Takotsubo syndrome in a cancer patient treated with a combination of anti-cancer drugs including immune checkpoint inhibitors: a case report.

Background: Takotsubo syndrome (TTS) is characterized by transient regional left ventricular (LV) dysfunction occurring in individuals exposed to physical or emotional stress. Various stressors are triggers for TTS in cancer patients, and anti-cancer drugs have recently been proposed as a trigger. Therefore, further studies are needed to clarify these triggers and avoid the unnecessary interruption of anti-cancer treatment. Case summary: A 66-year-old woman presented with dyspnoea 10 days after the initiation of atezolizumab in combination with bevacizumab. She had previously received osimertinib as first-line therapy for recurrent lung cancer after primary resection and atezolizumab in combination with bevacizumab, paclitaxel, and carboplatin as second-line therapy. She was admitted due to electrocardiography abnormalities and elevated troponin I and brain natriuretic peptide levels. Echocardiography revealed circumferential severe LV hypokinesis at the mid-ventricular level, with preserved wall motion at the base and apex. Cardiac catheterization performed after the attenuation of symptoms with 20 mg of intravenous furosemide showed normal coronary arteries. Cardiac magnetic resonance imaging on Day 4 revealed increases in T1 and T2 values and extracellular volume fraction; however, neither myocardial infiltration of inflammatory cells or myocardial necrosis was observed in endomyocardial samples obtained on the day of her arrival. Atypical TTS was suspected, and she was treated with perindopril, bisoprolol, and spironolactone. Magnetic resonance imaging 1.5 months after the onset of TTS showed improvements in LV contractility, T1 and T2 values, and the extracellular volume fraction. Discussion: A more detailed understanding of the relationship between anti-cancer drugs and TTS is crucial for preventing interruptions to anti-cancer therapy.

Unraveling the influence of TTF-1 expression on immunotherapy outcomes in PD-L1-high non-squamous NSCLC: a retrospective multicenter study.

Introduction: Several studies explored the association between thyroid transcription factor-1 (TTF-1) and the therapeutic efficacy of immunotherapy. However, the effect of TTF-1 on the therapeutic efficacy of programmed death-1 (PD-1) inhibitor/chemoimmunotherapy in patients with non-squamous non-small cell lung cancer (non-Sq NSCLC) with a programmed death-ligand 1 (PD-L1) tumor proportion score of 50% or more who are highly susceptible to immunotherapy remains unresolved. Therefore, we evaluated whether TTF-1 has a clinical impact on this population. Methods: Patients with non-Sq NSCLC and high PD-L1 expression who received PD-1 inhibitor monotherapy or chemoimmunotherapy between May 2017 and December 2020 were retrospectively enrolled. Treatment efficacy was compared after adjusting for baseline differences using propensity score matching. Results: Among the 446 patients with NSCLC with high PD-L1 expression, 266 patients with non-Sq NSCLC were analyzed. No significant differences in therapeutic efficacy were observed between the TTF-1-positive and -negative groups in the overall and propensity score-matched populations. Of chemoimmunotherapy, pemetrexed containing regimen significantly prolonged progression-free survival compared to chemoimmunotherapy without pemetrexed, regardless of TTF-1 expression (TTF1 positive; HR: 0.46 (95% Confidence interval: 0.26-0.81), p<0.01, TTF-1 negative; HR: 0.29 (95% Confidence interval: 0.09-0.93), p=0.02). Discussion: TTF-1 expression did not affect the efficacy of PD-1 inhibitor monotherapy or chemoimmunotherapy in patients with non-Sq NSCLC with high PD-L1 expression. In this population, pemetrexed-containing chemoimmunotherapy demonstrated superior anti-tumor efficacy, irrespective of TTF-1 expression.

Triple combination therapy comprising osimertinib, an AXL inhibitor, and an FGFR inhibitor improves the efficacy of EGFR-mutated non-small cell lung cancer.

We previously reported that combined therapy with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib and AXL inhibitor ONO-7475 is effective in preventing the survival of drug-tolerant cells in high-AXL-expressing EGFR-mutated non-small cell lung cancer (NSCLC) cells. Nevertheless, certain residual cells are anticipated to eventually develop acquired resistance to this combination therapy. In this study, we attempted to establish a multidrug combination therapy from the first-line setting to overcome resistance to this combination therapy in high-AXL-expressing EGFR-mutated NSCLC. siRNA screening assay showed that fibroblast growth factor receptor 1 (FGFR1) knockdown induced pronounced inhibition of cell viability in the presence of the osimertinib-ONO-7475 combination, which activates FGFR1 by upregulating FGF2 via the c-Myc pathway. Cell-based assays showed that triple therapy with osimertinib, ONO-7475, and the FGFR inhibitor BGJ398 significantly increased apoptosis by increasing expression of proapoptotic factor Bim and reduced cell viability compared with that observed for the osimertinib-ONO-7475 therapy. Xenograft models showed that triple therapy considerably suppressed tumor regrowth. A novel therapeutic strategy of additional initial FGFR1 inhibition may be highly effective in suppressing the emergence of osimertinib- and ONO-7475-resistant cells.

Initial AXL and MCL-1 inhibition contributes to abolishing lazertinib tolerance in EGFR-mutant lung cancer cells.

Lazertinib, a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), demonstrates marked efficacy in EGFR-mutant lung cancer. However, resistance commonly develops, prompting consideration of therapeutic strategies to overcome initial drug resistance mechanisms. This study aimed to elucidate the adaptive resistance to lazertinib and advocate novel combination treatments that demonstrate efficacy in preventing resistance as a first-line treatment for EGFR mutation-positive NSCLC. We found that AXL knockdown significantly inhibited lung cancer cell viability in the presence of lazertinib, indicating that AXL activation contributes to lazertinib resistance. However, long-term culture with a combination of lazertinib and AXL inhibitors led to residual cell proliferation and increased the MCL-1 expression level, which was mediated by the nuclear translocation of the transcription factor YAP. Triple therapy with an MCL-1 or YAP inhibitor in combination with lazertinib and an AXL inhibitor significantly reduced cell viability and increased the apoptosis rate. These results demonstrate that AXL and YAP/MCL-1 signals contribute to adaptive lazertinib resistance in EGFR-mutant lung cancer cells, suggesting that the initial dual inhibition of AXL and YAP/MCL-1 might be a highly effective strategy in eliminating lazertinib-resistant cells.

Anoctamin-like protein 1 regulates repolarization in Paramecium behavioral responses.

Paramecium exhibits responsive behavior to environmental changes, moving either closer to or further away from stimuli. Electrophysiological experiments have revealed that these behavioral responses are controlled by membrane potentials. Anoctamin, a Ca2+-activated Cl- channel, is involved in the regulation of membrane potential in mammals. However, it remains uncertain whether Cl- channels like anoctamin regulate Paramecium behavior. Herein, replacement of external Cl- ions with acetate ion and application of Cl- channel blocker niflumic acid (NFA, 0.1 µM) increased spontaneous avoiding reactions (sARs). Hence, we hypothesized that anoctamin is involved in the stabilization of membrane potential fluctuation. Paramecium cells in which the anoctamin-like protein 1 gene was knocked down displayed frequent sARs in the culture medium without external stimulation. Treatment of anoctamin-like protein 1-knockdown cells with the Ca2+ chelator BAPTA or Ca-channel blocker nicardipine reversed the increase in sARs. Electrophysiological experiments revealed extension of membrane depolarization when positive currents were applied to anoctamin-like protein 1-knockdown cells. We concluded that anoctamin-like protein 1 works as a Cl-channel and stabilizes the membrane potential oscillation, reducing sARs.

Cardiovascular Magnetic Resonance Radiomics to Identify Components of the Extracellular Matrix in Dilated Cardiomyopathy.

BACKGROUND: Current cardiovascular magnetic resonance sequences cannot discriminate between different myocardial extracellular space (ECSs), including collagen, noncollagen, and inflammation. We sought to investigate whether cardiovascular magnetic resonance radiomics analysis can distinguish between noncollagen and inflammation from collagen in dilated cardiomyopathy. METHODS: We identified data from 132 patients with dilated cardiomyopathy scheduled for an invasive septal biopsy who underwent cardiovascular magnetic resonance at 3 T. Cardiovascular magnetic resonance imaging protocol included native and postcontrast T1 mapping and late gadolinium enhancement (LGE). Radiomic features were computed from the midseptal myocardium, near the biopsy region, on native T1, extracellular volume (ECV) map, and LGE images. Principal component analysis was used to reduce the number of radiomic features to 5 principal radiomics. Moreover, a correlation analysis was conducted to identify radiomic features exhibiting a strong correlation (r>0.9) with the 5 principal radiomics. Biopsy samples were used to quantify ECS, myocardial fibrosis, and inflammation. RESULTS: Four histopathological phenotypes were identified: low collagen (n=20), noncollagenous ECS expansion (n=49), mild to moderate collagenous ECS expansion (n=42), and severe collagenous ECS expansion (n=21). Noncollagenous expansion was associated with the highest risk of myocardial inflammation (65%). Although native T1 and ECV provided high diagnostic performance in differentiating severe fibrosis (C statistic, 0.90 and 0.90, respectively), their performance in differentiating between noncollagen and mild to moderate collagenous expansion decreased (C statistic: 0.59 and 0.55, respectively). Integration of ECV principal radiomics provided better discrimination and reclassification between noncollagen and mild to moderate collagen (C statistic, 0.79; net reclassification index, 0.83 [95% CI, 0.45-1.22]; P<0.001). There was a similar trend in the addition of native T1 principal radiomics (C statistic, 0.75; net reclassification index, 0.93 [95% CI, 0.56-1.29]; P<0.001) and LGE principal radiomics (C statistic, 0.74; net reclassification index, 0.59 [95% CI, 0.19-0.98]; P=0.004). Five radiomic features per sequence were identified with correlation analysis. They showed a similar improvement in performance for differentiating between noncollagen and mild to moderate collagen (native T1, ECV, LGE C statistic, 0.75, 0.77, and 0.71, respectively). These improvements remained significant when confined to a single radiomic feature (native T1, ECV, LGE C statistic, 0.71, 0.70, and 0.64, respectively). CONCLUSIONS: Radiomic features extracted from native T1, ECV, and LGE provide incremental information that improves our capability to discriminate noncollagenous expansion from mild to moderate collagen and could be useful for detecting subtle chronic inflammation in patients with dilated cardiomyopathy.

Nationwide data from comprehensive genomic profiling assays for detecting driver oncogenes in non-small cell lung cancer.

Driver oncogenes are investigated upfront at diagnosis using multi-CDx systems with next-generation sequencing techniques or multiplex reverse-transcriptase polymerase chain reaction assays. Additionally, from 2019, comprehensive genomic profiling (CGP) assays have been available in Japan for patients with advanced solid tumors who had completed or were expected to complete standard chemotherapy. These assays are expected to comprehensively detect the driver oncogenes, especially for patients with non-small cell lung cancer (NSCLC). However, there are no reports of nationwide research on the detection of driver oncogenes in patients with advanced NSCLC who undergo CGP assays, especially in those with undetected driver oncogenes at diagnosis. In this study, we investigated the proportion of driver oncogenes detected in patients with advanced NSCLC with undetectable driver oncogenes at initial diagnosis and in all patients with advanced NSCLC who underwent CGP assays. We retrospectively analyzed data from 986 patients with advanced NSCLC who underwent CGP assays between August 2019 and March 2022, using the Center for Cancer Genomics and Advanced Therapeutics database. The proportion of driver oncogenes newly detected in patients with NSCLC who tested negative for driver oncogenes at diagnosis and in all patients with NSCLC were investigated. Driver oncogenes were detected in 451 patients (45.7%). EGFR was the most common (16.5%), followed by KRAS (14.5%). Among the 330 patients with undetected EGFR, ALK, ROS1, and BRAF V600E mutations at diagnosis, 81 patients (24.5%) had newly identified driver oncogenes. CGP assays could be useful to identify driver oncogenes in patients with advanced NSCLC, including those initially undetected, facilitating personalized treatment.

Visceral Adipose Tissue Percentage Compared to Body Mass Index as Better Indicator of Surgical Outcomes in Women With Obesity and Endometrial Cancer.

STUDY OBJECTIVE: To assess the impact visceral adipose tissue percentage (VAT%) on surgical outcomes during minimally invasive surgery in obese women with endometrial cancer. DESIGN: Retrospective observational cohort study. SETTING: Mie University Hospital, Japan. PATIENTS: Of the 73 women (body mass index [BMI] >30 kg/m2) with obesity and primary endometrial cancer, 52 underwent robotic surgery, while 21 underwent laparoscopic surgery between April 2014 and December 2022. INTERVENTIONS: We investigated the correlation between surgical outcomes (operative time and blood loss) and obesity (BMI and visceral adipose tissue percentage [VAT%]). MEASUREMENTS AND MAIN RESULTS: Abdominal fat-related parameters were measured at the level of the umbilicus using preoperative computed tomography. A weak negative correlation was found between BMI and VAT% (CC = -0.313, p = .001). Multivariate analysis showed that VAT% had a stronger correlation to total and practical operative time than BMI (ß = 0.338 vs 0.267, ß = 0.311 vs 0.209, respectively) and was an independent predictor of blood loss. VAT% was an independent predictive marker prolonged for operative time and increased blood loss during lymphadenectomy. CONCLUSION: VAT% could be an indicator of surgical outcomes for patients with obesity and endometrial cancer.

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.

Optimal Protocol for Contrast-enhanced Free-running 5D Whole-heart Coronary MR Angiography at 3T.

Free-running 5D whole-heart coronary MR angiography (MRA) is gaining in popularity because it reduces scanning complexity by removing the need for specific slice orientations, respiratory gating, or cardiac triggering. At 3T, a gradient echo (GRE) sequence is preferred in combination with contrast injection. However, neither the injection scheme of the gadolinium (Gd) contrast medium, the choice of the RF excitation angle, nor the dedicated image reconstruction parameters have been established for 3T GRE free-running 5D whole-heart coronary MRA. In this study, a Gd injection scheme, RF excitation angles of lipid-insensitive binominal off-resonance RF excitation (LIBRE) pulse for valid fat suppression and continuous data acquisition, and compressed-sensing reconstruction regularization parameters were optimized for contrast-enhanced free-running 5D whole-heart coronary MRA using a GRE sequence at 3T. Using this optimized protocol, contrast-enhanced free-running 5D whole-heart coronary MRA using a GRE sequence is feasible with good image quality at 3T.

Effects of Combined Therapeutic Targeting of AXL and ATR on Pleural Mesothelioma Cells.

Few treatment options exist for pleural mesothelioma (PM), which is a progressive malignant tumor. However, the efficacy of molecular-targeted monotherapy is limited, and further therapeutic strategies are warranted to treat PM. Recently, the cancer cell-cycle checkpoint inhibitors have attracted attention because they disrupt cell-cycle regulation. Here, we aimed to establish a novel combinational therapeutic strategy to inhibit the cell-cycle checkpoint kinase, ATR in PM cells. The siRNA screening assay showed that anexelekto (AXL) knockdown enhanced cell growth inhibition when exposed to ATR inhibitors, demonstrating the synergistic effects of the ATR and AXL combination in some PM cells. The AXL and ATR inhibitor combination increased cell apoptosis via the Bim protein and suppressed cell migration when compared with each monotherapy. The combined therapeutic targeting of AXL and ATR significantly delayed regrowth compared with monotherapy. Thus, optimal AXL and ATR inhibition may potentially improve the PM outcome.

Two-dimensional phase-contrast MRI reveals changes in uterine arterial blood flow in pregnant women administered tadalafil for fetal growth restriction.

INTRODUCTION: We aimed to examine the effect of uterine arterial (UtA) blood flow changes after tadalafil treatment for fetal growth restriction (FGR) using two-dimensional (2D) phase-contrast magnetic resonance imaging (PC-MRI). METHODS: We recruited 14 pregnant women with FGR aged 20-44 years, at ≥20 weeks' gestation, between May 2019 and July 2020. They underwent 2D PC-MRI for UtA blood flow measurement 3 days (interquartile range: 2-4) after diagnosis. This group (FGR group) was compared with 14 gestational age (GA)-matched healthy pregnant women (control group). Six patients in the FGR group received treatment with tadalafil administered at 20 mg twice daily after the first MRI until delivery. They underwent a second MRI a week later. RESULTS: The median total UtA blood/body surface area was 420 mL/min/m2 (290-494) in the FGR group and 547 mL/min/m2 (433-681) in the control group (p = 0.01). Percent increase in blood flow were significantly different between the FGR cases treated with tadalafil and control at 15.8 % (14.3-21.3) and 4.2 % (3.6-8.7), respectively (p = 0.03). DISCUSSION: UtA blood flow in pregnant women with FGR was significantly lower than that in healthy pregnant women. Tadalafil is expected to improve UtA blood flow, thereby improving placental function in pregnant patients with FGR.

RNA interference reveals the escape response mechanism of Paramecium to mechanical stimulation.

In Paramecium, a mechanical stimulus applied to the posterior portion of the cell causes a transient increase in membrane permeability to potassium ions, transiently rendering the membrane in a hyperpolarized state. Hyperpolarization causes a transient increase in Cyclic adenosine monophosphate (cAMP) concentration in the cilia, resulting in a transient fast-forward swimming of the cell. Schultz and coworkers (1992) reported that a unique adenylate cyclase (AC)-coupled potassium channel is involved in the reaction underlying this response, which is known as the "escape response." However, the AC responsible for this reaction remains to be identified. Moreover, the molecular linkage between mechanoreception and AC activation has not been elucidated adequately. Currently, we can perform an efficient and simple gene-knockdown technique in Paramecium using RNA interference (RNAi). Paramecium is one of the several model organisms for which whole-genome sequences have been elucidated. The RNAi technique can be applied to whole genome sequences derived from the Paramecium database (ParameciumDB) to investigate the types of proteins that elicit specific biological responses and compare them with those of other model organisms. In this review, we describe the applications of the RNAi technique in elucidating the molecular mechanism underlying the escape response and identifying the AC involved in this reaction. The findings of this study highlight the advantages of the RNAi technique and ParameciumDB.

COVID-19 during pregnancy could potentially affect placental function.

OBJECTIVE: COVID-19 is an ongoing pandemic and has been extensively studied. However, the effects of COVID-19 during pregnancy, particularly on placental function, have not been verified. In this study, we used blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) to evaluate whether COVID-19 incidence during pregnancy has any lasting effects with respect to placental oxygenation. METHODS: This is a case-control study, in which eight cases of singleton pregnancies before 30 weeks gestation with COVID-19 mothers were included. Placental oxygenation was evaluated using BOLD-MRI after 32 weeks of gestation. BOLD-MRI was consecutively performed under normoxia (21% O2), hyperoxia (100% O2), and normoxia for 4 min each. Individual placental time-activity curves were evaluated to calculate the peak score (peakΔR2*) and the time from the start of maternal oxygen administration to the time of peakΔR2* (time to peakΔR2*). Eighteen COVID-19-free normal pregnancies from a previous study were used as the control group. RESULTS: No significant differences were found between the two groups regarding maternal background, number of days of delivery, birth weight, and placental weight. The parameter peakΔR2* was significantly decreased in the COVID-19 group (8 ± 3 vs. 5 ± 1, p < .001); however, there was no significant difference in time to peakΔR2* (458 ± 74 s vs. 471 ± 33 s, p = .644). CONCLUSIONS: In this study, BOLD-MRI was used to evaluate placental oxygenation during pregnancy in COVID-19-affected patients. COVID-19 during pregnancy decreased placental oxygenation even post-illness, but had no effect on fetal growth; further investigation of the possible effects of COVID-19 on the fetus and mother is warranted.

Microvascular Dysfunction in Patients with Idiopathic Dilated Cardiomyopathy: Quantitative Assessment with Phase Contrast Cine MR Imaging of the Coronary Sinus.

PURPOSE: The purposes of this study were to compare global coronary flow reserve (CFR) between patients with idiopathic dilated cardiomyopathy (DCM) and risk-matched controls using cardiac MRI (CMR), and to evaluate the relationship between global CFR and CMR left ventricular (LV) parameters. METHODS: Twenty-six patients with DCM and 26 risk-matched controls who underwent comprehensive CMR examination, including stress-rest coronary sinus flow measurement by phase contrast (PC) cine CMR were retrospectively studied. LV peak global longitudinal, radial, and circumferential strains (GLS, GRS, and GCS) were determined by feature tracking. RESULTS: Patients with DCM had significantly lower global CFR compared with the risk-matched controls (2.87 ± 0.86 vs. 4.03 ± 1.47, P = 0.001). Among the parameters, univariate linear regression analyses revealed significant correlation of global CFR with LV end-diastolic volume index (r = -0.396, P = 0.045), LV mass index (r = -0.461, P = 0.018), GLS (r = -0.558, P = 0.003), and GRS (r = 0.392, P = 0.047). Multiple linear regression analysis revealed GLS as the only independent predictor of global CFR (standardized ß = -0.558, P = 0.003). CONCLUSION: Global CFR was significantly impaired in patients with idiopathic DCM and independently associated with LV GLS, suggesting that microvascular dysfunction may contribute to deterioration of LV function in patients with idiopathic DCM.