Nelfinavir, an orally administered inhibitor of human immunodeficiency virus protease, inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. We conducted a randomized controlled trial to evaluate the clinical efficacy and safety of nelfinavir in patients with SARS-CoV-2 infection. We included unvaccinated asymptomatic or mildly symptomatic adult patients who tested positive for SARS-CoV-2 infection within 3 days before enrollment. The patients were randomly assigned (1:1) to receive oral nelfinavir (750 mg; thrice daily for 14 days) combined with standard-of-care or standard-of-care alone. The primary endpoint was the time to viral clearance, confirmed using quantitative reverse-transcription PCR by assessors blinded to the assigned treatment. A total of 123 patients (63 in the nelfinavir group and 60 in the control group) were included. The median time to viral clearance was 8.0 (95% confidence interval [CI], 7.0 to 12.0) days in the nelfinavir group and 8.0 (95% CI, 7.0 to 10.0) days in the control group, with no significant difference between the treatment groups (hazard ratio, 0.815; 95% CI, 0.563 to 1.182; P = 0.1870). Adverse events were reported in 47 (74.6%) and 20 (33.3%) patients in the nelfinavir and control groups, respectively. The most common adverse event in the nelfinavir group was diarrhea (49.2%). Nelfinavir did not reduce the time to viral clearance in this setting. Our findings indicate that nelfinavir should not be recommended in asymptomatic or mildly symptomatic patients infected with SARS-CoV-2. The study is registered with the Japan Registry of Clinical Trials (jRCT2071200023). IMPORTANCE The anti-HIV drug nelfinavir suppresses the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. However, its efficacy in patients with COVID-19 has not been studied. We conducted a multicenter, randomized controlled trial to evaluate the efficacy and safety of orally administered nelfinavir in patients with asymptomatic or mildly symptomatic COVID-19. Compared to standard-of-care alone, nelfinavir (750 mg, thrice daily) did not reduce the time to viral clearance, viral load, or the time to resolution of symptoms. More patients had adverse events in the nelfinavir group than in the control group (74.6% [47/63 patients] versus 33.3% [20/60 patients]). Our clinical study provides evidence that nelfinavir, despite its antiviral effects on SARS-CoV-2 in vitro, should not be recommended for the treatment of patients with COVID-19 having no or mild symptoms.
512 Background: Lenvatinib has been widely used as a leading oral multikinase inhibitor for advanced hepatocellular carcinoma (HCC) patients in real-world practice worldwide. However, in the global phase 3 study comparing the effectiveness of lenvatinib and sorafenib, only a limited population of patients were enrolled, excluding those who had a high-burden intrahepatic lesion or Child-Pugh class (C-P) B, who were likely to receive systemic therapy in the clinical practice. Currently, combination immunotherapy has replaced multikinase inhibitors as the standard first-line treatment. Therefore, this prospective study explored the safety and efficacy of lenvatinib in the patient population, which would be used in real-world practice. Methods: This was an open-label, multicenter, prospective study that enrolled patients who had advanced HCC with C-P A or B, treated with lenvatinib as first-line or second-line after atezolizumab plus bevacizumab (Atz + Bv) at 10 sites in Japan. The study included patients who had high tumor burden, defined as identifying either tumor volume of more than 50% of the liver, portal vein tumor thrombosis reaching the main trunk or the contralateral branch, or bile duct invasion at baseline (jRCTs031190017). Results: Between December 1, 2019, and September 30, 2021, 59 patients were recruited for this study. At the time of enrollment, 47 and 12 patients were classified as C-P A and B, respectively. This study included 11 patients with high tumor burden and 12 treated with second-line after Atz + Bv. All patients with high tumor burden and second-line treatment were classified as C-P A. Median overall survival of C-P A and B patients was 20.3 and 4.2 months, respectively. Similarly, progression-free survival according to modified RECIST (mRECIST) of C-P A and B patients was 4.8 and 2.8 months, respectively. Objective response rate (ORR) according to mRECIST in C-P A patients was 61.9%, whereas in C-P B patients was 25.0%. ORRs of high-burden group and second-line group were 80.0% and 40.0%, respectively. Major severe adverse events (AE) (≥grade 3) in C-P A patients were hypertension (41.3%) and proteinuria (23.9%). In contrast, those in C-P B patients were hyponatremia (41.7%), elevated aspartate aminotransferase (41.7%), hypertension (33.3%), decreased appetite (16.7%), diarrhea (16.7%), and proteinuria (16.7%). Discontinuation rate due to AE of C-P A and B patients was 17.4% and 33.3%, respectively. In high-burden and second-line groups, 10% and 20% discontinued lenvatinib due to AE, respectively. Conclusions: Lenvatinib is expected to be safe and effective in patients with advanced HCC who have a high tumor burden and second-line treatment after Atz + Bv, whereas liver function was maintained with C-P A. However, in C-P B, this study found lower efficacy and higher discontinuation rates due to AE compared with C-P A. Clinical trial information: s031190017 .
Abstract This study aimed to investigate the lesion and endoscopist factors associated with unintentional endoscopic piecemeal mucosal resection (uniEPMR) of colorectal lesions ≥ 10 mm. uniEPMR was defined from the medical record as anything other than a preoperatively planned EPMR. Factors leading to uniEPMR were identified by retrospective univariate and multivariate analyses of lesions ≥ 10 mm (adenoma including sessile serrated lesion and carcinoma) that were treated with endoscopic mucosal resection (EMR) at three hospitals. Additionally, a questionnaire survey was conducted to determine the number of cases treated by each endoscopist. A learning curve (LC) was created for each lesion size based on the number of experienced cases and the percentage of uniEPMR. Of 2557 lesions, 327 lesions underwent uniEPMR. The recurrence rate of uniEPMR was 2.8%. Multivariate analysis showed that lesion diameter ≥ 30 mm (odds ratio 11.83, 95% confidence interval 6.80–20.60, p < 0.0001) was the most associated risk factor leading to uniEPMR. In the LC analysis, the proportion of uniEPMR decreased for lesion sizes of 10–19 mm until 160 cases. The proportion of uniEPMR decreased with the number of experienced cases in the 20–29 mm range, while there was no correlation between the number of experienced cases and the proportion of uniEPMR ≥ 30 mm. These results suggest that 160 cases seem to be the minimum number of cases needed to be proficient in en bloc EMR. Additionally, while lesion sizes of 10–29 mm are considered suitable for EMR, lesion sizes ≥ 30 mm are not applicable for en bloc EMR from the perspective of both lesion and endoscopist factors.
Abstract Aims The MADIT‐ICD benefit score is used to stratify the risk of life‐threatening arrhythmia and non‐arrhythmic mortality. We sought to develop an implantable cardioverter defibrillator (ICD) benefit‐prediction score for Japanese patients with ICDs. Methods Patients who underwent ICD implantation as primary prophylaxis were retrospectively enrolled. Based on their MADIT‐ICD benefit scores, we developed a modified MADIT‐ICD benefit score adapted to the Japanese population. The primary endpoints were appropriate ICD therapy and all‐cause death without appropriate ICD therapy (non‐arrhythmic death). We used the Fine and Gray multivariate model and Cox proportional hazard regression to identify factors for adjusting the MADIT‐ICD benefit–risk score specifically for the Japanese population. The scoring points for the original MADIT‐ICD benefit score were adjusted to optimal points based on the multivariate analysis results in the population. Results The study enrolled 167 patients [age, 61.9 ± 12.3 years; male individuals, 138 (82.6%); cardiac resynchronization therapy, 73 (43.7%); ischaemic cardiomyopathy, 53 (31.7%)]. Fourteen patients received anti‐tachycardia pacing (ATP) therapy, and 23 received shock therapy as the initial appropriate ICD therapy. Non‐arrhythmic deaths occurred in 37 patients. The original MADIT‐ICD benefit score could not stratify non‐arrhythmic mortality in the Japanese population. The patients were reclassified into three groups according to the modified MADIT‐ICD benefit score. The modified MADIT‐ICD benefit score could effectively stratify the incidence of appropriate ICD therapy and non‐arrhythmic mortality. In the highest‐benefit group, the 10 year cumulative rates of appropriate ICD therapy and non‐arrhythmic mortality were 56.8% and 12.9%, respectively ( P < 0.01). In the intermediate‐benefit group, these rates were 20.2% and 40.2% ( P = 0.01). In the lowest‐benefit group, the incidence of non‐arrhythmic deaths was 68.1%, and no patient received appropriate ICD therapy. Conclusions The modified MADIT‐ICD benefit score may be useful for stratifying ICD candidates in the Japanese population.
Pancreatic solid pseudopapillary neoplasm (SPN) is a low-grade malignant neoplasm with a good prognosis. Clinically aggressive SPNs have rarely been reported but have not been analyzed in detail. In this study, we referred to this highly malignant type of SPN as high-grade SPN (HG-SPN) and compared its clinicopathological and genetic characteristics with conventional SPN (C-SPN) using immunohistochemistry and gene panel analyses. Five HG-SPNs and 15 C-SPNs were evaluated in this study. HG-SPNs share many pathologic characteristics: macroscopically, solid/cystic appearances, microscopically, pseudopapillary/pseudorosette pattern (100%), tumor cell loose cohesiveness (100%), thin/delicate vasculature (100%), tumor cell cytoplasmic vacuolization (100%), immunohistochemical positivity for β-catenin (nuclear expression) (100%), CD10 (80%), CD56 (80%), and vimentin (100%). Conversely, HG-SPNs showed distinct malignant features compared with C-SPNs: mean tumor size (11.7 vs. 2.9 cm, P <0.001); true necrosis (100% vs. 0%, P <0.001); high-grade nuclear atypia (100% vs. 0%, P <0.001); lymphatic and/or venous invasion (100% vs. 20%, P =0.004); mean mitotic count (4.38 vs. 0.05/high-power field, P <0.001); and mean Ki-67 labeling index (33.9% vs. 3.4%, P <0.001). All HG-SPN patients died of primary disease 3 to 36 months after surgery, while all C-SPN patients were alive without disease. Genetic studies have shown that all analyzed HG-SPNs have CTNNB1 mutations. Two HG-SPN cases showed RB1 mutations with altered immunohistochemical findings for RB1 and p16. Two HG-SPN cases had TP53 mutation and/or p53 overexpression. In conclusion, HG-SPNs show distinct malignant features and some genetic alterations that differ from C-SPNs, indicating the importance of differentiating between these 2 subtypes.
Introduction Previously, we conducted a clinical trial to evaluate the safety and efficacy of transdermal electrical stimulation (TdES) with skin electrodes to improve the visual functions in patients with retinitis pigmentosa (RP). No adverse events were related to the treatment during follow-up examinations, and TdES significantly improved the mean visual acuity and visual field sensitivity. Methods and analysis We developed a study protocol for a prospective, multicentre, randomised, double-masked and sham-controlled clinical trial, planned to commence on June 2021. We intend to compare the maintenance or improvement in best-corrected visual acuity, and safety of TdES using skin electrodes between patients with RP and the sham group. The primary endpoint comprises the superiority of the logarithm of the minimum angle of resolution (logMAR) visual acuity change at week 24 from baseline in the treatment and sham groups. Secondary endpoints involve the comparison of the treatment and sham groups at week 24 for the logMAR visual acuity, early treatment diabetic retinopathy study visual acuity, the mean deviation value of Humphrey field analyser 10-2, monocular Humphrey Esterman visual field test score, ellipsoid zone length, central foveal thickness and 25-item National Eye Institute Visual Function Questionnaire score. We intend to enrol 50 patients from three Japanese institutions within 1 year and follow them up for 1 years. Ethics and dissemination The protocol was approved by the institutional review board at the Chiba University Hospital and two other institutions, and was registered with the Japan Registry of Clinical Trials on 17 May 2021. The trial will be conducted in accordance with the principles of the Declaration of Helsinki, and is in accordance with Good Clinical Practice standards. The findings will be published in a peer-reviewed journal. Trial registration number JRCT2032210094.
Abstract Purpose Recent studies have proposed optimizing the position of the acetabular component based on spinal deformity and stiffness classification to avoid mechanical complication after total hip arthroplasty (THA). The aim of this study was to characterize the dynamic changes in cup alignment post-THA based on the spinopelvic classification and to evaluate the efficacy of cup placement of preventing dislocation. Methods This prospective study included a total of 169 consecutive patients awaiting THA who were classified into four groups based on spinal deformity (pelvic incidence minus lumbar lordosis) and spinal stiffness (change in sacral slope from the standing to seated positions). The cups were aligned based on the group with fluoroscopy. Additionally, postoperative radiographic inclination (RI), radiographic anteversion (RA) in standard anteroposterior radiograph, and lateral anteinclination (AI) in sitting and standing positions were measured. The cumulative incidence of dislocation was evaluated at a follow-up two years post-THA. Result RA was significantly greater in the group with normal spine alignment and stiff spine than in other groups ( P = 0.0006), and AI in the sitting position was lower than in other groups ( P = 0.012). Standing AI did not significantly differ between the groups. One posterior dislocation occurred during the study period (0.6%). Conclusion AI in the sitting position was lower in patients with normal spinal alignment and stiff spine despite larger RA in the standard anteroposterior radiographs. Consequently, with more anteversion in the normal spinal alignment and stiff spine group, spinopelvic parameters can help guide cup placement to prevent short-term dislocation post-THA.
