Lessons from a theory of change-driven evaluation of a global mental health funding portfolio.

BACKGROUND: Given the underinvestment in global mental health to-date, it is important to consider how best to maximize the impact of existing investments. Theory of Change (ToC) is increasingly attracting the interest of funders seeking to evaluate their own impact. This is one of four papers investigating Grand Challenges Canada's (GCC's) first global mental health research funding portfolio (2012-2016) using a ToC-driven approach. METHODS: A portfolio-level ToC map was developed through a collaborative process involving GCC grantees and other key stakeholders. Proposed ToC indicators were harmonised with GCC's pre-existing Results-based Management and Accountability Framework to produce a "Core Metrics Framework" of 23 indicators linked to 17 outcomes of the ToC map. For each indicator relevant to their project, the grantee was asked to set a target prior to the start of implementation, then report results at six-month intervals. We used the latest available dataset from all 56 projects in GCC's global mental health funding portfolio to produce a descriptive analysis of projects' characteristics and outcomes related to delivery. RESULTS: 12,999 people were trained to provide services, the majority of whom were lay or other non-specialist health workers. Most projects exceeded their training targets for capacity-building, except for those training lay health workers. Of the 321,933 people screened by GCC-funded projects, 162,915 received treatment. Most projects focused on more than one disorder and exceeded all their targets for screening, diagnosis and treatment. Fewer people than intended were screened for common mental disorders and epilepsy (60% and 54%, respectively), but many more were diagnosed and treated than originally proposed (148% and 174%, respectively). In contrast, the three projects that focused on perinatal depression exceeded screening and diagnosis targets, but only treated 43% of their intended target. CONCLUSIONS: Under- or over-achievement of targets may reflect operational challenges such as high staff turnover, or challenges in setting appropriate targets, for example due to insufficient epidemiological evidence. Differences in delivery outcomes when disaggregated by disorder suggest that these challenges are not universal. We caution implementers, funders and evaluators from taking a one-size-fits all approach and make several recommendations for how to facilitate more in-depth, multi-method evaluation of impact using portfolio-level ToC.

18F-sodium fluoride bone PET-CT in symptomatic lumbosacral transitional vertebra.

AIM: To analyse the relationship between 18F-labelled sodium fluoride (NaF) uptake and lumbar back pain in patients with lumbosacral transitional vertebra (LSTV) a congenital malformation of the lumbosacral spine. MATERIALS AND METHODS: The study population comprised 55 patients (mean age, 51.42 years; median age 52 years) with LSTV. All patients underwent integrated positron-emission tomography (PET)/computed tomography (CT) by injecting 0.06 mCi/kg of 18F-NaF. A three-point grading system was used to evaluate 18F-NaF uptake (grade 0, no uptake; grade 1, mild uptake; and grade 2, marked increase uptake. RESULTS: In total, 55 cases of LSTV (34 symptomatic and 21 asymptomatic) were included. Asymptomatic patients had no uptake in the majority of cases, i.e., grade 0 (n=18) and grade 1 (n=3), whereas symptomatic patients demonstrated focal increase tracer uptake of grade 2 (n=24), grade 1 (n=4), and grade 0 (n=6). There is a strong linear trend between the intensity of 18F-NaF uptake and presence of symptoms (p<0.0001). The sensitivity and specificity of 18F-NaF uptake at LSTV as a cause of pain were 82% (95% confidence interval [CI]: 65-93%) and 86% (95% CI: 64-97%). The positive and negative predictive values were 90% (95% CI: 74-98%) and 75% (95% CI: 53-90%). CONCLUSIONS: 18F-NaF PET/CT can be useful in evaluating back pain and 18F-NaF may be used as an adjunctive biological maker for assessing LSTV as a potential cause of pain.

The clinical significance of incidental soft tissue uptake on whole body 18F-sodium fluoride bone PET-CT.

18F-sodium fluoride (NaF) is a PET bone imaging agent and is commonly used in imaging patients with cancer; however, similar to technetium-99m medronic acid (99mTc-MDP), it can be useful in the evaluation of benign bone and joint conditions. NaF is an excellent bone-seeking agent with high bone uptake due to rapid single-pass extraction. It has negligible plasma protein binding, rapid blood, renal clearance, high bone uptake and almost all NaF delivered is retained by bone after a single pass of blood; however, uptake of NaF can be observed in non-osseous structures such as the arterial vasculature, gastrointestinal tract, genitourinary tract, and viscera. In this article, we present a spectrum of clinical cases with non-osseous NaF uptake in patients referred for cancer staging.

Early relapse after autologous hematopoietic cell transplantation remains a poor prognostic factor in multiple myeloma but outcomes have improved over time.

Duration of initial disease response remains a strong prognostic factor in multiple myeloma (MM) particularly for upfront autologous hematopoietic cell transplant (AHCT) recipients. We hypothesized that new drug classes and combinations employed prior to AHCT as well as after post-AHCT relapse may have changed the natural history of MM in this population. We analyzed the Center for International Blood and Marrow Transplant Research database to track overall survival (OS) of MM patients receiving single AHCT within 12 months after diagnosis (N=3256) and relapsing early post-AHCT (<24 months), and to identify factors predicting for early vs late relapses (24-48 months post-AHCT). Over three periods (2001-2004, 2005-2008, 2009-2013), patient characteristics were balanced except for lower proportion of Stage III, higher likelihood of one induction therapy with novel triplets and higher rates of planned post-AHCT maintenance over time. The proportion of patients relapsing early was stable over time at 35-38%. Factors reducing risk of early relapse included lower stage, chemosensitivity, transplant after 2008 and post-AHCT maintenance. Shorter post-relapse OS was associated with early relapse, IgA MM, Karnofsky <90, stage III, >1 line of induction and lack of maintenance. Post-AHCT early relapse remains a poor prognostic factor, even though outcomes have improved over time.

Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study.

Introduction of new myeloma therapies offers new options for patients refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). In this multicenter study, patients with relapsed multiple myeloma, who have received at least three prior lines of therapy, are refractory to both an IMiD (lenalidomide or pomalidomide) and a PI (bortezomib or carfilzomib), and have been exposed to an alkylating agent were identified. The time patients met the above criteria was defined as time zero (T0). Five hundred and forty-three patients diagnosed between 2006 and 2014 were enrolled in this study. Median age at T0 was 62 years (range 31-87); 61% were males. The median duration between diagnosis and T0 was 3.1 years. The median number of lines of therapy before T0 was 4 (range 3-13). The median overall survival (OS) from T0 for the entire cohort was 13 (95% confidence interval (CI) 11, 15) months. At least one regimen recorded after T0 in 462 (85%) patients, with a median (95% CI) progression-free survival and OS from T0 of 5 (4, 6), and 15.2 (13, 17) months, respectively. The study provides the expected outcome of relapsed multiple myeloma that is refractory to a PI and an IMiD, a benchmark for comparison of new therapies being evaluated.

Second primary malignancies in multiple myeloma: an overview and IMWG consensus.

Background: Therapeutic advancements following the introduction of autologous stem cell transplantation and 'novel' agents have significantly improved clinical outcomes for patients with multiple myeloma (MM). Increased life expectancy, however, has led to renewed concerns about the long-term risk of second primary malignancies (SPMs). This review outlines the most up-to-date knowledge of possible host-, disease-, and treatment-related risk factors for the development of SPMs in patients with MM, and provides practical recommendations to assist physicians. Design: A Panel of International Myeloma Working Group members reviewed the most relevant data published in the literature as full papers, or presented at meetings of the American Society of Clinical Oncology, American Society of Hematology, European Hematology Association, or International Myeloma Workshops, up to June 2016. Here, we present the recommendations of the Panel, based on this literature review. Results: Overall, the risk of SPMs in MM is low, multifactorial, and partially related to the length of patients' survival and MM intrinsic susceptibility. Studies suggest a significantly increased incidence of SPMs when lenalidomide is administered either following, or concurrently with, oral melphalan. Increased SPM incidence has also been reported with lenalidomide maintenance following high-dose melphalan, albeit to a lesser degree. In both cases, the risk of death from MM was significantly higher than the risk of death from SPMs, with lenalidomide possibly providing a survival benefit. No increase in SPM incidence was reported with lenalidomide plus dexamethasone (without melphalan), or with bortezomib plus oral melphalan, dexamethasone, or thalidomide. Conclusion: In general, the risk of SPMs should not alter the current therapeutic decision-making process in MM. However, regimens such as lenalidomide plus dexamethasone should be preferred to prolonged exposure to lenalidomide plus oral melphalan. SPM risk should be carefully discussed with the patient in the context of benefits and risks of different treatment options.

Ectopic Intrathymic Parathyroid adenoma demonstrated on Tc-99m Sestamibi SPECT-CT.

Intrathymic parathyroid adenoma is a rare cause of primary hyperparathyroidism. In this case, Tc-99m Sestamibi SPECT-CT successfully localized abnormal tracer uptake in the mediastinum with corresponding low density lesion on CT images suggestive of mediastinal parathyroid adenoma which late on confirmed on histopathology. After the median sternotomy a large intrathymic parathyroid adenoma was identified and excised. With the help of gamma probe the surgeons detect the lesion early and with more confidence as well as reducing the total operation time. Tc-99m Sestamibi SPECT-CT scintigraphy and gamma probe localization is recommended for preoperative and intra operative localization of ectopic parathyroid adenomas.

Cost-effectiveness of lenalidomide plus dexamethasone vs. bortezomib plus melphalan and prednisone in transplant-ineligible U.S. patients with newly-diagnosed multiple myeloma.

OBJECTIVE: To conduct a cost-effectiveness assessment of lenalidomide plus dexamethasone (Rd) vs bortezomib plus melphalan and prednisone (VMP) as initial treatment for transplant-ineligible patients with newly-diagnosed multiple myeloma (MM), from a U.S. payer perspective. METHODS: A partitioned survival model was developed to estimate expected life-years (LYs), quality-adjusted LYs (QALYs), direct costs and incremental costs per QALY and LY gained associated with use of Rd vs VMP over a patient's lifetime. Information on the efficacy and safety of Rd and VMP was based on data from multinational phase III clinical trials and a network meta-analysis. Pre-progression direct costs included the costs of Rd and VMP, treatment of adverse events (including prophylaxis) and routine care and monitoring associated with MM. Post-progression direct costs included costs of subsequent treatment(s) and routine care and monitoring for progressive disease, all obtained from published literature and estimated from a U.S. payer perspective. Utilities were obtained from the aforementioned trials. Costs and outcomes were discounted at 3% annually. RESULTS: Relative to VMP, use of Rd was expected to result in an additional 2.22 LYs and 1.47 QALYs (discounted). Patients initiated with Rd were expected to incur an additional $78,977 in mean lifetime direct costs (discounted) vs those initiated with VMP. The incremental costs per QALY and per LY gained with Rd vs VMP were $53,826 and $35,552, respectively. In sensitivity analyses, results were found to be most sensitive to differences in survival associated with Rd vs VMP, the cost of lenalidomide and the discount rate applied to effectiveness outcomes. CONCLUSIONS: Rd was expected to result in greater LYs and QALYs compared with VMP, with similar overall costs per LY for each regimen. Results of this analysis indicated that Rd may be a cost-effective alternative to VMP as initial treatment for transplant-ineligible patients with MM, with an incremental cost-effectiveness ratio well within the levels for recent advancements in oncology.

Long-term survival outcomes of reduced-intensity allogeneic or autologous transplantation in relapsed grade 3 follicular lymphoma.

Grade 3 follicular lymphoma (FL) has aggressive clinical behavior. To evaluate the optimal first transplantation approach in relapsed/refractory grade 3 FL patients, we compared the long-term outcomes after allogeneic (allo-) vs autologous hematopoietic cell transplantation (auto-HCT) in the rituximab era. A total of 197 patients undergoing first reduced-intensity conditioning (RIC) allo-HCT or first auto-HCT during 2000-2012 were included. Rituximab-naive patients were excluded. Allo-HCT recipients were younger, more heavily pretreated and had a longer interval between diagnosis and HCT. The 5-year probabilities of non-relapse mortality (NRM), relapse/progression, PFS and overall survival (OS) for auto-HCT vs allo-HCT groups were 4% vs 27% (P<0.001), 61% vs 20% (P<0.001), 36% vs 51% (P=0.07) and 59% vs 54% (P=0.7), respectively. On multivariate analysis, auto-HCT was associated with reduced risk of NRM (relative risk (RR)=0.20; P=0.001). Within the first 11 months post HCT, auto- and allo-HCT had similar risks of relapse/progression and PFS. Beyond 11 months, auto-HCT was associated with higher risk of relapse/progression (RR=21.3; P=0.003) and inferior PFS (RR=3.2; P=0.005). In the first 24 months post HCT, auto-HCT was associated with improved OS (RR=0.42; P=0.005), but in long-time survivors (beyond 24 months) it was associated with inferior OS (RR=3.6; P=0.04). RIC allo-HCT as the first transplant approach can provide improved PFS and OS, in long-term survivors.

Gene signature combinations improve prognostic stratification of multiple myeloma patients.

Multiple myeloma (MM) is a plasma cell neoplasm with significant molecular heterogeneity. Gene expression profiling (GEP) has contributed significantly to our understanding of the underlying biology and has led to several prognostic gene signatures. However, the best way to apply these GEP signatures in clinical practice is unclear. In this study, we investigated the integration of proven prognostic signatures for improved patient risk stratification. Three publicly available MM GEP data sets that encompass newly diagnosed as well as relapsed patients were analyzed using standardized estimation of nine prognostic MM signature indices and simulations of signature index combinations. Cox regression analysis was used to assess the performance of simulated combination indices. Taking the average of multiple GEP signature indices was a simple but highly effective way of integrating multiple GEP signatures. Furthermore, although adding more signatures in general improved performance substantially, we identified a core signature combination, EMC92+HZDCD, as the top-performing prognostic signature combination across all data sets. In this study, we provided a rationale for gene signature integration and a practical strategy to choose an optimal risk score estimation in the presence of multiple prognostic signatures.

111In-pentetreotide scintigraphy and 18F FDG PET-CT in differentiated thyroid carcinoma metastases with negative whole body radioiodine scan.

Metastases of differentiated thyroid cancer (DTC) can lose affinity to radioiodine with the passage of time, with resultant difficulty in management. Thyroid tumors are known to express somatostatin receptors and therefore 111In-pentetreotide, somatostatin analogue, can visualize tumors with high concentration of somatostatin receptors. We report a case of I-131 whole body scan (WBS) negative recurrent metastatic papillary thyroid carcinoma with positive 18F FDG PET-CT and 111In-pentetreotide scan. Somatostatin receptor scintigraphy (SRS) with 111In-pentetreotide may be useful both in the staging and monitoring of patients with non-iodine avid carcinoma of the thyroid. 111In-pentetreotide scan positive patients are potential candidates for somatostatin receptor-targeted therapy.

Insight into human protease activated receptor-1 as anticancer target by molecular modelling.

Protease-activated receptor 1 (PAR1) has been established as a promising target in many diseases, including various cancers. Strong evidence also suggests its role in metastasis. It is proved experimentally that PAR1 can induce numerous cell phenotypes, i.e. proliferation and differentiation. A strong link between PAR1 gene overexpression and high levels of ß-catenin was suggested by a study of the PAR1-Gα(13)-DVL axis in ß-catenin stabilization in cancers. An in vitro study was carried out to analyze PAR1 expression by flow cytometry on CD38+138+ plasma cells obtained from patients either at diagnosis (n: 46) (newly diagnosed multiple myeloma (NDMM)) or at relapse (n: 45) (relapsed/refractory multiple myeloma (RRMM)) and compared with the controls. Our previously synthesized benzoxazole (XT2B) and benzamide (XT5) derivatives were tested with in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, which revealed significant inhibitory activity on PAR1. We provide docking studies using Autodock Vina of these newly tested compounds to compare with the known PAR1 inhibitors in order to examine the binding mechanisms. In addition, the docking results are validated using HYDE binding assessment and a neural network (NN) scoring function.

Trace metals in water, sediment and bivalves of a tropical estuary, west coast of India.

Trace metal pollution was studied in water, sediment and three selected bivalves in Mandovi and Chapora estuaries of Goa. The trace metal in water and sediment of Mandovi was higher than in Chapora. The concentration in the tissues was in the range of 1205.2-2506.7 ppm for Paphia malabarica, 1906.2-2802.6 ppm for Perna viridis and 778.7-1607.5 ppm for Saccostrea cucullata in Mandovi estuary. Tha values for Chapora were 199.4-625.8 ppm for P. malabarica, 812.6-1220.2 for P. viridis and 392.5-418.6 ppm for S. cucullata. The anthropogenic input of metal in Mandovi estuary appears to be mainly responsible for the high accumulation of trace metals. These bivalves have potential to serve as indicator for metal contamination in seafood of Goa.

Defining and treating high-risk multiple myeloma.

Multiple myeloma (MM) is more recently being recognized as a heterogeneous group of disease with variability in outcomes based on specific clinical and biologic predictors. MM patients can be broadly categorized into standard, intermediate and high risk for disease relapse, morbidity and mortality. The high-risk features include patient-specific factors such as old age, poor performance status and comorbidities; clinical features such as primary plasma cell leukemia and extramedullary disease; disease-specific biologic features such as deletion 17p, t(4;14) and high-risk gene expression profiling signatures. The current paper reviews the available data on best therapeutic approaches for high-risk MM.

Renal insufficiency retains adverse prognostic implications despite renal function improvement following Total Therapy for newly diagnosed multiple myeloma.

Renal insufficiency (RI) is a frequent complication of multiple myeloma (MM) with negative consequences for patient survival. The improved clinical outcome with successive Total Therapy (TT) protocols was limited to patients without RI. We therefore performed a retrospective analysis of overall survival, progression-free survival and time to progression (TTP) of patients enrolled in TT2 and TT3 in relationship to RI present at baseline and pre-transplant. Glomerular filtration rate was graded in four renal classes (RCs), RC1-RC4 (RC1 ⩾90 ml/min/1.73 m(2), RC2 60-89 ml/min/1.73 m(2), RC3 30-59 ml/min/1.73 m(2) and RC4 <30 ml/min/1.73 m(2)). RC1-3 had comparable clinical outcomes while RC4 was deleterious, even after improvement to better RC after transplant. Among the 85% of patients with gene expression profiling defined low-risk MM, Cox regression modeling of baseline and pre-transplant features, which also took into consideration RC improvement and MM complete response (CR), identified the presence of metaphase cytogenetic abnormalities and baseline RC4 as independent variables linked to inferior TTP post-transplant, while MM CR reduced the risk of progression and TTP by more than 60%. Failure to improve clinical outcomes despite RI improvement suggested MM-related causes. Although distinguishing RC4 from RC<4, 46 gene probes bore no apparent relationship to MM biology or survival.

CXC chemokine ligand 12a enhances chondrocyte proliferation and maturation during endochondral bone formation.

OBJECTIVE: We investigated the roles of CXC chemokine ligand 12a (CXCL12a), also known as stromal cell-derived factor-1α (SDF-1α), in endochondral bone growth, which can give us important clues to understand the role of CXCL12a in osteoarthritis (OA). METHODS: Primary chondrocytes and tibial explants from embryonic 15.5 day-old mice were cultured with recombinant mouse CXCL12a. To assess the role of CXCL12a in chondrogenic differentiation, we conducted mesenchymal cell micromass culture. RESULTS: In tibia organ cultures, CXCL12a increased total bone length in a dose-dependent manner through proportional effects on cartilage and bone. In accordance with increased length, CXCL12a increased the protein level of proliferation markers, such as cyclin D1 and proliferating cell nuclear antigen (PCNA), in primary chondrocytes as well as in tibia organ culture. In addition, CXCL12a increased the expression of Runx2, Col10 and MMP13 in primary chondrocytes and tibia organ culture system, implying a role of CXCL12a in chondrocyte maturation. Micromass cultures of limb-bud mesenchymal progenitor cells (MPCs) revealed that CXCL12a has a limited effect on early chondrogenesis, but significantly promoted maturation of chondrocytes. CXCL12a induced the phosphorylation of p38 and Erk1/2 MAP kinases and IκB. The increased expression of cyclin D1 by CXCL12a was significantly attenuated by inhibitors of MEK1 and NF-κB. On the other hand, p38 and Erk1/2 MAP kinase and NF-κB signaling were associated with CXCL12a-induced expression of Runx2 and MMP13, the marker of chondrocyte maturation. CONCLUSION: CXCL12a promoted the proliferation and maturation of chondrocytes, which strongly suggest that CXCL12a may have a negative effect on articular cartilage and contribute to OA progression.