Findings from a discontinued clinical trial of favipiravir in high-risk patients with early-onset COVID-19.

INTRODUCTION: Favipiravir terminates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication. Accordingly, early administration of favipiravir to SARS-CoV-2-infected coronavirus disease 2019 (COVID-19) patients may be expected to suppress disease progression. METHODS: A randomized double-blind placebo-controlled trial was conducted to demonstrate efficacy of favipiravir in reducing disease progression in patients with mild COVID-19. The participants were unvaccinated patients with comorbidities and at risk of progression to severe disease. Patients were enrolled within 72 h of disease onset and randomized to receive either favipiravir (1800 mg/dose on Day 1 followed by 800 mg/dose) or matching placebo twice daily for 10 days. The primary endpoint was the proportion of patients requiring oxygen therapy within 28 days of randomization. RESULTS: The trial was discontinued after enrolling 84 patients due to slower than anticipated enrollment caused by rapid uptake of SARS-CoV-2-vaccines and the emergence of the Omicron variant. Results from the 84 patients demonstrated no significant difference in all clinical outcomes. In post-hoc analyses, favipiravir treatment showed higher efficacy in patients within 48 h of onset. No deaths or severe adverse events were documented in the favipiravir group. Plasma concentrations of favipiravir from Day 2 onward were maintained above 40 µg/mL. CONCLUSIONS: Conducting clinical trials for pathogens like SARS-CoV-2 that rapidly accumulate mutations leading to altered disease characteristics carries significant risks unless it can be done in a short period. Therefore, it would be important to prepare the comprehensive clinical trial platform that can appropriately and promptly evaluate drugs even under a pandemic.

Efficacy and Safety of Favipiravir in Moderate COVID-19 Pneumonia Patients without Oxygen Therapy: A Randomized, Phase III Clinical Trial.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), is an enveloped, single-stranded RNA virus. Favipiravir is an orally administrable antiviral drug whose mechanism of action is to selectively inhibit RNA-dependent RNA polymerase. A preliminary trial in COVID-19 patients reported significant improvements across a multitude of clinical parameters, but these findings have not been confirmed in an adequate well-controlled trial. We conducted a randomized, single-blind, placebo-controlled Phase III trial assessing the efficacy and safety of favipiravir in patients with moderate pneumonia not requiring oxygen therapy. METHODS: COVID-19 patients with moderate pneumonia (SpO2 ≥ 94%) within 10 days of onset of fever (temperature ≥ 37.5 °C) were assigned to receive either placebo or favipiravir (1800 mg twice a day on Day 1, followed by 800 mg twice a day for up to 13 days) in a ratio of 1:2. An adaptive design was used to re-estimate the sample size. The primary endpoint was a composite outcome defined as the time to improvement in temperature, oxygen saturation levels (SpO2), and findings on chest imaging, and recovery to SARS-CoV-2-negative. This endpoint was re-examined by the Central Committee under blinded conditions. RESULTS: A total of 156 patients were randomized. The median time of the primary endpoint was 11.9 days in the favipiravir group and 14.7 days in the placebo group, with a significant difference (p = 0.0136). Favipiravir-treated patients with known risk factors such as obesity or coexisting conditions provided better effects. Furthermore, patients with early-onset in the favipiravir group showed higher odds ratio. No deaths were documented. Although adverse events in the favipiravir group were predominantly transient, the incidence was significantly higher. CONCLUSIONS: The results suggested favipiravir may be one of options for moderate COVID-19 pneumonia treatment. However, the risk of adverse events, including hyperuricemia, should be carefully considered. TRIAL REGISTRATION: Clinicaltrials.jp number: JapicCTI-205238.

[Utility of the Predictive Score for Cisplatin-Induced Nephrotoxicity in Patients with Chemotherapy for Lung Cancer].

BACKGROUND: Cisplatin(CDDP)-induced nephrotoxicity(CIN)is a critical complication of chemotherapy. Among patients undergoing chemotherapy with CDDP, short-hydration, and magnesium supplementation for lung cancer, this study was conducted to evaluate the frequency of CIN and utility of the predictive score. METHODS: Patients who underwent chemotherapy with CDDP for lung cancer were retrospectively investigated. A multiple logistic regression analysis to detect the risk factors for CIN and receiver operating characteristic analysis to examine the discrimination of the predictive score were performed. RESULTS: A total of 111 patients were included, with a total count of chemotherapy courses of 402 and a median count of chemotherapy courses of 4. CIN occurred in 9.9% of the patients, with grade 2 and higher in 7.2% and 87% of the CIN cases detected in the initial course, respectively. The significantly independent risk factors for CIN included the number of chemotherapy courses, female gender, and predictive score. The discriminative power of the predictive score was moderate. CONCLUSION: The predictive score for CIN was simple and useful in patients undergoing chemotherapy for lung cancer with CDDP, short-hydration, and magnesium supplementation, even in late courses.

Comparison between stereotactic radiosurgery and whole-brain radiotherapy for 10-20 brain metastases from non-small cell lung cancer.

The efficacy and safety of stereotactic radiosurgery (SRS) in comparison with whole brain radiotherapy (WBRT) for brain metastases (BMs) remains unclear. The present study retrospectively reviewed 44 patients who received SRS or WBRT as an initial treatment for 10-20 BMs from non-small cell lung cancer between 2009 and 2016. Of the patients, 24 (54.5%) were treated with SRS and 20 (45.5%) were treated with WBRT. Overall survival (OS), time to intracranial progression (TTIP), neurological survival (NS), and prognostic factors were examined. OS did not significantly differ between the two groups: 7.3 months in the SRS group vs. 7.2 months in the WBRT group (P=0.502). Median TTIP was significantly shorter in the SRS group than in the WBRT group (7.1 vs. 19.1 months, P=0.009). In contrast, there were no significant differences in NS between the two groups (14.5 months in the SRS group vs. 12.9 months in the WBRT group, P=0.346). Univariate and multivariate analysis revealed that the type of initial treatment for BMs (WBRT or SRS) was not a significant prognostic factor (hazard ratio=0.80, 95% confidence interval: 0.42-1.52, P=0.502). However, histology, performance status, subsequent molecular targeted drugs, subsequent chemotherapy and salvage treatment were independent prognostic factors. There were no significant differences in OS and NS between treatment with SRS and treatment with WBRT in patients with 10-20 BMs, although TTIP was improved with WBRT. As an upfront treatment for 10-20 BMs, SRS may delay WBRT and the adverse events associated with WBRT.

A propensity score-matched comparison of the efficacies of OK-432 and talc slurry for pleurodesis for malignant pleural effusion induced by lung adenocarcinoma.

BACKGROUND: The choice of an optimal sclerosant for pleurodesis for malignant pleural effusion remains controversial. This retrospective clinical study compared the efficacy and safety of two sclerosants; talc slurry (talc-s) and OK-432. METHODS: We compared the characteristics, 30/90-day success rates, and adverse events in patients with lung adenocarcinoma who underwent pleurodesis by using either OK-432 or talc-s. Propensity score matching was used to compare the two scelrosants. RESULTS: Ninety-four patients (mean age=71.6±9.6 years) were included in this retrospective study, of whom 64 received OK-432 and 30 received talc-s. Seventy-three patients (77.6%) were initially diagnosed with clinical stage IV lung cancer, with a 28.7% epidermal growth factor receptor mutation frequency. The propensity score-matched cohort included 26 patients from each group. The 30-day success rates for OK-432 and talc-s were 80.7% and 76.9%, respectively (odds ratio: 1.26, 95% confidence interval: 0.33-4.77, p=0.73). Neither the overall incidence of adverse events nor the 90-day success rates differed significantly. Multivariate logistic regression revealed that the predictors of 30-day success were lower drainage volume on the previous day, particularly <250mL/day, the presence of full lung expansion, and pre-therapy with an epidermal growth factor receptor-tyrosine kinase inhibitor. The median post-pleurodesis survival time was 6.9 months, which was not significantly different between the study groups. CONCLUSIONS: Propensity score-matched analyses showed that pleurodesis using OK-432 and talc-s demonstrated comparable efficacy and safety profiles in patients with lung adenocarcinoma. This indicated that OK-432 could be a viable alternative to talc-s in this procedure.

[A Case of Acute Arterial Occlusion of the Lower Limb during Chemotherapy for Lung Cancer].

A 69-year-old man visited a clinic for left leg weakness. With suspicions of lung cancer and a metastatic brain tumor, he was referred to our hospital and was diagnosed with large cell neuroendocrine carcinoma, cT1bN0M1b (BRA), stage IV. After stereotactic radiosurgery for his brain metastasis, he was treated with chemotherapy containing cisplatin and irinotecan. A week after initiating chemotherapy, he suddenly developed severe right leg pain and adynamia. A computed tomography angiogram revealed occlusion of the right common femoral artery, and percutaneous thrombectomy was performed. The symptoms resolved completely, and he was discharged without any sequelae or recurrence. Acute arterial occlusion of the limbs during chemotherapy is uncommon and requires prompt diagnosis and treatment; hence, caution should be paid when it is clinically suspected.

Lack of effect of favipiravir, a novel antiviral agent, on QT interval in healthy Japanese adults.

OBJECTIVE: A thorough QT study of favipiravir, a novel antiviral agent, was conducted using a randomized, doubleblind, 4-group, 4-period crossover, placebo-and positive-controlled (open-label moxifloxacin) design. MATERIALS AND METHODS: 56 healthy Japanese adults of both sexes received single oral doses of favipiravir 1,200 and 2,400 mg (Avigan® Tablets, Toyama Chemical Co., Ltd.), moxifloxacin 400 mg, and a placebo. QT intervals after these treatments were measured under blinded conditions. The primary endpoint was the time-matched, placebo-adjusted change in corrected QT intervals using the Fridericia method (QTcF) from predose for favipiravir or moxifloxacin (ΔΔQTcF). RESULTS: Lower bounds of the two-sided 90% confidence interval of ΔΔQTcF values for moxifloxacin exceeded 3 msec at all time points, and the maximum value was 14.0 (11.8-16.1, 90% confidence interval) msec at 3 hours after administration. Similarly, maximum ΔΔQTcF values for favipiravir were 0.833 (-1.33-3.00) msec at 3 hours after administration of 1,200 mg, and 0.500 (-1.88-2.88) msec at 6 hours after administration of 2,400 mg. Calculation of the sample size using the ΔΔQTcF value of moxifloxacin indicated that 25 subjects would be sufficient for detection at a power of 90% or higher, which meets the criteria for assuring assay sensitivity. CONCLUSIONS: It is possible to use a smaller number of subjects in thorough QT studies in Japan than in Europe and the US utilizing moxifloxacin as a positive control. There were no detectable effects of favipiravir on the QT/QTc interval.

Expression of thymidylate synthase and dihydropyrimidine dehydrogenase in adenoid cystic carcinoma of the head and neck: correlation with clinical outcome.

The purpose of this study was to estimate the possibility of using thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and p53 as predictive values of clinical outcome in adenoid cystic carcinoma (ACC). The expressions of TS, DPD, and p53 were examined with immunohistochemistry in 27 ACC patients, and the association with clinicopathological factors was determined. Cases with high DPD expression had significantly higher distant metastasis rates compared to those with low DPD expression (p=0.001), whereas neither TS nor p53 expression showed any significant correlation to clinicopathological factors. Interestingly, six of 14 early-stage patients had distant metastases and all of their tumors showed high DPD expression. Kaplan-Meier analysis revealed that a solid histological pattern and distant metastasis correlated with a poor prognosis. In early-stage patients, whose tumor was completely resected, those with high TS or DPD expression had a worse prognosis compared to those with low expression, but the difference did not reach statistical significance (TS, p=0.178; DPD, p=0.251). Our results suggest that assessment of DPD expression in ACC may be a useful tool in determining the mode of treatment as well as evaluating clinical outcome.

Expression of thymidylate synthase and dihydropyrimidine dehydrogenase in oral squamous cell carcinoma: possible markers as predictors of clinical outcome.

CONCLUSIONS: Our results suggest that assessment of dihydropyrimidine dehydrogenase (DPD) in oral squamous cell carcinoma (OSCC) may be a useful tool in evaluating clinical outcomes. OBJECTIVE: The purpose of this study was to estimate the possibility of using thymidylate synthase (TS) and DPD as predictive values of clinical outcomes in OSCC. MATERIALS AND METHODS: The expression of TS and DPD was examined by immunohistochemistry (IHC) and the real-time reverse transcription-polymerase chain reaction method in 23 patients with OSCC, and the association with clinicopathological factors was determined. Immunohistochemical expression of p53 and P-glycoprotein (P-gp) was also examined. RESULTS: Neither TS protein nor TS mRNA expression showed any significant correlation to clinicopathological factors. In contrast, the patients with high DPD expression had significantly higher levels of recurrence compared with those with low DPD expression (p = 0.016). Similarly, six of seven patients with relapse had higher DPD mRNA expression values than the median value in the patients examined. On the other hand, no association was observed between TS or DPD and p53 or P-gp expressions.

[Inflammatory pseudotumor arising in the ethmoid sinus: a case report].

Inflammatory pseudotumors are rare and are characterized by solitary, demarcated lesions with numerous inflammatory cells, mesenchymal cells, and collagenous fibers. They usually occur in the lung, but have also been reported in the thyroid gland, pleura, liver, kidney, bile duct, spinal cord, testis, and soft tissues. Since inflammatory pseudotumors of the head and neck are very rare, their clinical and radiological features, prognosis, and therapeutic management have never been clearly described. We report a case of inflammatory pserdotumor arising in the ethmoid sinus and the clinical, radiological, and histopathological findings.

Infiltration of dendritic cells and NK cells into the sentinel lymph node in oral cavity cancer.

The sentinel lymph node (SLN) is regarded as the first tumor-draining lymph node, which may be the initial site activated by tumor antigens. To clarify the immunological functions of SLNs, a total of 89 tumor-free regional lymph nodes (41 SLNs and 48 non-SLNs) were obtained from 12 patients with oral cavity cancer, and infiltration of both DCs and NK cells was determined by immunohistochemistry. S-100+ and CD1a+ DCs infiltrated significantly into SLNs compared to non-SLNs. Analysis in each of the pN0 and pN+ patients showed that all the DC markers in pN0 patients and only S-100+ in pN+ patients were significantly more abundant in SLNs. Moreover, infiltration of CD83+ DCs was less in pN+ patients than in pN0 patients. These results suggest that more significant immune responses against cancer occur in SLNs than in non-SLNs. However the progression of disease including nodal disease may cause systemic immunosuppression.

A preliminary study on sentinel lymph node biopsy: feasibility and predictive ability in oral cavity cancer.

The main factor that affects the prognosis of patients with head and neck cancer (HNC) is regional lymph node metastases. For this reason, the accurate evaluation of neck metastases is required for neck management. This study investigates the sentinel lymph node identification and the accuracy of the histopathology of the sentinel lymph node in patients with HNC. Eleven patients with histologically proven oral squamous cell carcinoma accessible to radiocolloid injection were enrolled in this study. Using both lymphoscintigraphy and a handheld gamma probe, the sentinel lymph node could be identified in all 11 patients. Subsequently, the sentinel lymph nodes and the neck dissection specimen were examined for lymph node involvement due to tumor. The histopathology of sentinel lymph nodes was consistent with the pathological N classification in all 11 patients. Furthermore, the histopathology of sentinel lymph nodes was superior to physical examination, computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) scan. The results of this study indicate that sentinel lymph node identification is technically feasible and predicts cervical metastases in patients with oral cavity cancer. This may be a useful diagnostic technique for identifying lymph node disease in staging lymph node dissection.