Comparison of SP263 and 22C3 pharmDx assays to test programmed death ligand-1 (PD-L1) expression in surgically resected non-small cell lung cancer.

BACKGROUND: Atezolizumab, one of the immune checkpoint inhibitors, has been approved as an adjuvant treatment following resection and platinum-based chemotherapy in patients with stage II-IIIA non-small cell lung cancer with 1% or more programmed death ligand-1 (PD-L1) expression. The Food and Drug Administration (FDA) has approved SP263 as a companion diagnostic assay for adjuvant treatment with atezolizumab; however, in clinical practice, the 22C3 assay is most commonly used for advanced non-small cell lung cancer. Therefore, our study aimed to compare two PD-L1 assays, SP263 and 22C3, to evaluate whether 22C3 could replace SP263 when deciding whether to administer adjuvant atezolizumab. METHODS: We retrospectively and prospectively analyzed 98 patients who underwent surgical resection at Kanagawa Cancer Center (Japan). An immunohistochemistry assay was performed for all the cases with both SP263 and 22C3. We statistically analyzed the concordance of PD-L1 expression between SP263 and 22C3 assays. RESULTS: The concordance between the two assays using Cohen's kappa was κ = 0.670 (95% CI: 0.522-0.818) at the 1% cutoff and κ = 0.796 (95% CI: 0.639-0.954) at the 50% cutoff. The Spearman correlation coefficient of 0.874 (p < 0.01) indicated high concordance. PD-L1 expression with 22C3 resulted slightly higher than that with SP263. CONCLUSIONS: This study showed a high concordance of PD-L1 expression with the SP263 and 22C3 assays. Further studies examining the therapeutic effects of adjuvant atezolizumab are required.

Comparison between next-generation sequencing and multiplex polymerase chain reaction assays for nonsmall-cell lung cancer molecular diagnosis.

PURPOSE: Genetic mutation detection has become an important step in nonsmall-cell lung cancer (NSCLC) treatment because of the increasing number of drugs that target genomic rearrangements. A multiplex test that can detect multiple gene mutations prior to treatment is thus necessary. Currently, either next-generation sequencing (NGS)-based or polymerase chain reaction (PCR)-based tests are used. We evaluated the performance of the Oncomine Dx Target Test (ODxTT), an NGS-based multiplex biomarker panel test, and the AmoyDx Pan Lung Cancer PCR Panel (AmoyDx PLC panel), a real-time PCR-based multiplex biomarker panel test. MATERIALS AND METHODS: Patients with histologically diagnosed NSCLC and a sufficient sample volume to simultaneously perform the AmoyDx PLC panel and ODxTT-M were included in the study. The success and detection rates of both tests were evaluated. RESULTS: Biopsies revealed 116 cases of malignancies, 100 of which were NSCLC. Of these, 59 met the inclusion criteria and were eligible for analysis. The success rates were 100% and 98% for AmoyDx PLC panel and ODxTT-M, respectively. Nine driver mutations were detected in 35.9% and 37.3% of AmoyDx PLC and ODxTT-M panels, respectively. EGFR mutations were detected in 14% and 12% of samples using the AmoyDx PLC panel and ODxTT-M, respectively. Of the 58 cases in which both NGS and AmoyDx PLC panels were successful, discordant results were observed in seven cases. These differences were mainly due to different sensitivities of the detection methods used and the gene variants targeted in each test. DISCUSSION: The AmoyDx PLC panel, a PCR-based multiplex diagnostic test, exhibits a high success rate. The frequency of the nine genes targeted for treatment detected by the AmoyDx PLC panel was comparable to the frequency of mutations detected by ODxTT-M. Clinicians should understand and use the AmoyDx PLC panel and ODxTT-M with respect to their respective performances and limitations.

Mutation profile and programmed death ligand 1 status of patients with non-small cell lung cancer diagnosed with "adenocarcinoma" and "non-small cell carcinoma favor adenocarcinoma".

BACKGROUND: The terminology for lung cancer diagnosis in small biopsies was adopted in the 2015 World Health Organization classification. If non-small cell lung cancer (NSCLC) has no clear adenocarcinoma (AD) or squamous cell carcinoma morphology, the tumor is further classified based on mucin or immunohistochemical staining as NSCLC favor AD (NFAD), NSCLC favor squamous cell carcinoma, or NSCLC not otherwise specified. Since this new term was defined, the difference between AD and NFAD has not yet been fully explored. This study aimed to examine the differences in clinical background, gene alteration frequency, and programmed death ligand 1 (PD-L1) expression. METHODS: We included patients diagnosed with AD or NFAD with small samples, and who underwent testing with the Oncomine Dx target test between August 2019 and April 2023 in Kanagawa Cancer Center. RESULTS: This study comprised 268 patients. A total of 96 patients underwent surgery after AD or NFAD diagnosis. The clinical stage was more advanced and pathological N0 was lower in NFAD than in AD. The pathology of the surgical specimens revealed that solid predominant AD was significantly more common in NFAD than in AD (p < 0.001). In both AD and NFAD, EGFR mutation was the most frequent gene alteration, followed by KRAS mutation. The frequency of EGFR mutations was significantly higher in AD than in NFAD. PD-L1 expression was significantly higher in NFAD than in AD (p < 0.001). CONCLUSION: This study shows a clear difference between AD and NFAD in terms of cancer progression, pathological features of the main tumor, genetic characteristics, and PD-L1 expression.

Efficacy of osimertinib for lung squamous cell carcinoma with de novo EGFR T790M-positive: Case report and literature review.

Among epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancers, squamous cell carcinoma is less common and shows lower responsiveness to first-generation EGFR tyrosine kinase inhibitors (TKIs) compared to adenocarcinoma. However, the efficacy of osimertinib for squamous cell carcinoma with EGFR mutations is not well known. This study reports the case of a 57-year-old male diagnosed as having stage IIIC squamous cell lung cancer. Oncomine Dx Target Test identified EGFR exon19 deletion and de novo EGFR T790M mutation with variant allele frequencies (VAF) of 21.6% and 25.2%, respectively. The patient was treated with osimertinib after progression on chemoradiotherapy followed by durvalumab, and a partial response was maintained for more than 20 months. To predict EGFR-TKI efficacy, confirmation of gene mutations and VAF using next-generation sequencing is helpful.

High Fever, Wide Distribution of Viral Pneumonia, and Pleural Effusion are More Critical Findings at the First Visit in Predicting the Prognosis of COVID-19: A Single Center, retrospective, Propensity Score-Matched Case-Control Study.

Introduction: Currently, infection control measures for SARS-COV2 are being relaxed, and it is important in daily clinical practice to decide which findings to focus on when managing patients with similar background factors. Methods: We retrospectively evaluated 66 patients who underwent blood tests (complete blood count, blood chemistry tests, and coagulation tests) and thin slice CT between January 1 and May 31, 2020, and performed a propensity score-matched case-control study. Cases and controls were a severe respiratory failure group (non-rebreather mask, nasal high-flow, and positive-pressure ventilation) and a non-severe respiratory failure group, matched at a ratio of 1:3 by propensity scores constructed by age, sex, and medical history. We compared groups for maximum body temperature up to diagnosis, blood test findings, and CT findings in the matched cohort. Two-tailed P-values <0.05 were considered statistically significant. Results: Nine cases and 27 controls were included in the matched cohort. Significant differences were seen in maximum body temperature up to diagnosis (p=0.0043), the number of shaded lobes (p=0.0434), amount of ground-glass opacity (GGO) in the total lung field (p=0.0071), amounts of GGO (p=0.0001), and consolidation (p=0.0036) in the upper lung field, and pleural effusion (p=0.0117). Conclusion: High fever, the wide distribution of viral pneumonia, and pleural effusion may be prognostic indicators that can be easily measured at diagnosis in COVID-19 patients with similar backgrounds.

Neoadjuvant PD-1 Blockade in Non-Small Cell Lung Cancer: Current perspectives and Moving Forward.

Perioperative therapy for non-small cell lung cancer has been studied extensively in a bid to improve overall survival, as approximately half of the patients with surgically resectable tumors at the time of diagnosis relapse. In recent years, immune checkpoint inhibitor therapies, such as the anti-programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) blockade, have contributed to achieving an improved overall survival of patients with advanced stage lung cancer. Thus, the development of this treatment strategy has considerable potential to precipitate a breakthrough in cancer immunotherapy. PD-1/PD-L1 blockade has several potential immunological benefits when used as a neoadjuvant therapy. However, there are concerns associated with this neoadjuvant therapy. Many studies have reported its efficacy, but there is limited evidence regarding the long-term survival of patients. Similarly, it is unclear whether existing biomarkers are adequate for monitoring the prognosis of patients, or if new biomarkers are required. In this article, we present recent reports on neoadjuvant PD-1/PD-L1 blockade therapy and discuss its future challenges.

Comparison of next-generation sequencing and cobas EGFR mutation test v2 in detecting EGFR mutations.

BACKGROUND: As the number of genetic mutations that must be tested increases, the Oncomine Dx Target test (ODxTT), which can simultaneously detect multiple cancer-related genes is becoming the main test used in preference to single-molecule testing. In this study, we evaluated the performance of ODxTT and cobas EGFR mutation test v2 (cobas EGFR), one of the single-molecule tests, in detecting EGFR mutations. METHODS: Samples from 211 patients diagnosed with NS-NSCLC were tested simultaneously or sequentially with the cobas EGFR mutation test and ODxTT. We compared the success and detection rates of both tests and evaluated their equivalence by determining the concordance rate and k-coefficient of both tests. RESULTS: The success rate in detecting EGFR mutations was 95.7% for ODxTT and 100% for cobas EGFR. EGFR mutations were detected in 26.5% of samples with ODxTT and in 28.0% with cobas EGFR. For the 200 samples successfully analyzed with both tests, the concordance rate and k-coefficient were 97.5% and 0.938, respectively. ODxTT failed to detect two exon 19 deletion mutations (p.E746_P753delinsVS and p.E746_P753delinsLS), and cobas EGFR failed to detect three instances of an exon 19 deletion (p.L747_P753delinsS), L861R, and an exon 20 insertion. DISCUSSION: The success rate of ODxTT is slightly inferior to that of cobas EGFR. ODxTT shared a high concordance rate and k-coefficient with cobas EGFR in detecting EGFR mutations, but discordant results between the two tests were observed in a few cases, mainly due to the difference of detectable EGFR variants.

Longitudinal Analysis of Neutralizing Potency against SARS-CoV-2 in the Recovered Patients after Treatment with or without Favipiravir.

The effect of treatment with favipiravir, an antiviral purine nucleoside analog, for coronavirus disease 2019 (COVID-19) on the production and duration of neutralizing antibodies for SARS-CoV-2 was explored. There were 17 age-, gender-, and body mass index-matched pairs of favipiravir treated versus control selected from a total of 99 patients recovered from moderate COVID-19. These subjects participated in the longitudinal (>6 months) analysis of (i) SARS-CoV-2 spike protein's receptor-binding domain IgG, (ii) virus neutralization assay using authentic virus, and (iii) neutralization potency against original (WT) SARS-CoV-2 and cross-neutralization against B.1.351 (beta) variant carrying triple mutations of K417N, E484K, and N501Y. The results demonstrate that the use of favipiravir: (1) significantly accelerated the elimination of SARS-CoV-2 in the case vs. control groups (p = 0.027), (2) preserved the generation and persistence of neutralizing antibodies in the host, and (3) did not interfere the maturation of neutralizing potency of anti-SARS-CoV-2 and neutralizing breadth against SARS-CoV-2 variants. In conclusion, treatment of COVID-19 with favipiravir accelerates viral clearance and does not interfere the generation or maturation of neutralizing potency against both WT SARS-CoV-2 and its variants.

An intrathoracic giant tumour and vanishing lung cyst after tumour resection.

A 65-year-old woman was brought to the emergency unit with an approximately 6-month history of persistent fever and cough. Chest computed tomography (CT) demonstrated a 16-cm heterogeneous mass with adjacent large cyst (approximately 4.0 cm). The patient underwent CT-guided biopsy, and benign solitary fibrous tumour (SFT) was immunohistochemically diagnosed. As the symptoms were thought to be due to enlargement of the tumour, surgery was deemed necessary, and the tumour was successfully resected. Based on morphological and immunohistochemical examination of the resected specimen, the final diagnosis was dedifferentiated SFT (DSFT). Follow-up CT verified disappearance of the pulmonary cyst. The cyst was speculated to be caused by a check valve mechanism, which may also suggest a rapid growth of the tumour. At the time of writing, 2 years post-operatively, no tumour recurrence has been identified. This represents the first report of intrathoracic giant DSFT with a cystic lesion returning to normal lung parenchyma.

Two Cases of Severe COVID-19 Pneumonia Effectively Treated with Extracorporeal Membrane Oxygenation in Addition to Favipiravir and Corticosteroid.

Case 1: A 65-year-old man with novel coronavirus infection (COVID-19) complicated with acute respiratory failure. On admission, the patient was started on favipiravir and corticosteroid. However, due to a lack of significant improvement, he was introduced to mechanical ventilation and extracorporeal membrane oxygenation (ECMO). Although iliopsoas hematoma occurred as a complication, the patient recovered. Case 2: A 49-year-old man with COVID-19 had been started on favipiravir and corticosteroid. Due to progressive respiratory failure, the patient underwent mechanical ventilation and ECMO. The patient recovered without complications. We successfully treated these severe cases with a multimodal combination of pharmacological and non-pharmacological supportive therapy.

A case of COVID-19 pneumonia successfully treated with favipiravir (Avigan) in which serum SARS-CoV-2 RNA detected by LAMP method was clinically useful.

A 49-year-old Japanese male was managed by mechanical ventilation due to coronavirus disease 2019 (COVID-19) pneumonia. Favipiravir as an antiviral therapy, and anti-inflammatory treatment were administered. SARS-CoV-2 RNA was detected in serum by the loop-mediated isothermal amplification (LAMP) method on Day 9; favipiravir treatment was continued. On Day 13, negative serum RNA was confirmed, followed by mechanical ventilation was removed. On Day 23, LAMP negative was confirmed in nasopharynx, after that the patient discharged on Day 27. We could treat successfully for severe COVID-19 pneumonia based on the LAMP method. We consider this method will be useful in COVID-19 treatment.

Clinical Features of 154 COVID-19 Patients and the Parameters for the Effective Detection of Pneumonia at the Time of the Initial Diagnosis in Japan.

Objective We aimed to clarify clinical and laboratory characteristics of coronavirus disease 2019 (COVID-19) patients, and further explore the features to detect COVID-19 pneumonia at the first visit to community-based hospitals. Methods Diagnoses of COVID-19 were based on positive results from real-time reverse-transcription polymerase chain reaction testing of nasopharyngeal-swab specimens. We retrospectively reviewed the medical records of patients showing positive results. The clinical characteristics and results of blood tests were compared between the patients with and without pneumonia. The risk factors associated with pneumonia were then evaluated by a multivariable analysis. Results The study cohort comprised 154 patients, including 117 patients (76.0%) with pneumonia at first visit. Significant differences were seen in age, the frequency of fever, tachycardia, desaturation (peripheral oxygen saturation ≤95%), any comorbidity, neutrocyte count and fraction, lymphocyte count and fraction, platelet count, lactate dehydrogenase (LDH), C-reactive protein (CRP), and fibrinogen between the patients with and without pneumonia. Using a multivariable analysis, CRP ≥0.3 mg/dL and fibrinogen >400 mg/dL were found to be associated with the presence of pneumonia. Conclusion Community-based settings for screening COVID-19 patients should perform chest X-ray and blood tests for white blood cell fractions, fibrinogen, LDH, and CRP. Of these, elevations in the CRP and fibrinogen levels could be critically associated with the presence of COVID-19 pneumonia.

[A Case of Pneumocystin a Patient with Pneumonia That Developed during Chemotherapy for Sigmoid Cancer].

A 63-year-old man was diagnosed with advanced sigmoid cancer of pT3, pN0, sM1c, sP3, fStage Ⅳ post-operation. After CAPOX plus Bmab as the first-line chemotherapy, he underwent IRIS plus Bmab as the second-line chemotherapy. After 1 course of IRIS plus Bmab, he was admitted to the hospital for fever, dyspnea, and general fatigue. The white blood cell count was 6.2×10 3/mL, and the C-reactive protein was elevated to 12.9 mg/dL. The PaO2 of the artery blood gas analysis in room air was 46.3 mmHg, suggesting respiratory failure. He was diagnosed with PCP based on the bilateral diffused ground-glass opacities on chest CT along with an elevated serum b-D-glucan. The treatment of trimethoprim-sulfamethoxazole and steroid was then initiated. After the patient's clinical condition improved, he was discharged on day 27 post-admission.

Clinical Significance of Serum Hemeoxygenase-1 as a New Biomarker for the Patients with Interstitial Pneumonia.

Background: Serum hemeoxygenase-1 (HO-1) has been proposed to be a biomarker of lung disease activity and prognosis. The present study aimed at evaluating whether HO-1 could be a useful marker for evaluating disease activity and predicting prognosis in patients with interstitial pneumonia (IP). Materials and Methods: Serum HO-1 levels of newly diagnosed or untreated patients with IP were measured at hospitalization. We evaluated the relationships between serum HO-1 and other serum biomarkers, high resolution CT (HRCT) findings, and hospital mortality. Results: Twenty-eight patients with IP, including 14 having an acute exacerbation (AE) and 14 not having an AE, were evaluated. The patients having an AE had significantly higher HO-1 levels than those not having an AE (53.5 ng/mL vs. 24.1 ng/mL; p < 0.001), and the best cut-off level to discriminate between having an AE or not having an AE was 41.6 ng/mL. Serum HO-1 levels were positively correlated with serum levels of surfactant protein-D (r=0.66, p < 0.001) and the ground glass opacity score (calculated from HRCT; r=0.40, p=0.036). Patients who subsequently died in hospital had presented with significantly higher HO-1 levels than those who did not die in hospital (64.8 ng/mL vs. 32.0 ng/mL; p=0.009). Conclusion: Serum HO-1 may serve as a useful biomarker for detecting AE or predicting hospital mortality in patients with IP.

Characterization of DNA hypermethylation in two cases of peritoneal mesothelioma.

Malignant mesothelioma (MM) is a rare disease with a poor prognosis. Pleural mesothelioma, which is the most common type of MM, is considered to be caused by asbestos exposure and is increasing in incidence, with about 15,000 new cases diagnosed worldwide annually. On the other hand, peritoneal mesothelioma is a very rare type of MM; thus, its pathogenesis is even less understood than pleural mesothelioma. Recent research on the pathogenesis of malignant pleural mesothelioma has indicated that both epigenetic and genetic alterations contribute to tumorigenesis. Here, we hypothesize that peritoneal mesothelioma also has an epigenetic alteration in the same genes (Kazal-type serine peptidase inhibitor domain 1 (KAZALD1), transmembrane protein 30B (TMEM30B), and mitogen-activated protein kinase 13 (MAPK13)). Our goal is to identify DNA methylation of these three candidate genes in two peritoneal mesothelioma cases. Laser capture microdissection was used to separate diseased sections of formalin-fixed paraffin-embedded samples from one surgically resected tissue (epithelial type) and one autopsy tissue (sarcomatous type). Genomic DNA was subsequently extracted by the standard phenol chloroform method. The DNA was then treated with sodium bisulphite, and pyrosequencing analysis was used to quantitatively analyze the methylation of candidate genes reported to be hypermethylated in malignant pleural mesothelioma (KAZALD1, TMEM30B, and MAPK13). TMEM30B and MAPK13 were not methylated in either case. However, KAZALD1 was highly methylated in sarcomatoid-type peritoneal mesothelioma. We first report that the KAZALD1 gene was hypermethylated in sarcomatoid-type malignant peritoneal mesothelioma.