Association of TP53 Mutation Status and Sex with Clinical Outcome in NSCLC Treated with Immune Checkpoint Inhibitors: A Retrospective Cohort Study.

Purpose: Some studies suggest that TP53 mutations are associated with the response to immune checkpoint inhibitors (ICI) in patients with non-small cell lung cancer (NSCLC) and also contribute to sex disparities in several cancers. Thus, we hypothesized that TP53 mutations might serve as sex-dependent genomic biomarkers of ICI treatment response in patients with NSCLC. Materials and Methods: Clinical data of 100 patients with metastatic NSCLC treated with ICI monotherapy at Seoul National University Bundang Hospital (SNUBH) were retrospectively reviewed. Genomic and clinical datasets of TCGA and an ICI-treated lung cancer cohort (cBioPortal) were also analyzed. Results: In SNUBH cohort, no statistically significant difference was observed in disease control rate per the TP53 mutation status (p=0.503); however, female patients with TP53 mutated (MT) had a significantly prolonged median progression-free survival (PFS) compared to wild-type (WT) (6.1 months in TP53 MT vs. 2.6 months in TP53 WT; p=0.021). PD-L1 high (≥50%) expression was significantly enriched in female patients with TP53 MT (p=0.001). The analysis from publicly available dataset also revealed that females with NSCLC with TP53 MT showed significantly longer PFS than those with TP53 WT (p<0.001). In TCGA analysis, expression of immune-related genes, and TMB score in TP53 MT females were higher than in males without TP53 MT. Conclusion: Female patients with NSCLC with TP53 mutations had high PD-L1 expression and showed favorable clinical outcomes following ICI therapy, suggesting a need for further research to explore the role of TP53 mutations for sex disparities in response to ICI therapy.

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.

Diagnostic Approaches to Investigate JAK2-Unmutated Erythrocytosis Based on a Single Tertiary Center Experience.

INTRODUCTION: Erythrocytosis is attributed to various clinical and molecular factors. Many cases of JAK2-unmutated erythrocytosis remain undiagnosed. We investigated the characteristics and causes of JAK2-unmutated erythrocytosis. METHODS: We assessed the clinical and laboratory results of patients with erythrocytosis without JAK2 mutations and performed targeted next-generation sequencing (NGS) panels for somatic and germline mutations. RESULTS: In total, 117 patients with JAK2-unmutated erythrocytosis were included. The median hemoglobin and hematocrit levels were 17.9 g/dL and 53.4%, respectively. Erythropoietin levels were not below the reference range. Thrombotic events were reported in 17 patients (14.5%). Among JAK2-unmutated patients, 44 had undergone targeted panel sequencing consisting of myeloid neoplasm-related genes, and 16 had one or more reportable variants in ASXL1 (5/44), TET2, CALR, FLT3, and SH2B3 (2/44). Additional testing for germline causes revealed eight variants in seven genes in eight patients, including NF1, BPGM, EPAS1, PIEZO1, RHAG, SH2B3, and VHL genes. One NF1 pathogenic, one BPGM likely pathogenic, and six variants of undetermined significance were detected. CONCLUSION: Somatic and germline mutations were identified in 36.4% and 33.3 % of the JAK2-unmutated group; most variants had unknown clinical significance. Not all genetic causes have been identified; comprehensive diagnostic approaches are crucial for identifying the cause of erythrocytosis.

False-positive results of galactomannan assays in patients administered glucose-containing solutions.

Galactomannan (GM) is a polysaccharide cell wall component released by Aspergillus spp., and an immunoenzymatic GM assay is used for the diagnosis of invasive pulmonary aspergillosis. We evaluated the cause of strong positivity for GM in patients with no typical signs of aspergillosis. Repeat assays were performed using different instruments and reagent lots, but there were no differences in results among the assays. Patients with strongly positive GM results were investigated. Medication histories revealed that 14 of 23 patients had been administered total parenteral nutrition solution from one manufacturer and 4 patients had been administered dextrose solution from a different manufacturer before being tested. The results of GM assays conducted on samples of dextrose solution and the glucose fraction of the total parenteral nutrition solution were strongly positive, confirming the causes of the false-positive reactions. We hypothesize that a trace amount of GM was introduced into the glucose-containing solutions because glucoamylase, which is necessary for the saccharification step of glucose synthesis, was derived from Aspergillus niger. To enhance patient care and prevent unnecessary antifungal prescriptions, healthcare providers and manufacturers of healthcare products need to be aware of the possibility of false-positive reactions for GM.

Microplastic ingestion in aquatic and soil biota: A comprehensive review of laboratory studies on edible size and intake pattern.

Microplastic contamination is ubiquitous and can be transferred through the food chain to humans. However, studies on microplastic size have mainly focused on large animals with a body length >20 mm. To address this gap, we conducted a comprehensive review of 169 laboratory studies to determine the edible size of microplastics for macrofauna and flora in aquatic and soil biota. Our findings indicate that microplastics with a size of <300 µm and 1 µm, respectively, are edible for these organisms, which are positioned at the base of the food chain. We also analyzed intake and depuration patterns and identified factors affecting microplastic ingestion. Our study fills an important knowledge gap by identifying the range of microplastic sizes that can enter the food chain and be transferred to humans. The study findings have strong implications for the ecological risk assessment of microplastics and suggest a starting point for mitigating this threat.

A Phase II Study to Evaluate the Efficacy of Bortezomib in Combination with Thalidomide in Treatment-Naïve Waldenstrom Macroglobulinemia Patients.

PURPOSE: Despite the recent success of Bruton's tyrosine kinase (BTK) inhibitors for the treatment of Waldenstrom macroglobulinemia (WM), their indefinite treatment duration ultimately tantamount to substantial financial and emotional burden. On the other hand, fixed duration of proteasome inhibitors (PI) have shown rapid and reasonable response in WM treatment. Despite the well-known synergism between PI and immunomodulatory drugs (IMiD), there is no trials evaluating such combination in WM. MATERIALS AND METHODS: Based on above, we designed this phase II study to investigate the efficacy and safety of 6 cycles of 28-day bortezomib-thalidomide-dexamethasone (VTD) regimen for treatment-naïve WM. RESULTS: A total of 15 patients were enrolled: major response rate was 64.3%, and overall response rate was 78.6%. During the median follow-up of 41 months, median progression-free survival (PFS) was 13 months and overall survival 40 months. For responders, median duration of response was 13 months and median PFS 19 months. The most common adverse event (AE) of any grade was constipation (57.1%). The most common grade ≥ 3 AE was anemia (21.4%). CONCLUSION: All in all, we hereby provide proof-of-concept that PI + IMiD may be an attractive backbone for fixed duration treatment. It should be noted that granting the same level of access to newer drugs globally is virtually impossible. Thus efforts to develop regimens using readily available drugs to yield similar or adequate treatment outcomes should not be disregarded. In this sense, we believe our study holds its place for its novelty and eloquently addresses achieving the daunting societal quest of health equity.

Microfibers from cigarette butts can induce exoskeletal alteration in whiteleg shrimp (Penaeus vannamei).

Cigarette butts (CB) are a source of microfibers (MFs) in aquatic environments, posing a risk to the health of aquatic organisms. Research has been focused on examining the toxicity of CBs on ecological receptors, including invertebrates. More focus has been on death, growth, or movement inhibition of but less on exoskeletal effects in malacostracans. We evaluated the alteration in the carapace structure of whiteleg shrimp (Penaeus vannamei Boone, 1931) caused by MFs derived from CBs (CB-MF). Exposure to CB-MF damaged the gills, the main organs adsorbing calcium in shrimps to generate a hard carapace, disturbing calcium uptake via respiration. Rapid ecdysis caused on CB-MF exposure reduced the environmental adaptation capacity of crustaceans in the absence of normal pigments in the chromatophore of the carapace. These findings indicate that MFs released from CBs released into the aquatic environment can adversely affect exoskeletal alteration within the overall ecosystem.

Increased risk of venous and arterial thromboembolism in patients with colorectal cancer receiving cetuximab-based combination chemotherapy: A population-based study in Korea.

INTRODUCTION: Limited data exist on the risk of venous and arterial thromboembolisms (VTE and ATE) in patients receiving cetuximab plus chemotherapy. We aimed to determine the thromboembolic risk of patients with recurrent/metastatic colorectal cancer (CRC) treated with cetuximab plus chemotherapy compared to chemotherapy alone. METHODS: This population-based study used nationwide claims data from the Health Insurance Review and Assessment Service of South Korea from 2013 to 2020. Patients with recurrent/metastatic CRC treated with first-line oxaliplatin- or irinotecan-based doublets with or without cetuximab and no secondary prevention for VTE and ATE were included. Primary outcomes were the occurrence of any thromboembolic events, VTE, and ATE, which were determined using the cumulative incidence method incorporating death as a competing event. RESULTS: We identified 19,723 patients (cetuximab plus chemotherapy, N = 7630; chemotherapy alone, N = 12,093). The cumulative incidence of any thromboembolic events in patients with cetuximab plus chemotherapy was significantly higher than in those receiving chemotherapy alone (6-month, 5.62 % vs. 3.58 %, P < 0.0001). The rates of VTE (6-month, 5.11 % vs. 3.28 %, P < 0.0001) and ATE (6-month, 0.53 % vs. 0.32 %, P = 0.0218) were also higher in patients receiving cetuximab plus chemotherapy. In multivariable analysis, cetuximab plus chemotherapy was independently associated with developing any thromboembolic events (hazard ratio [HR], 1.63; 95 % confidence interval [CI], 1.42-1.87), VTE (HR, 1.62; 95 % CI, 1.40-1.87), and ATE (HR, 1.77; 95 % CI, 1.16-2.71). CONCLUSIONS: Cetuximab with irinotecan- or oxaliplatin-based doublet chemotherapy was associated with an increased risk of any thromboembolic events, VTE, and ATE; further studies are warranted to examine the underlying mechanisms.

Non-traditional species sensitivity distribution approaches to analyze hazardous concentrations of microplastics in marine water.

Owing to their ubiquitous nature, microplastics are a major environmental concern. This study reviewed the toxicity data of microplastics in marine water, and analyzed their species sensitivity distribution (SSD) curves and hazardous concentrations (HCs). Toxicity database of no-observed effect concentration (NOEC), 50% effect concentration (EC50), and highest observed no-effect concentration (HONEC), and lethal, developing, reproductive, biochemical, and behavioral toxicity endpoints was used. Using 169 chronic NOEC databases, all non-traditional toxicity endpoint databases showed stronger HC values, better fit, and more variable toxicity sensitivity than those derived from traditional values. Moreover, using 426 chronic NOEC, EC50, and HONEC data points, HC values calculated from traditional plus HONEC toxicity values showed weaker HC values, slightly better fit, and more variable toxicity sensitivity than those derived from traditional toxicity values. The SSD approach using non-traditional toxicity and marine water toxicity data can expand the marine water toxicity database, including information on SSD curves and HCs of diverse microplastics.

Potential effects of natural aging process on the characteristics and toxicity of facial masks: A zebrafish-based study.

The use of facial masks has increased and is therefore being recognized as a large source of environmental microplastics. Herein, we naturally aged disposable masks in a lake for eight weeks and compared the toxicity of mask-derived microplastics depending on the aging process using zebrafish (Danio rerio). Zebrafish were exposed to virgin and aged mask fragments (VF and AF, respectively) for eight weeks. The aging process induced cracks on the surface of mask fragments and chemical adsorption. Both VF and AFs damaged the zebrafish's liver, gills, and intestine and adversely affected their digestive ability, and their movement-aggression was decreased. These observations highlight the consequences of indiscriminately discarding masks or AFs following consumption. In conclusion, personal protective equipment waste in the environment should be appropriately managed to prevent negative impacts on aquatic organisms and, consequently, on humans via the food chain.

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.

Understanding hazardous concentrations of microplastics in fresh water using non-traditional toxicity data.

Microplastic pollution has become a major environmental problem, indicating the need to implement quantitative governance standards in combination with reducing or banning single-use plastic. Previous studies have predicted no-effect concentrations for limited microplastic-based toxicity data but have not considered environmentally relevant sizes, shapes, or polymers. To provide high quantity and quality data for microplastics of different sizes, shapes, or polymer compositions, non-traditional and traditional toxicity data may need to be considered in combination. In this study, we reviewed toxicity data for microplastics in freshwaters from 2018 to 2022 and analyzed the toxicity data using traditional and non-traditional methods. Based on 166 chronic traditional toxicity data points, the hazard concentration (HC) values calculated from non-traditional toxicity endpoints or all toxicity endpoints were lower than those calculated from traditional toxicity endpoints. Based on 398 chronic traditional plus non-traditional toxicity data points, the HC values calculated from traditional plus non-traditional values were higher than those calculated from traditional toxicity values. With these results, we developed a new framework for deriving microplastic-specific hazardous concentrations, one that especially considers non-traditional toxicity endpoints and values for microplastics. Overall, this study offers a basis for future management strategies and associated frameworks for mitigating microplastic toxicity.

Assessing the size-dependent effects of microplastics on zebrafish larvae through fish lateral line system and gut damage.

This study evaluated the size-dependent effects of high-density polyethylene (HDPE) fragments in zebrafish. Larvae were exposed to HDPE microplastic (MP) in three sizes, small (14.12 µm), medium (80.32 µm), and large (120.97 µm), at 20 mg/L. Size-dependent effects in terms of MP intake, subsequent gut damage, and behavioral changes were observed. The results showed that HDPE exposure did not affect the survivability of zebrafish larvae but caused two significant changes. First, exposure to large MPs caused the most serious damage to hair cells and mechanosensory receptors in the fish's lateral line system. Second, exposure to MPs < 100 µm resulted in their ingestion by larvae, thereby causing morphological changes in the gastrointestinal tract. All larvae exposed to MPs showed behavioral pattern changes associated with size differences. This study improves our understanding of the effects of MPs on aquatic organisms and highlights the need to implement efficient strategies for plastic waste management.

Interstitial pneumonitis associated with dasatinib treatment for chronic myeloid leukemia or acute lymphoblastic leukemia: case series and a literature review.

Dasatinib, a tyrosine kinase inhibitor, is usually prescribed for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. However, some patients may develop an intolerance to this drug over the years. Among various toxicities related to dasatinib, dasatinib-associated interstitial pneumonitis is not reported frequently in the literature yet. Moreover, published studies have reported only few cases of dasatinib-associated pneumonitis, almost exclusively in chronic myeloid leukemia. In this study, we describe three cases of dasatinib-associated interstitial pneumonitis in patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia (a 56-year-old man, a 34-year-old man, and a 46-year-old woman) at our institution. In all three patients, the time from the initiation of dasatinib therapy to the onset of interstitial pneumonitis varied greatly. Among them, one patient underwent a surgical lung biopsy, which revealed chronic granulomatous inflammation without any causative pathogen. In all patients, dasatinib was discontinued after the diagnosis of interstitial pneumonitis, and two patients were treated with systemic steroids. Although infrequent, dasatinib-induced pneumonitis should be considered a possible diagnosis in dasatinib-treated patients with fever and respiratory symptoms. In addition, hematologists and pulmonologists should be aware of this rare but critical toxicity.

Immunohistochemical Staining to Identify Concomitant Systemic Mastocytosis in Acute Myeloid Leukemia with RUNX1::RUNX1T1.

Systemic mastocytosis with associated hematological neoplasm (SM-AHN) poses diagnostic challenges because of the coexistence of atypical mast cell proliferation and hematological neoplasms. We assessed the presence of SM-AHN in patients with acute myeloid leukemia (AML) with RUNX1::RUNX1T1 from 2014 to 2020. Bone marrow (BM) samples were evaluated for mast cell aggregates using CD117 and CD25 immunohistochemical (IHC) staining. The KIT D816V variant burden at diagnosis and post induction was assessed using droplet digital PCR. Among 23 patients diagnosed as having AML with RUNX1::RUNX1T1, four (17.4%) were also diagnosed as having SM-AHN. No significant differences in clinical characteristics or overall survival (P=0.565) were observed between patients with or without SM-AHN, except for the presence of KIT variants (P=0.040). After induction therapy, IHC staining revealed the presence of mast cell aggregates in the BM, and the KIT D816V variant burden decreased with decreasing blast count and was similar in BM aspirates, smear slides, and sections. Concomitant SM-AHN was not infrequent in AML patients with RUNX1::RUNX1T1. This study showed the importance of CD117 and CD25 IHC staining after induction chemotherapy for SM-AHN screening, especially in patients with KIT variants.

Treatment and Bleeding Complications of Cancer-Associated Venous Thromboembolism: A Korean Population-Based Study.

OBJECTIVES: This study investigated the treatment pattern and the rate of bleeding complications in real-world practice in cancer-associated venous thromboembolism (CT) patients. METHODS: We used the Korean Health Insurance Review and Assessment Service database (2014-2018). Among patients with venous thromboembolism, patients with concomitant malignancy diagnostic codes were categorized as CT, while all others were categorized as non-CT. Treatments were categorized as direct oral anticoagulant (DOAC), parenteral anticoagulant (PAC), warfarin, and mixed anticoagulants. RESULTS: We identified 27,205 CT and 57,711 non-CT patients. DOACs were the most frequently used anticoagulants. The proportion of patients treated with PAC was higher in CT than in non-CT patients (35.7 vs. 19.5%; p < 0.01). In CT, the cumulative incidence of any/major bleeding was higher with DOAC (8.1%/3.9%) than with PAC (7.5%/3.2%; p = 0.04 and 0.01, respectively). However, there was no difference in major bleeding when compared with warfarin (p = 0.11) or mixed anticoagulants (p = 0.94). Overall, gastrointestinal (GI) cancer patients showed higher risks of bleeding. The cumulative incidence of major GI bleeding was higher with DOAC than with PAC (4.9 vs. 3.0%; p < 0.01), while there was no difference compared with warfarin (p = 0.59) or mixed anticoagulants (p = 0.80). Major bleeding with each DOAC showed no difference among entire CT (p = 0.94), GI cancer (p = 0.27), and genitourinary cancer (p = 0.88) patients. CONCLUSION: Five years after their introduction into clinical practice, DOACs have become the most prescribed anticoagulant in Korea. In our patient population, bleeding complications occurred more frequently in CT than in non-CT, especially in patients treated with DOACs.

Incidence of Venous Thromboembolism: The 3rd Korean Nationwide Study.

BACKGROUND: The incidence of venous thromboembolism (VTE) has gradually increased in the Korean population. This study aimed to evaluate the annual age- and sex-adjusted incidence rates (ASR) of VTE and anticoagulation trends between 2014 and 2018. METHODS: Using the Korean Health Insurance Review and Assessment Service database, we retrospectively identified VTE patients between 2014 and 2018 using both diagnostic and medication anticoagulant codes assigned within 6 months of the initial index event. Anticoagulant patterns were classified as follows: direct oral anticoagulants (DOAC), parenteral anticoagulants, warfarin, and mixed anticoagulation regimens. RESULTS: We identified 95,205 patients with VTE (female, 56.8%). The ASR for VTE per 100,000 person-years increased from 32.8 in 2014 to 53.7 cases in 2018 (relative risk of 1.63; 95% confidence interval, 1.6-1.67). The VTE incidence rates were 25 times higher in the ≥ 80 group than in the 30s group. VTE occurred 1.29 times more often in women than in men. The proportion of DOAC prescriptions increased from 40.5% to 72.8%, whereas warfarin prescriptions decreased from 27% to 5.6% in 2014 and 2018. CONCLUSION: In Korea, the ASRs of VTE continued to increase since 2014, but the rate of increase slowed in 2018. The VTE occurred more often in the elderly and in women. Five years after the introduction of DOACs in 2013, they accounted for 73% of all anticoagulants used to treat VTE.