Association of PD-L1 tumor proportion score ≥20% with early resistance to osimertinib in patients with EGFR-mutated NSCLC.

BACKGROUND: The relationship between epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance, including osimertinib, and programmed cell death-ligand 1 (PD-L1) expression status in EGFR-mutated non-small cell lung carcinoma (NSCLC) remains unclear. PATIENTS AND METHODS: We retrospectively analyzed 64 patients with unresectable advanced or metastatic NSCLC carrying EGFR exon 19 deletions (ex19del) or EGFR exon 21 L858R substitutions (L858R) who received osimertinib as the first-line treatment. We compared progression-free survival (PFS) between eligible patients with PD-L1 tumor proportion scores (TPS) ≥20% and PD-L1 TPS <20% using the Kaplan-Meier survival plots with a log-rank test. Multivariate analysis was performed to examine the poor prognostic factors of PFS. RESULTS: The PD-L1 TPS ≥20% group included 22 cases (median [range] age: 70.5 [33-86] years; 10 women [45.5%]; 11 current or ex-smokers [50%]); ECOG performance status (PS) of 0-1/2/3/4 was noted in 16/4/1/1 patients, respectively. The PD-L1 TPS <20% group included 42 patients (median [range] age 73 [43-88] years; 29 women [69%]; 12 current or ex-smokers [28.6%]); ECOG PS of 0-1/2/3/4 was noted in 33/6/3/0 cases, respectively. The median PFS was 9.1 and 28.1 months in the PD-L1 TPS ≥20% and PD-L1 TPS <20% groups, respectively (log-rank p = 0.013). Multivariate analysis revealed that PD-L1 TPS ≥20% was associated with PFS (hazard ratio: 2.35, 95% confidence interval: 1.09-5.08, p = 0.030). CONCLUSION: PD-L1 TPS ≥20% in patients with EGFR-mutated NSCLC may be associated with early resistance to osimertinib.

Programmed cell death ligand 1 measurement study in granulocyte colony-stimulating factor-producing lung cancer: an observational study.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF)-producing lung cancer induces severe inflammation and a high white blood cell (WBC) count and is associated with poor prognosis. A recent case of G-CSF-producing lung adenocarcinoma showed high expression of programmed cell death ligand 1 (PD-L1) and was treated with pembrolizumab as first-line therapy, which was extremely effective. We hypothesized that G-CSF-producing lung cancers are associated with high PD-L1 expression. METHODS: This retrospective study included patients diagnosed with lung cancer at Yokohama Municipal Citizen's Hospital (Kanagawa, Japan) between 2009 and 2019. The PD-L1 status of 13 patients with high plasma G-CSF levels (≥40 pg/mL) was assessed by conducting immunohistochemical analysis of tissue samples. RESULTS: Of the total patients, 11 were men and 2 were women, with a median age of 74 years (70-85 years). Four, five, and three patients had adenocarcinoma, squamous cell carcinoma, and others, respectively. The median G-CSF level and WBC count were 85.5 pg/mL (range, 40.8-484 pg/mL) and 15,550/µL (range, 6,190-56,800/µL), respectively. The PD-L1 tumor proportion scores (TPSs) were ≥50%, 1%-49%, and <1% in 9, 1, and 3 patients, respectively. The median overall survival time was 7.3 months. Pembrolizumab was administered in six patients as first-line treatment, with two patients showing partial response, one patient with stable disease, and three patients with progressive disease. All six patients had a PD-L1 TPS of ≥50%. CONCLUSION: G-CSF-producing lung cancers may be associated with increased PD-L1 expression. Although immune checkpoint inhibitors are an important treatment option for G-CSF-producing tumors, their effects are limited.

A case of slowly progressive malignant pericardial mesothelioma suggesting the involvement of BAP1 loss.

Malignant pericardial mesothelioma (MPM) is a rare tumour that arises from the mesothelial cells of the pericardium. No standard treatment has been established owing to a poor treatment response; therefore, MPM has a poor prognosis. We herein report a rare case of MPM in a 70-year-old man that was diagnosed immunohistopathologically using cell block sections of pericardial fluid and in which long-term survival for more than 3 years was achieved with only periodic pericardial drainage. Immunohistopathological staining investigations, especially BRCA1-associated protein 1 (BAP1) immunostaining using cell block sections of pericardial effusion, are effective in making a diagnosis of MPM. Well-differentiated papillary mesothelioma (WDPM) with BAP1 loss progresses to MPM in the long term, showing that BAP1 loss may induce phenotypical evolution of WDPM. BAP1 loss may also progress to malignant mesothelioma in situ and then to invasive mesothelioma. BAP1 immunohistochemistry should be considered for the early diagnosis of MPM.

A case of pulmonary tumor thrombotic microangiopathy following lymphedema on the lower extremities.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare manifestation of malignancy. The antemortem diagnosis is difficult, since patients present with rapidly progressive symptoms. We recently observed a case of PTTM following lymphedema of the lower extremities. We did not reach a diagnosis, even after performing BAL and TBLB. The patient manifested pulmonary hypertension and died on the 9th day of admission. Autopsy revealed a tumor embolism in the pulmonary arterioles accompanied by fibrocellular epithelial cell proliferation, but the primary organ was not identified. To our knowledge, this is the first reported case of PTTM with lymphedema.

Acute pancreatitis or severe increase in pancreatic enzyme levels following remdesivir administration in COVID-19 patients: an observational study.

Remdesivir has been shown to reduce recovery time and mortality among patients with coronavirus disease 2019 (COVID-19). However, data regarding the efficacy and safety of remdesivir use are limited in Japan. We conducted a single-center retrospective cohort study at Yokohama Municipal Citizen's Hospital, Kanagawa, Japan. Patients with COVID-19 pneumonia treated with remdesivir were included. The onset of acute pancreatitis and increased pancreatic enzyme levels and clinical, laboratory, treatment, and outcome data were collected and analyzed. A total of 201 patients were included. Among the 201 patients treated with remdesivir, 177 recovered from COVID-19. Increased pancreatic enzyme levels of grade 3 or higher or acute pancreatitis developed in 23 of the 201 patients. The potential etiopathogenetic effects of remdesivir on increased pancreatic enzyme levels of grade 3 or higher or acute pancreatitis were ascertained by reviewing the characteristics of patients hospitalized for COVID-19 who did not receive remdesivir treatment. Only 3 of 159 patients had increased pancreatic enzyme levels of grade 3 or higher during the treatment course. Multivariate analysis indicated remdesivir administration and severe COVID-19 infection by National Institute of Health standards as independent risk factors. Acute pancreatitis and severe increases in pancreatic enzyme levels were observed among patients with COVID-19 treated with remdesivir.

Legionella pneumophila pneumonia with rapid clinical course in a lung cancer patient.

We report an acute clinical course of pneumonia caused by Legionella pneumophila in a patient receiving chemotherapy for lung cancer and corticosteroid therapy. A 57-year-old man presented with fever and dyspnoea and was admitted to our hospital. Chest computed tomography revealed a new left lower lung infiltrate, tumour progression in the right upper lung region, metastases to lymph nodes and pleural effusion. The urinary antigen test for Legionella was positive. The patient's oxygen requirement increased on the day of admission, and he died the day after hospitalization. Legionnaires' disease may manifest with an acute presentation, and patients in Japan with physical risk factors for this disease could get infected despite the absence of environmental risk factors. Early treatment for suspected Legionnaire's disease should be considered.

TMEPAI/PMEPA1 enhances tumorigenic activities in lung cancer cells.

TMEPAI/PMEPA1 is a transmembrane protein that was originally identified as a prostatic RNA, the synthesis of which is induced by testosterone or its derivatives. We have recently identified TMEPAI as a direct target gene of transforming growth factor-ß (TGF-ß)/Smad signaling that participates in negative feedback control of the duration and intensity of TGF-ß/Smad signaling. TMEPAI is constitutively and highly expressed in many types of cancer and is associated with poor prognosis. Here, we report that TMEPAI is highly expressed in the lung adenocarcinoma cell lines Calu3, NCI-H23, and RERF-LC-KJ. Expression of TMEPAI in these cancer cells was significantly suppressed by a TGF-ß receptor kinase antagonist, SB208, and by TGF-ß neutralizing antibodies. These results suggest that constitutive expression of TMEPAI in these cancer cells depends on autocrine TGF-ß stimulation. Knockdown of TMEPAI in Calu3 and NCI-H23 cells enhanced levels of Smad2 phosphorylation and significantly suppressed cell proliferation in the presence of TGF-ß, indicating that highly expressed TMEPAI suppresses levels of Smad phosphorylation in these cancer cells and reduces the growth inhibitory effects of TGF-ß/Smad signaling. Furthermore, knockdown of TMEPAI in Calu3 and NCI-H23 cells suppressed sphere formation in vitro and tumor formation in s.c. tissues and in lungs after tail vein injection in NOD-SCID mice in vivo. Together, these experiments indicate that TMEPAI promotes tumorigenic activities in lung cancer cells.

Binding of lactoferrin to IGBP1 triggers apoptosis in a lung adenocarcinoma cell line.

BACKGROUND: Lactoferrin (Lf), an iron-binding protein present in mammalian secretions, plays important roles in cancer prevention by inducing apoptosis. MATERIALS AND METHODS: PC-14 lung adenocarcinoma cells were exposed to bovine Lf (bLf) protein and the expression of caspase-3 and apoptosis protease-activating factor-1 (APAF-1) was assessed. To investigate the molecular mechanism of apoptosis induced by bLf, a major Lf-binding protein was screened using a protein microarray with bLf protein as the probe. Protein interaction was demonstrated by co-immunoprecipitation, immunofluorescence and phosphatase activity assay. RESULTS: Lf directly suppressed the proliferation of the PC-14 cells by triggering their apoptosis. Lf was shown to bind specifically with a 36-kDa protein, immunoglobulin (CD79A)-binding protein 1 (IGBP1). The binding complex interacted with the catalytic subunit of protein phosphatase 2A (PP2A), thus reducing the phosphatase activity of PP2A and triggering apoptosis. CONCLUSION: Lf binds IGBP1 and promotes the acceleration of cellular apoptosis.