Online 4D ultrasound guidance for real-time motion compensation by MLC tracking.

PURPOSE: With the trend in radiotherapy moving toward dose escalation and hypofractionation, the need for highly accurate targeting increases. While MLC tracking is already being successfully used for motion compensation of moving targets in the prostate, current real-time target localization methods rely on repeated x-ray imaging and implanted fiducial markers or electromagnetic transponders rather than direct target visualization. In contrast, ultrasound imaging can yield volumetric data in real-time (3D + time = 4D) without ionizing radiation. The authors report the first results of combining these promising techniques-online 4D ultrasound guidance and MLC tracking-in a phantom. METHODS: A software framework for real-time target localization was installed directly on a 4D ultrasound station and used to detect a 2 mm spherical lead marker inside a water tank. The lead marker was rigidly attached to a motion stage programmed to reproduce nine characteristic tumor trajectories chosen from large databases (five prostate, four lung). The 3D marker position detected by ultrasound was transferred to a computer program for MLC tracking at a rate of 21.3 Hz and used for real-time MLC aperture adaption on a conventional linear accelerator. The tracking system latency was measured using sinusoidal trajectories and compensated for by applying a kernel density prediction algorithm for the lung traces. To measure geometric accuracy, static anterior and lateral conformal fields as well as a 358° arc with a 10 cm circular aperture were delivered for each trajectory. The two-dimensional (2D) geometric tracking error was measured as the difference between marker position and MLC aperture center in continuously acquired portal images. For dosimetric evaluation, VMAT treatment plans with high and low modulation were delivered to a biplanar diode array dosimeter using the same trajectories. Dose measurements with and without MLC tracking were compared to a static reference dose using 3%/3 mm and 2%/2 mm γ-tests. RESULTS: The overall tracking system latency was 172 ms. The mean 2D root-mean-square tracking error was 1.03 mm (0.80 mm prostate, 1.31 mm lung). MLC tracking improved the dose delivery in all cases with an overall reduction in the γ-failure rate of 91.2% (3%/3 mm) and 89.9% (2%/2 mm) compared to no motion compensation. Low modulation VMAT plans had no (3%/3 mm) or minimal (2%/2 mm) residual γ-failures while tracking reduced the γ-failure rate from 17.4% to 2.8% (3%/3 mm) and from 33.9% to 6.5% (2%/2 mm) for plans with high modulation. CONCLUSIONS: Real-time 4D ultrasound tracking was successfully integrated with online MLC tracking for the first time. The developed framework showed an accuracy and latency comparable with other MLC tracking methods while holding the potential to measure and adapt to target motion, including rotation and deformation, noninvasively.

Executive Summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

A multi-site validation in India of the line probe assay for the rapid diagnosis of multi-drug resistant tuberculosis directly from sputum specimens.

UNLABELLED: Rifampicin (R) and isoniazid (H) are key first-line anti-tuberculosis drugs. Failure to detect resistance to these two drugs early results in treatment failure and poor clinical outcomes. The study purpose was to validate the use of the GenoType MTBDRplus line probe assay (LPA) to detect resistance to R and H in Mycobacterium tuberculosis strains directly from smear-positive sputum samples in India. METHOD: Smear positive sputum specimens from 320 patients were subjected to LPA and results compared against those from conventional Lowenstein Jensen (LJ) culture and drug susceptibility testing (C&DST). All specimens with discordant R DST results were subjected to either sequencing of the rpoB gene and/or repeat DST on liquid culture (MGIT 960) at a National Reference Laboratory. RESULTS: Significantly higher proportion of interpretable results were observed with LPA compared to LJ C&DST (94% vs. 80%, p-value <0.01). A total of 248 patients had both LJ and LPA DST results available; 232 (93.5%) had concordant R DST results. Among the 16 discordant R DST results, 13 (81%) were resolved in agreement with LPA results. Final LPA performance characteristics were sensitivity 96% (CI: 90%-98%), specificity 99% (CI: 95%-99%), positive predictive value 99% (CI: 95%-99%), and negative predictive value 95% (CI: 89%-98%). The median turnaround testing time, including specimen transportation time, on LPA was 11 days as compared with 89 days for LJ C&DST. CONCLUSIONS: LPA proved highly accurate in the rapid detection of R resistance. The reduction in time to diagnosis may potentially enable earlier commencement of the appropriate drug therapy, leading to some reduction of transmission of drug-resistant strains.

Tuberculosis screening by tuberculosis skin test or QuantiFERON-TB Gold In-Tube Assay among an immigrant population with a high prevalence of tuberculosis and BCG vaccination.

RATIONALE: Each year 1 million persons acquire permanent U.S. residency visas after tuberculosis (TB) screening. Most applicants undergo a 2-stage screening with tuberculin skin test (TST) followed by CXR only if TST-positive at > 5 mm. Due to cross reaction with bacillus Calmette-Guérin (BCG), TST may yield false positive results in BCG-vaccinated persons. Interferon gamma release assays exclude antigens found in BCG. In Vietnam, like most high TB-prevalence countries, there is universal BCG vaccination at birth. OBJECTIVES: 1. Compare the sensitivity of QuantiFERON-TB Gold In-Tube Assay (QFT) and TST for culture-positive pulmonary TB. 2. Compare the age-specific and overall prevalence of positive TST and QFT among applicants with normal and abnormal CXR. METHODS: We obtained TST and QFT results on 996 applicants with abnormal CXR, of whom 132 had TB, and 479 with normal CXR. RESULTS: The sensitivity for tuberculosis was 86.4% for QFT; 89.4%, 81.1%, and 52.3% for TST at 5, 10, and 15 mm. The estimated prevalence of positive results at age 15-19 years was 22% and 42% for QFT and TST at 10 mm, respectively. The prevalence increased thereafter by 0.7% year of age for TST and 2.1% for QFT, the latter being more consistent with the increase in TB among applicants. CONCLUSIONS: During 2-stage screening, QFT is as sensitive as TST in detecting TB with fewer requiring CXR and being diagnosed with LTBI. These data support the use of QFT over TST in this population.

An integrated approach to rapid diagnosis of tuberculosis and multidrug resistance using liquid culture and molecular methods in Russia.

OBJECTIVE: To analyse the feasibility, cost and performance of rapid tuberculosis (TB) molecular and culture systems, in a high multidrug-resistant TB (MDR TB) middle-income region (Samara, Russia) and provide evidence for WHO policy change. METHODS: Performance and cost evaluation was conducted to compare the BACTEC MGIT 960 system for culture and drug susceptibility testing (DST) and molecular systems for TB diagnosis, resistance to isoniazid and rifampin, and MDR TB identification compared to conventional Lowenstein-Jensen culture assays. FINDINGS: 698 consecutive patients (2487 sputum samples) with risk factors for drug-resistant tuberculosis were recruited. Overall M. tuberculosis complex culture positivity rates were 31.6% (787/2487) in MGIT and 27.1% (675/2487) in LJ (90.5% and 83.2% for smear-positive specimens). In total, 809 cultures of M. tuberculosis complex were isolated by any method. Median time to detection was 14 days for MGIT and 36 days for LJ (10 and 33 days for smear positive specimens) and indirect DST in MGIT took 9 days compared to 21 days on LJ. There was good concordance between DST on LJ and MGIT (96.8% for rifampin and 95.6% for isoniazid). Both molecular hybridization assay results correlated well with MGIT DST results, although molecular assays generally yielded higher rates of resistance (by approximately 3% for both isoniazid and rifampin). CONCLUSION: With effective planning and logistics, the MGIT 960 and molecular based methodologies can be successfully introduced into a reference laboratory setting in a middle incidence country. High rates of MDR TB in the Russian Federation make the introduction of such assays particularly useful.

Diagnosis of smear-negative pulmonary tuberculosis in people with HIV infection or AIDS in resource-constrained settings: informing urgent policy changes.

The HIV epidemic has led to large increases in the frequency of smear-negative pulmonary tuberculosis, which has poor treatment outcomes and excessive early mortality compared with smear-positive disease. We used a combination of systematic review, document analysis, and global expert opinion to review the extent of this problem. We also looked at policies of national tuberculosis control programmes for the diagnosis of smear-negative pulmonary tuberculosis to assess their coverage, identify the diagnostic difficulties, and find ways to improve the diagnosis of this type of tuberculosis, with a focus on resource-constrained settings with high HIV infection rates. We propose that the internationally recommended algorithm for the diagnosis of smear-negative pulmonary tuberculosis should be revised to include HIV status, severity of AIDS and tuberculosis, and early use of chest radiography in the decision tree. Increased use of promising methods of diagnosis such as sputum liquefaction and concentration and increased availability of fluorescence microscopy should be explored and encouraged. Culturing of sputum in resource-constrained settings with high HIV infection rates should also be encouraged, existing facilities should be made full use of and upgraded, and effective quality-assurance systems should be used. Innovative ways to address human resources issues involved in addressing the diagnostic difficulties are also needed. The development of rapid, simple, and accurate tuberculosis diagnostic tools with applicability at point of care and remote location is essential. To achieve these goals, greater political commitment, scientific interest, and investment are needed.