Dual Catalysis of Gold Nanoclusters: Photocatalytic Cross-Dehydrogenative Coupling by Cooperation of Superatomic Core and Molecularly Modified Staples.

Thiolate-protected gold nanoclusters (AuNCs) have attracted significant attention as nano-catalysts, revealing a superatomic core and gold-thiolate staples as distinct structural units. Here, we demonstrate the unprecedented dual catalytic activity of thiolate-protected [Au25 (SR)18 ]- nanoclusters, involving both photosensitized 1 O2 generation by the Au13 superatomic core and catalytic carbon-carbon bond formation facilitated by Au2 (SR)3 staples. This synergistic combination of two different catalytic units enables efficient cross-dehydrogenative coupling of terminal alkynes and tertiary aliphatic amines to afford propargylamines in high yields of up to 93 %. Mixed-ligand AuNCs bearing both thiolate and alkynyl ligands revealed the intermediacy of the alkynyl-exchanged AuNCs toward both photosensitization and C-C bond-forming catalytic cycles. Density functional theory calculations also supported the intermediacy of the alkynyl-exchanged AuNCs. Thus, the use of ligand-protected metal nanoclusters has enabled the development of an exceptional multifunctional catalyst, wherein distinct nanocluster components facilitate cooperative photo- and chemo-catalysis.

Design and Evaluation of a Puncture Control Method for the Deflection of Ultrafine Needles due to Interfacial Passage-Proposal of Puncture Control Strategy for Increasing.

With the demand for sophisticated techniques to easily prevent the deflection of needles, robotic CT (computed tomography)-guided puncture with an ultrafine needle is being investigated. Quantification of deflection is essential for accurate puncture with ultrafine needles. Research on the quantification of deflection caused by tissue reaction forces to which the beveled surface of the needle tip is in progress, and this method has been applied for deflection reduction and needle steering within the tissue. However, when the needle tip passes through a tissue boundary, the needle deflects regardless of the direction of the beveled surface. Although several methods have been proposed to reduce the deflection caused by the boundary surface, no curve puncture method has been constructed using the deflection. This work aimed to construct a refraction model that can back-calculate the curved path from the body surface to the target. Assumptions of the refraction model were made based on the results of ex vivo examination, and the model was validated through in vivo examination. A refraction model in which the refraction angle is linearly proportional to the needle penetration angle relative to the boundary was hypothesized. Validation test revealed that the correlation coefficient exceeded 0.9, which was similar to that of the model and suggested the biological adaptability of the proposed model. A curve puncture method using this refraction model will be developed in the future.

Wrong-level spine surgery: A multicenter retrospective study.

BACKGROUND: Wrong-level spine surgery is a rare but serious complication of spinal surgery that increases patient harm and legal risks. Although such surgeries have been reported by many spine surgeons, they have not been adequately investigated. Therefore, this study aimed to examine the causes and preventive measures for wrong-level spine surgeries. METHODS: This study analyzed cases of wrong-level spine surgeries from 10 medical centers. Factors such as age, sex, body mass index, preoperative diagnosis, surgical details, surgeon's experience, anatomical variations, responses, and causes of the wrong-level spine surgeries were studied. The methods used by the surgeons to confirm the surgical level were also surveyed using a questionnaire for each surgical procedure and site. RESULTS: Eighteen cases (13 men and 5 women; mean age, 61.2 years; mean body mass index, 24.5 kg/m2) of wrong-level spine surgeries were evaluated in the study. Two cases involved emergency surgeries, three involved newly introduced procedures, and five showed anatomical variations. Wrong-level spine surgeries occurred more frequently in patients who underwent posterior thoracic surgery than in those who underwent other techniques (p < 0.01). Twenty-two spinal surgeons described the methods used to confirm the levels preoperatively and intraoperatively. In posterior thoracic laminectomies, half of the surgeons used preoperative markers to confirm the surgical level and did not perform intraoperative fluoroscopy. In posterior thoracic fusion, all surgeons confirmed the level using fluoroscopy preoperatively and intraoperatively. CONCLUSIONS: Wrong-level spine surgeries occurred more frequently in posterior thoracic surgeries. The thoracic spine lacks the anatomical characteristics observed in the cervical and lumbar spine. The large drop in the spinous process can make it challenging for surgeons to determine the positional relationship between the spinous process and the vertebral body. Moreover, unfamiliarity with the technique and anatomical variations were also risk factors for wrong-level spine surgeries.

Dicalcin suppresses invasion and metastasis of mammalian ovarian cancer cells by regulating the ganglioside-Erk1/2 axis.

Metastasis, a multistep process including cancer cell migration and invasion, is the major cause of mortality in patients with cancer. Here, we investigated the effect of dicalcin, a Ca2+-binding protein, on the invasion and metastasis of ovarian cancer (OC) cells. Extracellularly administered dicalcin bound to the membrane of OV2944 cells, mouse OC cells, and suppressed their migration in vitro; however, cell viability or proliferation were unaffected. Repeated intraperitoneal injection of a partial peptide of dicalcin (P6) prolonged the survival, and reduced the number of microcolonies in the livers of cancer-bearing mice. P6 bound to the ganglioside GM1b in a solid-phase assay; treatment with P6 inhibited the constitutive activation of Erk1/2 in OC cells, whereas excess administration of GM1b augmented Erk activity and cancer cell migration in vitro. Thus, dicalcin, a novel suppressor of invasion and metastasis of OC cells, acts via the GM1b-Erk1/2 axis to regulate their migration.

A Case of Perimesencephalic Subarachnoid Hemorrhage with Cerebral Venous Sinus Thrombosis due to Stenosis of the Junction of the Vein of Galen and Rectus Sinus.

Perimesencephalic subarachnoid hemorrhage (PMSAH) is a group of diseases characterized by bleeding around the brainstem. In recent years, it has been suggested that PMSAH is associated with the venous system. We report a case of PMSAH caused by stenosis of the junction of the vein of Galen (VG) and the rectus sinus (RS). A 39-year-old man presented with restlessness at work. He was administered diazepam, and a few minutes later, his consciousness became clear. Imaging showed subarachnoid hemorrhage (SAH) around the right midbrain, occlusion of the right sigmoid sinus and the right transverse sinus, stenosis of the junction of the VG and RS, T2 hyperintensity in the right middle temporal gyrus, and obstruction of the right vein of Labbe. The location of the SAH coincided with stenosis of the junction of the VG and RS. PMSAH was diagnosed due to the increase in intracranial venous pressure caused by the patient's sinus obstruction in addition to the stenosis of the junction of the VG and RS. It is necessary to pay attention to venous return when PMSAH is observed.

Development of Needle Guide Unit Considering Buckling Bone-Perforation Control Strategy Based on Computed Tomography-Guided Needle Insertion Robot.

A computed tomography (CT)-guided robotic assistance system is useful for needle insertion into metastatic carcinoma of vertebrae, which has limited pathways. However, the use of conventional needles in this procedure can result in bone fracture in the perforation area caused by the reaction force of the inserted needle. In this study, we developed a multistage retractable needle guide unit that avoids the buckling and crushing of the needle tip that commonly occur in 25-gauge ultrafine needles. First, we clarified a relationship between the shape of the guide and the termination factor when a buckling load is applied to the needle. Next, we revealed the point at which the plastic deformation of the needle occurred when the bone is drilled. Based on these results, we developed a guide unit with the reaction force set to an appropriate value. Finally, an evaluation test of bone needle insertion was conducted on porcine vertebrae with using the developed needle guide unit equipped with a 25-gauge needle. The needle penetrated the vertebra without buckling or crushing of the needle tip, which demonstrates the value of this multistage retractable needle guide unit when ultrafine needles are required. Clinical Relevance- Cancer tumors often metastasize to bones. There is a treatment called percutaneous vertebroplasty which restores the patient's quality of life by injecting poly (methyl methacrylate) (PMMA) into a bone. It helps to reinforce the bone that has become brittle due to cancer metastasis to the vertebral body or osteoporosis. This treatment often involves puncture of the vertebrae but the limited puncture pathway makes it difficult to perform the treatment manually. Therefore it is necessary to construct a system that supports accurate puncture by a robot such as the proposed method.

Facilitatory Effect of Extending the Course Duration on Dissemination of Educational Content.

The physiological practice course at Saitama Medical University provides students with the opportunity to learn physiological principles through wet labs and discussions. To develop a more effective method for maximizing learning outcomes, we extended the course's schedule from one day (1d) to two days (2d) per theme, evaluated self-administered questionnaires between two different years (pre and post-change), and examined whether the increased course length affected learning outcomes. Within the 2018 curriculum year, every theme of the course was completed in a day, including experiments in the wet lab and discussions. In 2019, each theme was assessed for two days. The second-year undergraduate medical students anonymously submitted the self-assessment questionnaire that addressed several aspects, such as understanding of the theme, through a 5-point Likert scale. The average Likert scores varied from 4 to 4.5 point for all questions, and significant differences were not found between the 1d and 2d courses. However, the ratio of students with the highest points increased for one question of the 2d course: 43.6% (1d) to 53.4% (2d) for understanding. Further, the standard deviation (SD) values decreased in the 2d course for every question: 0.29 (1d) to 0.15 (2d) for interest, 0.33 (1d) to 0.19 (2d) for understanding, 0.30 (d) to 0.17 (d) for communication, 0.34 (1d) to 0.19 (2d) for general evaluation. This reduction in the SD values indicated that the educational content was imparted more efficiently to students in the 2d course. Thus, we concluded that extending the course time facilitated dissemination of educational content for every theme. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-022-01563-4.

Robotic Cytology using Extra-Fine Needles : -Proposal of Puncture Control Strategy for Increasing Collection Amount.

Fine needle aspiration cytology requires accurate needle insertion into a tumor and sufficient amount collection of samples, which highly depends on the skill of the physician. The advantage of the diagnosis is to minimize the tissue damage with the fine needle, while, when the amount of the sample sucked from the lesion is not enough for the definite diagnosis, the procedure has to be repeated until satisfying them. Although numerous research reported a robot-assisted insertion method to improve the accuracy of needle placement with fine needles, there was less research to address the efficient tissue collection. Ideally, the amount of the samples can be satisfied for the diagnosis even if an extra-fine needle (e.g. 25-gauge) is used. This paper proposes a novel needle insertion method for increasing the amount of the tissue sample with the extra-fine needle. The proposed insertion method comprises the round-trip insertion motion and trajectory rerouting with the nature of the bevel-tipped needle. The phantom study's result showed the equivalency of the aspiration amount between a physician's manual procedure with a 22-gauge needle and the proposed method with a 25-gauge needle (4.5 ± 1.0 mg vs 5.1 ± 0.7 mg). The results suggested that the proposed robotic aspiration method can increase the sampling amount with the extra-fine needle in the fine needle aspiration cytology.

Gene expression signatures as candidate biomarkers of response to PD-1 blockade in non-small cell lung cancers.

Although anti-PD-1/PD-L1 monotherapy has achieved clinical success in non-small cell lung cancer (NSCLC), definitive predictive biomarkers remain to be elucidated. In this study, we performed whole-transcriptome sequencing of pretreatment tumor tissue samples and pretreatment and on-treatment whole blood samples (WB) samples obtained from a clinically annotated cohort of NSCLC patients (n = 40) treated with nivolumab (anti-PD-1) monotherapy. Using a single-sample gene set enrichment scoring method, we found that the tumors of responders with lung adenocarcinoma (LUAD, n = 20) are inherently immunogenic to promote antitumor immunity, whereas those with lung squamous cell carcinoma (LUSC, n = 18) have a less immunosuppressive tumor microenvironment. These findings suggested that nivolumab may function as a molecular targeted agent in LUAD and as an immunomodulating agent in LUSC. In addition, our study explains why the reliability of PD-L1 expression on tumor cells as a predictive biomarker for the response to nivolumab monotherapy is quite different between LUAD and LUSC.

Assessing countermeasures during a hepatitis A virus outbreak among men who have sex with men.

BACKGROUND: A hepatitis A epidemic occurred among men who have sex with men (MSM) in Japan in 2017-2018. In this study, we employ a parsimonious mathematical model to epidemiologically investigate the dynamics of infection, aiming to evaluate the effectiveness of campaign-based interventions among MSM to raise awareness of the situation. METHODS: A mathematical model describing a mixture of human-to-human transmission and environmental transmission was fitted to surveillance data. Taking seasonally varying environmental transmission into account, we estimated the reproduction number of hepatitis A virus during the course of epidemic, and, especially, the abrupt decline in this reproduction number following campaign-based interventions. RESULTS: The reproduction number prior to the countermeasures ranged from 2.6 to 3.1 and then began to decrease following campaign-based interventions. After the first countermeasure, the reproduction number decreased, but the epidemic remained supercritical (i.e., Rt > 1). The value of Rt dropped well below one following the second countermeasure, which used web articles to widely disseminate information about the epidemic risk. CONCLUSIONS: Although the effective reproduction number, Rt, changes because of both intrinsic and extrinsic factors, the timing of the examined countermeasures against hepatitis A in the MSM population was consistent with the abrupt declines observed in Rt. Even without vaccination, the epidemic was brought under control, and risky behaviors may have been changed by the increase in situation awareness reached through web articles.

Dicalcin suppresses in vitro trophoblast attachment in human cell lines.

Implantation is a highly organized process that involves an interaction between a competent blastocyst and a receptive uterus. Despite significant research efforts, the molecular mechanisms governing this complex process remain elusive. Here, we investigated the effect of dicalcin, an S100-like Ca2+-binding protein, on the attachment of choriocarcinoma cells (BeWo cells) onto a monolayer of endometrial carcinoma cells (Ishikawa cells). Extracellularly administered dicalcin bound to both BeWo and Ishikawa cells. Pretreatment of BeWo spheroids with dicalcin reduced the attachment ratio of the spheroids onto the monolayer, whereas that of Ishikawa cells showed no apparent change. We identified the partial amino acid sequence of human dicalcin that exhibited maximum suppression for BeWo spheroid attachment. Transmission electron microscopy analysis revealed that the dicalcin-derived peptide caused a dilation of the intercellular junction between BeWo and ISK cells. Peptide treatment of BeWo spheroids downregulated the expression of integrinαvß3 in BeWo cells, and induced alterations in their phalloidin-staining pattern, as measured by the length of each F-actin fiber and the thickness of the cortical stress fiber. Thus, dicalcin affects reorganization of the intracellular actin meshwork and subsequently the intensity of attachment, functioning as a novel suppressor of implantation.

Association of immune-related pneumonitis with clinical benefit of anti-programmed cell death-1 monotherapy in advanced non-small cell lung cancer.

BACKGROUND: The association between the development of checkpoint inhibitor pneumonitis (CIP) with tumor response and survival has remained unclear so far. The aim of the present study was to evaluate the association between CIP and the clinical efficacy of anti-programmed cell death-1 antibody in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Between January 2016 and August 2019, 203 advanced NSCLC patients were administered with nivolumab or pembrolizumab. Comparisons were made between patients with and without CIP. We evaluated the time-to-treatment failure (TTF), progression-free survival (PFS), and overall survival (OS). RESULTS: CIP was observed in 28 (14%) patients. CIP was associated with a longer PFS (18.9 months [95% confidence interval, CI: 8.7 months-not reached] vs. 3.9 months [95% CI: 3.4-5.1 months, p < 0.01]) and longer OS (27.4 [95% CI: 20.7 months-not reached] vs. 14.8 months [95% CI: 11.2-17.9 months, p = 0.003]). Most patients discontinued the immune checkpoint inhibitor (ICI) treatment when they developed CIP. Seven patients (25%) lived for more than 300 days from treatment discontinuation and did not show any long-term tumor growth after treatment discontinuation. CONCLUSION: CIP was associated with prolonged PFS and OS. Additionally, 25% of CIP patients did not show any tumor growth for long periods after treatment discontinuation. Careful management of CIP can help in obtaining the best clinical efficacy from anti-PD-1 antibody.

Synthesis of polyenylpyrrole derivatives with selective growth inhibitory activity against T-cell acute lymphoblastic leukemia cells.

T-cell acute lymphoblastic leukemia (T-ALL) is a hardly curable disease with a high relapse rate. 20 analogs were synthesized based on the structures of two kinds of fungi-derived polyenylpyrrole products (rumbrin (1) and auxarconjugatin-B (2)) to suppress the growth of T-ALL-derived cell line CCRF-CEM and tested for growth-inhibiting activity. The octatetraenylpyrrole analog gave an IC50 of 0.27 µM in CCRF-CEM cells, while it did not affect Burkitt lymphoma-derived cell line Raji and the cervical cancer cell line HeLa, or the oral cancer cell line HSC-3 (IC50 > 10 µM). This compound will be a promising compound for developing T-ALL-specific drugs.

Relationship between Programmed Cell Death Protein Ligand 1 Expression and Immune-related Adverse Events in Non-small-cell Lung Cancer Patients Treated with Pembrolizumab.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) can lead to immune-related adverse events (irAEs). A correlation between the development of irAEs and efficacy has been suggested; however, it is unclear whether there is a relationship between programmed death ligand 1 (PD-L1) expression and the development of these events. METHODS: We performed a retrospective study of advanced or metastatic non-small cell lung cancer (NSCLC) patients who were treated with pembrolizumab monotherapy at our institution between May 2015 and April 2018 (n = 44). Patients were categorized into two groups, specifically those with irAEs (irAE group) or without (non-irAE group), and we evaluated the objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Predictors of irAEs were examined by multivariate analysis. RESULTS: irAEs of any grade occurred in 31 (70.5%) patients. The median PFS was 10.9 months in the irAE group versus 3.7 months in the non-irAE group (P < 0.001). ORR and DCR were also higher in the irAE group than in the non-irAE group. Furthermore, high PD-L1 expression (≥50%) was a predictive factor of irAE based on logistic regression (P = 0.004). CONCLUSIONS: In patients with advanced NSCLC treated with pembrolizumab monotherapy, ORR, DCR, and PFS were significantly better in the irAE group than in the non-irAE group. High PD-L1 expression, at the time of pretreatment, was identified as an independent predictor of irAE development. We believe that more careful management of irAEs for individuals with high PD-L1 expression is needed to improve clinical benefits. Further, PD-L1 expression might be useful for ICI risk management.

A Remarkable Clinical Response to Pembrolizumab in a Rare Spindle Cell Carcinoma of the Lung.

Spindle cell carcinoma of the lung consists of only spindle-shaped tumor cells, and accounts for approximately 13.3% of all sarcomatoid carcinomas (SCs), which are a rare subtype of poorly differentiated non-small cell lung cancer (NSCLC). Spindle cell carcinoma of the lung has very poor prognosis owing to resistance to chemotherapy and radiotherapy. This case report describes a 76-year-old man who presented with complaints of dry cough and right-sided neck pain and was later diagnosed with spindle cell carcinoma of the lung. He had a medical history of type 2 diabetes, angina pectoris, atrial fibrillation, hypertension, hyperlipidemia, and hepatitis B and a 20 pack-year history of smoking. A computed tomography (CT) scan revealed a mass with a thick-walled cavity in the right upper lobe of the lung. His neck pain was consistent with PET-CT images, indicating metastases due to invasion of lung cancer cells. The expression of PD-L1 in more than 90% of the tumor cells of the lung biopsy tissue led to the administration of pembrolizumab. The lung and metastatic tumors dramatically decreased in size after 9 weeks, and no tumor regrowth was observed over 11 courses of pembrolizumab administration. To the best of our knowledge, there are no previous reports describing the use of pembrolizumab for spindle cell carcinoma of the lung. This case report suggests that immunotherapy could be a promising treatment option for rare types of lung cancers, including spindle cell carcinoma.

High stretch cycling inhibits the morphological and biological decidual process in human endometrial stromal cells.

PURPOSE: Subendometrial myometrium exerts wave-like activity throughout the menstrual cycle, and uterine peristalsis is markedly reduced during the implantation phase. We hypothesized that abnormal uterine peristalsis has an adverse effect on the endometrial decidualization process. We conducted an in vitro culture experiment to investigate the effect of cyclic stretch on the morphological and biological endometrial decidual process. METHODS: Primary human endometrial stromal cells (HESCs) were isolated from hysterectomy specimens and incubated with or without 8-bromo-cyclic adenosine monophosphate (8-br-cAMP) and medroxyprogesterone acetate (MPA) for 3 days. After decidualization, cultures were continued for 24 hours with or without cyclic stretch using a computer-operated cell tension system. RESULTS: Cyclic stretch significantly repressed expression of decidual markers including insulin-like growth factor-binding protein 1 (IGFBP1), prolactin (PRL), forkhead box O1 (FOXO1), and WNT4 on decidualized HESCs. In addition, cyclic stretch of decidualized HESCs affected the decidual morphological phenotype to an elongated shape. The alternation of F-actin localization in decidualized HESCs was not observed in response to cyclic stretch. CONCLUSIONS: These data suggest that cyclic stretch inhibits the morphological and biological decidual process of HESCs. Our findings imply that uterine abnormal contractions during the implantation period impair endometrial decidualization and contribute to infertility.

High Sensitivity In Vivo Imaging of Cancer Metastasis Using a Near-Infrared Luciferin Analogue seMpai.

Bioluminescence imaging (BLI) is useful to monitor cell movement and gene expression in live animals. However, D-luciferin has a short wavelength (560 nm) which is absorbed by tissues and the use of near-infrared (NIR) luciferin analogues enable high sensitivity in vivo BLI. The AkaLumine-AkaLuc BLI system (Aka-BLI) can detect resolution at the single-cell level; however, it has a clear hepatic background signal. Here, to enable the highly sensitive detection of bioluminescence from the surrounding liver tissues, we focused on seMpai (C15H16N3O2S) which has been synthesized as a luciferin analogue and has high luminescent abilities as same as AkaLumine. We demonstrated that seMpai BLI could detect micro-signals near the liver without any background signal. The solution of seMpai was neutral; therefore, seMpai imaging did not cause any adverse effect in mice. seMpai enabled a highly sensitive in vivo BLI as compared to previous techniques. Our findings suggest that the development of a novel mutated luciferase against seMpai may enable a highly sensitive BLI at the single-cell level without any background signal. Novel seMpai BLI system can be used for in vivo imaging in the fields of life sciences and medicine.

Visualization of activity-regulated BDNF expression in the living mouse brain using non-invasive near-infrared bioluminescence imaging.

Altered levels of brain-derived neurotrophic factor (BDNF) have been reported in neurologically diseased human brains. Therefore, it is important to understand how the expression of BDNF is controlled under pathophysiological as well as physiological conditions. Here, we report a method to visualize changes in BDNF expression in the living mouse brain using bioluminescence imaging (BLI). We previously generated a novel transgenic mouse strain, Bdnf-Luciferase (Luc), to monitor changes in Bdnf expression; however, it was difficult to detect brain-derived signals in the strain using BLI with d-luciferin, probably because of incomplete substrate distribution and light penetration. We demonstrate that TokeOni, which uniformly distributes throughout the whole mouse body after systematic injection and produces a near-infrared bioluminescence light, was suitable for detecting signals from the brain of the Bdnf-Luc mouse. We clearly detected brain-derived bioluminescence signals that crossed the skin and skull after intraperitoneal injection of TokeOni. However, repeated BLI using TokeOni should be limited, because repeated injection of TokeOni on the same day reduced the bioluminescence signal, presumably by product inhibition. We successfully visualized kainic acid-induced Bdnf expression in the hippocampus and sensory stimulation-induced Bdnf expression in the visual cortex. Taken together, non-invasive near-infrared BLI using Bdnf-Luc mice with TokeOni allowed us to evaluate alterations in BDNF levels in the living mouse brain. This will enable better understanding of the involvement of BDNF expression in the pathogenesis and pathophysiology of neurological diseases.

Development of near-infrared firefly luciferin analogue reacted with wild-type and mutant luciferases.

Interestingly, only the D-form of firefly luciferin produces light by luciferin-luciferase (L-L) reaction. Certain firefly luciferin analogues with modified structures maintain bioluminescence (BL) activity; however, all L-form luciferin analogues show no BL activity. To this date, our group has developed luciferin analogues with moderate BL activity that produce light of various wavelengths. For in vivo bioluminescence imaging, one of the important factors for detection sensitivity is tissue permeability of the number of photons emitted by L-L reaction, and the wavelengths of light in the near-infrared (NIR) range (700-900 nm) are most appropriate for the purpose. Some NIR luciferin analogues by us had performance for in vivo experiments to make it possible to detect photons from deep target tissues in mice with high sensitivity, whereas only a few of them can produce NIR light by the L-L reactions with wild-type luciferase and/or mutant luciferase. Based on the structure-activity relationships, we designed and synthesized here a luciferin analogue with the 5-allyl-6-dimethylamino-2-naphthylethenyl moiety. This analogue exhibited NIR BL emissions with wild-type luciferase (λmax = 705 nm) and mutant luciferase AlaLuc (λmax = 655 nm).

Association Between Skin Reaction and Clinical Benefit in Patients Treated with Anti-Programmed Cell Death 1 Monotherapy for Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Anti-programmed cell death 1 antibody is a standard therapy for advanced non-small cell lung cancer (NSCLC). However, immune-related adverse events (irAEs), such as skin reactions, are frequently observed. Although skin reactions are associated with clinical efficacy in melanoma, this association in advanced NSCLC and predictors of irAEs remain unclear. Accordingly, this study identified potential correlations of skin reactions with clinical efficacy and clinical predictors of development of skin reactions. SUBJECTS, MATERIALS, AND METHODS: We retrospectively surveyed patients with advanced NSCLC who received nivolumab or pembrolizumab monotherapy at Sendai Kousei Hospital (n = 155) during January 2016 to April 2018. Treatment efficacy was evaluated in patients with and without skin reactions, and associated predictive markers were determined. A 6-week landmark analysis was conducted to assess the clinical benefit of early skin reactions. RESULTS: Skin reactions were observed in 51 patients with a median time to onset of 6.4 weeks. The overall response rate (ORR) was significantly higher in patients with skin reactions (57% vs. 19%, p < .001). Median progression-free survival (PFS) durations of 12.9 and 3.5 months and overall survival durations of not reached and 11.4 months were observed in patients with and without skin reactions, respectively. In the 6-week landmark analysis, the ORR was significantly higher in patients with skin reactions, and skin reactions were significantly associated with increased PFS. A multivariate analysis identified pre-existing rheumatoid factor (RF) as an independent predictor of skin reactions. CONCLUSION: Skin reactions appeared beneficial in patients treated with nivolumab/pembrolizumab for advanced NSCLC and could be predicted by pre-existing RF. Further large-scale validations studies are warranted. IMPLICATIONS FOR PRACTICE: This single-institutional medical record review that included 155 patients with advanced non-small cell lung cancer who were treated with nivolumab or pembrolizumab monotherapy revealed that overall response rate and progression-free survival were significantly better in patients with skin reactions. Pre-existing rheumatoid factor was an independent predictor of skin reactions.