Phase II Efficacy and Safety of 80 mg Osimertinib in Patients With Leptomeningeal Metastases Associated With Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer (BLOSSOM).

PURPOSE: Leptomeningeal metastases (LMs) exhibit a high incidence in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) post-treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). This investigation evaluates the efficacy, safety, and pharmacokinetics of 80 mg once daily osimertinib in patients with LMs resistant to prior first- or second-generation EGFR TKIs. MATERIALS AND METHODS: In this phase II multicenter, open-label, single-arm study, 80 mg osimertinib was administered to patients with EGFR-mutated NSCLC who had developed LMs subsequent to treatment with prior EGFR TKIs. The primary end point was overall survival (OS), assessed alongside objective response rate by the blinded independent central review (BICR) and a pharmacokinetic analysis of plasma and cerebrospinal fluid (CSF) on the first day of cycles 3 and 6. RESULTS: A total of 73 patients diagnosed with LM were treated with osimertinib, including 64 patients evaluable for the LM efficacy set-T790M negative (n = 62) and T790M positive (n = 2). The median OS in the full-analysis set was 15.6 months (95% CI, 11.5 to 20.2). The objective response rate for LM was 51.6%, including a 15.6% complete response, and the disease control rate was 81.3% by BICR in the LM efficacy evaluable set. The median LM progression-free survival by BICR was 11.2 months (95% CI, 7.7 to 15.3), the duration of response was 12.6 months (95% CI, 7.6 to 17.7), and OS was 15.0 months (95% CI, 11.3 to 18.7). Pharmacokinetic analysis showed that the CSF to free plasma osimertinib ratio was 22%. Most safety profiles were grade 1 and 2. CONCLUSION: The study demonstrates significant intracranial efficacy and survival benefits of 80 mg once daily osimertinib in NSCLC patients with LMs. The data support considering daily 80 mg of osimertinib as a treatment option for EGFR-mutated NSCLC patients with LMs, irrespective of T790M mutation status.

Effect of direct-acting antivirals on disease burden of hepatitis C virus infection in South Korea in 2007-2021: a nationwide, multicentre, retrospective cohort study.

Background: It is unclear whether direct-acting antivirals (DAAs) treatment improves the disease burden in hepatitis C virus (HCV) infection. This study aimed to investigate the effect of DAA treatment on the reduction of disease burden in patients with HCV infection using individual participant data. Methods: This nationwide multicentre retrospective cohort study recruited patients with HCV infection from 29 tertiary institutions in South Korea. The data collection was done from medical records in each institution. The study included the untreated patients and the DAAs-treated patients and excluded those with a history of interferon-based treatments. Disease burden was the primary outcome, as represented by disability-adjusted life years (DALYs). Improvement in fibrosis after DAA treatment was assessed using APRI, FIB-4 index, and liver stiffness (LS) as assessed by transient elastography. Clinical outcomes were hepatocellular carcinoma (HCC), decompensation, and mortality. Findings: Between January 1, 2007, and February 17, 2022, data from 11,725 patients with HCV infection, 8464 (72%) of whom were treated with DAAs, were analysed. DAA treatment significantly improved APRI- (median 0.64 [interquartile range (IQR), 0.35-1.31]-0.33 [0.23-0.52], p < 0.0001), FIB-4- (median 2.42 [IQR, 1.48-4.40]-1.93 [1.31-2.97], p < 0.0001), and liver LS-based fibrosis (median 7.4 [IQR, 5.3-12.3]-6.2 [4.6-10.2] kPa, p < 0.0001). During the median follow-up period of 27.5 months (IQR, 10.6-52.4), 469 patients died (4.0%), 586 (5.0%) developed HCC, and 580 (4.9%) developed decompensation. The APRI-based DALY estimate was significantly lower in the DAA group than in the untreated group (median 4.55 vs. 5.14 years, p < 0.0001), as was the FIB-4-based DALY estimate (median 5.43 [IQR, 3.00-6.44] vs. 5.79 [3.85-8.07] years, p < 0.0001). The differences between the untreated and DAA groups were greatest in patients aged 40-60 years. In multivariable analyses, the DAA group had a significantly reduced risk of HCC, decompensation, and mortality compared with the untreated group (hazard ratios: 0.41 [95% confidence interval (CI), 0.34-0.48], 0.31 [95% CI, 0.30-0.38], and 0.22 [95% CI, 0.17-0.27], respectively; p < 0.0001). Interpretation: Our findings suggest that DAA treatment is associated with the improvement of liver-related outcomes and a reduction of liver fibrosis-based disease burden in patients with HCV infection. However, further studies using liver biopsy are needed to clarify the effect of DAA treatment on the reduction in the exact fibrosis-based disease burden beyond noninvasive tests. Funding: The Korea Disease Control and Prevention Agency.

Nomogram for radiation-induced lymphopenia in patients receiving intensity-modulated radiotherapy based-chemoradiation therapy for newly diagnosed glioblastoma: A multi-institutional study.

Purpose: Severe lymphopenia (SLP) has emerged as a significant prognostic factor in glioblastoma. Intensity-modulated radiation therapy (IMRT)-based radiation therapy (RT) is suggested to minimize the risk of SLP. This study aimed to evaluate SLP incidence based on multi-institutional database in patients with GBM treated with IMRT and develop a predictive nomogram. Patients and methods: This retrospective study reviewed data from 348 patients treated with IMRT-based concurrent chemoradiation therapy (CCRT) at two major hospitals from 2016 to 2021. After multivariate regression analysis, a nomogram was developed and internally validated to predict SLP risk. Results: During treatment course, 21.0% of patients developed SLP and SLP was associated with poor overall survival outcomes in patients with GBM. A newly developed nomogram, incorporating gender, pre-CCRT absolute lymphocyte count, and brain mean dose, demonstrated fair predictive accuracy (AUC 0.723). Conclusions: This study provides the first nomogram for predicting SLP in patients with GBM treated with IMRT-based CCRT, with acceptable predictive accuracy. The findings underscore the need for dose optimization and radiation planning to minimize SLP risk. Further external validation is crucial for adopting this nomogram in clinical practice.

A comparative study of volar locking-plate fixation with corticocancellous and pure cancellous bone grafts for scaphoid nonunion with dorsal intercalated segmental instability secondary to scaphoid humpback deformity.

INTRODUCTION: Bone grafts for scaphoid nonunion with deformity include cortcicocancellous or pure cancellous bone grafts. This study compared the outcomes between two types of bone grafts when employing a volar locking-plate in patients with scaphoid nonunion with dorsal intercalated segmental instability (DISI). PATIENTS AND METHODS: This retrospective study included 34 patients with scaphoid nonunion and DISI due to humpback deformity treated between March 2017 and January 2022. Two types of bone grafts were obtained from iliac crest. Twenty of the corticocancellous (CC) group underwent a wedge-shaped graft, while 14 patients of the pure cancellous (C-only) group received graft chips. In both groups, a 1.5-mm anatomically pre-contoured locking plate was used for fixation. Radiographic evaluations included the union rate and carpal alignment including scapholunate angle (SLA), radiolunate angle (RLA), intrascaphoid angle (ISA) and scaphoid height to length ratio (HLR). Clinical assessments encompassed wrist range-of-motion, grip strength, and patient-reported outcomes. RESULTS: Nineteen of the 20 patients in the CC group and 12 of the 14 patients in the C-only group respectively, achieving osseous union. The mean follow-up period in CC group was 14.7 (range, 12 ∼ 24) months and that in C-only group was 12.6 (range, 12 ∼ 15) months. Postoperatively, there were no significant intergroup differences of radiographic parameters including SLA (CC; 49.9° ± 6.7° vs. C-only; 48.9° ± 3.5°, P = 0.676), RLA (1.7° ± 6.4° vs. 2.4° ± 3.3°, P = 0.74), ISA (36° ± 7.5° vs. 36.6° ± 12.2°, P = 0.881), and HLR (0.54 ± 0.09 vs. 0.53 ± 0.05, P = 0.587). Clinical outcomes, including the flexion-extension arc (137° ± 30° vs. 158° ± 33°, P = 0.122), grip strength (93.4 % ± 15.4% vs. 99.5 % ± 16.7 %, P = 0.39), Quick Disabilities of the Arm, Shoulder, and Hand scores (11.2 ± 8.3 vs. 12.5 ± 7.7, P = 0.74) and Mayo Wrist Scores (81.2 ± 13.1 vs. 89 ± 11.4, P = 0.242) also showed no significant intergroup differences. CONCLUSIONS: Volar locking-plate fixation with pure cancellous bone grafts achieved outcomes comparable to those achieved with corticocancellous bone grafts in scaphoid nonunion with deformity, possibly due to the biomechanical advantages of the volar plate to provide structural supports.

Fibrotic Burden in Patients With Hepatitis B Virus-Related Cirrhosis Is Independently Associated With Poorer Kidney Outcomes.

BACKGROUND: We investigated whether higher fibrotic burden was independently associated with poorer kidney outcomes in patients with hepatitis B virus (HBV)-related cirrhosis. METHODS: A total of 1691 patients with radiologically diagnosed HBV-related cirrhosis but without baseline chronic kidney disease (CKD) who underwent transient elastography (TE) between March 2012 and August 2018 were selected. The study outcome was the composite of development of incident CKD, defined as the occurrence of estimated glomerular filtration rate (eGFR) <60 mL/minute/1.73 m2 or proteinuria (≥1+ on dipstick test) on 2 consecutive measurements during follow-up, 50% decline in eGFR or onset of end-stage kidney disease (initiation of chronic dialysis), or all-cause mortality. RESULTS: The mean age was 53.4 years and 1030 (60.9%) patients were male. During 8379 person-years of follow-up (median 5.2 years), 60 (3.5%) patients experienced study outcomes. When stratified according to TE-defined fibrotic burden, multivariable Cox models revealed that risk of poorer kidney outcomes was 2.77-fold (95% confidence interval, 1.16-6.63; P < .001) higher in patients with liver stiffness range indicating cirrhosis (≥11.7 kPa), compared to those without significant liver fibrosis (<7.9 kPa). These associations remained significant even after adjusting for vigorous confounders. CONCLUSIONS: Higher fibrotic burden assessed using TE was independently associated with poorer kidney outcomes in patients with HBV-related cirrhosis.

Loss of Krüppel-like factor-10 facilitates the development of chemical-induced liver cancer in mice.

BACKGROUND: Krüppel-like factor 10 (KLF10) is involved in a positive feedback loop that regulates transforming growth factor ß (TGFß) signaling, and TGFß plays an important role in the pathogenesis of liver disease. Here, we investigated whether KLF10 deletion affects the development of liver fibrosis and hepatocellular carcinoma (HCC). METHODS: We induced KLF10 deletion in C57BL/6 mice. Liver fibrosis was induced by feeding a diet high in fat and sucrose (high-fat diet [HFD]), whereas HCC was produced by intraperitoneal administration of N-diethylnitrosamine (DEN). An in vitro experiment was performed to evaluate the role of KLF10 in the cancer microenvironment using Hep3B and LX2 cells. An immunohistochemical study of KLF10 expression was performed using human HCC samples from 60 patients who had undergone liver resection. RESULTS: KLF10 deletion resulted in an increased DEN-induced HCC burden with significant upregulation of SMAD2, although loss of KLF10 did not alter HFD-induced liver fibrosis. DEN-treated mice with KLF10 deletion exhibited increased levels of mesenchymal markers (N-cadherin and SNAI2) and tumor metastasis markers (matrix metalloproteinases 2 and 9). KLF10 depletion in Hep3B and LX2 cells using siRNA was associated with increased invasiveness. Compared with co-culture of KLF10-preserved Hep3B cells and KLF10-intact LX2 cells, co-culture of KLF10-preserved Hep3B cells and KLF10-depleted LX2 cells resulted in significantly enhanced invasion. Low KLF10 expression in resected human HCC specimens was associated with poor survival. CONCLUSION: The results of this study suggest that loss of KLF10 facilitates liver cancer development with alteration in TGFß signaling.

Impact of boost sequence in concurrent chemo-radiotherapy on newly diagnosed IDH-wildtype glioblastoma multiforme.

BACKGROUND: The standard of care for glioblastoma multiforme (GBM) is maximal surgical resection followed by conventional fractionated concurrent chemoradiotherapy (CCRT) with a total dose of 60 Gy. However, there is currently no consensus on the optimal boost technique for CCRT in GBM. METHODS: We conducted a retrospective review of 398 patients treated with CCRT between 2016 and 2021, using data from two institutional databases. Patients were divided into two groups: those receiving sequential boost (SEB, N = 119) and those receiving simultaneous integrated boost (SIB, N = 279). The primary endpoint was overall survival (OS). To minimize differences between the SIB and SEB groups, we conducted propensity score matching (PSM) analysis. RESULTS: The median follow-up period was 18.6 months. Before PSM, SEB showed better OS compared to SIB (2-year, 55.6% vs. 44.5%, p = 0.014). However, after PSM, there was no significant difference between two groups (2-year, 55.6% vs. 51.5%, p = 0.300). The boost sequence was not associated with inferior OS before and after PSM (all p-values > 0.05). Additionally, the rates of symptomatic pseudo-progression were similar between the two groups (odds ratio: 1.75, p = 0.055). CONCLUSIONS: This study found no significant difference in OS between SEB and SIB for GBM patients treated with CCRT. Further research is needed to validate these findings and to determine the optimal boost techniques for this patient population.

Effects of Statin Treatment on the Development of Tendinopathy: A Nationwide Population-Based Cohort Study.

Background: Previous longitudinal cohort studies have reported the conflicting results of the relationship between statin use and the development of tendinopathy disorder. It is unclear if there is a relationship between statin use, particularly the type or cumulative doses, and the development of tendinopathy disorder. Purpose: To investigate an association between statin treatment and the development of tendinopathy. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 594,130 participants were enrolled in this study in 2002 and evaluated until 2015. There were 84,102 statin users and 168,204 nonusers (controls) selected at a ratio of 1:2 using propensity score matching analysis. The types of included tendinopathy were as follows: (1) trigger finger, (2) radial styloid tenosynovitis, (3) elbow epicondylitis, (4) rotator cuff tendinopathy, and (5) Achilles tendinitis. Cox proportional hazards models with time-varying covariates were constructed to identify the association between statin use and tendinopathy development. Results: Statin treatments regardless of statin types were associated with a significantly greater risk of all types of tendinopathy development (hazard ratio, 1.435; 95% CI, 1.411-1.460) compared with no statin treatment. A trend toward risk reduction was observed according to cumulative statin doses, which was indicated by hazard ratios of 2.337 (95% CI, 2.269-2.406), 2.210 (95% CI, 2.132-2.290), and 1.1 (95% CI, 1.098-1.146) in patients with cumulative defined daily doses of 90, 91-180, and >180, respectively. Conclusion: This nationwide population-based cohort study suggests that statin use regardless of the statin type was associated with a greater risk of tendinopathy compared with that of nonusers. The risk of tendinopathy development was diluted with the increasing cumulative defined daily dose.

Surgical Outcomes of Percutaneous Pinning and Open Locking Plating in Patients With Intra-articular Fractures of the Base of the Fifth Metacarpal.

PURPOSE: The purpose of the study was to demonstrate the results of surgical treatment, including percutaneous K-wire fixation after closed reduction (CRKF) or locking plate fixation after open reduction (ORPF), in patients with intra-articular fractures of the base of the fifth metacarpal. METHODS: We retrospectively reviewed data of 29 patients who received surgical treatment for closed, intra-articular fractures of the base of the fifth metacarpal and were followed up for at least 1 year after surgery. Sixteen of the 29 patients underwent CRKF, whereas 13 patients underwent ORPF. Attempts were made to address intra-articular step-off with closed reduction in all the patients; however, if inadequate, ORPF was performed. Clinical outcomes were evaluated using Disabilities of the Arm, Shoulder, and Hand scores, visual analog scale pain scores, the total active motion (TAM) of the little finger, and grip strength. Osseous union and posttraumatic arthritis of the fifth carpometacarpal joint were also evaluated. RESULTS: K-wire fixation after closed reduction was performed for 13 simple fractures and 3 comminuted fractures; ORPF was performed for 6 simple fractures and 7 comminuted fractures. All the patients had satisfactory subjective outcomes with over 90% grip strength compared with that on the contralateral side and nearly full TAM. All the patients in both the groups achieved osseous union. There were five cases of grade 1 posttraumatic arthritis after CRKF and seven cases of grade 1 posttraumatic arthritis after ORPF. CONCLUSIONS: Surgical treatment provided satisfactory results in patients with intra-articular fractures of the base of the fifth metacarpal treated with either CRKF or ORPF. Our data showed that the patients who underwent CPKF had good results, and those who underwent ORPF after attempt failure of close reduction also had good results. Our experience suggests that ORPF can be a backup plan when CRKF cannot be accomplished in a satisfactory way. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Comparison of decline in renal function between patients with chronic hepatitis B with or without antiviral therapy.

BACKGROUND AND AIMS: Renal function can deteriorate in patients with chronic hepatitis B (CHB). We compared the risk of renal function decline between patients with untreated and treated CHB receiving antiviral therapy. METHODS: This retrospective study included 1061 untreated CHB patients, and 366 on tenofovir alafenamide (TAF), 190 on besifovir dipivoxil maleate (BSV), and 2029 on entecavir (ETV). The primary outcome was renal function decline, a ≥ one-stage increase in chronic kidney disease for ≥3 consecutive months. RESULTS: The incidence and risk of renal function decline were significantly higher in the 1:1 propensity score-matched treated group (588 pairs) than in the untreated (2.7 per 1000 person-years [PYs] vs. 1.3 per 1000 PYs, adjusted hazard ratio [aHR] = 2.29, all p < 0.001). The matched TAF group (222 pairs) showed a similar risk for the primary outcome (aHR = 1.89, p = 0.107) despite a significantly higher incidence thereof, compared to the untreated (3.9 vs. 1.9 per 1000 PYs, p = 0.042). The matched BSV and untreated groups (107 pairs) showed no significant differences in the incidence and risk. However, ETV users (541 pairs) carried a significantly higher outcome incidence and risk than the matched untreated (3.6 vs. 1.1 per 1000 PYs, aHR = 1.05, all p < 0.001). Compared to each matched untreated group, changes in the estimated glomerular filtration rate over time were greater in the ETV group (p = 0.010), despite being similar in the TAF (p = 0.073) and BSV groups (p = 0.926). CONCLUSIONS: Compared with untreated patients, TAF or BSV users showed similar risk, whereas ETV users showed a higher risk of renal function decline.

The care cascade for hepatitis C virus and prognosis of chronic hepatitis C patients treated with antiviral agents in a tertiary hospital.

BACKGROUND: Some studies have analyzed the frequency of HCV RNA testing and actual treatment among anti-HCV positive patients in Korea, which has a low prevalence of HCV infection. This study aimed to analyze the diagnosis process, treatment results, and prognosis according to care cascade in patients who are anti-HCV positive. METHODS: Three thousand two hundred fifty-three anti-HCV positive patients presented to a tertiary hospital between January 2005 and December 2020. The number of patients who underwent HCV RNA testing, treatment, and proportion of sustained virologic response (SVR) according to the type of antivirals was investigated. We investigated the cumulative incidence of hepatocellular carcinoma (HCC) and liver cirrhosis. RESULTS: Of a total of 3,253 people, 1,177 (36.2%) underwent HCV RNA testing and 858 (72.9%) were positive for HCV RNA. 494 (57.6%) of HCV RNA positive patients received antiviral treatment, and 443 (89.7%) of initiated hepatitis C treatment experienced SVR. Of the 421 treated patients, 16 (14.2%) developed HCC. The cumulative incidence of HCC at 15 years was significantly different according to the presence of liver cirrhosis (10/83, 29.5% vs. 6/338, 10.8%, p < 0.001). The cumulative incidences of HCC or liver cirrhosis did not show significant differences according to the presence of SVR12 (14/388, 13.2% vs. 2/33, 52.5%, p = 0.084, 21/319, 15.0%, vs. 3/22, 28.7%, p = 0.051). CONCLUSIONS: Owing to the introduction of direct-acting antivirals, high SVR12 was achieved, but the proportion of anti-HCV positive patients who received HCV RNA testing and treatment was not high. HCC surveillance after SVR12 is recommended for chronic hepatitis C patients with cirrhosis.

Pharmacogenomic profiling reveals molecular features of chemotherapy resistance in IDH wild-type primary glioblastoma.

BACKGROUND: Although temozolomide (TMZ) has been used as a standard adjuvant chemotherapeutic agent for primary glioblastoma (GBM), treating isocitrate dehydrogenase wild-type (IDH-wt) cases remains challenging due to intrinsic and acquired drug resistance. Therefore, elucidation of the molecular mechanisms of TMZ resistance is critical for its precision application. METHODS: We stratified 69 primary IDH-wt GBM patients into TMZ-resistant (n = 29) and sensitive (n = 40) groups, using TMZ screening of the corresponding patient-derived glioma stem-like cells (GSCs). Genomic and transcriptomic features were then examined to identify TMZ-associated molecular alterations. Subsequently, we developed a machine learning (ML) model to predict TMZ response from combined signatures. Moreover, TMZ response in multisector samples (52 tumor sectors from 18 cases) was evaluated to validate findings and investigate the impact of intra-tumoral heterogeneity on TMZ efficacy. RESULTS: In vitro TMZ sensitivity of patient-derived GSCs classified patients into groups with different survival outcomes (P = 1.12e-4 for progression-free survival (PFS) and 3.63e-4 for overall survival (OS)). Moreover, we found that elevated gene expression of EGR4, PAPPA, LRRC3, and ANXA3 was associated to intrinsic TMZ resistance. In addition, other features such as 5-aminolevulinic acid negative, mesenchymal/proneural expression subtypes, and hypermutation phenomena were prone to promote TMZ resistance. In contrast, concurrent copy-number-alteration in PTEN, EGFR, and CDKN2A/B was more frequent in TMZ-sensitive samples (Fisher's exact P = 0.0102), subsequently consolidated by multi-sector sequencing analyses. Integrating all features, we trained a ML tool to segregate TMZ-resistant and sensitive groups. Notably, our method segregated IDH-wt GBM patients from The Cancer Genome Atlas (TCGA) into two groups with divergent survival outcomes (P = 4.58e-4 for PFS and 3.66e-4 for OS). Furthermore, we showed a highly heterogeneous TMZ-response pattern within each GBM patient using in vitro TMZ screening and genomic characterization of multisector GSCs. Lastly, the prediction model that evaluates the TMZ efficacy for primary IDH-wt GBMs was developed into a webserver for public usage ( http://www.wang-lab-hkust.com:3838/TMZEP ). CONCLUSIONS: We identified molecular characteristics associated to TMZ sensitivity, and illustrate the potential clinical value of a ML model trained from pharmacogenomic profiling of patient-derived GSC against IDH-wt GBMs.

Effect of Bevacizumab Treatment in Cerebral Radiation Necrosis : Investigation of Response Predictors in a Single-Center Experience.

OBJECTIVE: Bevacizumab is a feasible option for treating cerebral radiation necrosis (RN). We investigated the clinical outcome of RN after treatment with bevacizumab and factors related to the initial response and the sustained effect. METHODS: Clinical data of 45 patients treated for symptomatic RN between September 2019 and February 2021 were retrospectively collected. Bevacizumab (7.5 mg/kg) was administered at 3-week intervals with a maximum four-cycle schedule. Changes in the lesions magnetic resonance image (MRI) scans were examined for the response evaluation. The subgroup analysis was performed based on the initial response and the long-term maintenance of the effect. RESULTS: Of the 45 patients, 36 patients (80.0%) showed an initial response, and eight patients (17.8%) showed delayed worsening of the corresponding lesion. The non-responders showed a significantly higher incidence of diffusion restriction on MRI than the responders (100.0% vs. 25.0%, p<0.001). The delayed worsening group showed a significantly higher proportion of glioma pathology than the maintenance group (87.5% vs. 28.6%, p=0.005). Cumulative survival rates with sustained effect were significantly higher in the groups with non-glioma pathology (p=0.019) and the absence of diffusion restriction (p<0.001). Pathology of glioma and diffusion restriction in MRI were the independent risk factors for non-response or delayed worsening after initial response. CONCLUSION: The initial response of RN to bevacizumab was favorable, with improvement in four-fifths of the patients. However, a certain proportion of patients showed non-responsiveness or delayed exacerbations. Bevacizumab may be more effective in treating RN in patients with non-glioma pathology and without diffusion restriction in the MRI.

Clinical Outcomes of Moderately Hypofractionated Concurrent Chemoradiotherapy for Newly Diagnosed Glioblastoma.

PURPOSE: Hypofractionated radiotherapy (HypoRT) has recently been implemented in patients with glioblastoma (GBM) receiving concurrent temozolomide. Lymphopenia during treatment (LDT) is considered an important prognostic factor of clinical outcomes for GBM. We aimed to investigate the outcomes of HypoRT. MATERIALS AND METHODS: Among 223 patients with GBM, 145 and 78 were treated with conventionally fractionated RT (ConvRT, 60 Gy in 30 fractions) and HypoRT (58.5 Gy in 25 fractions), respectively. To balance characteristics between the two groups, propensity score matching (PSM) was performed. RESULTS: Patients in the HypoRT group were older and had smaller tumors than those in the ConvRT group (p<0.05). Furthermore, dose distributions to the brain were significantly lower in HypoRT than in ConvRT (p<0.001). Changes in absolute lymphocyte counts (ALC) during treatment were significantly lower after HypoRT than after ConvRT (p=0.018). With a median follow-up of 16.9 months, HypoRT showed comparable progression-free survival (9.9 months vs. 10.5 months) and overall survival (27.2 months vs. 26.6 months) to ConvRT (all p>0.05). Multivariable analysis before PSM revealed that ≥grade 2 LDT at 6 months was associated with inferior outcomes. Subsequent analysis demonstrated that HypoRT significantly reduced the rate of ≥grade 2 LDT at 6 months post-RT before and after PSM. CONCLUSION: HypoRT with 58.5 Gy in 25 fractions could provide comparable oncologic outcomes and significantly reduce the ALC changes. In addition, HypoRT decreased the LDT. Further investigation should be warranted to suggest the significance of reduced LDT through HypoRT affecting survival outcomes.

Impact of Postural Changes on Sinonasal Pressure After Endoscopic Endonasal Surgery.

BACKGROUND: Postoperative management following endoscopic endonasal surgery (EES) is important to prevent cerebrospinal fluid leak and preserve the integrity of the nasoseptal flap. No consensus regarding an optimal posture in the postoperative period has been established. We hypothesized that sinonasal pressure (SNP) can represent intracranial pressure affecting the sellar floor in the absence of the sellar bone after surgery. This study provides evidence for the effect of postural changes and recommends optimal posture to reduce SNP following EES. METHODS: The authors conducted a retrospective analysis of 50 patients who underwent reconstruction for skull base defects with nasoseptal flap after EES for resection of suprasellar tumor between March 2020 and August 2020. The Spiegelberg intracranial pressure probe was placed through the nostril over the nasoseptal flap. SNPs were measured in Fowler' (45° tilt) and supine positions, respectively, daily for the first 3 days immediately after EES. RESULTS: For the first 3 days after surgery, the mean SNP in Fowler' position (24.82 mmHg; standard deviation, 12.23 mmHg) was lower than that in the supine position (28.42 mmHg; standard deviation, 12.33 mmHg) (P < 0.01). There were no significant differences in mean SNP for age, sex, tumor size, presence of hydrocephalus, and body mass index. CONCLUSIONS: There was a significant correlation between Fowler' position and a decrease in SNP measurements. Placing a patient in Fowler' position after surgery can decrease the SNP. We recommend that patients should be placed in a Fowler' position as an optimal position after surgery.

A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Loss-of-function HSD17ß13 mutations protect against the development of chronic liver disease. HSD17ß13 inhibition represents a potential approach to treat liver diseases, such as non-alcoholic steatohepatitis (NASH). ARO-HSD is an RNA interference (RNAi) therapeutic designed to selectively reduce expression of HSD17ß13 mRNA in hepatocytes. In this study, we evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically suspected NASH. METHODS: The safety, tolerability, and pharmacodynamics of ARO-HSD were evaluated in 32 NHVs and 18 patients with confirmed/clinically suspected NASH. Double-blind NHV cohorts received single escalating doses of ARO-HSD (25, 50, 100, or 200 mg) or placebo subcutaneously on Day 1. Open-label patient cohorts received ARO-HSD (25, 100, or 200 mg) subcutaneously on Days 1 and 29. Liver biopsy was performed pre-dose and on Day 71 to evaluate expression levels of HSD17ß13 mRNA and protein. RESULTS: ARO-HSD treatment was well tolerated with no treatment-related serious adverse events or drug discontinuations. The most frequently reported treatment-emergent adverse events were mild injection site reactions, which were short in duration. Mean changes in hepatic HSD17ß13 mRNA from baseline to Day 71 were: -56.9% (25 mg), -85.5% (100 mg), and -93.4% (200 mg). The mean HSD17ß13 mRNA reduction was 78.6% (p <0.0001) across pooled cohorts. Hepatic HSD17ß13 protein levels were similarly reduced across doses. In patients, mean changes in alanine aminotransferase from baseline to Day 71 were -7.7% (25 mg), -39.3% (100 mg), and -42.3% (200 mg) (p <0.001 for pooled cohorts). CONCLUSIONS: ARO-HSD was well tolerated at doses ≤200 mg. This proof-of-concept study demonstrated that short-term treatment with ARO-HSD reduces hepatic HSD17ß13 mRNA and protein expression, which is accompanied by reductions in alanine aminotransferase. GOV NUMBER: NCT04202354. IMPACTS AND IMPLICATIONS: There is an unmet medical need for new therapies to treat alcohol-related and non-alcoholic liver disease. ARO-HSD is a small-interfering RNA designed to silence HSD17ß13 expression and hence to phenocopy the protective effect seen in individuals with HSD17ß13 loss-of-function. The reductions in HSD17ß13 expression and in transaminases seen with ARO-HSD administration represent an initial step towards clinical validation of HSD17ß13, a drug target with substantial genetic validation, as an important modulator of human liver disease.

Equilibria of semi-volatile isothiazolinones between air and glass surfaces measured by gas chromatography and Raman spectroscopy.

Trace amounts of semi-volatile organic compounds (SVOCs) of the two isothiazolinones of 2-methylisothiazol-3(2H)-one (MIT) and 2-octyl-4-isothiazolin-3-one (OIT) were detected both in the air and on glass surfaces. Equilibria of SVOCs between air and glass were examined by solid phase microextraction-gas chromatography/mass spectrometry (SPME-GC/MS). Surface to air distribution ratios of Ksa for MIT and OIT were determined to be 5.10 m and 281.74 m, respectively, suggesting more abundant MIT in the gas phase by a factor of ∼55. In addition, a facile method of silver nanocube (AgNC)-assisted surface-enhanced Raman scattering (SERS) has been developed for the rapid and sensitive detection of MIT and OIT on glass surfaces. According to MIT and OIT concentration-correlated SERS intensities of Raman peaks at ∼1585 cm-1 and ∼1125 cm-1, respectively. Their calibration curves have been obtained in the concentration ranges between 10-3 to 10-10 M and 10-3 to 10-11 M with their linearity of 0.9986 and 0.9989 for MIT and OIT, respectively. The limits of detection (LODs) of the two isothiazolinones were estimated at 10-10 M, and 10-11 M for MIT and OIT, respectively. Our results indicate that AgNC-assisted SERS spectra are a rapid and high-ultrasensitive method for the quantification of MIT and OIT in practical applications. The development of analytical methods and determination of the Ksa value obtained in this study can be applied to the prediction of the exposure to MIT and OIT from various chemical products and dynamic behaviors to assess human health risks in indoor environments.

Functional recovery and muscle atrophy in pre-clinical models of peripheral nerve transection and gap-grafting in mice: effects of 4-aminopyridine.

We recently demonstrated a repurposing beneficial effect of 4-aminopyridine (4-AP), a potassium channel blocker, on functional recovery and muscle atrophy after sciatic nerve crush injury in rodents. However, this effect of 4-AP is unknown in nerve transection, gap, and grafting models. To evaluate and compare the functional recovery, nerve morphology, and muscle atrophy, we used a novel stepwise nerve transection with gluing (STG), as well as 7-mm irreparable nerve gap (G-7/0) and 7-mm isografting in 5-mm gap (G-5/7) models in the absence and presence of 4-AP treatment. Following surgery, sciatic functional index was determined weekly to evaluate the direct in vivo global motor functional recovery. After 12 weeks, nerves were processed for whole-mount immunofluorescence imaging, and tibialis anterior muscles were harvested for wet weight and quantitative histomorphological analyses for muscle fiber cross-sectional area and minimal Feret's diameter. Average post-injury sciatic functional index values in STG and G-5/7 models were significantly greater than those in the G-7/0 model. 4-AP did not affect the sciatic functional index recovery in any model. Compared to STG, nerve imaging revealed more misdirected axons and distorted nerve architecture with isografting. While muscle weight, cross-sectional area, and minimal Feret's diameter were significantly smaller in G-7/0 model compared with STG and G-5/7, 4-AP treatment significantly increased right TA muscle mass, cross-sectional area, and minimal Feret's diameter in G-7/0 model. These findings demonstrate that functional recovery and muscle atrophy after peripheral nerve injury are directly related to the intervening nerve gap, and 4-AP exerts differential effects on functional recovery and muscle atrophy.