Tamil Nadu Dr. J Jayalalithaa Fisheries University

Rapid assessment of severity is crucial for timely intervention and improved patient outcomes in heatstroke (HS). However, existing biomarkers are limited in their accuracy and accessibility in ER settings. A prospective pilot study was conducted to assess urinary liver fatty acid-binding protein (L-FABP) levels using a point-of-care testing (POCT) upon HS. Severity was estimated using initial Sequential Organ Failure Assessment (SOFA) scores, and outcomes were measured using modified Rankin Scale (mRS) scores. In 78 severe HS patients, semi-quantitative L-FABP measurements were performed in ER and patients were divided as P-group (positive group, L-FABP ≧ 12.5 ng/mL on POCT) and N-group (negative group: L-FABP < 12.5ng/mL, on POCT). urinary L-FABP concentrations were also measured on admission, with a median concentration of 48.3 ng/mL. The positive correlation was observed between urinary L-FABP concentration and pulse rate (r = 0.300, P < 0.01) and lactate (r = 0.259, P < 0.01). The POCT of L-FABP showed promise in predicting severity, as indicated by higher concentrations in patients with higher initial SOFA scores. Furthermore, the comparison between semi-quantitative POCT measurements and urine concentrations of L-FABP measured by enzyme-linked immunosorbent assay (ELISA) revealed significant differences among three POCT groups (POC Range < 12.5 ng/ml, 12.6–100 ng/ml, and 55 > 100 ng/ml, P = 0.001). Additionally, patients in the POCT positive group had significantly worse outcomes at discharge compared to the negative group, although this difference diminished over time. The study demonstrates the feasibility and potential utility of POCT for initial L-FABP in estimating severity in HS patients. This rapid and accessible testing method may aid in early field triage and intervention, ultimately improving patient outcomes in the management of HS.

Ten-eleven translocation-2 (TET2) gene mutations are observed in 12–20% of adult patients with acute myeloid leukemia (AML). The prognostic impact of TET2 mutations in patients with AML and myelodysplastic syndromes has been reported in several studies; however, their results remain controversial. Therefore, we aimed to analyze the prevalence and significance of TET2 mutations in patients with AML. Data were obtained from 331 patients with AML according to the Hematologic Malignancies-SCREEN-Japan 01 and 02 studies, which were prospective multicenter genomic profiling analyses. We found a distinct type of TET2 mutations, with a particularly detrimental prognosis in the patients. Thirty-five patients with TET2 ‘significant’ mutations were identified (26 with frameshift mutations and nine with nonsense mutations). The proportion of patients with TET2 mutations was 31.7% (10.6% and 21.1% in the TET2 significant and non-significant mutation groups). The TET2 significant mutation group had a shorter OS than the TET2 non-significant mutation or wild-type TET2 group (median: 15.9 vs. 35.0 vs. 25.9 months). Regarding the response to chemotherapy according to TET2 status, the complete response (CR) or CR with incomplete count recovery rate was 37.1% in the TET2 significant mutation group and 46.6% in the non-significant mutation or wild-type group. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) improved patient prognosis in the TET2 non-significant mutation or wild-type TET2 group; however, allo-HSCT did not affect prognosis in the TET2 significant mutation group. This study indicates that certain TET2 mutations in patients with AML may have detrimental effects. 

Severe acute graft-versus-host disease (GVHD) can occur during allogeneic hematopoietic stem cell transplantation (allo-HSCT), causing considerable morbidity and mortality. Although several biomarkers have been reported for predicting acute GVHD, they are often difficult to measure in routine clinical practice. Recently, three-dimensional computed tomography (3D-CT) has been used to quantify the detailed bronchial structure, which might correlate with acute GVHD. We retrospectively evaluated 55 patients who underwent their first allo-HSCT at our hospital between 2016 and 2020. Using 3D-CT analysis, the airway inner luminal area (Ai), wall area (WA), and wall thickness (WT) were measured at each third- to fifth-generation bronchus. Values were adjusted according to body surface area (BSA). Ratios of values at neutrophil engraftment to those of pre-conditioning were assessed. In the cohort, Ai/BSA narrowed, WA/BSA enlarged, and WT/BSA thickened during neutrophil engraftment compared with pre-conditioning. The cumulative incidence of grade II–IV acute GVHD after allo-HSCT was 24%. The ratio of WA/BSA at neutrophil engraftment to that of pre-conditioning in fourth-generation bronchi (WA4/BSA) was significantly lower in patients with grade II–IV acute GVHD compared with those with grade 0–I (0.99 vs. 1.08, P < 0.01). The ratio of WA4/BSA of < 0.955 was significantly associated with the incidence of grade II–IV acute GVHD (< 0.955; 60% vs. ≥ 0.955; 16%, P < 0.01). This is the first study to demonstrate that 3D-CT analyses could quantify changes in bronchial structure during neutrophil engraftment after allo-HSCT; these changes might correlate with the incidence of severe acute GVHD.

Background/Objectives: Unrelated bone marrow transplantation (BMT) is a curative treatment for hematological malignancies. While HLA mismatch is a recognized risk factor in unrelated BMT, the significance of non-HLA single nucleotide polymorphisms (SNPs) remains uncertain. Cytokines play key roles in several aspects of unrelated BMT. Although the relationship between cytokine gene SNPs and BMT outcomes has been examined, the findings obtained have been inconsistent; therefore, further investigations in additional cohorts are warranted. Methods: Four SNPs in the IL2, IL6, IFN-gamma, and TGF-beta1 genes were retrospectively genotyped in 822 malignant patients and their corresponding donors who received unrelated BMT through the Japan Marrow Donor Program with compatibility at minimum HLA-A, -B, and -DRB1. The relationships between these SNP genotypes and BMT outcomes were statistically analyzed. Results: The donor interleukin-6 (IL6) SNP, rs1800796, also known as -572G>C and -634C/G, was associated with the relapse of the original disease in both univariable and multivariable regression analyses (minimum p-value = 0.0013), and the cumulative incidence curve analysis identified CC as a risk genotype (p-value = 0.0012). None of these SNPs correlated with overall survival. Conclusions: The donor IL6 SNP, rs1800796, may serve as a useful predictor of tumor relapses if validated.

AbstractAimDurvalumab plus tremelimumab (Dur/Tre) is a first‐line systemic treatment option for unresectable hepatocellular carcinoma (uHCC). However, the management of severe immune‐mediated adverse events (imAEs) is challenging. Therefore, we investigated the relationship between severe imAEs and antitumor responses in patients with uHCC treated with Dur/Tre.MethodsWe included 157 patients with uHCC treated with Dur/Tre in this multicenter, retrospective study and analyzed the relationship between progression‐free survival (PFS)/antitumor response and severe imAEs requiring high‐dose corticosteroid treatment.ResultsThirty‐two patients (20.4%) developed severe imAEs, including enterocolitis/diarrhea (n = 10), liver injury (n = 9), interstitial lung disease (n = 5), rashes (n = 4), cytokine‐release syndrome/fever (n = 2), pancreatitis (n = 2), and others (n = 4) (median follow‐up period, 6.8 months). Infliximab was administered in six patients with steroid‐refractory enterocolitis. Although the objective response rate (ORR) and disease control rate (DCR) were significantly higher with first‐line therapy than with later‐line therapy (p = 0.026), the frequency of severe imAEs was not significantly different (p = 0.221). The ORR and DCR in patients with and without severe imAEs were 15.6% and 17.6% and 65.6% and 47.2%, respectively, with no significant differences. Five patients with severe imAEs, including rashes and liver injury, showed objective responses (partial response + complete response). Among patients who achieved an objective response, the PFS at 10 months was good (100% and 70.3% with and without high‐dose corticosteroids, respectively).ConclusionsSevere imAEs of Dur/Tre treatment requiring high‐dose corticosteroid treatment did not affect antitumor efficacy, which differed depending on the type of imAEs. Therefore, appropriately managing imAEs is essential to guide sequential treatment.

BACKGROUND: Restenosis after carotid artery stenting (CAS) is associated with the risk of developing ischemic stroke. We aimed to evaluate the inhibitory effect of cilostazol addition on in-stent restenosis (ISR) in patients treated with CAS. METHODS: In a randomized, open-label, blind-end point trial, patients with symptomatic and asymptomatic carotid artery stenosis and scheduled for CAS were randomly assigned to adding cilostazol (50 or 100 mg, twice per day) on other antiplatelets from 3 days before CAS or not adding cilostazol. Concomitant use of other antiplatelets was unrestricted. ISR was diagnosed by a peak systolic velocity of at least 1.75 m/s on duplex ultrasonography. The primary outcome was incidence of ISR within 2 years after CAS. Secondary outcomes included occurrences of cardiovascular events or any death and hemorrhagic events. RESULTS: Participants were recruited from December 2010 to September 2015. Although the sample size was initially set to be 900 (450 in each group), 631 patients (mean age 69.9 years, 558 men, 325 in the cilostazol, and 306 in the noncilostazol group) were included in the primary analysis. Within 2 years’ follow-up, ISR occurred in 31 of 325 patients (cumulative incidence 10.8%) in the cilostazol group and 46 of 306 patients (19.6%) in the noncilostazol group (hazard ratio, 0.64 [95% CI, 0.41–1.0]; P =0.056). In the exploratory analysis, incidence of ISR beyond 30 days after CAS was lower in the cilostazol group than in the noncilostazol group (10.3% versus 19.3%; P =0.040). Incidences of cardiovascular events or any death and hemorrhagic events were similar between the groups (6.2% versus 6.7% and 2.3% versus 1.4%, respectively). CONCLUSIONS: The addition of cilostazol to other antiplatelet agents could contribute to the reduction of ISR in the chronic stage of patients who underwent CAS, the authenticity of which depends on further studies with sufficient statistical power. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01261234.

Abstract Neuronavigation has become an indispensable system for brain tumor surgery, and the fence-post method is useful for removal of intramedullary tumors. However, accurate registration is difficult in the lateral or prone position, and the fence-post method is hesitated. Skull registration is considered to be highly accurate, and we have found a method to perform skull registration with a limited amount of exposed skull. We have found a method to perform skull registration with a limited number of exposed skulls, and we report the results of the fence-post method using this method. from May 2023 to August 2024, patients who underwent the fence-post method in the lateral or supine position were included in the study. The navigation system was a StealthStation S8 (Medtronic), and skull registration was performed from CT. If impossible, a skull section was made in the navigation system according to the surgical site, and registration was performed using the skull localized in the surgical field. We encluded 11 cases, five with glioma and six with metastatic brain tumors. Two cases required a craniotomy larger than 10 cm for temporal lobectomy, and in these cases, skull registration was possible without any special modification. In the other 9 cases, the craniotomy was less than 10 cm, and normal skull registration was not possible, but the skull was limited to the operative field, and the fence-post technique was performed. Three cases of glioma were subtotal, and the others were total resections without complications. If the skull is localized to the operative field and sectioned within the navigation system, skull-based registration will be possible, improving the accuracy of the fence-post method and contributing to the safety of the surgery.

AbstractThe expression of programmed cell death‐ligand 1 (PD‐L1) and mutation in epidermal growth factor receptor (EGFR) are biomarkers used for perioperative treatment of lung adenocarcinoma. However, the clinical significance of PD‐L1 expression in surgically resected EGFR‐mutant lung adenocarcinoma remains unclear. We conducted a real‐world database of patients with surgically resected lung adenocarcinoma from 2015 to 2018 was constructed across 21 centers in Japan. The association among PD‐L1 expression, EGFR mutations, and prognosis was evaluated. Among 847 patients, PD‐L1 expression was negative (tumor proportion score [TPS] < 1%) in 429 (51%), weakly positive (TPS = 1%–49%) in 275 (32%), and strongly positive (TPS ≥50%) in 143 (17%) patients. EGFR mutations were detected in 331 (39%) patients. PD‐L1 expression was associated with poor recurrence‐free survival (RFS) (p < .001) in both EGFR‐mutant and wild‐type patients. However, in EGFR‐mutant patients, PD‐L1 expression was not associated with overall survival (OS) (p = .506). Multivariable analysis confirmed an association between PD‐L1 expression and RFS but not OS. Furthermore, in EGFR‐mutant patients treated with EGFR‐tyrosine kinase inhibitor (EGFR‐TKI) treatment post‐relapse, PD‐L1 expression was not associated with overall response rate (p = .714), disease control rate (p = .554), or progression‐free survival (p = .660). In conclusion, PD‐L1 expression predicted poor RFS‐independent EGFR status but did not show any association with OS in EGFR‐mutant patients. The efficacy of post‐relapse EGFR‐TKI treatment was independent of PD‐L1 expression. The significance of PD‐L1 expression in perioperative EGFR‐TKI therapy should be evaluated.

Background/Objectives: Trans-resveratrol (Res) has been reported to possess many biological activities, including neuroprotective effects, owing to its anti-inflammatory and antioxidant properties. However, Res has very low water solubility, which limits its therapeutic application. In this work, we formulated water-soluble micellar formulations incorporating Res using polyethylene glycol monostearate (stPEG). Methods: These formulations (stPEG/Res) were developed using five types of stPEG containing 10, 25, 40, 55 and 140 PEG repeat units. The formulations were characterized for Res content, water solubility, particle size, zeta potential, precipitation, biodistribution, and efficacy against neuronal and motor dysfunction in intracerebral hemorrhage (ICH). Results: Intravenous administration of stPEG40/Res, which demonstrated particle size, water solubility, and biodistribution properties suitable for intravenous administration, suppressed neurological and motor dysfunction following in a collagenase-induced ICH mouse model. These effects were inhibited by zinc protoporphyrin-9, an inhibitor of the antioxidant enzyme heme oxygenase-1, suggesting that Res contributes to antioxidant enzyme expression and anti-inflammatory activity. Conclusions: The stPEG/Res micellar formulation developed in this study may offer a promising therapeutic approach for ICH treatment.

The efficacy of antifibrotic agents in idiopathic pulmonary fibrosis (IPF) has been demonstrated and early introduction is recommended, especially in patients with preserved performance status (PS). We aimed to determine the proportion of untreated IPF cases using real-world data and to assess the factors associated with non-intervention.

AbstractFibroblast growth factor receptors (FGFRs) are a highly conserved family of transmembrane receptor tyrosine kinases with multiple roles in the regulation of key cellular processes. Specific FGFR mutations have been observed in several types of cancers, including gastric carcinoma and cholangiocarcinoma. Dose escalation data of 24 Japanese patients with solid tumors treated with Tasurgratinib (previously known as E7090), a potent, selective FGFR1–3 inhibitor, was reported in a phase I, first‐in‐human, single‐center study. Based on the safety, pharmacokinetic, and pharmacodynamic profiles observed in this study, the recommended dose of 140 mg once daily was selected for the expansion part (Part 2), a multicenter expansion of the dose‐finding study restricted to patients with tumors harboring FGFR gene alterations. Safety and preliminary efficacy were assessed in Part 2. Pharmacodynamic pharmacogenomic markers (serum phosphate, FGF23, and 1,25‐(OH)2‐vitamin D, circulating tumor DNA) and pharmacokinetic profiles were also evaluated. A total of 16 patients were enrolled in Part 2, six with cholangiocarcinoma and 10 with gastric cancer. The most common treatment‐emergent adverse events were hyperphosphatemia, palmar‐plantar erythrodysesthesia syndrome, and paronychia. Five partial responses (83.3%) in cholangiocarcinoma patients and one partial response (11.1%) in gastric cancer patients were observed; median progression‐free survival was 8.26 months (95% confidence interval [CI] 3.84, not evaluable [NE]) and 3.25 months (95% CI 0.95, 4.86), and overall survival was 22.49 months (95% CI 6.37, NE) and 4.27 months (95% CI 2.23, 7.95), respectively, in the two groups. In conclusion, Tasurgratinib 140 mg has a tolerable safety profile with good clinical efficacy in patients with cholangiocarcinoma harboring FGFR2 gene rearrangements.

Ishiguchi H., Yoshiga Y., Shimizu A., Fukuda M., Omuro A., Hisaoka M., Nakashima Y., Fujita M., Hashimoto S., Omuro T., Ariyoshi T., Kobayashi S., Okamura T., Sano M.

Abstract Background In Japan, the authorized period (2–4 h) between oral administration of 5-aminolevulinic acid hydrochloride (5-ALA) and transurethral resection for non-muscle invasive bladder cancer (NMIBC) may restrict photodynamic diagnosis (PDD) usage. Therefore, this prospective, single-arm, phase III study aimed to evaluate the diagnostic accuracy and safety of PDD at an extended administration period (4–8 h). Methods From January 2022 to May 2023, 161 patients with NMIBC were enrolled from eight hospitals. The primary endpoint was the blue light (BL) sensitivity of pathologically positive biopsies. The secondary endpoints were a comparison of the specificity and positive and negative prediction rates under BL and white light (WL) conditions. Results A total of 1242 specimens comprising 337 histological NMIBC specimens were analyzed. BL-sensitivity was 95.3%. Its lower limit of 95% confidence interval (92.4–97.3%) exceeded the threshold (70%) of non-inferiority to authorized usage. Sensitivity and specificity were significantly higher and lower for BL than those for WL (95.3% vs. 61.1%, P < 0.001; 52.7% vs. 95.2%, P < 0.001), respectively. The positive and negative predictive rates were significantly lower and higher for BL than those for WL (42.9% vs. 82.7%, P < 0.001; 96.8% vs. 86.8%, P < 0.001), respectively. Of the 145 patients receiving 5-ALA, 136 (93.8%) and 75 (51.7%) experienced 377 adverse events and 95 adverse reactions, respectively, most of which were grade 1 or 2. Conclusion For extended period, the efficacy of PDD for NMIBC was similar to that of authorized period, in terms of higher sensitivity and lower specificity compared with WL, and the safety was acceptable.