Treatment utilization and outcomes in elderly patients with locally advanced esophageal carcinoma: A review of the National Cancer Database

For elderly patients with locally advanced esophageal cancer, therapeutic approaches and outcomes in a modern cohort are not well characterized. Patients ≥70 years old with clinical stage II and III esophageal cancer diagnosed between 1998 and 2012 were identified from the National Cancer Database and stratified based on treatment type. Variables associated with treatment utilization were evaluated using logistic regression and survival evaluated using Cox proportional hazards analysis. Propensity matching (1:1) was performed to help account for selection bias. A total of 21,593 patients were identified. Median and maximum ages were 77 and 90, respectively. Treatment included palliative therapy (24.3%), chemoradiation (37.1%), trimodality therapy (10.0%), esophagectomy alone (5.6%), or no therapy (12.9%). Age ≥80 (OR 0.73), female gender (OR 0.81), Charlson-Deyo comorbidity score ≥2 (OR 0.82), and high-volume centers (OR 0.83) were associated with a decreased likelihood of palliative therapy versus no treatment. Age ≥80 (OR 0.79) and Clinical Stage III (OR 0.33) were associated with a decreased likelihood, while adenocarcinoma histology (OR 1.33) and nonacademic cancer centers (OR 3.9), an increased likelihood of esophagectomy alone compared to definitive chemoradiation. Age ≥80 (OR 0.15), female gender (OR 0.80), and non-Caucasian race (OR 0.63) were associated with a decreased likelihood, while adenocarcinoma histology (OR 2.10) and high-volume centers (OR 2.34), an increased likelihood of trimodality therapy compared to definitive chemoradiation. Each treatment type demonstrated improved survival compared to no therapy: palliative treatment (HR 0.49) to trimodality therapy (HR 0.25) with significance between all groups. Any therapy, including palliative care, was associated with improved survival; however, subsets of elderly patients with locally advanced esophageal cancer are less likely to receive aggressive therapy. Care should be taken to not unnecessarily deprive these individuals of treatment that may improve survival

The first reported case of a patient with pancreatic cancer treated with cone beam computed tomography-guided stereotactic adaptive radiotherapy (CT-STAR)

BACKGROUND: Online adaptive stereotactic radiotherapy allows for improved target and organ at risk (OAR) delineation and inter-fraction motion management via daily adaptive planning. The use of adaptive SBRT for the treatment of pancreatic cancer (performed until now using only MRI or CT on rails-guided adaptive radiotherapy), has yielded promising outcomes. Herein we describe the first reported case of cone beam CT-guided stereotactic adaptive radiotherapy (CT-STAR) for the treatment of pancreatic cancer. CASE PRESENTATION: A 61-year-old female with metastatic pancreatic cancer presented for durable palliation of a symptomatic primary pancreatic mass. She was prescribed 35 Gy/5 fractions utilizing CT-STAR. The patient was simulated utilizing an end-exhale CT with intravenous and oral bowel contrast. Both initial as well as daily adapted plans were created adhering to a strict isotoxicity approach in which coverage was sacrificed to meet critical luminal gastrointestinal OAR hard constraints. Kilovoltage cone beam CTs were acquired on each day of treatment and the radiation oncologist edited OAR contours to reflect the patient\u27s anatomy-of-the-day. The initial and adapted plan were compared using dose volume histogram objectives, and the superior plan was delivered. Use of the initial treatment plan would have resulted in nine critical OAR hard constraint violations. The adapted plans achieved hard constraints in all five fractions for all four critical luminal gastrointestinal structures. CONCLUSIONS: We report the successful treatment of a patient with pancreatic cancer treated with CT-STAR. Prior to this treatment, the delivery of ablative adaptive radiotherapy for pancreatic cancer was limited to clinics with MR-guided and CT-on-rails adaptive SBRT technology and workflows. CT-STAR is a promising modality with which to deliver stereotactic adaptive radiotherapy for pancreatic cancer

Prospective in silico evaluation of cone-beam computed tomography-guided stereotactic adaptive radiation therapy (CT-STAR) for the ablative treatment of ultracentral thoracic disease

PURPOSE: We conducted a prospective, in silico study to evaluate the feasibility of cone-beam computed tomography (CBCT)-guided stereotactic adaptive radiation therapy (CT-STAR) for the treatment of ultracentral thoracic cancers (NCT04008537). We hypothesized that CT-STAR would reduce dose to organs at risk (OARs) compared with nonadaptive stereotactic body radiation therapy (SBRT) while maintaining adequate tumor coverage. METHODS AND MATERIALS: Patients who were already receiving radiation therapy for ultracentral thoracic malignancies underwent 5 additional daily CBCTs on the ETHOS system as part of a prospective imaging study. These were used to simulate CT-STAR, in silico RESULTS: Seven patients were accrued, 6 with intraparenchymal tumors and 1 with a subcarinal lymph node. CT-STAR was feasible in 34 of 35 simulated fractions. In total, 32 dose constraint violations occurred when the P CONCLUSIONS: CT-STAR widened the dosimetric therapeutic index of ultracentral thorax SBRT compared with nonadaptive SBRT. A phase 1 protocol is underway to evaluate the safety of this paradigm for patients with ultracentral early-stage NSCLC

Cost-effectiveness of total neoadjuvant therapy with short-course radiotherapy for resectable locally advanced rectal cancer

Importance: Short-course radiotherapy and total neoadjuvant therapy (SCRT-TNT) followed by total mesorectal excision (TME) has emerged as a new treatment paradigm for patients with locally advanced rectal adenocarcinoma. However, the economic implication of this treatment strategy has not been compared with that of conventional long-course chemoradiotherapy (LCCRT) followed by TME with adjuvant chemotherapy. Objective: To perform a cost-effectiveness analysis of SCRT-TNT vs LCCRT in conjunction with TME for patients with locally advanced rectal cancer. Design, Setting, and Participants: A decision analytical model with a 5-year time horizon was constructed for patients with biopsy-proven, newly diagnosed, primary locally advanced rectal adenocarcinoma treated with SCRT-TNT or LCCRT. Markov modeling was used to model disease progression and patient survival after treatment in 3-month cycles. Data on probabilities and utilities were extracted from the literature. Costs were evaluated from the Medicare payer\u27s perspective in 2020 US dollars. Sensitivity analyses were performed for key variables. Data were collected from October 3, 2020, to January 20, 2021, and analyzed from November 15, 2020, to April 25, 2021. Exposures: Two treatment strategies, SCRT-TNT vs LCCRT with adjuvant chemotherapy, were compared. Main Outcomes and Measures: Cost-effectiveness was evaluated using the incremental cost-effectiveness ratio and net monetary benefits. Effectiveness was defined as quality-adjusted life-years (QALYs). Both costs and QALYs were discounted at 3% annually. Willingness-to-pay threshold was set at $50 000/QALY. Results: During the 5-year horizon, the total cost was$41 355 and QALYs were 2.21 for SCRT-TNT; for LCCRT, the total cost was $54 827 and QALYs were 2.12, resulting in a negative incremental cost-effectiveness ratio (-$141 256.77). The net monetary benefit was $69 300 for SCRT-TNT and$51 060 for LCCRT. Sensitivity analyses using willingness to pay at $100 000/QALY and$150 000/QALY demonstrated the same conclusion. Conclusions and Relevance: These findings suggest that SCRT-TNT followed by TME incurs lower cost and improved QALYs compared with conventional LCCRT followed by TME and adjuvant chemotherapy. These data offer further rationale to support SCRT-TNT as a novel cost-saving treatment paradigm in the management of locally advanced rectal cancer

Nfil3/E4bp4 is required for the development and maturation of NK cells in vivo

Nuclear factor interleukin-3 (Nfil3; also known as E4-binding protein 4) is a basic region leucine zipper transcription factor that has antiapoptotic activity in vitro under conditions of growth factor withdrawal. To study the role of Nfil3 in vivo, we generated gene-targeted Nfil3-deficient (Nfil3−/−) mice. Nfil3−/− mice were born at normal Mendelian frequency and were grossly normal and fertile. Although numbers of T cells, B cells, and natural killer (NK) T cells were normal in Nfil3−/− mice, a specific disruption in NK cell development resulted in severely reduced numbers of mature NK cells in the periphery. This defect was NK cell intrinsic in nature, leading to a failure to reject MHC class I–deficient cells in vivo and reductions in both interferon γ production and cytolytic activity in vitro. Our results confirm the specific and essential requirement of Nfil3 for the development of cells of the NK lineage

Multidisciplinary management of acromegaly: A consensus.

The 13th Acromegaly Consensus Conference was held in November 2019 in Fort Lauderdale, Florida, and comprised acromegaly experts including endocrinologists and neurosurgeons who considered optimal approaches for multidisciplinary acromegaly management. Focused discussions reviewed techniques, results, and side effects of surgery, radiotherapy, and medical therapy, and how advances in technology and novel techniques have changed the way these modalities are used alone or in combination. Effects of treatment on patient outcomes were considered, along with strategies for optimizing and personalizing therapeutic approaches. Expert consensus recommendations emphasize how best to implement available treatment options as part of a multidisciplinary approach at Pituitary Tumor Centers of Excellence

Anxiety, concerns and COVID-19: Cross-country perspectives from families and individuals with neurodevelopmental conditions

BACKGROUND: The COVID-19 pandemic had a major impact on the mental health and well-being of children with neurodevelopmental conditions (NDCs) and of their families worldwide. However, there is insufficient evidence to understand how different factors (e.g., individual, family, country, children) have impacted on anxiety levels of families and their children with NDCs developed over time. METHODS: We used data from a global survey assessing the experience of 8043 families and their children with NDCs (mean of age (m) = 13.18 years, 37% female) and their typically developing siblings (m = 12.9 years, 45% female) in combination with data from the European Centre for Disease Prevention and Control, the University of Oxford, and the Central Intelligence Agency (CIA) World Factbook, to create a multilevel data set. Using stepwise multilevel modelling, we generated child-, family- and country-related factors that may have contributed to the anxiety levels of children with NDCs, their siblings if they had any, and their parents. All data were reported by parents. RESULTS: Our results suggest that parental anxiety was best explained by family-related factors such as concerns about COVID-19 and illness. Children’s anxiety was best explained by child-related factors such as children’s concerns about loss of routine, family conflict, and safety in general, as well as concerns about COVID-19. In addition, anxiety levels were linked to the presence of pre-existing anxiety conditions for both children with NDCs and their parents. CONCLUSIONS: The present study shows that across the globe there was a raise in anxiety levels for both parents and their children with NDCs because of COVID-19 and that country-level factors had little or no impact on explaining differences in this increase, once family and child factors were considered. Our findings also highlight that certain groups of children with NDCs were at higher risk for anxiety than others and had specific concerns. Together, these results show that anxiety of families and their children with NDCs during the COVID-19 pandemic were predicted by very specific concerns and worries which inform the development of future toolkits and policy. Future studies should investigate how country factors can play a protective role during future crises

Prokineticin 1 modulates IL-8 expression via the calcineurin/NFAT signaling pathway

AbstractProkineticins and their receptors are expressed in various cellular compartments in human endometrium, with prokineticin 1 (PROK1) showing a dynamic pattern of expression across the menstrual cycle and during pregnancy. Previous studies suggest that PROK1 can play an important role in implantation and early pregnancy by inducing vascular remodeling and increasing vascular permeability. Here we demonstrate that PROK1 induces the expression of IL-8, a chemokine with angiogenic properties, in endometrial epithelial Ishikawa cells stably expressing prokineticin receptor 1 and in human first trimester decidua. We also show that IL-8 promoter activity is induced by PROK1 and that this requires the presence of AP1 and NFAT motifs. The role of calcineurin/NFAT signaling pathway is confirmed by the use of specific chemical inhibitors. Additionally, PROK1 induces the expression of the regulator of calcineurin 1 isoform 4 (RCAN1-4) via the calcineurin/NFAT pathway. A modulatory role for RCAN1-4 is demonstrated by RCAN1-4 overexpression which results in the inhibition of PROK1-induced IL-8 expression whereas reduction in RCAN1-4 endogenous expression results in an increase in PROK1-induced IL-8 production. Our findings show that in endometrial cells PROK1 can activate the calcineurin/NFAT pathway to induce IL-8 expression and that this is negatively modulated by the induction of expression of RCAN1-4

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701