The rapid urban expansion in the past decade has in turn reduced global terrestrial NPP, with a net loss of 22.4 Tg Carbon per year (Tg C year−1). Although small compared to total terrestrial NPP and fossil fuel carbon emissions worldwide, the urbanization-induced decrease in NPP offset 30% of the climate-driven increase (73.6 Tg C year−1) over the same period. Our findings highlight the urgent need for global strategies to address urban expansion, enhance natural carbon sinks, and increase agricultural productivity.The global urbanization rate is accelerating; however, data limitations have far prevented robust estimations of either global urban expansion or its effects on terrestrial net primary productivity (NPP). Here, using a high resolution dataset of global land use/cover (GlobeLand30), we show that global urban areas expanded by an average of 5694 km Robust estimates of either urban expansion worldwide or the effects of such phenomenon on terrestrial net primary productivity (NPP) are lacking. Here the authors used the new dataset of global land use to show that the global urban areas expanded largely between 2000 and 2010, which in turn reduced terrestrial NPP globally. As the initial production stage in which atmospheric carbon dioxide (CO2) is fixed by plants, terrestrial net primary productivity (NPP) increased by ~190 Tg C year−1 between 1982 and 19993. The NPP increase occurred despite the projected decrease in terrestrial carbon uptake from climate-carbon cycle simulations5. However, temporal trends of global terrestrial NPP since 2000, as well as its underlying mechanics, remain uncertain in the context of climate variability and anthropogenic disturbance 8. As one of the important components of human-associated disturbance, urban land expansion and its effects on terrestrial NPP have been widely examined using a case-based approach12. However, these interactions cannot be accurately estimated at a global scale due to the lack of reliable global land-use data with a high spatiotemporal resolution14. Furthermore, at the global scale, it is difficult to clarify the relative roles of climate variability and urban land expansion on terrestrial NPP16.The terrestrial biosphere is a large carbon sink in the global carbon cycle, with a net carbon uptake of 1–4 Pg C year18. Here, we use this dataset to analyze the change in global urban lands from 2000 to 2010 in much greater detail than has previously been possible. Here, the urban lands mainly refer to the area modified by human activities, including all kinds of habitation, industrial and mining area, transportation facilities, interior urban green zones and water bodies18. We then estimated global terrestrial NPP using the Moderate Resolution Imaging Spectrometer (MODIS) NPP dataset (MOD17A3), the Carnegie–Ames–Stanford Approach (CASA)20 and one of the Lund-Potsdam-Jena Dynamic Global Vegetation Model (LPJ-Hydrology)21. On this basis, change in the global terrestrial NPP was further analyzed using the approach of multi-model ensemble mean (MMEM). To isolate the effects of climate variability and urban expansion from other mechanisms , we estimated terrestrial NPP as ‘urban-expansion-based NPP’ and ‘climate-variability-based NPP’ in two separate simulations, in which either climate drivers or urban land areas were held constant. Specifically, urban-expansion-based NPP was simulated by holding fixed climate drivers and varied urban land use. Conversely, climate-variability-based NPP was calculated using a fixed urban land distribution  and a varied climate driver from 2000 to 2010. Further details of our approach are provided in Methods. As results, we found that global urban expansion remarkably reduced the terrestrial NPP over the period 2000–2010 (22.4 Tg C year−1), which offset 30% of the climate-variability-driven NPP increase. In doing so we provide a comprehensive assessment of urbanization-induced NPP change in comparison with climate-variability-driven change.GlobeLand30, one of the newly developed dataset with a 30-m resolution, has the advantages of both spatiotemporal detail and data accuracy (see Methods)22. Specifically, the world’s urban area increased by 5694 km2 per year over this 10-year interval, which represents ~5% of total urban area in 2000. As projected, there were big differences among urban expansion area on each continent  accounted for 21% of the worldwide total 10, assuming same NPP performance (and thus NPP loss rate) of all urban lands with the urban expansion area between 2000 and 2010. In addition, prior research found that urban land development not only reduced terrestrial NPP, but also resulted in the loss of a significant amount of fertile agricultural soil26. However, it is not currently certain whether this phenomenon exists at the global scale. Figure 2) was converted from cropland, it is approximately twice the area of converted cropland in Africa (2536 km2).Although only occupying a small proportion of the earth’s land surface (0.04%), newly urbanized areas in the period 2000–2010 had a disproportionately effect on global terrestrial NPP. Specifically, global urban expansion was associated with a 22.4 Tg C year27. In Africa, the proportion was only 37% probably owing to human-induced soil nutrient depletion29. In addition, the low proportion for South America could be associated with the widespread distribution of low and medium quality soil across the continent30. Given the ever-growing human population and looming impacts of climate variability on agricultural yields31, this sacrifice of highly fertile land for urban growth has potentially significant implications for terrestrial NPP and even crop production worldwide.Figure −1). Figure −2 year−1, as compared to the maximum reduction of ~21 g C m−2 year−1 due to climate variability. The NPP losses from urban expansion were mainly clustered in the temperate zones of eastern China, northern Indian subcontinent, eastern North America, and Europe . We also found the greatest climate-variability-induced increases in the NPP at the temperate and high latitudes of the Northern Hemisphere, where warming lengthened the growing season  of the increase in the NPP resulting from climate variability over the same period , annual increase in global terrestrial NPP between 2000 and 2010 was ~97.4 Tg C year2 concertration 38. Despite this, however, vegetation growth can be enhanced in urban environment39. This enhancement can be associated with the introduction of highly productive vegetation, as well as heat-island effect in urban area40. Nevertheless, such growth enhancement is likely insufficient to offset the direct loss of productivity caused by the replacement of productive vegetation with impervious surfaces. Furthermore, we found that global urban expansion reduced global terrestrial NPP from 2000 to 2010 by an amount approximately equal to 9% of worldwide carbon emissions from fossil fuels and cement production. Considering the projected increases in urban land use36 and fossil-fuel-consumption emissions41, additional research and policy are needed to regulate urban land growth at both national and international levels43. Furthermore, we note that global urban expansion has already caused large losses in fertile lands. The effects of the increases in cropland productivity that can be achieved via climate variability adaption strategies 44 may be largely limited by the fast urban expansion at a global scale.Urban expansion not only substantially transforms the landscape, but also alters biogeochemical cycle and the photosynthetic productivity of terrestrial ecosystems. Past studies have shown that urban expansion reduced terrestrial NPP at the city to country scale due to the replacement of natural vegetation into impervious surfaces46. However, in comparison, there is a lack of consensus on the NPP trend since 2000. Zhao and Running6 reported a drought-induced reduction in global terrestrial NPP of 0.55 Pg C from 2000 to 20096. However, Medlyn47 and Samanta et al.48 argued that this estimate could be biased by temperature dependence, gap-filling of satellite data, and generally weak correlations with field observations48. In addition, Potter et al.7 estimated that global terrestrial NPP increased by 0.14 Pg C during the same period7. The confliction could be associated with the different approaches they employed to model the effects of environmental stress on terrestrial NPP7. Our findings partly agree with ref. 7, reporting an increase in the NPP during 2000–2010. Furthermore, spatial pattern of the NPP anomalies in our analysis was similar to that reported by refs. 7.As for the effects of climate variability on the terrestrial NPP, past studies have consistently shown a climate-variability-induced increase for the period 1982–199916. We found that the NPP reduction associated with urban expansion (22.4 Tg C year−1) offset a substantial fraction (30%) of the increase in the NPP due to climate variability (73.6 Tg C year−1) during the period 2000–2010. In particular, the contribution of urban expansion was even more pronounced in newly urbanized areas, accounting for an average of 71% of the total NPP change in the study period. This reveals that, at a global scale, urban expansion was the main driving force behind terrestrial NPP changes in newly urbanized areas. Similar results have also been reported previously16. In addition, climate variability accounted for 37% of the total change in the terrestrial NPP during this period. Factors other than climate variability and urban expansion explained an average of 62% of the total NPP change in some regions, including the boreal region of northern Russia and Asia. These results are partly in agreement with ref. 15, which reported a dominant control of climate variability and residual factors on the terrestrial NPP in the areas with natural vegetation.Despite the widely documented evidence of individual effects of urban expansion and climate variability on the terrestrial NPP, little is known about their interactive effects when integrating the two factors as a whole, especially at a global scale49. In addition, while previous studies have mostly focused on land use/cover changes related to natural vegetation, in this context, carbon cycle models should incorporate urban land development as one of their critical components50.Together, our work provides a comprehensive assessment of the remarkable effects of global urban expansion on the terrestrial NPP in comparison with climate-variability-driven changes. Despite it, multiple uncertainties still remain in our results when separating the effects of urban expansion and climate variability on the terrestrial NPP. For instances, urban landscapes usually include various land cover types such as trees, lawns, and impervious surfaces, all of which exhibit different levels of productivity. It is particularly difficult to simulate urban NPP accurately without complex experimental designs. Besides addressing land cover types, other biological, chemical, and physical factors, including topography, air pollutants, and nitrogen deposition should be given further consideration14 developed the first 30-m global land-cover dataset (FROM-GLC) using the satellite-based data from Landsat Thematic Mapper (TM) and Enhanced Thematic Mapper Plus (ETM+). However, its usefulness in deriving global urban expansion is limited because of inadequate temporal coverage. The GlobeLand30 dataset, which covers the years 2000 and 2010 at a 30-m resolution, has advantages on both spatiotemporal details and data accuracy18. In past studies, the GlobeLand30 dataset was evaluated through sample-based validation or comparison with existing land-cover products by third-party researchers from more than 10 countries18. Here, accuracy of the GlobeLand30 dataset was further evaluated by comparing it to the Global Human Built-up And Settlement Extent (HBASE) dataset using the method proposed by refs. 52. According to the box-plot analysis of the kappa coefficient, the GlobeLand30 dataset has an overall higher accuracy at fifteen urban ecoregions than the HBASE dataset , including the University of Maryland land-cover map, the MODIS land-cover maps, and the GlobCover land-cover maps. Because of the mismatch between fine urban expansion and coarse land-cover maps, it is difficult to derive accurate urban land use change using these maps. Reference53 and the results from two ecosystem models . On this basis, changes in the global terrestrial NPP were estimated by using the approach of multi-model ensemble mean (MMEM). To isolate the effects of climate variability and urban expansion from other mechanisms, two separate experiments were conducted—an ‘urban-expansion-driven’ simulation and a ‘climate-variability-driven’ simulation, respectively. Urban-expansion-based NPP was then estimated by holding climate drivers fixed and varying urban lands from 2000 to 2010. In contrast, climate-variability-based NPP was estimated by holding urban lands fixed (at its 2000 level) and varying climate drivers from 2000 to 2010. The relative contributions of urban expansion/climate variability/residual factor were alternately examined as proportions between the trends of climate-variability-based NPP/urban-expansion-based NPP/residual factor and the sum of their absolute values.To effectively capture the detail distribution of urban land use/cover, the GlobeLand30 dataset was employed to detect global urban expansion from 2000 to 2010. In addition, global terrestrial NPP was estimated over the period 2001–2010 using the MODIS NPP dataset  from the MODIS gross and net primary productivity algorithms (MOD17A2/A3)21. The CASA, a light use efficiency (LUE) model54, is widely used to estimate terrestrial NPP at regional to global scales56. According to this approach, the NPP (g C m−2) in a given location x and time t is calculated as follows:S is solar surface irradiance, MJ m−2); FPAR is the fraction of photosynthetic active radiation absorbed by green vegetation, which is calculated using satellite-derived normalized differential vegetation index (NDVI) data; the factor 0.5 represents the fact that approximately half the incoming shortwave solar radiation is in the photosynthetic active radiation wavelength (0.4–0.7)19; and account for the effects of very high and very low temperature stress, respectively; W represents moisture stress factor; and εmax is maximum LUE. The maximum LUE  is uncertain across land use/cover types, spatial scales and vegetation coverage58. Several methods are available to derive the εmax, including eddy covariance technology, productivity model inversion and quantum efficiency reckoning59. The modified least square algorithm, which was proposed by ref. 57, was proved to be effective in simulating the εmax57. According to this algorithm, the term εmax was calibrated as:i represents the samples for a specific land use/cover type; j is the number of samples; m represents field NPP values; n is the product of S, FPAR, T1, T2 and W;x is the maximum LUE to be determined. By minimizing the errors between field-measured NPP (m) and the term n, εmax was calibrated for each land use/cover type.We simulated global terrestrial NPP using the CASA and one of the Lund-Potsdam-Jena Dynamic Global Vegetation Model (LPJ-Hydrology)57. The values of our simulated are listed in Supplementary Table −1 for any other land use/cover type  to 0.660 g C MJ−1 for evergreen broadleaf forest (EBF). These values were mostly between 0.389 g C MJ−1 proposed in ref. 19 and the prescribed values employed when producing the MODIS NPP product (MOD17A2/A3)53. In addition, our calibrated εmax values were similar to those proposed by other studies57.To fit the CASA model, land use/cover data were further compiled by combining the GlobeLand30 dataset with one of the MODIS product  classification scheme). That is, urban land cover was compiled from the GlobeLand30 dataset using Geographic Information System (GIS). In addition, natural vegetation including evergreen needleleaf forest (ENF), evergreen broadleaf forest (EBF), deciduous needleleaf forest (DNF), deciduous broadleaf forest (DBF), mixed forest (MF), shrub, savanna, and grassland, was compiled from the MCD12Q1 dataset. Based on this, the CASA model was calibrated using the algorithm of modified least squares with a total of 2843 field-based NPP records from the corrected Global Primary Production Data Initiative (GPPDI) dataset. A detailed description of the calibration steps can be found in refs. 21. The original Lund-Potsdam-Jena Dynamic Global Vegetation Model (LPJ-DGVM) simulates photosynthesis, respiration, fires, growth, and competition of different plant functional types (PFTs) through explicit representations of vegetation structure, dynamics, competition between PFT populations and soil biogeochemistry61. However, the LPJ-DGVM often requires a long spin-up simulation from bare soil to reach an equilibrium state of vegetation and soil carbon pools62. Reference21 proposed the LPJ-Hydrology, which incorporates satellite-derived land use/cover data into the LPJ-DGVM instead of dynamically simulating it. Here, the LPJ-Hydrology was conducted prescribing the land use/cover input at its 2006 state to simulate the terrestrial NPP. Following general protocol, we first span-up the LPJ-Hydrology for 1000 years to reach equilibrium state of the vegetation and soil pools61. The model was then continuously executed to estimate the terrestrial NPP using climate and CO2 data for the period 2000–2010 as inputs. To facilitate the comparability of the NPP results from the CASA and the LPJ-Hydrology, we kept the input data of both models the same or identical. Concretely, the CASA was driven by the data on temperature, precipitation, solar radiation and NDVI from 2000 to 2010. In addition, the LPJ-Hydrology was forced by temperature, precipitation, number of wet days, cloud cover and CO2 concentration over the same period. To validate the CASA and the LPJ-Hydrology, our estimated NPP results were compared with the field-based NPP records from the GPPDI dataset. Significant correlations were found between the field-based NPP and our simulated NPP from both the CASA  and the LPJ-Hydrology   from annual terrestrial NPP, respectively. We found that increases in the terrestrial NPP occurred over large areas of North America, Western Europe and Eastern Asia  and fixed urban land distribution at its 2000 state. That is, the CASA was driven by varied observations of temperature and precipitation from 2000 to 2010, with other drivers unchanged . Similarly, the LPJ-Hydrology was forced by varied observations of temperature and precipitation from 2000 to 2010 and some other averaged observations including number of wet days, cloud cover and atmospheric CO2 concentration over the same period. To reflect natural land cover in pre-urban condition, pre-urban NPP in newly urbanized area during 2000–2010 was obtained using a neighborhood proxy method11. The pre-urban condition was defined as a condition of the original vegetation distribution prior to urban land development. Therefore, the pre-urban NPP represents the NPP in the absence of urban land development. We assumed that nearby non-urban land surfaces are the best proxy for urban lands before it is transformed. That is, the pre-urban NPP in urban cells was calculated by replacing their current NPP (post-urban NPP) with the mean post-urban NPP of nearby non-urban cells that corresponded to their original natural vegetation11. On this basis, the climate-variability-based NPP was compiled by aggregating pre-urban NPP in urban areas and the NPP results from the climate-variability-driven simulation for non-urban area.To ensure consistency with the interactive framework between urban ecosystems and environmental changesNPP2010) is zero), NPP variation caused by urban expansion was calculated for the newly urbanized areas (2000–2010) as negative pre-urban NPP (NPP2000) .In the urban-expansion-driven simulation, urban-expansion-based NPP was projected using changing urban land use/cover for 2000–2010 and constant climate drivers . The pre-urban NPP in the newly urbanized areas from 2000 to 2010 were first estimated using a neighborhood proxy method. By assuming urban lands as a carbon source  and actual NPP  were calculated based on the following Equation:y is the climate-variability-based/actual terrestrial NPP (g C m−2 year−1); t is the corresponding time (year); β0 is the intercept; β1 reflects the trend of the climate-driven/actual terrestrial NPP; and ε is the residual error.To analyze the relative contribution of urban expansion/climate variability/residual factor on the change of the terrestrial NPP, the trends of actual/climate-variability-based NPP were calculated using linear regression analyses with time  as the independent variable and corresponding NPP data as the dependent variable. Thus, the trends of the climate-variability-based (ΔNPPurban-expansion-based) was also calculated as the slope of urban-expansion-based NPP versus the corresponding time, by assuming a fixed rate of urban land expansion over the period 2000–2010. In addition, the trend of residual factor (ΔRes), which was not explained by urban expansion and climate variability, was calculated as the difference between the estimated actual NPP trend  and the sum of the trends of climate-variability-based (ΔNPPclimate-driver-based) and urban-expansion-based NPP (ΔNPPurban-expansion-based).Similarly, the trend of urban-expansion-based NPP (ΔContr.Urb), climate variability (Contr.Clim), and residual factor (Contr.Res) were determined as proportions between the trends of climate-variability-based NPP, urban-expansion-based NPP, residual factor and the sum of their absolute values . The dataset was produced using more than 20,000 Landsat and Chinese HJ-1 satellite images with a resolution of 30-m18. Besides the GlobeLand30, one of the land cover dataset from MODIS products  was also collected from the Earth Observing System (EOS) Data Gateway at the Land Processes Distributed Active Archive Center (https://lpdaac.usgs.gov/data/get-started-data/collection-overview/). Specifically, the MCD12Q1 dataset from IGBP classification scheme was obtained for the year 2006 to capture the details of natural vegetation distribution.GlobeLand30 dataset for 2000 and 2010 was obtained from the National Geomatics Center of China  were obtained for 2000–2010 at 1-km resolution.http://hydrology.princeton.edu/data.php). These datasets were produced by combining observation-based records with National Centers for Environmental Prediction/National Center for Atmospheric Research (NCEP/NCAR) reanalysis data64. In addition, monthly cloud cover and wet-day frequency data were obtained from the Climatic Research Unit (CRU), University of East Anglia (https://crudata.uea.ac.uk/cru/data/hrg/cru_ts_3.24.01/). To match the spatial resolution of the satellite-derived MODIS datasets , all of the climate datasets were resampled to a resolution of 1-km although this does not increase the effective resolution of the data.The climate datasets in this study include mean temperature, total precipitation, downward shortwave solar radiation, cloud cover, and wet-day frequency. Specifically, historical records of monthly temperature and total precipitation for 2000–2010 were retrieved from the Physical Sciences Division of the NOAA Earth System Research Laboratory (ESRL). Monthly solar radiation data were provided by the Terrestrial Hydrology Research Group at Princeton University  with 1:5 000 000 FAO-UNESCO Soil Map of the World . In addition, dataset on global soil nutrients was also collected from ref. 25.The soil data were obtained from the Harmonized World Soil Database (HWSD), which was produced via a collaboration among the Food and Agriculture Organization (FAO) of the United Nations, International Institute for Applied Systems Analysis (IIASA), ISRIC-World Soil Information, Chinese Academy of Sciences, and the Joint Research Centre of the European Commission (JRC)66. The GPPDI dataset covers 2523 individual sites and 5164 half-degree grid cells. It underwent extensive reviews under the Ecosystem Model-Data Intercomparison process. Here, the datasets were downloaded from Oak Ridge National Laboratory (http://daac.ornl.gov//NPP/guides/NPP_GPPDI.html). In addition, grain yield data in 2005 for 232 cities in China were compiled from statistical books, which was downloaded from China’s economic and social development statistics database (http://tongji.cnki.net/kns55).The global terrestrial NPP data in this study were compiled from corrected GPPDI dataset2 dataset was obtained from the U.S. NOAA Earth System Research Laboratory (https://www.esrl.noaa.gov/gmd/ccgg/trends). Both CO2 and other greenhouse gases have been measured at a globally distributed network of air sampling sites for several decades67. On this basis, mean CO2 concentration was obtained to produce the dataset68.The COThe details of the aforementioned datasets are listed in Supplementary Table Supplementary Information


In this paper, we consider several designs for nitride-based vertical-cavity surface-emitting lasers (VCSELs) with a top semiconductor-metal subwavelength grating (SMSG) as the facet mirror. The constructions of the bottom distributed Bragg reflectors (DBRs) used in the VCSEL designs were inspired by devices demonstrated recently by several research groups. A multiparameter numerical analysis was performed, based on self-consistent thermal and electrical simulations. The results show that, in the case of small aperture VCSEL designs, dielectric-based DBRs with metallic or GaN channels enable equally efficient heat dissipation to designs with monolithically integrated DBRs. In the case of broad aperture designs enabled by SMSGs, monolithically integrated DBRs provide much more efficient heat dissipation in comparison to all other considered designs. Gallium nitride-based vertical-cavity surface-emitting lasers (VCSELs) are currently under development, with potential for use as light sources in optical communication, optical storage, laser printers, and biosensors ,2,3,4. GThe nitride-based DBRs reported thus far in the literature show poor electrical conductivity for both p- and n-type materials. In the case of AlGaN/GaN DBRs, the acceptable mismatch between lattice constants in the layers results in low refractive index contrast and hence many DBR periods are necessary to achieve total reflectivity. Increasing the refractive index contrast by raising the mole fraction of aluminum in AlGaN leads to defects in the crystal lattice and consequently to lower both electrical conductivity and laser efficiency . The proGaN DBRs . On the GaN DBRs . MoreoveGaN DBRs . Very hiGaN DBRs , we calcDielectric DBRs offer an alternative to nitride-based DBRs. However, they are not free from drawbacks. On the one hand, they have high-contrast refractive index and on the other they are insulators with very low thermal conductivity. Dielectric DBRs require an intracavity injection scheme, which can be achieved using a tunnel junction (TJ) or indium tin oxide (ITO) layer. The fabrication of VCSELs composed of two dielectric mirrors ,14 requiIn the past, high-contrast gratings (HCGs) have been investigated as a possible alternative to DBRs, enabling the vertical dimension of VCSEL to be reduced, emitted wavelength tuning and polarization stability . HoweverRecently, we proposed a monolithic HCG (MHCG) providing total optical power reflectance for refractive indices of MHCGs larger than 1.75 . Our num∘C .We also proposed an original approach to current injection based on the use of a semiconductor-metal subwavelength grating (SMSG) as the top mirror of a VCSEL . This soIn BR pairs  decreaseAn alternative approach is the use of lattice-matched AlInN/GaN DBRs , which crors. In , metal cWe analyzed and compared several designs for nitride-based VCSELs with semiconductor-metal subwavelength gratings in terms of thermal and electrical properties. All designs have similar cavity constructions, but their bottom DBRs have various compositions. The schematics of the simulated devices are shown in e to 0.5 . Currente to 0.5 .The active region is composed of five 3-nm thick Ink is the thermal conductivity of the medium, T is temperature and g is the volumetric power density of the heat sources. The volumetric power density of the heat sources is described by the following equations: V is the electric potential. Equations  are addressed in  of 8 μm . The fir of 8 μm ,36, such W/(m·K) , contribTo explore the possibility of improving thermal management, a very similar structure was considered to that proposed in , in whicComparison of Calculations for an analogous laser with a SiOspreader , which aThe low effective thermal conductivity of AlInN/GaN DBRs  . These che VCSEL b in compGold channels improve heat extraction from the active region, reducing the total thermal resistance of the device to a level comparable to that of VCSEL with SL AlN/GaN DBRs (Structure 2). These conclusions are confirmed in An important question concerns the optimal parameters for the gold channels. A similar concept enabling heat to bypass the DBR was proposed by SONY , in whicease see  with resThere are a number of possible approaches to the fabrication of bottom DBRs in the case of small aperture VCSELs, offering efficient heat extraction from the laser. In terms of the technological effort required, fabricating a VCSEL with a SiOSMSG VCSELs enable vertical current injection into very large active regions, up to 40 × 40 μm2 . This isμm2 ,13,14,23The modified Structures 3a and 3b enable heat flux to bypass the dielectric DBRs. For example, This paper presents an extensive thermal analysis of new designs for a nitride-based semiconductor-metal subwavelength grating (SMSG) vertical-cavity surface-emitting laser (VCSEL) with various constructions of bottom distributed Bragg reflectors (DBRs). We considered bottom DBRs composed of AlInN/GaN (Structure 1), AlN/GaN with superlattice (SL) (Structure 2), SiOsistance  and a di


Mycobacterium tuberculosis (MTB) isolates in Nepal. We isolated and genotyped 498 MDR-MTB isolates collected from April 2009 to March 2013 and analyzed the patients’ background information. Our results showed that the lineage 2 (Beijing family) was the most predominant lineage , followed by lineage 3 . Lineage 4 was the third most prevalent  followed by lineage 1 . The lineages were significantly associated with geographic region, ethnic group, age and sex of patients. The Beijing genotype was found to have an important role in transmitting MDR-TB in Nepal and was significantly associated with the eastern region, mongoloid ethnic group and younger age group. We conclude that early diagnosis and treatment including molecular-epidemiological surveillance of MDR-TB cases will help to control transmission of MDR-TB in Nepal.Multidrug-resistant tuberculosis (MDR-TB) is an emerging public health problem in Nepal. Despite the implementation of a successful TB control program in Nepal, notifications of MDR-TB are increasing, yet the reasons are unknown. The objective of this study was to understand the genetic diversity and epidemiological characteristics of MDR- Mycobacterium tuberculosis(MTB) resistant to both isoniazid (INH) and rifampin (RIF), the two most effective first-line anti-TB drugs1. In 2016, the World Health Organization (WHO) recognized drug-resistant TB as a continuing threat with an estimated 600,000 new TB cases with RIF resistance, of which 490,000 cases were MDR-TB. Almost half of the above MDR-TB cases were in India, China and the Russian Federation1.Multidrug-resistant tuberculosis (MDR-TB) is caused by 1. The Nepal government’s National TB Program (NTP) has recognized MDR-TB to be a great challenge to the national TB control program and a major public health concern in Nepal2. The Nepalese 2011/12 MDR-TB survey showed MDR-TB to be 2.2% in new and 15.4% in retreatment TB cases2. Despite Nepal having an effective TB control program under the supervision of the WHO, notification of MDR-TB was found to be increasing year on year, with the number of new cases of MDR-TB increasing consecutively for five fiscal years from 2011 to 20152. In the Nepal National TB Program (NTP) annual report 2014/15, out of an estimated 1,000 MDR-TB cases, only 379 cases were diagnosed and treated2, suggesting substantial limitations in the management of MDR-TB, especially outside the capital city of Kathmandu valley. Furthermore, a high rate of primary quinolone resistance among MDR-TB cases is also increasing3. The reasons for the emergence of MDR-TB in Nepal are not clearly understood.Nepal, situated in between India and China, the two countries with the greatest TB burden, also experiences many TB cases every year. In 2016, Nepal reported an estimated TB incidence and mortality of 154 and 22, respectively, per 100,000 inhabitants2 which entails administration of standardized treatment regimens. All MDR-TB patients receive 20 months of the standard regimen with 8 months of intensive phase involving kanamycin, levofloxacin, pyrazinamide, cycloserine and ethionamide, with a 12 month continuation phase using the same drugs except kanamycin.Under the supervision of NTP, cases of DR-TB are managed by DR-TB treatment centers distributed throughout the country. From Kathmandu, the NTP’s national TB center (NTC) and the German Nepal TB project (GENETUP) provides culture and drug susceptibility testing (DST). Treatment of DR-TB is performed under the NTP guidelines4. Using spoligotyping the global population of MTB can be classified into four main lineages, lineage 1(Indo-Oceanic lineage), lineage 2 , lineage 3  and lineage 4 (Euro-American family)5. Previous studies have demonstrated a relationship between drug resistance and genotype of MTB8, while other studies failed to find an association9. The Beijing genotype is reported to have unusual characteristics such as hyper-virulence, higher pathogenicity, a greater ability to overcome immunity afforded by BCG vaccination and frequent association with MDR-TB11. Previous studies from Nepal13 have demonstrated high genetic diversity of MTB isolates. In the study conducted from 2009 to 201012, the authors described the first phylogenetic diversity of MTB isolates in Nepal with the CAS/Delhi family being the most dominant , followed by Beijing family . However, most of the isolates were non-MDR (245/261) and were mostly from the Kathmandu valley. Importantly, in a few MDR isolates (16/261), most isolates  were of the Beijing family followed by the CAS family , suggesting the need for further studies on genetic diversity of MDR-MTB isolates in Nepal. However, there has been no comprehensive molecular epidemiological study of MDR-MTB isolates to aid in our understanding of the emergence of MDR-TB in Nepal.Genotyping of MTB strains is important to understand their molecular epidemiology and transmission dynamics. Among commonly used genotyping methods, spoligotyping is a rapid and convenient method that can simultaneously detect and differentiate lineages of MTBTo understand the emerging public health problem of MDR-TB in Nepal, we genotyped 498 MDR-MTB isolates collected from all geographic regions of the country between April 2009 and March 2013. The aim of this study was to gain insights into the genetic background of these selected MDR-MTB isolates and any association with the TB patients’ background information so as to understand the factors associated with the emergence MDR-TB in Nepal.The geographical location and sample size of all 498 MDR-MTB isolates is shown in Fig. plus line probe assay whereas 39 isolates were characterized by the Genotype MTBDRplus assay only. Of the 459 isolates characterized by phenotypic DST, 393 isolates were resistant to three or more first-line anti-TB drugs and 66 isolates were resistant to isoniazid (INH) and rifampicin(RIF) only. All the 39 isolates characterized by MTBDRplus were resistant to INH and RIF.Among the 498 MDR-MTB isolates, DST of 459 isolates were characterized by both phenotypic (DST) as well as by Genotype MTBDROf the 498 spoligotype results, a total 78 different spoligotypes were identified. Of these, 56 spoligotypes for 458 92%) of the isolates were already defined in spoligo international types (SITs), while 32 spoligotypes from 40 (8%) of the isolates had a new spoligotype patterns and were classified as orphan types. The orphan types that did not match to any known lineages in the SITVIT database were further characterized by large sequence polymorphism (LSP) for lineage confirmation (Table % of the Different lineages of MDR-MTB isolates were found to be significantly associated (P < 0.0001) with different geographical regions of the country Table . The LinAs the Beijing family was the most prevalent lineage of MDR-MTB isolates in Nepal, we wanted to understand the association of this strain family with geographical region. The Beijing and non-Beijing family of isolates were significantly associated (P < 0.001) with different regions Table . The oddthpercentile, median and 75thpercentile of the variance were 23, 30, and 42 years old, respectively. Based on this calculation, the age variance was divided into four categories, 0–23, 24–30, 31–42, and >42.Different lineages were also found to be significantly associated with patient’s age, ethnic group and sex Table . RegardiFor in-depth investigation, we divided strains into two groups, Beijing family and non-Beijing family, and found that the Beijing family was significantly associated with ethnic group and patient age Table . Table 412, our study demonstrates that the Beijing family is the most prevalent MDR-MTB lineage in Nepal.To our knowledge, this is the first investigation of genetic diversity of MDR-TB isolates covering all MDR-TB treatment centers and sub centers of the national TB program in Nepal. A diverse population of MTB was observed, showing 78 different spoligotype-based genotypes. About half of the isolates  belonged to Lineage 2, Beijing family and about one third  mapped to the Lineage 3, CAS/Delhi family. These 2 families of MTB accounted to  of the total population of MDR-MTB isolates indicating their epidemic spread in Nepal. Although, the previous study showed that CAS/Delhi family was the most prevalent MTB lineage in non MDR-TB Nepal14 but lower than reported in China (75%)15, Vietnam (71%)16 and Thailand (72.4%)17. Nepal is surrounded by two major TB burden countries, China (including Tibet) to the north where Beijing family is dominant19 and India to the east, west and south where the CAS/Delhi family is dominant20. Despite the present situation of an open border, frequent people-to-people contact with India, and the dominance of CAS/Delhi family in non MDR-MTB strains12, we found the Beijing family to be the most prevalent in MDR-MTB strains in Nepal. The association of Beijing family is frequently associated with MDR-TB in Asia17 and our findings suggest that Beijing family is also the leading cause of MDR-TB in Nepalese population.The prevalence of Beijing family in MDR-TB in our study was higher than reported in India (35%)21  in this study population, a significant association was not seen between sex and Beijing family  or the use of whole genome sequencing for comprehensive understanding disease dynamics of MDR-TB in Nepal.Our results suggest that, despite the presence of diverse genotypes of MDR-MTB strains in Nepal, the Beijing family is the dominant MTB genotype linked to MDR-TB in Nepal. Our study suggests that Beijing-family strains are expanding by virtue of their distribution in high population densities, ethnic groupings, and, the higher mobility of younger age groups. We believe that the Beijing family is driving MDR-TB in Nepal and assume that its role in association with MDR-TB will increase in the future. Thus, we consider that the Beijing family of MDR-MTB is an emerging threat for the control of MDR-TB in Nepal. Recently, Nepal has strengthened its capacity to diagnose and manage MDR-TB by performing DST for all MDR-TB samples, expanded use of GeneXpert and introduced molecular diagnosis facility in Kathmandu. Additionally, we suggest introducing genotyping as a component of regular MDR-TB diagnosis in Nepal. The correct treatment of MDR-TB is of course the main clinical issue, regardless of the lineage of the causative MDR-TB strains. However, within the present context of the limited resources, we would like to suggest initiating intensive care and management of at least Beijing MDR-TB patients and some critical cases from other lineages, if intensive management of all MDR-TB patients is difficult. Some of the intensive management options would be isolated treatment and epidemiological surveillance of these patients, which may help to find new cases from their epidemiological links, understand risk factors and develop strategies for control and management of MDR-TB in Nepal. With the advancement of molecular laboratory science, rapid diagnostic biochemical and molecular methods such as whole genome sequencing will be used for TB diagnosis and management. Nepal should therefore prepare in advance to take advantage of upcoming innovations for the control and management of MDR-TB in Nepal.plus (Hain Life Science) for identification of MTB complex and resistance to INH and RIF. Finally, from the 877 registered patients, 498 patients’ samples that were confirmed to be MDR-MTB from culture, DST of INH and RIF and genotyping results were selected for analysis in this study  were registered in the national MDR-TB program from April 2009 to Mar 2013. Among those registered patients, the majority were cat II failures without DST analysis because during the study period culture and DST facilities were not available outside the Kathmandu valley. After registration of patients, an initial sample was sent to Kathmandu for culture and DST. All positive cultures were then tested for phenotypic DST and Genotype MTBDRSample processing, culture, DST and DNA extraction were performed at the German Nepal TB Project (GENETUP), National Reference Laboratory, Kathmandu. Samples were processed at bio-safety level 3 facility of GENETUP under direct supervision of NTP and WHO. Spoligotyping and Large Sequence Polymorphism (LSP) testing were performed at Hokkaido University, Japan.30.DST for isoniazid , rifampicin , streptomycin , and ethambutol  were performed by the indirect proportional method on Lowenstein-Jensen medium with critical concentrations of 0.2 μg/ml INH, 40 μg/ml RIF, 4 μg/ml STR and 2 μg/ml EMBplusVer 2 31. Briefly, colonies from positive cultures were suspended in 300 µl of DNA free distilled water and heated for 20 min at 95 °C. The heated sample was incubated in an ultra-sonic water bath for 15 min and centrifuged for 5 min at 10,000 × g. DNA from the supernatant was used for PCR amplification.DNA was prepared for PCR following the manufacturers protocol using the Genotype MTBDRplus assay was performed according to the manufactures recommend protocol using the Genotype MTBDRplusVer 2. Briefly,target DNA was amplified using a multiplex PCR mastermix(50 µl /tube) and theHot starTaqDNA Polymerase . Results were evaluated and interpreted following the manufacturers instruction32.Genotype MTBDR4. Briefly, the DR region was amplified with a pair of primers, and the resulting PCR products were hybridized to a set of 43 spacer-specific oligonucleotide probes, which were immobilized in the membrane and hybridized DNA fragments were detected. Results were compared with the SITVITWEB database33 (http://www.pasteur-guadeloupe.fr:8081/SITVIT_ONLINE/) to determine spoligointernational Type (SIT). Spoligotyping patterns that were not identified by SITVITWEB were further analyzed by LSP34.Spoligotyping of MTB clinical isolates was performed as described previously34.A PCR-based technique was applied for the identification of isolates belonging to orphan or new spoligotypes using the specific primers for the expected regions of difference (RD) for each lineage as describedp value less than 0.05 was considered statistical significant. Univariate analysis was performed to calculate the odds ratio with 95% confidence interval to understand risk of MDR-TB between Beijing and non-Beijing family in different situations. Furthermore, for multivariant analysis patient’s characteristics and outcome of MDR-MTB lineages were entered in the SPSS software version 19 . Logistic regression was used for multivariate analysis of potential predictors of Beijing and Non-Beijing family MDR-TB; with P < 0.05 used as a threshold for statistically significant interactions. The default “enter” method was used.Microsoft excel was used to analyze the data. Pearson’s chi square test was used to compare different variances. A th Sep 2013 and approved by Ethical Review Board on 29th Nov 2013.This study proposal was submitted to Nepal Health Research Council (NHRC) with register no 136/2013 on 20


Purpose: To perform a multi-institutional analysis following treatment of limited osseous and/or nodal metastases in patients using a novel hypofractionated image-guided radiotherapy with simultaneous-integrated boost (HIGRT-SIB) technique.Methods: Consecutive patients treated with HIGRT-SIB for ≤5 active metastases at Duke University Medical Center or Durham Veterans' Affairs Medical Center between 2013 and 2018 were analyzed to determine toxicities and recurrence patterns following treatment. Most patients received 50 Gy to the PTVboost and 30 Gy to the PTVelect simultaneously in 10 fractions. High-dose treatment volume recurrence (HDTVR) and low-dose treatment volume recurrence (LDTVR) were defined as recurrences within PTVboost and PTVelect, respectively. Marginal recurrence (MR) was defined as recurrence outside PTVelect, but within the adjacent bone or nodal chain. Distant recurrence (DR) was defined as recurrences not meeting HDTVR, LDTVR, or MR criteria. Freedom from pain recurrence (FFPR) was calculated in patients with painful osseous metastases prior to HIGRT-SIB. Outcome rates were estimated at 12 months using the Kaplan-Meier method.Results: Forty-two patients met inclusion criteria with 59 sites treated with HIGRT-SIB . Median time from diagnosis to first metastasis was 31 months and the median age at HIGRT-SIB was 69 years. The most common primary tumors were prostate (36%), gastrointestinal (24%), and lung (24%). Median follow-up was 11 months. One acute grade ≥3 toxicity (febrile neutropenia) occurred after docetaxel administration immediately following HIGRT-SIB. Four patients developed late grade ≥3 toxicities: two ipsilateral vocal cord paralyzes and two vertebral compression fractures. The overall pain response rate was 94% and the estimated FFPR at 12 months was 72%. The estimated 12 month rate of HDTVR, LDTVR, MR, and DR was 3.6, 6.2, 7.6, and 55.8%, respectively. DR preceded MR, HDTVR, or LDTVR in each instance. The estimated 12 month probability of in-field and marginal control was 90.0%.Conclusion: Targeting areas at high-risk for occult disease with a lower radiation dose, while simultaneously boosting gross disease with HIGRT in patients with limited osseous and/or nodal metastases, has a high rate of treated metastasis control, a low rate of MR, acceptable toxicity, and high rate of pain palliation. Further investigation with prospective trials is warranted. Ever since Hellman and Weichselbaum proposed the existence of the oligometastatic state  as a corCurrent radiotherapy techniques to treat oligometastases typically utilize stereotactic body radiotherapy principles including small margins and steep dose gradients , 8 to miIn an attempt to prevent marginal recurrence (MR) and avoid subjecting patients to another course of treatment, we investigated a simultaneous-integrated boost (SIB) technique when delivering HIGRT. We hypothesized that treating a larger elective volume (including areas at high-risk of harboring occult disease) with a lower dose considered to be well-tolerated by nearby organs at risk, while simultaneously boosting gross disease to a higher dose, would decrease MR with an acceptable toxicity profile.18F-fluorodeoxyglucose-PET scans.Consecutively treated patients with lymph node and/or osseous metastases treated with the HIGRT-SIB technique in the Department of Radiation Oncology at Duke University Medical Center or the Durham Veterans' Affairs Medical Center prior to October 1, 2018 were identified. Patients >18 years of age with pathologically confirmed solid tumor malignancy of any primary site with five or fewer active metastatic sites at the time of HIGRT-SIB were included in this analysis. The combination of computed tomography (CT) and nuclear medicine imaging  were used to quantify the number of active metastatic sites prior to HIGRT-SIB. All prostate cancer patients were staged with a combination of CT scans and technetium-99 m bone scans, while all other patients were staged with a combination of CT scans and boost), dose per fraction to PTV receiving elective dose (PTVelect), number of fractions, gross tumor volume , PTVboost (cm3), PTVelect (cm3), and date of death or last follow-Up.We extracted the following information from medical records: age at HIGRT-SIB, gender, primary tumor site, tumor histology, primary tumor treatment, systemic therapy, time to metastatic disease, number of active metastatic sites, largest diameter of metastasis (cm), biomarker level before and after HIGRT-SIB , presence of painful metastasis prior to HIGRT-SIB, dose per fraction to PTV receiving boost dose .Patients were typically simulated supine with raised arms in a customized immobilization device, with respiratory management and intravenous contrast as indicated with 2–3 mm CT slices. The GTV was contoured on each axial slice. An elective CTV was contoured encompassing the gross disease and areas at high-risk of occult spread, including the surrounding nodal chain or contiguous bone. Typically, in the case of bony spine metastases, the entire vertebrae was included in the CTV as well as the spinal cord and canal at that level. The CTV was expanded by 5–7 mm in each direction to generate the PTVboost and 30 Gy to PTVelect over 10 fractions. Organs at risk were contoured and assigned dose constraints compiled from published prospective and retrospective analyses  or intensity-modulated radiotherapy (IMRT) with cone beam computed tomography (CBCT) alignment approved by the physician prior to each fraction. Patients were seen once weekly during HIGRT-SIB for assessment of acute toxicity, 4–6 weeks after treatment, and then follow-up and imaging performed as clinically indicated.The most frequently prescribed dose-fractionation was 50 Gy to the PTVanalyses –16. The boost. LDTVR was defined as clinical and/or radiographic recurrence within the PTVelect. MR was defined as clinical or radiographic recurrence outside the PTVelect but within the same bone or nearby lymph node chain. Distant recurrence (DR) was defined as clinical or radiographic recurrence at a new site outside the PTVelect that did not meet criteria for MR. Three authors  independently reviewed each clinical and radiographic recurrence, and a consensus categorization was reached in every case.The primary outcome was the probability of in-field and marginal control. Events that contributed to this primary outcome include high-dose treatment volume recurrence (HDTVR), low-dose treatment volume recurrence (LDTVR), and MR. HDTVR was defined as clinical and/or radiographic progression or recurrence within the PTVFor metastases from prostate, thyroid, or gastrointestinal primaries with elevated biomarkers prior to treatment, biochemical recurrence (BR) was defined as biomarker elevation above the pre-HIGRT-SIB level. Overall survival (OS) was defined as the time from HIGRT-SIB start to death or last follow-up date. Disease-free survival (DFS) was defined as the time from HIGRT-SIB start to first recurrence , death, or last follow-up date, whichever was sooner.Acute and late toxicities were measured using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Improvement in pain was defined as any decrease in severity on a 10-point scale after HIGRT-SIB. Pain recurrence was defined as equating or exceeding the metastasis pain severity from the pre-HIGRT-SIB level on a 10-point scale. Freedom from pain recurrence (FFPR) was calculated from the time of HIGRT-SIB start to pain recurrence in patients with painful osseous metastases prior to treatment.Demographic, tumor, and treatment characteristics were summarized with N (%) for categorical variables and median (interquartile range) for continuous variables for all metastases or patients, where applicable. Median length of follow-up was calculated from the start of HIGRT-SIB until death or last contact date for all patients. Crude event rates for each of the previously defined clinical endpoints were calculated out of the applicable populations . For HDTVR, LDTVR, MR, and probability of in-field and marginal control rates were calculated out of the total number of metastatic sites. Probability of in-field and marginal recurrence was also stratified by whether the metastasis was nodal or osseous and groups were compared with a log-rank test. For DR, OS, and DFS, rates were calculated out of the total number of patients. For BR, the rate was calculated for the total number of patients with pre-HIBRT-SIB elevated biomarkers. For FFPR, the rate was calculated out of the total number of patients with painful osseous sites of disease. Estimates and 95% confidence intervals (CI) of 1- and 2 year rates and median time to event for clinical endpoints were estimated using the Kaplan-Meier (K-M) method. Additionally, K-M estimates of the primary endpoint were calculated for nodal vs. osseous metastases, and K-M estimates of DFS were calculated by number of active metastases at time of HIGRT-SIB. Differences in in-field or marginal recurrence or DFS by metastasis location and number, respectively, were compared between the groups using a log-rank test. Statistical analysis was performed using R version 3.4.3 , with KaBetween July 2013 and October 2018, 42 patients met the inclusion criteria and 59 sites were treated with HIGRT-SIB. Demographic, disease, and treatment characteristics are summarized in boost were 12.4 and 30.0 cm3, respectively. The median net PTV enlargement to generate the PTVelect was 164 cm3 with respect to PTVboost. All but four patients received a prescribed dose of 50 and 30 Gy in 10 fractions to the PTVboost and PTVelect, respectively. Three patients were selectively underdosed to meet spinal cord or brachial plexus constraints, and one patient received 30 and 20 Gy in five fractions to the PTVboost and PTVelect, respectively.Among the 59 sites treated with HIGRT-SIB, 53% were nodal and 47% were osseous. Nearly one-half (46%) of all nodal or osseous metastases were in an abdominopelvic site, and nearly one-quarter (24%) were in the cervical, thoracic, or lumbar spine. The median GTV and PTVLate grade ≥3 toxicity following HIGRT-SIB was noted in four patients. Two of these were vertebral compression fractures; one requiring kyphoplasty and another treated with long-term narcotics for pain that limited the patient's activities of daily living. The two other grade ≥3 toxicities occurred in patients with esophageal cancer treated to the supraclavicular fossa and/or upper mediastinum who developed ipsilateral vocal cord paralysis. One of these patients had hoarseness prior to HIGRT-SIB, and underwent multiple esophageal dilations for grade 2 dysphagia. The other patient manifested hoarseness 32 months after completing HIGRT-SIB that did not improve with vocal cord injection. Of note, both of these patients had received prior thoracic chemoradiation therapy for their primary disease and one of the two patients underwent subsequent esophagectomy.There were 12 patients with painful bony metastases in the study and 11 of them reported pain relief following treatment. The estimated 12 month FFPR was 72%. In total, there were 16 painful osseous metastatic sites treated, with 15 (94%) noted as having a decrease in severity following treatment.p = 0.33, After a median follow-up of 11 months (interquartile range 6–24 months), there were five marginal or in-field recurrences . The estAfter review of individual isodose lines, daily CBCT, and diagnostic surveillance imaging, the crude number of events for HDTVR, LDTVR, MR, and DR were 2, 1, 2, and 21, respectively . The estelect.Further exploring MR, one occurred in a patient with lower extremity melanoma initially treated with wide local excision and inguinal nodal dissection who later received HIGRT-SIB for ipsilateral external and common iliac lymph node oligometastases. A biopsy-proven recurrence developed in the surgically dissected inguinal region, which was not included in the PTVelect, right between the junctions of the radiotherapy fields. The second HIGRT-SIB course treated the right supraclavicular fossa, where a LDTVR likely occurred due to an insufficiently treated subcentimeter oligometastasis that was visible on CT, but not avid on pre-treatment positron emission tomography (PET).Additionally, a lung cancer patient developed both MR and LDTVR following two separate courses of HIGRT-SIB. This patient initially received 60 Gy to the primary lung tumor and mediastinal lymph nodes with concurrent carboplatin and paclitaxel. The first course of HIGRT-SIB targeted an isolated left upper mediastinal nodal recurrence while attempting to avoid overlap with the initial fields. As depicted in boost 6 months after HIGRT-SIB. The second HDTVR occurred 25 months following HIGRT-SIB in one of five treated para-aortic lymph nodes in the setting of chronic immunosuppression and a new primary bladder malignancy.Both HDTVRs occurred in patients with prostate cancer. One patient with castrate-resistance developed widespread osseous metastases on the initial surveillance scan and shortly thereafter demonstrated disease progression within the PTVOf the 23 patients with biochemically-detectable malignancies, 11 met our definition of BR. The median time to BR was 18 months. Among those with BR, the elevated laboratory value preceded any clinical or radiographic recurrence in 73% of patients.Eight deaths occurred during the follow-up period . The medDespite increasing enthusiasm for and growing evidence supporting the treatment of limited or “oligo” metastases with radiation, the optimal radiotherapy technique is unknown. Most of the evidence supporting the use of radiation for limited metastases has been accomplished using small fields directed at gross disease with a minimal margin to decrease the likelihood for toxicity. However, as progression near treated tumors occurs at a significant rate, we sought to decrease the likelihood of such by including an elective, lower-dose volume including adjacent areas at high-risk of harboring occult disease. With this technique, we found high treated tumor control rates, consistent with prior reports using HIGRT , 19–37. elect may have reduced nearby progression. Prior studies describing patterns of progression following HIGRT to nodal metastases report 26–55% recurrence rates in adjacent lymph nodes (The high rate of treated tumor control (96% at 12 months) seen in our patients treated with this HIGRT-SIB technique was promising. Our results are comparable with reported 12 month local control rates in other studies of HIGRT in oligometastastic patients with spinal (>80%) , 38, 39,ph nodes , 13, 25.ph nodes , 38, 39.ph nodes . We noteThis HIGRT-SIB technique was well-tolerated, as both acute and late grade ≥3 toxicity rates were low (≤ 10%). Importantly, we did not observe any bowel obstruction, bowel perforation, gastrointestinal hemorrhage, myelopathy, or death due to HIGRT treatment. Comparison of our observed toxicity rate is difficult due to the heterogeneity of treatment sites included in this analysis. However, our results compare favorably with existing reports, including a recently reported prospective randomized trial of standard of care (SOC) treatment with HIGRT vs. SOC alone in patients with 1–5 metastatic sites that found 29% experienced acute grade ≥2 toxicity with three treatment-related grade 5 events . AnotherWe found that HIGRT-SIB resulted in a high subjective pain response (>90%) that was also durable, with 72% of patients reporting continued pain improvement at 12 months. The pain response rate seen in our study was higher than the rate of 66% reported for all patients treated on the multi-fraction palliative radiotherapy arm of RTOG 97-14  as well elect. For non-spine osseous metastases a generous elective volume could be included and for patients with limited lymph node metastases, we targeted occult spread throughout the contiguous lymph node chain and not just the immediate vicinity around the involved node. We were able to treat large volume oligometastases with this technique. Finally, we were able to deliver treatments using commonly available CBCT image-guidance and without more advanced spine SBRT techniques, indicating that many centers may be able to adopt our HIGRT-SIB technique as a tool to treat oligometastatic, oligorecurrent, or oligoprogressive patients in their clinic.While others have used a SIB technique to treat limited metastases, our technique is novel in several ways. First, patients in this study were most commonly received 10 fractions, delivering an established oligometastatic treatment dose of 50 Gy along with an elective dose of 30 Gy, the latter of which is commonly utilized to treat metastatic disease in multiple anatomic sites. Additionally, for osseous spinal metastases we included the entire involved vertebrae, including the posterior elements and spinal canal, in the PTVPrior reports of a SIB technique for spinal metastases have utilized a CTV that included the vertebral body and selected, but not all, posterior elements in order to meet spinal cord constraints delivering one fraction of 21–24 Gy to the GTV and 18 Gy electively, or alternatively three fractions delivering 30 Gy to the GTV and 24 Gy electively . For lymThere are several limitations to our retrospective analysis. First, it is subject to effects from unidentified, potentially confounding variables in this very heterogeneous population. Second, the number of patients is small and the duration of follow-up is short, and therefore may not adequately capture all late toxicities and recurrences. Finally, a major limitation is the lack of a control arm  to compare the rates of marginal and treated site recurrence with the experimental HIGRT-SIB technique; however, efforts are currently underway to identify patients treated with standard HIGRT at our centers and further analyses will be forthcoming.elect has similar rates of local control, decreases MR, improves DFS, lengthens systemic therapy-free intervals or delays switching systemic therapies, and/or results in a similar or better toxicity profile compared to standard HIGRT. Importantly, prospective trials are indicated to determine if the described HIGRT-SIB technique increases the overall palliative pain response rate and/or provides more durable pain relief in patients with osseous metastases compared to traditional palliative external beam radiotherapy.In conclusion, targeting areas at high-risk of occult disease by treating a larger elective volume while simultaneously boosting gross disease with HIGRT in patients with limited osseous and/or nodal metastases has acceptable rates of acute and late toxicity with low rates of marginal or in-field recurrence. HIGRT-SIB showed a high rate of overall pain response that was durable. Further investigation with a prospective trial is warranted to determine if HIGRT-SIB with a PTVThe datasets generated for this study are available on request to the corresponding author.The retrospective research was completed under a protocol approved by the Duke University Medical Center Institutional Review Board (Pro00101071) and a protocol approved by the Durham VA Health Care System Institutional Review Board (MIRB #1740). Research was conducted under waivers of consent, HIPAA authorization, and decedent notification at both institutions.CJ, JS, and MM contributed conception and design of the study and organized the database. CJ and HW performed the statistical analysis. CJ wrote the first draft of the manuscript. MM, JS, HW, BC, JP, and MP wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with the authors JS and MM.


The best strategy for surveillance testing in stage II and III colon cancer patients following curative treatment is unknown. Previous randomized controlled trials have suffered from design limitations and yielded conflicting evidence. This observational comparative effectiveness research study was conducted to provide new evidence on the relationship between post-treatment surveillance testing and survival by overcoming the limitations of previous clinical trials.This was a retrospective cohort study of the Surveillance, Epidemiology, and End Results database combined with Medicare claims (SEER-Medicare). Stage II and III colon cancer patients diagnosed from 2002 to 2009 and between 66 to 84 years of age were eligible. Adherence to surveillance testing guidelines—including carcinoembryonic antigen, computed tomography, and colonoscopy—was assessed for each year of follow-up and overall for up to three years post-treatment. Patients were categorized as More Adherent and Less Adherent according to testing guidelines. Patients who received no surveillance testing were excluded. The primary outcome was 5-year cancer-specific survival; 5-year overall survival was the secondary outcome. Inverse probability of treatment weighting (IPTW) using generalized boosted models was employed to balance covariates between the two surveillance groups. IPTW-adjusted survival curves comparing the two groups were performed by the Kaplan-Meier method. Weighted Cox regression was used to obtain hazard ratios (HRs) with 95% confidence intervals (CIs) for the relative risk of death for the Less Adherent group versus the More Adherent group.There were 17,860 stage II and III colon cancer cases available for analysis. Compared to More Adherent patients, Less Adherent patients experienced slightly better 5-year cancer-specific survival  and worse 5-year noncancer-specific survival  for years 2 to 5 of follow-up. There was no difference between the groups in overall survival .More surveillance testing did not improve 5-year cancer-specific survival compared to less testing and there was no difference between the groups in overall survival. The results of this study support a risk-stratified, shared decision-making surveillance strategy to optimize clinical and patient-centered outcomes for colon cancer patients in the survivorship phase of care.The online version of this article (10.1186/s12885-019-5613-5) contains supplementary material, which is available to authorized users. Recent studies indicate that approximately 20% of stage II and III colon cancer patients will have a recurrence of their cancer within 5 years following curative treatment (surgery ± adjuvant chemotherapy) –4. In thObservational comparative effectiveness research can provide high quality, nuanced evidence beyond that which may be feasible or ethical in RCT designs evaluating survival outcomes , 24. ThiStudy methodology has been described although some differences will be presented herein . The stuDiagnostic and procedure codes from the International Classification of Diseases, Ninth and Tenth Edition ICD-9/10); International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3); Current Procedural Terminology (CPT); and Healthcare Common Procedure Coding System (HCPCS) were utilized to obtain relevant treatment, surveillance, comorbidity , 28, and0; InternFor patients who received surgery as their only primary treatment, their final treatment date was their surgery date. For patients who received adjuvant chemotherapy, their final treatment date was the last date of sequential chemotherapy treatment  or 6 months from the first chemotherapy date for patients who received chemotherapy > 6 months.In determining adherence with NCCN Surveillance Guidelines, we considered receipt of surveillance tests that were established for their ability to detect new colon cancers and intraluminal, locoregional, and distant metastatic recurrences. Hence, we did not include physical exams in determining adherence with guidelines . In eachFor the assessment of yearly and overall surveillance, we modified our original strategy in order to capture the totality of the surveillance experience . For CEAIn determining overall surveillance, all years of complete follow-up up to 3 years post-treatment were assessed, and patients were classified as More Adherent or Less Adherent (Nonadherent patients were excluded). For patients with only 1 year of complete follow-up, their Year 1 classification was also their overall classification. For patients with two or 3 years of complete follow-up, their yearly classifications were combined to create an overall classification. Thus, for patients with 2–3 years of complete follow-up, their yearly surveillance assessments determined their overall surveillance classification. The overall classification scheme for patients with two or 3 years of complete follow-up is contained in Additional file P value < 0.05.Demographic and clinical variables for the unweighted study population were compared across the two categories of overall surveillance (More vs. Less). Pearson’s chi-square was applied to detect differences in categorical variables. Median follow-up time and 25% cancer death time between the two groups were calculated by the Kaplan-Meier method with differences evaluated by the log-rank test. Statistical significance was defined as In observational comparative effectiveness studies—where treatment is not randomized—appropriate methods to control for potential differences in confounding variables between the treatment groups is paramount . GeneralFive-year survival curves for the study population were obtained by the Kaplan-Meier method which incorporated IPTW. The weighted Cox proportional hazards model was used to obtain adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for the relative hazard  of five-year colon cancer-specific, cancer-specific , noncancer-specific, and overall mortality from the last date of treatment. The survival analysis revealed nearly identical hazard ratios for colon cancer-specific and cancer-specific survival, thus, only cancer-specific mortality is reported. We initially planned to obtain separate models according to treatment . However, when we analyzed both models, the associations between surveillance status and all survival outcomes were highly similar. Thus, all patients were combined. The proportional hazards assumption was assessed for surveillance status graphically  and by evaluating the interaction with time in the survival models. Although there was slight evidence of a declining hazard ratio (moving to the null) over time for cancer-specific survival, there was not sufficient evidence to indicate a violation of the proportional hazards assumption.n = 17,825) are shown in Table Demographic and clinical characteristics of the study population  with long-term follow-up. These investigators evaluated higher vs. lower frequency surveillance testing using CEA/CT. At the completion of the trial, there were no differences between the groups in either cancer-specific or overall survival. The only other observational study to evaluate more vs. less frequent surveillance testing was recently published by Snyder et al. [Earlier RCTs on this topic were hampered by a number of limitations which resulted in conflicting evidence , 17. Recr et al. . This stConsistent with the results reported by the authors of the three aforementioned studies , 4, 44, Our findings in an older adult colon cancer population indicate that there is considerable latitude regarding adherence with surveillance guidelines and the relationship with cancer-specific survival. Given the demonstration that treatment for cancer can result in financial (in addition to treatment-related) toxicity, lower cost/less intensive surveillance strategies might be attractive for many patients in the US and other first world countries, as well as in more resource-challenged environments –48. RegaThis study has a number of strengths. We leveraged the powerful SEER-Medicare database which contains demographic, comorbidity, tumor-related, treatment, follow-up, vital status, and cause of death information for cancer patients diagnosed in one of the 17 SEER regions in the US. The SEER-Medicare files contain an enormous amount of claims data with redundancies across file types. This helps to ensure the accuracy of information, which is a limitation of claims-based studies. Finally, we developed an individual-level classification scheme to assess surveillance testing for up to 3 years following treatment completion. We feel that our approach, which was based on obtaining an individual-level, holistic evaluation of surveillance reflecting what patients actually received, is a significant strength of this study.These results should be interpreted with full consideration of the study’s limitations. The main limitation concerns judgments regarding comparative effectiveness using an observational study design. The gold standard for determining treatment efficacy is the RCT, but these designs are often not ethical (randomizing to receive no surveillance testing despite recommendations) or feasible due to the costs of enrolling a large number of patients with years of follow-up , 24. OurA criticism of this study could relate to the surveillance classification scheme. Unlike a controlled trial, every variation of surveillance testing received in real world clinical settings had to be categorized and combined for up to 3 years of follow-up. Although one could possibly differ with the classification scheme used in this study, the study conclusions are the same. That is, more surveillance testing did not confer a cancer-specific or overall survival benefit compared to less testing. Another weakness of the study is that information on tumor recurrence cannot be observed via the SEER-Medicare database and the reason for testing is unavailable. Thus, it was not possible to differentiate true surveillance testing of asymptomatic patients from diagnostic testing in patients presenting with symptoms. Finally, our conclusions concerning the older adult/elderly colon cancer population may not be directly generalizable to younger patients.In a population of older adults with stage II and III colon cancer, more surveillance testing did not result in better cancer-specific or overall survival. These results support an individualized surveillance testing strategy that considers patients’ preferences, risk assessment of recurrence, and other individual-level clinical factors . In conjunction with results from recent studies , 4, 44, Additional file 1:Table S1. ICD-O-3, ICD-9/10-CM, CPT, HCPCS, and Revenue Center Codes. (DOCX 13 kb)Additional file 2:Table S2. Classification scheme for overall surveillance assessments. (DOCX 12 kb)Additional file 3:Table S3. Unweighted and Weighted Means According to Adherence Status and the Unweighted Study Population. (DOCX 19 kb)


During therapeutic evaluation, FDG-PET is considered as the reference imaging technique, because it can be performed much earlier than MRI which lacks specificity. Persistence of significant FDG uptake after treatment, notably before maintenance therapy, is an independent pejorative prognostic factor, especially for patients with a complete biological response. So FDG-PET and medullary flow cytometry are complementary tools for detection of minimal residual disease before maintenance therapy. However, the definition of PET metabolic complete response should be standardized. In patients with smoldering multiple myeloma, the presence of at least one hyper-metabolic lytic lesions on FDG-PET may be considered as a criterion for initiating therapy. FDG-PET is also indicated for initial staging of a solitary plasmacytoma so as to not disregard other bone or extra-medullary localizations. Development of nuclear medicine offer new perspectives for MM imaging. Recent PET tracers are willing to overcome limitations of FDG. (11)C-Methionine, which uptake reflects the increased protein synthesis of malignant cells seems to correlate well with bone marrow infiltration. Lipid tracers, such as Choline or acetate, and some peptide tracers, such as (68) Ga-Pentixafor, that targets CXCR4 , are other promising PET ligands. 18F-fludarabine and immuno-PET targeting CD138 and CD38 also showed promising results in preclinical models.The interest of 18Fluoro-deoxyglucose (FDG) positron emission tomography (PET) imaging in the management of patients with multiple myeloma (MM) for the workup at diagnosis and for therapeutic evaluation has recently been demonstrated. FDG-PET is a powerful imaging tool for bone lesions detection at initial diagnosis with high sensitivity and specificity values. The independent pejorative prognostic value on progression-free survival (PFS) and overall survival (OS) of baseline PET-derived parameters (presence of extra-medullary disease (EMD), number of focal bone lesions (FLs), and maximum standardized uptake values [SUV Multiple myeloma (MM) is a hematological neoplasm characterized by the clonal proliferation of malignant plasma cells in the bone marrow. It is almost always preceded by an initial monoclonal gammopathy of undetermined significance (MGUS), that then develops into asymptomatic or Smoldering MM (SMM), which constitutes an intermediate clinical stage between MGUS and MM.The rate of progression from MGUS to MM is 0.5–1% per year, and that of SMM to MM 10% per year for the first 5 years, with the thresholds of serum M protein and spinal plasmacytosis differing between both classifications. SMM is a heterogeneous classification including patients with a very slow progression to proven MM  and patients progressing very rapidly to symptomatic MM in <2 years (high-risk SMM). The definition of symptomatic MM, a clinical stage requiring treatment, typically based on the presence of CRAB criteria   is a reliable imaging for initial staging, therapeutic monitoring and relapse workup in MM, especially because of its prognostic potential (Recent data suggest that positron emission tomography (PET) using otential . Moreoveotential . More remax values , allowing detection of additional lesions, with sensitivity, and specificity greater than MRI –7, 20. IAccording to recent update data of the Southeastern Minnesota cohort  with a lFDG-PET showed prognostic value in patients with SMM and symptomatic MM.Even if the latest international recommendations of the IMWG  indicateMoreover, in SMM, a positive FDG-PET defined by the presence of FL without underlying osteolytic lesions is associated with a rapid progression to symptomatic MM. Indeed, in a cohort of 122 SMM patients, Siontis et al.  showed tn = 239) treated using the Total Therapy 3 strategy , Jung et al. , with no clear SUVmax cutoff predictive of PFS or OS . In a smg et al.  confirme3 for the PFS and 77.6 cm3 for the OS. A second larger study of 192 patients confirmed the poor prognostic value of a high MTVWB, which was also similar for a high Total lesion glycolysis (TLG) WB (3 at baseline significantly decreased PFS and OS after adjustment for known prognostic factors. Combined with the gene expression profiling prognostic score (GEP70), a TLGWB > 205 g identified a high-risk subgroup and separated ISS II patients into two subgroups, with a similar outcome to ISS I and ISS III patients.More complex PET biomarkers, such as functional volumes and tumor heterogeneity, have also been studied or are being evaluated with promising results. First pre-therapeutic assessment of the whole-body total metabolic volume of FL and EMD (MTVWB) in 47 patients showed a poor prognostic value of high values on PFS and OS , with be(TLG) WB . Indeed,Finally, as described by Carlier et al.  for 66 pFDG-PET is considered as the reference imaging technique for therapeutic evaluation in MM with a strong independent prognostic value . FDG-PETFDG-PET, coupled with a biological technique for the detection of minimal residual disease (MRD), makes it possible to improve the definition of complete response  clearly All large prospective studies above mentioned have demonstrated the strong and independent prognostic impact of FDG-PET results after therapy of symptomatic MM.The Little Rock team first showed in 2009 that normalization of FDG uptake of FL after chemotherapy induction cycles (before the transplant procedure) was associated with better EFS and OS . The samThe Bologna group then showed that after induction therapy, a SUV > 4.2 was associated with a reduced PFS . Three mp = 0.01; OS at 24 months of 94.2 vs. 72.9%: p = 0.03). In addition, multivariate analysis revealed that normalization of pre-maintenance FDG-PET was independently associated with longer PFS, such as absence of EMD at diagnosis and at least a very good partial biological response after three cycles of induction therapy.The Imajem study more recently confirmed the major benefit of FDG-PET in therapeutic evaluation . Whereasp < 0.001) and biochemical response (p = 0.025) appeared as independent prognostic factors, with a more discriminative hazard ratio for ΔSUVmax analysis (>−25 vs. ≤−25%) which identified patients with improved median PFS.Moreover, for the Imajem patients presenting a FDG-avid MM defined by lesion intensity higher than liver background, the prognostic value of FDG-PET after three cycles of induction therapy was also reported . Indeed,p = 0.05), whereas in patients with positive PET, SUVmax was inversely correlated with the duration of the response (P < 0.01).The benefit of post-ASCT FDG-PET was also reported in 2013 in a prospective series of 77 patients assessed by FDG-PET 3 months after ASCT, and then every 6–12 months during follow-up . The durHowever, the definition of CMR was not the same in these different clinical studies and a standardization of FDG-PET interpretation criteria should be done. Definition of cut-offs for FDG-PET positivity/negativity after therapy for MRD evaluation is currently underway. Preliminary results of a combined analysis of two European prospective trials have been presented by Zamagni et al. at the 2018 annual meeting of the ASH . In thismax and the presence of EMD resulted in a longer TTP.Although existing data are less available, FDG-PET seems to have also a prognostic impact at relapse workup. In a small series of 37 MM patients suspected of relapse after ASCT, it was shown that the absence of FL was a favorable prognostic factor for time to progression (TTP) and OS . The premax (>15.9) was an independent negative prognostic factor on the PFS as was a high TLG of the hottest lesion (>98.1 g). Interestingly, 15% of the patients were FDG-PET positive without re-ascending the monoclonal peak and no change in the level of serum free-light chains.More recently, in a retrospective series of 40 confirmed relapsed patients, Nantes' group have described that the presence of at least 6 FL in the peripheral skeleton was an independent pejorative prognostic factor on both the PFS and the OS by multivariate analysis . MoreoveFinally, scarce data on the value of FDG-PET before or after allo-SCT are available but two retrospective studies of heavily pre-treated MM patients showed FDG-PET results prior to and after allo-SCT were strongly associated with the outcome , 45.It has been recently reported in a 227 patients study with an initial diagnosis of symptomatic MM a FDG-PET negativity rate of 11% . It was 11C-Methionine, which uptake reflects the increased protein synthesis of malignant cells seems to correlate well with bone marrow infiltration and could be more sensitive than FDG to detect intra- and extra-medullary MM lesions .11 was proposed years ago in a preliminary study in comparison to FDG on 10 patients affected by symptomatic MM (18F-Choline presented similar results on 21 patients with symptomatic MM (11- or 18F-) has a better detection rate as compared to FDG in MM patients at staging. However, unfavorable physiological biodistribution (increased background of the liver parenchyma and of the bone marrow) is a limitation.Choline is a lipid PET tracer clinically used for the evaluation of relapse of prostate cancer. This tracer labeled with Cmatic MM  and showmatic MM . Then it11C-Acetate) and FDG at diagnosis of symptomatic MM also showed acetate would reveal more lesions  is a G-protein-coupled chemokine receptor family implicated in the process of cell migration as well as in the homing process of hematopoietic stem cells to the bone marrow, angiogenesis and cell proliferation.In multiple myeloma, CXCR4 expression is associated to disease progression and poor prognosis . Most ex68Ga-Pentixafor, that targets CXCR4 is a promising PET ligand . Ongoing prospective trials will try to establish the concordance between CMR and MRD negativity in the bone marrow to confirm the complementary role of functional imaging with modern biological tools for the detection of MRD inside and outside the bone marrow. We recommend to perform FDG-PET at initial work-up and after therapy (before maintenance) for detection of EMD, for patients with oligo/non-secretory MM and if a MRD assessment is performed. At relapse it is probably the best imaging technique to differentiate active disease from morphological scars and remodeling. Other PET tracers may also show interest in FDG-negative patients but should be evaluated in prospective clinical trials.BJ and FK-B wrote the paper. CB, TC, CT, CN, EZ, LB, A-VM, MC, PM, and CB-M critically revised and improved the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Heart disease has been the leading cause of death in the United States since 1910 and cancer the second leading cause of death since 1933. However, cancer emerged recently as the leading cause of death in many US states. The objective of this study was to provide an in-depth analysis of age-standardized annual state-specific mortality rates for heart disease and cancer.International Classification of Diseases, 10th Revision [ICD-10] codes I00–I09, I11, I13, and I20–I51) and malignant neoplasms (ICD-10 codes C00–C97). We calculated age-standardized annual state-specific mortality rate ratios (MRRs) as heart disease mortality rate divided by cancer mortality rate.We used population-based mortality data from 1999 through 2016 to compare 2 underlying cause-of-death categories: diseases of heart , indicating predominance of heart disease mortality nationwide. Median state-specific MRR decreased annually through 2010, reaching a low of 1.00 , indicating that predominance of heart disease mortality prevailed in approximately half of states. Median state-specific MRR increased to 1.03  in 2016. In 2016, age-standardized cancer mortality exceeded that for heart disease in 19 states. State-level transitions were most apparent for people aged 65 to 84 and affected men, women, and all racial/ethnic groups.State-level data indicated heterogeneity across US states in the predominance of heart disease mortality relative to cancer mortality. Timing and magnitude of transitions toward cancer mortality predominance varied by state. In the early 1900s, the United States went through an epidemiologic transition in which chronic diseases displaced acute infections as the leading causes of death. Heart disease was the leading cause of death nationally from 1910 through 2016, except from 1918 through 1920 . For exaNow the United States is going through another epidemiologic transition, in which cancer may eventually become the leading cause of death nationally –4. SinceAlthough heart disease was the leading cause of death nationally as of 2016 , it is nInternational Classification of Diseases, 10th Revision (ICD-10)  . We obta(ICD-10) . We defiWe compared age-standardized annual state-specific mortality rates for heart disease and cancer by using mortality rate ratios (MRRs), calculated as heart disease mortality rate divided by cancer mortality rate. We then made categories of MRRs .Data on age-standardized rates were based mostly on 10-year age categories  and the year 2000 standard US population , sex , and race/ethnicity . In some states, data were sparse for certain racial/ethnic groups. Therefore, we combined the first 3 calendar years of data (1999–2001) and the last 3 calendar years of data (2014–2016) to calculate stable state-specific MRRs for racial/ethnic groups. In those analyses, we considered states where heart disease or cancer mortality counts in racial/ethnic groups were less than 20 deaths per 3-year period to have insufficient data, and we did not calculate MRRs for those subgroups in those states. Although we did not round MRR calculations during our analysis, tabulated results were rounded to 2 decimal places.Data were analyzed by using SAS version 9.4 (SAS Institute), Microsoft Excel 2016 (Microsoft Corporation), ArcMap version 10.4 (Esri), and R 3.4.3 (The R Foundation).Age-standardized mortality rates were used to calculate MRRs because the relationship between age and heart disease mortality differs from the relationship between age and cancer mortality ,11, and In secondary analyses, actual mortality counts were used rather than age-standardized mortality rates to calculate unadjusted mortality count ratios (MCRs). The MCR compares the absolute number of heart disease deaths with the absolute number of cancer deaths. Comparisons of MCRs across states or calendar years may be influenced by state-specific age distributions or population aging over time. When we analyzed unadjusted MCRs, all patterns observed in our age-standardized analysis were still evident, with only minor differences. Therefore, the conclusions drawn in this report would not change, so we did not report results from the unadjusted analyses.In 1999, age-standardized heart disease mortality exceeded that for cancer in all 50 states . New YorFrom 1999 through 2016, age-standardized cancer mortality exceeded heart disease mortality (MRR <1.00) in several calendar years in 27 states . Higher In 2016, age-standardized cancer mortality exceeded heart disease mortality in 19 states . MinnesoState-level transitions from heart disease to cancer as the leading cause of death from 1999 to 2016 were most apparent in the group aged 65 to 84, for both men and women . Among mSome patterns were consistent across all racial/ethnic groups: strong predominance of heart disease mortality among people aged 85 or older, especially women; numerous state-specific transitions from heart disease predominance to cancer predominance in the group aged 65 to 84; and the predominance of cancer mortality among people younger than 65, especially women . Heart dThe transition from heart disease to cancer as the leading cause of death has occurred in many US states. Our analysis, based on age-standardized annual state-specific heart disease and cancer mortality rates, showed that from 1999 through 2016, the state-specific cancer mortality rate exceeded that for heart disease in more than half of US states in several calendar years. The timing and magnitude of transition varied by state. State-specific transitions toward cancer as the leading cause of death occurred most rapidly through the mid- to late-2000s, tapering off in more recent years. In 2016, heart disease mortality was either lower than cancer mortality or was less than 10% higher than cancer mortality in most states, whereas in 1999, heart disease mortality had been more than 20% higher than cancer mortality in nearly all states.Cancer mortality tends to exceed heart disease mortality at younger ages, whereas heart disease mortality tends to predominate at older ages . One stuThe transition toward cancer as the leading cause of death applies to both sexes and to all racial/ethnic groups. One study showed that cancer mortality first surpassed heart disease mortality nationally among non-Hispanic Asians and Pacific Islanders in 2000 and among Hispanics in 2009 . Our anaThe driving force behind these transitions, as documented in previous reports, is a decline in heart disease mortality –8,14. PoAlthough the relationship between heart disease and cancer mortality at the national level is well known, few state-specific in-depth explorations of heart disease versus cancer mortality are available. One such study, using mortality data from 2006 through 2009, described a transition toward cancer mortality predominance in Kentucky and Texas ,25. ThisOur study has limitations. The validity of our study depends on the accuracy and completeness of death certificate data. We used data on underlying cause of death to be consistent with the National Center for Health Statistics’ methodology for ranking causes of death , althougThe oft-repeated message that “heart disease is the leading cause of death in the United States,” while true at the national level as of 2016, obscures the heterogeneity in the relative predominance of heart disease mortality or cancer mortality across states and over time. Our longitudinal analysis of state-level data enriches our understanding of this epidemiologic transition toward cancer becoming the leading cause of death in the United States. Our findings can aid public health and medical professionals in interpreting vital statistics, creating public health messaging, and setting priorities in chronic disease prevention and control programs, particularly at the state level.