Ultrasound-Guided Modified Thread Carpal Tunnel Release for Carpal Tunnel Syndrome: A Pilot Study.

PURPOSE: This study aimed to investigate the effectiveness and safety of modified thread carpal tunnel release (mTCTR) using Smartwire-01 in patients with carpal tunnel syndrome (CTS). MATERIALS AND METHODS: Patients with CTS who required CTR were enrolled. Symptom severity and functional status were assessed using the Boston Carpal Tunnel Syndrome Questionnaire-Symptom Severity Scale (BCTQ-SSS) and Functional Status Scale (BCTQ-FSS), and pain was assessed using a numerical rating scale (NRS) at 4, 8, and 12 weeks after mTCTR. The scores were compared with the pre-procedural scores. The electrophysiologic study and median nerve cross-sectional area (CSA) measurements at the wrist before and 12 weeks after mTCTR were compared. RESULTS: A total of 11 patients were included. No adverse effects were reported throughout the study period. The NRS, BCTQ-SSS, and BCTQ-FSS scores significantly improved at 4 weeks after mTCTR, and this improvement persisted throughout the follow-up period (NRS and BCTQ-SSS, P < 0.001; BCTQ-FSS, P = 0.012). After 12 weeks, the latency and velocity of the median sensory nerve action potential significantly improved, compared with those before mTCTR (latency, 5.4 ± 1.3 to 4.7 ± 1.1 ms, P = 0.01; velocity 27.8 ± 6.8 to 31.8 ± 7.4 m/s, P = 0.019). No significant change was observed in the median nerve CSA before and after mTCTR. CONCLUSION: mTCTR using Smartwire-01 is a safe and effective procedure and a possible alternative to surgery.

Identification of depression in patients with acute coronary syndrome using multiple serum biomarkers.

BACKGROUND: Biomarkers for depression in patients with acute coronary syndrome (ACS) have not been identified. METHODS: This study evaluated multiple serum biomarkers for depressive disorders after ACS. Thirteen serum biomarkers associated with seven functional systems, along with sociodemographic/clinical characteristics, were evaluated in 969 patients within 2 weeks after ACS onset (acute phase). In total, 711 patients were evaluated for depressive disorder using DSM-IV criteria 1 year later (chronic phase). Logistic regression was used for the analysis. RESULTS: Depressive disorders were observed in 378 patients (39.0%) in the acute phase of ACS and 183 patients (25.7%) in the chronic phase. The weighted scores of five serum biomarkers (high-sensitivity C-reactive protein, interleukin-6, homocysteine, troponin I, and creatine kinase-MB) were significantly associated with depressive disorder diagnosis in the acute phase, and the weighted scores of three other biomarkers (tumor necrosis factor-alpha, interleukin-1 beta, and homocysteine) were significantly associated with depressive disorders in the chronic phase, in a dose-dependent manner after adjusting for relevant covariates (all P-values <0.001). CONCLUSIONS: The combination of several serum biomarkers exhibited robust associations with depressive disorders in both the acute and chronic phases of ACS.

Predicting suicidal ideation using multiple serum biomarkers in patients with acute coronary syndrome.

BACKGROUND: Biomarkers for suicidal behavior in patients with acute coronary syndrome (ACS) have yet to be elucidated. This study aimed to identify a panel of serum biomarkers associated with suicidal ideation (SI) in patients with ACS. METHODS: The study evaluated 969 patients within 2 weeks of ACS (acute phase) and 711 patients 12 months later (chronic phase). The evaluation included 14 serum biomarkers covering 7 functional systems, socio-demographic/clinical characteristics, and SI assessed by the "suicidal thoughts" item of the Montgomery-Åsberg Depression Rating Scale. Logistic regression models were used to analyze the data. The results showed that 195 patients (20.1 %) had SI in the acute phase, and 87 patients (12.2 %) had SI in the chronic phase. RESULTS: A combination of five serum biomarkers (tumor necrosis factor-α, interleukin-1ß, folate, troponin I, and creatine kinase-MB) was significantly associated with SI in the acute phase, and a combination of three serum biomarkers (tumor necrosis factor-α, interleukin-1ß, and folate) was significantly associated with SI in the chronic phase in a clear dose-dependent manner (all P-values < 0.001) after adjustment for relevant covariates. DISCUSSION: These findings suggest that the application of a combination of multiple serum biomarkers could improve the predictability of SI in patients with ACS at both acute and chronic phases.

Use of Serum Biomarkers to Aid Antidepressant Selection in Depressive Patients.

Objective: : This study aimed to identify serum biomarkers prospectively associated with remission at 12 weeks in out-patients with depressive disorders receiving stepwise psychopharmacotherapy, according to the main antidepressant used during the treatment period. Methods: : This study included 1,024 depressive outpatients initially treated using antidepressant monotherapy, followed by alternating pharmacological strategies during the acute phase (3-12 weeks; 3-week interval). Fourteen serum biomarkers, sociodemographics, and clinical characteristics were evaluated at baseline. Based on the use frequency and mechanism of action, four main antidepressant types were distinguished: escitalopram, other selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and mirtazapine. A Hamilton Depression Rating Scale score ≤ 7 was take to indicate remission. Results: : Lower high-sensitivity C-reactive protein levels were correlated with remission at 12 weeks for all antidepressant types. Lower interleukin (IL)-6 levels and tumor necrosis factor-alpha levels were associated with remission using escitalopram and other SSRIs respectively. Lower IL-1ß and leptin levels, predicted remission in association with SSRIs including escitalopram. For SNRIs, remission at 12 weeks was predicted by lower IL-4 and IL-10 levels. For mirtazapine, remission at 12 weeks was associated with lower leptin levels, and higher serotonin and folate levels. Conclusion: : Baseline serum status, as estimated by nine serum markers, may help clinicians determine the most appropriate antidepressant to achieve remission in the acute phase of depression.

The moderating role of circadian gene polymorphisms in the relationship between sleep disturbance and circulating lymphocyte subsets in colorectal cancer patients.

AIM: We investigated the impact of sleep disturbance on immune status in colorectal cancer (CRC) patients with consideration of the moderating role of circadian clock gene polymorphisms. METHODS: A prospective longitudinal study design was used to collect information regarding sleep disturbance. Blood samples for immunologic assays were obtained the day before the first (baseline) and last cycles of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. Clinical sleep disturbance was compared between the two-time points using the Pittsburgh Sleep Quality Index (PSQI) global score. We analysed single-nucleotide polymorphisms in rs2278749, rs3749474, rs2291738, rs17031614, and rs2287161. The dependent variables included changes in the percentages of CD4+, CD8+, CD19+, and CD16/56+ lymphocytes between the two-time points. The results were analysed using moderated regression analysis; the p-values were adjusted using the false discovery rate. RESULTS: Among the 104 patients, no significant dyadic associations were observed between changes in lymphocyte percentages and the PSQI global score. However, the moderated regression analysis revealed five significant associations (rs2287161 with CD8+, rs2278749 and rs2291738 with CD19+, and rs17031614 with CD4+ and CD16/56+ lymphocytes). The inclusion of each interaction resulted in a significant increase (5.7-10.7%) in the variance explained by changes in lymphocyte percentage. CONCLUSION: Patients with specific circadian gene allele types may be more susceptible to immune dysregulation when experiencing sleep disturbances. Considering that sleep disturbance is a modifiable factor that can impact immune regulation, it is essential to prioritise the management of sleep disturbances in CRC patients receiving FOLFOX chemotherapy.

Peripheral Markers of Suicidal Behavior: Current Findings and Clinical Implications.

Biomarkers of suicidal behavior (SB), particularly peripheral biomarkers, may aid in the development of preventive and intervention strategies. The peripheral biomarkers of SB should be easily accessible, cost-effective, and minimally invasive. To identify peripheral biomarkers of SB, we summarized the current knowledge related to SB biomarkers with a focus on suicidal outcomes (suicidal ideation [SI], suicide risk [SR], suicide attempt [SA], and suicide death [SD]), measured site (center or periphery), and study design (cross-sectional or longitudinal). We also evaluated the central findings to validate the findings of peripheral biomarkers of SB. We found reduced peripheral interleukin (IL)-2 levels in individuals with a recent SA, higher cerebrospinal fluid (CSF) IL-6 levels in patients with a current SR and future SD, higher CSF tumor necrosis factor-α levels for current and future SRs, higher high-sensitivity C-reactive protein levels and lower peripheral total cholesterol levels for recent SAs, lower peripheral 5-HT levels for present SR, and a lower folate level for future SR and SA within 1 year. Previous studies have shown inconsistent associations of low peripheral leptin levels with SR and recent SA; therefore, further study is required. Given the multiple determinants of SB and weak associations with single biological markers, combinations of potential biological markers rather than single markers may improve the screening, diagnosis, and prediction of SB.

Inflammatory markers of symptomatic remission at 6 months in patients with first-episode schizophrenia.

Neuroinflammation contributes to the pathophysiology of various mental illnesses including schizophrenia. We investigated peripheral inflammatory cytokines as a biomarker for predicting symptomatic remission in patients with first-episode schizophrenia. The study included 224 patients aged 15-60 years who fulfilled the criteria for schizophrenia spectrum disorder with a treatment duration ≤6 months. Serum levels of tumor necrosis factor (TNF) -α, interferon-γ, interleukin (IL)-1α, IL-1ß, IL-6, IL-8, IL-10, and IL-12 were measured. Psychotic symptoms, depressive symptoms, and general functioning were assessed using the Positive and Negative Syndrome Scale, Beck Depression Inventory (BDI), Calgary Depression Scale for Schizophrenia, and Personal and Social Performance scale, respectively. Duration of untreated psychosis (DUP) was also recorded. We investigated the factors associated with remission for each sex in logistic regression analysis. In total, 174 patients achieved remission at the 6-month follow-up (females, 83.5%; males, 70.9%). Remission was associated with older age and lower BDI scores in male patients and with lower TNF-α levels and shorter DUP in female patients. Our findings suggest that peripheral inflammatory cytokines may impede early symptomatic remission in female patients with schizophrenia. In addition, depressive symptoms in males and long DUP in females may be poor prognostic factors for early remission in patients with first-episode psychosis.

Anti-Inflammatory Effect of Cinnamomum japonicum Siebold's Leaf through the Inhibition of p38/JNK/AP-1 Signaling.

Cinnamomum japonicum Siebold (CJ) branch bark, commonly known as Japanese cinnamon, has been used for various culinary and medicinal applications for many centuries. Although the efficacy of CJ branch bark's anti-inflammatory and antioxidant activity for the treatment of various diseases has been confirmed, the efficacy of CJ leaves (CJLs) has not been examined. We therefore investigated whether CJL3, an ethyl acetate extract of a 70% ethanol CJL extract, exerts anti-inflammatory effects on lipopolysaccharide (LPS)-activated Kupffer cells, specialized macrophages found in the liver. Liver inflammation can activate Kupffer cells, inducing the release of pro-inflammatory molecules that contribute to tissue damage. We found that CJL3 has high 2,2-diphenyl-1-picrylhydrazyl and 2,2-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) radical-scavenging activity. Among the CJL extracts, CJL3 exhibited the greatest polyphenol content, with protocatechuic acid and 4-hydroxybenzoic acid being the most abundant. In addition, we verified that CJL3, which has strong antioxidant properties, ameliorates LPS-induced pro-inflammatory responses by inhibiting p38/JNK/AP-1 signaling. CJL3 therefore has potential for treating liver disease, including hepatitis.

Correlations of psychological distress with plasma cytokine levels and gene mutations in acral and non-acral melanoma.

Background: The presence of psychological distress has negatively affected the course and prognosis of melanoma. Psychological distress is influenced by cytokines and gene mutations, particularly in cancer, but no studies have investigated this phenomenon in melanoma patients. This study investigated the correlations of psychological distress, plasma cytokine levels, and gene mutations in melanoma patients, focusing on melanoma sites and TNM stages. Methods: This study prospectively evaluated melanoma patients who visited Chonnam National University Hwasun Hospital from September 2020 to March 2021. Melanoma sites were divided into acral and non-acral sites. Anxiety and depression were evaluated using the Hospital Anxiety and Depression Scale, and quality of life was evaluated with EuroQol-5 Dimensions. Plasma cytokine levels, and depression- and cytokine-related gene mutations were analyzed. Results: This study included 151 melanoma patients. Anxiety was found in 14.6% of the patients, and depression in 29.8%. The melanoma sites were not significantly associated with anxiety, depression, or quality of life. However, psychological distress was significantly associated with the plasma cytokines IL-2, IL-4, IL-5, IL-10, IL-12, TNF-α and IFN-γ. COMT, SLC6A4, SLC6A3, and IL-12b gene mutations were also associated with melanoma sites and TNM stage, anxiety, and QOL. Conclusion: Psychological distress was associated with plasma cytokine levels and depression- and cytokine-related gene mutations. Using psychiatric intervention and emotional support, cytokine levels related to melanoma can be changed, which may have positive effects on the prognosis and treatment of melanoma. More careful follow-up, evaluation, and management are needed for patients with gene mutations.

Identification of genes from ten oncogenic pathways associated with mortality and disease progression in glioblastoma.

Glioblastoma multiforme (GBM) is the most malignant brain tumor with an extremely poor prognosis. The Cancer Genome Atlas (TCGA) database has been used to confirm the roles played by 10 canonical oncogenic signaling pathways in various cancers. The purpose of this study was to evaluate the expression of genes in these 10 canonical oncogenic signaling pathways, which are significantly related to mortality and disease progression in GBM patients. Clinicopathological information and mRNA expression data of 525 patients with GBM were obtained from TCGA database. Gene sets related to the 10 oncogenic signaling pathways were investigated via Gene Set Enrichment Analysis. Multivariate Cox regression analysis was performed for all the genes significantly associated with mortality and disease progression for each oncogenic signaling pathway in GBM patients. We found 12 independent genes from the 10 oncogenic signaling pathways that were significantly related to mortality and disease progression in GBM patients. Considering the roles of these 12 significant genes in cancer, we suggest possible mechanisms affecting the prognosis of GBM. We also observed that the expression of 6 of the genes significantly associated with a poor prognosis of GBM, showed negative correlations with CD8+ T-cells in GBM tissue. Using a large-scale open database, we identified 12 genes belonging to 10 well-known oncogenic canonical pathways, which were significantly associated with mortality and disease progression in patients with GBM. We believe that our findings will contribute to a better understanding of the mechanisms underlying the pathophysiology of GBM in the future.

Association between Peripheral Inflammatory Cytokines and Cognitive Function in Patients with First-Episode Schizophrenia.

In this study, we investigated the impact of inflammatory cytokines on the cognitive performance of patients with schizophrenia. The included patients met the criteria for schizophrenia spectrum disorder and were aged between 15 and 40 years, with a duration of illness ≤1 year. Plasma tumor necrosis factor (TNF)-α; interferon-γ; and interleukin (IL)-1ß, IL-6, IL-8, IL-10, and IL-12 levels were measured. A computerized neurocognitive battery, measures for social cognitive function, and clinical measures were administered. A total of 174 patients with first-episode psychosis were enrolled. The TNF-α level was negatively correlated with scores on the digit span, verbal learning, and Wisconsin card sorting tests, and the number of correct responses on the continuous performance test (CR-CPT), whereas a positive correlation was detected with the trail making test (TMT)-B time. The interferon-γ level was negatively correlated with performance on the false belief and visual learning tests. The IL-1ß level was positively correlated with the TMT-A time and CPT reaction time, whereas it was negatively correlated with the CR-CPT and performance on the visual learning and social cognitive tests. The IL-12 level was negatively correlated with the CR-CPT and false belief test. Our results suggest that proinflammatory cytokines are associated with cognitive impairment in patients with schizophrenia.

A synthetic lethal strategy using PARP and ATM inhibition for overcoming trastuzumab resistance in HER2-positive cancers.

Despite its clinical efficacy in HER2-positive cancers, resistance to trastuzumab inevitably occurs. The DNA damage response (DDR) pathway is essential for maintaining genomic stability and cell survival. However, the role of the DDR pathway in HER2-positive tumors and trastuzumab resistance remains elusive. In this study, we verified that increased PARP1 expression in trastuzumab-resistant (TR) cells, owing to its augmented stability by escape from proteasomal degradation, confers tolerability to trastuzumab-induced DNA damage. Interruption of PARP1 in TR cells restrains its cellular growth, while simultaneously activating ATM to retain its genome stability. Dual inhibition of PARP and ATM induces synthetic lethality in TR cells by favoring the toxic NHEJ pathway instead of the HRR pathway. Our results highlight the potential of clinical development of DDR-targeting strategies for trastuzumab-resistant HER2-positive cancer patients.

High DKK3 expression related to immunosuppression was associated with poor prognosis in glioblastoma: machine learning approach.

BACKGROUND: Glioblastoma multiforme (GBM) is an aggressive malignant primary brain tumor. Wnt/ß-catenin is known to be related to GBM stemness. Cancer stem cells induce immunosuppressive and treatment resistance in GBM. We hypothesized that Wnt/ß-catenin-related genes with immunosuppression could be related to the prognosis in patients with GBM. METHODS: We obtained the clinicopathological data of 525 patients with GBM from the brain cancer gene database. The fraction of tumor-infiltrating immune cells was evaluated using in silico flow cytometry. Among gene sets of Wnt/ß-catenin pathway, Dickkopf-3 (DKK3) gene related to the immunosuppressive response was found using machine learning. We performed gene set enrichment analysis (GSEA), network-based analysis, survival analysis and in vitro drug screening assays based on Dickkopf-3 (DKK3) expression. RESULTS: In analyses of 31 genes related to Wnt/ß-catenin signaling, high DKK3 expression was negatively correlated with increased antitumoral immunity, especially CD8 + and CD4 + T cells, in patients with GBM. High DKK3 expression was correlated with poor survival and disease progression in patients with GBM. In pathway-based network analysis, DKK3 was directly linked to the THY1 gene, a tumor suppressor gene. Through in vitro drug screening, we identified navitoclax as an agent with potent activity against GBM cell lines with high DKK3 expression. CONCLUSIONS: These results suggest that high DKK3 expression could be a therapeutic target in GBM. The results of the present study could contribute to the design of future experimental research and drug development programs for GBM.

Prospective associations of multimodal serum biomarkers with 12-week and 12-month remission in patients with depressive disorders receiving stepwise psychopharmacotherapy.

Prognostic biomarkers for depression treatment outcomes have yet to be elucidated. This study sought to evaluate whether a multi-modal serum biomarker panel was prospectively associated with 12-week and 12-month remission in outpatients with depressive disorders receiving stepwise psychopharmacotherapy. At baseline, 14 serum biomarkers and socio-demographic/clinical characteristics were evaluated in 1094 patients. They received initial antidepressant monotherapy followed, as required by a protocol of successive alternative pharmacological strategies administered in 3-week steps during the acute (3-12 week) phase (N = 1086), and in 3-month steps during the continuation (6-12 month) phase (N = 884). Remission was defined as a Hamilton Depression Rating Scale score of ≤ 7. Remission was achieved in 490 (45.1%) over the 12-week, and in 625 (70.7%) over the 12-month, treatment periods. Combination scores of four serum biomarkers (high-sensitivity C-reactive protein, interleukin-1 beta, interleukin-6, and leptin) were prospectively associated with 12-week remission; and four (high-sensitivity C-reactive protein, tumor necrosis factor-alpha, interleukin-1 beta, and brain-derived neurotrophic factor) were prospectively associated with 12-month remission in a clear gradient manner (P-values < 0.001) and after adjustment for relevant covariates. These associations were evident after the Step 1 treatment monotherapy but weakened with increasing treatment steps, falling below statistical significance after 4 + treatment steps. Application of combined multiple serum biomarkers, particularly on inflammatory markers, could improve predictability of remission at acute and continuation treatment phases for depressive disorders. Patients with unfavourable biomarkers might require alternative treatment regimes for better outcomes.

Efficacy of Cytokine-Induced Killer Cell Immunotherapy for Patients With Pathologically Pure Glioblastoma.

The most common malignant central nervous system tumor is glioblastoma multiforme (GBM). Cytokine-induced killer (CIK) cell therapy is a promising type of adoptive cell immunotherapy for various cancers. We previously conducted a randomized clinical trial on CIK cell therapy in patients with GBM. The aim of this study was to evaluate the efficacy of CIK immunotherapy for patients with pathologically pure GBM, using data from our previous randomized clinical trial. The difference between overall survival (OS) and progression-free survival (PFS) according to CIK immunotherapy was analyzed using the Kaplan-Meier method. Hazard ratios were calculated using univariate and multivariate Cox regression analyses to determine whether CIK cell immunotherapy was independently associated with higher OS and PFS in patients with pure GBM. A total of 156 eligible patients were included in the modified intention-to-treat (mITT) population. We confirmed that 125 (80.1%) GBM samples were pure GBM tumors without the presence of other types of tumors. For patients with pure GBM, Kaplan-Meier analysis showed no significant difference in OS between the CIK cell treatment and control groups. However, multivariate Cox regression demonstrated CIK cell immunotherapy as an independent predictor of greater OS (hazard ratio, 0.59; 95% CI, 0.36-0.97; p = 0.038) and PFS (hazard ratio, 0.55; 95% CI, 0.36-0.84; p = 0.001) in patients with pathologically pure GBM in the mITT population. This study showed that CIK cell immunotherapy combined with conventional temozolomide chemoradiotherapy could prolong OS and PFS in patients with newly diagnosed pathologically pure GBM, with no significant adverse events related to treatment. However, unlike the results of multivariate Cox analysis, no statistical significance of CIK cell immunotherapy in OS in Kaplan-Meier analysis raises a question. Further studies are required to validate these results.

Identification of highly selective type II kinase inhibitors with chiral peptidomimetic tails.

Identification of highly selective type II kinase inhibitors is described. Two different chiral peptidomimetic scaffolds were introduced on the tail region of non-selective type II kinase inhibitor GNF-7 to enhance the selectivity. Kinome-wide selectivity profiling analysis showed that type II kinase inhibitor 7a potently inhibited Lck kinase with great selectivity (IC50 of 23.0 nM). It was found that 7a and its derivatives possessed high selectivity for Lck over even structurally conserved all Src family kinases. We also observed that 7a inhibited Lck activation in Jurkat T cells. Moreover, 7a was found to alleviate clinical symptoms in DSS-induced colitis mice. This study provides a novel insight into the design of selective type II kinase inhibitors by adopting chiral peptidomimetic moieties on the tail region.

Interaction effect of the serum interleukin-6 level and anxiety on the 12-week pharmacotherapeutic responses of patients with depressive disorders.

BACKGROUND: Despite the pathogenic role played by interleukin-6 (IL-6) signaling in depression, the association between baseline peripheral IL-6 signaling and the antidepressant treatment responses noted in clinical studies remains controversial. We investigated the effects of the baseline serum IL-6 (sIL-6) level and anxiety symptoms on the 12-week remission rate of depressed outpatients who received stepwise antidepressant treatments. METHODS: At baseline, sIL-6 levels were measured, and anxiety symptoms were evaluated using the Hospital Anxiety Depression Scale-Anxiety subscale (HADS-A), in 1094 patients. All received stepwise antidepressant treatment. Subsequently, 12-week remission, defined as a Hamilton Depression Rating Scale (HAMD) score ≤ 7, was assessed. RESULTS: The individual and interaction effects of the sIL-6 level (as a binary [low vs. high, based on the median value of 1.65 pg/mL] or continuous variable) and the HADS-A score (as a binary [<12 vs. ≥12] or continuous variable) on the 12-week remission rate were analyzed using logistic regression models after adjusting for relevant covariates. Patients with both low sIL-6 levels (<1.65 pg/mL) and HADS-A scores <12 had the highest 12-week remission rate; a significant interaction effect was also apparent. This effect was significant even when the data were analyzed as continuous variables. CONCLUSIONS: Our study suggests that the sIL-6 level can serve as a biomarker predicting the outcome of antidepressant treatment according to the severity of anxiety symptoms.

Gemcitabine and cisplatin plus durvalumab with or without tremelimumab in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, single-centre, phase 2 study.

BACKGROUND: Immunotherapies have shown clinical activity in patients with advanced biliary tract cancer, for which outcomes remain poor despite standard of care treatment with gemcitabine and cisplatin. We aimed to evaluate gemcitabine and cisplatin plus durvalumab with or without tremelimumab as first-line treatment in patients with advanced biliary tract cancer. METHODS: This open-label, single-centre, phase 2 study was conducted at Seoul National University Hospital. Eligible patients were treatment-naïve adults aged 18 years or older with histologically proven unresectable or recurrent biliary tract cancer, at least one measurable lesion based on the Response Evaluation Criteria in Solid Tumors (version 1.1), an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of 12 weeks or longer, and adequate healthy organ and bone marrow function. Initially, all patients received one 3-week cycle of gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) on day 1 and 8 followed by gemcitabine and cisplatin plus durvalumab (1120 mg) and tremelimumab (75 mg) on day 1 of each cycle, starting with the second cycle (chemotherapy followed by chemotherapy plus durvalumab and tremelimumab group). Following protocol amendment, patients were recruited to receive gemcitabine and cisplatin plus durvalumab, starting on day 1 of the first cycle (chemotherapy plus durvalumab group) or gemcitabine and cisplatin plus durvalumab and tremelimumab also from day 1 of the first cycle (chemotherapy plus durvalumab and tremelimumab group) in parallel and allocated using a random block method. Assessors and patients were not masked to the treatment group. The primary endpoint was objective response rate, assessed in the efficacy population (ie, patients who were treated at least until the first tumour response assessment). This study is registered with ClinicalTrials.gov, NCT03046862 (active). FINDINGS: Between March 2, 2017, and Feb 13, 2020, 128 patients were enrolled (32 in the chemotherapy followed by chemotherapy plus durvalumab and tremelimumab group, 49 in the chemotherapy plus durvalumab group, and 47 in the chemotherapy plus durvalumab and tremelimumab group). Four patients (two in the chemotherapy followed by chemotherapy plus durvalumab and tremelimumab group and two in the chemotherapy plus durvalumab group) were excluded and 124 were evaluable for tumour response. The median duration of follow-up was 48·2 months (IQR 41·5-49·4) for the chemotherapy followed by chemotherapy plus durvalumab and tremelimumab group, 26·6 months (19·0-27·9) for the chemotherapy plus durvalumab group, and 24·2 months (20·7-31·7) for the chemotherapy plus durvalumab and tremelimumab group. 82 (66%) of 124 patients achieved an objective response (15 [50%] of 30 in the chemotherapy followed by chemotherapy plus durvalumab and tremelimumab group, 34 [72%] of 47 in the chemotherapy plus durvalumab group, and 33 [70%] of 47 in the chemotherapy plus durvalumab and tremelimumab group). The most common grade 3 and 4 adverse events were decreased neutrophil count (67 [53%] of 126), anaemia (50 [40%]), and decreased platelet count (24 [19%]), with no unexpected safety events. No adverse events leading to discontinuation or death occurred. INTERPRETATION: Gemcitabine and cisplatin plus immunotherapy showed promising efficacy and acceptable safety in patients with biliary tract cancer. Gemcitabine and cisplatin plus durvalumab are being evaluated in the phase 3, TOPAZ-1 study (NCT03875235) as first-line treatment in patients with advanced biliary tract cancer. FUNDING: AstraZeneca; National Research Foundation of Korea (Grant No. 2021R1A2C2007430).

Inhibition of WEE1 Potentiates Sensitivity to PARP Inhibitor in Biliary Tract Cancer.

PURPOSE: Up to 20% of patients with biliary tract cancer (BTC) have alterations in DNA damage response (DDR) genes, including homologous recombination (HR) genes. Therefore, the DDR pathway could be a promising target for new drug development in BTC. We aim to investigate the anti-tumor effects using poly(ADP-ribose) polymerase (PARP) and WEE1 inhibitors in BTC. MATERIALS AND METHODS: We used 10 BTC cell lines to evaluate an anti-tumor effect of olaparib (a PARP inhibitor) and AZD1775 (a WEE1 inhibitor) in in vitro. Additionally, we established SNU869 xenograft model for in vivo experiments. RESULTS: In this study, we observed a modest anti-proliferative effect of olaparib. DNA double-strand break (DSB) and apoptosis were increased by olaparib in BTC cells. However, olaparib-induced DNA DSB was repaired through the HR pathway, and G2 arrest was induced to secure the time for repair. As AZD1775 typically regulates the G2/M checkpoint, we combined olaparib with AZD1775 to abrogate G2 arrest. We observed that AZD1775 downregulated p-CDK1, a G2/M cell cycle checkpoint protein, and induced early mitotic entry. AZD1775 also decreased CtIP and RAD51 expression and disrupted HR repair. In xenograft model, olaparib plus AZD1775 treatment reduced tumor growth more potently than did monotherapy with either drug. CONCLUSION: This is the first study to suggest that olaparib combined with AZD1775 can induce synergistic anti-tumor effects against BTC. Combination therapy that blocks dual PARP and WEE1 has the potential to be further clinically developed for BTC patients.

Prominent Asymmetric Muscle Weakness and Atrophy in Seronegative Immune-Mediated Necrotizing Myopathy.

Immune-mediated necrotizing myopathy, a new subgroup of inflammatory myopathies, usually begins with subacute onset of symmetrical proximal muscle weakness. A 35-year-old male presented with severe asymmetric iliopsoas atrophy and low back pain with a previous history of left lower extremity weakness. Although his first left lower extremity weakness occurred 12 years ago, he did not receive a clear diagnosis. Magnetic resonance imaging of both thigh muscles showed muscle edema and contrast enhancement in patch patterns, and the left buttock and thigh muscles were more atrophied compared to the right side. Serum creatine kinase levels were elevated, and serologic testings were all negative. Genetic testing using a targeted gene-sequencing panel for neuromuscular disease including myopathy identified no pathogenic variants. Muscle biopsy on the right vastus lateralis showed scattered myofiber necrosis with phagocytosis and an absence of prominent inflammatory cells, consistent with seronegative necrotizing myopathy. Thus, unusual asymmetric muscle weakness and atrophy can be a manifestation of inflammatory myopathy.