How tuberculosis programs can navigate the world of social health insurance.

Many countries with a high tuberculosis (TB) burden are adopting social health insurance (SHI) schemes. However, the national TB programs (NTPs) of these countries are only just starting to grapple with the effects of SHI on their operations. Here, we review the rationale for analyzing TB programs in light of the changes brought by SHI. We consider the influence of certain purchasing decisions on TB care and prevention, and the opportunities that SHI may present for NTPs to broaden private sector engagement, extract TB data across the health sector, and facilitate quality improvement efforts. We also explore which functions are likely to be performed by SHI systems, which require special attention with the advent of SHI, and the metrics that indicate how much of TB care seeking and treatment can be reached and influenced by SHI. SHI presents certain risks for TB programs, but also opportunities to adapt to a more modern health system and to bring quality TB care and treatment to more people.

Onions and prevalence surveys: how to analyze and quantify tuberculosis case-finding gaps.

Finding the missing 4 million tuberculosis (TB) patients is one of the greatest challenges facing the TB community. The optimal approaches to this will vary by country, but there is no consistent process for analyzing the potential benefit of different strategies, or for deciding which approaches are most appropriate for a given setting. Here, I bring together the Onion Model-as a way to think through health system structures-and evidence from prevalence surveys. The result is a structured process for prioritizing different strategies for case finding. Outcomes vary widely by setting, pointing to the importance of each country undertaking such a prioritization process.

Cost and cost-effectiveness of tuberculosis treatment shortening: a model-based analysis.

BACKGROUND: Despite improvements in treatment success rates for tuberculosis (TB), current six-month regimen duration remains a challenge for many National TB Programmes, health systems, and patients. There is increasing investment in the development of shortened regimens with a number of candidates in phase 3 trials. METHODS: We developed an individual-based decision analytic model to assess the cost-effectiveness of a hypothetical four-month regimen for first-line treatment of TB, assuming non-inferiority to current regimens of six-month duration. The model was populated using extensive, empirically-collected data to estimate the economic impact on both health systems and patients of regimen shortening for first-line TB treatment in South Africa, Brazil, Bangladesh, and Tanzania. We explicitly considered 'real world' constraints such as sub-optimal guideline adherence. RESULTS: From a societal perspective, a shortened regimen, priced at USD1 per day, could be a cost-saving option in South Africa, Brazil, and Tanzania, but would not be cost-effective in Bangladesh when compared to one gross domestic product (GDP) per capita. Incorporating 'real world' constraints reduces cost-effectiveness. Patient-incurred costs could be reduced in all settings. From a health service perspective, increased drug costs need to be balanced against decreased delivery costs. The new regimen would remain a cost-effective option, when compared to each countries' GDP per capita, even if new drugs cost up to USD7.5 and USD53.8 per day in South Africa and Brazil; this threshold was above USD1 in Tanzania and under USD1 in Bangladesh. CONCLUSION: Reducing the duration of first-line TB treatment has the potential for substantial economic gains from a patient perspective. The potential economic gains for health services may also be important, but will be context-specific and dependent on the appropriate pricing of any new regimen.

Somatic gene mutation analysis of triple negative breast cancers.

OBJECTIVES: The aims of this study were to analyze triple negative breast cancer (TNBC) using an expanded next generation sequencing (NGS) assay, assess the clinical relevance using a recently described database, and correlate tumor morphology with detected genetic alterations. METHODS: DNA was isolated from twenty primary TNBCs and genes of interest were enriched and sequenced with hybrid capture, followed by variant detection and functional and clinical annotation. The JAX-CTP™ assay detects actionable variants in the form of single nucleotide variations, small insertions and deletions (≤50 bp), and copy number variants in 358 genes in specimens containing a neoplastic cell content of ≥50%. The JAX-CKB is a comprehensive database that curates tumor phenotype, genetic variant and protein effect, therapeutic relevance, and available treatment options. RESULTS: 18/20 (90%) of TNBCs contained at least one somatic mutation detected by the JAX-CTP™. MYC amplification was the most common alteration, present in 75% of tumors. TP53, AURKA, and KDR mutations were each present in 30% (6/20) of cases. Related recruiting clinical trials, extracted from JAX-CKB, included 166 for breast cancer, of which 17 were specific to only the TNBC subtype. All 17 trials were testing at least one therapy that targets a mutation identified in this sample set. The majority (89%) of tumors with basal-like histologic features had MYC amplification. CONCLUSIONS: The expanded gene panel identified a variety of clinically actionable gene alterations in TNBCs. The identification of such variants increases the possibility for new therapeutic interventions and clinical trial eligibility for TNBC patients.

Patient costs during tuberculosis treatment in Bangladesh and Tanzania: the potential of shorter regimens.

OBJECTIVE: To estimate the costs incurred by patients during the intensive and continuation phases of the current 6-month tuberculosis (TB) regimen in Bangladesh and Tanzania, and thus identify potential benefits to patients of a shorter, 4-month treatment regimen. DESIGN: The validated Stop TB patient cost questionnaire was adapted and used in interviews with 190 patients in the continuation phase of treatment with current regimens. RESULTS: In both countries, overall patient costs were lower during 2 months of the continuation phase (US$74 in Tanzania and US$56 in Bangladesh) than during the 2 months of the intensive phase of treatment (US$150 and US$111, respectively). However, continuation phase patient costs still represented 89% and 77% of the 2-month average national income in the respective countries. Direct travel costs in some settings were kept low by local delivery system features such as community treatment observation. Lost productivity and costs for supplementary foods remained significant. CONCLUSIONS: Although it is not a straightforward exercise to determine the exact magnitude of likely savings, a shorter regimen would reduce out-of-pocket expenses incurred by patients in the most recent 2 months of the continuation phase and allow an earlier return to productive activities.

Personalized therapy for breast cancer.

Breast cancer is a complex disease characterized by many morphological, clinical and molecular features. For many years, this disease has been classified according to histopathologic criteria, known as the tumor, node and metastasis (TNM) staging system. Clinical criteria that include immunohistochemical markers, such as the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2), provide a classification of breast cancer and dictates the optimal therapeutic approach for treatment. With genomic techniques, such as real-time reverse transcriptase PCR (RT-PCR), microarrays, next-generation sequencing, and whole-exome sequencing, breast cancer diagnostics is going through a significant evolution. Genomic and transcriptomic technologies make the analysis of gene expression signatures and mutation status possible so that tumors may now be classified more accurately with respect to diagnosis and prognosis. The -omic era has also made the possible identification of new biomarkers involved in breast cancer development, survival and invasion that can be gradually incorporated either into clinical testing or clinical trials. Together, clinical and molecular criteria can contribute to a more personalized management of the breast cancer patient. This article will present the progress made in the diagnosis and management of breast cancer using molecular information provided by genomic and transcriptomic technologies.

Implications of the current tuberculosis treatment landscape for future regimen change.

BACKGROUND: The current tuberculosis (TB) treatment landscape has been studied extensively, but researchers rarely consider how it creates challenges or opportunities for future regimen change. METHODS: In 166 stakeholder interviews in the TB high-burden countries (HBCs), we investigated areas of first-line TB treatment and control that would affect, and be affected by, a future TB regimen change. Responses were compared with existing standardized data. RESULTS: Public sector regimens are converging towards a single standard, which facilitates comparison with a single control arm from clinical trials. However, final product design is challenging if the goal is fixed-dose combinations and patient kits, whose current widespread use addresses continuing weaknesses in drug management. Any product must address broad groups, as relatively low levels of drug susceptibility testing (DST) do not allow for individualized therapy. Finally, the protection of new drugs from the development of resistance will be challenging, as the implementation of directly observed therapy and public-private mix programs is incomplete, and substantial private sectors have been identified as early adopters of these drugs. CONCLUSIONS: Health systems for TB treatment and control must be improved not only to allow better implementation of current treatments but also to set the stage for implementation of new, improved TB regimens.

Tuberculosis regimen change in high-burden countries.

BACKGROUND: Experience with past tuberculosis (TB) regimen changes can guide future regimen changes. METHODS: To explore the process, major players and procedural success factors for recent public sector TB regimen changes, we conducted 166 interviews of country stakeholders in 21 of the 22 TB high-burden countries (HBCs). RESULTS: Stakeholders described 40 distinct regimen changes for drug-susceptible TB. Once countries committed to considering a change, the average timing was ∼1 year for decision-making and ∼2 years for roll-out. Stakeholders more often cited concerns that were program-based (e.g., logistics and cost) rather than patient-focused (e.g., side effects), and patient representatives were seldom part of decision making. Decision-making bodies in higher-income HBCs had more formalized procedures and fewer international participants. Pilot studies focused on logistics were more common than effectiveness studies, and the evidence base was often felt to be insufficient. Once implementation started, weaknesses in drug management were often exposed, with additional complications if local manufacturing was required. Best practices for regimen change included early engagement of budgeting staff, procurement staff, regulators and manufacturers. CONCLUSIONS: Future decision makers will benefit from strengthened decision-making bodies, patient input, early and comprehensive planning, and regimens and evidence that address local, practical implementation issues.

Estimating the market for tuberculosis drugs in industrialized and developing nations.

BACKGROUND: The successful introduction of new drugs into low- and middle-income countries requires an understanding of the existing market size and market dynamics for the therapeutic area of interest. The drug markets in these countries are, however, less well understood than those in high-income countries. METHODS: The global market for tuberculosis (TB) drugs was estimated by studying in detail six high-burden countries and four high-income countries, followed by extrapolation. Data were derived from existing pharmaceutical audit databases and interviews with government officials, medical staff and suppliers. RESULTS: The use of qualitative inputs to inform the collection of quantitative information, notably to identify where the major flows of TB drugs are located, allowed a confident estimate of the global market for first-line TB drugs. Final ranges were US$261-316 million or US$310-418 million, depending on whether case notification rates or incidence were used for extrapolations. CONCLUSIONS: An estimation of the global TB drug market is made more reliable by a qualitative understanding of TB drug distribution pathways, which differ greatly among countries. The understanding of this structure in key high-burden countries provides the basis for a simpler update of the market estimate in the future.

Patterns of disease progression and outcomes in a randomized trial testing ABVD alone for patients with limited-stage Hodgkin lymphoma.

BACKGROUND: In the National Cancer Institute of Canada Clinical Trials Group/Eastern Cooperative Oncology Group HD.6 trial, progression-free survival was better in patients randomized to therapy that included radiation, compared to doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD) alone. We now evaluate patterns of progression and subsequent outcomes of patients with progression. PATIENTS AND METHODS: After a median of 4.2 years, 33 patients have progressed. Two radiation oncologists determined whether sites of progression were confined within radiation fields. Freedom from second progression (FF2P) and freedom from second progression or death (FF2P/D) were compared. RESULTS: Reviewers agreed for the extended (kappa = 0.87) and involved field (kappa = 1.0) analyses. Progression after ABVD alone was more frequently confined within both the extended (20/23 vs. 3/10; P = 0.002) and involved fields (16/23 vs. 2/10; P = 0.02). There was no difference in FF2P between groups [5-year estimate 99% (radiation) versus 96% (ABVD alone)] [hazard ratio (HR) = 3.14, 95% confidence interval (CI) 0.63-15.6; P = 0.14]; the 5-year estimates of FF2P/D were 94% in each group (HR = 1.04, 95% CI 0.41-2.63; P = 0.93). CONCLUSION: Treatment that includes radiation reduces the risk of progressive Hodgkin lymphoma in sites that receive this therapy, but we are unable to detect differences in FF2P or FF2P/D.

Let's make Golgi.

Does the Golgi self-organize or does it form around an instructive template? Evidence on both sides is piling up, but a definitive conclusion is proving elusive.

Searching for a spindle matrix.

New evidence supports the idea of a nonmicrotubule spindle matrix, but the debate about the reality of this structure continues.

Quantitative hemoglobin tomography with diffuse near-infrared spectroscopy: pilot results in the breast.

The authors describe what is, to the best of their knowledge, the first quantitative hemoglobin concentration images of the female breast that were formed with model-based reconstruction of near-infrared intensity-modulated tomographic data. The results in 11 patients, including two with breast tumors with pathologic correlation, are summarized. Hemoglobin concentration appears to correlate with tumor vascularity without the need for exogenous contrast material and thereby has intrinsic diagnostic value.

Bispecific Antibody MDX-210 for Treatment of Advanced Ovarian and Breast Cancer.

A large number of monoclonal antibodies (MAbs) to various tumor cell lines have been developed (1). However, MAbs have thus far had limited therapeutic impact in oncology, probably in part because many murine MAbs do not effectively recruit immune effector mechanisms, such as complement fixation and antibody-dependent cell-mediated cytotoxicity (ADCC) in humans. Additionally, although humanized MAbs are being developed, when used therapeutically their immunological effectiveness may be limited by high concentrations of nonspecific immunoglobulin (Ig) in patient serum. These nonspecific Ig will compete with conventional MAbs for binding to Type I Fc receptors (FcγRI) on immune effector cells, and may therefore limit conventional MAbs ability to recruit an immune response. Recently, however, clinical efficacy of a humanized MAb directed against HER-2/neu in patients with advanced breast cancer has been demonstrated (2-4). Preclinical data suggests that mechanistically this activity may be as a consequence of modulation of important biologic properties of the HER-2/neu receptor itself, as opposed to through an immunologic mechanism of tumor cell destruction.

Mammography in 53,803 women from the New Hampshire mammography network.

PURPOSE: To describe measures of mammography performance in a geographically defined population and evaluate the interpreter's use of the Breast Imaging Reporting and Data System (BI-RADS). MATERIALS AND METHODS: Mammographic data from 47,651 screening and 6,152 diagnostic examinations from November 1, 1996, to October 31, 1997, were linked to 1,572 pathologic results. Mammographic outcomes were based on BI-RADS assessments and recommendations reported by the interpreting radiologist. The consistency of BI-RADS recommendations was evaluated. RESULTS: Screening mammography had a sensitivity of 72.4% (95% CI: 66.4%, 78.4%), specificity of 97.3% (95% CI: 97.25%, 97.4%), and positive predictive value of 10.6% (95% CI: 9.1%, 12.2%). Diagnostic mammography had higher sensitivity, 78.1% (95% CI: 71.9%, 84.3%); lower specificity, 89.3% (95% CI: 88.5%, 90.1%); and better positive predictive value, 17.1% (95% CI: 14.5%, 19.8%). The cancer detection rate with screening mammography was 3.3 per 1,000 women, with a biopsy yield of 22.4%, whereas the interval cancer rate was 1. 2 per 1,000. Nearly 80% of screening-detected invasive malignancies were node negative. The recall rate for screening mammography was 8. 3%. Ultrasonography was used in 3.5% of screening and 17.5% of diagnostic examinations. BI-RADS recommendations were generally consistent, except for probably benign assessments. CONCLUSION: The sensitivity of screening mammography in this population-based sample is lower than expected, although other performance indicators are commendable. BI-RADS "probably benign" assessments are commonly misused.