Pharmacokinetically-targeted dosed everolimus maintenance therapy in lymphoma patients.

BACKGROUND: Everolimus, an mTOR inhibitor, is active in refractory lymphomas. However, toxicity with flat dosing limits its usage. Speculatively, pharmacokinetically-targeted dosing could improve tolerability. Therefore, we studied serum-trough dosing with rituximab as maintenance after high-dose cyclophosphamide (HDC) consolidation in lymphoma patients. PATIENTS/METHODS: After HDC, everolimus was dosed to serum trough levels (goal 3-15 ng/mL), with quarterly rituximab infusions for 1 year while maintaining < grade II non-hematologic and < grade III hematologic toxicities. Adult patients in first PR/CR with: mantle cell, transformed, double-hit, or high risk chronic lymphocytic leukemia or in second PR for any relapsed B cell lymphoma were eligible. Prophylaxis was given for encapsulated organisms, HSV and PCP. Serum IgG levels were maintained > 500 mg/dL. RESULTS: 49 patients, median age: 59.0 years enrolled; MCL (26), CLL (10), transformed lymphoma (7), and other histologies (6). During the life of the study, the most frequent everolimus dosing has been 2.5 mg daily or 2.5 mg every other day; at these doses, serum levels are within the therapeutic range and non-hematologic toxicity is rare. At a median follow-up of 27.1 months, three patients remain on active therapy. Two patients withdrew secondary to potentially-attributable adverse events including a bacterial pneumonia and a viral pneumonia; this low rate of discontinuation compares well to other long-term everolimus trials. While a 58 and 76% EFS at 30 months for the entire cohort and MCL cohort, respectively, compares similarly to previously published HDC/rituximab data, longer follow-up is required. CONCLUSIONS: Pharmacokinetically-targeted dosing appears to increase everolimus tolerability. This finding may be applicable to other patient populations.

Ion Transport and Competition Effects on NaTi2(PO4)3 and Na4Mn9O18 Selective Insertion Electrode Performance.

We evaluate the efficiency and capacity of electrochemically reversible insertion electrodes for use in targeted ion removal applications in aqueous solutions. The relative attributes of insertion material chemistry are evaluated by comparing the performance of two different sodium insertion materials, NaTi2(PO4)3 and Na4Mn9O18, in different electrolyte environments. We performed experiments over a range of solution compositions containing both sodium and other non-inserting ions, and we then developed mechanistic insight into the effects of solution concentration and composition on overpotential losses and round trip Coulombic efficiency. In dilute aqueous streams, performance was limited by the rate of ion transport from the bulk electrolyte region to the electrode interface. This leads to slow rates of ion removal, large overpotentials for ion insertion, parasitic charge loss due to water electrolysis, and lower round trip Coulombic efficiencies. This effect is particularly large for insertion electrodes with redox potentials exceeding the water stability window. In solutions with high background concentrations of non-inserting ions, the accumulation of non-inserting ions at the electrode interface limits inserting ion flux and leads to low ion removal capacity and round trip Coulombic efficiency.

Benchmarking of surgical complications in gynaecological oncology: prospective multicentre study.

OBJECTIVE: To explore the impact of risk-adjustment on surgical complication rates (CRs) for benchmarking gynaecological oncology centres. DESIGN: Prospective cohort study. SETTING: Ten UK accredited gynaecological oncology centres. POPULATION: Women undergoing major surgery on a gynaecological oncology operating list. METHODS: Patient co-morbidity, surgical procedures and intra-operative (IntraOp) complications were recorded contemporaneously by surgeons for 2948 major surgical procedures. Postoperative (PostOp) complications were collected from hospitals and patients. Risk-prediction models for IntraOp and PostOp complications were created using penalised (lasso) logistic regression using over 30 potential patient/surgical risk factors. MAIN OUTCOME MEASURES: Observed and risk-adjusted IntraOp and PostOp CRs for individual hospitals were calculated. Benchmarking using colour-coded funnel plots and observed-to-expected ratios was undertaken. RESULTS: Overall, IntraOp CR was 4.7% (95% CI 4.0-5.6) and PostOp CR was 25.7% (95% CI 23.7-28.2). The observed CRs for all hospitals were under the upper 95% control limit for both IntraOp and PostOp funnel plots. Risk-adjustment and use of observed-to-expected ratio resulted in one hospital moving to the >95-98% CI (red) band for IntraOp CRs. Use of only hospital-reported data for PostOp CRs would have resulted in one hospital being unfairly allocated to the red band. There was little concordance between IntraOp and PostOp CRs. CONCLUSION: The funnel plots and overall IntraOp (≈5%) and PostOp (≈26%) CRs could be used for benchmarking gynaecological oncology centres. Hospital benchmarking using risk-adjusted CRs allows fairer institutional comparison. IntraOp and PostOp CRs are best assessed separately. As hospital under-reporting is common for postoperative complications, use of patient-reported outcomes is important. TWEETABLE ABSTRACT: Risk-adjusted benchmarking of surgical complications for ten UK gynaecological oncology centres allows fairer comparison.

Transverse closure of mesenterico-portal vein after vein resection in pancreatoduodenectomy.

BACKGROUND: Resection of the involved mesenteric-portal vein (MPV) is increasingly performed in pancreatoduodenectomy. The primary aim of this study is to assess the rate of R0 resection in transverse closure (TC) versus segmental resection with end-to-end (EE) closure and the secondary aims are to assess the short-term morbidity and long-term survival of TC versus EE. METHODS: Patients undergoing pancreatoduodenectomy with MPV resection were identified from a prospectively database. The reconstruction technique were examined and categorized. Clinical, pathological, short-term and long-term survival outcomes were compared between groups. RESULTS: 110 patients underwent PD with MPV resection of which reconstruction was performed with an end-to-end technique in 92 patients (84%) and transverse closure technique in 18 patients (16%). Patients undergoing transverse closure tended to have had a shorter segment of vein resected (≤2 cm) compared to the end-to-end (83% vs. 43%; P = 0.004) with no difference in R0 rate. Short-term morbidity was similar. The median and 5-year survival was 30.0 months and 18% respectively for patients undergoing transverse closure and 28.6 months and 7% respectively for patients undergoing end-to-end reconstruction (P = 0.766). CONCLUSION: Without compromising the R0 rate, transverse closure to reconstruct the mesenteric-portal vein is shown to be feasible and safe in the setting when a short segment of vein resection is required during pancreatoduodenectomy. Synopsis - We describe a vein closure technique, transverse closure, which avoids the need for a graft, or re-implantation of the splenic vein when resection of the mesenteric-portal vein confluence is required during pancreatoduodenectomy.

Predictors of complications in gynaecological oncological surgery: a prospective multicentre study (UKGOSOC-UK gynaecological oncology surgical outcomes and complications).

BACKGROUND: There are limited data on surgical outcomes in gynaecological oncology. We report on predictors of complications in a multicentre prospective study. METHODS: Data on surgical procedures and resulting complications were contemporaneously recorded on consented patients in 10 participating UK gynaecological cancer centres. Patients were sent follow-up letters to capture any further complications. Post-operative (Post-op) complications were graded (I-V) in increasing severity using the Clavien-Dindo system. Grade I complications were excluded from the analysis. Univariable and multivariable regression was used to identify predictors of complications using all surgery for intra-operative (Intra-op) and only those with both hospital and patient-reported data for Post-op complications. RESULTS: Prospective data were available on 2948 major operations undertaken between April 2010 and February 2012. Median age was 62 years, with 35% obese and 20.4% ASA grade ⩾3. Consultant gynaecological oncologists performed 74.3% of operations. Intra-op complications were reported in 139 of 2948 and Grade II-V Post-op complications in 379 of 1462 surgeries. The predictors of risk were different for Intra-op and Post-op complications. For Intra-op complications, previous abdominal surgery, metabolic/endocrine disorders (excluding diabetes), surgical complexity and final diagnosis were significant in univariable and multivariable regression (P<0.05), with diabetes only in multivariable regression (P=0.006). For Post-op complications, age, comorbidity status, diabetes, surgical approach, duration of surgery, and final diagnosis were significant in both univariable and multivariable regression (P<0.05). CONCLUSIONS: This multicentre prospective audit benchmarks the considerable morbidity associated with gynaecological oncology surgery. There are significant patient and surgical factors that influence this risk.

Quantitative Analysis of Diffusion Weighted MR Images of Brain Tumor Using Signal Intensity Gradient Technique.

The purpose of this study was to evaluate the role of diffusion weighted-magnetic resonance imaging (DW-MRI) in the examination and classification of brain tumors, namely, glioma and meningioma. Our hypothesis was that as signal intensity variations on diffusion weighted (DW) images depend on histology and cellularity of the tumor, analysing the signal intensity characteristics on DW images may allow differentiating between the tumor types. Towards this end the signal intensity variations on DW images of the entire tumor volume data of 20 subjects with glioma and 12 subjects with meningioma were investigated and quantified using signal intensity gradient (SIG) parameter. The relative increase in the SIG values (RSIG) for the subjects with glioma and meningioma was in the range of 10.08-28.36 times and 5.60-9.86 times, respectively, compared to their corresponding SIG values on the contralateral hemisphere. The RSIG values were significantly different between the subjects with glioma and meningioma (P < 0.01), with no overlap between RSIG values across the two tumors. The results indicate that the quantitative changes in the RSIG values could be applied in the differential diagnosis of glioma and meningioma, and their adoption in clinical diagnosis and treatment could be helpful and informative.

Patient-reporting improves estimates of postoperative complication rates: a prospective cohort study in gynaecological oncology.

BACKGROUND: Most studies use hospital data to calculate postoperative complication rates (PCRs). We report on improving PCR estimates through use of patient-reporting. METHODS: A prospective cohort study of major surgery performed at 10 UK gynaecological cancer centres was undertaken. Hospitals entered the data contemporaneously into an online database. Patients were sent follow-up letters to capture postoperative complications. Grade II-V (Clavien-Dindo classification) patient-reported postoperative complications were verified from hospital records. Postoperative complication rate was defined as the proportion of surgeries with a Grade II-V postoperative complication. RESULTS: Patient replies were received for 1462 (68%) of 2152 surgeries undertaken between April 2010 and February 2012. Overall, 452 Grade II-V (402 II, 50 III-V) complications were reported in 379 of the 1462 surgeries. This included 172 surgeries with 200 hospital-reported complications and 231 with 280 patient-reported complications. All (100% concordance) 36 Grade III-V and 158 of 280 (56.4% concordance) Grade II patient-reported complications were verified on hospital case-note review. The PCR using hospital-reported data was 11.8% (172 out of 1462; 95% CI 11-14), patient-reported was 15.8% (231 out of 1462; 95% CI 14-17.8), hospital and verified patient-reported was 19.4% (283 out of 1462; 95% CI 17.4-21.4) and all data were 25.9% (379 out of 1462; 95% CI 24-28). After excluding Grade II complications, the hospital and patient verified Grade III-V PCR was 3.3% (48 out of 1462; 95% CI 2.5-4.3). CONCLUSION: This is the first prospective study of postoperative complications we are aware of in gynaecological oncology to include the patient-reported data. Patient-reporting is invaluable for obtaining complete information on postoperative complications. Primary care case-note review is likely to improve verification rates of patient-reported Grade II complications.

Bone and cartilage demonstrate changes localized to bone marrow edema-like lesions within osteoarthritic knees.

OBJECTIVE: Our objective is to understand the biological and mechanical pathways linking cartilage, bone, and marrow changes in the progression of osteoarthritis (OA). The aim of the present study was to evaluate bone structure and composition within bone marrow edema-like lesion (BMEL) regions associated with knee OA. METHODS: Tibial plateau specimens (n = 18) were collected from 10 subjects with knee OA during total knee arthroplasty (TKA). Magnetic resonance (MR) imaging was used to identify BMEL and quantify metrics of cartilage composition. Micro-computed tomography (µCT) and high-resolution peripheral quantitative computed tomography (HR-pQCT) were used to quantify density and microstructure of the subchondral trabecular bone. Fourier transform infrared (FTIR) spectroscopy was used to quantify tissue composition. RESULTS: Trabecular bone within BMEL was higher in volume fraction, with more and thicker trabeculae that were more plate-like in structure compared to unaffected regions. BMEL trabecular tissue composition had decreased phosphate and carbonate content. Marrow infiltration by a fibrous collagen network and evidence of increased bone remodeling were present. Structural and compositional changes were specifically localized to regions underlying cartilage degradation. CONCLUSION: These results support the paradigm of focal interactions among bone, marrow, and cartilage in the progression of knee OA. Quantitative evaluation of tissue changes and interactions may aid in the understanding of disease pathophysiology and provide imaging markers for disease progression.

Mineral composition is altered by osteoblast expression of an engineered G(s)-coupled receptor.

Activation of the G(s) G protein-coupled receptor Rs1 in osteoblasts increases bone mineral density by 5- to 15-fold in mice and recapitulates histologic aspects of fibrous dysplasia of the bone. However, the effects of constitutive G(s) signaling on bone tissue quality are not known. The goal of this study was to determine bone tissue quality in mice resulting from osteoblast-specific constitutive G(s) activation, by the complementary techniques of FTIR spectroscopy and synchrotron radiation micro-computed tomography (SRµCT). Col1(2.3)-tTA/TetO-Rs1 double transgenic (DT) mice, which showed osteoblast-specific constitutive G(s) signaling activity by the Rs1 receptor, were created. Femora and calvariae of DT and wild-type (WT) mice (6 and 15 weeks old) were analyzed by FTIR spectroscopy. WT and DT femora (3 and 9 weeks old) were imaged by SRµCT. Mineral-to-matrix ratio was 25% lower (P = 0.010), carbonate-to-phosphate ratio was 20% higher (P = 0.025), crystallinity was 4% lower (P = 0.004), and cross-link ratio was 11% lower (P = 0.025) in 6-week DT bone. Differences persisted in 15-week animals. Quantitative SRµCT analysis revealed substantial differences in mean values and heterogeneity of tissue mineral density (TMD). TMD values were 1,156 ± 100 and 711 ± 251 mg/cm(3) (mean ± SD) in WT and DT femoral diaphyses, respectively, at 3 weeks. Similar differences were found in 9-week animals. These results demonstrate that continuous G(s) activation in murine osteoblasts leads to deposition of immature bone tissue with reduced mineralization. Our findings suggest that bone tissue quality may be an important contributor to increased fracture risk in fibrous dysplasia patients.

Anaesthesia for caesarean section in a patient with Gitelman's syndrome.

Gitelman's syndrome is a rare autosomal recessive salt-losing renal tubulopathy characterised by hypomagnesaemia, hypocalciuria and secondary aldosteronism, which results in hypokalaemia and metabolic alkalosis. The syndrome is a variant of a group of renal diseases termed Bartter's syndrome. Diagnosis is based on clinical symptoms and biochemical abnormalities. Sources of information on Gitelman's syndrome in pregnancy are scarce and anaesthetic management is challenging. Close monitoring and supplementation of potassium and magnesium are required to avoid possible obstetric and life threatening complications for both mother and child.