The combined inhibition of SLC1A3 and glutaminase in osimertinib-resistant EGFR mutant cells.

BACKGROUND: We investigated the unknown mechanisms of osimertinib-resistant EGFR-mutant lung cancer. METHODS: An osimertinib-resistant cell line (PC-9/OsmR2) was established through continuous exposure to osimertinib using an EGFR exon 19 deletion (19Del) lung adenocarcinoma cell line (PC-9). EGFR 19Del (M1), L858R/T790M/C797S (M6), and L858R/C797S (M8) expression vectors were introduced into Ba/F3 cells. A second osimertinib-resistant line (M1/OsmR) was established through continuous exposure to osimertinib using M1 cells. RESULTS: SLC1A3 had the highest mRNA expression level in PC-9/OsmR2 compared to PC-9 cells by microarray analysis and SLC1A3 was increased by flow cytometry. In PC-9/OsmR2 cells, osimertinib sensitivity was significantly increased in combination with siSLC1A3. Because SLC1A3 functions in glutamic acid transport, osimertinib with a glutaminase inhibitor (CB-839) or an SLC1A3 inhibitor (TFB-TBOA) increased the sensitivity. Also, CB-839 plus TFB-TBOA without osimertinib resulted in greater susceptibility than did CB-839 or TFB-TBOA plus osimertinib. Comprehensive metabolome analysis showed that the M1/OsmR cells had significantly more glutamine and glutamic acid than M1 cells. CB-839 plus osimertinib exerted a synergistic effect on M6 cells and an additive effect on M8 cells. CONCLUSION: Targeting glutaminase and glutamic acid may overcome the osimertinib-resistant EGFR-mutant lung cancer.

Clinical Features of Patients With Hematological Malignancies Treated at the Palliative Care Unit.

Background: In Japan, the number of patients with aggressive hematological malignancies (PHMs) admitted at the palliative care unit (PCU) in their end-of-life (EOL) stage was fewer than that of patients with solid tumors due to several reasons. The assessment of patient characteristics and the methods of survival prediction among PHMs in the EOL stage are warranted. Objectives: This study aimed to identify the current medical status and the method of survival prediction among PHMs treated at the PCU. Setting/Subjects/Measurements: We retrospectively analyzed the clinical data of 25 PHMs treated at our PCU between January 2017 and December 2020. The association between survival time and the palliative prognostic score (PAP) and palliative prognostic index (PPI) was analyzed. Results: The average age of the PHMs was higher than that of patients with lung cancer as a control. The median survival time of the PHMs was shorter than the control group. Most PHMs could not receive standard chemotherapy, and the most common cause of death was disease-related organ failure. Significant associations were observed between the survival time and each PAP/PPI value in patients with malignant lymphoma, but not in those with leukemia. Conclusion: The PHMs in the PCU had a lower median survival time than the control group. These results were induced by the result of patient selection to avoid treatment-related severe toxicity. The survival prediction using the PAP and PPI was less accurate in patients with leukemia.

Subcutaneous infusion of neurosecretory protein GL promotes fat accumulation in mice.

We recently identified a novel small secretory protein, neurosecretory protein GL (NPGL), in the vertebrate hypothalamus. We revealed that NPGL is involved in energy homeostasis using intracerebroventricular infusion in rodents. However, the effect of NPGL through peripheral administration remains to be elucidated and may be important for therapeutic use. In this study, we performed subcutaneous infusion of NPGL in mice for 12 days and found that it accelerated fat accumulation in white adipose tissue (WAT) without increasing in body mass gain and food intake. The mass of the testis, liver, kidney, heart, and gastrocnemius muscle remained unchanged. Analysis of mRNA expression by quantitative reverse transcription-polymerase chain reaction showed that proopiomelanocortin was suppressed in the hypothalamus by the infusion of NPGL. We observed a decreasing tendency in serum triglyceride levels due to NPGL, while serum glucose, insulin, leptin, and free fatty acids levels were unchanged. These results suggest that the peripheral administration of NPGL induces fat accumulation in WAT via the hypothalamus.

Interferon-γ Produced by EBV-Positive Neoplastic NK-Cells Induces Differentiation into Macrophages and Procoagulant Activity of Monocytes, Which Leads to HLH.

Epstein-Barr virus (EBV)-positive T- or NK-cell neoplasms show progressive systemic inflammation and abnormal blood coagulation causing hemophagocytic lymphohistiocytosis (HLH). It was reported that inflammatory cytokines were produced and secreted by EBV-positive neoplastic T- or NK-cells. These cytokines can induce the differentiation of monocytes into macrophages leading to HLH. To clarify which products of EBV-positive neoplastic T- or NK-cells have effects on monocytes, we performed a co-culture assay of monocytes with the supernatants of EBV-positive T- or NK-cell lines. The expression of differentiation markers, the phagocytosis ability, and the mRNA expression of the inflammatory cytokines of THP-1, a monocytic cell line, clearly increased after culturing with the supernatants from EBV-NK-cell lines. Co-culturing with the supernatants promoted the expression of CD80 and CD206 as well as M1 and M2 macrophage markers in human monocytes. Co-culturing with the supernatants of EBV-NK-cell lines significantly enhanced the procoagulant activity and the tissue factor expression of monocytes. Interferon (IFN)-γ was elevated extremely not only in the supernatant of EBV-NK-cell lines but also in the plasma of EBV-positive NK-cell neoplasms patients accompanying HLH. Finally, we confirmed that IFN-γ directly enhanced the differentiation into M1-like macrophages and the procoagulant activity of monocytes. Our findings suggest that IFN-γ may potentially serve as a therapeutic target to regulate HLH in EBV-positive NK-cell neoplasms.

IgA Vasculitis in a Lung Cancer Patient During Chemoradiotherapy.

A 72-year-old man with locally advanced lung squamous cell carcinoma experienced red purpura on the lower legs and hematuria when the disease progressed during definitive chemoradiotherapy. He had renal dysfunction and proteinuria. Biopsy specimens of the skin lesion and kidney revealed immunoglobulin A vasculitis. Potential causes such as paraneoplastic syndrome and cancer treatment have been proposed. The administration of steroids rapidly improved the symptoms. The presentation of immunoglobulin A vasculitis is accompanied by malignancies. Clinicians should keep this syndrome in mind, even during curative-intent treatment.

Lung cancer metastasis to the pancreas mimicking autoimmune pancreatitis.

The unique radiological manifestation mimicking autoimmune pancreatitis caused by lung cancer metastasis to the pancreas has not previously been reported. The incidence of pancreatic secondary tumors has previously been reported to be approximately 15% in autopsy cases of malignant tumors, and it is unusual for thoracic oncologists to find that the second common primary tumor site of metastatic pancreas tumor is the lung.

Do Elderly Lung Cancer Patients Aged ≥75 Years Benefit from Immune Checkpoint Inhibitors?

Lung cancer patients ≥75 years represent nearly 40% of all lung cancer patients and continue to increase. If elderly patients have a good performance status and adequate organ function, they can be treated the same as non-elderly patients. However, few comparative studies limited to elderly patients (≥75 years) have been conducted. We review the evidence on using immune check inhibitors for the treatment of elderly patients (≥75 years old) with advanced non-small cell lung cancer. Prospective randomized or non-randomized, retrospective, registrational, insurance-based, and community-based studies have shown that elderly (≥75 years) and non-elderly patients are similarly treated with immune check inhibitors effectively and safely. However, such analyses have not shown that immune check inhibitors are significantly more effective than chemotherapy alone. In addition, patient selection might be critically performed to administer immune check inhibitors in the elderly because they are more likely to have a poor performance status with comorbidities, which lead to little benefit, even in non-elderly patients. There is a need for more evidence showing the benefit of immune check inhibitors in non-small cell lung cancer patients ≥75 years.