Co-morbidities and mortality in patients with sickle cell disease in England: A 10-year cohort analysis using hospital episodes statistics (HES) data.

Patients with a primary diagnosis of sickle cell disease (SCD) with or without crisis during the 10-year period January 2009 to December 2018 were identified in the HES Admitted Patient Care (APC) dataset and matched with the Office for National Statistics (ONS) mortality dataset. Three sub-cohorts were defined: 'crises', 'transfusions' and 'other SCD'. APC records were examined for co-morbidities commonly associated with SCD and 10-year mortality rates compared with the general population. After data cleaning and exclusions, 9503 patients remained (entire cohort), with 1171, 201, and 8131 in crises, transfusions, and other SCD sub-cohorts, respectively. Median numbers of co-morbidities per patient were 2 (Interquartile range (IQR): 1-4), 2 (IQR: 1-3), and 1 (IQR: 0-2) in the crises, transfusions, and other SCD sub-cohorts, respectively. The majority of patients in the crises (63.2%) and transfusions (56.3%) cohorts had ≥2 co-morbidities, compared with 25.3% in the other SCD sub-cohort. Crude 10-year mortality rate was 5.3% (entire cohort), compared with 8.0% (crises) and 11.4% (transfusions) sub-cohorts; all rates were substantially higher than in age-sex matched general population. Our study adds further evidence that morbidity and mortality associated with SCD in England is high.

Routine management, healthcare resource use and patient and carer-reported outcomes of patients with transfusion-dependent ß-thalassaemia in the United Kingdom: A mixed methods observational study.

Objectives: We evaluated routine healthcare management, clinical status and patient- and carer-reported outcomes in UK paediatric and adult patients with transfusion-dependent ß-thalassaemia (TDT). Methods: A multi-centre, observational mixed-methodology study evaluated 165 patients (50% male; median age 24.1 [interquartile range (IQR)] 11.8-37.2] years) from nine UK centres. Results: Patients had a mean of 13.7 (standard deviation [SD] ±3.2) transfusion episodes/year (mean retrospective observation period 4.7 [±0.7] years). The median (IQR) for iron overload parameters at the last assessment during the observation period were: serum ferritin (n = 165) 1961.0 (1090.0-3003.0) µg/L (38% > 2500 µg/L); R2 liver iron (n = 119) 5.4 (2.9-11.6) mg/g (16% ≥15 mg/g); T2* cardiac iron (n = 132) 30.3 (22.0-37.1) ms (10% < 10 ms). All patients received ≥1 iron chelator during the observation period; 21% received combination therapy. Patients had a mean of 7.8 (±8.1) non-transfusion-related hospital attendances or admissions/year. Adult patients' mean EQ-5D utility score was 0.69 (±0.33; n = 94 [≥16 years]) and mean Transfusion-dependent quality of life score was 58.6 (±18.4; n = 94 [≥18 years]). For Work Productivity and Activity impairment, mean activity impairment for patients ≥18 years (n = 88) was 48% (±32%) and for carers (n = 29) was 28% (±23%). Conclusions: TDT presents significant burden on patients, carers and healthcare resources.

Co-morbidities and mortality associated with transfusion-dependent beta-thalassaemia in patients in England: a 10-year retrospective cohort analysis.

A retrospective cohort analysis to explore 10-year mortality and prevalence of transfusion-dependent ß-thalassaemia (TDT)-associated co-morbidities in patients with TDT was undertaken using Hospital Episode Statistics (HES) data from the National Health Service (NHS) in England. A 10-year forward-looking cohort analysis for the period 2009-2018 was completed using HES admitted patient care (APC), outpatient data, and linked HES/Office of National Statistics mortality data for patients with ß-thalassaemia (ICD-10 diagnosis code D56.1). TDT-associated co-morbidity rates were high in the 612 patients with TDT, with 76% having at least one co-morbidity, 54% suffering from two of more, and 37% three or more. The three most common TDT-associated co-morbidities, occurring in more than one third of patients were: endocrine disorders (excluding diabetes) 40%, osteoporosis 40%, and diabetes 34%. Cardiac disease was observed in 18% of patients overall, with atrial fibrillation and heart failure being the most common with a prevalence of 11% and 9%, respectively. The crude 10-year mortality rate in the TDT cohort was 6·2% (38/612), significantly greater than the 1·2% age/sex-adjusted mortality rate of the general population (P < 0·001). These data support the notion that the unmet need in TDT remains significant, with high rates of co-morbidity and mortality.

Health state utilities associated with treatment for transfusion-dependent ß-thalassemia.

OBJECTIVES: Transfusion-dependent ß-thalassemia (TDT) is a genetic disease that affects production of red blood cells. Conventional treatment involves regular red blood cell transfusions and iron chelation, which has a substantial impact on quality of life. While potentially curative, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with risk of complications, including graft-versus-host disease (GvHD). Gene addition therapy, a novel treatment approach, involves autologous transplantation of the patient's own genetically modified hematopoietic stem cells. The purpose of this study was to estimate utilities associated with treatment approaches for TDT. METHODS: General population respondents in England valued eight health state vignettes (developed with clinician, patient, and parent input) in time trade-off interviews. RESULTS: A total of 207 participants completed interviews (49.8% female; mean age = 43.2 years). Mean (SD) utilities for the pre-transplant health states were 0.73 (0.25) with oral chelation and 0.63 (0.32) with subcutaneous chelation. Mean utilities for the transplant year were 0.62 (0.35) for gene addition therapy, 0.47 (0.39) for allo-HSCT, and 0.39 (0.39) for allo-HSCT with acute GvHD. Post-transplant utilities were 0.93 (0.15) for transfusion independent, 0.75 (0.25) for 60% transfusion reduction, and 0.51 (0.38) for chronic GvHD. Acute and chronic GvHD were associated with significant disutility (acute = - 0.09, p < 0.0001; chronic = - 0.42, p < 0.0001). CONCLUSIONS: Utilities followed expected patterns, with logical differences between treatment options for TDT and substantially greater utility for transfusion independence than for ongoing treatment involving transfusion and chelation. These utilities may be useful in cost-utility models estimating the value of treatments for TDT.

Treatment patterns and clinical outcomes with pazopanib in patients with advanced soft tissue sarcomas in a compassionate use setting: results of the SPIRE study.

BACKGROUND: A named patient program (NPP) was designed to provide patients with advanced soft-tissue sarcoma (aSTS) access to pazopanib, a multitargeted tyrosine kinase inhibitor. The SPIRE study was a retrospective chart review of participating patients. PATIENTS AND METHODS: Eligibility criteria for the NPP and SPIRE mirrored those of the pivotal phase-III study, PALETTE, which compared pazopanib with placebo in patients ≥18 years with aSTS and whose disease had progressed during or following prior chemotherapy or were otherwise unsuitable for chemotherapy. Outcomes of interest included treatment patterns, treatment duration, relative dose intensity, progression-free survival (PFS), overall survival (OS), clinical benefit rate, adverse events (AEs) and reasons for treatment discontinuation. RESULTS: A total of 211 patients were enrolled (median age 56 years; 60% female). Most patients received pazopanib in second- and third-line therapy (28.0% and 28.4%, respectively), followed by fourth line (19.0%) and ≥ fifth line (18.5%). The median duration of pazopanib treatment was 3.1 months (95% CI: 2.8-3.8), with a mean daily dose of 715 mg equating to 92% of recommended dose. Median OS was 11.1 months and clinical benefit rate was 46%. There was evidence of some clinical benefit across most histological subtypes. At study end, 40% of patients were alive and of these, 18% remained on pazopanib. Thirteen percent (13%) of patients discontinued pazopanib due to AEs. CONCLUSIONS: The SPIRE study demonstrated activity of pazopanib in heavily pretreated aSTS patients in a compassionate use setting. No new safety concerns were noted. Reassuringly, the relative dose intensity of pazopanib was 92%.

BRCA1/2 mutations associated with progression-free survival in ovarian cancer patients in the AGO-OVAR 16 study.

OBJECTIVE: AGO-OVAR 16 demonstrated that pazopanib maintenance therapy significantly increased progression-free survival (PFS) in patients with ovarian cancer whose disease had not progressed after first-line therapy. In a sub-study, we evaluated the effect of clinically important germline BRCA1 and BRCA2 mutations on PFS. METHODS: Of 940 AGO-OVAR 16 participants, 664 had BRCA1/2 exon sequencing data (pazopanib, n=335; placebo, n=329). A Cox model was used to test the association between genetic variants and PFS. RESULTS: Ninety-seven of 664 patients (15%) carried clinically important BRCA1/2 mutations (BRCA1/2 carriers: pazopanib 14%, placebo 16%). Median PFS was longer in BRCA1/2 mutation carriers than in BRCA1/2 non-carriers in the placebo arm (30.3 vs 14.1 months, hazard ratio, 0.48; 95% confidence interval [CI]: 0.29-0.78; P=0.0031); a similar non-significant trend was noted with pazopanib (30.2 vs 17.7 months, hazard ratio, 0.64; 95% CI: 0.40-1.03; P=0.069). Among BRCA1/2 non-carriers, PFS was longer for pazopanib-treated patients than placebo-treated patients (17.7 vs 14.1 months, hazard ratio, 0.77; 95% CI: 0.62-0.97; P=0.024). Among BRCA1/2 carriers, there was no significant PFS difference between treatments, although numbers were small (pazopanib, 46; placebo, 51), resulting in a wide CI (hazard ratio, 1.36; 95% CI: 0.66-2.82). CONCLUSIONS: Patients with clinically important BRCA1/2 mutations had better prognosis. BRCA1/2 mutation status might be added as strata in future trials in primary ovarian cancer.

Molecular effects of Lapatinib in the treatment of HER2 overexpressing oesophago-gastric adenocarcinoma.

BACKGROUND: Lapatinib, a dual EGFR and HER2 inhibitor has shown disappointing results in clinical trials of metastatic oesophago-gastric adenocarcinomas (OGAs), and in vitro studies suggest that MET, IGFR, and HER3 confer resistance. This trial applied Lapatinib in the curative neoadjuvant setting and investigated the feasibility and utility of additional endoscopy and biopsy for assessment of resistance mechanisms ex vivo and in vivo. METHODS: Patients with HER2 overexpressing OGA were treated for 10 days with Lapatinib monotherapy, and then in combination with three cycles of Oxaliplatin and Capecitabine before surgery. Endoscopic samples were taken for molecular analysis at: baseline including for ex vivo culture +/- Lapatinib to predict in vivo response, post-Lapatinib monotherapy and at surgery. Immunohistochemistry (IHC) and proteomic analysis was performed to assess cell kinetics and signalling activity. RESULTS: The trial closed early (n=10) due to an anastomotic leak in two patients for which a causative effect of Lapatinib could not be excluded. The reduction in Phosphorylated-HER2 (P-HER2) and P-EGFR in the ex vivo-treated biopsy demonstrated good correlation with the in vivo response at day 10. Proteomic analysis pre and post-Lapatinib demonstrated target inhibition (P-ERBB2, P-EGFR, P-PI3K, P-AKT, and P-ERK) that persisted until surgery. There was also significant correlation between the activation of MET with the level of P-Erk (P=0.0005) and P-PI3K : T-PI3K (total PI3K) ratio (P=0.0037). There was no significant correlation between the activation status of IGFR and HER3 with downstream signalling molecules. CONCLUSIONS: Additional endoscopy and biopsy sampling for multiple biomarker endpoints was feasible and confirmed in vitro data that MET is likely to be a significant mechanism of Lapatinib resistance in vivo.

How much does it cost a specialist palliative care unit to manage constipation in patients receiving opioid therapy?

The burden of constipation from the patient's perspective has been well described. The aim of this study was to evaluate the cost of managing constipation in patients taking opioids in a specialist palliative care inpatient unit. A retrospective review of the medical records of 58 patients (70 admissions) who died during a six-month period was undertaken to identify prescribing patterns for opioids and oral laxatives and tasks associated with managing constipation in these patients. A prospective time and motion study also was undertaken, whereby staff recorded the time and resources required to perform each task. These data were then applied to the actual frequency recorded in the retrospective review to calculate the direct cost of managing constipation in those 70 admissions during that six-month period. There was no discernable pattern in oral laxative prescribing. The mean cost of managing constipation was 29.81 pounds (48.74 USD) per admission, with staff time accounting for 85% of the cost. The most time-consuming activity was staff discussion about bowel management, which occurred at least once daily for doctors and twice for nurses and involved up to eight members of staff at a time. The cost of managing constipation is skewed in that it costs 30 pounds (49 USD) or less in 71% of admissions but exceeded 100 pounds (163 USD) in 5%. In the latter group, earlier and/or more effective intervention for constipation could lead to clinical and economic benefits.

The angiogenic factor midkine is regulated by dexamethasone and retinoic acid during alveolarization and in alveolar epithelial cells.

BACKGROUND: A precise balance exists between the actions of endogenous glucocorticoids (GC) and retinoids to promote normal lung development, in particular during alveolarization. The mechanisms controlling this balance are largely unknown, but recent evidence suggests that midkine (MK), a retinoic acid-regulated, pro-angiogenic growth factor, may function as a critical regulator. The purpose of this study was to examine regulation of MK by GC and RA during postnatal alveolar formation in rats. METHODS: Newborn rats were treated with dexamethasone (DEX) and/or all-trans-retinoic acid (RA) during the first two weeks of life. Lung morphology was assessed by light microscopy and radial alveolar counts. MK mRNA and protein expression in response to different treatment were determined by Northern and Western blots. In addition, MK protein expression in cultured human alveolar type 2-like cells treated with DEX and RA was also determined. RESULTS: Lung histology confirmed that DEX treatment inhibited and RA treatment stimulated alveolar formation, whereas concurrent administration of RA with DEX prevented the DEX effects. During normal development, MK expression was maximal during the period of alveolarization from postnatal day 5 (PN5) to PN15. DEX treatment of rat pups decreased, and RA treatment increased lung MK expression, whereas concurrent DEX+RA treatment prevented the DEX-induced decrease in MK expression. Using human alveolar type 2 (AT2)-like cells differentiated in culture, we confirmed that DEX and cAMP decreased, and RA increased MK expression. CONCLUSION: We conclude that MK is expressed by AT2 cells, and is differentially regulated by corticosteroid and retinoid treatment in a manner consistent with hormonal effects on alveolarization during postnatal lung development.