Are Current Survival Prediction Tools Useful When Treating Subsequent Skeletal-related Events From Bone Metastases?

BACKGROUND: Bone metastasis in advanced cancer is challenging because of pain, functional issues, and reduced life expectancy. Treatment planning is complex, with consideration of factors such as location, symptoms, and prognosis. Prognostic models help guide treatment choices, with Skeletal Oncology Research Group machine-learning algorithms (SORG-MLAs) showing promise in predicting survival for initial spinal metastases and extremity metastases treated with surgery or radiotherapy. Improved therapies extend patient lifespans, increasing the risk of subsequent skeletal-related events (SREs). Patients experiencing subsequent SREs often suffer from disease progression, indicating a deteriorating condition. For these patients, a thorough evaluation, including accurate survival prediction, is essential to determine the most appropriate treatment and avoid aggressive surgical treatment for patients with a poor survival likelihood. Patients experiencing subsequent SREs often suffer from disease progression, indicating a deteriorating condition. However, some variables in the SORG prediction model, such as tumor histology, visceral metastasis, and previous systemic therapies, might remain consistent between initial and subsequent SREs. Given the prognostic difference between patients with and without a subsequent SRE, the efficacy of established prognostic models-originally designed for individuals with an initial SRE-in addressing a subsequent SRE remains uncertain. Therefore, it is crucial to verify the model's utility for subsequent SREs. QUESTION/PURPOSE: We aimed to evaluate the reliability of the SORG-MLAs for survival prediction in patients undergoing surgery or radiotherapy for a subsequent SRE for whom both the initial and subsequent SREs occurred in the spine or extremities. METHODS: We retrospectively included 738 patients who were 20 years or older who received surgery or radiotherapy for initial and subsequent SREs at a tertiary referral center and local hospital in Taiwan between 2010 and 2019. We excluded 74 patients whose initial SRE was in the spine and in whom the subsequent SRE occurred in the extremities and 37 patients whose initial SRE was in the extremities and the subsequent SRE was in the spine. The rationale was that different SORG-MLAs were exclusively designed for patients who had an initial spine metastasis and those who had an initial extremity metastasis, irrespective of whether they experienced metastatic events in other areas (for example, a patient experiencing an extremity SRE before his or her spinal SRE would also be regarded as a candidate for an initial spinal SRE). Because these patients were already validated in previous studies, we excluded them in case we overestimated our result. Five patients with malignant primary bone tumors and 38 patients in whom the metastasis's origin could not be identified were excluded, leaving 584 patients for analysis. The 584 included patients were categorized into two subgroups based on the location of initial and subsequent SREs: the spine group (68% [399]) and extremity group (32% [185]). No patients were lost to follow-up. Patient data at the time they presented with a subsequent SRE were collected, and survival predictions at this timepoint were calculated using the SORG-MLAs. Multiple imputation with the Missforest technique was conducted five times to impute the missing proportions of each predictor. The effectiveness of SORG-MLAs was gauged through several statistical measures, including discrimination (measured by the area under the receiver operating characteristic curve [AUC]), calibration, overall performance (Brier score), and decision curve analysis. Discrimination refers to the model's ability to differentiate between those with the event and those without the event. An AUC ranges from 0.5 to 1.0, with 0.5 indicating the worst discrimination and 1.0 indicating perfect discrimination. An AUC of 0.7 is considered clinically acceptable discrimination. Calibration is the comparison between the frequency of observed events and the predicted probabilities. In an ideal calibration, the observed and predicted survival rates should be congruent. The logarithm of observed-to-expected survival ratio [log(O:E)] offers insight into the model's overall calibration by considering the total number of observed (O) and expected (E) events. The Brier score measures the mean squared difference between the predicted probability of possible outcomes for each individual and the observed outcomes, ranging from 0 to 1, with 0 indicating perfect overall performance and 1 indicating the worst performance. Moreover, the prevalence of the outcome should be considered, so a null-model Brier score was also calculated by assigning a probability equal to the prevalence of the outcome (in this case, the actual survival rate) to each patient. The benefit of the prediction model is determined by comparing its Brier score with that of the null model. If a prediction model's Brier score is lower than the null model's Brier score, the prediction model is deemed as having good performance. A decision curve analysis was performed for models to evaluate the "net benefit," which weighs the true positive rate over the false positive rate against the "threshold probabilities," the ratio of risk over benefit after an intervention was derived based on a comprehensive clinical evaluation and a well-discussed shared-decision process. A good predictive model should yield a higher net benefit than default strategies (treating all patients and treating no patients) across a range of threshold probabilities. RESULTS: For the spine group, the algorithms displayed acceptable AUC results (median AUCs of 0.69 to 0.72) for 42-day, 90-day, and 1-year survival predictions after treatment for a subsequent SRE. In contrast, the extremity group showed median AUCs ranging from 0.65 to 0.73 for the corresponding survival periods. All Brier scores were lower than those of their null model, indicating the SORG-MLAs' good overall performances for both cohorts. The SORG-MLAs yielded a net benefit for both cohorts; however, they overestimated 1-year survival probabilities in patients with a subsequent SRE in the spine, with a median log(O:E) of -0.60 (95% confidence interval -0.77 to -0.42). CONCLUSION: The SORG-MLAs maintain satisfactory discriminatory capacity and offer considerable net benefits through decision curve analysis, indicating their continued viability as prediction tools in this clinical context. However, the algorithms overestimate 1-year survival rates for patients with a subsequent SRE of the spine, warranting consideration of specific patient groups. Clinicians and surgeons should exercise caution when using the SORG-MLAs for survival prediction in these patients and remain aware of potential mispredictions when tailoring treatment plans, with a preference for less invasive treatments. Ultimately, this study emphasizes the importance of enhancing prognostic algorithms and developing innovative tools for patients with subsequent SREs as the life expectancy in patients with bone metastases continues to improve and healthcare providers will encounter these patients more often in daily practice. LEVEL OF EVIDENCE: Level III, prognostic study.

Does the Presence of Missing Data Affect the Performance of the SORG Machine-learning Algorithm for Patients With Spinal Metastasis? Development of an Internet Application Algorithm.

BACKGROUND: The Skeletal Oncology Research Group machine-learning algorithm (SORG-MLA) was developed to predict the survival of patients with spinal metastasis. The algorithm was successfully tested in five international institutions using 1101 patients from different continents. The incorporation of 18 prognostic factors strengthens its predictive ability but limits its clinical utility because some prognostic factors might not be clinically available when a clinician wishes to make a prediction. QUESTIONS/PURPOSES: We performed this study to (1) evaluate the SORG-MLA's performance with data and (2) develop an internet-based application to impute the missing data. METHODS: A total of 2768 patients were included in this study. The data of 617 patients who were treated surgically were intentionally erased, and the data of the other 2151 patients who were treated with radiotherapy and medical treatment were used to impute the artificially missing data. Compared with those who were treated nonsurgically, patients undergoing surgery were younger (median 59 years [IQR 51 to 67 years] versus median 62 years [IQR 53 to 71 years]) and had a higher proportion of patients with at least three spinal metastatic levels (77% [474 of 617] versus 72% [1547 of 2151]), more neurologic deficit (normal American Spinal Injury Association [E] 68% [301 of 443] versus 79% [1227 of 1561]), higher BMI (23 kg/m2 [IQR 20 to 25 kg/m2] versus 22 kg/m2 [IQR 20 to 25 kg/m2]), higher platelet count (240 × 103/µL [IQR 173 to 327 × 103/µL] versus 227 × 103/µL [IQR 165 to 302 × 103/µL], higher lymphocyte count (15 × 103/µL [IQR 9 to 21× 103/µL] versus 14 × 103/µL [IQR 8 to 21 × 103/µL]), lower serum creatinine level (0.7 mg/dL [IQR 0.6 to 0.9 mg/dL] versus 0.8 mg/dL [IQR 0.6 to 1.0 mg/dL]), less previous systemic therapy (19% [115 of 617] versus 24% [526 of 2151]), fewer Charlson comorbidities other than cancer (28% [170 of 617] versus 36% [770 of 2151]), and longer median survival. The two patient groups did not differ in other regards. These findings aligned with our institutional philosophy of selecting patients for surgical intervention based on their level of favorable prognostic factors such as BMI or lymphocyte counts and lower levels of unfavorable prognostic factors such as white blood cell counts or serum creatinine level, as well as the degree of spinal instability and severity of neurologic deficits. This approach aims to identify patients with better survival outcomes and prioritize their surgical intervention accordingly. Seven factors (serum albumin and alkaline phosphatase levels, international normalized ratio, lymphocyte and neutrophil counts, and the presence of visceral or brain metastases) were considered possible missing items based on five previous validation studies and clinical experience. Artificially missing data were imputed using the missForest imputation technique, which was previously applied and successfully tested to fit the SORG-MLA in validation studies. Discrimination, calibration, overall performance, and decision curve analysis were applied to evaluate the SORG-MLA's performance. The discrimination ability was measured with an area under the receiver operating characteristic curve. It ranges from 0.5 to 1.0, with 0.5 indicating the worst discrimination and 1.0 indicating perfect discrimination. An area under the curve of 0.7 is considered clinically acceptable discrimination. Calibration refers to the agreement between the predicted outcomes and actual outcomes. An ideal calibration model will yield predicted survival rates that are congruent with the observed survival rates. The Brier score measures the squared difference between the actual outcome and predicted probability, which captures calibration and discrimination ability simultaneously. A Brier score of 0 indicates perfect prediction, whereas a Brier score of 1 indicates the poorest prediction. A decision curve analysis was performed for the 6-week, 90-day, and 1-year prediction models to evaluate their net benefit across different threshold probabilities. Using the results from our analysis, we developed an internet-based application that facilitates real-time data imputation for clinical decision-making at the point of care. This tool allows healthcare professionals to efficiently and effectively address missing data, ensuring that patient care remains optimal at all times. RESULTS: Generally, the SORG-MLA demonstrated good discriminatory ability, with areas under the curve greater than 0.7 in most cases, and good overall performance, with up to 25% improvement in Brier scores in the presence of one to three missing items. The only exceptions were albumin level and lymphocyte count, because the SORG-MLA's performance was reduced when these two items were missing, indicating that the SORG-MLA might be unreliable without these values. The model tended to underestimate the patient survival rate. As the number of missing items increased, the model's discriminatory ability was progressively impaired, and a marked underestimation of patient survival rates was observed. Specifically, when three items were missing, the number of actual survivors was up to 1.3 times greater than the number of expected survivors, while only 10% discrepancy was observed when only one item was missing. When either two or three items were omitted, the decision curves exhibited substantial overlap, indicating a lack of consistent disparities in performance. This finding suggests that the SORG-MLA consistently generates accurate predictions, regardless of the two or three items that are omitted. We developed an internet application (https://sorg-spine-mets-missing-data-imputation.azurewebsites.net/) that allows the use of SORG-MLA with up to three missing items. CONCLUSION: The SORG-MLA generally performed well in the presence of one to three missing items, except for serum albumin level and lymphocyte count (which are essential for adequate predictions, even using our modified version of the SORG-MLA). We recommend that future studies should develop prediction models that allow for their use when there are missing data, or provide a means to impute those missing data, because some data are not available at the time a clinical decision must be made. CLINICAL RELEVANCE: The results suggested the algorithm could be helpful when a radiologic evaluation owing to a lengthy waiting period cannot be performed in time, especially in situations when an early operation could be beneficial. It could help orthopaedic surgeons to decide whether to intervene palliatively or extensively, even when the surgical indication is clear.

Regulatory cascade involving transcriptional and N-end rule pathways in rice under submergence.

The rice SUB1A-1 gene, which encodes a group VII ethylene response factor (ERFVII), plays a pivotal role in rice survival under flooding stress, as well as other abiotic stresses. In Arabidopsis, five ERFVII factors play roles in regulating hypoxic responses. A characteristic feature of Arabidopsis ERFVIIs is a destabilizing N terminus, which functions as an N-degron that targets them for degradation via the oxygen-dependent N-end rule pathway of proteolysis, but permits their stabilization during hypoxia for hypoxia-responsive signaling. Despite having the canonical N-degron sequence, SUB1A-1 is not under N-end rule regulation, suggesting a distinct hypoxia signaling pathway in rice during submergence. Herein we show that two other rice ERFVIIs gene, ERF66 and ERF67, are directly transcriptionally up-regulated by SUB1A-1 under submergence. In contrast to SUB1A-1, ERF66 and ERF67 are substrates of the N-end rule pathway that are stabilized under hypoxia and may be responsible for triggering a stronger transcriptional response to promote submergence survival. In support of this, overexpression of ERF66 or ERF67 leads to activation of anaerobic survival genes and enhanced submergence tolerance. Furthermore, by using structural and protein-interaction analyses, we show that the C terminus of SUB1A-1 prevents its degradation via the N-end rule and directly interacts with the SUB1A-1 N terminus, which may explain the enhanced stability of SUB1A-1 despite bearing an N-degron sequence. In summary, our results suggest that SUB1A-1, ERF66, and ERF67 form a regulatory cascade involving transcriptional and N-end rule control, which allows rice to distinguish flooding from other SUB1A-1-regulated stresses.

Can a Bayesian belief network for survival prediction in patients with extremity metastases (PATHFx) be externally validated in an Asian cohort of 356 surgically treated patients?

BACKGROUND AND PURPOSE: Predicted survival may influence the treatment decision for patients with skeletal extremity metastasis, and PATHFx was designed to predict the likelihood of a patient dying in the next 24 months. However, the performance of prediction models could have ethnogeographical variations. We asked if PATHFx generalized well to our Taiwanese cohort consisting of 356 surgically treated patients with extremity metastasis. PATIENTS AND METHODS: We included 356 patients who underwent surgery for skeletal extremity metastasis in a tertiary center in Taiwan between 2014 and 2019 to validate PATHFx's survival predictions at 6 different time points. Model performance was assessed by concordance index (c-index), calibration analysis, decision curve analysis (DCA), Brier score, and model consistency (MC). RESULTS: The c-indexes for the 1-, 3-, 6-, 12-, 18-, and 24-month survival estimations were 0.71, 0.66, 0.65, 0.69, 0.68, and 0.67, respectively. The calibration analysis demonstrated positive calibration intercepts for survival predictions at all 6 timepoints, indicating PATHFx tended to underestimate the actual survival. The Brier scores for the 6 models were all less than their respective null model's. DCA demonstrated that only the 6-, 12-, 18-, and 24-month predictions appeared useful for clinical decision-making across a wide range of threshold probabilities. The MC was < 0.9 when the 6- and 12-month models were compared with the 12-month and 18-month models, respectively. INTERPRETATION: In this Asian cohort, PATHFx's performance was not as encouraging as those of prior validation studies. Clinicians should be cognizant of the potential decline in validity of any tools designed using data outside their particular patient population. Developers of survival prediction tools such as PATHFx might refine their algorithms using data from diverse, contemporary patients that is more reflective of the world's population.

Social interactions upregulate hemolymph tryptophan and tyrosine levels in the male lobster cockroach.

In the present study, we found that tryptophan (TRP) and tyrosine (TYR) levels are increased in hemolymph of male Nauphoeta cinerea after social contact with either male or female conspecifics. Hemolymph was collected from individual males before and after the social interactions, and samples were analyzed by HPLC-ECD; analyte identities were confirmed by UPLC/MS. After a male-male first encounter fight, hemolymph TRP and TYR levels were significantly increased in dominants compared with the levels before the encounter. Conversely, TRP and TYR in subordinates were maintained at levels similar to those before the encounter. While after-fight TRP and TYR levels were significantly higher in dominants than subordinates, no significant differences were found in the contestants before the fight. Moreover, contact with an isolated male antenna was sufficient to stimulate attack behavior and increase hemolymph TRP and TYR titers to levels similar to those seen in dominants. After a male-female interaction, two distinct outcomes could be observed. Either hemolymph TRP and TYR levels were increased in successfully mated males, or TRP and TYR levels were unchanged in males that only exhibited premating wing-raising behavior but failed in mating. After contacting the antenna of a socially naïve male with an isolated female antenna, three patterns of behavior and related amino acid response were observed: 1) only premating wing-raising behavior with significant increase of TRP and TYR levels, 2) only attack behavior with significant increase of TRP and TYR levels, and 3) mixed wing-raising and attack behaviors with no significant changes in TRP and TYR levels. The present results show a robust response of hemolymph TRP and TYR to social contact. In light of previously characterized responses in pheromone and juvenile hormone levels, these amine responses suggest that the physiological response of N. cinerea to social contact is multi-dimensional.

A prospective, multicenter, noninterventional study in Taiwan to evaluate the safety and tolerability of lacosamide as adjunctive therapy for epilepsy in clinical practice.

RATIONALE: Lacosamide (LCM) was initially approved in Taiwan in March 2014 for use as adjunctive therapy for focal impaired awareness seizures and secondarily generalized seizures (SGS) in patients with epilepsy ≥16 years of age. The efficacy and tolerability of adjunctive LCM for the treatment of patients with focal seizures have been demonstrated in randomized, placebo-controlled trials. However, the trials do not reflect a flexible dose setting. This study (EP0063) was conducted to assess the safety and tolerability of LCM in real-world clinical practice in Taiwan. Effectiveness of LCM was also assessed as an exploratory objective. METHODS: EP0063 was a multicenter, prospective, noninterventional study with an expected observation period of 12 months ±â€¯60 days. Eligible patients were ≥16 years of age, had focal impaired awareness seizures and/or SGS (in line with approved indication in Taiwan at the time of the study), were taking at least one concomitant antiseizure medication (ASM), and had at least one seizure in the 3 months before baseline. Patients were prescribed LCM by their treating physician in the course of routine clinical practice. The primary safety variable was treatment-emergent adverse events (TEAEs) spontaneously reported to, or observed by, the treating physician. Based on safety data from previous studies of LCM and known side effects of other ASMs, certain TEAEs (including but not limited to cardiac and electrocardiogram, suicidality, and rash related terms) were analyzed separately. Effectiveness variables included Clinical Global Impression of Change (CGIC) and change in 28-day seizure frequency from baseline to 12 months (or final visit), and freedom from focal seizures. RESULTS: A total of 171 patients were treated with LCM, of whom 139 (81.3%) completed the study. The Kaplan-Meier estimated 12-month retention was 82.9%. Patients had a mean (standard deviation [SD], range) age of 38.5 (14.0, 16-77) years, and 96 (56.1%) were male. Patients were taking a mean (SD, range) of 2.8 (1.1, 1-6) ASMs at baseline. Mean (SD, range) duration of LCM treatment was 288.7 (111.9, 2-414) days, and the mean (SD, range) daily dosage of LCM was 205.0 (82.7, 50.0-505.2) mg/day. Overall, 95 (55.6%) patients reported at least one TEAE, most commonly dizziness (33 [19.3%] patients). Drug-related TEAEs were reported in 74 (43.3%) patients, and drug-related TEAEs leading to discontinuation of LCM were reported in 14 (8.2%) patients. Two (1.2%) patients died during LCM treatment, which were considered not related to LCM. Two (1.2%) patients had suicidality-related TEAEs; these TEAEs were considered either not related to LCM or the relationship was not recorded. Rash-related TEAEs were reported in five (2.9%) patients (considered LCM-related in two patients). Based on the CGIC, at 12 months (or final visit), 109 (63.7%) patients were considered to have improved, 54 (31.6%) had no change, and the remaining eight (4.7%) were minimally worse. At 12 months (or final visit), the median percentage change in focal seizure frequency was -50.0. During the first 6 months of the study, 21 (12.3%) patients were free from focal seizures; 37 (21.6%) patients were free from focal seizures in the last 6 months of the study; and 14 (8.2%) were free from focal seizures for the full 12 months of the study. CONCLUSIONS: Results of this prospective, noninterventional study suggest that adjunctive LCM was generally safe and well tolerated in this patient group in real-world practice in Taiwan. Effectiveness was also favorable, with more than 60% of patients considered to be improved by their physician at 12 months (or final visit).

Guided Growth Improves Coxa Valga and Hip Subluxation in Children with Cerebral Palsy.

BACKGROUND: Spastic hip subluxation or dislocation that is associated with an excessive coxa valga deformity is a common pathologic condition in children with cerebral palsy (CP) that is often treated with large bone reconstructive procedures. Guided growth techniques (such as stapling, plate, or transphyseal screw) have been widely used to alter the growth axis in patients with a lower-limb deformity but only a few reports have described their use in patients with coxa valga deformities. QUESTIONS/PURPOSES: (1) Does guided growth surgery using a transphyseal screw combined with adductor tenotomy prevent progressive coxa valga deformity and lateral hip subluxation in children with CP? (2) What factors influence the correction of coxa valga deformity and the success of hip stabilization? (3) What complications were associated with this operation and how often did children treated with it undergo reoperation? METHODS: From 2012 to 2016, at our institution, three authors (H-CH, KNK, K-WW) retrospectively studied data on children with CP who underwent guided growth of the hip for progressive bilateral hip subluxation associated with coxa valga deformities. A single percutaneous screw was inserted across the inferomedial portion of proximal femoral physis in an AP view and centered along femoral neck in lateral view under fluoroscopy guidance. During the period, we treated 25 consecutive children with CP who had progressive hip subluxation with coxa valga deformities. The indications for surgery were migration percentage > 30% and head-shaft angle > 155° with at least 2 years growth remaining. Of those, 13 patients underwent guided growth alone, and 48% (12) underwent a combination of guided growth and adductor tenotomy. Of the 25 patients treated with this approach, 96% (24) were available for follow-up with complete data at a minimum of 2 years follow-up (mean 50 months; range 25 to 72). All children (17 boys and seven girls; 48 hips) underwent surgery at a mean age of 8 years (range 5 to 12). With regard to the gross motor function classification system, three patients were Level 1, four patients were Level II, seven patients were Level III, seven were Level IV, and three were Level V. Radiographic parameters including the head-shaft angle, Hilgenreiner's epiphyseal angle, acetabular index, and Reimer's migration percentage were assessed before surgery and at the latest follow-up examination by one author (H-CH). Complications and reoperations were assessed by chart review. During the period in question, we generally offered secondary reconstructive surgery to patients who underwent a guided growth procedure once their subluxation progressed. RESULTS: With the data available, the coxa valga and lateral hip subluxation improved in terms of the reduction of head-shaft angle by a mean of 13° ± 7° (95% CI 11 to 15; p < 0.001) and the reduction of the migration percentage by 10% ± 11% (95% CI 7 to 13; p < 0.001). After controlling for potentially confounding variables like gender, gross motor function classification system, Hilgenreiner's epiphyseal angle and acetabular index, we found that longer follow-up duration (r = 0.234; p < 0.001) and a smaller preoperative migration percentage (r = -0.258; p = 0.004) were associated with larger changes in the head-shaft angle. In terms of complications, we found that the proximal femoral physis grew off the screw tip in 44% (21 of 48 hips) at a mean of 28 months. Among these, 31% of hips (15 of 48) in 33% of patients (eight of 24) underwent replacement with a longer screw. Among the 17% of hips (eight of 48) in 21% of patients (five of 24) who had progressive lateral subluxation and underwent secondary reconstructive surgery, we found that their preoperative acetabular index was higher (mean 29° versus 21°; p < 0.001), as was their head-shaft angle (mean 166° versus 162°; p = 0.045), and migration percentage (mean 54% versus 36 %; p < 0.001). CONCLUSIONS: Although guided growth with single transphyseal screw did not create as large a degree of varus as proximal femoral osteotomy, it did stabilize the hip in children with cerebral palsy with migration percentage less than 50% in our series. It is a simple procedure that can be of benefit to children with cerebral palsy with unstable hip. Reoperation in patients where the physis has grown off the screw tip can be a problem; fortunately, it is a rather minor procedure to replace with a longer screw. LEVEL OF EVIDENCE: Level III, therapeutic study.

Clinical, Electroencephalographic Features and Prognostic Factors of Cefepime-Induced Neurotoxicity: A Retrospective Study.

BACKGROUND: The incidence of cefepime-induced neurotoxicity (CIN) has been previously underestimated, and there have only been sporadic reports from critical neurological settings. The present study aimed to investigate the potential factors associated with disease development, electroencephalography (EEG) sub-classification, and outcome measures. METHODS: The 10-year medical records of patients who underwent EEG between 2007 and 2016 at a tertiary medical center in Taiwan, and developed encephalopathy after cefepime therapy were retrospectively reviewed. Age- and sex-matched controls were included for further analysis. Demographic data, the occurrence of clinical seizures, non-convulsive status epilepticus (NCSE), use of antiepileptic drugs (AEDs), receiving maintenance or urgent hemodialysis, EEG findings, and functional outcomes were analyzed. The Chi-square test and a logistic regression model were applied to survey significant prognostic factors relating to mortality. RESULTS: A total of 42 CIN patients were identified, including 25 patients from wards and 17 from intensive care units; their mean age was 75.8 ± 11.8 years. Twenty-one patients (50%) had chronic kidney disease, and 18 (43%) had acute kidney injury. Among these patients, 32 (76%) received appropriate cefepime dose adjustment. Three patients had a normal renal function at the time of CIN onset. The logistic regression model suggested that maintenance hemodialysis and longer duration of cefepime use were independently associated with the development of CIN, with odds ratios of 3.8 and 1.2, respectively. NCSE was frequently noted in the CIN patients (64%). Generalized periodic discharge with or without triphasic morphology was the most common EEG pattern (38%), followed by generalized rhythmic delta activity and generalized spike-and-waves. AEDs were administered to 86% of the patients. A total of 17 patients (40%) did not survive to hospital discharge. Adequate cefepime dose adjustment and early cefepime discontinuation led to a better prognosis. CONCLUSIONS: CIN was associated with high mortality and morbidity rates. Neurotoxic symptoms could still occur when the cefepime dose was adjusted, or in patients with normal renal function. Patients with maintenance hemodialysis or a longer duration of cefepime therapy tended to develop CIN. Early recognition of abnormal EEG findings allowed for the withdrawal of the offending agent, resulting in clinical improvements and a better prognosis at discharge.

Low and High Frequency Hippocampal Stimulation for Drug-Resistant Mesial Temporal Lobe Epilepsy.

OBJECTIVE: Electrical stimulation of the hippocampus offers the possibility to treat patients with mesial temporal lobe epilepsy (MTLE) who are not surgical candidates. We report long-term follow-up results in five patients receiving low or high frequency hippocampal stimulation for drug-resistant MTLE. MATERIALS AND METHODS: The patients underwent stereotactic implantation of quadripolar stimulating electrodes in the hippocampus. Two of the patients received unilateral electrode implantation, while the other three received bilateral implantation. Stimulation of the hippocampal electrodes was turned ON immediately after the implantation of an implantable pulse generator, with initial stimulation parameters: 1 V, 90-150 µs, 5 or 145 Hz. The frequency of seizures was monitored and compared with preimplantation baseline data. RESULTS: Two men and three women, aged 27-61 years were studied, with a mean follow-up period of 38.4 months (range, 30-42 months). The baseline seizure frequency was 2.0-15.3/month. The five patients had an average 45% (range 22-72%) reduction in the frequency of seizures after hippocampal stimulation over the study period. Low frequency hippocampal stimulation decreased the frequency of seizures in two patients (by 54% and 72%, respectively). No implantation- or stimulation-related side effects were reported. CONCLUSIONS: Electrical stimulation of the hippocampus is a minimally invasive and reversible method that can improve seizure outcomes in patients with drug-resistant MTLE. The optimal frequency of stimulation varied from patient to patient and therefore required individual setting. These experimental results warrant further controlled studies with a large patient population to evaluate the long-term effect of hippocampal stimulation with different stimulation parameters.

Nephroscope-assisted single trocar peritoneal dialysis catheter insertion improves catheter survival compared with laparoscopic technique: Ten-year experience of a single-center.

BACKGROUND: An ideal technique for peritoneal dialysis (PD) catheter insertion should provide a long-term functioning catheter until permanent renal replacement therapy becomes available. We developed a technique using the nephroscope-assisted single-trocar approach in 2011. In this study, we report the outcomes, learning curve analysis and cost-effectiveness analysisof the nephroscopic approach compared with the traditional laparoscopic approach. METHOD: Between January 2005 and December 2020, we retrospectively reviewed 511 patients who received PD catheter insertions using the laparoscopic or nephroscopic approach. We compared the baseline characteristics of the patients, surgical outcomes, and complications of the two groups. We further analyzed the nephroscopic group to determine the cost-effectiveness analysis, learning curve and the complication frequency between the learning and mastery periods of the nephroscopic approach. RESULTS: A total of 208 patients underwent laparoscopic PD catheter insertion, whereas 303 patients received nephroscopic surgery. The median catheter survival in the nephroscopic group is significantly longer (43.1 vs. 60.5 months, p = 0.019). The incidence of peritonitis (29.3% vs.20.8%, p = 0.035) and exit site infection (12.5% vs. 6.6%, p = 0.019) were significantly lower in the nephroscopic group. The cost-effectiveness analysis showed a medical expense reduction of 16000 USD annually by using the nephroscopic technique. There was no difference in the frequency of surgical complications between the learning and mastery phases when examining the learning curve analysis for the nephroscopic technique. CONCLUSIONS: Compared with the traditional laparoscopic approach, the nephroscopic technique effectively prolonged catheter survival and reduces health care cost by reducing infectious complications. The low complication rate during the learning phase of surgery makes the procedure safe for patients and surgeons.

The relationship between health-promoting behaviors and resilience in patients with chronic kidney disease.

This cross-sectional research study explored differences in health-promoting behavior and resilience among three groups of chronic kidney disease patients (high-risk, early chronic kidney disease; early CKD and pre-end stage renal disease; pre-ESRD) treated at the Nephrology outpatient clinic in northern Taiwan. A total of 150 CKD outpatients were interviewed using structured questionnaires including a CKD Health to Promote Lifestyle Scale, and resilience scale. We found that the pre-ESRD group had lower resilience than either high-risk or early CKD groups. Factors affecting pre-ESRD resilience were gender, occupational status, diabetes and health-promoting behaviors. Factors affecting resilience of the high-risk group included level of education and health-promoting behaviors while factors affecting resilience in the early CKD group involved whether they are employed and health promoting behaviors. A significant positive correlation was found between health promoting behavior and resilience in all study subjects. Multiple regression analysis found that factors which could effectively predict resilience in patients at high-risk for CKD were gender, whether the patient had a job, nutrition, self-actualization, and stress level, accounting for 69.7% of the variance. Therefore, nursing education should focus on health promotion advocacy throughout the life of not only patients but also their families.

Survival Outcomes of Patients with Esophageal Cancer Who Did Not Proceed to Surgery after Neoadjuvant Treatment.

BACKGROUND: This retrospective study examined outcomes in esophageal squamous cell carcinoma (ESCC) patients who did not undergo surgical resection after neoadjuvant chemoradiotherapy (nCRT). METHODS: Patients receiving nCRT between 2012 and 2020 were divided into two groups: group 1 (scheduled surgery) and group 2 (no surgery). Group 2 was further categorized into subgroups based on reasons for not proceeding to surgery: group 2a (disease progression), group 2b (poor general conditions), and group 2c (patient refusal). Overall survival (OS) was the primary outcome. RESULTS: Group 1 comprised 145 patients, while subgroups 2a, 2b, and 2c comprised 24, 16, and 31 patients, respectively. The 3-year OS rate was significantly lower in group 2 compared with group 1 (34% versus 56%, p < 0.001). A subgroup analysis showed varying 3-year OS rates: 13% for group 2a, 25% for group 2b, and 58% for group 2c (p < 0.001). Propensity score matching for group 2c and group 1 revealed no significant difference in 3-year OS rates (p = 0.91). CONCLUSION: One-third of ESCC patients receiving nCRT did not undergo surgical resection. Overall survival in this group was generally poorer, except for those who refused surgery (group 2c).

Clinical impact of therapeutic drug monitoring for newer anti-seizure medications in patients with epilepsy: A real-world observation study.

BACKGROUND: The clinical value of therapeutic drug monitoring (TDM) for newer anti-seizure medications (ASMs) remains uncertain. This study aimed to assess the impact of newer ASM TDM on clinical decision making in patients with epilepsy. METHODS: We retrospectively identified all plasma requests for newer ASM level measurement as part of routine clinical management in the outpatient departments of seven medical institutes across Taiwan between September 2016 and May 2019. Data collected from reviewed medical records included clinical and medication details, indications for TDM request, test results, interpretation, and impact on patient management. RESULTS: A total of 682 visits with 1051 plasma samples were included. The most frequently analyzed ASMs were levetiracetam (36.1%), oxcarbazepine (18.4%), and lamotrigine (12.0%). Reasons for TDM included poorly controlled seizures (55.3%), concerns about drug-drug interactions (12.3%), and suspicion of drug overdose (10.6%). 68.8% of samples were within the orienting therapeutic range, even for patients with poorly controlled seizures. TDM for non-adherence concerns showed 54.3% below the orienting therapeutic range, while ASM-related adverse events assessment only 8.9% showed levels exceeding the orienting therapeutic range. Following TDM results, 64.2% of cases had medication adjustments, mainly dosage increases. Overall, 55.9% of newer ASM TDM visit showed improved outcomes, including reduced seizures (47.5%) and fewer ASM-related side effects (8.4%). CONCLUSIONS: These findings suggest that appropriate utilization of TDM for newer ASMs provides clinical benefits in adjunct to complement clinical decision making in the management of epilepsy patients in a real-world clinical setting.

Juvenile Myoclonic Epilepsy: Seizure and Social Outcomes in Taiwan.

Patients with juvenile myoclonic epilepsy (JME) may not achieve seizure freedom despite optimal treatment with antiseizure medications (ASMs). The aim of this study was to investigate the clinical and social features of patients with JME, and to determine the factors associated with outcomes. We retrospectively identified 49 patients with JME (25 females, mean age 27.6 ± 8.9 years) who were assessed at the Epilepsy Centre of Linkou Chang Gung Memorial Hospital in Taiwan. The patients were divided into two groups, those who were seizure-free and those with ongoing seizures according to their seizure outcome at the last follow-up for one year. Clinical features and social status were compared between these two groups. Twenty-four (49%) of the JME patients were seizure-free for at least one year, while 51% continued to experience seizures despite being treated with multiple ASMs. The presence of epileptiform discharges in the last electroencephalogram and seizures during sleep were significantly associated with worse seizure outcomes (p < 0.05). The patients who were seizure-free had a higher employment rate compared to those who continued to experience seizures (75% vs. 32%, p = 0.004). Despite receiving ASM treatment, a considerable proportion of the patients with JME continued to have seizures. Moreover, poor seizure control was associated with a lower employment rate, which may lead to negative socioeconomic consequences related to JME.

Determining patients with spinal metastases suitable for surgical intervention: A cost-effective analysis.

BACKGROUND: Both nonoperative and operative treatments for spinal metastasis are expensive interventions. Patients' expected 3-month survival is believed to be a key factor to determine the most suitable treatment. However, to the best of our knowledge, no previous study lends support to the hypothesis. We sought to determine the cost-effectiveness of operative and nonoperative interventions, stratified by patients' predicted probability of 3-month survival. METHODS: A Markov model with four defined health states was used to estimate the quality-adjusted life years (QALYs) and costs for operative intervention with postoperative radiotherapy and radiotherapy alone (palliative low-dose external beam radiotherapy) of spine metastases. Transition probabilities for the model, including the risks of mortality and functional deterioration, were obtained from secondary and our institutional data. Willingness to pay thresholds were prespecified at $100,000 and $150,000. The analyses were censored after 5-year simulation from a health system perspective and discounted outcomes at 3% per year. Sensitivity analyses were conducted to test the robustness of the study design. RESULTS: The incremental cost-effectiveness ratios were $140,907 per QALY for patients with a 3-month survival probability >50%, $3,178,510 per QALY for patients with a 3-month survival probability <50%, and $168,385 per QALY for patients with independent ambulatory and 3-month survival probability >50%. CONCLUSIONS: This study emphasizes the need to choose patients carefully and estimate preoperative survival for those with spinal metastases. In addition to reaffirming previous research regarding the influence of ambulatory status on cost-effectiveness, our study goes a step further by highlighting that operative intervention with postoperative radiotherapy could be more cost-effective than radiotherapy alone for patients with a better survival outlook. Accurate survival prediction tools and larger future studies could offer more detailed insights for clinical decisions.

Comparison of eight modern preoperative scoring systems for survival prediction in patients with extremity metastasis.

BACKGROUND: Survival is an important factor to consider when clinicians make treatment decisions for patients with skeletal metastasis. Several preoperative scoring systems (PSSs) have been developed to aid in survival prediction. Although we previously validated the Skeletal Oncology Research Group Machine-learning Algorithm (SORG-MLA) in Taiwanese patients of Han Chinese descent, the performance of other existing PSSs remains largely unknown outside their respective development cohorts. We aim to determine which PSS performs best in this unique population and provide a direct comparison between these models. METHODS: We retrospectively included 356 patients undergoing surgical treatment for extremity metastasis at a tertiary center in Taiwan to validate and compare eight PSSs. Discrimination (c-index), decision curve (DCA), calibration (ratio of observed:expected survivors), and overall performance (Brier score) analyses were conducted to evaluate these models' performance in our cohort. RESULTS: The discriminatory ability of all PSSs declined in our Taiwanese cohort compared with their Western validations. SORG-MLA is the only PSS that still demonstrated excellent discrimination (c-indexes>0.8) in our patients. SORG-MLA also brought the most net benefit across a wide range of risk probabilities on DCA with its 3-month and 12-month survival predictions. CONCLUSIONS: Clinicians should consider potential ethnogeographic variations of a PSS's performance when applying it onto their specific patient populations. Further international validation studies are needed to ensure that existing PSSs are generalizable and can be integrated into the shared treatment decision-making process. As cancer treatment keeps advancing, researchers developing a new prediction model or refining an existing one could potentially improve their algorithm's performance by using data gathered from more recent patients that are reflective of the current state of cancer care.

A prospective, randomized study assessing different modalities for flushing totally implanted vascular access device in children with malignancy.

BACKGROUND: The totally implanted vascular access device (TIVAD) is commonly used in patients with malignant tumors requiring chemotherapy or long-term intravenous infusion and those with difficulty placing peripheral venous catheters. It could also be used to draw blood in pediatric patients. Thus, how to maintain the patency and longevity of TIVAD is always emphasized. METHODS: In this prospective study, TIVAD was randomly infused in patients under 18 years with three different concentrations of heparinized solutions: 10 mL with 100 U/mL heparin, 20 mL with 10 U/mL heparin, and 30 mL with 10 U/mL heparin. RESULTS: A total of 81 patients (46 males and 35 females) were enrolled in this study from August 2, 2013 to February 1, 2017. The mean age of those who received TIVAD implantation was 7.2 ± 5.3 years, and the mean duration of using TIVAD was 1027.6 ± 369.1 days. Patients without catheter occlusion events experienced significantly shorter hospitalizations, fewer admissions, and fewer punctures than those with catheter occlusion events (p < 0.05). The administration and frequency of blood transfusions, history of bacteremia, and medication history did not increase the risk of catheter occlusion, but puncture frequency increased this risk. In patients with catheter occlusion events (38/81, 46.9%), catheter patency was restored after instillation of urokinase solution. CONCLUSION: In this study, the risk of TIVAD catheter occlusion was only related to puncture frequency regardless of the heparin flush composition or patient characteristics. A high puncture frequency of TIVAD during the 3.5-year study period significantly increased the risk of catheter occlusion. Besides, flushing and locking solutions for TIVAD using heparin at 10 U/mL was effective as using heparin at 100 U/mL regardless of the flushing volume of 10, 20, or 30 mL.

The prognostic impact of lymph node dissection for clinically node-negative upper urinary tract urothelial carcinoma in patients who are treated with radical nephroureterectomy.

BACKGROUND: To evaluate the prognostic impact of lymph node dissection (LND) in patients who underwent radical nephroureterectomy (RNU) with bladder cuff excision (BCE) for clinically node-negative (cN0) upper urinary tract urothelial carcinoma (UTUC). METHODS: We retrospectively enrolled 520 patients with cN0 UTUC in a single tertiary referral center from 2000 to 2015. The patients were divided into three groups: patients with and without pathologically proved lymph node metastasis (pN1-3 and pN0, respectively) and patients without LND (pNx). We analyzed associations between overall survival (OS)/ disease-free survival (DFS)/ cancer-specific survival (CSS) and clinical characteristics. RESULTS: The patients were divided into three groups (pN1-3, pN0 and pNx with 20, 303, and 197 patients, respectively). OS/DFS/CSS in the pN1-3 group were significantly worse (all p<0.001) compared with the pN0 group. However, there were no significant differences between the pNx and pN0 groups. In the multivariate analyses, CSS was only affected by age [(hazard ratio (HR) = 1.03, p = 0.008]), positive surgical margin (HR = 3.38, p<0.001) and pathological T3-4 stages (HR = 4.07, p<0.001). In the subgroup analyses for patients with LND, locally advanced disease (pT3 and pT4) had significantly more metastases [T3-4: 13.91% (16/115) vs. T0-2: 1.92% (4/208), p<0.001]. CONCLUSIONS: In the pN0 group, LND for cN0 UTUC did not show therapeutic benefits in terms of DFS, CSS, and OS. However, LND with RNU allowed optimal tumor staging, through patients still had a poor prognosis. Clinically occult LN metastases were found in 6.2% of our patients.

Robot-Assisted Radiofrequency Ablation Combined with Thermodynamic Simulation for Epilepsy Reoperations.

Repeat craniotomies to treat recurrent seizures may be difficult, and minimally invasive radiofrequency ablation is an alternative therapy. On the basis of this procedure, we aimed to develop a more reliable methodology which is helpful for institutions where real-time image monitoring or electrophysiologic guidance during ablation are not available. We used simulation combined with a robot-assisted radiofrequency ablation (S-RARFA) protocol to plan and execute brain epileptic tissue lesioning. Trajectories of electrodes were planned on the robot system, and time-dependent thermodynamics was simulated with radiofrequency parameters. Thermal gradient and margin were displayed on a computer to calculate ablation volume with a mathematic equation. Actual volume was measured on images after the ablation. This small series included one pediatric and two adult patients. The remnant hippocampus, corpus callosum, and irritative zone around arteriovenous malformation nidus were all treated with S-RARFA. The mean error percentage of the volume ablated between preoperative simulation and postoperative measurement was 2.4 ± 0.7%. No complications or newly developed neurologic deficits presented postoperatively, and the patients had little postoperative pain and short hospital stays. In this pilot study, we preliminarily verified the feasibility and safety of this novel protocol. As an alternative to traditional surgeries or real-time monitoring, S-RARFA served as successful seizure reoperation with high accuracy, minimal collateral damage, and good seizure control.