Nomogram for radiation-induced lymphopenia in patients receiving intensity-modulated radiotherapy based-chemoradiation therapy for newly diagnosed glioblastoma: A multi-institutional study.

Purpose: Severe lymphopenia (SLP) has emerged as a significant prognostic factor in glioblastoma. Intensity-modulated radiation therapy (IMRT)-based radiation therapy (RT) is suggested to minimize the risk of SLP. This study aimed to evaluate SLP incidence based on multi-institutional database in patients with GBM treated with IMRT and develop a predictive nomogram. Patients and methods: This retrospective study reviewed data from 348 patients treated with IMRT-based concurrent chemoradiation therapy (CCRT) at two major hospitals from 2016 to 2021. After multivariate regression analysis, a nomogram was developed and internally validated to predict SLP risk. Results: During treatment course, 21.0% of patients developed SLP and SLP was associated with poor overall survival outcomes in patients with GBM. A newly developed nomogram, incorporating gender, pre-CCRT absolute lymphocyte count, and brain mean dose, demonstrated fair predictive accuracy (AUC 0.723). Conclusions: This study provides the first nomogram for predicting SLP in patients with GBM treated with IMRT-based CCRT, with acceptable predictive accuracy. The findings underscore the need for dose optimization and radiation planning to minimize SLP risk. Further external validation is crucial for adopting this nomogram in clinical practice.

External validation of subclassification system and progression pattern analysis in hepatocelluar carcinoma with macroscopic vascular invasion.

BACKGROUND AND PURPOSE: The present study aimed to validate the performance of a previously proposed subclassification model to predict prognosis after combined transarterial chemoembolization (TACE) and external beam radiotherapy (RT) for hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) in an independent cohort that received the same first-line treatment for the patients with the similar disease extent characteristics, and analyzed the progression patterns as well as progression-free survival (PFS). MATERIALS AND METHODS: This study was conducted using prospectively collected data from the XXXXX HCC registry for newly diagnosed, previously untreated HCC between 2005 and 2018. Finally, 417 patients who satisfied the eligibility criteria were included and analyzed. RESULTS: The median PFS and overall survival (OS) were 5.2 and 13.9 months, respectively. Similar to a previous study, subclassification of patients into very low-, low-, intermediate-, and high-risk groups showed a median OS of 98.4, 18.3, 9.7, and 5.8 months, respectively (P < 0.001). Additionally, subclassification of patients into the very low-, low-, intermediate-, and high-risk groups showed median PFS of 18.7, 6.7, 3.3, and 2.3 months, respectively (p < 0.001). Overall, intrahepatic progression was the most common pattern of progression; however, extrahepatic progression was more common in the intermediate- and high-risk groups. CONCLUSION: The previously proposed subclassification model was successfully validated in an independent cohort. Treatment modification should be considered in the intermediate- and high-risk patient groups because of their frequent extrahepatic as well as intrahepatic progressions after combined TACE and RT.

Risk of retinopathy in women with pregnancy-induced hypertension: a nationwide population-based cohort study of 9-year follow-up after delivery.

BACKGROUND: The retina is potentially associated with several physiological, hormonal, and metabolic changes during pregnancy. The few available epidemiologic studies of ocular changes in pregnancy have mainly concerned retinopathies. Pregnancy-induced hypertension, which leads to ocular manifestations including blurred vision, photopsia, scotoma, and diplopia, might induce reactive changes in the retinal vessels. Although several studies have suggested the existence of pregnancy-induced hypertension-related retinal ocular disease, there are few large cohort studies on this topic. OBJECTIVE: This study aimed to investigate the risk of major retinal diseases including central serous chorioretinopathy, diabetic retinopathy, retinal vein occlusion, retinal artery occlusion, and hypertensive retinopathy in the long-term postpartum stage according to the presence of previous pregnancy-induced hypertension in a large cohort based on the Korean National Health Insurance Database. STUDY DESIGN: On the basis of Korean health data, 909,520 patients who delivered from 2012 to 2013 were analyzed. Among them, patients who had previous ocular diseases or hypertension and multiple births were excluded. Finally, 858,057 mothers were assessed for central serous chorioretinopathy (ICD-10: H35.70), diabetic retinopathy (ICD-10: H36.0, E10.31, E10.32, E11.31, E11.32, E12.31, E13.31, E13.32, E14.31, E14.32), retinal vein occlusion (ICD-10: H34.8), retinal artery occlusion (ICD-10: H34.2), and hypertensive retinopathy (ICD-10: H35.02) for 9 years after delivery. Enrolled patients were divided into 2 groups: 10,808 patients with and 847,249 without pregnancy-induced hypertension. The primary outcomes were the incidence of central serous chorioretinopathy, diabetic retinopathy, retinal vein occlusion, retinal artery occlusion, and hypertensive retinopathy 9 years after delivery. Clinical variables were age, parity, cesarean delivery, gestational diabetes mellitus, and postpartum hemorrhage. In addition, pregestational diabetes mellitus, kidney diseases, cerebrovascular diseases, and cardiovascular diseases were adjusted. RESULTS: Postpartum retinal disease during the 9 years after delivery and total retinal diseases showed higher rates in patients with pregnancy-induced hypertension. In detail, the rates of central serous chorioretinopathy (0.3% vs 0.1%), diabetic retinopathy (1.79% vs 0.5%), retinal vein occlusion (0.19% vs 0.1%), and hypertensive retinopathy (0.62% vs 0.05%) were higher than those found in patients without pregnancy-induced hypertension. After adjusting for confounding factors, pregnancy-induced hypertension was associated with development of postpartum retinopathy, with a >2-fold increase (hazard ratio, 2.845; 95% confidence interval, 2.54-3.188). Furthermore, pregnancy-induced hypertension affected the development of central serous chorioretinopathy (hazard ratio, 3.681; 95% confidence interval, 2.667-5.082), diabetic retinopathy (hazard ratio, 2.326; 95% confidence interval, 2.013-2.688), retinal vein occlusion (hazard ratio, 2.241; 95% confidence interval, 1.491-3.368), and hypertensive retinopathy (hazard ratio, 11.392; 95% confidence interval, 8.771-14.796) after delivery. CONCLUSION: A history of pregnancy-induced hypertension increases the risk of central serous chorioretinopathy, diabetic retinopathy, retinal vein occlusion, and hypertensive retinopathy according to 9-year long-term ophthalmologic follow-up.

A single-center prospective study regarding time to return to activities of daily living after craniotomy for brain tumors.

BACKGROUND: There are few studies on the time to return to activities of daily living (ADL) after craniotomy in patients with brain tumors. This study aimed to investigate the duration before returning to ADLs after craniotomy for brain tumors and present data that can provide information and guidelines on the appropriate time needed. METHODS: Patients (n = 183 of 234) who underwent craniotomy for brain tumors between April 2021 and July 2021 capable of self-care upon discharge were enrolled, and data of 158 were collected. The start time of 85 ADL items was prospectively investigated for 4 months postoperatively, using the self-recording sheet. RESULTS: Over 89% and 87% of the patients performed basic ADL items within a month and instrumental ADL items within 2 months (medians: within 18 days), except for a few. Regarding work, 50% of the patients returned within 4 months. Washing hair with a wound was performed at 18 days of median value, after 4 months of dyeing/perming hair, 6 days of drinking coffee/tea, after 4 months of air travel, and 40 days of complementary and alternative medicine. In patients with infratentorial tumors or surgical problems, return times were much later for various items. CONCLUSIONS: It is possible to provide practical information and guidelines on the duration to return to ADL after craniotomy in brain tumor patients. These study findings also reduce uncertainty about recovery and daily life and help patients return to their daily life at the appropriate time, thereby maintaining function and daily well-being after surgery.

Regional lymph node recurrence after stereotactic body radiation therapy for lung cancer: Patterns of recurrence, treatment approaches, and clinical outcomes (KROG 21-09).

PURPOSE: To present the multi-institutional data on patterns of recurrence, treatment approaches, and clinical outcomes for regional lymph node (LN) recurrence after stereotactic body radiation therapy (SBRT) for primary lung cancer. MATERIALS AND METHODS: The medical records of 114 patients who experienced regional LN recurrence as the first recurrence after lung SBRT were retrospectively reviewed. Patterns of recurrence were classified as local recurrence, regional recurrence, and distant metastasis. Clinical outcomes including progression-free survival (PFS) and overall survival (OS) were analyzed. RESULTS: Half of the patients had regional LN recurrence only. The most common simultaneous recurrence was distant metastasis (38.6 %). Common sites of regional recurrence were ipsilateral hilar (47.2 %), ipsilateral upper mediastinal (40.6 %), and subcarinal (42.5 %) LN stations. 24 (21.1 %) patients underwent salvage radiation therapy (RT), and 44 (38.6 %) patients underwent palliative treatment. Better OS was observed in the salvage RT group (p = 0.025). The 1-year PFS and OS rates were 27.7 % and 55.2 %, respectively, with salvage RT, 14.0 % and 39.9 %, respectively, with palliative treatment, and 22.8 % and 26.8 %, respectively, with no additional treatment. Multivariate analysis showed that salvage RT (PFS, HR 0.463, p = 0.050; OS, HR 0.312, p = 0.002), palliative treatment (PFS, HR 0.436, p = 0.013; OS, HR 0.553, p = 0.050), and simultaneous distant metastasis (PFS, HR 2.335, p = 0.005; OS, HR 1.726, p = 0.054) affected clinical outcomes. CONCLUSION: Many cases of regional LN recurrence are confined to the locoregional area of patients, and appropriate treatment can improve the prognosis of these patients.

CEO's Childhood Experience of Natural Disaster and CSR Activities.

Interest in the drivers of firms' corporate social responsibility (CSR) is growing. However, little is known about the influence of a CEO's childhood experience of natural disasters on CSR. Using archival data, we explore this relationship by offering three mechanisms that may account for how the CEO's childhood experience of natural disaster is related to their CSR. More specifically, while prior research has established a positive relationship based on the post-traumatic growth theory, we show that the dual mechanisms of prosocial values and a CEO's risk aversion explain the positive relationship. We further find that the positive relationship is stronger (1) when CEOs have longer career horizons and (2) when community social capital is high. This study contributes to both research and managerial implications on the topics of CEO's childhood experience and CSR. In particular, this study advances the upper echelon theory by revealing that a CEO's childhood experience of natural disaster is a useful yet relatively underexplored variable that can help explain the substantial variations in firms' CSR. Moreover, we emphasize that a CEO's career horizons and level of community social capital are important variables that further amplify the effect of a CEO's childhood experience of natural disaster on the firm's CSR commitment.

Treatment Outcomes after Dose-Escalated Moderately Hypofractionated Radiotherapy for Frail Patients with High-Grade Glioma.

For high-grade glioma (HGG) patients with old age or poor performance status, hypofractionated radiotherapy (hypoRT) in 10-15 fractions is recommended. Also, limited data exist on the impact of salvage treatment after progression in frail patients. We retrospectively analyzed the outcomes of dose-escalated hypoRT in 40 frail HGG patients who were treated with hypoRT between 2013 and 2021. With a median biologically effective dose of 71.7 Gy, a total dose of 56 Gy in 20 fractions was the most frequently used regimen (53.7%). The median age and Karnofsky Performance Status of patients were 74 years and 70, respectively. Most patients (n = 31, 77.5%) were diagnosed with glioblastoma, IDH-wildtype, CNS WHO grade 4. Only 10 (25.0%) patients underwent surgical resection, and 28 (70.0%) patients received concurrent temozolomide during hypoRT. With a median follow-up of 9.7 months, the median overall survival (OS) was 12.2 months. Of the 30 (75.0%) patients with disease progression, only 12 patients received salvage treatment. The OS after progression differed significantly depending on salvage treatment (median OS, 9.6 vs. 4.6 months, p = 0.032). Dose-escalated hypoRT in 20 fractions produced survival outcomes outperforming historical data for frail patients.

The Feasibility of Stereotactic Body Proton Beam Therapy for Pancreatic Cancer.

Background/Purpose: This study aimed to evaluate the clinical outcomes of stereotactic body proton beam therapy (SBPT) for pancreatic cancer. Methods: This retrospective study included 49 patients who underwent SBPT for pancreatic cancer between 2017 and 2020. Survival outcomes, bowel-related toxicities, and failure patterns were analysed. SBPT was performed after induction chemotherapy in 44 (89.8%) patients. The dose-fractionation scheme included 60 gray (Gy) relative biological effectiveness (RBE) in five fractions (n = 42, 85.7%) and 50 GyRBE in five fractions (n = 7, 14.3%). The median follow-up was 16.3 months (range, 1.8−45.0 months). Results: During follow-up, the best responses were complete response, partial response, and stable disease in four (8.2%), 13 (26.5%), and 31 (63.3%) patients, respectively. The 2-year overall survival, progression-free survival, and local control (LC) rates were 67.6%, 38.0%, and 73.0%, respectively. Grade ≥ 3 gastroduodenal (GD) toxicity occurred in three (6.1%) patients. Among them, one patient underwent endoscopic haemostasis. The other two patients received surgical management. They were followed up without disease progression for >30 months after SBPT. Overall, there was no significant dosimetric difference between the grade ≥ 2 and lower toxicity groups. Conclusions: SBPT provides relatively high LC rates with acceptable toxicities in pancreatic cancer.

Toxicity of Proton Therapy versus Photon Therapy on Salvage Re-Irradiation for Non-Small Cell Lung Cancer.

This study evaluated the toxicity associated with radiation techniques on curative re-irradiation (re-RT) in patients with thoracic recurrence of non-small cell lung cancer (NSCLC). From 2011 to 2019, we retrospectively reviewed the data of 63 patients with salvage re-RT for in-field or marginal recurrence of NSCLC at two independent institutions. Re-RT techniques using X-ray beams and proton beam therapy (PBT) were also included. Re-RT had a 2-year overall survival (OS) and local progression-free survival of 48.0% and 52.0%, respectively. Fifteen patients experienced grade 3 or higher toxicity after re-RT. The complication rates were 18.2% (4/22) and 26.8% (11/41) in PBT patients and X-ray patients, respectively. Airway or esophageal fistulas occurred in seven patients (11.1%). Fistulas or severe airway obstruction occurred in patients with tumors adjacent to the proximal bronchial tree and esophagus, who underwent hypofractionated radiotherapy (RT) or concurrent chemotherapy, and with a higher dose exposure to the esophagus. In conclusion, salvage re-RT was feasible even in patients with local recurrence within the previous RT field. PBT showed similar survival outcomes and toxicity to those of other techniques. However, thoracic re-RT should be performed carefully considering tumor location and RT regimens such as the fraction size and concurrent chemotherapy.

Salvage proton beam therapy for locoregional recurrence of non-small cell lung cancer.

PURPOSE: This study aimed to evaluate the clinical outcomes and toxicities of salvage proton beam therapy (PBT) in patients with locoregional recurrent non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We retrospectively reviewed 53 patients who received salvage PBT for locoregionally recurrent NSCLC between January 2016 and December 2019. The median clinical target volume (CTV) was 71.2 cm3 (range, 13.3 to 1,200.7 cm3). The median prescribed dose was 64.0 cobalt gray equivalent (CGE) (range, 45.0 to 70.0 CGE). One-third of the patients (32.1%) received concurrent chemoradiotherapy (CCRT). RESULTS: The patients' median age was 67 years (range, 44 to 86 years). The initial treatments were surgery in 31 (58.5%), definitive CCRT in 12 (22.6%), and definitive radiotherapy in 10 (18.9%) patients. The median disease-free interval (DFI) was 14 months (range, 3 to 112 months). Thirty-seven patients (69.8%) had a previous radiotherapy history. Among them, 18 patients (48.7%) had in-field recurrence. The median follow-up time after salvage PBT was 15.0 months (range, 3.5 to 49.3 months). During the follow-up period, 26 patients (49.1%) experienced disease progression: local in 13 (24.5%), regional in 14 (26.5%), and distant metastases in 15 (26.5%). The 2-year overall survival (OS) rate, local control rate, and progression-free survival rate were 79.2%, 68.2%, and 37.1%, respectively. Shorter DFI (≤12 months; p = 0.015) and larger CTV (>80 mL; p = 0.014) were associated with poor OS. Grade 3 toxicities occurred in 8 patients (15.1%): esophagitis in 2, dermatitis in 3, and pulmonary toxicities in 4. CONCLUSION: Salvage PBT for locoregionally recurrent NSCLC was effective, and treatment-related toxicities were tolerable.

Bioequivalence of the pharmacokinetics between tofacitinib aspartate and tofacitinib citrate in healthy subjects.

Tofacitinib is an oral disease-modifying anti-rheumatic drug to selectively inhibit Janus kinases. Tofacitinib is a representative small molecule inhibitor that is used to treat many diseases including rheumatoid arthritis and various autoimmune conditions. Unlike biological agents, tofacitinib has several advantages, including the ability to be administered orally and a short half-life. This study aimed to evaluate the bioequivalence of the pharmacokinetics (PK) between tofacitinib aspartate 7.13 mg (test formulation) and tofacitinib citrate 8.08 mg (reference formulation; Xeljanz®) in healthy subjects. A randomized, open-label, single-dose, 2-sequence, 2-period, 2-treatment crossover trial was conducted in 41 healthy volunteers. A total of 5 mg of tofacitinib as the test or the reference formulation was administered, and serial blood samples were collected up to 14 hours after dosing for PK analyses. The plasma concentration of tofacitinib was determined by ultra-performance liquid chromatography-tandem mass spectrometry. A non-compartmental analysis was used to estimate the PK parameters. A total of 35 subjects completed the study and the study drug was well-tolerated. The mean maximum concentration (Cmax) and area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) for the test formulation were 52.67 ng/mL and 133.86 ng∙h/mL, respectively, and 50.61 ng/mL and 133.49 h∙ng/mL for the reference formulation, respectively. The geometric mean ratios (90% confidence intervals) of the Cmax and AUClast between the 2 formulations were 1.041 (0.944-1.148) and 1.003 (0.968-1.039), respectively. Tofacitinib aspartate exhibited bioequivalent PK profiles to those of the reference formulation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04278391.

Investigation of isotope dilution mass spectrometric (ID-MS) method to determine niacin in infant formula, breakfast cereals and multivitamins.

An isotope dilution LC/mass spectrometric (ID-LC/MS) method was developed as a candidate reference method for the accurate determination of niacin in infant formula, breakfast cereals and multivitamin. After spiking nicotinamide-d(4) as an internal standard, infant formula and breakfast cereal samples were hydrolysed under alkaline condition. Samples were then analysed in SRM mode to detect nicotinic acid and nicotinic acid-d(4) at m/z 124→80 and 127→84, respectively. In the case of multivitamin sample that contains mainly free nicotinamide, LC/MS monitored nicotinamide and nicotinamide-d(4) at their SRM channels of m/z 123→80 and m/z 127→84, respectively, after simple extraction. The repeatability and reproducibility were tested for the validation of the developed ID/LC-MS method. Additionally, the developed analytical method was applied to determine total niacin contents in homogenised infant formula, homogenised multivitamin, and commercially available products including different types of infant formula, breakfast cereals, and multivitamin tablets.