A CT-based deep learning system for automatic assessment of aortic root morphology for TAVI planning.

Accurate planning of transcatheter aortic valve implantation (TAVI) is important to minimize complications, and it requires anatomic evaluation of the aortic root (AR), commonly performed through 3D computed tomography (CT) image analysis. Currently, there is no standard automated solution for this process. Two convolutional neural networks with 3D U-Net architectures (model 1 and model 2) were trained on 310 CT scans for AR analysis. Model 1 performs AR segmentation and model 2 identifies the aortic annulus and sinotubular junction (STJ) contours. After training, the two models were integrated into a fully automated pipeline for geometric analysis of the AR. Results were validated against manual measurements of 178 TAVI candidates. The trained CNNs segmented the AR, annulus, and STJ effectively, resulting in mean Dice scores of 0.93 for the AR, and mean surface distances of 0.73 mm and 0.99 mm for the annulus and STJ, respectively. Automatic measurements were in good agreement with manual annotations, yielding annulus diameters that differed by 0.52 [-2.96, 4.00] mm (bias and 95% limits of agreement for manual minus algorithm). Evaluating the area-derived diameter, bias, and limits of agreement were 0.07 [-0.25, 0.39] mm. STJ and sinuses diameters computed by the automatic method yielded differences of 0.16 [-2.03, 2.34] and 0.1 [-2.93, 3.13] mm, respectively. The proposed tool is a fully automatic solution to quantify morphological biomarkers for pre-TAVI planning. The method was validated against manual annotation from clinical experts and showed to be quick and effective in assessing AR anatomy, with potential for time and cost savings.

Coronary Perfusion After Valve-in-Valve Transcatheter Aortic Valve Implantation in Small Aortic Root: In Vitro Experimental Assessment.

Coronary flow obstruction following transcatheter aortic valve-in-valve implantation (VIV-TAVI) is associated with a high mortality risk. The aim of this work was to quantify the coronary perfusion after VIV-TAVI in a high-risk aortic root anatomy. 3D printed models of small aortic root were used to simulate the implantation of a TAVI prosthesis (Portico 23) into surgical prostheses (Trifecta 19 and 21). The aortic root models were tested in a pulsatile in vitro bench setup with a coronary perfusion simulator. The tests were performed at baseline and post-VIV-TAVI procedure in aligned and misaligned commissural configurations under simulated hemodynamic rest and exercise conditions. The experimental design provided highly controllable and repeatable flow and pressure conditions. The left and right coronary mean flow did not differ significantly at pre- and post-VIV-TAVI procedure in any tested configurations. The commissural misalignment did not induce any significant alterations to the coronary flow. High-risk aortic root anatomy did not trigger coronary ostia obstruction or coronary flow alteration after transcatheter aortic valve implantation in a surgical bioprosthesis as shown from in-vitro flow loop tests.

Hybrid fibroin/polyurethane small-diameter vascular grafts: from fabrication toin vivopreliminary assessment.

To address the need of alternatives to autologous vessels for small-calibre vascular applications (e.g. cardiac surgery), a bio-hybrid semi-degradable material composed of silk fibroin (SF) and polyurethane (Silkothane®) was herein used to fabricate very small-calibre grafts (Øin= 1.5 mm) via electrospinning. Bio-hybrid grafts werein vitrocharacterized in terms of morphology and mechanical behaviour, and compared to similar grafts of pure SF. Similarly, two native vessels from a rodent model (abdominal aorta and vena cava) were harvested and characterized. Preliminary implants were performed on Lewis rats to confirm the suitability of Silkothane® grafts for small-calibre applications, specifically as aortic insertion and femoral shunt. The manufacturing process generated pliable grafts consisting of a randomized fibrous mesh and exhibiting similar geometrical features to rat aortas. Both Silkothane® and pure SF grafts showed radial compliances in the range from 1.37 ± 0.86 to 1.88 ± 1.01% 10-2mmHg-1, lower than that of native vessels. The Silkothane® small-calibre devices were also implanted in rats demonstrating to be adequate for vascular applications; all the treated rats survived the surgery for three months after implantation, and 16 rats out of 17 (94%) still showed blood flow inside the graft at sacrifice. The obtained results lay the basis for a deeper investigation of the interaction between the Silkothane® graft and the implant site, which may deal with further analysis on the potentialities in terms of degradability and tissue formation, on longer time-points.

On-Chip Platelet Activation Assessment: Microfluidic Emulation of Shear Stress Profiles Induced by Mechanical Circulatory Support Devices.

Mechanical circulatory support devices (MCSDs), although proved to be a pillar in the clinical setting of advanced heart failure, are afflicted by thromboembolic complications. Shear-mediated platelet activation has been recognized to drive thromboembolic events in patients implanted with MCSDs. Despite this, to date, a clinically reliable diagnostic test for assessing platelet response to stress stimuli is still missing. Here, we describe and apply the previously developed device thrombogenicity emulation methodology to the design of a microfluidic platform able to replicate shear stress profiles representative of MCSDs. The device-specific shear-mediated platelet activation is finally assessed by the platelet activity state assay, which measures real-time thrombin production, as a marker of platelet activation level. This technique can be employed to emulate the shear stress patterns of different MCSDs, such as mechanical heart valves, ventricular assist devices, and stents.

The effect of turbulence modelling on the assessment of platelet activation.

Pathological platelet activation by abnormal shear stresses is regarded as a main clinical complication in recipients of cardiovascular mechanical devices. In order to improve their performance computational fluid dynamics (CFD) are used to evaluate flow fields and related shear stresses. CFD models are coupled with mathematical models that describe the relation between fluid dynamics variables, and in particular shear stresses, and the platelet activation state (PAS). These models typically use a Lagrangian approach to compute the shear stresses along possible platelet trajectories. However, in the case of turbulent flow, the choice of the proper turbulence closure is still debated for both concerning its effect on shear stress calculation and Lagrangian statistics. In this study different numerical simulations of the flow through a mechanical heart valve were performed and then compared in terms of Eulerian and Lagrangian quantities: a direct numerical simulation (DNS), a large eddy simulation (LES), two Reynolds-averaged Navier-Stokes (RANS) simulations (SST k-ω and RSM) and a "laminar" (no turbulence modelling) simulation. Results exhibit a large variability in the PAS assessment depending on the turbulence model adopted. "Laminar" and RSM estimates of platelet activation are about 60% below DNS, while LES is 16% less. Surprisingly, PAS estimated from the SST k- ω velocity field is only 8% less than from DNS data. This appears more artificial than physical as can be inferred after comparing frequency distributions of PAS and of the different Lagrangian variables of the mechano-biological model of platelet activation. Our study indicates how much turbulence closures may affect platelet activation estimates, in comparison to an accurate DNS, when assessing blood damage in blood contacting devices.

Aortic hemodynamics assessment prior and after valve sparing reconstruction: A patient-specific 4D flow-based FSI model.

INTRODUCTION: Valve-sparing root replacement (VSRR) of the ascending aorta is a life-saving procedure for the treatment of aortic aneurysms, but patients remain at risk for post-operative events involving the downstream native aorta, the mechanism for which is uncertain. It is possible that proximal graft replacement of the ascending aorta induces hemodynamics alterations in the descending aorta, which could trigger adverse events. Herein, we present a fluid-structure interaction (FSI) protocol, based on patient-specific geometry and boundary conditions, to assess impact of proximal aortic grafts on downstream aortic hemodynamics and distensibility. METHODS: Cardiac magnetic resonance (CMR), including MRA, cine-CMR and 4D flow sequences, was performed prior and after VSRR on one subject. Central blood pressure was non-invasively acquired at the time of the CMR: data were used to reconstruct the pre- and post-VSRR model and derive patient-specific boundary conditions for the FSI and a computational fluid dynamic (CFD) analysis with the same settings. Results were validated comparing the predicted velocity field against 4D flow dataset, over four landmarks along the aorta, and the predicted distensibility against the cine-CMR derived value. RESULTS: Instantaneous velocity magnitudes extracted from 4D flow and FSI were similar (p > 0.05), while CFD-predicted velocity was significantly higher (p < 0.001), especially in the descending aorta of the pre-VSRR model (vmax was 73 cm/s, 76 cm/s and 99 cm/s, respectively). As measured in cine-CMR, FSI predicted an increase in descending aorta distensibility after grafting (i.e., 4.02 to 5.79 10-3 mmHg-1). In the descending aorta, the post-VSRR model showed increased velocity, aortic distensibility, stress and strain and wall shear stress. CONCLUSIONS: Our Results indicate that i) the distensibility of the wall cannot be neglected, and hence the FSI method is necessary to obtain reliable results; ii) graft implantation induces alterations in the hemodynamics and biomechanics along the thoracic aorta, that may trigger adverse vessel remodeling.

Fluid dynamics characterization and thrombogenicity assessment of a levitating centrifugal pump with different impeller designs.

Technical guidelines nowadays recommend and regulate the use Computational Fluid Dynamics (CFD) to assess the performance of medical devices. CFD coupled to blood damage models has emerged as a powerful tool to evaluate the hemocompatibility of blood recirculating devices. The present study is aimed at evaluating the hydrodynamic performance and the thrombogenic potential of two prototypes of magnetically levitating centrifugal pumps. The two devices differ in the impeller configuration - 6-blades vs. 12-blades - and have been designed to be used in Cardiopulmonary Bypass (CPB) circuits during open heart surgery and in Extracorporeal Membrane Oxygenation (ECMO) to support patients with severe cardiac or respiratory failure. The pumps have been modelled using Direct Numerical Simulation coupled to Lagrangian analysis to predict platelet activation due to abnormal shear stress histories. Numerical results have been compared with experimental data in terms of head generation for different working points. Results show that the 6-blades pump has i) smaller stagnation areas, ii) lower stress levels and iii) higher strain rate, resulting in a lower thrombogenic potential, whereas the 12-blade impeller guarantees a more stable performance at high flow rates, suggesting its preferential use for more demanding applications, such as CPB.

4D MDCT in the assessment of the tricuspid valve and its spatial relationship with the right coronary artery: A customized tool based on computed tomography for the planning of percutaneous procedures.

Multidetector computed tomography (MDCT) is currently the imaging technique of choice for the assessment of tricuspid valve (TV) annulus geometry and relationship with the right coronary artery (RCA). However, standardized protocols with a full 3D analysis are still lacking to plan percutaneous procedures for functional tricuspid regurgitation (FTR). A novel customized 4-dimensional tool based on MDCT data was developed and provided accurate information on TV annulus morphology (3D-perimeter, 2D-Area, maximum and minimum diameters, eccentricity index), function and distance to the RCA, crucial for patient selection of percutaneous TV procedures.

Evaluation of 4D flow MRI-based non-invasive pressure assessment in aortic coarctations.

Severity of aortic coarctation (CoA) is currently assessed by estimating trans-coarctation pressure drops through cardiac catheterization or echocardiography. In principle, more detailed information could be obtained non-invasively based on space- and time-resolved magnetic resonance imaging (4D flow) data. Yet the limitations of this imaging technique require testing the accuracy of 4D flow-derived hemodynamic quantities against other methodologies. With the objective of assessing the feasibility and accuracy of this non-invasive method to support the clinical diagnosis of CoA, we developed an algorithm (4DF-FEPPE) to obtain relative pressure distributions from 4D flow data by solving the Poisson pressure equation. 4DF-FEPPE was tested against results from a patient-specific fluid-structure interaction (FSI) simulation, whose patient-specific boundary conditions were prescribed based on 4D flow data. Since numerical simulations provide noise-free pressure fields on fine spatial and temporal scales, our analysis allowed to assess the uncertainties related to 4D flow noise and limited resolution. 4DF-FEPPE and FSI results were compared on a series of cross-sections along the aorta. Bland-Altman analysis revealed very good agreement between the two methodologies in terms of instantaneous data at peak systole, end-diastole and time-averaged values: biases (means of differences) were +0.4 mmHg, -1.1 mmHg and +0.6 mmHg, respectively. Limits of agreement (2 SD) were ±0.978 mmHg, ±1.06 mmHg and ±1.97 mmHg, respectively. Peak-to-peak and maximum trans-coarctation pressure drops obtained with 4DF-FEPPE differed from FSI results by 0.75 mmHg and -1.34 mmHg respectively. The present study considers important validation aspects of non-invasive pressure difference estimation based on 4D flow MRI, showing the potential of this technology to be more broadly applied to the clinical practice.

Microfluidic approaches for the assessment of blood cell trauma: a focus on thrombotic risk in mechanical circulatory support devices.

INTRODUCTION: Mechanical circulatory support devices (MCSDs) are emerging as a valuable therapeutic option for the management of end-stage heart failure. However, although recipients are routinely administered with anti-thrombotic (AT) drugs, thrombosis persists as a severe post-implant complication. Conventional clinical assays and coagulation markers demonstrate partial ability in preventing the onset of thrombosis. Through years, different laboratory techniques have been proposed as potential tools for the evaluation of platelets' hemostatic response in MCSD recipients. Most rely on platelet aggregation tests; they are performed in static or low shear conditions, neglecting the prominent contribution of MCSD shear-induced mechanical load in enhancing platelet activation (PA). On the other hand, those tests able to account for shear-induced PA have limited possibility of effective clinical translation. AIMS AND METHODS: Advances on this side have been addressed by microfluidic technology. Microfluidic devices have been developed for AT drug monitoring under flow, able to replicate physiological and/or constant shear flow conditions in vitro. In this paper, we present a newly developed microfluidic platform able to expose platelets to MCSD-specific dynamic shear stress patterns. We performed in vitro tests circulating human platelets in the microfluidic platform and quantifying the dynamics of PA by means of the Platelet Activity State (PAS) assay. RESULTS: Our results prove the feasibility of using microfluidics for the diagnosis of MCSD-related thrombotic risk. This study paves the way for the development of a miniaturized point-of-care device for monitoring AT drug regimen. Such a system may have significant impact on limiting the incidence of thrombosis in MCSD recipients.

In vitro assessment of mitral valve function in cyclically pressurized porcine hearts.

Recent approaches to the in vitro experimental study of cardiac fluid mechanics involve the use of whole biological structures to investigate in the lab novel therapeutic approaches for the treatment of heart pathologies. To enhance reliability and repeatability, the influence of the actuation strategy of the experimental apparatuses on the biomechanics of biological structures needs to be assessed. Using echography and intracardiac high-speed imaging, we compared the mitral valve (MV) anatomo-functional features (coaptation areas/lengths, papillary muscles-valvular plane distances) in two passive-beating-heart mock loops with internal (IPML) or external (EPML) pressurization of the ventricular chamber. Both apparatuses showed fluid dynamic conditions that closely resembled the physiology. The MVs analyzed in the EPML presented coaptation areas and lengths that were systematically higher, and exhibited greater variability from early-to peak-systole, as compared to those in the IPML. Moreover, in the EPML, the MV leaflets exhibited a convexity with high curvature toward the atrium. With the IPML, MV coaptation lengths ranged similar to available clinical data and the papillary muscles-valve plane distances were more stable throughout systole. In conclusion, both the apparatuses allow for reproducing in vitro the left heart hemodynamics, in terms of flow rates and pressures, with proper mitral valve continence. Results suggest that the IPML is more suitable for replicating the physiological MV functioning, while the EPML may have more potential as a model for the study of MV pathologies.

A numerical performance assessment of a commercial cardiopulmonary by-pass blood heat exchanger.

We developed a numerical model, based on multi-physics computational fluid dynamics (CFD) simulations, to assist the design process of a plastic hollow-fiber bundle blood heat exchanger (BHE) integrated within the INSPIRE(TM), a blood oxygenator (OXY) for cardiopulmonary by-pass procedures, recently released by Sorin Group Italia. In a comparative study, we analyzed five different geometrical design solutions of the BHE module. Quantitative geometrical-dependent parameters providing a comprehensive evaluation of both the hemo- and thermo-dynamics performance of the device were extracted to identify the best-performing prototypical solution. A convenient design configuration was identified, characterized by (i) a uniform blood flow pattern within the fiber bundle, preventing blood flow shunting and the onset of stagnation/recirculation areas and/or high velocity pathways, (ii) an enhanced blood heating efficiency, and (iii) a reduced blood pressure drop. The selected design configuration was then prototyped and tested to experimentally characterize the device performance. Experimental results confirmed numerical predictions, proving the effectiveness of CFD modeling as a reliable tool for in silico identification of suitable working conditions of blood handling medical devices. Notably, the numerical approach limited the need for extensive prototyping, thus reducing the corresponding machinery costs and time-to-market.

Microfabricated polyester conical microwells for cell culture applications.

Over the past few years there has been a great deal of interest in reducing experimental systems to a lab-on-a-chip scale. There has been particular interest in conducting high-throughput screening studies using microscale devices, for example in stem cell research. Microwells have emerged as the structure of choice for such tests. Most manufacturing approaches for microwell fabrication are based on photolithography, soft lithography, and etching. However, some of these approaches require extensive equipment, lengthy fabrication process, and modifications to the existing microwell patterns are costly. Here we show a convenient, fast, and low-cost method for fabricating microwells for cell culture applications by laser ablation of a polyester film coated with silicone glue. Microwell diameter was controlled by adjusting the laser power and speed, and the well depth by stacking several layers of film. By using this setup, a device containing hundreds of microwells can be fabricated in a few minutes to analyze cell behavior. Murine embryonic stem cells and human hepatoblastoma cells were seeded in polyester microwells of different sizes and showed that after 9 days in culture cell aggregates were formed without a noticeable deleterious effect of the polyester film and glue. These results show that the polyester microwell platform may be useful for cell culture applications. The ease of fabrication adds to the appeal of this device as minimal technological skill and equipment is required.

Molecular assessment of the elastic properties of collagen-like homotrimer sequences.

Knowledge of the mechanical behavior of collagen molecules is critical for understanding the mechanical properties of collagen fibrils that constitute the main architectural building block of a number of connective tissues. In this study, the elastic properties of four different type I collagen 30-residue long molecular sequences, were studied by performing stretching simulations using the molecular mechanics approach. The energy-molecular length relationship was achieved by means of the geometry optimization procedure for collagen molecule strains up to 10%. The energy was interpolated by a second order function, and the second order of the derivative with respect to the mean length corresponded to the molecule stiffness. According to the hypothesis of linear elastic behavior, except for one sequence, the elastic modulus was around 2.40 GPa. These values are larger than fibril values, and they confirm the hypothesis that tendon mechanical properties are deeply related to tendon hierarchical structure. A possible explanation of the lowest values obtained for one sequence (1.33-1.53 GPa) is provided and discussed.

Economic burden of acute myeloid leukemia: a literature review.

OBJECTIVE: The primary objective was to examine the economic burden associated with acute myeloid leukemia (AML), a deadly hematological malignancy. AML is the most common form of acute leukemia in adults, particularly in individuals over 60 years of age; AML also accounts for 15-20% of childhood leukemia. MATERIALS AND METHODS: A systematic review was conducted of relevant studies published in the English language. Economic analyses of AML published between 1990 and 2002 were identified from electronic data sources using broad search criteria. Additional studies were obtained by manual searches of bibliographies of articles identified in the electronic searches. Articles were screened for relevance and included if the main theme included some element of AML cost of treatment, cost drivers, or cost-effectiveness. Studies reporting only drug prices without a formal comparison or analysis were not included. RESULTS: Twenty-nine studies were included in the review. Although information was limited on the comprehensive economic burden of AML from a societal perspective, the costs appear to be split equally between direct and indirect costs. Direct costs of AML from a public payer perspective were available for a few countries such as the Netherlands, Sweden, US (Medicare), and Italy. These studies found that the key cost drivers appear to be hospitalization length of stay related to initial chemotherapy, relapse of disease, and bone marrow transplant (BMT) and peripheral blood stem cell transplant (PBSCT). Several cost analyses have been published comparing the different treatment strategies; however, most of them were published in the early 1990s, and their analysis revolved around cost-comparison rather than comprehensive cost-effectiveness. The published studies investigated pharmacological agents (e.g., idarubicin, daunorubicin, mitoxantrone, fludarabine and combination therapies), as well as BMT, PBSCT, and the treatment of complications. CONCLUSION: Studies addressing the economic costs and burden of AML are relatively sparse in the international literature. Possible reasons for such a lack of information appear to include the low incidence rate of AML (e.g., about 260,000 new cases were reported in 2002 in the world) and the fact that it primarily afflicts older adults >60 years of age, making broad, well-designed economic analyses a challenge for most researchers. However, due to the high cost associated with the medical procedures (e.g., BMT, PBSCT) and the aging of the world population, further research is warranted.

A retrospective analysis of health care costs for bone fractures in women with early-stage breast carcinoma.

BACKGROUND: In this retrospective data base study, the authors sought to estimate direct costs for bone fractures in women age > or =65 years with early-stage breast carcinoma and to compare those costs with treatment costs for bone fractures in older women without early-stage breast carcinoma. METHODS: Direct costs for bone fractures in patients with early-stage breast carcinoma, which consist of excess treatment costs for bone fracture and excess costs of long-term care for bone fracture, were evaluated by using the 1997-1998 Standard Analytical File. The statistical significance of the difference in inpatient costs, medical treatment costs, and long-term care admission rates were determined with the t test and the Fisher chi-square test, respectively. RESULTS: For older women with early-stage breast carcinoma, the direct costs for bone fracture were estimated at $45,579, and 57% of those costs came from treating the bone fracture (32% came from inpatient hospital costs, and 25% came from noninpatient hospital costs), 25% came from other excess treatment costs, and 18% came from excess long-term care costs. The women who had early-stage breast carcinoma and sustained bone fracture did not differ significantly from the women without early-stage breast carcinoma who sustained a bone fracture. CONCLUSIONS: Bone fracture was associated with high direct costs in older women with early-stage breast carcinoma. Additional research should include appropriate, incidence-based studies to investigate the potential benefit of an intervention for preventing bone fracture in this increasingly large patient population.

Quality of life and economic considerations in the management of prostate cancer.

The purpose of this article was to provide an overview of the morbidity and mortality of prostate cancer, QOL issues and the economic impact of the disease. We searched Medline (from 1990 onwards) for all studies dealing with prostate cancer epidemiology, treatment, screening and staging, and critically reviewed the most relevant articles, focusing on pharmacoeconomic issues. Prostate cancer is the most common cancer in men. In the US, new estimated cases of prostate cancer represented 14.8% of all new cancer cases for 2000, with estimated deaths from prostate cancer comprising 5.8% of all deaths from cancer. Current options for prostate cancer management include radical prostatectomy, cryosurgery, radiotherapy, hormone therapy and watchful waiting. Many of the long-term effects of treatment, such as urinary incontinence, impotence and radiation-induced proctitis, have a large impact on patients' quality of life and, in some patients, may offset the clinical benefits. Regulatory bodies and managed care organisations are assigning increasing importance to the evaluation of QOL benefits as an independent clinical endpoint and a measure of patient satisfaction. Several screening programmes for early detection of prostate cancer, mostly based on prostate-specific antigen (PSA) measurement or digital rectal examination, have been proposed, but their routine implementation in all asymptomatic elderly men has been questioned. There is still no definite proof that patient outcomes are improved by extensive PSA screening. Furthermore, the total cost of a screening programme is difficult to define since it extends well beyond the initial test. Several instruments are used for QOL assessment in prostate cancer, some of which have been specifically developed for, or adapted to, patients with this disease, such as the Functional Assessment Cancer Therapy (FACT) tool, Prostate Cancer Treatment Outcome Questionnaire (PCTO-Q) and Prostate Cancer Specific Quality of Life Instrument (PROSQOLI). More than 50% of treatment costs for prostate cancer are accrued during the patient's last year of life, and total initial care costs decrease with increasing age. In the US, initial average inpatient costs were estimated at $US 2253, in 1995, for men aged > or =80 years, compared with $US 4540 for men aged 35-64 years. In recent years, treatments based on combined modalities (i.e. radiotherapy/prostatectomy plus hormonal therapies) have emerged. Although cost-effectiveness analyses of various treatment options have been attempted, the strength of their conclusions appears to be limited by the lack of homogeneous literature data on the effects of such interventions on survival and morbidity.

Breast cancer management: quality-of-life and cost considerations.

The purpose of this article was to provide a literature-based extensive overview of the quality-of-life and cost issues posed by the management of breast cancer. Incidence and mortality rates vary widely in different countries. Breast cancer accounts approximately for one-fifth of all deaths in women aged 40-50 years. The 1994-1998 incidence rate in the US population was on average 114.3 per 100 000 women. Treatment options include surgery, radiotherapy and drug therapy (cytotoxic and endocrine drugs). All treatment options affect patients' health-related quality of life (HR-QOL) in various ways. The use of cytotoxic agents has a particularly large HR-QOL impact. HR-QOL questionnaires are complex tools, not routinely used in breast cancer trials.Worldwide, around 10 million individuals develop cancer each year; this figure is expected to increase to 15 million in 2020. For all cancers, the total economic burden of this disease worldwide was projected by the authors to be in the range of $US 300-400 billion in 2001 (about $US 100-140 billion as direct costs and the remainder as indirect costs [morbidity and mortality]). According to the National Institute of Health (NIH), the total cost of cancer was estimated at $US 156.7 billion in 2001 in US ($US 56.4 billion as direct costs, $US 15.6 as indirect morbidity costs, and $US 84.7 billion as indirect mortality costs). Based on limited information, in the US, breast cancer can be projected to account for about one-fifth/one-fourth of the total cost of cancer. Breast cancer treatment costs are higher in the US than in other developed countries. Both direct and indirect costs are dependent on disease stage. The per-patient costs for initial care in 1992 were estimated at $US 10 813, for continuing care at $US 1084 and for terminal care at $US 17 886. Stage-specific costs provide information for cost-effectiveness analyses of cancer-control initiatives, such as screening programmes. Economic studies on breast cancer are heterogeneous, and the cost estimates made are not easily generalisable. The cost of treatment for breast cancer in developing countries is < or =5% of that in developed regions.

Screening, prevention and socioeconomic costs associated with the treatment of colorectal cancer.

Colorectal cancer (CRC), the third most prevalent cancer worldwide, imposes a significant economic and humanistic burden on patients and society. One study conservatively estimated the annual expenditures for colorectal cancer to be approximately dollars US 5.3 billion in 2000, including both direct and indirect costs. However, other investigators estimated inpatient costs alone incurred in the US in 1994 to be around dollars US 5.14 billion. Therefore, the economic burden of colorectal cancer in the US could be projected to be somewhere in the range of dollars US 5.5-6.5 billion by considering that inpatient costs approximate 80% of total direct costs. No worldwide data have been published, but assuming that the US represents 25-40% of total expenditures in oncology, as seen for breast and lung cancers, a rough estimate for colorectal cancer would be in the range of dollars US 14-22 billion. Screening helps increase patient survival by diagnosing colorectal cancer early. The ideal method among the four tests most used (faecal occult blood test, flexible sigmoidoscopy, colonoscopy and double contrast barium enema) has not been identified. Economic studies of colorectal cancer screening are complex because of the many variables involved, as well as the fact that the outcomes must be followed for many years, and the lack of consensus on screening guidelines. Intuitively, modelling colorectal cancer is one way to overcome these hurdles; published modelling studies predict colorectal cancer screening programs to be within the threshold of dollars US 40000 per life-year saved. The faecal occult blood test appears to be the only clearly effective test, both from a clinical and an economic viewpoint. Important limitations are the invasiveness and inconvenience of the screening procedures, except faecal occult blood test. Patients' comfort and satisfaction are essential in improving compliance with screening recommendations, which appears to be low even in the US (35% of the general population aged over 40 years and 60% of the high-risk population), the country with the highest awareness and compliance in the world. Since colorectal cancer is generally a disease of the elderly, its economic burden is expected to grow in the near future, mainly due to population aging. Potential avenues to pursue in order to contain or reduce the economic burden of colorectal cancer would be the design and implementation of efficient screening programmes, the improvement of patient awareness and compliance with screening guidelines, the development of appropriate prevention programs (i.e. primary and secondary), and earlier diagnosis.

The health economics of bladder cancer: a comprehensive review of the published literature.

The aim of this paper was to conduct a critical systematic review of the available literature on the clinical and economic burden of bladder cancer in developed countries, with a focus on the cost effectiveness of interventions aimed at reducing that burden.Forty-four economic studies were included in the review. Because of long- term survival and the need for lifelong routine monitoring and treatment, the cost per patient of bladder cancer from diagnosis to death is the highest of all cancers, ranging from 96000-187000 US dollars (2001 values) in the US. Overall, bladder cancer is the fifth most expensive cancer in terms of total medical care expenditures, accounting for almost 3.7 billion US dollars (2001 values) in direct costs in the US. Screening for bladder cancer in the general population is currently not recommended. The economic value of relatively new and less expensive urine assays and molecular urinary tumour markers has not been assessed. However, the literature suggests that screening patients suspected of having bladder cancer and using less invasive diagnostic procedures is cost effective. Very few cost-effectiveness studies have evaluated intravesical therapies such as bacillus Calmette-Guérin and mitomycin in the management of superficial disease and no robust recommendations can be drawn. Economic analyses suggest that non-surgical treatment strategies for the management of invasive disease aiming at bladder preservation may not be cost effective, because they have not consistently demonstrated survival benefits and do not eliminate the need for subsequent radical cystectomy. The literature suggests that the current conventional frequent follow-up and monitoring of patients can be cost effectively replaced by less frequent and less invasive monitoring, and should rely more heavily on intravesical chemotherapy to reduce the need for cystoscopies. Bladder cancer is a fairly common and costly malignancy. Nevertheless, the existing literature only contributes marginally to our knowledge concerning the burden of bladder cancer and the economic value of various interventions. The limited value of the literature in this area may be attributed to (i) being published as abstracts rather than full peer-reviewed evaluations; (ii) employing questionable methodologies; and (iii) being in many cases nearly obsolete, rendering them less relevant to, if not in conflict with, current clinical practice. Consequently, opportunities exist to conduct meaningful economic research in all areas of the management of bladder cancer, including screening, diagnosis, follow-up and treatment, especially with respect to new and innovative pharmaceutical and other technologies.