Risk of COVID-19 death in cancer patients: an analysis from Guy's Cancer Centre and King's College Hospital in London.

BACKGROUND: Using an updated dataset with more patients and extended follow-up, we further established cancer patient characteristics associated with COVID-19 death. METHODS: Data on all cancer patients with a positive reverse transcription-polymerase chain reaction swab for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) at Guy's Cancer Centre and King's College Hospital between 29 February and 31 July 2020 was used. Cox proportional hazards regression was performed to identify which factors were associated with COVID-19 mortality. RESULTS: Three hundred and six SARS-CoV-2-positive cancer patients were included. Seventy-one had mild/moderate and 29% had severe COVID-19. Seventy-two patients died of COVID-19 (24%), of whom 35 died <7 days. Male sex [hazard ratio (HR): 1.97 (95% confidence interval (CI): 1.15-3.38)], Asian ethnicity [3.42 (1. 59-7.35)], haematological cancer [2.03 (1.16-3.56)] and a cancer diagnosis for >2-5 years [2.81 (1.41-5.59)] or ≥5 years were associated with an increased mortality. Age >60 years and raised C-reactive protein (CRP) were also associated with COVID-19 death. Haematological cancer, a longer-established cancer diagnosis, dyspnoea at diagnosis and raised CRP were indicative of early COVID-19-related death in cancer patients (<7 days from diagnosis). CONCLUSIONS: Findings further substantiate evidence for increased risk of COVID-19 mortality for male and Asian cancer patients, and those with haematological malignancies or a cancer diagnosis >2 years. These factors should be accounted for when making clinical decisions for cancer patients.

Charting the sequence-activity landscape of peptide inhibitors of translation termination.

Apidaecin (Api), an unmodified 18-amino-acid-long proline-rich antibacterial peptide produced by bees, has been recently described as a specific inhibitor of translation termination. It invades the nascent peptide exit tunnel of the postrelease ribosome and traps the release factors preventing their recycling. Api binds in the exit tunnel in an extended conformation that matches the placement of a nascent polypeptide and establishes multiple contacts with ribosomal RNA (rRNA) and ribosomal proteins. Which of these interactions are critical for Api's activity is unknown. We addressed this problem by analyzing the activity of all possible single-amino-acid substitutions of the Api variants synthesized in the bacterial cell. By conditionally expressing the engineered api gene, we generated Api directly in the bacterial cytosol, thereby bypassing the need for importing the peptide from the medium. The endogenously expressed Api, as well as its N-terminally truncated mutants, retained the antibacterial properties and the mechanism of action of the native peptide. Taking advantage of the Api expression system and next-generation sequencing, we mapped in one experiment all the single-amino-acid substitutions that preserve or alleviate the on-target activity of the Api mutants. Analysis of the inactivating mutations made it possible to define the pharmacophore of Api involved in critical interactions with the ribosome, transfer RNA (tRNA), and release factors. We also identified the Api segment that tolerates a variety of amino acid substitutions; alterations in this segment could be used to improve the pharmacological properties of the antibacterial peptide.

Solitary Conjunctivocorneal Plasmacytoma Arising After Cataract Surgery.

PURPOSE: To report a case of solitary plasmacytoma of the conjunctiva with corneal encroachment and to review the literature of all published cases. METHODS: A 70-year-old man presented with 1-month history of pain and watering in the right eye, 7 months after undergoing cataract surgery in the same eye. RESULTS: The mass was surgically excised. Pathology and immunohistochemistry were consistent with plasmacytoma. Staging studies found no evidence of systemic disease. CONCLUSIONS: To our knowledge, this is the first case of plasmacytoma in the literature to involve the cornea. This case was not associated with systemic disease. Surgical excision and brachytherapy remain options for cases without corneal involvement.

The relative importance of factors predicting outcome for myeloma patients at different ages: results from 3894 patients in the Myeloma XI trial.

Disease factors such as tumor burden and molecular risk affect myeloma patient outcomes as well as patient factors that impact the capacity to deliver treatment. How the relative importance of these factors changes with patient age has not previously been investigated comprehensively. We analyzed data from 3894 patients of all ages uniformly treated in a large clinical trial of myeloma patients, Myeloma XI. Even with novel therapeutic approaches progression-free survival (PFS) and overall survival (OS) are affected by age with a stepwise reduction in PFS and OS with each decade increase. Renal function deteriorated with increasing age whilst the frequency of t(4;14) and del(17p) decreased and gain(1q) increased. The relative contribution of performance status, international staging score and molecular risk to progression-free and overall survival varied by age group. Molecular events have a larger effect on outcome in younger patients with their relative contribution diminishing in the elderly. Performance status is important for patient outcome at all ages suggesting that physical frailty may be a more important predictor of outcome than age itself. Significant differences in the factors driving patient outcomes at different ages are important to consider as we design disease segmentation strategies to deliver personalized treatment approaches.

A clinical prediction model for outcome and therapy delivery in transplant-ineligible patients with myeloma (UK Myeloma Research Alliance Risk Profile): a development and validation study.

BACKGROUND: Tolerability of treatments for multiple myeloma can depend on the characteristics of the patient being treated. We aimed to develop and validate a risk profile, using routinely collected data, that could predict overall survival in patients with multiple myeloma who were ineligible for stem-cell transplantation. METHODS: We used patient data from two randomised controlled trials done in patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation (the NCRI Myeloma XI study [NCRI-XI, n=1852] and the MRC Myeloma IX study [MRC-IX, n=520]), to develop the UK Myeloma Research Alliance Risk Profile (MRP) for overall survival. We used multivariable Cox regression with a least absolute shrinkage and selection operator penalty term. Multiple imputation by chained equations was used to account for missing data in the development and internal validation of the model. The MRP was internally validated in NCRI-XI and externally validated in MRC-IX. The D-statistic was estimated in the developed model and used to internally and externally validate the model according to prespecified criteria. FINDINGS: The MRP included WHO performance status, International Staging System, age, and C-reactive protein concentration as prognostic variables. The MRP was prognostic of overall survival and was successfully internally validated in NCRI-XI and externally validated in MRC-IX (D-statistic NCRI-XI: 0·840 [95% CI 0·718-0·963] and MRC-IX: 0·654 [0·497-0·811]). The MRP groups defining low-risk, medium-risk, and high-risk patients were associated with progression-free survival and early mortality. A decrease in the percentage of protocol dose delivered and quality of life at baseline were associated with increased risk. The MRP groups remained prognostic in patients exposed to different therapeutic combinations and in patients with genetic high-risk disease defined according to both the UK and International Myeloma Working Group definitions. INTERPRETATION: We have developed and externally validated a risk profile for overall survival containing widely available clinical parameters. This risk profile could aid decision making in patients with multiple myeloma ineligible for stem-cell transplantation, but further external validation is required. FUNDING: Medical Research Council, Novartis, Schering Health Care, Chugai, Pharmion, Celgene, Ortho Biotech, Cancer Research UK, Celgene, Merck Sharp & Dohme, and Amgen.

Subclonal TP53 copy number is associated with prognosis in multiple myeloma.

Multiple myeloma (MM) is a genetically heterogeneous cancer of bone marrow plasma cells with variable outcome. To assess the prognostic relevance of clonal heterogeneity of TP53 copy number, we profiled tumors from 1777 newly diagnosed Myeloma XI trial patients with multiplex ligation-dependent probe amplification (MLPA). Subclonal TP53 deletions were independently associated with shorter overall survival, with a hazard ratio of 1.8 (95% confidence interval, 1.2-2.8; P = .01). Clonal, but not subclonal, TP53 deletions were associated with clinical markers of advanced disease, specifically lower platelet counts (P < .001) and increased lactate dehydrogenase (P < .001), as well as a higher frequency of features indicative of genomic instability, del(13q) (P = .002) or del(1p) (P = .006). Biallelic TP53 loss-of-function by mutation and deletion was rare (2.4%) and associated with advanced disease. We present a framework for identifying subclonal TP53 deletions by MLPA, to improve patient stratification in MM and tailor therapy, enabling management strategies.

Apparent diffusion coefficient of vertebral haemangiomas allows differentiation from malignant focal deposits in whole-body diffusion-weighted MRI.

OBJECTIVES: The aim of this study was to identify apparent diffusion coefficient (ADC) values for typical haemangiomas in the spine and to compare them with active malignant focal deposits. METHODS: This was a retrospective single-institution study. Whole-body magnetic resonance imaging (MRI) scans of 106 successive patients with active multiple myeloma, metastatic prostate or breast cancer were analysed. ADC values of typical vertebral haemangiomas and malignant focal deposits were recorded. RESULTS: The ADC of haemangiomas (72 ROIs, median ADC 1,085×10-6mm2s-1, interquartile range 927-1,295×10-6mm2s-1) was significantly higher than the ADC of malignant focal deposits (97 ROIs, median ADC 682×10-6mm2s-1, interquartile range 583-781×10-6mm2s-1) with a p-value < 10-6. Receiver operating characteristic (ROC) analysis produced an area under the curve of 0.93. An ADC threshold of 872×10-6mm2s-1 separated haemangiomas from malignant focal deposits with a sensitivity of 84.7 % and specificity of 91.8 %. CONCLUSIONS: ADC values of classical vertebral haemangiomas are significantly higher than malignant focal deposits. The high ADC of vertebral haemangiomas allows them to be distinguished visually and quantitatively from active sites of disease, which show restricted diffusion. KEY POINTS: • Whole-body diffusion-weighted MRI is becoming widely used in myeloma and bone metastases. • ADC values of vertebral haemangiomas are significantly higher than malignant focal deposits. • High ADCs of haemangiomas allows them to be distinguished from active disease.

Constitutional mutation in CDKN2A is associated with long term survivorship in multiple myeloma: a case report.

BACKGROUND: Multiple Myeloma is a cancer of plasma cells associated with significantly reduced survival. Long term survivorship from myeloma is very rare and despite advances in its treatment the disease is generally considered incurable. We report a patient diagnosed with myeloma carrying a germline mutation of a tumour suppressor gene who has effectively been cured. CASE PRESENTATION: A 36-year-old woman was diagnosed with IgG lambda myeloma in 1985. She was treated with melphalan chemotherapy followed by high-dose melphalan and autologous stem cell rescue and since remained in complete remission despite not having received any additional therapy. After eliciting a prior history of multiple primary melanomas and breast cancer, she was tested for and shown to be a carrier for a germline mutation in CDKN2A. CONCLUSIONS: This is the second case report of germline mutation of CDKN2A being associated with myeloma. CDKN2A is a stabiliser of p53. Long term survivorship after high dose DNA damaging chemotherapy with melphalan in this patient is compatible with an increased chemo-sensitivity due to impairment of the DNA repair pathway.

Antagonistic human FcγRIIB (CD32B) antibodies have anti-tumor activity and overcome resistance to antibody therapy in vivo.

Therapeutic antibodies have transformed cancer therapy, unlocking mechanisms of action by engaging the immune system. Unfortunately, cures rarely occur and patients display intrinsic or acquired resistance. Here, we demonstrate the therapeutic potential of targeting human (h) FcγRIIB (CD32B), a receptor implicated in immune cell desensitization and tumor cell resistance. FcγRIIB-blocking antibodies prevented internalization of the CD20-specific antibody rituximab, thereby maximizing cell surface accessibility and immune effector cell mediated antitumor activity. In hFcγRIIB-transgenic (Tg) mice, FcγRIIB-blocking antibodies effectively deleted target cells in combination with rituximab, and other therapeutic antibodies, from resistance-prone stromal compartments. Similar efficacy was seen in primary human tumor xenografts, including with cells from patients with relapsed/refractory disease. These data support the further development of hFcγRIIB antibodies for clinical assessment.

Inhibitory FcγRIIb (CD32b) becomes activated by therapeutic mAb in both cis and trans and drives internalization according to antibody specificity.

A major feature that distinguishes type I from type II anti-CD20 monoclonal antibodies (mAbs) and reduces their therapeutic efficacy is the tendency to internalize from the cell surface. We have shown previously that the extent of internalization correlates with the capacity of type I mAb to simultaneously engage both CD20 and the inhibitory Fcγ receptor, FcγRIIb, in a bipolar configuration. Here, we investigated whether mAbs directed at other B-cell surface receptors also engaged FcγRIIb and whether this interaction promoted internalization. Most mAbs engaged and activated FcγRIIb, with the strength of activation related to the level of mAb bound to the cell surface. However, engagement did not affect internalization of most mAb-ligated receptors, either in cell lines or primary chronic lymphocytic leukemia cells with the exception of CD19 and CD38. Furthermore, at high cell concentrations/density both cis and trans interactions between cell-surface bound mAb and FcγRIIb were evident, but trans interactions did not inhibit type I anti-CD20 mAb-mediated internalization. These data identify that FcγRIIb is engaged by many mAbs in both cis and trans configurations, triggering its activation, but that internalization via FcγRIIb occurs for only a select subset. These findings have implications when designing new antibody-based therapeutics.

Management of median arcuate ligament syndrome in patients who require pancreaticoduodenectomy.

Pancreaticoduodenectomy is the standard treatment for localised neoplasms of the pancreatic head. The operation can be performed safely in specialist units but good outcome is compromised if postoperative blood flow to the liver and biliary tree is inadequate. Coeliac artery occlusion with blood supply to the liver arising from the superior mesenteric artery via the gastroduodenal artery is difficult to recognise, especially intraoperatively. Recognition of absent hepatic artery pulsation after occlusion of the gastroduodenal artery opens a dilemma: should the resection be abandoned or should vascular reconstruction be undertaken, adding risk to an already complex procedure? We describe two cases with a resectable pancreatic endocrine tumour in which coeliac artery occlusion caused by median arcuate ligament compression was identified from cross-sectional imaging and reconstructions. We highlight two different strategies to correct the vascular insufficiency and allow safe pancreatic resection.