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.

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.

The spindle-assembly checkpoint: aiming for a perfect mitosis, every time.

Checkpoints reduce the frequency of errors in cell division by delaying the progress of the cell cycle until certain processes are complete. The spindle-assembly checkpoint prevents the onset of anaphase until a bipolar spindle is present and all chromosomes are attached to the spindle. Evidence from yeast and mammalian cells suggests that kinetochores are at least one source of the signal that stops the cell cycle. Recent studies in budding yeast have begun to define the signal-transduction pathway involved in the spindle-assembly checkpoint, but details of the endpoint of the pathway, where these signals interact with the cell-cycle machinery, remain to be characterized.

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.

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.

Aberrantly segregating centromeres activate the spindle assembly checkpoint in budding yeast.

The spindle assembly checkpoint is the mechanism or set of mechanisms that prevents cells with defects in chromosome alignment or spindle assembly from passing through mitosis. We have investigated the effects of mini-chromosomes on this checkpoint in budding yeast by performing pedigree analysis. This method allowed us to observe the frequency and duration of cell cycle delays in individual cells. Short, centromeric linear mini-chromosomes, which have a low fidelity of segregation, cause frequent delays in mitosis. Their circular counterparts and longer linear mini-chromosomes, which segregate more efficiently, show a much lower frequency of mitotic delays, but these delays occur much more frequently in divisions where the mini-chromosome segregates to only one of the two daughter cells. Using a conditional centromere to increase the copy number of a circular mini-chromosome greatly increases the frequency of delayed divisions. In all cases the division delays are completely abolished by the mad mutants that inactivate the spindle assembly checkpoint, demonstrating that the Mad gene products are required to detect the subtle defects in chromosome behavior that have been observed to arrest higher eukaryotic cells in mitosis.

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.

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.

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.

Statewide study of diagnostic agreement in breast pathology.

BACKGROUND: This study assessed the degree of diagnostic agreement among community-based general pathologists reading slides of representative breast tissue specimens and tested whether diagnostic variability is associated with type of breast specimen (e.g., core needle or excisional biopsy) or slide quality. METHODS: Twenty-six of the 44 eligible pathologists working at community-based pathology practices in New Hampshire participated. Each pathologist evaluated slides of breast tissue obtained from 30 case subjects randomly selected from a statewide breast pathology database. The diagnostic categories used were benign, benign with atypia, noninvasive malignant, and invasive malignant. The levels of agreement (i.e., kappa coefficients) for the diagnoses were assessed. RESULTS: Agreement was high among pathologists for assignment of diagnostic category (kappa coefficient = 0.71) and was nearly perfect for their selection of benign versus malignant categories (kappa coefficient = 0.95). There was less agreement for the categories of noninvasive malignant and benign with atypia (kappa coefficients of 0.59 and 0.22, respectively). There was no apparent relationship between levels of diagnostic agreement and specimen type or perceived slide quality. CONCLUSIONS: Diagnostic agreement for breast tissue specimens is high overall among community-based pathologists, but clinically relevant disagreements may occur in the assessment of noninvasive malignant diagnoses. The establishment of reread policies for certain diagnostic categories may reduce the possibility that diagnostic misclassification will lead to overtreatment or undertreatment. The high degree of diagnostic reproducibility for invasive cancerous lesions of the breast suggests that it is unnecessary for a central review of these lesions in national cancer trials.

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.

Pathologists' agreement with experts and reproducibility of breast ductal carcinoma-in-situ classification schemes.

Several histologic classifications for breast ductal carcinoma in situ (DCIS) have been proposed. This study assessed the diagnostic agreement and reproducibility of three DCIS classifications (Holland [HL], modified Lagios [LA], and Van Nuys [VN]) by comparing the interpretations of pathologists without expertise in breast pathology with those of three breast pathology experts, each a proponent of one classification. Seven nonexpert pathologists in New Hampshire and three experts evaluated 40 slides of DCIS according to the three classifications. Twenty slides were reinterpreted by each nonexpert pathologist. Diagnostic accuracy (nonexperts compared with experts) and reproducibility were evaluated using inter- and intrarater techniques (kappa statistic). Final DCIS grade and nuclear grade were reported most accurately among nonexpert pathologists using HL (kappa = 0.53 and 0.49, respectively) compared with LA and VN (kappa = 0.29 and 0.35, respectively, for both classifications). An intermediate DCIS grade was assessed most accurately using HL and LA, and a high grade (group 3) was assessed most accurately using VN. Diagnostic reproducibility was highest using HL (kappa = 0.49). The VN interpretation of necrosis (present or absent) was reported more accurately than the LA criteria (extensive, focal, or absent; kappa = 0.59 and 0.45, respectively), but reproducibility of each was comparable (kappa = 0.48 and 0.46, respectively). Intrarater agreement was high overall. Comparing all three classifications, final DCIS grade was reported best using HL. Nuclear grade (cytodifferentiation) using HL and the presence or absence of necrosis were the criteria diagnosed most accurately and reproducibly. Establishing one internationally approved set of interpretive definitions, with acceptable accuracy and reproducibility among both pathologists with and without expertise in breast pathology interpretation, will assist researchers in evaluating treatment effectiveness and characterizing the natural history of DCIS breast lesions.

Accelerated radiation therapy for primary lymphoma of the brain.

BACKGROUND AND PURPOSE: We report the results of a pilot study of the use of accelerated radiation therapy for 10 patients with primary lymphoma of the brain. MATERIALS AND METHODS: There were five females and five males with a median age of 60 years (range 31-77 years) and a median Karnofsky performance status of 60 (range 30-90). Nine patients underwent biopsies only and one patient underwent a partial resection. The radiation therapy consisted of 50 Gy in 25 fractions over 13 consecutive days to the whole brain including all meningeal surfaces. Two fractions were delivered daily with a minimum interval of 6 h between fractions. Treatment was delivered daily right through the weekend with no treatment interruptions. RESULTS: To date nine patients have died. The median survival was 17 months. Seven patients have demonstrated definite evidence of recurrence (six in the brain and one with positive CSF cytology only). There have been two autopsies, one of which demonstrated diffusely recurrent tumor and the other showing residual disease and radiation demyelination and small areas of necrosis in the pons which undoubtedly was the cause of death at 5 months. One patient alive and free of recurrence at 69 months has bilateral radiation retinopathy and an undiagnosed degenerative neurologic condition. CONCLUSION: We conclude that this accelerated schedule of radiation therapy is ineffective in improving survival in primary lymphoma of the brain and is associated with unacceptable increased toxicity.

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.

Sonography of the placenta with emphasis on pathological correlation.

The placenta is a most interesting but unfortunately often ignored and misunderstood organ. Included in its many functions are fetal oxygenation and nutrition as well as a myriad of endocrinological contributions and protein synthesis. The sonologist is strongly encouraged to study this amazing structure with ultrasound because significant pathology afflicts the placenta, often before affecting the fetus. Placental abnormalities, therefore, can be an "early warning system" for fetal problems. Recognition of clinically important lesions (abruption, accreta) as well as important anatomical variants (intervillous thrombosis, septal cyst) is crucial for the physician who performs and interprets prenatal ultrasound. This article discusses the common abnormalities of the placenta and highlights some correlative pathological processes, which will serve to enhance the reader's understanding of sonographic findings. A practical approach is presented with respect to assessment of the hypoechoic lesion, placental infarction, thick placenta, placenta previa, abruption, placenta accreta, and placental tumors.

Taxol effect: bizarre mitotic figures (abnormal spindle asters) in a malignant peritoneal effusion: report of a case.

Taxol (Paclitaxol) is a diterpenoid taxane derivative found in the bark and needles of the Western yew, Taxus brevifolia, indigenous to the old growth forests of the Pacific Northwest. As compared with other antineoplastic agents (vinca alkaloids and colchicine) that enhance microtubule disassembly, taxol promotes microtubule polymerization. In interphase cells, abnormal microtubular bundles or arrays are seen. In mitotic cells, abnormal spindle asters form. Such morphologic changes have been described frequently in cell culture systems and in in vitro systems using fresh tumor tissue. To our knowledge, these changes have not been described in a peritoneal effusion specimen from a patient with stage III ovarian cancer treated with taxol. In addition, the mitotic stabilization produced interpretative difficulties in evaluating the peritoneal fluid because a vast majority of the presumed malignant cells were in mitosis and, hence, not evaluable by ordinary cytologic criteria.