ABSTRACT
Objective@#Electroconvulsive seizure (ECS) is a potent treatment modality for various neuropsychiatric diseases, including Parkinson disease (PD). Recent animal studies showed that repeated ECS activates autophagy signaling, the impairment of which is known to be involved in PD. However, the effectiveness of ECS on PD and its therapeutic mechanisms have not yet been investigated in detail. @*Methods@#Systemic injection of a neurotoxin 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP), which destroys dopaminergic neurons in the substantia nigra compacta (SNc), in mice was utilized to induce an animal model of PD. Mice were treated with ECS 3 times per week for 2 weeks. Behavioral changes were measured with a rotarod test. Molecular changes related to autophagy signaling in midbrain including SNc, striatum, and prefrontal cortex were analyzed with immunohistochemistry and immunoblot analyses. @*Results@#Repeated ECS treatments normalized the motor deficits and the loss of dopamiergic neurons in SNc of the MPTP PD mouse model. In the mouse model, LC3-II, an autophagy marker, was increased in midbrain while decreased in prefrontal cortex, both of which were reversed by repeated ECS treatments. In the prefrontal cortex, ECS-induced LC3-II increase was accompanied with AMP-activated protein kinase (AMPK)-Unc-51-like kinase 1-Beclin1 pathway activation and inhibition of mamalian target of rapamycin signaling which promotes autophagy initiation. @*Conclusion@#The findings revealed the therapeutic effects of repeated ECS treatments on PD, which could be attributed to the neuroprotective effect of ECS mediated by AMPK-autophagy signaling.
ABSTRACT
Benzodiazepines have been widely used as anxiolytics, sedatives, hypnotics, anticonvulsants, or central muscle relaxants since the 1960s despite significant adverse effects, the potential for misuse, and consequent overdose. Benzodiazepines exert their pharmacological action by binding to gamma-aminobutyric acid type A (GABA-A) receptors in the brain and facilitateing the inhibitory actions of the neurotransmitter GABA. Recent findings have also elucidated the effects of benzodiazepines on the allosteric modulation of GABA-A receptors, including receptor subtypes and transmembrane proteins, which is a significant step in our understanding of GABA pharmacology. In clinical practice, the use of benzodiazepines to treat psychiatric disorders has been limited due to the challenges associated with the long-term use, namely the risks of abuse, misuse, and overdose, as well as withdrawal effects. Furthermore, the approval of selective serotonin reuptake inhibitors for anxiety disorders has led to their extensive use as a first-line pharmacological option and they have also been promoted in various practice guidelines for the treatment of anxiety disorders. However, although recent systematic reviews and meta-analyses have shown that benzodiazepines are useful and effective drugs for the treatment of various neuropsychiatric disorders, including anxiety, debates over the clinical use of benzodiazepines continue. More than 60 years after the introduction of benzodiazepines in clinical practice, it is necessary to revisit the controversies associated with benzodiazepine use and to update the discussion current approach to practice with thethrough an understanding of the new data on their pharmacological actions and to identify appropriate indications according to the new diagnostic systems of psychiatric disorders through an extensive literature review.
ABSTRACT
Clonazepam, a 7-nitrobenzodiazepine, has been used for the treatment of various neuropsychiatric disorders such as seizures, sleep disorders, panic disorders, anxiety, and movement disorders. However, clonazepam is officially approved as a therapeutic drug only for epilepsy and panic disorders in Korea. This raises ethical issues in clinical practice, as clonazepam is prescribed off-label for most neuropsychiatric disorders in many other countries as well. The misuse and abuse of clonazepam as a recreational drug have also been commonly reported in global literature. In this review, as a therapeutic drug as the authors aim to highlight the pharmacological aspects, clinical effects, and potential addictive risks of clonazepam use, by reviewing the current literature on clonazepam to increase its clinical use by accurately understanding and identifying its psychopharmacological benefits and characteristics. However, establishing the risk/benefit ratio of clonazepam for use in specific clinical situations is difficult because of the lack of adequate updated data. Therefore, the use of clonazepam needs to be approached from the point of view of personalized drug treatment rather than following fixed guidelines which would not reflect the current real-world clinical practices.
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Purpose@#Several predictive models have been developed to predict the pathological complete response (pCR) after neoadjuvant chemotherapy (NAC); however, few are broadly applicable owing to radiologic complexity and institution-specific clinical variables, and none have been externally validated. This study aimed to develop and externally validate a machine learning model that predicts pCR after NAC in patients with breast cancer using routinely collected clinical and demographic variables. @*Methods@#The electronic medical records of patients with advanced breast cancer who underwent NAC before surgical resection between January 2017 and December 2020 were reviewed. Patient data from Seoul National University Bundang Hospital were divided into training and internal validation cohorts. Five machine learning techniques, including gradient boosting machine (GBM), support vector machine, random forest, decision tree, and neural network, were used to build predictive models, and the area under the receiver operating characteristic curve (AUC) was compared to select the best model. Finally, the model was validated using an independent cohort from Seoul National University Hospital. @*Results@#A total of 1,003 patients were included in the study: 287, 71, and 645 in the training, internal validation, and external validation cohorts, respectively. Overall, 36.3% of the patients achieved pCR. Among the five machine learning models, the GBM showed the highest AUC for pCR prediction (AUC, 0.903; 95% confidence interval [CI], 0.833–0.972).External validation confirmed an AUC of 0.833 (95% CI, 0.800–0.865). @*Conclusion@#Commonly available clinical and demographic variables were used to develop a machine learning model for predicting pCR following NAC. External validation of the model demonstrated good discrimination power, indicating that routinely collected variables were sufficient to build a good prediction model.
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Purpose@#Since tumor mutational burden (TMB) and gene expression profiling (GEP) have complementary effects, they may have improved predictive power when used in combination. Here, we investigated the ability of TMB and GEP to predict the immunotherapy response in patients with non–small cell lung cancer (NSCLC) and assessed if this combination can improve predictive power compared to that when used individually. @*Materials and Methods@#This retrospective cohort study included 30 patients with NSCLC who received immune checkpoint inhibitors (ICI) therapy at the Seoul National University Bundang Hospital. programmed cell death-ligand-1 (PD-L1) protein expression was assessed using immunohistochemistry, and TMB was measured by targeted deep sequencing. Gene expression was determined using NanoString nCounter analysis for the PanCancer IO360 panel, and enrichment analysis were performed. @*Results@#Eleven patients (36.7%) showed a durable clinical benefit (DCB), whereas 19 (63.3%) showed no durable benefit (NDB). TMB and enrichment scores (ES) showed significant differences between the DCB and NDB groups (p=0.044 and p=0.017, respectively); however, no significant correlations were observed among TMB, ES, and PD-L1. ES was the best single biomarker for predicting DCB (area under the curve [AUC], 0.794), followed by TMB (AUC, 0.679) and PD-L1 (AUC, 0.622). TMB and ES showed the highest AUC (0.837) among other combinations (AUC [TMB and PD-L1], 0.777; AUC [PD-L1 and ES], 0.763) and was similar to that of all biomarkers used together (0.832). @*Conclusion@#The combination of TMB and ES may be an effective predictive tool to identify patients with NSCLC patients who would possibly benefit from ICI therapies.
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Purpose@#We aimed to develop a prognostic model to assist palliative care referral at least 3 months before death in advanced cancer patients treated at an outpatient medical oncology clinic. @*Materials and Methods@#In this prospective cohort study, a total of 200 patients were enrolled at a tertiary cancer center in South Korea. The major eligibility criterion was an expected survival of less than a year as estimated by their oncologists. We analyzed the influences of known prognostic factors along with chemotherapy status, mid-arm circumference, and triceps skinfold thickness on survival time. @*Results@#The mean age of the patients was 64.5 years, 36% were female, and the median survival time was 7.6 months. In the multivariate analysis, we found 6 significant factors related to poor survival: a poor Eastern Cooperative Oncology Group (ECOG) performance status (≥2), not undergoing chemotherapy, anorexia, a low lymphocyte level (<12%), a high lactate dehydrogenase (LDH) level (≥300 IU/L), and a low mid-arm circumference (<23 cm). We developed a prognostic model (score, 0-8.0) to predict 3-month survival based on the multivariate analysis. Patients who scored ≥4.0 points had a short survival of less than 3 months (p<0.001). The discriminating ability of the prognostic model using the area under the receiver operating characteristic curve (AUC) was 0.88. @*Conclusion@#The prognostic model using ECOG performance status, chemotherapy status, anorexia, lymphocytes, LDH, and mid-arm circumference can predict 3-month survival in medical oncology outpatients. It can alert oncologists to refer patients to palliative care specialists before it is too late.
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Purpose@#We aimed to assess the real-world efficacy of nab-paclitaxel in metastatic breast cancer patients. @*Materials and Methods@#This is a retrospective study performed in two tertiary referral hospitals in Korea. Patients with metastatic breast cancer treated with nab-paclitaxel (Abraxane®) between March 2016 and March 2020 were enrolled. @*Results@#A total of 102 patients with metastatic breast cancer were included. Patients were heavily pre-treated with a median of four prior lines of chemotherapy (5 lines when including endocrine therapy in hormone-receptor-positive patients), and 66 patients (64.7%) were exposed to taxanes in the metastatic setting. According to St. Gallen molecular subtypes, 36 patients (35.3%) were luminal A, 28 (27.5%) were luminal B, 18 (17.7%) were human epidermal growth factor receptor 2–positive and 20 (19.6%) had triple-negative disease. Fifty patients (49.0%) were treated with a 3-weekly regimen (260 mg/m2 on day 1 every 3 weeks), and 52 (51.0%) were treated with a weekly regimen (100 mg/m2 every week). Objective response rate was 22.9%. After a median follow-up of 22.0 months, median progression-free survival (PFS) was 4.0 months (95% confidence interval [CI], 2.6 to 4.8) and median overall survival was 8.7 months (95% CI, 7.5 to 11.2). Patients treated with weekly regimen had longer PFS compared to 3-weekly regimen (5.5 vs. 2.3 months, p < 0.001). Multivariate analysis revealed the treatment regimen as an independent prognostic factor for PFS. There was no grade 3 or 4 hypersensitivity reaction. @*Conclusion@#This real-world data shows that nab-paclitaxel is a reasonable treatment option in heavily pre-treated and/or taxane-exposed metastatic breast cancer patients.
ABSTRACT
Objective@#Electroconvulsive therapy (ECT) has been the most potent treatment option for treatment-resistant schizophrenia (TRS). However, the underlying neural mechanisms of ECT in schizophrenia remain largely unclear. This paper examines studies that investigated structural and functional changes after ECT in patients with schizophrenia. @*Methods@#We carried out a systematic review with following terms: ‘ECT’, ‘schizophrenia’, and the terms of various neuroimaging modalities. @*Results@#Among the 325 records available from the initial search in May 2020, 17 studies were included. Cerebral blood flow in the frontal, temporal, and striatal structures was shown to be modulated (n=3), although the results were divergent. Magnetic resonance spectroscopy (MRS) studies suggested that the ratio of N-acetyl-aspartate/creatinine was increased in the left prefrontal cortex (PFC; n=2) and left thalamus (n=1). The hippocampus and insula (n=6, respectively) were the most common regions of structural/functional modulation, which also showed symptom associations. Functional connectivity of the default mode network (DMN; n=5), PFC (n=4), and thalamostriatal system (n=2) were also commonly modulated. @*Conclusion@#Despite proven effectiveness, there has been a dearth of studies investigating the neurobiological mechanisms underlying ECT. There is preliminary evidence of structural and functional modulation of the hippocampus and insula, functional changes in the DMN, PFC, and thalamostriatal system after ECT in patients with schizophrenia. We discuss the rationale and implications of these findings and the potential mechanism of action of ECT. More studies evaluating the mechanisms of ECT are needed, which could provide a unique window into what leads to treatment response in the otherwise refractory TRS population.
ABSTRACT
Objectives@#Clozapine is the most effective atypical antipsychotic agent for the treatment-resistant schizophrenia (TRS), however, only 40%–70% of TRS patients respond to clozapine. Moreover, TRS encompasses various symptom dimensions. Therefore, augmentation with other medications for clozapine is frequently applied. However, the prescription pattern of clozapine and combined medications in Korea is yet to be examined. This study aims to investigate the maintenance treatment pattern of clozapine and augmentation agents in one Korean tertiary hospital. @*Methods@#The patients with schizophrenia spectrum disorders under clozapine maintenance, defined as one-year clozapine continuation, were subjected for analysis. Medication data at one-year time-point after clozapine initiation was extracted and analyzed. @*Results@#Among total 2897 patients having clozapine prescription experience from January 2000 to December 2018, 1011 patients were on clozapine maintenance. The mean age of clozapine initiation was 30.2 ± 11.3 years, and the maintenance dose of clozapine was 217.8 ± 124.3 mg/day. Combination rate of antipsychotics, mood stabilizers, and antidepressants were 43.5%, 25.3%, 38.6%, respectively. Most frequently prescribed drugs in each category were aripiprazole, valproate, and sertraline. Olanzapine equivalent dose of combined antipsychotics was 10.4 ± 7.7 mg/day. Male patients were prescribed higher dose of combined antipsychotics and higher rate of antidepressants. Female patients had later onset of clozapine prescription. Patients with two or more combined antipsychotics were prescribed higher dose of clozapine and higher rate of antidepressants compared to patients with one combined antipsychotic. @*Conclusions@#Taken together, among the patients taking clozapine, a substantial rate of patients were under polypharmacy. The present findings based on the real-world prescription pattern could provide the valuable clinical information on the treatment of TRSrelated conditions.
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Purpose@#Angiosarcoma is a highly aggressive mesenchymal tumor. Although systemic chemotherapy is often considered for the inoperable or metastatic angiosarcoma, the outcome of such treatment is unsatisfactory and poorly delineated. @*Materials and Methods@#We reviewed electronic medical records of 75 patients with angiosarcoma who were treated with systemic chemotherapy for inoperable or metastatic disease. Patients were classified as having liver involvement if they had either primary or metastatic hepatic lesions. @*Results@#Among the patients evaluated, 51 patients were male (68%) and 24 patients (32%) had primary cutaneous angiosarcoma. Liver involvement was present in 28 patients (37.3%). A total of 59 patients received first-line weekly paclitaxel (wPac) and showed an objective response rate (ORR) of 23.7% (n=14), a median progression free survival (mPFS) of 4.0 months (95% confidence interval [CI] 3.0–6.1), and a median overall survival (mOS) of 10.2 months (95% CI 7.0–14.6). Among patients without liver involvement, patients receiving wPac (n=35) had significantly prolonged mPFS (5.8 vs. 3.2 months, respectively, p=0.014) with a tendency for prolonged mOS (13.8 vs. 11.6 months, respectively, p=0.13) than those receiving other regimens (n=12). A total of 24 patients received second- or later-line pazopanib monotherapy and showed an ORR of 16.7% (n=4), a mPFS of 2.4 months (95% CI 1.8–4.3) and a mOS of 5.4 months (95% CI 3.5–NA). @*Conclusion@#Treatment with first-line wPac and later-line pazopanib seems to provide survival benefit, especially for patients with advanced angiosarcoma without liver involvement.
ABSTRACT
Background@#High-dose chemotherapy followed by autologous stem cell transplantation (HDC-ASCT) as a consolidation treatment is a promising approach for eligible patients with newly diagnosed primary central nervous system lymphoma (PCNSL). @*Methods@#In this retrospective analysis, 22 patients with newly diagnosed PCNSL received chemotherapy with rituximab, methotrexate, procarbazine, and vincristine. Those who showed complete or partial response subsequently received consolidation HDC-ASCT with a thiotepa-based conditioning regimen but did not undergo radiotherapy. @*Results@#The PCNSL patients had a median age of 57 years (range, 49‒67 yr); of the total patients, 9.1% had a performance status of 2 or higher, and 72.1% had multiple lesions.Approximately 82% of patients received six cycles of induction chemotherapy, which was well tolerated with excellent disease control. The rate of confirmed or unconfirmed complete response increased from 45.5% at the period of interim analysis to 81.8% prior to the initiation of HDC-ASCT. With a median follow-up of 19.6 months (range, 7.5‒56.5 mo), the 2-year progression-free survival and overall survival estimates were 84% and 88%, respectively. No treatment-related deaths occurred. Grade 3 toxicity was recorded in 90.9% of the patients after undergoing the HDC-ASCT, and the most common grade 3 adverse event was febrile neutropenia without sepsis. @*Conclusion@#The discussed treatment approach is feasible in patients with newly diagnosed PCNSL, yielding encouraging results.
ABSTRACT
Clozapine is the first and most effective atypical antipsychotic drug for treatment-resistant schizophrenia (TRS). After withdrawal of clozapine due to concerns of agranulocytosis, clozapine was reintroduced with a comprehensive safety monitoring system, the clozapine patient monitoring system (CPMS). The reintroduction was a response to the pressure from psychiatrists and patients with TRS and their families. Clozapine is still the best single agent for the treatment of TRS. However, approximately 30% of patients with TRS still show psychotic symptoms. In patients with clozapine-resistant schizophrenia (CRS), augmentation of other antipsychotic agents could be considered after a thorough evaluation of proper clozapine treatment. In this review, the status of clozapine in patients with TRS and CRS will be discussed.
ABSTRACT
The development of immune checkpoint inhibitors has improved the long-term survival of patients with several types of cancers, including bladder and renal cell carcinomas. Atezolizumab, an anti-programmed death-ligand 1 monoclonal antibody, became the first immune checkpoint inhibitor to receive the US Food and Drug Administration approval for the treatment of advanced bladder cancer in 2016. Four additional immune checkpoint inhibitors have shown a durable efficacy and have been approved for the treatment of metastatic bladder cancers with progressive disease after treatment with platinum-containing chemotherapy. Currently, trials are exploring the effectiveness of these immune checkpoint inhibitors for first-line or perioperative cancer treatments. The treatment paradigm for advanced and metastatic renal cell carcinomas has also evolved rapidly since the introduction of immune checkpoint inhibitors. Various combinations with immune checkpoint inhibitors, such as nivolumab plus ipilimumab and pembrolizumab plus axitinib, have shown better efficacy than the treatment with sunitinib as first-line treatment for metastatic renal cell carcinoma. The challenges include the development of biomarkers to guide the selection of optimal patients to receive the therapies, the optimization of the sequences of immune checkpoint inhibitors, and the determination of more effective combinations with immune checkpoint inhibitors.
ABSTRACT
Objective@#Electroconvulsive therapy (ECT) has been the most potent treatment option for treatment-resistant schizophrenia (TRS). However, the underlying neural mechanisms of ECT in schizophrenia remain largely unclear. This paper examines studies that investigated structural and functional changes after ECT in patients with schizophrenia. @*Methods@#We carried out a systematic review with following terms: ‘ECT’, ‘schizophrenia’, and the terms of various neuroimaging modalities. @*Results@#Among the 325 records available from the initial search in May 2020, 17 studies were included. Cerebral blood flow in the frontal, temporal, and striatal structures was shown to be modulated (n=3), although the results were divergent. Magnetic resonance spectroscopy (MRS) studies suggested that the ratio of N-acetyl-aspartate/creatinine was increased in the left prefrontal cortex (PFC; n=2) and left thalamus (n=1). The hippocampus and insula (n=6, respectively) were the most common regions of structural/functional modulation, which also showed symptom associations. Functional connectivity of the default mode network (DMN; n=5), PFC (n=4), and thalamostriatal system (n=2) were also commonly modulated. @*Conclusion@#Despite proven effectiveness, there has been a dearth of studies investigating the neurobiological mechanisms underlying ECT. There is preliminary evidence of structural and functional modulation of the hippocampus and insula, functional changes in the DMN, PFC, and thalamostriatal system after ECT in patients with schizophrenia. We discuss the rationale and implications of these findings and the potential mechanism of action of ECT. More studies evaluating the mechanisms of ECT are needed, which could provide a unique window into what leads to treatment response in the otherwise refractory TRS population.
ABSTRACT
Clozapine is the first and most effective atypical antipsychotic drug for treatment-resistant schizophrenia (TRS). After withdrawal of clozapine due to concerns of agranulocytosis, clozapine was reintroduced with a comprehensive safety monitoring system, the clozapine patient monitoring system (CPMS). The reintroduction was a response to the pressure from psychiatrists and patients with TRS and their families. Clozapine is still the best single agent for the treatment of TRS. However, approximately 30% of patients with TRS still show psychotic symptoms. In patients with clozapine-resistant schizophrenia (CRS), augmentation of other antipsychotic agents could be considered after a thorough evaluation of proper clozapine treatment. In this review, the status of clozapine in patients with TRS and CRS will be discussed.
ABSTRACT
The development of immune checkpoint inhibitors has improved the long-term survival of patients with several types of cancers, including bladder and renal cell carcinomas. Atezolizumab, an anti-programmed death-ligand 1 monoclonal antibody, became the first immune checkpoint inhibitor to receive the US Food and Drug Administration approval for the treatment of advanced bladder cancer in 2016. Four additional immune checkpoint inhibitors have shown a durable efficacy and have been approved for the treatment of metastatic bladder cancers with progressive disease after treatment with platinum-containing chemotherapy. Currently, trials are exploring the effectiveness of these immune checkpoint inhibitors for first-line or perioperative cancer treatments. The treatment paradigm for advanced and metastatic renal cell carcinomas has also evolved rapidly since the introduction of immune checkpoint inhibitors. Various combinations with immune checkpoint inhibitors, such as nivolumab plus ipilimumab and pembrolizumab plus axitinib, have shown better efficacy than the treatment with sunitinib as first-line treatment for metastatic renal cell carcinoma. The challenges include the development of biomarkers to guide the selection of optimal patients to receive the therapies, the optimization of the sequences of immune checkpoint inhibitors, and the determination of more effective combinations with immune checkpoint inhibitors.
ABSTRACT
Purpose@#Although the number of elderly patients with breast cancer is increasing as the population ages, their treatment is controversial. We evaluated the prognostic factors associated with survival in elderly breast cancer patients and assessed the impact of comorbidity on prognosis. @*Methods@#This study included 362 patients (aged ≥65 years) who underwent surgery for breast cancer in our institution between 2003 and 2014. The patients were divided into early-aged (65–74 years) and late-aged (≥75 years) groups. Comorbidity was parametrized using the Charlson comorbidity index (CCI). Kaplan–Meier analysis was used to analyze overall survival (OS) and distant metastasis-free survival (DMFS). Prognostic factors were evaluated by Cox proportional hazards regression. @*Results@#The surgical method, subtypes, stage, and oncological features were similar between early- and late-aged groups; however, smaller proportions of patients in the late-aged group received chemotherapy (12.9% vs. 45.5%) and endocrine therapy (55.3% vs. 73.3%). In multivariable analysis, the poor prognostic factors associated with DMFS and OS were high CCI, high histologic grade, and advanced stage. Chemotherapy, endocrine therapy, and radiotherapy were not significantly related to DMFS and OS. @*Conclusion@#In this study, adjuvant treatments did not affect the prognosis of elderly patients with breast cancer. To clarify the effects of adjuvant therapies in these patients, a large-scale retrospective study that considers not only tumor characteristics but also life expectancy is necessary.
ABSTRACT
Modified electroconvulsive therapy (ECT) which started in 1950s is a safe and efficacious treatment for several mental disorders including mood disorders and psychotic disorders. However, its usage in present days is still limited by misconceptions and stigmata of ECT. This paper overviews the background from which the stigmata of ECT stemmed and the current status of stigmata surrounding ECT among the public and medical professionals. In addition, a few potential strategies for reducing stigmata of ECT are provided in this review.
ABSTRACT
Modified electroconvulsive therapy (ECT) which started in 1950s is a safe and efficacious treatment for several mental disorders including mood disorders and psychotic disorders. However, its usage in present days is still limited by misconceptions and stigmata of ECT. This paper overviews the background from which the stigmata of ECT stemmed and the current status of stigmata surrounding ECT among the public and medical professionals. In addition, a few potential strategies for reducing stigmata of ECT are provided in this review.