Current status of advance care planning, palliative care consultation, and end-of-life care in patients with glioblastoma in South Korea.

BACKGROUND: Given the typical trajectory of glioblastoma, many patients lose decision-making capacity over time, which can lead to inadequate advance care planning (ACP) and end-of-life (EOL) care. We aimed to evaluate patients' current ACP and EOL care status. PATIENTS AND METHODS: We conducted a cohort study on 205 patients referred to oncologists at a Korean tertiary hospital between 2017 and 2022. We collected information on sociodemographic factors, cancer treatment, palliative care consultation, ACP, legal documents on life-sustaining treatment (LST) decisions, and aggressiveness of EOL care. RESULTS: With a median follow-up time of 18.3 months: 159 patients died; median overall survival: 20.3 months. Of the 159 patients, 11 (6.9%) and 63 (39.6%) had advance directive (AD) and LST plans, respectively, whereas 85 (53.5%) had neither. Among the 63 with LST plans, 10 (15.9%) and 53 (84.1%) completed their forms through self-determination and family determination, respectively. Of the 159 patients who died, 102 (64.2%) received palliative care consultation (median time: 44 days from the first consultation to death) and 78 (49.1%) received aggressive EOL care. Those receiving palliative care consultations were less likely to receive aggressive EOL care (83.3% vs 32.4%, P < .001), and more likely to use more than 3 days of hospice care at EOL (19.6% vs 68.0%, P < .001). CONCLUSIONS: The right to self-determination remains poorly protected among patients with glioblastoma, with nearly 90% not self-completing AD or LST plan. As palliative care consultation is associated with less aggressive EOL care and longer use of hospice care, physicians should promptly introduce patients to ACP conversations and palliative care consultations.

Skeletal-Related Events in Patients With Multiple Myeloma: A Comprehensive Retrospective Cohort Study.

BACKGROUND: Multiple myeloma (MM) patients are at risk of skeletal-related events (SREs) like spinal cord compression, pathologic fractures, bone surgery, and radiation to bone. Real-world data regarding SREs in MM are limited. METHODS: We conducted a large, retrospective, nationwide cohort study using the Korean Health Insurance Review and Assessment Service (HIRA) database from 2007 to 2018. RESULTS: Over a 12-year study period, we identified 6,717 patients who developed symptomatic MM. After a median follow-up of 35.1 months (interquartile range [IQR], 20.8-58.2 months), 43.6% of these patients experienced SREs, and 39.6% had four or more SREs. One in five patients (20.0%) experienced pathologic fractures within the first year of follow-up. The median time to first SRE was 9.6 months (IQR, 1.2-25.8 months), with 3.0 months in the group with prior SREs and 19.8 months in the group without prior SREs. During follow-up, 78.5% of patients received bisphosphonates. Multiple logistic regression analysis revealed several factors associated with an increased risk of SREs, including being female (odds ratio [OR], 1.44), aged 50 or older (OR, 1.87), having cerebrovascular disease (OR, 1.34), undergoing first-line chemotherapy regimens not containing bortezomib or lenalidomide (OR, 1.49), and being in the group with prior SREs and bisphosphonate use (OR, 5.63), compared to the group without prior SREs and without bisphosphonate use. CONCLUSION: This population-based study is the first to report the incidence and risk factors of SREs in Korean MM patients, which can be used to assess their bone health.

Machine learning-based model to predict delirium in patients with advanced cancer treated with palliative care: a multicenter, patient-based registry cohort.

This study aimed to present a new approach to predict to delirium admitted to the acute palliative care unit. To achieve this, this study employed machine learning model to predict delirium in patients in palliative care and identified the significant features that influenced the model. A multicenter, patient-based registry cohort study in South Korea between January 1, 2019, and December 31, 2020. Delirium was identified by reviewing the medical records based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. The study dataset included 165 patients with delirium among 2314 patients with advanced cancer admitted to the acute palliative care unit. Seven machine learning models, including extreme gradient boosting, adaptive boosting, gradient boosting, light gradient boosting, logistic regression, support vector machine, and random forest, were evaluated to predict delirium in patients with advanced cancer admitted to the acute palliative care unit. An ensemble approach was adopted to determine the optimal model. For k-fold cross-validation, the combination of extreme gradient boosting and random forest provided the best performance, achieving the following accuracy metrics: 68.83% sensitivity, 70.85% specificity, 69.84% balanced accuracy, and 74.55% area under the receiver operating characteristic curve. The performance of the isolated testing dataset was also validated, and the machine learning model was successfully deployed on a public website ( http://ai-wm.khu.ac.kr/Delirium/ ) to provide public access to delirium prediction results in patients with advanced cancer. Furthermore, using feature importance analysis, sex was determined to be the top contributor in predicting delirium, followed by a history of delirium, chemotherapy, smoking status, alcohol consumption, and living with family. Based on a large-scale, multicenter, patient-based registry cohort, a machine learning prediction model for delirium in patients with advanced cancer was developed in South Korea. We believe that this model will assist healthcare providers in treating patients with delirium and advanced cancer.

Longitudinal Comparative Analysis of Circulating Tumor DNA and Matched Tumor Tissue DNA in Patients with Metastatic Colorectal Cancer Receiving Palliative First-Line Systemic Anti-Cancer Therapy.

Purpose: This study aimed to compare tumor tissue DNA (ttDNA) and circulating tumor DNA (ctDNA) to explore the clinical applicability of ctDNA and to better understand clonal evolution in patients with metastatic colorectal cancer undergoing palliative first-line systemic therapy. Materials and Methods: We performed targeted sequencing analysis of 88 cancer-associated genes using germline DNA, ctDNA at baseline (baseline-ctDNA), and ctDNA at progressive disease (PD-ctDNA). The results were compared with ttDNA data. Results: Among 208 consecutively enrolled patients, we selected 84 (41 males; median age 59, range 35 to 90) with all four sample types available. A total of 202 driver mutations were found in 34 genes. ttDNA exhibited the highest mutation frequency (n=232), followed by baseline-ctDNA (n=155) and PD-ctDNA (n=117). Sequencing ctDNA alongside ttDNA revealed additional mutations in 40 patients (47.6%). PD-ctDNA detected 13 novel mutations in 10 patients (11.9%) compared to ttDNA and baseline-ctDNA. Notably, 7 mutations in 5 patients (6.0%) were missense or nonsense mutations in APC, TP53, SMAD4, and CDH1 genes. In baseline-ctDNA, higher maximal variant allele frequency (VAF) values (p=0.010) and higher VAF values of APC (p=0.012), TP53 (p=0.012), and KRAS (p=0.005) mutations were significantly associated with worse overall survival. Conclusion: While ttDNA remains more sensitive than ctDNA, our ctDNA platform demonstrated validity and potential value when ttDNA was unavailable. Post-treatment analysis of PD-ctDNA unveiled new pathogenic mutations, signifying cancer's clonal evolution. Additionally, baseline-ctDNA's VAF values were prognostic after treatment.

Opioid use and subsequent delirium risk in patients with advanced cancer in palliative care: a multicenter registry study.

The prevalent use of opioids for pain management in patients with advanced cancer underscores the need for research on their neuropsychiatric impacts, particularly delirium. Therefore, we aimed to investigate the potential association between opioid use and the risk of delirium in patients with advanced cancer admitted to the acute palliative care unit. We conducted a retrospective observational study utilizing a multicenter, patient-based registry cohort by collecting the data from January 1, 2019, to December 31, 2020, in South Korea. All data regarding exposures, outcomes, and covariates were obtained through retrospective chart reviews by a team of specialized medical professionals with expertise in oncology. Full unmatched and 1:1 propensity-score matched cohorts were formed, and stratification analysis was conducted. The primary outcome, delirium, was defined and diagnosed by the DSM-IV. Of the 2,066 patients with advanced cancer, we identified 42.8% (mean [SD] age, 64.4 [13.3] years; 60.8% male) non-opioid users and 57.2% (62.8 [12.5] years; 55.9% male) opioid users, respectively. Opioid use was significantly associated with an increased occurrence of delirium in patients with advanced cancer (OR, 2.02 [95% CI 1.22-3.35]). The risk of delirium in patients with advanced cancer showed increasing trends in a dose-dependent manner. High-dose opioid users showed an increased risk of delirium in patients with advanced cancer compared to non-opioid users (low-dose user: OR, 2.21 [95% CI 1.27-3.84]; high-dose user: OR, 5.75 [95% CI 2.81-11.77]; ratio of OR, 2.60 [95% CI 1.05-6.44]). Patients with old age, male sex, absence of chemotherapy during hospitalization, and non-obese status were more susceptible to increased risk of delirium in patients with cancer. In this multicenter patient-based registry cohort study, we found a significant, dose-dependent association between opioid use and increased risk of delirium in patients with advanced cancer. We also identified specific patient groups more susceptible to delirium. These findings highlight the importance of opioid prescription in these patients with advanced cancer, balancing effective doses for pain management and adverse dose-inducing delirium.

Development of a Prediction Model for Delirium in Hospitalized Patients with Advanced Cancer.

Purpose: Delirium is a common neurocognitive disorder in patients with advanced cancer and is associated with poor clinical outcomes. As a potentially reversible phenomenon, early recognition of delirium by identifying the risk factors demands attention. To develop a model to predict the occurrence of delirium in hospitalized patients with advanced cancer. Materials and Methods: This retrospective study included patients with advanced cancer admitted to the oncology ward of four tertiary cancer centers in Korea for supportive cares and excluded those discharged due to death. The primary endpoint was occurrence of delirium. Sociodemographic characteristics, clinical characteristics, laboratory findings, and concomitant medication were investigated for associating variables. The predictive model developed using multivariate logistic regression was internally validated by bootstrapping. Results: From January 2019 to December 2020, 2,152 patients were enrolled. The median age of patients was 64 years, and 58.4% were male. A total of 127 patients (5.9%) developed delirium during hospitalization. In multivariate logistic regression, age, body mass index, hearing impairment, previous delirium history, length of hospitalization, chemotherapy during hospitalization, blood urea nitrogen and calcium levels, and concomitant anti-depressant use were significantly associated with the occurrence of delirium. The predictive model combining all four categorized variables showed the best performance among the developed models (area under the curve 0.831, sensitivity 80.3%, and specificity 72.0%). The calibration plot showed optimal agreement between predicted and actual probabilities through internal validation of the final model. Conclusion: We proposed a successful predictive model for the risk of delirium in hospitalized patients with advanced cancer.

Home-based supportive care in advanced cancer: systematic review.

OBJECTIVES: This study systematically reviewed the literature on the effect of home-based supportive care (HbSC) programmes on the quality of life (QoL) of patients with advanced cancer. METHODS: The research question 'Do home-based supportive care programmes for patients with advanced cancer improve their QoL?' was addressed. After registering the plan with PROSPERO (CRD42022341237), literature published from 1 January 1990 to 30 May 2023 was searched on PubMed, Embase, Cochrane database, CINAHL and Web of Science, and reviewed for inclusion based on predefined criteria. This review only included trial studies published in English. RESULTS: Of 5,276 articles identified, 17 studies were judged suitable for inclusion in this review. The components of HbSC programmes included home visits, patient and caregiver education, home nursing, psychotherapy, exercise, telephone consultation, and multidisciplinary team meetings. Nine studies reported improvements in QoL, including social functioning, emotional functioning, and subjective QoL. CONCLUSION: HbSC programmes appear to enable the improvement of the QoL of patients with advanced cancer. The area of QoL that shows improvement could vary depending on the HbSC components. More studies that address HbSC programmes are needed to select patients at the proper time and provide suitable programmes for patients to benefit most.

Parkin-Mediated Mitophagy by TGF-ß Is Connected with Hepatic Stellate Cell Activation.

Hepatic stellate cells (HSCs) are the main contributors to the development and progression of liver fibrosis. Parkin is an E3 ligase involved in mitophagy mediated by lysosomes that maintains mitochondrial homeostasis. Unfortunately, there is little information regarding the regulation of parkin by transforming growth factor-ß (TGF-ß) and its association with HSC trans-differentiation. This study showed that parkin is upregulated in fibrotic conditions and elucidated the underlying mechanism. Parkin was observed in the cirrhotic region of the patient liver tissues and visualized using immunostaining and immunoblotting of mouse fibrotic liver samples and primary HSCs. The role of parkin-mediated mitophagy in hepatic fibrogenesis was examined using TGF-ß-treated LX-2 cells with mitophagy inhibitor, mitochondrial division inhibitor 1. Parkin overexpression and its colocalization with desmin in human tissues were found. Increased parkin in fibrotic liver homogenates of mice was observed. Parkin was expressed more abundantly in HSCs than in hepatocytes and was upregulated under TGF-ß. TGF-ß-induced parkin was due to Smad3. TGF-ß facilitated mitochondrial translocation, leading to mitophagy activation, reversed by mitophagy inhibitor. However, TGF-ß did not change mitochondrial function. Mitophagy inhibitor suppressed profibrotic genes and HSC migration mediated by TGF-ß. Collectively, parkin-involved mitophagy by TGF-ß facilitates HSC activation, suggesting mitophagy may utilize targets for liver fibrosis.

Clinical validity of oncogenic driver genes detected from circulating tumor DNA in the blood of lung cancer patients.

Background: This study aimed to evaluate the concordance of oncogenic driver mutations between tumor tissues and circulating tumor DNA (ctDNA) in patients with lung cancer. In addition, this study attempted to reveal the clinical utility of ctDNA in lung cancer treatment. Methods: Recurrent or metastatic non-small cell lung cancer (NSCLC) patients were prospectively enrolled in this study. Tumor tissue and serial blood samples were obtained from newly diagnosed patients (Cohort A) or patients treated with targeted therapy (Cohort B) and targeted gene panel sequencing was conducted to identify tumor mutational profiles. Results: At the time of diagnosis, patients in Cohort A with a high cell-free DNA (cfDNA) concentration had poorer overall survival than those with a low cfDNA concentration. The sensitivity and precision of ctDNA analysis in pre-treatment patients compared with those of tissue sequencing were 58.4% and 61.5%, respectively. Known lung cancer-associated variants of oncogenic driver genes, including EGFR and KRAS, and tumor suppressor genes, including TP53 and APC, were frequently detected in the ctDNA of the patients (76.9%). An association between smoking and TP53 mutation status was observed in both tissues and ctDNA (P=0.005 and 0.037, respectively). In addition, the EGFR T790M resistance mutation was detected solely from the ctDNA of two patients after treatment with an EGFR tyrosine kinase inhibitor. Conclusions: ctDNA may be a reliable prognostic biomarker with an additional role in treating patients with lung cancer. Further analyses are necessary to understand the properties of ctDNA and widen its clinical use.

Incidence and Clinical Impact of Endovenous Glue-Induced Hypersensitivity Among Patients Who Underwent Endovenous Cyanoacrylate Ablation Procedures: A Registry-Based Cohort Study.

BACKGROUND: The characteristics of endovenous glue-induced hypersensitivity (EGIH) remain unclear. OBJECTIVE: To assess the clinical impacts on patients with EGIH after endovenous cyanoacrylate-glue ablation (CA). MATERIALS AND METHODS: A prospectively designed endovenous CA-specific registry was created, and a total of 335 limbs from 173 patients who underwent endovenous CA were enrolled for a cohort study. RESULTS: Symptomatic EGIH was observed in 55 (31.8%) patients. Beyond the target vein area, systemic side effects were noted in 5.8% of the treated patients after CA. The median onset time was 13 postoperative days (range: 1-35 days). The median duration was 7 days, but about 10.9% of the affected patients experienced symptoms lasting longer than 4 weeks. In the EGIH and non-EGIH groups, significant improvements in venous clinical severity score and Chronic Venous Insufficiency Quality of Life Questionnaire-14 scores were observed 3 months postoperatively. The development of EGIH did not affect the postoperative patient-reported satisfaction scores ( p = .524). CONCLUSION: EGIH is observed in a substantial proportion of patients. The side effects do not affect the clinical outcomes and patient-reported outcome measures. Further studies are required on the detailed pathogenesis and definition of EGIH.

Mobilization of hematopoietic stem cells with lenograstim in multiple myeloma patients: Prospective multicenter observational study (KMM122).

BACKGROUND: Current guidelines recommend using filgrastim or tbo-filgrastim to mobilize hematopoietic progenitor cells in an autologous setting. However, previous studies have suggested other forms of granulocyte colony-stimulating factor (G-CSF) are equally efficacious, possibly with fewer leukaphereses required. Thus, we prospectively studied the efficacy of lenograstim, a glycosylated recombinant form of G-CSF, in multiple myeloma (MM) patients. METHODS: From November 2011 to January 2020, 98 MM patients undergoing autologous stem cell transplant (ASCT) from five academic centers in Korea were enrolled. Patients were mobilized with subcutaneous lenograstim (Neutrogin®) with fixed doses of 10 µg/kg for 4 days. RESULTS: Most of the patients ( N  = 90, 91.8%) achieved at least the targets of 2 × 106 CD34+ cells/kg body weight, and more than half of MM patients ( N  = 57, 58.2%) reached a target of 5 × 106 CD34+ cells/kg body weight. The mobilization failure rate was 8.2% ( N  = 8). The median number of CD34 + cell/kg using G-CSF only was 5.25 × 106 /kg (range 0.49-13.47). Adverse events included transfusion (TF, N  = 53, 54.1%), bone pain ( N  = 6, 6.1%), fever ( N  = 2, 2.0%), and gastrointestinal troubles ( N  = 2, 2.0%). There were no grade 3 or 4 adverse events during mobilization. Body surface area (BSA) at mobilization and platelet TF were factors associated with CD34+ collection. Most patients achieved neutrophil ( N  = 93, 98.9%) and platelet ( N  = 89, 95.7%) engraftment. CONCLUSION: Lenograstim can safely and effectively mobilize stem cells in MM autologous settings.

The effect of metformin or dipeptidyl peptidase 4 inhibitors on clinical outcomes in metastatic non-small cell lung cancer treated with immune checkpoint inhibitors.

BACKGROUND: Preclinical data have shown the immunomodulatory effects of metformin and dipeptidyl peptidase 4 (DPP4) inhibitors in patients with diabetes. However, its clinical impact remains unclear in lung cancer. METHODS: Between 2017 and 2021, 466 patients received ICI monotherapy. Patients were categorized into concurrent (MET; metformin or combination of metformin and DPP4 inhibitor) and without concomitant (NMET; nonmetformin/DPP4 inhibitors) administration of metformin and DPP4 inhibitors groups at least 8 weeks before and during ICI therapy. The primary objectives were the objective response rate (ORR) and progression-free survival (PFS). The second objective was to evaluate the overall survival (OS) and the occurrence of immune-related adverse events (irAEs). RESULTS: Among 466 patients, 89 (19.0%) and 377 (81%) were categorized into the MET and NMET groups, respectively. MET group had a significantly higher ORR (MET group: 24.7% vs. NMET group: 14.8%, p = 0.025) and longer PFS than those in the NMET group (MET group 5.1 month vs. NMET group 2.8 months, p = 0.018). After patients were stratified based on the prior line of therapy and PD L1 expression status, the PFS of the second-line therapy and PD L1 ≥50 was significantly higher in the MET than in the NMET group. The proportion of patients experiencing all-grade irAEs was numerically higher in the MET group (19.1%) than in the NMET group (14.3%), without statistical significance (p = 0.382). CONCLUSIONS: Concurrent use of metformin and DPP4 inhibitors with ICIs significantly improved the clinical outcomes without increasing the incidence of irAEs in NSCLC.

Performance of mid-upper arm circumference and other prognostic indices based on inflammation and nutrition in oncology outpatients: a tertiary cancer center study.

BACKGROUND: We aimed to compare the performance of established inflammation and nutrition-based prognostic indices with a relatively novel index 'mid-upper arm circumference (MUAC)' in outpatients with advanced cancer. METHODS: This study was a secondary analysis of a prospective cohort study that enrolled 200 outpatients with advanced cancer visiting a medical oncology clinic at a tertiary hospital. All patients were followed until death, and the Glasgow Prognostic Score (GPS), modified GPS (mGPS), Prognostic Nutritional Index (PNI), neutrophil/lymphocyte ratio (NLR), C-reactive protein/albumin ratio (CAR), and MUAC were compared by calculating the area under the receiver operating characteristic curves (AUROCs). RESULTS: The mean age of the patients was 64.4 years, 64.0% were male, and the median overall survival was 32.4 weeks [95% confidence interval (CI): 5.6-142.7]. Overall, all indices showed similarly high AUROCs for estimating 12-week (0.68 to 0.75) and 24-week survival (0.67 to 0.74). When confined to the GPS, mGPS, and MUAC, the AUROCs for 12-week survival were 0.75 (95% CI: 0.66-0.82), 0.74 (95% CI: 0.65-0.82), and 0.72 (95% CI: 0.64-0.79), respectively. For 24-week survival, the AUROCs were 0.70 (95% CI: 0.62-0.76), 0.67 (95% CI: 0.60-0.74), and 0.72 (95% CI: 0.64-0.79), respectively. MUAC had the highest specificity for estimating 12-week survival (86.0%), while GPS showed the highest sensitivity for estimating 12-week survival (81.1%). CONCLUSIONS: Inflammation and nutrition-based prognostic indices showed similar acceptable accuracies in estimating the 12- and 24-week survival of oncology outpatients. Notably, a simple and non-invasive index MUAC, showed comparable performance with established indices including GPS and mGPS.

Clinical Outcomes of Operating an Acute Palliative Care Unit at a Comprehensive Cancer Center.

PURPOSE: Acute palliative care units (APCUs) are inpatient services in tertiary hospitals that provide intensive symptom management and assist in hospital discharge for transitions to hospice care. We aimed to analyze the clinical outcomes of operating an APCU at a comprehensive cancer center. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 1,440 consecutive patients admitted to the APCU and analyzed demographic and clinical information, discharge outcomes, symptom assessments using the Edmonton Symptom Assessment System, spiritual distress, and financial distress. RESULTS: The median age of patients was 67.0 (range, 23-97) years, and 41% were female. The most common primary cancer types were lung (21.9%), hepatopancreatobiliary (14.1%), and colorectal cancers (12.9%). The median length of stay was 8.0 days (range, 1-60 days), and 31.0% of patients died in the APCU. Death in the APCU showed a significant decrease over time, and overall inpatient death in oncology wards did not increase after APCU opening. In total, 44.7% of patients were discharged to government-certified hospice centers. The proportion of patients discharged to certified hospice centers increased from 32.2% in 2015 to 62.4% in 2018. Among 715 patients with a follow-up evaluation 1 week after admission, Edmonton Symptom Assessment System symptom scores, spiritual distress, and financial distress showed statistically significant improvements compared with the baseline symptom scores (P < .001). This improvement was limited to patients who did not die in the APCU. CONCLUSION: Patients with advanced cancer admitted to the APCU may experience significant improvements in distressing symptoms. The majority of patients requiring transition to hospice were successfully transferred to certified hospice centers. The percentage discharged alive improved over time.

Real-World Outcomes of Ruxolitinib in Patients With Myelofibrosis Focusing on Red Blood Cell Transfusion: A Multicenter Study From the MPN Working Party of the Korean Society of Hematology.

INTRODUCTION/BACKGROUND: Ruxolitinib is an established treatment for myelofibrosis (MF) that has demonstrated clinical benefit by reducing spleen size and debilitating MF-related symptoms. However, despite the efficacy of ruxolitinib, anemia remains a major adverse event that causes dose modification or discontinuation in real-world practice. Additionally, dependence on red blood cell (RBC) transfusion (TF) is common during treatment; therefore, we explored the outcome of ruxolitinib therapy with a primary focus on RBC TF. PATIENTS/METHODS: We retrospectively reviewed the medical records of 123 MF patients treated with ruxolitinib between January 2012 and April 2020 at eight academic centers in Korea. RESULTS: At ruxolitinib initiation, 38 patients (30.9%) underwent ≥ 2 units of RBC TF over 8 weeks. The most common reason for permanent discontinuation was intolerant anemia (10/63, 15.9%). The most common reasons for temporary interruption were nonhematologic toxicity (26/55, 21.1%), anemia (23/55, 18.7%) and thrombocytopenia (13/55, 10.6%). Among the 123 patients in the study, 57 (46.3%), 42 (34.1%), and 40 patients (32.5%) who were receiving or stopped ruxolitinib therapy had a status of RBC TF dependence, long-term RBC TF dependence, or severe RBC TF dependence, respectively. The presence of ≥ 2 units of RBC transfusion over 8 weeks at ruxolitinib initiation was an independent risk factor for persistent RBC TF dependence. CONCLUSION: The requirement for RBC TF is commonly encountered during treatment of MF with ruxolitinib, particularly among those with pre-existing ≥ 2 units of RBC TF over 8 weeks. For those patients, overcoming the barrier of maintenance TF is demanding.

Profilometric, volumetric, and esthetic analysis of guided bone regeneration with L-shaped collagenated bone substitute and connective tissue graft in the maxillary esthetic zone: A case series with 1-year observational study.

PURPOSE: The aim of this study was to evaluate 1-year stability and maintenance of peri-implant soft and hard tissues after guided bone regeneration (GBR) with L-shaped collagenated bone substitute and subepithelial connective tissue graft (CTG) in the maxillary anterior region using profilometric, volumetric, and esthetic analyses. METHODS: Fourteen peri-implant defects were grafted with L-shaped collagenated bone substitute, and 5 months after implant placement with GBR, reentry surgery in combination with CTG was performed in all participants. CBCT scans and STL files were acquired at baseline (after implant surgery, T1), reentry surgery (T2), and 1-year follow-up (T3). The profilometric and volumetric changes of the peri-implant tissues were measured, and the pink esthetic score (PES) was assessed at T3. RESULTS: One year after GBR and CTG at the buccal aspect of the maxillary esthetic zone, the mean thickness of the hard tissue (HT) decreased (HT0: -0.87 ± 0.67 mm, HT1: -0.74 ± 0.75 mm, HT2: -0.92 ± 0.48 mm, 45-HT: -0.87 ± 0.73 mm) and the corresponding thickness of the soft tissue (ST) increased (ST0: 0.96 ± 1.06 mm, ST1: 0.85 ± 0.95 mm, ST2: 0.38 ± 0.82 mm, 45-ST: 0.12 ± 0.62 mm), and as a result, there was no statistically significant difference in the total tissue thickness between T1 and T3 (p < 0.05). The mean volumetric changes of the peri-implant tissues increased after 1-year of implant surgery (T1-T2: 1.52 ± 0.83 mm, T2-T3: -0.88 ± 1.04 mm, T1-T3: 0.64 ± 0.90 mm), and a statistically significant difference was shown in all compared time periods (p < 0.05). The mean PES score was 8.07 ± 1.54 at T3 (range, 6-10). CONCLUSION: Within the limitations of this 1-year follow-up study, GBR with an L-shaped collagenated bone substitute and subepithelial CTG in the maxillary esthetic zone was beneficial for stable and maintainable peri-implant hard and soft tissues.

Characteristics of Sweet syndrome in patients with or without malignancy.

Sweet syndrome is a neutrophilic dermatosis occasionally associated with malignancies. Due to its rarity, the clinical features of Sweet syndrome are still unclear. Thus, we aimed to analyze clinical features, treatment, and outcomes of these patients according to associated disease. We conducted a retrospective, longitudinal cohort study from January 2000 to August 2020. We reviewed the medical records of 52 patients with Sweet syndrome. The median age of patients was 57.5 years old (range, 17-84), and 48.1% were female. Of the 52 patients analyzed, 27 patients (51.9%) had malignancy-associated Sweet syndrome. Sweet syndrome was diagnosed concurrently with (N = 8), before (N = 5), and after (N = 14) the diagnosis of malignancy. The idiopathic Sweet syndrome was most common in the non-malignancy group (56.0%). Myelodysplastic syndrome was the most common malignancy associated with Sweet syndrome (47.6%). Leukopenia (p = 0.005), anemia (p < 0.001), and thrombocytopenia (p = 0.008) were significantly associated with malignancy. The majority of patients showed rapid improvement of symptoms after steroid administration. The symptoms of some patients with malignancy did not improve with steroid alone; however, their symptoms often improved when steroids were combined with a treatment for the associated malignancy. Relapse and aggravation of Sweet syndrome were common in the malignancy group. Sweet syndrome showed a broad spectrum of clinical features related to various diseases. Sweet syndrome often occurred as a paraneoplastic feature. Therefore, active systemic evaluation is needed in the first diagnosis of Sweet syndrome without clear etiology.

Cetuximab resistance induced by hepatocyte growth factor is overcome by MET inhibition in KRAS, NRAS, and BRAF wild-type colorectal cancers.

PURPOSE: Recent evidence has highlighted the role of hepatocyte growth factor (HGF) as a putative biomarker to predict EGFR inhibitor resistance. This study investigated the impact of plasma HGF levels on EGFR inhibition and the counter effect of MET inhibition in KRAS, NRAS, and BRAF (RAS/RAF) wild-type colorectal cancers (CRCs). METHODS: Plasma HGF levels were analyzed with clinical outcomes of patients with metastatic CRC (mCRC) receiving palliative first-line chemotherapy. Then, in vitro experiments were conducted to validate the clinical findings and to establish pre-clinical evidence of MET inhibition by capmatinib. RESULTS: A total of 80 patients were included: cetuximab + FOLFIRI (n = 35) and bevacizumab + FOLFIRI (n = 45). Both progression-free survival (PFS) and overall survival (OS) were significantly lesser in the high vs low HGF group: median 11.8 vs. 24.7 months, respectively, for PFS (p = 0.009), and median 21.1 months vs. not reached, respectively, for OS (p = 0.018). The difference was significantly evident in the cetuximab group. In five RAS/RAF wild-type CRC cells, the addition of HGF activated ERK1/2 and AKT via MET phosphorylation, resulting in cetuximab resistance in vitro. In cetuximab-sensitive Caco-2 and SNU-C4 cells, capmatinib overcame cetuximab resistance in the presence of HGF by attenuating HGF-induced MET signaling activation. CONCLUSION: Patients with mCRC receiving cetuximab + FOLFIRI who presented with high plasma HGF levels had significantly worse PFS and OS. Cetuximab resistance induced by HGF was mediated by AKT and ERK activation and overcome by MET inhibition in vitro.

Amphiregulin can predict treatment resistance to palliative first-line cetuximab plus FOLFIRI chemotherapy in patients with RAS wild-type metastatic colorectal cancer.

Amphiregulin (AREG) is an epidermal growth factor receptor (EGFR) ligand. The aim of this study was to investigate the effects of baseline plasma AREG levels in KRAS, NRAS, and BRAF wild-type metastatic colorectal cancer (CRC) on treatment outcome with palliative first-line cetuximab + FOLFIRI chemotherapy. Chemotherapy outcomes were analyzed based on baseline plasma AREG levels. The clinical findings were further validated using an in vitro model of CRC. Among 35 patients, the progression-free survival (PFS) was significantly inferior in patients with high AREG than in those with low AREG levels: 10.9 vs. 24.2 months, respectively (p = 0.008). However, after failure of first-line chemotherapy, AREG levels were associated with neither PFS (4.8 vs. 11.6 months; p = 0.215) nor overall survival (8.4 vs. 13.3 months; p = 0.975). In SNU-C4 and Caco-2 cells which were relatively sensitive to cetuximab among the seven CRC cell lines tested, AREG significantly decreased the anti-proliferative effect of cetuximab (p < 0.05) via AKT and ERK activation. However, after acquiring cetuximab resistance with gradual exposure for more than 6 months, AREG neither increased colony formation nor activated AKT and ERK after cetuximab treatment. Our results suggest that plasma AREG is a potential biomarker to predict clinical outcomes after cetuximab-based chemotherapy.

Augmentation Stability of Guided Bone Regeneration for Peri-Implant Dehiscence Defects with L-shaped Porcine-Derived Block Bone Substitute.

Block bone substitutes have better augmentation stability for guided bone regeneration (GBR) than particulate bone substitutes. This study sought to determine whether GBR with an L-shaped porcine block bone (DPBM-C) differs from GBR with an L-shaped bovine block bone (DBBM-C) based on clinical, radiographic, and volumetric outcomes for peri-implant dehiscence defects. A total of 42 peri-implant defects were grafted with 20 L-shaped DPBM-C and 22 DBBM-C groups. The horizontal and vertical thicknesses of the augmented hard tissue were measured using sagittal cone-beam computed tomography, and the volumetric tissue change was evaluated by stereolithography image superimposition. Postoperative discomfort, early wound healing outcomes, and implant stability were also assessed. Among the clinical (subjective pain and swelling, wound dehiscence, membrane exposure, and periotest values), radiographic (changes in horizontal and vertical hard tissue thickness), and volumetric parameters of the L-shaped DPBM-C and DBBM-C groups during the healing period, only the periotest values showed a statistically significant difference (0.67 ± 1.19, p = 0.042). Within the limitations of this study, an L-shaped DPBM-C is not inferior to an L-shaped DBBM-C based on their clinical, radiographic, and volumetric outcomes for GBR of peri-implant dehiscence defects.