Six country vignettes: Strengthening radiotherapy and theranostics.

BACKGROUND: For cancer patient populations worldwide, the synchronous scale-up of diagnostics and treatments yields meaningful gains in survival and quality of life. Among advanced cancer therapies, radiotherapy (RT) and theranostics are key to achieving practical, high-quality, and personalized precision medicine - targeting disease manifestations of individual patients and broad populations, alike. Aiming to learn from one another across different world regions, the six country vignettes presented here depict both challenges and victories in de novo establishment or improvement of RT and theranostics infrastructure. METHODS: The International Atomic Energy Agency (IAEA) convened global RT and theranostics experts from diverse world regions and contexts to identify relevant challenges and report progress in their own six countries: Belgium, Brazil, Costa Rica, Jordan, Mongolia, and South Africa. These accounts are collated, compared, and contrasted herein. RESULTS: Common challenges persist which could be more strategically assessed and addressed. A quantifiable discrepancy entails personnel. The estimated radiation oncologists (ROs), nuclear medicine physicians (NMPs), and medical physicists (MPs for RT and nuclear medicine) per million inhabitants in the six collective countries respectively range between 2.69-38.00 ROs, 1.00-26.00 NMPs, and 0.30-3.45 MPs (Table 1), reflecting country-to-country inequities which largely match World Bank country-income stratifications. CONCLUSION: Established goals for RT and nuclear medicine advancement worldwide have proven elusive. The pace of progress could be hastened by enhanced approaches such as more sustainably phased implementation; better multinational networking to share lessons learned; routine quality and safety audits; as well as capacity building employing innovative, resource-sparing, cutting-edge technologic approaches. Bodies such as ministries of health, professional societies, and the IAEA shall serve critical roles in convening and coordinating more innovative RT and theranostics translational research, including expanding nuanced global database metrics to inform, reach, and potentiate milestones most meaningfully. POLICY SUMMARY: Aligned with WHO 25×25 NCDs target; WHA70.12 and WHA76.5 resolutions.

Clinical Outcomes, Blood Utilization, and Ethical Considerations for Pediatric Patients in a Bloodless Medicine and Surgery Program.

BACKGROUND: Pediatric patients requesting bloodless care represent a challenging clinical situation, as parents cannot legally refuse lifesaving or optimal interventions for their children. Here, we report clinical outcomes for the largest series of pediatric inpatients requesting bloodless care and also discuss the ethical considerations. METHODS: We performed a single-institution retrospective cohort study assessing 196 pediatric inpatients (<18 years of age) who requested bloodless care between June 2012 and June 2016. Patient characteristics, transfusion rates, and clinical outcomes were compared between pediatric patients receiving bloodless care and those receiving standard care (including transfusions if considered necessary by the clinical team) (n = 37,271). Families were informed that all available measures would be undertaken to avoid blood transfusions, although we were legally obligated to transfuse blood if the child's life was threatened. The primary outcome was composite morbidity or mortality. Secondary outcomes included percentage of patients transfused, individual morbid events, length of stay, total hospital charges, and total costs. Subgroup analyses were performed after stratification into medical and surgical patients. RESULTS: Of the 196 pediatric patients that requested bloodless care, 6.1% (n = 12) received an allogeneic blood component, compared to 9.1% (n = 3392) for standard care patients ( P = .14). The most common indications for transfusion were perioperative bleeding and anemia of prematurity. None of the transfusions were administered under a court order. Overall, pediatric patients receiving bloodless care exhibited lower rates of composite morbidity compared to patients receiving standard care (2.6% vs 6.2%; P = .035). There were no deaths in the bloodless cohort. Individual morbid events, length of stay, and total hospital charges/costs were not significantly different between the 2 groups. After multivariable analysis, bloodless care was not associated with a significant difference in composite morbidity or mortality (odds ratio [OR], 0.37; 95% confidence interval [CI], 0.12-1.11; P = .077). CONCLUSIONS: Pediatric patients receiving bloodless care exhibited similar clinical outcomes compared to patients receiving standard care, although larger studies with adequate power are needed to confirm this finding. There were no mortalities among the pediatric bloodless cohort. Although a subset of our pediatric bloodless patients received an allogeneic transfusion, no patients required a court order. When delivered in a collaborative and patient-centered manner, blood transfusions can be safely limited among pediatric patients.

PET-based response assessment criteria for diffuse gliomas (PET RANO 1.0): a report of the RANO group.

Response Assessment in Neuro-Oncology (RANO) response criteria have been established and were updated in 2023 for MRI-based response evaluation of diffuse gliomas in clinical trials. In addition, PET-based imaging with amino acid tracers is increasingly considered for disease monitoring in both clinical practice and clinical trials. So far, a standardised framework defining timepoints for baseline and follow-up investigations and response evaluation criteria for PET imaging of diffuse gliomas has not been established. Therefore, in this Policy Review, we propose a set of criteria for response assessment based on amino acid PET imaging in clinical trials enrolling participants with diffuse gliomas as defined in the 2021 WHO classification of tumours of the central nervous system. These proposed PET RANO criteria provide a conceptual framework that facilitates the structured implementation of PET imaging into clinical research and, ultimately, clinical routine. To this end, the PET RANO 1.0 criteria are intended to encourage specific investigations of amino acid PET imaging of gliomas.

FDG-PET/CT for investigation of pyrexia of unknown origin: a cost of illness analysis.

BACKGROUND: Our study aims to explore the current utilisation of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in the diagnostic pathway of pyrexia of unknown origin (PUO) and associated cost of illness in a large tertiary teaching hospital in Australia. METHOD: 1257 febrile patients between June 2016 and September 2022 were retrospectively reviewed. There were 57 patients who met the inclusion criteria of "classical PUO", of which FDG-PET/CT was performed in 31 inpatients, 15 outpatients and 11 inpatients did not have an FDG-PET/CT scan. The patient demographics, clinical characteristics and inpatient cost were analysed, together with the diagnostic performance of FDG-PET/CT and impact on clinical management. RESULT: The mean age, length of stay and total cost of admission were higher for inpatients who received FDG-PET/CT versus those who did not. The median cost per patient-bed-day did not differ between the two groups. Inpatients who received earlier FDG-PET/CTs (≤ 7 days from admission) had shorter length of stays and lower total cost compared to those who received a later scan. A negative FDG-PET/CT scan, demonstrating no serious or life-threatening abnormalities resulted in subsequent discharge from hospital or outpatient clinic in 7/10 (70%) patients. There were 11/40 (28%) scans where ancillary abnormalities were identified, requiring further evaluation. CONCLUSION: FDG-PET/CT showed high diagnostic accuracy and significant impact on patient management in patients with PUO. FDG-PET/CT performed earlier in admission for PUO was associated with shorter length of stay and lower total cost.

StrainNet: Improved Myocardial Strain Analysis of Cine MRI by Deep Learning from DENSE.

Purpose: To develop a three-dimensional (two dimensions + time) convolutional neural network trained with displacement encoding with stimulated echoes (DENSE) data for displacement and strain analysis of cine MRI. Materials and Methods: In this retrospective multicenter study, a deep learning model (StrainNet) was developed to predict intramyocardial displacement from contour motion. Patients with various heart diseases and healthy controls underwent cardiac MRI examinations with DENSE between August 2008 and January 2022. Network training inputs were a time series of myocardial contours from DENSE magnitude images, and ground truth data were DENSE displacement measurements. Model performance was evaluated using pixelwise end-point error (EPE). For testing, StrainNet was applied to contour motion from cine MRI. Global and segmental circumferential strain (Ecc) derived from commercial feature tracking (FT), StrainNet, and DENSE (reference) were compared using intraclass correlation coefficients (ICCs), Pearson correlations, Bland-Altman analyses, paired t tests, and linear mixed-effects models. Results: The study included 161 patients (110 men; mean age, 61 years ± 14 [SD]), 99 healthy adults (44 men; mean age, 35 years ± 15), and 45 healthy children and adolescents (21 males; mean age, 12 years ± 3). StrainNet showed good agreement with DENSE for intramyocardial displacement, with an average EPE of 0.75 mm ± 0.35. The ICCs between StrainNet and DENSE and FT and DENSE were 0.87 and 0.72, respectively, for global Ecc and 0.75 and 0.48, respectively, for segmental Ecc. Bland-Altman analysis showed that StrainNet had better agreement than FT with DENSE for global and segmental Ecc. Conclusion: StrainNet outperformed FT for global and segmental Ecc analysis of cine MRI.Keywords: Image Postprocessing, MR Imaging, Cardiac, Heart, Pediatrics, Technical Aspects, Technology Assessment, Strain, Deep Learning, DENSE Supplemental material is available for this article. © RSNA, 2023.

Methods of Bloodless Care, Clinical Outcomes, and Costs for Adult Patients Who Decline Allogeneic Transfusions.

BACKGROUND: Providing bloodless medical care for patients who wish to avoid allogeneic transfusion can be challenging; however, previous studies have demonstrated favorable outcomes when appropriate methods are used. Here, we report one of the largest series of patients receiving bloodless care, along with the methods used to provide such care, and the resulting outcomes. METHODS: In a retrospective cohort study, 1111 adult inpatients (age ≥18 years) at a single institution who declined allogeneic transfusion for religious or personal reasons between June 2012 and June 2016 were included, and the patient blood management methods are described. Patient characteristics, laboratory data, and transfusion rates, as well as clinical outcomes (morbidity, mortality, and length of stay) were compared to all other patients in the hospital who received standard care, including transfusions if needed (n = 137,009). Medical and surgical patients were analyzed as subgroups. The primary outcome was composite morbidity (any morbid event: infectious, thrombotic, ischemic, renal, or respiratory). Secondary outcomes included individual morbid events, in-hospital mortality, length of stay, total hospital charges, and costs. RESULTS: The bloodless cohort had more females and a lower case mix index, but more preadmission comorbidities. Mean nadir hemoglobin during hospitalization was lower in the bloodless (9.7 ± 2.6 g/dL) compared to the standard care (10.1 ± 2.4 g/dL) group (P < .0001). Composite morbidity occurred in 14.4% vs 16.0% (P = .16) of the bloodless and standard care patients, respectively. Length of stay and in-hospital mortality were similar between the bloodless and standard care patients. After Bonferroni adjustment for multiple comparisons, hospital-acquired infection occurred less frequently in the bloodless compared to the standard care cohort (4.3% vs 8.3%) (P < .0001) in the medical patient subgroup, but not in the surgical subgroup. After propensity score adjustment in a multivariable model and adjustment for multiple comparisons, bloodless care was associated with less risk of hospital-acquired infection (OR, 0.56; 95% CI, 0.35-0.83; P = .0074) in the medical subgroup, but not in the surgical subgroup. Median total hospital charges (by 8.5%; P = .0017) and costs (by 8.7%; P = .0001) were lower in the bloodless compared to the standard care cohort, when all patients were included. CONCLUSIONS: Overall, adult patients receiving bloodless care had similar clinical outcomes compared to patients receiving standard care. Medical (but not surgical) bloodless patients may be at less risk for hospital-acquired infection compared to those receiving standard care. Bloodless care is cost-effective and should be considered as high-value practice.

The value of FDG PET/CT imaging in outcome prediction and response assessment of lymphoma patients treated with immunotherapy: a meta-analysis and systematic review.

PURPOSE: Treatment strategies of lymphoid malignancies have been revolutionized by immunotherapy. Because of the inherent property of Hodgkin lymphoma and some subtypes of non-Hodgkin lymphoma as a highly FDG-avid tumor, functional 18F-FDG PET/CT imaging is already embedded in their routine care. Nevertheless, the question is whether it is still valuable in the context of these tumors being treated with immunotherapy. Herein, we will review the value of 18F-FDG PET/CT imaging lymphoid tumors treated with immunotherapy regimens. METHODS: A comprehensive literature search of the PubMed database was conducted on the value of the 18F-FDG PET/CT for immunotherapy response monitoring of patients with malignant lymphoma. The articles were considered eligible if they met all of the following inclusion criteria: (a) clinical studies on patients with different types of malignant lymphoma, (b) treatment with anti-CD20 antibodies, immune checkpoint inhibitors or immune cell therapies, (c) and incorporated PET/CT with 18F-FDG as the PET tracer. RESULTS: From the initial 1488 papers identified, 91 were ultimately included in our study. In anti-CD20 therapy, the highest pooled hazard ratios (HRs) of baseline, early, and late response monitoring parameters for progression-free survival (PFS) belong to metabolic tumor volume (MTV) (3.19 (95%CI: 2.36-4.30)), maximum standardized uptake value (SUVmax) (3.25 (95%CI: 2.08-5.08)), and Deauville score (DS) (3.73 (95%CI: 2.50-5.56)), respectively. These measurements for overall survival (OS) were MTV (4.39 (95%CI: 2.71-7.08)), DS (3.23 (95%CI: 1.87-5.58)), and DS (3.64 (95%CI: 1.40-9.43)), respectively. Early and late 18F-FDG PET/CT response assessment in immune checkpoint inhibitors (ICI) and immune cell therapy might be an effective tool for prediction of clinical outcome. CONCLUSION: For anti-CD20 therapy of lymphoma, the MTV as a baseline 18F-FDG PET/CT-derived parameter has the highest HRs for PFS and OS. The DS as visual criteria in early and late response assessment has higher HRs for PFS and OS compared to the international harmonization project (IHP) visual criteria in anti-CD20 therapy. Early changes in 18F-FDG PET parameters may be predictive of response to ICIs and cell therapy in lymphoma patients.

Monte Carlo calculated calibration settings for commercially available nuclear medicine ionization chambers.

PURPOSE: A method for calculating nuclear medicine ionization chamber (NMIC) calibration settings with a Monte Carlo model is presented and validated against physical measurements. This work provides Monte Carlo-calculated calibration settings for select isotopes with no current manufacturer recommendations and a method by which NMIC manufacturers or standards laboratories can utilize highly detailed specifications to calculate comprehensive lists of calibration settings for general isotopes. METHODS: A Monte Carlo model of a Capintec PET series NMIC was developed and used to calculate the chamber response to relevant radioactive decay products over an energy range relevant to nuclear medicine. The photon detection efficiency (PDE) of a high purity germanium (HPGe) detector was modeled and physically validated to facilitate measurements of NMIC calibration settings with HPGe detector spectroscopy. Modeled NMIC response to various isotopes was compared against spectroscopic measurements and National Institute of Standards and Technology (NIST)-validated calibration settings to validate the Monte Carlo-calculated NMIC calibration settings. RESULTS: HPGe detector PDE was validated against the physical measurements to within 3.3 % $3.3\%$ at 95 % $95\%$ confidence and used to measure calibration settings, which produced activity readings 0.7 % $0.7\%$ , 1.6 % $1.6\%$ , 0.8 % $0.8\%$ , and 1.0 % $1.0\%$ different than those validated by NIST for 11 $^{11}$ C, 18 $^{18}$ F, 68 $^{68}$ Ga, and 64 $^{64}$ Cu respectively. The Monte Carlo model of the NMIC reproduced measured calibration settings to within 7 % $7\%$ at 95 % $95\%$ confidence for isotopes with a sufficiently small yield of low energy photons. CONCLUSIONS: A method of calculating NMIC calibration settings with Monte Carlo modeling has been developed and validated against HPGe detector spectroscopy. NMIC manufacturers or standards laboratories can use more detailed specifications of the chamber geometries to extend the applicability of this method to a wider range of isotopes.

Automated processing of solid target 86Y using enriched SrO powder.

86Y (t1/2 = 14.74 h, 32% ß+) has significant potential in theranostic applications as a simultaneous PET imaging partner to 90Y-labelled antibody therapy. However, the complex and costly nature of producing 86Y has led to this radiometal being difficult for hospitals and researchers to obtain. The aim of this work was to develop a simple and cost-efficient method for safely producing 86Y. Our approach was twofold: to develop a method of target preparation that would significantly increase the cost efficiency of producing 86Y, and to design and construct an automated purification system that would eliminate manual radiation handling risks and exposure. Multiple automated productions of high radionuclidic purity (99.45%) 86Y were performed resulting in saturation yields of between 518 MBq/µA and 1332 MBq/µA, dependent on target thickness.

Assessment of cellular and molecular metrics for dose selection in an in vivo comet assay: A case study with MDI.

The in vivo comet assay can evaluate the genotoxic potential of a chemical in theoretically any tissue that can be processed to a single cell suspension. This flexibility enables evaluation of point-of-contact tissues using a relevant route of test material administration; however, assessing cytotoxicity is essential for the interpretation of comet results. Histopathological evaluation is routinely utilized to assess cytotoxicity, but temporal- and cell-specific considerations may compromise applicability to the comet assay. In the present study, 1,1'-methylenebis(4-isocyanatobenzene) (4,4'-MDI) was administered to rats for 6 h by nose-only inhalation, and the comet assay was conducted to evaluate genotoxicity in the site-of-contact tissue (bronchoalveolar lavage cells) and distal tissues (liver and glandular stomach). Given the reactive nature of MDI, cellular and molecular metrics at the site-of-contact- including inflammation, macrophage activation, apoptosis/necrosis, and oxidative stress- were used to set appropriate exposure concentrations, in addition to the standard systemic measures of toxicity. In the range-finding study, a concentration of 4 mg/m3 was considered the maximum noninflammatory concentration; hence target concentrations of 2, 5, and 11 mg/m3 were selected for the comet study. In the lung lavage, MDI exposure substantially increased total protein and ß-glucuronidase, along with cellular apoptosis. Although MDI did not increase the comet assay response (% tail DNA) in any of the tissues examined, the positive control (ethyl methanesulfonate, EMS) significantly increased % tail DNA in all tissues. In total, these data indicate that appropriate cellular and molecular measurements may facilitate dose selection to discern cellular status in the comet assay.

Equitable Access to Liver Transplant: Bridging the Gaps in the Social Determinants of Health.

The COVID-19 pandemic and social justice movement have highlighted the impact of social determinants of health (SDOH) and structural racism in the United States on both access to care and patient outcomes. With the evaluation for liver transplantation being a highly subjective process, there are multiple ways for SDOH to place vulnerable patients at a disadvantage. This policy corner focuses on three different methods to reverse the deleterious effects of SDOH-identify and reduce implicit bias, expand and optimize telemedicine, and improve community outreach.

Medical imaging and nuclear medicine: a Lancet Oncology Commission.

The diagnosis and treatment of patients with cancer requires access to imaging to ensure accurate management decisions and optimal outcomes. Our global assessment of imaging and nuclear medicine resources identified substantial shortages in equipment and workforce, particularly in low-income and middle-income countries (LMICs). A microsimulation model of 11 cancers showed that the scale-up of imaging would avert 3·2% (2·46 million) of all 76·0 million deaths caused by the modelled cancers worldwide between 2020 and 2030, saving 54·92 million life-years. A comprehensive scale-up of imaging, treatment, and care quality would avert 9·55 million (12·5%) of all cancer deaths caused by the modelled cancers worldwide, saving 232·30 million life-years. Scale-up of imaging would cost US$6·84 billion in 2020-30 but yield lifetime productivity gains of $1·23 trillion worldwide, a net return of $179·19 per $1 invested. Combining the scale-up of imaging, treatment, and quality of care would provide a net benefit of $2·66 trillion and a net return of $12·43 per $1 invested. With the use of a conservative approach regarding human capital, the scale-up of imaging alone would provide a net benefit of $209·46 billion and net return of $31·61 per $1 invested. With comprehensive scale-up, the worldwide net benefit using the human capital approach is $340·42 billion and the return per dollar invested is $2·46. These improved health and economic outcomes hold true across all geographical regions. We propose actions and investments that would enhance access to imaging equipment, workforce capacity, digital technology, radiopharmaceuticals, and research and training programmes in LMICs, to produce massive health and economic benefits and reduce the burden of cancer globally.

Global costs, health benefits, and economic benefits of scaling up treatment and imaging modalities for survival of 11 cancers: a simulation-based analysis.

BACKGROUND: In addition to increased availability of treatment modalities, advanced imaging modalities are increasingly recommended to improve global cancer care. However, estimates of the costs and benefits of investments to improve cancer survival are scarce, especially for low-income and middle-income countries (LMICs). In this analysis, we aimed to estimate the costs and lifetime health and economic benefits of scaling up imaging and treatment modality packages on cancer survival, both globally and by country income group. METHODS: Using a previously developed model of global cancer survival, we estimated stage-specific cancer survival and life-years gained (accounting for competing mortality) in 200 countries and territories for patients diagnosed with one of 11 cancers (oesophagus, stomach, colon, rectum, anus, liver, pancreas, lung, breast, cervix uteri, and prostate) representing 60% of all cancer diagnoses between 2020 and 2030 (inclusive of full years). We evaluated the costs and health and economic benefits of scaling up packages of treatment (chemotherapy, surgery, radiotherapy, and targeted therapy), imaging modalities (ultrasound, x-ray, CT, MRI, PET, single-photon emission CT), and quality of care to the mean level of high-income countries, separately and in combination, compared with no scale-up. Costs and benefits are presented in 2018 US$ and discounted at 3% annually. FINDINGS: For the 11 cancers studied, we estimated that without scale-up (ie, with current availability of treatment, imaging, and quality of care) there will be 76·0 million cancer deaths (95% UI 73·9-78·6) globally for patients diagnosed between 2020 and 2030, with more than 70% of these deaths occurring in LMICs. Comprehensive scale-up of treatment, imaging, and quality of care could avert 12·5% (95% UI 9·0-16·3) of these deaths globally, ranging from 2·8% (1·8-4·3) in high-income countries to 38·2% (32·6-44·5) in low-income countries. Globally, we estimate that comprehensive scale-up would cost an additional $232·9 billion (95% UI 85·9-422·0) between 2020 and 2030 (representing a 6·9% increase in cancer treatment costs), but produce $2·9 trillion (1·8-4·0) in lifetime economic benefits, yielding a return of $12·43 (6·47-33·23) per dollar invested. Scaling up treatment and quality of care without imaging would yield a return of $6·15 (2·66-16·71) per dollar invested and avert 7·0% (3·9-10·3) of cancer deaths worldwide. INTERPRETATION: Simultaneous investment in cancer treatment, imaging, and quality of care could yield substantial health and economic benefits, especially in LMICs. These results provide a compelling rationale for the value of investing in the global scale-up of cancer care. FUNDING: Harvard TH Chan School of Public Health and National Cancer Institute.

The longevity society.

As the demographic transition enters a new stage of a longevity transition, focus needs to extend beyond an ageing society towards a longevity society. An ageing society focuses on changes in the age structure of the population, whereas a longevity society seeks to exploit the advantages of longer lives through changes in how we age. Achieving a longevity society requires substantial changes in the life course and social norms, and involves an epidemiological transition towards a focus on delaying the negative effects of ageing. The broad changes required to achieve healthy longevity include an increased focus on healthy life expectancy, a shift from intervention towards preventive health, a major public health agenda to avoid increases in health inequality, the establishment of longevity councils to ensure coordinated policy across government departments, and intergenerational assessment of policies, to ensure that in adapting to longer lives, policies are not skewed towards older people. A longevity society represents a new stage for humanity and requires deep-seated notions about age and ageing to be challenged if society is to make the best use of the additional time that longevity brings.

The longevity economy.

The fact that people are on average living healthier, longer lives than previously has the potential to be positive for the economy, offsetting the negative economic effects of an ageing society. A longevity economy will see a shift in the mix of sectors in the economy, with both health and education expanding further and new financial products arising. Such an economy has the potential to contribute to growth in gross domestic product through employment and human capital. Shifting to a longevity economy requires less reliance on policies stated purely in terms of age, and more extension of existing policies aimed at diverse needs and circumstances to older age groups. This shift will be needed to counter inequality within age groups. A life course perspective is also required, to ensure a focus on intergenerational equity and a better understanding of the needs of older individuals that are not health driven.

The economic value of targeting aging.

Developments in life expectancy and the growing emphasis on biological and 'healthy' aging raise a number of important questions for health scientists and economists alike. Is it preferable to make lives healthier by compressing morbidity, or longer by extending life? What are the gains from targeting aging itself compared to efforts to eradicate specific diseases? Here we analyze existing data to evaluate the economic value of increases in life expectancy, improvements in health and treatments that target aging. We show that a compression of morbidity that improves health is more valuable than further increases in life expectancy, and that targeting aging offers potentially larger economic gains than eradicating individual diseases. We show that a slowdown in aging that increases life expectancy by 1 year is worth US$38 trillion, and by 10 years, US$367 trillion. Ultimately, the more progress that is made in improving how we age, the greater the value of further improvements.

Response Evaluation and Survival Prediction After PD-1 Immunotherapy in Patients with Non-Small Cell Lung Cancer: Comparison of Assessment Methods.

Immunotherapy using programmed death-1 blockers is a promising modality for non-small cell lung cancer (NSCLC). Therefore, defining the most accurate response criteria for immunotherapy monitoring is of great importance in patient management. This study aimed to compare the correlation between survival outcome and response assessment by PERCIST, version 1.0; immunotherapy-modified PERCIST (imPERCIST); RECIST, version 1.1; and immunotherapy-modified RECIST (iRECIST) in NSCLC patients. Methods: Seventy-two patients with NSCLC who were treated with nivolumab or pembrolizumab and had baseline and follow-up 18F-FDG PET/CT data were analyzed. The patients were categorized into responders (complete or partial response) and nonresponders (stable or progressive disease) according to PERCIST1 and PERCIST5 (analyzing the peak SUV normalized by lean body mass [SULpeak] of 1 or up to 5 lesions), imPERCIST1, imPERCIST5, RECIST, and iRECIST. The correlation between achieved response and overall survival (OS) was compared. Results: The overall response rate and the overall disease control rate of the study population were 29% and 74%, respectively. The OS and progression-free survival (PFS) of patients with complete and partial response were statistically comparable. The OS and PFS were significantly different between responders and nonresponders (20.3 vs. 10.6 mo, P = 0.001, for OS and 15.5 vs. 2.2 mo, P < 0.001, for PFS, respectively). Twenty-three (32%) patients with progressive disease according to PERCIST5 had controlled disease according to imPERCIST5; follow-up of patients showed that 22% of these patients had pseudoprogression. The overall incidence of pseudoprogression was 7%. The response rate was 25% and 24% according to PERCIST1 and PERCIST5 (P = 0.2) and 32% and 29% according to imPERCIST1 and imPERCIST5 (P = 0.5), respectively, indicating no significant difference between analyzing the SULpeak of only the most 18F-FDG-avid lesion and analyzing up to the 5 most 18F-FDG-avid lesions. Conclusion: The achieved response by all conventional and immunotherapy-modified methods correlated strongly with patients' survival outcome, with significantly longer OS and PFS in responders than in nonresponders according to all assessed definitions. The most 18F-FDG-avid lesion according to PERCIST and imPERCIST accurately reflects the overall metabolic response.

Genome-wide assessment of antimicrobial tolerance in Yersinia pseudotuberculosis under ciprofloxacin stress.

Yersinia pseudotuberculosis is a Gram-negative bacterium capable of causing gastrointestinal infection and is closely related to the highly virulent plague bacillus Yersinia pestis. Infections by both species are currently treatable with antibiotics such as ciprofloxacin, a quinolone-class drug of major clinical importance in the treatment of many other infections. Our current understanding of the mechanism of action of ciprofloxacin is that it inhibits DNA replication by targeting DNA gyrase, and that resistance is primarily due to mutation of this target site, along with generic efflux and detoxification strategies. We utilized transposon-directed insertion site sequencing (TraDIS or TnSeq) to identify the non-essential chromosomal genes in Y. pseudotuberculosis that are required to tolerate sub-lethal concentrations of ciprofloxacin in vitro. As well as highlighting recognized antibiotic resistance genes, we provide evidence that multiple genes involved in regulating DNA replication and repair are central in enabling Y. pseudotuberculosis to tolerate the antibiotic, including DksA (yptb0734), a regulator of RNA polymerase, and Hda (yptb2792), an inhibitor of DNA replication initiation. We furthermore demonstrate that even at sub-lethal concentrations, ciprofloxacin causes severe cell-wall stress, requiring lipopolysaccharide lipid A, O-antigen and core biosynthesis genes to resist the sub-lethal effects of the antibiotic. It is evident that coping with the consequence(s) of antibiotic-induced stress requires the contribution of scores of genes that are not exclusively engaged in drug resistance.

Assessment of Simplified Methods for Quantification of 18F-FDHT Uptake in Patients with Metastatic Castration-Resistant Prostate Cancer.

18F-fluorodihydrotestosterone (18F-FDHT) PET/CT potentially provides a noninvasive method for assessment of androgen receptor expression in patients with metastatic castration-resistant prostate cancer (mCRPC). The objective of this study was to assess simplified methods for quantifying 18F-FDHT uptake in mCRPC patients and to assess effects of tumor perfusion on these 18F-FDHT uptake metrics. Methods: Seventeen mCRPC patients were included in this prospective observational multicenter study. Test and retest 30-min dynamic 18F-FDHT PET/CT scans with venous blood sampling were performed in 14 patients. In addition, arterial blood sampling and dynamic 15O-H2O scans were obtained in a subset of 6 patients. Several simplified methods were assessed: Patlak plots; SUV normalized to body weight (SUVBW), lean body mass (SUVLBM), whole blood (SUVWB), parent plasma activity concentration (SUVPP), area under the parent plasma curve (SUVAUC,PP), and area under the whole-blood input curve (SUVAUC,WB); and SUVBW corrected for sex hormone-binding globulin levels (SUVSHBG). Results were correlated with parameters derived from full pharmacokinetic 18F-FDHT and 15O-H2O. Finally, the repeatability of individual quantitative uptake metrics was assessed. Results: Eighty-seven 18F-FDHT-avid lesions were evaluated. 18F-FDHT uptake was best described by an irreversible 2-tissue-compartment model. Replacing the continuous metabolite-corrected arterial plasma input function with an image-derived input function in combination with venous sample data provided similar Ki results (R2 = 0.98). Patlak Ki and SUVAUC,PP showed an excellent correlation (R2 > 0.9). SUVBW showed a moderate correlation to Ki (R2 = 0.70, presumably due to fast 18F-FDHT metabolism. When calculating SUVSHBG, correlation to Ki improved (R2 = 0.88). The repeatability of full kinetic modeling parameters was inferior to that of simplified methods (repeatability coefficients > 36% vs. < 28%, respectively). 18F-FDHT uptake showed minimal blood flow dependency. Conclusion:18F-FDHT kinetics in mCRPC patients are best described by an irreversible 2-tissue-compartment model with blood volume parameter. SUVAUC,PP showed a near-perfect correlation with the irreversible 2-tissue-compartment model analysis and can be used for accurate quantification of 18F-FDHT uptake in whole-body PET/CT scans. In addition, SUVSHBG could potentially be used as an even simpler method to quantify 18F-FDHT uptake when less complex scanning protocols and accuracy are required.

Multicenter Interrater Reliability in the Endoscopic Assessment of Velopharyngeal Function Using a Video Instruction Tool.

OBJECTIVE: Assess interrater agreement of endoscopic assessment of velopharyngeal (VP) function before and after viewing the video instruction tool (VIT). We hypothesized improvement in interrater agreement using the Golding-Kushner scale (GKS) after viewing the VIT. STUDY DESIGN: Prospective study. SETTING: Multi-institutional. METHODS: Sixteen fellowship-trained pediatric otolaryngologists who treat velopharyngeal insufficiency (VPI) rated 50 video segments using the GKS before and after watching the VIT. Raters assessed gap size percentage and lateral pharyngeal wall (LPW), soft palate (SP), and posterior pharyngeal wall (PPW) movement. Intraclass correlation coefficient was estimated for these continuous measures. Raters also indicated the presence of a palatal notch, Passavant's ridge, and aberrant pulsations (categorical variables). Fleiss κ coefficient was used for categorical variables. Wilcoxon signed-rank test was performed on the difference between the pre/post individual video ratings. RESULTS: Reliability improved for all continuous variables after watching the instructional video. The improvement was significant for PPW (0.22-0.30, P < .001), SP (left: 0.63-0.68, P < .001 and right: 0.64-0.68, P = .001), and LPW (left: 0.49-0.54, P = .01 and right: 0.49-0.54, P = .09) but not significant for gap size (0.65-0.69, P = .36). Among categorical variables, agreement on Passavant's ridge significantly improved (0.30-0.36, P = .03). CONCLUSION: Exposure to a video instruction tool improves interrater agreement of endoscopic assessment of VP function. Significant improvement was observed in our primary end points, specifically posterior pharyngeal wall movement, soft palate movement, and lateral pharyngeal wall movement. There was less impact of the VIT on the interrater agreement of the categorical variables, palatal notch, Passavant's ridge, and aberrant pulsations.