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Background: Approximately 30%-45% of patients with nondialysis CKD have iron deficiency. Iron therapy in CKD has focused primarily on supporting erythropoiesis. In patients with or without anemia, there has not been a comprehensive approach to estimating the association between serum biomarkers of iron stores, and mortality and cardiovascular event risks., Methods: The study included 5145 patients from Brazil, France, the United States, and Germany enrolled in the Chronic Kidney Disease Outcomes and Practice Patterns Study, with first available transferrin saturation (TSAT) and ferritin levels as exposure variables. We used Cox models to estimate hazard ratios (HRs) for all-cause mortality and major adverse cardiovascular events (MACE), with progressive adjustment for potentially confounding variables. We also used linear spline models to further evaluate functional forms of the exposure-outcome associations., Results: Compared with patients with a TSAT of 26%-35%, those with a TSAT ≤15% had the highest adjusted risks for all-cause mortality and MACE. Spline analysis found the lowest risk at TSAT 40% for all-cause mortality and MACE. Risk of all-cause mortality, but not MACE, was also elevated at TSAT ≥46%. Effect estimates were similar after adjustment for hemoglobin. For ferritin, no directional associations were apparent, except for elevated all-cause mortality at ferritin ≥300 ng/ml., Conclusions: Iron deficiency, as captured by TSAT, is associated with higher risk of all-cause mortality and MACE in patients with nondialysis CKD, with or without anemia. Interventional studies evaluating the effect on clinical outcomes of iron supplementation and therapies for alternative targets are needed to better inform strategies for administering exogenous iron., (Copyright © 2021 by the American Society of Nephrology.)

Purpose: The heart has been identified as a potential significant organ at risk in patients with locally advanced non-small cell lung cancer treated with radiation. Practice patterns and radiation dose delivered to the heart in routine practice in academic and community settings are unknown., Methods and Materials: Between 2012 and 2017, 746 patients with stage III non-small cell lung cancer were treated with radiation within the statewide Michigan Radiation Oncology Quality Consortium (MROQC). Cardiac radiation dose was characterized, including mean and those exceeding historical or recently proposed Radiation Therapy Oncology Group and NRG Oncology constraints. Sites were surveyed to determine dose constraints used in practice. Patient-, anatomic-, and treatment-related associations with cardiac dose were analyzed using multivariable regression analysis and inverse probability weighting., Results: Thirty-eight percent of patients had a left-sided primary, and 80% had N2 or N3 disease. Median prescription was 60 Gy (interquartile range, 60-66 Gy). Twenty-two percent of patients were prescribed 60 Gy in 2012, which increased to 62% by 2017 (P < .001). Median mean heart dose was 12 Gy (interquartile range, 5-19 Gy). The volume receiving 30 Gy (V30 Gy) exceeded 50% in 5% of patients, and V40 Gy was >35% in 3% of cases. No heart dose constraint was uniformly applied. Intensity modulated radiation therapy (IMRT) usage increased from 33% in 2012 to 86% in 2017 (P < .001) and was significantly associated with more complex cases (larger planning target volume, higher stage, and preexisting cardiac disease). In multivariable regression analysis, IMRT was associated with a lower percent of the heart receiving V30 Gy (absolute reduction = 3.0%; 95% confidence interval, 0.5%-5.4%) and V50 Gy (absolute reduction = 3.6%; 95% confidence interval, 2.4%-4.8%) but not mean dose. In inverse probability weighting analysis, IMRT was associated with 29% to 48% relative reduction in percent of the heart receiving V40-V60 Gy without increasing lung or esophageal dose or compromising planning target volume coverage., Conclusions: Within MROQC, historical cardiac constraints were met in most cases, yet 1 in 4 patients received a mean heart dose exceeding 20 Gy. Future work is required to standardize heart dose constraints and to develop treatment approaches that allow for constraints to be met without compromising other planning goals., (Copyright © 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background/Aims The goal of phase I clinical trials for cytotoxic agents is to find the maximum dose with an acceptable risk of severe toxicity. The most common designs for these dose-finding trials use a binary outcome indicating whether a patient had a dose-limiting toxicity. However, a patient may experience multiple toxicities, with each toxicity assigned an ordinal severity score. The binary response is then obtained by dichotomizing a patient's richer set of data. We contribute to the growing literature on new models to exploit this richer toxicity data, with the goal of improving the efficiency in estimating the maximum tolerated dose. Methods We develop three new, related models that make use of the total number of dose-limiting and low-level toxicities a patient experiences. We use these models to estimate the probability of having at least one dose-limiting toxicity as a function of dose. In a simulation study, we evaluate how often our models select the true maximum tolerated dose, and we compare our models with the continual reassessment method, which uses binary data. Results Across a variety of simulation settings, we find that our models compare well against the continual reassessment method in terms of selecting the true optimal dose. In particular, one of our models which uses dose-limiting and low-level toxicity counts beats or ties the other models, including the continual reassessment method, in all scenarios except the one in which the true optimal dose is the highest dose available. We also find that our models, when not selecting the true optimal dose, tend to err by picking lower, safer doses, while the continual reassessment method errs more toward toxic doses. Conclusion Using dose-limiting and low-level toxicity counts, which are easily obtained from data already routinely collected, is a promising way to improve the efficiency in finding the true maximum tolerated dose in phase I trials.

Purpose: This study aimed to analyze the potential clinical impact of the differences between planned and accumulated doses on the development and use of normal tissue complication probability (NTCP) models., Methods and Materials: Thirty patients who were previously treated with stereotactic body radiation therapy for liver cancer and for whom the accumulated dose was computed were assessed retrospectively. The linear quadratic equivalent dose at 2 Gy per fraction and generalized equivalent uniform dose were calculated for planned and accumulated doses. Stomach and duodenal Lyman-Kutcher-Burman NTCP models (α/β = 2.5; n = .09) were developed on the basis of planned and accumulated generalized equivalent uniform doses and the differences between the models assessed. In addition, the error in determining the probability of toxicity on the basis of the planned dose was evaluated by comparing planned doses in the NTCP model that were created from accumulated doses., Results: The standard, planned-dose NTCP model overestimates toxicity risk for both the duodenal and stomach models at doses that are below approximately 20 Gy (6 fractions) and underestimates toxicity risk for doses above approximately 20 Gy (6 fractions). Building NTCP models with accumulated rather than planned doses changes the predicted risk by up to 16% (mean: 6%; standard deviation: 7%) for duodenal toxicity and 6% (mean: 2%; standard deviation: 2%) for stomach toxicity. For a protocol that plans a 10% iso-toxicity risk to the duodenum, a 15.7 Gy (6 fractions) maximum dose constraint would be necessary when using standard NTCP models on the basis of a planned dose and a 17.6 Gy (6 fractions) maximum dose would be allowed when using NTCP models on the basis of accumulated doses., Conclusions: Assuming that accumulated dose is a more accurate representation of the true delivered dose than the planned dose, this simulation study indicates the need for prospective clinical trials to evaluate the impact of building NTCP models on the basis of accumulated doses.

Purpose: Investigate the impact on prostate orientation caused by use and removal of a Foley catheter, and the dosimetric impact on men prospectively treated with prostate stereotactic body radiotherapy (SBRT)., Methods: Twenty-two men underwent a CT simulation with a Foley in place (FCT), followed immediately by a second treatment planning simulation without the Foley (TPCT). The change in prostate orientation was determined by rigid registration of three implanted transponders between FCT and TPCT and compared to measured orientation changes during treatment. The impact on treatment planning and delivery was investigated by analyzing the measured rotations during treatment relative to both CT scans, and introducing rotations of ±15° in the treatment plan to determine the maximum impact of allowed rotations., Results: Removing the Foley caused a statistically significant prostate rotation (P < 0.0028) compared to normal biological motion in 60% of patients. The largest change in rotation due to removing a Foley occurs about the left-right axis (tilt) which has a standard deviation two to five times larger than changes in rotation about the Sup-Inf (roll) and Ant-Post (yaw) axes. The change in tilt due to removing a Foley for prone and supine patients was -1.1° ± 6.0° and 0.3° ± 7.4°, showing no strong directional bias. The average tilt during treatment was -1.6° ± 7.1° compared to the TPCT and would have been -2.0° ± 7.1° had the FCT been used as the reference. The TPCT was a better or equivalent representation of prostate tilt in 82% of patients, vs 50% had the FCT been used for treatment planning. However, 92.7% of fractions would still have been within the ±15° rotation limit if only the FCT were used for treatment planning. When rotated ±15°, urethra V 105% = 38.85Gy  < 20% was exceeded in 27% of the instances, and prostate (CTV) coverage was maintained above D 95%  > 37 Gy in all but one instance., Conclusions: Removing a Foley catheter can cause large prostate rotations. There does not appear to be a clear dosimetric benefit to obtaining the CT scan with a Foley catheter to define the urethra given the changes in urethral position from removing the Foley catheter. If urethral sparing is desired without the use of a Foley, utilization of an MRI to define the urethra may be necessary, or a pseudo-urethral planning organ at risk volume (PRV) may be used to limit dosimetric hot spots., (© 2018 American Association of Physicists in Medicine.)

Objectives/hypothesis: The aim of this study was to determine if drug-induced sleep endoscopy (DISE) was predictive of success for patients undergoing transoral robotic surgery (TORS) and multilevel procedures for sleep apnea., Study Design: Retrospective case series of patients who underwent TORS surgery for sleep apnea METHODS: Before and after polysomnograms were analyzed to assess improvement, success, and cure. Improvement was defined as any decrease in apnea-hypopnea index (AHI), success as an AHI <20 with a decrease >50%, and cure as an AHI <5. DISE videos were scored using the NOHL (nose, oropharynx, hypopharynx, larynx) and VOTE (velum, oropharynx, tongue, epiglottis) classification systems., Results: One hundred one patients were available for analysis. Eighty-seven percent of patients had an improvement in their AHI. Fifty-one percent met criteria for success, whereas 17% were cured. The degree of collapse at individual NOHL and VOTE subsites as well as total additive scores did not predict improvement, success, or cure. Patients with no oropharyngeal lateral collapse in the VOTE classification system were more likely to improve following surgery (P = .001); however, this effect did not hold for success or cure. Multivariate analysis of DISE variables was not predictive of success., Conclusions: In obstructive sleep apnea patients, there is a 51% success rate and a 17% cure rate. DISE, as scored by the NOHL and VOTE system, did not readily identify patients who would benefit most from surgery. Patients with lateral oropharyngeal collapse may be poorer candidates. Prospective, larger studies are required to further evaluate the use of DISE in predicting success following TORS., Level of Evidence: 4 Laryngoscope, 127:971-976, 2017., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: To determine biomarkers of recurrence and survival in patients with spindle cell variant squamous cell carcinoma (SpSCC) of the head and neck., Study Design: Retrospective case control study., Setting: Tertiary academic center., Subjects and Methods: Thirty-two SpSCC patients (mean age, 68.8) between 1987 and 2009 were identified and reviewed. A tissue microarray (TMA) was constructed from tumor specimens. Tumor biomarkers under study included p16, epidermal growth factor receptor (EGFR), p53, EZH2, cyclin D1, CD104, HGFa, p21, and cMET. An additional TMA was constructed from patients with non-SpSCC oral cavity squamous cell carcinoma for comparative purposes. The main outcomes were overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS)., Results: In the SpSCC cohort, tumors positive for cMet had worse OS (P < .001). Patients positive for cMet (P = .007), cyclin D1 (P = .019), and p16 (P = .004) had worse DSS. Recurrence-free survival was also worse in patients with tumors positive for cMet (P = .037), cyclin D1 (P = .012), and p16 (P < .001). Compared with the oral cavity cohort, there was a significantly larger proportion of patients in the SpSCC group with tumors staining positive for cMet and a lower proportion of tumors positive for cyclin D1., Conclusion: cMet, cyclin D1, and p16 are predictive tumor biomarkers for risk of recurrence and worse DSS in patients with SpSCC., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.)

Background: Recent data show patients with advanced colorectal cancer (CRC) are surviving longer. What is unknown is how specific treatment modalities affect long-term survival. Conditional survival, or survival prognosis based on time already survived, is becoming an acceptable means of estimating prognosis for long-term survivors. We evaluated the impact of cancer-directed surgery on long-term survival in patients with advanced CRC., Methods: We used Surveillance, Epidemiology, and End Results data to identify 64,956 patients with advanced (Stage IV) CRC diagnosed from 2000-2009. Conditional survival estimates by stage, age, and cancer-directed surgery were obtained based on Cox proportional hazards regression model of disease-specific survival., Results: A total of 64,956 (20.1%) patients had advanced disease at the time of diagnosis. The proportion of those patients who underwent cancer-directed surgery was 65.1% (n = 42,176). Cancer-directed surgery for patients with advanced stage disease was associated with a significant improvement in traditional survival estimates compared to patients who did not undergo surgery (hazard ratio = 2.22 [95% confidence interval, 2.17-2.27]). Conditional survival estimates show improvement in conditional 5-y disease-specific survival across all age groups, demonstrating sustained survival benefits for selected patients with advanced CRC., Conclusions: Five-year disease-specific conditional survival improves dramatically over time for selected patients with advanced CRC who undergo cancer-directed surgery. This information is important in determining long-term prognosis and will help inform treatment planning for advanced CRC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Overall cancer incidence is decreasing, whereas melanoma cases are increasing. Conditional survival estimates offer a more accurate prognosis for patients the farther they are from time of diagnosis. The effect of age and stage on a melanoma patient's conditional survival estimate is unknown. Surveillance, Epidemiology, and End Results data were utilized to identify newly diagnosed cutaneous melanoma patients (N=95 041), from 1998 to 2005, with up to 12 years of follow-up. Estimates of disease-specific survival by stage and age were determined by Cox regression analysis and transformed to estimated conditional 5-year survival. Localized melanoma patients have an excellent 5-year survival at diagnosis and over subsequent years. For patients with localized and regional disease, an age effect is present for disease-specific mortality when comparing older patients (70-79 years) with younger patients (<30 years): hazard ratio (HR) for mortality 3.79 [95% confidence interval (CI) 3.01-4.84] and HR 2.36 (95% CI 1.93-2.91), respectively. No age effect difference is observed in disease-specific survival for advanced disease: HR 1.14 (95% CI 0.87-1.53). Over time, conditional survival estimates improve for older patients with localized and regional disease. This improvement is not seen in distant disease, neither is the age gradient. Disease-specific mortality and conditional survival for patients with localized and regional melanomas are initially impacted by older age, with effects dissipating over time. Age does not affect survival in patients with advanced disease. Understanding the conditional 5-year disease-specific survival of melanoma based on age and stage can help patients and physicians, informing decision-making about treatment and surveillance., Competing Interests: The authors have no conflict of interest to disclose.

Background: The largest growth noted among differentiated thyroid cancer (DTC) diagnosis is in low-risk cancers. Trends in imaging after the diagnosis of DTC are understudied. Hypothesizing a reduction in imaging use due to rising low-risk disease, the authors evaluated postdiagnosis imaging patterns over time and patient characteristics that are associated with the likelihood of imaging., Methods: Using the Surveillance, Epidemiology, and End Results-Medicare database, the authors identified patients diagnosed with localized, regional, or distant DTC between 1991 and 2009. Medicare claims were reviewed for use of neck ultrasound, iodine-131 (I-131) scan, or positron emission tomography (PET) scan within 3 years after diagnosis. Trends in imaging use were evaluated using regression analyses. Multivariable logistic regression was used to estimate the likelihood of imaging based on patient characteristics., Results: A total of 23,669 patients were included. Compared with patients diagnosed between 1991 and 2000, those diagnosed between 2001 and 2009 were more likely to have localized disease (P<.001) and tumors measuring <1 cm (P<.001). Use of neck ultrasound and I-131 scans increased in patients with localized disease (P ≤.001 and P = .003, respectively), regional disease (P<.001 and P<.001, respectively), and distant metastasis (P = .001 and P = .015, respectively). Patients diagnosed after 2000 were more likely to undergo neck ultrasound (odds ratio, 2.15; 95% confidence interval, 2.02-2.28) and I-131 scan (odds ratio, 1.44; 95% confidence interval, 1.35-1.54). Compared with 1996 through 2004, PET scan use from 2005 to 2009 increased 32.4-fold (P≤.001) in patients with localized disease, 13.1-fold (P<.001) in patients with regional disease, and 33.4-fold (P<.001) in patients with distant DTC., Conclusions: Despite an increase in the diagnosis of low-risk disease, the use of postdiagnosis imaging increased among patients with all stages of disease. The largest growth observed was in the use of PET after 2004., (© 2015 American Cancer Society.)

Background: Thyroid cancer is an increasingly common malignancy. Although likelihood of survival from well-differentiated thyroid cancer can vary by disease severity, it is not known how patients' life expectancies change the farther they are from time of diagnosis., Methods: Using data from the Surveillance, Epidemiology, End Results (SEER) registry, we selected patients diagnosed with well-differentiated thyroid cancer (N=43,392) between 1998 and 2005. Patients were followed for up to 12 years. Conditional survival estimates by SEER stage and age were obtained based on Cox proportional hazards regression model of disease-specific survival., Results: Patients with localized thyroid cancer have excellent conditional 5-year survival, irrespective of where they are in their survivorship phase. Patients with regional thyroid cancer have relatively stable conditional 5-year survival, whereas for patients with distant thyroid cancer there is gradual improvement the farther from time of diagnosis. Age and gender influence conditional survival. Similarly, age has a strong effect on disease-specific survival for patients with thyroid cancer with localized (hazard ratio [HR] 88.7 [95% confidence interval {CI} 26.3-552), comparing age ≥80 with <30 years), regional (HR 105 [95% CI 52.6-250]), and distant disease [HR 86.8 (95% CI 32.5-354)]. Male gender is also associated with a significantly worse disease-specific survival among patients with regional disease (HR 1.56 [95% CI 1.31-1.85]) but not among patients with localized or distant disease., Conclusion: Cancer stage, gender, age at diagnosis, and length of time already survived can influence conditional survival for patients with thyroid cancer. Understanding the conditional 5-year disease-specific survival of well-differentiated thyroid cancer is key to creating treatment plans and tailoring surveillance.

Background: Death is uncommon in thyroid cancer patients, and the factors important in predicting survival remain inadequately studied. The objective of this study was to assess prognostic effects of patient, tumor, and treatment factors and to determine prognostic groups for thyroid cancer survival., Methods: Using data from the Surveillance, Epidemiology, and End Results Program (SEER), we evaluated overall and disease-specific survival (DSS) in 43 392 well-differentiated thyroid cancer patients diagnosed from 1998 through 2005. Multivariable analyses were performed using Cox proportional hazards regression, survival trees, and random survival forest. Similar analyses were performed using National Cancer Data Base data, with overall survival (OS) evaluated in 131 484 thyroid cancer patients diagnosed from 1998 through 2005. Relative importance of factors important to survival was assessed based on the random survival forest analyses., Results: Using survival tree analyses, we identified 4 distinct prognostic groups based on DSS (P < .0001). The 5-year DSS of these prognostic groups was 100%, 98%, 91%, 64%, whereas the 10-year survival was 100%, 96%, 85%, and 50%. Based on random survival forest analyses, the most important factors for DSS were SEER stage and age at diagnosis. For OS, important prognostic factors were similar, except age at diagnosis demonstrated marked importance relative to SEER stage. Similar results for OS were found using National Cancer Data Base data., Conclusion: This study identifies distinct prognostic groups for thyroid cancer and illustrates the importance of patient age to both disease-specific and OS. These findings have implications for patient education and thyroid cancer treatment.

Context: Although variation in radioactive iodine (RAI) use for thyroid cancer has been demonstrated, the role of region and nonclinical correlates of use within risk groups has not been investigated., Objective: The objective of the study was to determine the correlates of RAI use within risk groups., Design/setting/patients: Use of RAI was evaluated across 9 US regions in 85 948 patients with well-differentiated thyroid cancer diagnosed between 2004 and 2008 at 986 hospitals associated with the US National Cancer Database. Cancers were then categorized as low risk (tumor size ≤ 1 cm and American Joint Committee on Cancer stage I disease), medium risk (neither low nor high-risk), and high risk (American Joint Committee on Cancer stage III or IV). Within each risk stratum, the role of region and nonclinical correlates of RAI use were evaluated using hierarchical logistic regression., Main Outcome Measure: Use of RAI was measured., Results: Rates of RAI use varied across geographic regions from 49% to 66%. Regional differences persisted after controlling for patient and hospital characteristics and evaluating less vs more intensive regions within low-risk [odds ratio (OR) 0.36 (95% confidence interval [CI] 0.25-0.53)], medium-risk [OR 0.23 (95% CI 0.16-0.34)], and high-risk cancers [OR 0.30 (95% CI 0.19-0.49)]. Patterns of RAI use were similar in medium- and high-risk patients. The most nonclinical correlates of use were in low-risk patients., Conclusion: Similar treatment patterns for the heterogeneous medium-risk thyroid cancer patients compared with the high-risk patients suggest more intensive management in patients with medium-risk disease. The large number of nonclinical correlates of RAI use, including region, imply controversy over indications for RAI.

Background: Although use of efficacious interventions, including antiretrovirals (ARVs), has dramatically reduced the rate of mother-to-child transmission of human immunodeficiency virus, the safety of in utero ARV exposure remains of concern., Methods: Data regarding 1112 infants enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Group protocol P1025 born between 2002 and 2007 were analyzed for this study. Congenital anomalies were classified based on the Metropolitan Atlanta Congenital Defects Program guidelines. Associations between congenital anomalies and timing of first in utero exposure to ARVs were evaluated by logistic regression analysis., Results: Congenital anomalies were identified and confirmed in 61 of the 1112 infants, resulting in a prevalence of 5.49/100 live births (95% confidence interval, 4.22-6.99). Among the 80 anomalies identified, the organ systems involved included cardiovascular (n = 33), musculoskeletal (n = 15), renal (n = 9), genitourinary (n = 6), craniofacial (n = 4), and central nervous system (n = 2). First trimester exposure to efavirenz was associated with a significantly increased risk of congenital anomalies (odds ratio, 2.84; 95% confidence interval, 1.13-7.16). No significant associations were observed between exposure to other individual ARVs or classes of ARVs started at any time during pregnancy and infant congenital anomalies., Conclusions: The observed rate of congenital anomalies in this cohort is higher than previously reported for the general population, but it is consistent with rates observed in other recent studies of children born to human immunodeficiency virus-infected women. Cardiovascular anomalies occurred most frequently. With the exception of a known teratogen (efavirenz), no statistically significant associations between in utero exposure to ARVs and congenital anomalies were identified.