Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL.

Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins. Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR immunoglobulin stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR immunoglobulin stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. To address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29 856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed "satellites," were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL.

Comparison of autologous and allogeneic hematopoietic cell transplantation strategies in patients with primary plasma cell leukemia, with dynamic prediction modeling.

Primary plasma cell leukemia (pPCL) is a rare and challenging malignancy. There are limited data regarding optimum transplant approaches. We therefore undertook a retrospective analysis from 1998-2014 of 751 patients with pPCL undergoing one of four transplant strategies; single autologous transplant (single auto), single allogeneic transplant (allo-first) or a combined tandem approach with an allogeneic transplant following an autologous transplant (auto-allo) or a tandem autologous transplant (auto-auto). To avoid time bias, multiple analytic approaches were employed including Cox models with time-dependent covariates and dynamic prediction by landmarking. Initial comparisons were made between patients undergoing allo-first (n=70) versus auto-first (n=681), regardless of a subsequent second transplant. The allo-first group had a lower relapse rate (45.9%, 95% confidence interval [95% CI]: 33.2-58.6 vs. 68.4%, 64.4-72.4) but higher non-relapse mortality (27%, 95% CI: 15.9-38.1 vs. 7.3%, 5.2-9.4) at 36 months. Patients who underwent allo-first had a remarkably higher risk in the first 100 days for both overall survival and progression-free survival. Patients undergoing auto-allo (n=122) had no increased risk in the short term and a significant benefit in progression-free survival after 100 days compared to those undergoing single auto (hazard ratio [HR]=0.69, 95% CI: 0.52- 0.92; P=0.012). Auto-auto (n=117) was an effective option for patients achieving complete remission prior to their first transplant, whereas in patients who did not achieve complete remission prior to transplantation our modeling predicted that auto-allo was superior. This is the largest retrospective study reporting on transplantation in pPCL to date. We confirm a significant mortality risk within the first 100 days for allo-first and suggest that tandem transplant strategies are superior. Disease status at time of transplant influences outcome. This knowledge may help to guide clinical decisions on transplant strategy.

Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia.

BIRC3 is a recurrently mutated gene in chronic lymphocytic leukemia (CLL) but the functional implications of BIRC3 mutations are largely unexplored. Furthermore, little is known about the prognostic impact of BIRC3 mutations in CLL cohorts homogeneously treated with first-line fludarabine, cyclophosphamide, and rituximab (FCR). By immunoblotting analysis, we showed that the non-canonical nuclear factor-κB pathway is active in BIRC3-mutated cell lines and in primary CLL samples, as documented by the stabilization of MAP3K14 and by the nuclear localization of p52. In addition, BIRC3-mutated primary CLL cells are less sensitive to flu-darabine. In order to confirm in patients that BIRC3 mutations confer resistance to fludarabine-based chemoimmunotherapy, a retrospective multicenter cohort of 287 untreated patients receiving first-line FCR was analyzed by targeted next-generation sequencing of 24 recurrently mutated genes in CLL. By univariate analysis adjusted for multiple comparisons BIRC3 mutations identify a poor prognostic subgroup of patients in whom FCR treatment fails (median progression-free survival: 2.2 years, P<0.001) similar to cases harboring TP53 mutations (median progression-free survival: 2.6 years, P<0.0001). BIRC3 mutations maintained an independent association with an increased risk of progression with a hazard ratio of 2.8 (95% confidence interval 1.4-5.6, P=0.004) in multivariate analysis adjusted for TP53 mutation, 17p deletion and IGHV mutation status. If validated, BIRC3 mutations may be used as a new molecular predictor to select high-risk patients for novel frontline therapeutic approaches.

The management of acute and chronic hyponatraemia.

Hyponatraemia is the most common electrolyte abnormality encountered in clinical practice; despite this, the work-up and management of hyponatraemia remain suboptimal and varies among different specialist groups. The majority of data comparing hyponatraemia treatments have been observational, up until recently. The past two years have seen the publication of several randomised control trials investigating hyponatraemia treatments, both for chronic and acute hyponatraemia. In this article, we aim to provide a background to the physiology, cause and impact of hyponatraemia and summarise the most recent data on treatments for acute and chronic hyponatraemia, highlighting their efficacy, tolerability and adverse effects.

Diagnosis and Management of Central Diabetes Insipidus in Adults.

Central diabetes insipidus (CDI) is a clinical syndrome which results from loss or impaired function of vasopressinergic neurons in the hypothalamus/posterior pituitary, resulting in impaired synthesis and/or secretion of arginine vasopressin (AVP). AVP deficiency leads to the inability to concentrate urine and excessive renal water losses, resulting in a clinical syndrome of hypotonic polyuria with compensatory thirst. CDI is caused by diverse etiologies, although it typically develops due to neoplastic, traumatic, or autoimmune destruction of AVP-synthesizing/secreting neurons. This review focuses on the diagnosis and management of CDI, providing insights into the physiological disturbances underpinning the syndrome. Recent developments in diagnostic techniques, particularly the development of the copeptin assay, have improved accuracy and acceptability of the diagnostic approach to the hypotonic polyuria syndrome. We discuss the management of CDI with particular emphasis on management of fluid intake and pharmacological replacement of AVP. Specific clinical syndromes such as adipsic diabetes insipidus and diabetes insipidus in pregnancy as well as management of the perioperative patient with diabetes insipidus are also discussed.

TP53 Mutations Identified Using NGS Comprise the Overwhelming Majority of TP53 Disruptions in CLL: Results From a Multicentre Study.

Limited data exists to show the correlation of (tumour protein 53) TP53 mutation detected by Next generation sequencing (NGS) and the presence/absence of deletions of 17p13 detected by FISH. The study which is the largest series to date includes 2332 CLL patients referred for analysis of del(17p) by FISH and TP53 mutations by NGS before treatment. Using a 10% variant allele frequency (VAF) threshold, cases were segregated into high burden mutations (≥10%) and low burden mutations (<10%). TP53 aberrations (17p [del(17p)] and/or TP53 mutation) were detected in 320/2332 patients (13.7%). Using NGS analysis, 429 TP53 mutations were identified in 303 patients (13%). Of these 238 (79%) and 65 (21%) were cases with high burden and low burden mutations respectively. In our cohort, 2012 cases did not demonstrate a TP53 aberration (86.3%). A total of 159 cases showed TP53 mutations in the absence of del(17p) (49/159 with low burden TP53 mutations) and 144 cases had both TP53 mutation and del(17p) (16/144 with low burden mutations). Only 17/2332 (0.7%) cases demonstrated del(17p) with no TP53 mutation. Validated NGS protocols should be used in clinical decision making to avoid missing low-burden TP53 mutations and can detect the vast majority of TP53 aberrations.

IgD Subtype But Not IgM or Non-Secretory Is a Prognostic Marker for Poor Survival Following Autologous Hematopoietic Cell Transplantation in Multiple Myeloma. Results From the EBMT CALM (Collaboration to Collect Autologous Transplant Outcomes in Lymphomas and Myeloma) Study.

BACKGROUND: The Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study has provided an opportunity to evaluate the real-world outcomes of patients with myeloma. The aim of this study was to compare the outcome according to the different subtypes of myeloma using CALM data. PATIENTS: This study compared overall survival (OS), progression-free survival (PFS), and complete remission (CR) and the impact of novel versus non-novel drug containing induction regimens prior to autologous hematopoietic cell transplantation (HCT) of 2802 patients with "usual" and "rare" myelomas. RESULTS: Our data suggest that IgM and non-secretory myeloma have superior PFS and OS compared with IgD myeloma and outcomes comparable to those for usual myeloma. Patients who received novel agent induction had higher rates of CR prior to transplant. Non-novel induction regimens were associated with inferior PFS but no difference in OS. Although not the primary focus of this study, we show that poor mobilization status is associated with reduced PFS and OS, but these differences disappear in multivariate analysis suggesting that poor mobilization status is a surrogate for other indicators of poor prognosis. CONCLUSION: We confirm that IgD myeloma is associated with the worst prognosis and inferior outcomes compared with the other isotypes.

Developing and Testing the Diagnostic Accuracy of a Brief Nursing Dysphagia Screen.

PURPOSE: The aim of the study was to develop and test the Groppo-Lawless nurse-initiated screen designed to identify patients diagnosed with pneumonia who are at risk for dysphagia. DESIGN: This is a two-phase methodological study. METHODS: Phase 1 involved three steps. First, risk factors (n = 27) for dysphagia were identified from the literature. Next, frequency of these risk factors was calculated from a chart review of patients diagnosed with pneumonia (N = 301). Finally, frequency of risk factors among those patients who failed the 3-oz water trial (n = 56) were calculated, and a five-item instrument, the Groppo-Lawless Dysphagia Screen, was constructed. In Phase 2, nurses' results using the screen were compared to blinded results of speech-language pathologists. FINDINGS: Sensitivity (81.1%), specificity (96.4%), and diagnostic odds ratio (22.43) were calculated. CONCLUSIONS/CLINICAL RELEVANCE: Given the strong psychometric properties of this screen, its use by nurses may increase the number of appropriate speech-language pathologist referrals among patients diagnosed with pneumonia.

Liver X receptor inhibition potentiates mitotane-induced adrenotoxicity in ACC.

Adrenocortical carcinoma (ACC) is a rare aggressive malignancy with a poor outcome largely due to limited treatment options. Here, we propose a novel therapeutic approach through modulating intracellular free cholesterol via the liver X receptor alpha (LXRα) in combination with current first-line pharmacotherapy, mitotane. H295R and MUC-1 ACC cell lines were pretreated with LXRα inhibitors in combination with mitotane. In H295R, mitotane (20, 40 and 50 µM) induced dose-dependent cell death; however, in MUC-1, this only occurred at a supratherapeutic concentration (200 µM). LXRα inhibition potentiated mitotane-induced cytotoxicity in both cell lines. This was confirmed through use of the CompuSyn model which showed moderate pharmacological synergism and was indicative of apoptotic cell death via an increase in annexinV and cleaved-caspase 3 expression. Inhibition of LXRα was confirmed through downregulation of cholesterol efflux pumps ABCA1 and ABCG1; however, combination treatment with mitotane attenuated this effect. Intracellular free-cholesterol levels were associated with increased cytotoxicity in H295R (r2 = 0.5210) and MUC-1 (r2 = 0.9299) cells. While both cell lines exhibited similar levels of free cholesterol at baseline, H295R were cholesterol ester rich, whereas MUC-1 were cholesterol ester poor. We highlight the importance of LXRα mediated cholesterol metabolism in the management of ACC, drawing attention to its role in the therapeutics of mitotane sensitive tumours. We also demonstrate significant differences in cholesterol storage between mitotane sensitive and resistant disease.

Impact of field number and beam angle on functional image-guided lung cancer radiotherapy planning.

To investigate the effect of beam angles and field number on functionally-guided intensity modulated radiotherapy (IMRT) normal lung avoidance treatment plans that incorporate hyperpolarised helium-3 magnetic resonance imaging (3He MRI) ventilation data. Eight non-small cell lung cancer patients had pre-treatment 3He MRI that was registered to inspiration breath-hold radiotherapy planning computed tomography. IMRT plans that minimised the volume of total lung receiving ⩾20 Gy (V20) were compared with plans that minimised 3He MRI defined functional lung receiving ⩾20 Gy (fV20). Coplanar IMRT plans using 5-field manually optimised beam angles and 9-field equidistant plans were also evaluated. For each pair of plans, the Wilcoxon signed ranks test was used to compare fV20 and the percentage of planning target volume (PTV) receiving 90% of the prescription dose (PTV90). Incorporation of 3He MRI led to median reductions in fV20 of 1.3% (range: 0.2-9.3%; p = 0.04) and 0.2% (range: 0 to 4.1%; p = 0.012) for 5- and 9-field arrangements, respectively. There was no clinically significant difference in target coverage. Functionally-guided IMRT plans incorporating hyperpolarised 3He MRI information can reduce the dose received by ventilated lung without comprising PTV coverage. The effect was greater for optimised beam angles rather than uniformly spaced fields.

(32)P in the treatment of myeloproliferative disorders.

UNLABELLED: (32)P has been available for the treatment of myeloproliferative neoplasms (MPNs) for over seventy years. It was first used in 1938 by John H Lawrence in the treatment of polycythaemia and chronic leukaemias. With the introduction of agents such as hydroxycarbamide, interferon and anagrelide the role of (32)P has been diminished. Today, Polycythaemia Rubra Vera (PRV) and Essential Thrombocythaemia (ET) remain the only myeloproliferative conditions in which (32)P is indicated. MATERIALS AND METHODS: We carried out a retrospective review of all patients who had received 32P in Northern Ireland over a 24 year period. The time to successful response, duration of response, and associated complications were reviewed. RESULTS: (32)P was successful in inducing remission in 90% of patients. This remission was sustained following one dose without the need for further therapy in 37% of cases. 47% required repeated doses. 26% required recommencement of alternative therapies. No cases of thrombosis, myelofibrosis or acute leukaemia were observed. DISCUSSION: We conclude that (32)P is a well-tolerated and efficacious treatment option in the elderly. We discuss our results compared with previous work in this area. (32)P will continue to be offered to elderly patients in our practice.

Understanding adaptive capacity and capacity to innovate in social-ecological systems: Applying a gender lens.

Development policy increasingly focuses on building capacities to respond to change (adaptation), and to drive change (innovation). Few studies, however, focus specifically on the social and gender differentiation of capacities to adapt and innovate. We address this gap using a qualitative study in three communities in Solomon Islands; a developing country, where rural livelihoods and well-being are tightly tied to agriculture and fisheries. We find the five dimensions of capacity to adapt and to innovate (i.e. assets, flexibility, learning, social organisation, agency) to be mutually dependant. For example, limits to education, physical mobility and agency meant that women and youth, particularly, felt it was difficult to establish relations with external agencies to access technical support or new information important for innovating or adapting. Willingness to bear risk and to challenge social norms hindered both women's and men's capacity to innovate, albeit to differing degrees. Our findings are of value to those aspiring for equitable improvements to well-being within dynamic and diverse social-ecological systems.

A synthesis of convergent reflections, tensions and silences in linking gender and global environmental change research.

This synthesis article joins the authors of the special issue "Gender perspectives in resilience, vulnerability and adaptation to global environmental change" in a common reflective dialogue about the main contributions of their papers. In sum, here we reflect on links between gender and feminist approaches to research in adaptation and resilience in global environmental change (GEC). The main theoretical contributions of this special issue are threefold: emphasizing the relevance of power relations in feminist political ecology, bringing the livelihood and intersectionality approaches into GEC, and linking resilience theories and critical feminist research. Empirical insights on key debates in GEC studies are also highlighted from the nine cases analysed, from Europe, the Americas, Asia, Africa and the Pacific. Further, the special issue also contributes to broaden the gender approach in adaptation to GEC by incorporating research sites in the Global North alongside sites from the Global South. This paper examines and compares the main approaches adopted (e.g. qualitative or mixed methods) and the methodological challenges that derive from intersectional perspectives. Finally, key messages for policy agendas and further research are drawn from the common reflection.

A 75-year-old woman with acquired haemophilia disguised by warfarin treatment.

Acquired haemophilia is a rare coagulation disorder more commonly seen in elderly patients. Diagnosis and effective treatment can be delayed if patients are on warfarin treatment, as the bleeding symptoms may be erroneously attributed to this agent. We present a case report of a 75-year-old woman whose unexplained, severe and persistent bleeding was treated with surgical decompression and plasma transfusions, an appropriate management based on the assumption that warfarin was the cause of the bleeding. It was only when the patient's international normalised ratio returned to normal that a persistent abnormal activated partial thromboplastin time was noted. This delayed the correct diagnosis and treatment. Awareness of acquired haemophilia as a possible cause of sudden bleeding should be encouraged, and the wider dissemination of any relevant experience of similar cases would also be welcome.

Dosimetric evaluation of inspiration and expiration breath-hold for intensity-modulated radiotherapy planning of non-small cell lung cancer.

The purpose of this study was to compare target coverage and lung tissue sparing between inspiration and expiration breath-hold intensity-modulated radiotherapy (IMRT) plans for patients with non-small cell lung cancer (NSCLC). In a prospective study, seven NSCLC patients gave written consent to undergo both moderate deep inspiration and end-expiration breath-hold computed tomography (CT), which were used to generate five-field IMRT plans. Dose was calculated with a scatter and an inhomogeneity correction algorithm. The percentage of the planning target volume (PTV) receiving 90% of the prescription dose (PTV(90)), the volume of total lung receiving >or=10 Gy (V(10)) and >or=20 Gy (V(20)) and the mean lung dose (MLD) were compared by the Student's paired t-test. Compared with the expiration plans, the mean +/- SD reductions for V(10), V(20) and MLD on the inspiration plans were 4.0 +/- 3.7% (p = 0.031), 2.5 +/- 2.3% (p = 0.028) and 1.1 +/- 0.7 Gy (p = 0.007), respectively. Conversely, a mean difference of 1.1 +/- 1.1% (p = 0.044) in PTV(90) was demonstrated in favour of expiration. When using IMRT, inspiration breath-hold can reduce the dose to normal lung tissue while expiration breath-hold can improve the target coverage. The improved lung sparing at inspiration may outweigh the modest improvements in target coverage at expiration.