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R-GEM-Lenalidomide versus R-GEM-P as second-line treatment of diffuse large B-cell lymphoma: results of the UK NRCI phase II randomised LEGEND trial.
No full textOutcome of patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) remains poor, highlighting the need for novel treatment approaches. The multicentre randomised phase II LEGEND trial evaluated lenalidomide in combination with rituximab, methylprednisolone and gemcitabine (R-GEM-L) vs. standard R-GEM-P as second-line treatment of DLBCL. The study closed early to recruitment after the planned interim analysis failed to demonstrate a complete response (CR) rate of ≥ 40% in either arm. Among 34 evaluable patients, 7/18 (38.9%) achieved CR with R-GEM-L and 3/16 (18.8%) with R-GEM-P. Median event-free and overall survival was 3.5/3.8 months and 10.8/8.3 months for R-GEM-L and R-GEM-P, respectively. The incidence of grade ≥ 3 toxicities was 52% in R-GEM-L and 83% in R-GEM-P. Efficacy and tolerability of R-GEM-L seem comparable with R-GEM-P and other standard salvage therapies, but a stringent design led to early trial closure. Combination of lenalidomide with gemcitabine-based regimens should be further evaluated in r/r DLBCL
The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group.
No full textThe term monoclonal gammopathy of renal significance (MGRS) was introduced by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) in 2012. The IKMG met in April 2017 to refine the definition of MGRS and to update the diagnostic criteria for MGRS-related diseases. Accordingly, in this Expert Consensus Document, the IKMG redefines MGRS as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined haematological criteria for treatment of a specific malignancy. The diagnosis of MGRS-related disease is established by kidney biopsy and immunofluorescence studies to identify the monotypic immunoglobulin deposits (although these deposits are minimal in patients with either C3 glomerulopathy or thrombotic microangiopathy). Accordingly, the IKMG recommends a kidney biopsy in patients suspected of having MGRS to maximize the chance of correct diagnosis. Serum and urine protein electrophoresis and immunofixation, as well as analyses of serum free light chains, should also be performed to identify the monoclonal immunoglobulin, which helps to establish the diagnosis of MGRS and might also be useful for assessing responses to treatment. Finally, bone marrow aspiration and biopsy should be conducted to identify the lymphoproliferative clone. Flow cytometry can be helpful in identifying small clones. Additional genetic tests and fluorescent in situ hybridization studies are helpful for clonal identification and for generating treatment recommendations. Treatment of MGRS was not addressed at the 2017 IKMG meeting; consequently, this Expert Consensus Document does not include any recommendations for the treatment of patients with MGRS
What are physiotherapists and occupational therapists doing in services that replace acute hospital admission? A systematic review.
No full textBACKGROUND
Alternatives to acute hospital admission are required to accommodate the increasing pressures on health services. Since physiotherapists and occupational therapists are integral to inpatient teams, they may also be integral to admission replacement services, and thus their roles in these services merit investigation.
AIMS
Primarily to determine the presence and roles of physiotherapists and occupational therapists in services replacing acute hospital admission. The secondary outcome is to determine the impact of therapists in such services.
METHODS
Five electronic databases were searched, with keywords related to therapy, discharge and admission replacement. Inclusion criteria were that studies explicitly described at least one therapist role within a service replacing acute hospital admissions. Two authors independently reviewed all potentially eligible studies. Two reviewers independently assessed data extracted from included studies into a standardised data extraction form.
RESULTS
Fifteen studies (3 Hospital at Home, 12 Early Supported Discharge) were included. Both clinical (e.g. exercise prescription) and non-clinical (e.g. organisation and study outcome assessments) therapist roles were described in different admission substitution services. Some roles were only reported among teams, not individually ascribed to therapists.
CONCLUSIONS
The roles of therapists in services that replace hospital admission are rarely described in detail, with wide variation in reported roles, including across service types and patient populations. This review could not determine the impact of individual therapists on patient or service-level outcomes. Future studies need to more clearly define therapist roles and impact
Unmet needs of women with GDM: a health needs assessment in Sandwell, West Midlands.
No full textBACKGROUND
Gestational diabetes mellitus (GDM) affects over 4% of pregnancies in England. We investigated GDM epidemiology within ethnically diverse population and the current offer of services to women with previous GDM to reduce their type 2 diabetes mellitus (T2DM) risk.
METHODS
(i) Analysis of routinely collected maternity data examining GDM incidence and risk factors; (ii) local authority self-assessment questionnaire on public health interventions targeting women with previous GDM and (iii) service development discussions regarding the current pathway and areas for improvement.
RESULTS
Of 9390 births between 2014 and 2018, 6.8% had a record of GDM. High body mass index (BMI), maternal age, and ethnicity (South Asian and some mixed ethnic backgrounds) were independent predictors of GDM. There were no public health commissioned services specifically targeting women with previous GDM. Weaknesses in transition from secondary to primary care and areas for improvement when screening for GDM were identified.
CONCLUSIONS
GDM burden in this population was high. Awareness should be raised on the importance of regular glucose testing and lifestyle modification to delay or prevent progression to T2DM, particularly within high risk groups. The potential for health visitors to contribute to this should be explored. Commissioners should review evidence to develop a flexible lifestyle services model to meet the specific needs of these women
Vogt-Koyanagi-Harada disease.
No full textVogt-Koyanagi-Harada disease is a rare, multisystem, autoimmune disorder with numerous clinical manifestations, mediated through a T-helper 1 response against melanocytes in the eye, inner ear, central nervous system, hair and skin. We describe a 20-year-old British-Honduran man with recent worsening headache and photophobia, vomiting and visual blurring. On examination, his pupils reacted sluggishly and visual acuities were bilaterally reduced. Optical coherence tomography showed gross retinal swelling and neurosensory detachments. MR scan of the brain was normal, but cerebrospinal fluid showed a reactive picture with 258 ×10 lymphocytes./L (normal ≤5×10/L). Following treatment with immunosuppression (prednisolone, tacrolimus, mycophenolate mofetil, adalimumab), he made a full recovery. Clinicians should consider Vogt-Koyanagi-Harada disease in patients presenting with headache with acute profound visual loss. A prompt diagnosis and immunosuppressive therapy can lead to complete resolution
Mechanical circulatory support in the heart failure population.
No full textPURPOSE OF REVIEW
Use of durable left ventricular assist devices (LVADs) has increased considerably in recent years because of the insufficient supply of donor hearts for cardiac transplantation and improvement in outcomes from refinements in technology. This review examines clinical utility of these devices and summarizes the most recent evidence supporting the use of LVAD therapy.
RECENT FINDINGS
There continues to be significant advancements made in LVAD technology, which has resulted in improvements in the rates of adverse events and overall patient quality of life. Specifically, less invasive and improved surgical techniques have resulted in fewer incidence of pump thrombosis and stringent blood pressure management have been shown to significantly decrease stroke rates.
SUMMARY
The continued advances in LVAD therapy have resulted in significant improvement in overall survival; however, complication rates remain relatively high. Future work will focus on improvements in adverse outcomes and ultimately the possibility that LVADs will be a viable alternative to transplantation in patients with end-stage heart failure
New Directions in Vulvar Cancer Pathology.
No full textPURPOSE OF REVIEW
The aim of this article is to provide clinicians and pathologists with an understanding of the aetiopathology, pathogenesis and classification of vulval neoplasia and their molecular correlates.
RECENT FINDINGS
There is an increased understanding of subcellular changes in vulvar malignancies. These provide the direction for further research and aid personalised treatment for patients. The article explores concepts of the aetiology of vulvar cancer and updates the reader with the equivalence of terminology of preneoplastic vulval disease. The differential diagnosis of squamous neoplasia and their clinicopathological correlation is detailed. The salient findings from recent literature into the understanding of the disease of squamous cell neoplasia and rare vulvar malignancies are summarised
Evolution of the burden of active hepatitis C virus infection in England from September 2015 to September 2016: a repeated cross-sectional analysis.
No full textOBJECTIVE
To evaluate the impact of treatment with new direct-acting antivirals (DAAs) on the prevalent hepatitis C virus (HCV) population in England.
DESIGN
A repeated cross-sectional analysis.
SETTING
Four secondary care hospitals in England.
PARTICIPANTS
Patients who, in 2015 and/or 2016, had chronic HCV infection and were alive were eligible, regardless of the type of HCV intervention received.
OUTCOME MEASURES
Data including intravenous drug use (IVDU) status, HCV genotype, cirrhosis status, HCV treatment history, vital status and treatment outcomes were collected at two time points in 2015 and 2016 using electronic case report forms.
RESULTS
There were 1605 and 1355 patients with active chronic HCV in 2015 and 2016, respectively. Between 2015 and 2016, the proportion of patients with current IVDU increased (10.3% vs 14.5%, respectively), while that of patients with cirrhosis (28.2% vs 22.4%) and treatment-experienced patients (31.2% vs 27.1%) decreased. Among patients whose treatment outcome was known by 2016, high cure rates were observed, with an overall sustained virological response rate of 93.2%. From 2015 to 2016, there was a progressive increase in the proportion of treated patients who were non-cirrhotic, with current IVDU and non-liver transplant recipients.
CONCLUSIONS
The characteristics of patients with HCV remaining in contact with specialised care evolved with a changing landscape of treatment and related health policy. With increasing access to DAAs in UK, high cure rates were achieved in the study cohort
Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: A multicenter, randomized, double-blind, placebo-controlled phase II trial.
No full textBACKGROUND & AIMS
Primary sclerosing cholangitis (PSC) is an inflammatory, cholestatic and progressively fibrotic liver disease devoid of effective medical intervention. NGM282, an engineered, non-tumorigenic FGF19 analogue, potently regulates CYP7A1-mediated bile acid homeostasis. We assessed the activity and safety of NGM282 in patients with PSC.
METHODS
In this double-blind, placebo-controlled phase II trial, 62 patients who had PSC confirmed by cholangiography or biopsy and an elevated alkaline phosphatase (ALP) >1.5 × the upper limit of normal were randomly assigned 1:1:1 to receive NGM282 1 mg, 3 mg or placebo once daily for 12 weeks. The primary outcome was the change in ALP from baseline to week 12. Secondary and exploratory outcomes included changes in serum biomarkers of bile acid metabolism and fibrosis. Efficacy analysis was by intention-to-treat.
RESULTS
At 12 weeks, there were no significant differences in the mean change from baseline in ALP between the NGM282 and placebo groups, and therefore, the primary endpoint was not met. However, NGM282 significantly reduced levels of 7alpha-hydroxy-4-cholesten-3-one (a marker of hepatic CYP7A1 activity, LS mean differences -6.2 ng/ml (95% CI -10.7 to -1.7; p = 0.008) and -9.4 ng/ml (-14.0 to -4.9; p <0.001) in the NGM282 1 mg and 3 mg groups, respectively, compared with placebo) and bile acids. Importantly, fibrosis biomarkers that predict transplant-free survival, including Enhanced Liver Fibrosis score and Pro-C3, were significantly improved following NGM282 treatment. Most adverse events were mild to moderate in severity, with gastrointestinal symptoms more frequent in the NGM282 treatment groups.
CONCLUSIONS
In patients with PSC, NGM282 potently inhibited bile acid synthesis and decreased fibrosis markers, without significantly affecting ALP levels.
LAY SUMMARY
We present for the first time, the clinical and laboratory effects of a first-in-class, engineered analogue of the endocrine hormone FGF19 in patients with primary sclerosing cholangitis (PSC). By incorporating non-invasive markers of fibrosis, beyond standard liver injury markers, we show that NGM282 impacted on fibrosis turnover and hepatic inflammation without changing alkaline phosphatase. Our findings demonstrate the complexities of using highly potent rational agents in PSC, and furthermore challenge the dogma about what the appropriate endpoints should be for trials in PSC