Immunotherapy With Radiotherapy for Brain Metastases in Patients With NSCLC: NEJ060.

Introduction: Immune checkpoint inhibitor (ICI)-based treatment has become standard treatment for patients with advanced NSCLC. We aimed to determine the survival benefit of upfront radiotherapy for brain metastases (BMs) in patients with NSCLC who received ICI alone (ICI-alone) or with chemotherapy (ICI-chemo). Methods: This study included consecutive patients with NSCLC having BMs who received ICI alone or ICI-chemo at 50 institutes between February 2017 and September 2021. The presence of BMs was confirmed by imaging before treatment. Treatment outcomes were compared between patients who did and did not receive upfront radiotherapy for BMs. Potential confounding factors were adjusted between the groups through inverse probability treatment weighting (IPTW) analysis and overlap weighting (OW) analysis with propensity scores. Results: Patients were grouped as ICI-alone cohort, 224 patients (upfront-radiotherapy group, 135 patients; no-radiotherapy group, 89 patients) and ICI-chemo cohort, 367 patients (upfront-radiotherapy group, 212 patients; no-radiotherapy group, 155 patients). In the ICI-alone cohort, the overall survival of the upfront-radiotherapy group was significantly longer than that of the no-radiotherapy group (IPTW-adjusted hazards ratio [HR] = 0.45 [95% confidence interval [CI]: 0.29-0.72], OW-adjusted HR = 0.52 [95% CI: 0.35-0.77]). In contrast, in the ICI-chemo cohort, the OS of the upfront-radiotherapy group was not significantly different from that of the no-radiotherapy group (IPTW-adjusted HR = 1.02 [95% CI: 0.70-1.48], OW-adjusted HR = 0.93 [95% CI: 0.65-1.33]). Conclusions: Upfront radiotherapy for BMs was associated with longer overall survival in patients with NSCLC who received ICI alone; however, it did not exhibit survival benefits in the patients who received ICI-chemo.

Clinical Outcome of Nivolumab Plus Ipilimumab in Patients with Locally Advanced Non-Small-Cell Lung Cancer with Relapse after Concurrent Chemoradiotherapy followed by Durvalumab.

Nivolumab plus ipilimumab showed promising efficacy in patients with metastatic non-small-cell lung cancer (NSCLC). The efficacy of the nivolumab plus ipilimumab combination regimen in NSCLC patients who relapse after durvalumab consolidation following concurrent chemoradiotherapy (CCRT) has not been determined. Between January 2021 and June 2022, clinical data were retrospectively extracted from the medical records of patients with NSCLC who received nivolumab plus ipilimumab after CCRT and durvalumab consolidation. A total of 30 patients were included in this analysis. The median number of durvalumab treatment cycles was 11. Median PFS and OS with nivolumab plus ipilimumab were 4.2 months (95% confidence interval [CI]: 0.7-7.7) and 18.5 months (95% CI: 3.5-33.5), respectively. The 6-month and 12-month PFS rates were 46.7% (95% CI: 28.8-64.5) and 36.4% (95% CI: 19.0-53.7). In multivariate analysis, a significant correlation was observed between a durvalumab treatment duration of 6 months or more and PFS (p = 0.04) as well as OS (p = 0.001). Grade 3 adverse events, including pneumonitis, dermatitis, and colitis, occurred in 10% of the patients. This study suggests that nivolumab plus ipilimumab is effective, especially in patients who have received durvalumab for 6 months or more, and tolerable for patients who relapsed after durvalumab following CCRT.

Mobile medial pivot (lateral slide)-type total knee arthroplasty exhibited different motion patterns between under anaesthesia and weight-bearing condition.

PURPOSE: Total knee arthroplasty (TKA), which has medial pivot and mobile-bearing mechanisms, has been developed and clinically used. However, the in vivo dynamic kinematics of the mobile medial pivot-type TKA (MMPTKA) is unclear. This study analysed the in vivo kinematics of MMPTKA in weight-bearing and nonweight-bearing conditions. METHODS: The study included 10 knees that underwent primary TKA using MMPTKA. After TKA, lateral view radiographs of the knee in full extension, 90° of flexion and passive full flexion were taken under general anaesthesia in the nonweight-bearing condition. At least 6 months postoperatively, knee motion during squatting from a weight-bearing standing position was observed using a flat-panel detector and analysed using the three-dimensional-to-two-dimensional image registration technique. RESULTS: Under anaesthesia: in passive full flexion, the anteroposterior (AP) locations of the femoral component's medial and lateral distal points were 10.2 and 16.0 mm posterior, and the rotational angles of the femoral component's X-axis (FCX) and insert were 8.1° external rotation and 18.5° internal rotation to full extension, respectively. Squatting: the AP translations of the femoral component's medial and lateral most distal points were 2.2 and 6.4 mm, and the rotational angles of the FCX and insert were 5.7° and 1.6° external rotation, respectively. Significant differences were observed in the AP translation of the femoral component's medial and lateral most distal points and changes in the insert's rotational angle when comparing under anaesthesia and squatting. CONCLUSIONS: The kinematics of the insert in MMPTKA was significantly influenced by loading and muscle contraction. The femoral component exhibited substantial external rotation and posterior translation under anaesthesia, which may contribute to achieving an optimal range of motion. The insert remained relatively stable during squatting and minimal rotation was observed, indicating good stability. MMPTKA was expected to demonstrate rational kinematics by incorporating mobile and medial pivot mechanisms. LEVEL OF EVIDENCE: Level IV, prospective biomechanical case series study.

Comparing region of interest selection and whole-field analysis for measurement of ciliary beat frequency in high-speed video analysis.

BACKGROUND: Ciliary beat frequency (CBF) is crucial in mucociliary clearance. High-speed video analysis (HSVA) is commonly used to measure CBF but lacks standardization. We compared visual observation and computer-assisted calculation using fast Fourier transformation (FFT) in freshly collected bronchial ciliary epithelial cells and cultured cells. METHODS: Bronchial epithelial cells were obtained from 12 patients who required bronchoscopic examination. Eighty-five videos of ciliary movement of freshly collected and cultured cells were recorded and used to calculate CBF using manual observation, region of interest (ROI) selection, and whole-field analysis. RESULTS: CBF measured by the ROI selection method strongly correlated with that measured using manual observation, especially in freshly collected cells. However, 27.8% of the manual observation method values were doubled in the ROI selection method, probably because a round trip of cilia was calculated as two cycles and needed to be corrected to 1/2 value. Upon increasing the number of ROIs, the results of the ROI selection method came closer to that of WFA. CONCLUSIONS: Computer-assisted calculation using FFT can aid in measuring CBF; however, current methods require visual confirmation. Further automated evaluation techniques are needed to establish more standardized and generalized CBF measurement methods using HSVA.

Three-dimensional imaging evaluation of facial swelling after orthognathic surgery with compression and Kinesio taping therapy: a randomized clinical trial.

Background: Postoperative swelling is a common complication of orthognathic surgery. The authors used three-dimensional (3D) image analysis and body surface temperature to determine the effects of compression taping (CT) and Kinesio taping (KT) by the epidermis, dermis, and fascia method (EDF-KT) on postoperative swelling. Materials and methods: The authors conducted a prospective, parallel-group, randomized controlled trial. Among the 162 patients diagnosed with jaw deformity and who underwent orthognathic surgery from August 2020 to October 2022, 105 patients (men: 36, women: 69, mean age: 28.27±8.92) underwent Le Fort type I + sagittal split ramus osteotomy (SSRO) or SSRO and were included in this study. Patients were randomly divided into three groups: EDF-KT group (n=31), CT group (n=41), and no tape group (control group, n=30). All taping was performed immediately postoperatively and removed on postoperative day (POD) 5. Three-dimensional images of the participants' faces were obtained preoperatively and at PODs 3, 7, 30, and 90 using a hand-held 3D imaging system and infrared thermography. Results: No significant difference was observed in postoperative swelling and postoperative body surface temperature between the groups at each time point. The CT group showed a trend towards reduced swelling on PODs 3 and 7 and a trend toward residual swelling on POD 90. The EDF-KT group showed a trend towards an increase in postoperative body surface temperature. Conclusion: CT taping may not be appropriate for postoperative swelling control, suggesting that EDF-KT may affect body surface temperature. Further validation of the efficacy of KT for jaw deformities is needed.

Discovery of non-genomic drivers of YAP signaling modulating the cell plasticity in CRC tumor lines.

In normal intestines, a fetal/regenerative/revival cell state can be induced upon inflammation. This plasticity in cell fate is also one of the current topics in human colorectal cancer (CRC). To dissect the underlying mechanisms, we generated human CRC organoids with naturally selected genetic mutation profiles and exposed them to two different conditions by modulating the extracellular matrix (ECM). Among tested mutation profiles, a fetal/regenerative/revival state was induced following YAP activation via a collagen type I-enriched microenvironment. Mechanistically, YAP transcription was promoted by activating AP-1 and TEAD-dependent transcription and suppressing intestinal lineage-determining transcription via mechanotransduction. The phenotypic conversion was also involved in chemoresistance, which could be potentially resolved by targeting the underlying YAP regulatory elements, a potential target of CRC treatment.

PD-L1 mRNA derived from tumor-educated platelets as a potential immunotherapy biomarker in non-small cell lung cancer.

Background: To date, the role of programmed death ligand-1 (PD-L1) messenger RNA (mRNA) derived from tumor-educated platelets (TEPs) has not been well investigated in patients with advanced non-small cell lung cancer (NSCLC). A few reports have examined whether mRNA in TEPs can predict the clinical responses of patients with advanced NSCLC following immunotherapy. This study aimed to identify novel biomarkers to improve the clinical benefits and outcomes of NSCLC patients. Methods: Advanced NSCLC patients receiving a combination of immunotherapy and chemotherapy, or immunotherapy alone as a first- or second-line treatment at the Fudan University Shanghai Cancer Center were enrolled in this study. All the patients had wild-type epidermal growth factor receptor/anaplastic lymphoma kinase. The patients were enrolled in clinical trials for immune checkpoint inhibitors (ICIs), including nivolumab, pembrolizumab, atezolizumab, durvalumab, tremelimumab, and camrelizumab. Tumoral PD-L1 expression was tested by immunohistochemistry (PD-L1 22C3 pharmDx kit, Agilent, Santa Clara, CA, USA) in archived tissue samples, when available, to calculate the tumor proportion scores (TPSs). RNA and exosomal RNA of blood were isolated before immunotherapy using the Yunying RNA extraction kit (Yunying Medicine, Shanghai, China). The concentration and quality of the RNA was determined using a Qubit fluorometer (Life Technologies, Carlsbad, CA, USA). Finally, we analyzed the predictive value of TEP-derived PD-L1 mRNA expression and association with the level of the tumoral PD-L1 expression. Results: In total, 72 patients were enrolled in this study. Most of the patients were male (n=54, 75.0%), had adenocarcinoma (n=49, 68.1%). We found there was no significant correlation between the TEP-derived mRNA of PD-L1 and tumoral PD-L1 expression based on the results of the Pearson Correlation test (r=-0.19, P=0.233). Based on the median of PD-L1 mRNA, 72 patients were divided into a high PD-L1 group and a low PD-L1 group. We found that 19 patients (44.4%) responded to immunotherapy [partial response or progression-free survival (PFS) >6 months] in the high PD-L1 group, but only five patients (13.9%) responded to immunotherapy in the low PD-L1 group (P<0.01). The median PFS of the low PD-L1 group was lower than that of the high PD-L1 group (2.8 vs. 8.3 months, P<0.001). For the patients who were treated with immunotherapy alone (n=64), a similar PFS advantage was observed in the high PD-L1 group (2.8 vs. 8.0 months, P=0.002). Conclusions: This article presented the first data on TEP-derived PD-L1 mRNA in advanced NSCLC patients following immunotherapy and showed the potential advantage of using it as the surrogate biomarker for predicting the PFS and overall survival of patients following immunotherapy.

AXL signal mediates adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutant tumor cells.

Recently, novel Kirsten rat sarcoma viral oncogene homolog (KRAS) inhibitors have been clinically developed to treat KRAS G12C-mutated non-small cell lung cancer (NSCLC) patients. However, achieving complete tumor remission is challenging. Therefore, the optimal combined therapeutic intervention with KRAS G12C inhibitors has a potentially crucial role in the clinical outcomes of patients. We investigated the underlying molecular mechanisms of adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC cells to devise a strategy preventing drug-tolerant cell emergence. We demonstrate that AXL signaling led to the adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC, activation of which is induced by GAS6 production via YAP. AXL inhibition reduced the viability of AXL-overexpressing KRAS G12C-mutated lung cancer cells by enhancing KRAS G12C inhibition-induced apoptosis. In xenograft models of AXL-overexpressing KRAS G12C-mutated lung cancer treated with KRAS G12C inhibitors, initial combination therapy with AXL inhibitor markedly delayed tumor regrowth compared with KRAS G12C inhibitor alone or with the combination after acquired resistance to KRAS G12C inhibitor. These results indicated pivotal roles for the YAP-GAS6-AXL axis and its inhibition in the intrinsic resistance to KRAS G12C inhibitor.

Clinical features of patients with connective tissue disease with anti-human upstream binding factor antibodies: A single-center retrospective study.

Anti-human upstream-binding factor (anti-hUBF) antibodies have been reported predominantly in patients with connective tissue diseases (CTDs); these have also been reported in patients without CTDs such as hepatocellular carcinoma. Because of the low frequency of expression and few case reports, there is no consensus on the clinical significance of these antibodies. Thus, we aimed to examine the clinical features of patients with anti-hUBF antibodies and analyzed 1042 patients with clinically suspected CTDs. The presence of anti-hUBF antibodies was screened using immunoprecipitation assays. Of the 1042 patients, 19 (1.82%) tested positive for anti-hUBF antibodies; among them, 10 (56%) were diagnosed with undifferentiated CTD (UCTD), six with systemic sclerosis (SSc) and three with other diseases. Five of the 10 patients with UCTD were referred to our hospital with suspected SSc. None of the five patients fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria, but three scored seven points, a relatively high score. Six anti-hUBF-positive patients with SSc had a significantly lower modified Rodnan skin score (mRSS) than that of anti-hUBF-negative patients with SSc (2 [0-2] vs 7 [0-49], p < 0.01). Compared with anti-topoisomerase I-positive patients, anti-hUBF-positive patients had a significantly lower mRSS (2 [0-2] vs 13 [0-42], p < 0.01) and lower incidence of scleroderma renal crisis (0 of 6 vs 8 of 184, p < 0.01). Compared with anti-centromere-positive patients, anti-hUBF-positive patients had a higher incidence of interstitial lung disease (ILD), but the difference was not statistically significant (4 of 6 vs 19 of 239). In conclusion, anti-hUBF antibodies were predominantly detected in patients with CTDs and UCTD. In patients with CTDs, SSc exhibited a high ratio, displaying a lower mRSS and higher incidence of ILD. In patients with UCTD, careful follow-up is recommended as they may develop CTDs in the future.

Comparative evaluation of iStent versus iStent inject W combined with phacoemulsification in open angle glaucoma.

PURPOSE: The study aimed to compare the 12-month post-operative outcomes of iStent and iStent inject W (inject W), and the factors associated with their success in open-angle glaucoma. METHODS: This single-center, retrospective comparative case series evaluated the medical records of patients who underwent iStent (comprising 1 stent) or inject W (comprising 2 stents) implantation with cataract surgery for primary open-angle glaucoma and normal tension glaucoma between January 2019 and March 2022. The 12-month post-operative efficacy outcomes included intraocular pressure (IOP), glaucoma medications, and survival analysis of the probability of success. "Failure" was defined as any of the following conditions compared to baseline: 1) IOP elevation, 2) increased glaucoma medication, or 3) IOP decline not exceeding 20% when glaucoma medication scores were comparable, and 4) need for additional glaucoma surgery. The safety outcomes included intra- and post-operative adverse events and changes in the best-corrected visual acuity and visual field. RESULTS: The study comprised 55 eyes in the iStent and 105 in the inject W groups. At 12 months, treatment success was achieved in 66.0% of iStent and 78.4% of inject W eyes. The mean IOP was lower, and the percent reduction from baseline was equal in iStent-treated eyes (8.0% reduction, 14.8 mmHg to 13.7 mmHg, P<0.01) and inject W-treated eyes (11.9% reduction, 15.0 mmHg to 13.8 mmHg, P<0.01) (between-group comparison, P = 0.23). The mean medication burden decreased significantly from 2.5 to 1.1 for iStent (55.0% reduction, P<0.01) and 2.9 to 1.7 for iStent inject (46.8% reduction, P<0.01), with no significant differences between the two groups (P = 0.17). Both devices exhibited excellent safety. CONCLUSIONS: Both devices significantly reduced IOP and glaucoma medication 12 months post-operatively. The outcome measures did not differ significantly between the two groups, and lower baseline IOP was predictive of surgical failure.

Prospective Observational Study of Ramucirumab Plus Docetaxel After Combined Chemoimmunotherapy in Patients With Non-Small-Cell Lung Cancer.

BACKGROUND: A history of pre-administration of immune checkpoint inhibitors has been reported to be associated with good outcomes of ramucirumab (RAM) plus docetaxel (DOC) combination therapy for advanced non-small-cell lung cancer (NSCLC). However, existing knowledge on the clinical significance of RAM and DOC following combined chemoimmunotherapy is limited. Therefore, we evaluated the efficacy and safety of RAM plus DOC therapy after combined chemoimmunotherapy and attempted to identify the predictors of its outcomes. PATIENTS AND METHODS: This multicenter, prospective study investigated the efficacy and safety of RAM plus DOC after combined chemoimmunotherapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were the objective response rate (ORR), disease control rate (DCR), overall survival (OS), and incidence of adverse events. An exploratory analysis measured serum cytokine levels at the start of treatment. RESULTS: Overall, 44 patients were enrolled from 10 Japanese institutions between April 2020 and June 2022. The median PFS and OS were 6.3 and 22.6 months, respectively. Furthermore, the ORR and DCR were 36.4% and 72.7%, respectively. The high vascular endothelial growth factor D (VEGF-D) group had a significantly shorter PFS and OS. A combination of high VEGF-A and low VEGF-D levels was associated with a longer PFS. CONCLUSION: Our results showed that RAM plus DOC after combined chemoimmunotherapy might be an effective and relatively feasible second-line treatment for patients with advanced NSCLC in a real-world setting.

First-line nivolumab plus ipilimumab with or without chemotherapy for Japanese patients with non-small cell lung cancer: LIGHT-NING study.

OBJECTIVE: As first-line treatment for stage IV or recurrent non-small cell lung cancer, combination immunotherapy with nivolumab and ipilimumab, with or without chemotherapy, had demonstrated survival benefits over chemotherapy; however, data on Japanese patients are limited. METHODS: LIGHT-NING was a multicenter, observational study and retrospectively collected data. In this interim analysis, we analyzed patients who received combination immunotherapy between 27 November 2020 and 31 August 2021 for the treatment status, safety objectives (treatment-related adverse events and immune-related adverse events incidences), and effectiveness objectives (objective response rate and progression-free survival) to determine the characteristics and early safety information. RESULTS: We analyzed 353 patients, with a median follow-up of 7.1 (interquartile range, 5.0-9.7) months. Overall, 60.1 and 39.9% received nivolumab plus ipilimumab with and without chemotherapy, respectively. In these cohorts, the median age was 67 and 72 years; 10.8 and 35.5% were aged ≥75 years; 80.2 and 79.4% were male; 5.2 and 13.5% had a performance score ≥ 2; 32.1 and 27.0% developed grade 3-4 immune-related adverse events; treatment-related deaths were observed in 6 (2.8%) and 5 (3.5%) patients, respectively. Grade 3-4 immune-related adverse event incidence was the highest within the first month of treatment in both cohorts, although the immune-related adverse event risk persisted throughout. No new safety signals were observed at this interim analysis. The median progression-free survival was 6.0 (95% confidence interval, 5.2-7.6) and 5.8 (4.3-7.0) months in nivolumab plus ipilimumab with and without chemotherapy cohorts, respectively. CONCLUSIONS: LIGHT-NING offers valuable insights into combination immunotherapy for untreated patients with stage IV or recurrent non-small cell lung cancer in Japanese real-world settings.

A phase II study of atezolizumab with bevacizumab, carboplatin, and paclitaxel for patients with EGFR-mutated NSCLC after TKI treatment failure (NEJ043 study).

INTRODUCTION: Treatment options for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) after EGFR-tyrosine kinase inhibitor (TKI) treatment failure are limited. An exploratory analysis of 26 patients in the IMpower150 study indicated that treatment with atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) was effective in patients with EGFR-mutated NSCLC. This phase II study was conducted to assess the efficacy of ABCP in EGFR-mutated NSCLC patients after TKI treatment. METHODS: Patients with non-squamous NSCLC harboring sensitizing EGFR mutations were enrolled. ABCP therapy was administered every 3 weeks for four cycles, followed by maintenance therapy with atezolizumab and bevacizumab. The primary endpoint was progression-free survival (PFS) according to extramural review (ER). Key secondary endpoints and preplanned analysis included overall survival (OS), overall response rate (ORR), and differences in the efficacy of ABCP according to prior EGFR-TKI administration, liver metastases, and brain metastases. RESULTS: Sixty patients from 26 centers were enrolled. Median PFS was 7.4 months (95% confidence interval [CI]: 5.7-8.2). The median OS was 23.1 months (95% CI: 13.1-not reached), and the ORR was 55.9%. PFS was significantly shorter in patients who had received osimertinib as a first-line treatment (7.2 months vs. 7.4 months, hazard ratio [HR] 1.932, p = 0.023), those with brain metastases (5.7 months vs. 8 months, HR 1.86, p = 0.032), or those with liver metastases (5.4 months vs. 7.9 months, HR 2.779, p = 0.003). CONCLUSIONS: Although this study did not meet the primary endpoint, ABCP showed clinically meaningful efficacy in EGFR-mutated NSCLC patients.

Mutations in the genes responsible for the synthesis of furan fatty acids resolve the light-induced off-odor in soybean oil.

Soybean oil is the second most produced edible vegetable oil and is used for many edible and industrial materials. Unfortunately, it has the disadvantage of 'reversion flavor' under photooxidative conditions, which produces an off-odor and decreases the quality of edible oil. Reversion flavor and off-odor are caused by minor fatty acids in the triacylglycerol of soybean oil known as furan fatty acids, which produce 3-methyl-2,4-nonanedione (3-MND) upon photooxidation. As a solution to this problem, a reduction in furan fatty acids leads to a decrease in 3-MND, resulting in a reduction in the off-odor induced by light exposure. However, there are no reports on the genes related to the biosynthesis of furan fatty acids in soybean oil. In this study, four mutant lines showing low or no furan fatty acid levels in soybean seeds were isolated from a soybean mutant library. Positional cloning experiments and homology search analysis identified two genes responsible for furan fatty acid biosynthesis in soybean: Glyma.20G201400 and Glyma.04G054100. Ectopic expression of both genes produced furan fatty acids in transgenic soybean hairy roots. The structure of these genes is different from that of the furan fatty acid biosynthetic genes in photosynthetic bacteria. Homologs of these two group of genes are widely conserved in the plant kingdom. The purified oil from the furan fatty acid mutant lines had lower amounts of 3-MND and reduced off-odor after light exposure, compared with oil from the wild-type.

Multicenter, Retrospective Study to Evaluate Necitumumab Plus Cisplatin and Gemcitabine After Immune Checkpoint Inhibitors in Advanced Squamous Cell Lung Cancer in Japan: The NINJA Study.

Introduction: Necitumumab plus gemcitabine and cisplatin (GCN) is a standard therapy for patients with advanced lung squamous cell carcinoma (LSqCC). However, the efficacy and tolerability of GCN in second-line or later treatment for patients previously treated with immune checkpoint inhibitors (ICIs) remain unknown. Methods: This multicenter, retrospective, cohort study assessed the efficacy and tolerability of GCN initiated between November 1, 2019 and March 31, 2022 as second-line to fourth-line treatment in patients with advanced LSqCC who had been pretreated with ICIs. The primary end point was progression-free survival (PFS). Results: A total of 93 patients from 35 institutions in Japan were enrolled. The median PFS, median overall survival (OS), and objective response rate were 4.4 months (95% confidence interval [CI]: 3.8-5.3), 13.3 months (95% CI: 9.6-16.5), and 27.3% (95% CI: 18.3-37.8), respectively. The median PFS, median OS, and objective response rate for second-line, third-line, and fourth-line treatment groups were 4.8 months, 3.8 months, and 4.3 months (p = 0.24); 15.7 months, 11.6 months, and 10.1 months (p = 0.06); and 31.0%, 13.6%, and 37.5% (p = 0.22), respectively. The severity of GCN-related skin disorders was associated with longer PFS (p < 0.05) and OS (p < 0.05). The frequencies of grade ≥3 skin disorders, hypomagnesemia, pneumonitis, and febrile neutropenia were 16.1%, 7.5%, 1.1%, and 4.3%, respectively. There were no treatment-related deaths. Conclusions: GCN for ICI-pretreated patients with LSqCC seems tolerable and offers promising efficacy regardless of treatment line, and ICI pretreatment might enhance GCN efficacy.

The effects of the first versus second glaucoma drainage implant surgery in patients with primary open-angle glaucoma.

BACKGROUND: To investigate the outcome of non-valved glaucoma drainage implant surgery (GDIS) in primary open-angle glaucoma (POAG) patients divided in the first GDI group (patients who underwent the first GDIS) and the second GDI group (patients who underwent the second GDIS because of the failed first GDIS). METHODS: Intraocular pressure (IOP), visual acuity (VA), visual field defect (VFD), medication score (MS), survival rate of GDIS, complications, and patient background was retrospectively analyzed. Two success criteria were set: Criteria (1) IOP reduction ≥ 20% and 5 < IOP ≤ 21, Criteria (2) IOP reduction ≥ 20% and 5 < IOP ≤ 14. RESULTS: There were 136 eyes of 109 patients in the first GDI group and 32 eyes of 27 patients in the second GDI group. In the first GDI group and II, mean preoperative IOP was 26.7 ± 6.7 mmHg and 23.7 ± 3.5 mmHg, respectively (P = 0.09). No statistically significant difference in postoperative IOP reduction was found between the two groups (P = 0.39). At 5-years postoperative, the Criteria 1 (Criteria 2) survival rate in the first GDI group and the second GDI group was 60.4% (31.7%) and 61.2% (25.6%), respectively (Criteria 1: hazard ratio [HR]: 0.64, 95% confidence interval [CI]: 0.30-1.35 [P = 0.24]; Criteria 2: HR: 0.81, 95% CI: 0.46-1.44, P = 0.48). No significant difference in VA, VFD change, MS, or complications was observed. Young patient age was the only significant factor for failure in the first GDI group (odds ratio: 0.95, 95% confidence interval: 0.91-1.00, P = 0.03). CONCLUSION: The second GDIS may be as effective as the first GDIS for IOP reduction in POAG patients, however, there is a high risk of failure in young-age patients and the surgery may be ineffective in eyes requiring Criteria 2.

Dynamics of iron metabolism in patients with bloodstream infections: a time-course clinical study.

The close relationship between infectious diseases and iron metabolism is well known, but a more detailed understanding based on current knowledge may provide new insights into the diagnosis and treatment of infectious diseases, considering the growing threat of antibiotic-resistant bacteria. This study investigated adult patients with bloodstream infections, temporal changes, and relationships between blood levels of iron and related markers, including hepcidin and lipocalin-2 (LCN2). We included 144 samples from 48 patients (mean age 72 years, 50% male), with 30 diagnosed with sepsis. During the acute phase of infection, blood levels of hepcidin and LCN2 increased rapidly, whereas iron levels decreased, with values in 95.8% of cases below the normal range (40-188 µg/dL). Later, hepcidin and LCN2 decreased significantly during the recovery phase, and the decreased iron concentrations were restored. In the case of persistent inflammation, iron remained decreased. Acute LCN2 levels were significantly higher in patients with sepsis (p < 0.01). Hypoferremia induced by increased hepcidin would reduce iron in the environment of extracellular pathogens, and the increased LCN2 would inhibit siderophores, resulting in the prevention of the pathogen's iron acquisition in each manner during the acute phase of bloodstream infection.

A phase 2 trial of durvalumab treatment following radiation monotherapy in patients with non-small cell lung cancer ineligible for stage III chemoradiotherapy: The SPIRAL-RT study.

BACKGROUND: Although concurrent chemoradiotherapy (CCRT) followed by durvalumab is the standard treatment for patients with stage III non-small cell lung cancer (NSCLC), only half of the patients are allowed to receive CCRT in real-world settings. We evaluated the efficacy and safety of durvalumab after radiation monotherapy for NSCLC patients who are ineligible for chemoradiotherapy. METHODS: A single-arm, prospective, open-label, multicenter phase II trial was conducted in Japan. The patients received radiation (54-66 Gy) followed by durvalumab (10 mg/kg every 2 weeks for up to 12 months). The primary endpoint was the 1-year progression-free survival (PFS) rate. The secondary endpoints were the objective response rate (ORR), PFS, overall survival (OS), and safety. RESULTS: Between September 2019 and April 2021, 33 patients were enroled from eight institutions. The median patient age was 79 years, and the majority of patients were male (78.8%). The 1-year PFS rate was 39.1% (90% confidence interval [CI]: 24.7-54.6%). Three patients (9.1%) had a performance status of 2. The ORR was 42.4% (95% CI: 27.2-59.2%). The median PFS and OS were 8.9 (95% CI: 7.4-19.4) and 20.8 (95% CI: 15.8-not estimable) months, respectively. The most common adverse event was radiation pneumonitis (51.5%). The median treatment duration was 6.4 (range: 0.50-12.0) months for durvalumab. At the endpoint, 30.3% (10/33) of the patients had completed 1 year of durvalumab therapy. CONCLUSIONS: Durvalumab is an effective treatment with tolerable toxicity following radiation monotherapy in stage III NSCLC patients who are ineligible for chemoradiotherapy. TRIAL REGISTRATION: JMA-IIA00434 (jRCT).

Fast Gas-Adsorption Kinetics in Supraparticle-Based MOF Packings with Hierarchical Porosity.

Metal-organic frameworks (MOFs) are microporous adsorbents for high-throughput gas separation. Such materials exhibit distinct adsorption characteristics owing to the flexibility of the crystal framework in a nanoparticle, which can be different from its bulk crystal. However, for practical applications, such particles need to be compacted into macroscopic pellets, creating mass-transport limitations. In this work, this problem is addressed by forming materials with structural hierarchy, using a supraparticle-based approach. Spherical supraparticles composed of nanosized MOF particles are fabricated by emulsion templating and they are used as the structural component forming a macroscopic material. Zeolitic imidazolate framework-8 (ZIF-8) particles are used as a model system and the gas-adsorption kinetics of the hierarchical material are compared with conventional pellets without structural hierarchy. It is demonstrated that a pellet packed with supraparticles exhibits a 30 times faster adsorption rate compared to an unstructured ZIF-8 powder pellet. These results underline the importance of controlling structural hierarchy to maximize the performance of existing materials. In the hierarchical MOFs, large macropores between the supraparticles, smaller macropores between individual ZIF-8 primary particles, and micropores inherent to the ZIF-8 framework collude to combine large surface area, defined adsorption sites, and efficient mass transport to enhance performance.

Unexpected Diffuse Alveolar Hemorrhage After Bronchoscopy.

CASE PRESENTATION: A 71-year-old woman sought treatment for a nonproductive cough. The patient had experienced no episodes of hemoptysis or shortness of breath. Her illness history included lumbago and dry mouth. The patient did not smoke and had no significant family medical history or medication use. She had no allergies to any food or drugs. Blood test results, including a CBC count, biochemical examination, and coagulation, were unremarkable. Autoantibody screening revealed positive antinuclear antibody findings with a titer of speckled and nucleolar, and anti-Ro/SSA antibodies were elevated at 240 U/mL (normal range, < 7.0 U/mL). Chest CT scan imaging showed a slight infiltrative shadow of the bilateral lower lobes. Because the patient was suspected to have interstitial pneumonia resulting from Sjögren disease, we decided to perform fiber optic bronchoscopy with BAL for evaluation of interstitial lung disease.