone health during the pandemic.

Cutaneous toxicities in patients with melanoma receiving checkpoint inhibitor therapy: a retrospective review. The experience of a single large specialist institution.

Checkpoint inhibitor (CPI) therapy has significantly improved overall survival for metastatic melanoma, and is now approved for use in the adjuvant setting. Modulating the immune system is recognized to cause cutaneous immune-related adverse events (irAEs). We conducted a retrospective observational cohort study of adult patients with melanoma at our tertiary referral centre, who received CPI therapy from 2006 to March 2018. This is the single largest study of cutaneous irAEs occurring on CPI therapy in patients with melanoma to date and encompasses 12 years. The results showed that cutaneous toxicity occurs in 24% of patients but is generally manageable, with < 5% patients discontinuing treatment.

AURIEL-PsO: a randomized, double-blind phase III equivalence trial to demonstrate the clinical similarity of the proposed biosimilar MSB11022 to reference adalimumab in patients with moderate-to-severe chronic plaque-type psoriasis.

BACKGROUND: MSB11022 is a proposed adalimumab biosimilar. OBJECTIVES: To compare the efficacy, safety and immunogenicity of MSB11022 with reference adalimumab. METHODS: AURIEL-PsO was a double-blind randomized controlled equivalence trial, in which patients with moderate-to-severe chronic plaque-type psoriasis were randomized 1 : 1 to MSB11022 or reference adalimumab. The primary end point was ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) at week 16, with a prespecified equivalence interval of ± 18%. Patients with a ≥50% improvement in PASI at week 16 were eligible to enter a double-blind extension period: patients receiving MSB11022 continued treatment, and patients receiving reference adalimumab were rerandomized 1 : 1 either to continue reference adalimumab or to switch to MSB11022. Other efficacy end points and safety, immunogenicity and pharmacokinetic parameters were evaluated at scheduled visits up to weeks 52 (efficacy and immunogenicity), 54 and 66 (safety). RESULTS: In total, 443 patients were randomized. The difference in PASI 75 response rates at week 16 between the treatment arms was -1·9%, and the 95% confidence interval (-7·8% to 4·1%) was within the prespecified equivalence interval. No notable difference in the incidence of treatment-emergent adverse events was observed between treatment arms up to the end of the trial, and no new safety signals were observed. Following treatment switch at week 16, no clinically meaningful differences in safety or immunogenicity were seen between treatment arms through to the end of the observation period. CONCLUSIONS: Therapeutic equivalence between MSB11022 and reference adalimumab was demonstrated. AURIEL-PsO provides evidence to support the similarity of both products with regard to efficacy, safety and immunogenicity. What's already known about this topic? Adalimumab is a fully human antitumour necrosis factor-α monoclonal antibody, indicated for the treatment of multiple inflammatory disorders, including psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel diseases and ankylosing spondylitis. MSB11022 is a proposed adalimumab biosimilar that has shown structural and functional similarity to the reference product in an extensive analytical comparability exercise. MSB11022 has demonstrated bioequivalence and comparable safety and immunogenicity profiles in a phase I study in healthy volunteers. What does this study add? This phase III study confirmed equivalent efficacy for MSB11022 and reference adalimumab in patients without any immunomodulation comedication in moderate-to-severe chronic plaque-type psoriasis at week 16. The efficacy, safety and immunogenicity of MSB11022 and reference adalimumab were similar over the respective observation periods (week 52 for efficacy and immunogenicity, week 66 for safety). A switch from reference adalimumab to MSB11022 at week 16 did not impact efficacy, safety or immunogenicity.

Automatic Quality Assessment of Transperineal Ultrasound Images of the Male Pelvic Region, Using Deep Learning.

Ultrasound guidance is not in widespread use in prostate cancer radiotherapy workflows. This can be partially attributed to the need for image interpretation by a trained operator during ultrasound image acquisition. In this work, a one-class regressor, based on DenseNet and Gaussian processes, was implemented to automatically assess the quality of transperineal ultrasound images of the male pelvic region. The implemented deep learning approach was tested on 300 transperineal ultrasound images and it achieved a scoring accuracy of 94%, a specificity of 95% and a sensitivity of 92% with respect to the majority vote of 3 experts, which was comparable with the results of these experts. This is the first step toward a fully automatic workflow, which could potentially remove the need for ultrasound image interpretation and make real-time volumetric organ tracking in the radiotherapy environment using ultrasound more appealing.

The impact of BMI and smoking on risk of revision following knee and hip replacement surgery: evidence from routinely collected data.

OBJECTIVE: The aim of this study was to assess the association of body mass index (BMI) and smoking with risk of revision following total knee replacement (TKR) and total hip replacement (THR). DESIGN: Primary care data, from the Clinical Practice Research Datalink (CPRD), was linked to inpatient hospital records, from Hospital Episode Statistics Admitted Patient Care (HES APC), and covered 1997 to 2014. Parametric survival models, with BMI and smoking status included as explanatory variables, were estimated for 10-year risk of revision and mortality, and were extrapolated to estimate lifetime risk of revision. FINDINGS: TKR and THR cohorts included 10,260 and 10,961 individuals, respectively. For a change in BMI from 25 to 35, the 10-year risk of revision is expected change from 4.6% (3.3-6.4%) to 3.7% (2.6-5.1%) for TKR and 3.7% (2.8-5.1%) to 4.0% (2.8-5.7%) for THR for an otherwise average patient profile. Meanwhile, changing from a non-smoker to a current smoker is expected to change the risk of revision from 4.1% (3.1-5.5%) to 2.8% (1.7-4.7%) for TKR and from 3.8% (2.8-5.3%) to 2.9% (1.9-4.7%) for THR for an otherwise average patient profile. Estimates of lifetime risk were also similar for different values of BMI or smoking status. CONCLUSIONS: Obesity and smoking do not appear to have a meaningful impact on the risk of revision following TKR and THR.

Novel method for rapid toxicity screening of magnetic nanoparticles.

Iron oxide nanoparticles have attracted a great deal of research interest and have been widely used in bioscience and clinical research including as contrast agents for magnetic resonance imaging, hyperthermia and magnetic field assisted radionuclide therapy. It is therefore important to develop methods, which can provide high-throughput screening of biological responses that can predict toxicity. The use of nanoelectrodes for single cell analysis can play a vital role in this process by providing relatively fast, comprehensive, and cost-effective assessment of cellular responses. We have developed a new method for in vitro study of the toxicity of magnetic nanoparticles (NP) based on the measurement of intracellular reactive oxygen species (ROS) by a novel nanoelectrode. Previous studies have suggested that ROS generation is frequently observed with NP toxicity. We have developed a stable probe for measuring intracellular ROS using platinized carbon nanoelectrodes with a cavity on the tip integrated into a micromanipulator on an upright microscope. Our results show a significant difference for intracellular levels of ROS measured in HEK293 and LNCaP cancer cells before and after exposure to 10 nm size iron oxide NP. These results are markedly different from ROS measured after cell incubation with the same concentration of NP using standard methods where no differences have been detected. In summary we have developed a label-free method for assessing nanoparticle toxicity using the rapid (less than 30 minutes) measurement of ROS with a novel nanoelectrode.

Mechanisms of obesity in Prader-Willi syndrome.

Obesity is the most common cause of metabolic complications and poor quality of life in Prader-Willi syndrome (PWS). Hyperphagia and obesity develop after an initial phase of poor feeding and failure to thrive. Several mechanisms for the aetiology of obesity in PWS are proposed, which include disruption in hypothalamic pathways of satiety control resulting in hyperphagia, aberration in hormones regulating food intake, reduced energy expenditure because of hypotonia and altered behaviour with features of autism spectrum disorder. Profound muscular hypotonia prevents PWS patients from becoming physically active, causing reduced muscle movements and hence reduced energy expenditure. In a quest for the aetiology of obesity, recent evidence has focused on several appetite-regulating hormones, growth hormone, thyroid hormones and plasma adipocytokines. However, despite advancement in understanding of the genetic basis of PWS, there are contradictory data on the role of satiety hormones in hyperphagia and data regarding dietary intake are limited. Mechanistic studies on the aetiology of obesity and its relationship with disease pathogenesis in PWS are required. . In this review, we focused on the available evidence regarding mechanisms of obesity and potential new areas that could be explored to help unravel obesity pathogenesis in PWS.

Polyphenols and health: Interactions between fibre, plant polyphenols and the gut microbiota.

A high-fibre diet and one rich in fruit and vegetables have long been associated with lower risk of chronic disease. There are several possible mechanisms underpinning these associations, but one likely important factor is the production of bioactive molecules from plant-based foods by the bacteria in the colon. This links to our growing understanding of the role of the gut microbiome in promoting health. Polyphenolic-rich plant foods have been associated with potential health effects in many studies, but the bioavailability of polyphenol compounds, as eaten, is often very low. Most of the ingested molecules enter the large intestine where they are catabolised to smaller phenolic acids that may be the key bioactive effectors. Dietary fibres, present in plant foods, are also fermented by the bacteria to short-chain fatty acids, compounds associated with several beneficial effects on cell turnover, metabolism and eating behaviour. Polyphenols and fibre are often eaten together, but there is a lack of research investigating the interaction between these two groups of key substrates for the colonic bacteria. In a project funded by the Biotechnology and Biological Sciences Research Council Diet and Health Research Industry Club, we are investigating whether combining different fibres and polyphenol sources can enhance the production of bioactive phenolic acids to promote health. This could lead to improved dietary recommendations and to new products with enhanced potential health-promoting actions.

A loss of host-derived MMP-7 promotes myeloma growth and osteolytic bone disease in vivo.

Matrix metalloproteinases (MMPs) play a critical role in cancer pathogenesis, including tumor growth and osteolysis within the bone marrow microenvironment. However, the anti-tumor effects of MMPs are poorly understood, yet have significant implications for the therapeutic potential of targeting MMPs. Host derived MMP-7 has previously been shown to support the growth of bone metastatic breast and prostate cancer. In contrast and underscoring the complexity of MMP biology, here we identified a tumor-suppressive role for host MMP-7 in the progression of multiple myeloma in vivo. An increase in tumor burden and osteolytic bone disease was observed in myeloma-bearing MMP-7 deficient mice, as compared to wild-type controls. We observed that systemic MMP-7 activity was reduced in tumor-bearing mice and, in patients with multiple myeloma this reduced activity was concomitant with increased levels of the endogenous MMP inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1). Our studies have identified an unexpected tumour-suppressive role for host-derived MMP-7 in myeloma bone disease in vivo, and highlight the importance of elucidating the effect of individual MMPs in a disease-specific context.

Tumour-derived alkaline phosphatase regulates tumour growth, epithelial plasticity and disease-free survival in metastatic prostate cancer.

BACKGROUND: Recent evidence suggests that bone-related parameters are the main prognostic factors for overall survival in advanced prostate cancer (PCa), with elevated circulating levels of alkaline phosphatase (ALP) thought to reflect the dysregulated bone formation accompanying distant metastases. We have identified that PCa cells express ALPL, the gene that encodes for tissue nonspecific ALP, and hypothesised that tumour-derived ALPL may contribute to disease progression. METHODS: Functional effects of ALPL inhibition were investigated in metastatic PCa cell lines. ALPL gene expression was analysed from published PCa data sets, and correlated with disease-free survival and metastasis. RESULTS: ALPL expression was increased in PCa cells from metastatic sites. A reduction in tumour-derived ALPL expression or ALP activity increased cell death, mesenchymal-to-epithelial transition and reduced migration. Alkaline phosphatase activity was decreased by the EMT repressor Snail. In men with PCa, tumour-derived ALPL correlated with EMT markers, and high ALPL expression was associated with a significant reduction in disease-free survival. CONCLUSIONS: Our studies reveal the function of tumour-derived ALPL in regulating cell death and epithelial plasticity, and demonstrate a strong association between ALPL expression in PCa cells and metastasis or disease-free survival, thus identifying tumour-derived ALPL as a major contributor to the pathogenesis of PCa progression.

Erythema action spectrum of topical 8-methoxypsoralen-sensitized skin re-evaluated: implications for routine clinical practice.

BACKGROUND: Published methodology used to determine psoralen plus ultraviolet A (PUVA) erythemal action spectrum does not reflect current clinical practice for psoralen sensitization. We re-evaluated the PUVA action spectrum using aqueous 8-methoxypsoralen (8-MOP) 2·6 mg L(-1) as used routinely in current clinical practice. OBJECTIVES: To determine the UVA erythema action spectrum of topical 8-MOP-sensitized normal skin. METHODS: Twenty healthy volunteers with skin phototypes I-V were recruited. Forearms were psoralen-sensitized at 37 °C for 10 min. Six UVA irradiations at 10-nm intervals between 325 and 375 nm were randomly allocated to forearm sites and were applied using a 10-nm bandwidth irradiation monochromator. The visual minimal phototoxic dose (MPD) was recorded on each site at 96 h. RESULTS: Volunteer Boston phototypes were: I, n = 2; II, n = 6; III, n = 6; IV, n = 5 and V, n = 1. The mean MPD (J cm(-2) ) for all subjects at each wavelength was as follows: 325 nm, 0·64 (SD 0·37); 335 nm, 0·80 (SD 0·58); 345 nm, 0·96 (SD 0·55); 355 nm, 1·50 (SD 0·85); 365 nm, 2·19 (SD 0·90); and 375 nm, 2·89 (SD 1·06). Therefore, the relative sensitization at each wavelength (erythemal action spectrum) was: 1, 0·83, 0·67, 0·43, 0·29 and 0·22. There were significant differences between the PUVA erythemal effectiveness at different wavelengths but none between skin types. CONCLUSIONS: This study has established the erythemal action spectrum for bath/soak PUVA therapy as is currently performed. In all volunteers, the peak sensitivity was at 325 nm. All volunteers showed a similar trend across the wavelengths studied irrespective of skin type. The determination of the action spectrum for PUVA-induced erythema is important as it permits reliable estimates of erythemal efficacy of any UVA source where the emission spectrum of the lamp is known or can be measured.

Needle-free nasal delivery of glucagon for treatment of diabetes-related severe hypoglycemia: toxicology of polypropylene resin used in delivery device.

CONTEXT: The intranasal route is a promising route of administration for several emergency rescue drugs including naloxone and glucagon. Glucagon nasal powder (GNP) is a novel, needle-free delivery system for intranasal administration of glucagon for the treatment of severe hypoglycemia, an infrequent but serious complication of insulin use in patients with diabetes. The GNP delivery device is a compact, highly portable, single-use nasal powder dosing device constructed of polypropylene that allows for simple, single-step administration. OBJECTIVE: To evaluate the toxicological profile of the polypropylene resin used in the actuator part of the delivery device that will contact skin and nasal mucosal membranes of the patient, we performed an in vitro cytotoxicity study, a skin sensitization study and an irritation (intracutaneous reactivity) study in animal models. METHODS: Extracts of the actuator of the GNP device were generated from HAM F12 medium with 10% fetal bovine serum, 0.9% sodium chloride (NaCl) or sesame oil. The in vitro cytotoxicity test was performed in cultured L929 mouse fibroblasts. Skin sensitization analysis was performed in 10 guinea pigs according to the Magnusson-Kligman method, using a maximization method with Freund's Complete Adjuvant. Irritation following intracutaneous/intradermal treatment with device extracts (NaCl and sesame oil extractants) was assessed in three New Zealand White rabbits. RESULTS: In vitro cytotoxicity test: Both undiluted and diluted extract showed no toxicity (i.e. no abnormal morphology, cell death or cell lysis) toward L929 fibroblasts (cytotoxicity grade 0). Sensitization test in guinea pigs: Challenge with device extracts did not evoke positive responses in test animals previously induced with device extracts. The net response value represented an incidence rate of 0% and a net dermal irritation score value of 0.00. Irritation (intracutaneous/intradermal) test in New Zealand White rabbits: Device extracts and corresponding vehicle controls caused similar irritation reactions. The difference between the mean scores for the device extracts and the corresponding vehicle controls was less than 1.0. CONCLUSIONS: Extracts of the polypropylene resin of the GNP delivery device are not cytotoxic, do not result in dermal sensitization and do not cause irritation when applied topically or intracutaneously. Given the infrequent use and very short duration of exposure to the nasal mucosa during administration of GNP, the polypropylene resin of the GNP device actuator will likely not cause adverse dermal sensitization effects or irritation effects in humans and can, therefore, be considered for use as a delivery device in clinical trials assessing the efficacy and safety of GNP for the treatment of insulin-using patients experiencing episodes of severe hypoglycemia.

The advantages of creating a positive radiation safety culture in the higher education and research sectors.

The safety culture of any organisation plays a critical role in setting the tone for both effective delivery of service and high standards of performance. By embedding safety at a cultural level, organisations are able to influence the attitudes and behaviours of stakeholders. To achieve this requires the ongoing commitment of heads of organisations and also individuals to prioritise safety no less than other competing goals (e.g. in universities, recruitment and retention are key) to ensure the protection of both people and the environment. The concept of culture is the same whatever the sector, e.g. medical, nuclear, industry, education, and research, but the higher education and research sectors within the UK are a unique challenge in developing a strong safety culture. This report provides an overview of the challenges presented by the sector, the current status of radiation protection culture, case studies to demonstrate good and bad practice in the sector and the practical methods to influence change.