Progression free survival of myeloma patients who become IFE-negative correlates with the detection of residual monoclonal free light chain (FLC) by mass spectrometry.

Deeper responses are associated with improved survival in patients being treated for myeloma. However, the sensitivity of the current blood-based assays is limited. Historical studies suggested that normalisation of the serum free light chain (FLC) ratio in patients who were negative by immunofixation electrophoresis (IFE) was associated with improved outcomes. However, recently this has been called into question. Mass spectrometry (MS)-based FLC assessments may offer a superior methodology for the detection of monoclonal FLC due to greater sensitivity. To test this hypothesis, all available samples from patients who were IFE negative after treatment with carfilzomib and lenalidomide-based induction and autologous stem cell transplantation (ASCT) in the Myeloma XI trial underwent FLC-MS testing. FLC-MS response assessments from post-induction, day+100 post-ASCT and six months post-maintenance randomisation were compared to serum FLC assay results. Almost 40% of patients had discordant results and 28.7% of patients with a normal FLC ratio had residual monoclonal FLC detectable by FLC-MS. FLC-MS positivity was associated with reduced progression-free survival (PFS) but an abnormal FLC ratio was not. This study demonstrates that FLC-MS provides a superior methodology for the detection of residual monoclonal FLC with FLC-MS positivity identifying IFE-negative patients who are at higher risk of early progression.

Short communication: Circadian variations and day-to-day variability of clinical signs used for the early diagnosis of pneumonia within and between calves.

For rational antimicrobial use, a timely and correct diagnosis of bovine respiratory disease, especially pneumonia, in calves is required. Current approaches often rely on clinical signs observed at a single time point, and do not take potential diurnal patterns in the manifestation of these clinical signs into account. Therefore, the aim of this pilot study was to investigate how clinical signs utilized for the (early) detection of pneumonia vary both within and between calves, throughout the day and across days. A longitudinal study was conducted in which 36 pre-weaned Holstein-Friesian calves were clinically examined eight times over the course of 48 h. The following parameters were considered: respiratory rate, type of respiration, dyspnea, stridor, induced cough (trachea reflex), spontaneous cough, eye and nasal discharge, ear positions, head tilt, rectal temperature, diarrhea, milk residue, body posture, Wisconsin and Davis BRD scorecard. The advent of thoracic ultrasonography (TUS) enables detection of (sub)clinical pneumonia in a more reliable way, compared to the diagnosis based solely on clinical signs. In this study, 14% (5/36) of the calves had an ultrasound confirmed pneumonia (consolidation ≥1 cm in depth). No variations were observed in the prevalence of clinical signs at the various time points of the day. However, we did observe a difference in the manifestation of clinical signs in individual calves (intra) and between (inter) them. Due to the significant intra-calf variability, diagnosing pneumonia based solely on a single observation of clinical signs, is likely to be insufficient. Hence, misdiagnosis might lead to incorrect use of antimicrobials.

The ability of post-chemoradiotherapy DWI ADCmean and 18F-FDG SUVmax to predict treatment outcomes in head and neck cancer: impact of human papilloma virus oropharyngeal cancer status.

OBJECTIVES: To evaluate the ability of post-chemo-radiotherapy (CRT) diffusion-weighted-MRI apparent diffusion coefficient (ADCmean) and 18F-FDG PET maximum standardized uptake value (SUVmax) to predict disease-free survival (DFS) in head and neck squamous cell carcinoma (HNSCC), and to determine whether this ability is influenced by human papillomavirus oropharyngeal cancer (HPV-OPC) status. METHODS: This prospective cohort observational study included 65 participants (53 male, mean ± SD age 59.9 ± 7.9 years, 46 HPV-OPC) with stage III or IV HNSCC. Primary tumour and nodal ADCmean (pre-treatment, 6- and 12-weeks post-CRT) and SUVmax (12-weeks post-CRT) were measured. Variables were compared with 2-year DFS (independent t-test/Mann-Whitney test) and overall DFS (Cox regression), before and after accounting for HPV-OPC status. Variables were also compared between HPV-OPC and other HNSCC subgroups after stratifying for DFS. RESULTS: Absolute post-CRT ADCmean values predicted 2-year DFS and overall DFS for all participants (p = 0.03/0.03, 6-week node; p = 0.02/0.03 12-week primary tumour) but not in the HPV-OPC subgroup. In participants with DFS, percentage interval changes in primary tumour ADCmean at 6- and 12-weeks were higher in HPV-OPC than other HNSCC (p = 0.01, 6 weeks; p = 0.005, 12 weeks). The 12-week post-CRT SUVmax did not predict DFS. CONCLUSION: Absolute post-CRT ADCmean values predicted DFS in HNSCC but not in the HPV-OPC subgroup. Amongst participants with DFS, post-CRT percentage interval changes in primary tumour ADCmean were significantly higher in HPV-OPC than in other HNSCC. Knowledge of HPV-OPC status is crucial to the clinical utilisation of post-CRT DWI-MRI for the prediction of outcomes.

'TB or not TB': the conundrum of pre-European contact tuberculosis in the Pacific.

Tuberculosis (TB) is a major global health threat, infecting one-third of the world's population. Despite this prominence, the age, origin and spread of the disease have been topics of contentious debate. Molecular studies suggest that Mycobacterium tuberculosis 'sensu stricto', the most common strain of TB infecting humans today, originated in Africa and from there spread into Europe and Asia. The M. tuberculosis strains most commonly found across the Pacific and the Americas today are most closely related to European strains, supporting a hypothesis that the disease only reached these regions relatively recently via European sailors or settlers. However, this hypothesis is inconsistent with palaeopathological evidence of TB-like lesions in human remains from across the Pacific that predate European contact. Similarly, genetic evidence from pre-European South American mummies challenges the notion of a European introduction of the disease into the Pacific. Here, we review the complex evidence for the age and origin of TB in the Pacific, and discuss key gaps in our knowledge and how these may be addressed. This article is part of the theme issue 'Insights into health and disease from ancient biomolecules'.

Imaging in the investigation and management of Staphylococcus aureus bacteraemia: a role for advanced imaging techniques.

Staphylococcus aureus bacteraemia (SAB) continues to affect ∼25,000 patients in the UK per year with a high crude mortality of 30% at 90 days. Prompt source control improves outcomes in sepsis and SAB and is included in sepsis guidelines. A recent clinical trial of adjunctive antibiotic treatment in SAB found that the majority of recurrences of SAB were associated with a failure of source management. In this condition, the ability to control the source of infection may be limited by the ability to detect a focus of infection. Echocardiogram is now a routinely used tool to detect such unknown foci in the form of unexpected infectious vegetations. We review the literature to explore the utility of advanced imaging techniques, such as [18F]fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and magnetic resonance imaging (including whole-body MRI), to detect foci which may otherwise be missed. As unknown foci are associated with increased mortality, we propose that increasing the detection of foci could enable improved source control and result in improved outcomes in SAB.

Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma.

Glioblastoma (GBM) is an aggressive cancer with a very poor prognosis. Generally viewed as weakly immunogenic, GBM responds poorly to current immunotherapies. To understand this problem more clearly we used a combination of natural killer (NK) cell functional assays together with gene and protein expression profiling to define the NK cell response to GBM and explore immunosuppression in the GBM microenvironment. In addition, we used transcriptome data from patient cohorts to classify GBM according to immunological profiles. We show that glioma stem-like cells, a source of post-treatment tumour recurrence, express multiple immunomodulatory cell surface molecules and are targeted in preference to normal neural progenitor cells by natural killer (NK) cells ex vivo. In contrast, GBM-infiltrating NK cells express reduced levels of activation receptors within the tumour microenvironment, with hallmarks of transforming growth factor (TGF)-ß-mediated inhibition. This NK cell inhibition is accompanied by expression of multiple immune checkpoint molecules on T cells. Single-cell transcriptomics demonstrated that both tumour and haematopoietic-derived cells in GBM express multiple, diverse mediators of immune evasion. Despite this, immunome analysis across a patient cohort identifies a spectrum of immunological activity in GBM, with active immunity marked by co-expression of immune effector molecules and feedback inhibitory mechanisms. Our data show that GBM is recognized by the immune system but that anti-tumour immunity is restrained by multiple immunosuppressive pathways, some of which operate in the healthy brain. The presence of immune activity in a subset of patients suggests that these patients will more probably benefit from combination immunotherapies directed against multiple immunosuppressive pathways.

The effect of a novel Bayesian penalised likelihood PET reconstruction algorithm on the assessment of malignancy risk in solitary pulmonary nodules according to the British Thoracic Society guidelines.

PURPOSE: British Thoracic Society (BTS) guidelines advocate using FDG PET-CT with the Herder model to estimate malignancy risk in solitary pulmonary nodules (SPNs). Qualitative and semi-quantitative assessment of SPN uptake is based upon analysis of Ordered Subset Expected Maximisation (OSEM) PET images. Our aim was to assess the effect of a Bayesian Penalised Likelihood (BPL) PET reconstruction on the assessment of SPN FDG uptake and estimation of malignancy risk (Herder score). METHODS: Subjects with SPNs who underwent FDG PET-CT between 2014-2017, with histological confirmation of malignancy or histological/imaging follow-up confirmation of benignity were included. Two blinded readers independently classified SPN uptake on both OSEM and BPL (BTS score; 1 = none; 2 = ≤ mediastinal blood pool (MBP); 3 = >MBP but ≤ 2x liver; 4 = >2x liver), with resultant calculation of the Herder score (%) for both reconstructions. RESULTS: 97 subjects with 75 (77%) malignant SPNs were included. BPL increased the BTS score in 25 (26%) SPNs; 9 SPNs (7 malignant) increased from BTS score 2 to 3, 16 (13 malignant) from BTS score 3 to 4, with a mean Herder score increase of 18 ±â€¯22%. The mean Herder score for all SPNs with BPL was higher than OSEM (73 ±â€¯29 vs 68 ±â€¯32%, p = 0.001). There was no difference in Herder model diagnostic performance between BPL and OSEM, with similar areas under the curve (0.84 vs 0.83, p = 0.39). CONCLUSION: BPL increases the Herder score in 26% of SPNs compared to OSEM but does not alter the diagnostic performance of the Herder model.

Loco-regional staging of malignant pleural mesothelioma by integrated 18F-FDG PET/MRI.

AIM: To examine the performance of 18F-FDG PET/MRI in the loco-regional staging of malignant pleural mesothelioma (MPM). METHODS: Consecutive subjects with MPM undergoing pre-operative staging with 18F-FDG PET/CT who underwent a same day integrated 18F-FDG PET/MRI were prospectively studied. Clinical TNM staging (AJCC 7th edition) was performed separately and in consensus by two readers on the 18F-FDG PET/MRI studies, and compared with staging by 18F-FDG PET/CT, and with final pathological stage, determined by a combination of intra-operative and histological findings. RESULTS: 10 subjects (9 male, mean age 68 years) with biopsy-proven MPM (9 epithelioid tumours, 1 biphasic) were included. One subject underwent neo-adjuvant chemotherapy between imaging and surgery and was excluded from the clinical versus pathological stage analysis. Pathological staging was concordant with staging by 18F-FDG PET/MRI in 67% (n = 6) of subjects, and with 18F-FDG PET/CT staging in 33% (n = 3). Pathological T stage was concordant with 18F-FDG PET/MRI in 78% (n = 7), and with 18F-FDG PET/CT in 33% (n = 3) of subjects. Pathological N stage was concordant with both 18F-FDG PET/MRI and 18F-FDG PET/CT in 78% (n = 7) of cases. No subject had metastatic disease. There was good inter-observer agreement for overall PET/MRI staging (weighted kappa 0.63) with moderate inter-reader agreement for T staging (weighted kappa 0.59). All 6 subjects with prior talc pleurodesis demonstrated mismatch between elevated FDG uptake and restricted diffusion in areas of visible talc deposition. CONCLUSION: Clinical MPM staging by 18F-FDG PET/MRI is feasible, and potentially provides more accurate loco-regional staging than PET/CT, particularly in T staging.

Correction: Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond.

Following the publication of this article the authors noted that the MRD data under the Table 1 column "Remark" of Aspire should go to that of Pollux. The authors wish to apologize for any inconvenience caused. The corrected table is attached to this correction.

Palatine tonsil SUVmax on FDG PET-CT as a discriminator between benign and malignant tonsils in patients with and without head and neck squamous cell carcinoma of unknown primary.

AIM: To analyse the maximum standardised uptake value (SUVmax) ratio between tonsils in patients with and without tonsillar carcinoma to determine useful diagnostic thresholds. MATERIALS AND METHODS: Positron-emission tomography (PET)/computed tomography (CT) examinations of patients with suspected head and neck squamous cell carcinoma (SCC) and controls from April 2013 to September 2016 were reviewed retrospectively. Tonsillar SUVmax ratios (ipsilateral/contralateral for malignant tonsils, maximum/minimum for patients without [controls]) were calculated and used to construct a receiver operating characteristic (ROC) curve. RESULTS: Twenty-five patients had tonsillar carcinoma (mean SUVmax ratio of 2, range 0.89-5.4) and 86 patients acted as controls (mean SUVmax ratio of 1.1, range 1-1.5). Using the ROC, the most accurate SUVmax ratio for identifying malignancy was >1.2 (77% sensitivity, 86% specificity). A potentially more clinically useful SUVmax ratio is ≥1.6 with 62% sensitivity and 100% specificity. CONCLUSION: An SUVmax ratio between tonsils of ≥1.6 is highly suspicious for SCC and could be used to direct site of biopsy. Some malignant tonsils had normal FDG uptake; therefore, PET/CT should not be used to exclude tonsillar cancer. Minor asymmetrical uptake is frequently seen in non-malignant tonsils and does not necessarily require further investigation. Due to the single centre nature of this study and the recognised variation in SUV measurements between PET scans, other centres may need to develop their own cut-offs.

High power single-mode delivery of mid-infrared sources through chalcogenide fiber.

Mechanically robust and low loss single-mode arsenic sulfide fibers are used to deliver high power mid-infrared sources. Anti-reflection coatings were deposited on the fiber facets, enabling 90% transmission through 20 cm length fibers. 10.3 W was transmitted through an anti-reflection coated fiber at 2053 nm, and uncoated fibers sustained 12 MW/cm2 intensities on the facet without failure. A Cr:ZnSe laser transmitted >1 W at 2520 nm, and a Fe:ZnSe laser transmitted 0.5 W at 4102 nm. These results indicate that by improving the anti-reflection coatings and using a high beam quality mid-infrared source, chalcogenide fibers can reliably deliver ≥10 W in a single mode, potentially out to 6.5 µm.

Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1905 trial patients.

Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10-7), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10-14) and 1.68 (P=2.18 × 10-14), respectively. Patients with 'double-hit' defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10-27) for all patients and 3.19 (P=1.23 × 10-18) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10-15), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment.

Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond.

Despite enormous advances, management of multiple myeloma (MM) remains challenging. Multiple factors impact the decision to treat or which regimen to use at MM relapse/progression. Recent major randomized controlled trials (RCTs) showed widely varying progression-free survivals (PFS), ranging from a median of 4 months (MM-003) to 23.6 months (ASPIRE). Based on these RCTs, next-generation proteasome inhibitors (carfilzomib and ixazomib), next-generation immunomodulatory agent (pomalidomide), and monoclonal antibodies (elotuzumab and daratumumab) were approved for relapsed and refractory MM. Daratumumab, targeting CD38, has multiple mechanisms of action including modulation of the immunosuppressive bone marrow micro-environment. In addition to the remarkable single agent activity in refractory MM, daratumumab produced deep responses and superior PFS in MM when combined with lenalidomide/dexamethasone, or bortezomib/dexamethasone. Other anti-CD38 antibodies, such as isatuximab and MOR202, are undergoing assessment. Elotuzumab, targeting SLAMF7, yielded superior response rates and PFS when combined with lenalidomide/dexamethasone. New combinations of these next generation novel agents and/or antibodies are undergoing clinical trials. Venetoclax, an oral BH3 mimetic inhibiting BCL2, showed single agent activity in MM with t(11;14), and is being studied in combination with bortezomib/dexamethasone. Selinexor, an Exportin-1 inhibitor, yielded promising results in quad- or penta-refractory MM including patients resistant to daratumumab. Pembrolizumab, an anti-PD1 check-point inhibitor, is being tested in combination with lenalidomide/dexamethasone or pomalidomide/dexamethasone. Chimeric antigen receptor-T cells targeting B-cell maturation antigen have yielded deep responses in RRMM. Finally, salvage autologous stem cell transplantation (ASCT) remains an important treatment in MM relapsing/progressing after a first ASCT. Herein, the clinical trial data of these agents are summarized, cautious interpretation of RCTs highlighted, and algorithm for salvage treatment of relapse/refractory MM proposed.

PET/CT and PET/MRI in head and neck malignancy.

Combined 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET)/computed tomography (CT) has an established role in the staging of difficult cases of head and neck (HN) squamous cell carcinoma (SCC), looking for an unknown primary, assessing response post-chemotherapy at 3-6 months, and differentiating relapse from treatment effects in patients suspected to have tumour recurrence. The PET NECK trial, comparing PET/CT surveillance versus neck dissection in advanced head and neck cancer showed survival was similar among patients who underwent PET/CT-guided surveillance and those who underwent planned neck dissection, but surveillance was more cost-effective. There is growing interest in the use of hypoxia PET tracers, especially in targeting radiotherapy, where the radiotherapy dose can be boosted in regions of hypoxia; the use of 68Ga peptide tracers in neuroendocrine malignancy and also in the growing field of combined PET/magnetic resonance imaging (MRI). PET/MRI has the advantage of increased anatomical detail and radiation dose reduction combined with the molecular and metabolic data from PET, although PET/CT has the advantage in better sensitivity for imaging lung metastases. Thus far, there is good agreement between PET/CT and PET/MRI with high correlation between semi-quantitative measurements in primary, nodal, osseous, and soft-tissue lesions imaging. PET/MRI may indeed provide greater accuracy than the currently available imaging procedures in the staging and later treatment response evaluation in HNSCC.

Prevention and management of adverse events of Novel agents in multiple myeloma: A consensus of the european myeloma network.

During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drugs classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events.Leukemia accepted article preview online, 18 December 2017. doi:10.1038/leu.2017.353.