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Osimertinib is a third‐generation epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitor (TKI) that has shown marked antitumor activity in patients with EGFR‐mutated non–small‐cell lung cancer (NSCLC). However, these effects are transient and most patients develop resistance. Reversible drug‐tolerant persister (DTP) cells are defined as a small subpopulation of cells with markedly reduced sensitivity and non‐genetic acquired resistance to EGFR‐TKIs. Notch is a transmembrane receptor that plays an important role in tumorigenesis. We previously reported that there is significant crosstalk between the Notch and EGFR pathways in NSCLC. Moreover, the Notch pathway is associated with resistance to previous‐generation EGFR‐TKIs. However, the role of Notch in osimertinib resistance is not fully understood. In this study, we evaluated whether Notch is involved in osimertinib resistance. We show that NOTCH1 and Notch target genes are upregulated in osimertinib DTP cells, and that the addition of a γ‐secretase inhibitor (GSI), a Notch inhibitor, impairs drug‐tolerant persistence in vitro and in vivo. Compared with osimertinib, combined GSI and osimertinib suppress phospho‐ERK partly by enhancing DUSP1 expression. Furthermore, Notch1 and HES1 were upregulated after EGFR‐TKI treatment in half of human EGFR‐mutated NSCLC tumor tissues. These results suggest that the combination of GSI and osimertinib may be a potential therapy for EGFR‐mutated NSCLC. The Notch pathway is activated in osimertinib drug‐tolerant persister cells and might be targeted for EGFR‐mutated patients in their osimertinib treatment.

Epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) elicit potent cell cycle arrest in EGFR‐mutant non–small‐cell lung cancer (NSCLC) cells. However, little is known about the mechanisms through which these drugs alter the tumor phenotype that contributes to the immune escape of EGFR‐mutant cells. Using EGFR‐mutant NSCLC cell lines and tissue samples from patients, we investigated the changes in immune checkpoints expressed in tumor cells following EGFR inhibition. Subsequently, we also analyzed the role of soluble factors from the dying tumor cells in the activation of immune signaling pathways involved in therapy resistance. Upon EGFR‐TKI treatment, we found that EGFR‐mutant cells upregulated the expression of innate immune checkpoint CD24 in vitro. We then analyzed biopsy samples from six patients who developed resistance to a first‐generation EGFR‐TKI without the acquired T790M mutation. Immunohistochemistry revealed that levels of tumor CD24 expression were increased upon treatment compared with those from pre‐treatment samples. Monocyte‐derived macrophages facilitated antibody‐dependent cellular phagocytosis when EGFR‐TKI‐treated EGFR‐mutant cells were incubated with anti‐CD24 antibodies in vitro, suggesting that CD24 may be a therapeutical target for EGFR‐mutant lung cancer. Moreover, EGFR inhibition accelerated the release of cell‐free DNA (cfDNA) from dying tumor cells, which activated the type I interferon signaling pathways in human THP‐1 monocytes in a stimulator of interferon genes‐dependent manner. Our study indicates that EGFR inhibition in EGFR‐mutant NSCLC cells fosters a tumor microenvironment associated with immune escape. Thus, CD24 targeted therapy and cfDNA monitoring may contribute to improved treatment outcomes in patients with EGFR‐mutant NSCLC. EGFR inhibition in EGFR‐mutant lung cancer cells results in the upregulation of tumor CD24. It also accelerates the release of tumor‐derived cell‐free DNA, triggering the type I interferon pathways. These biomarkers are potential targets to overcome the resistance to EGFR‐targeted therapy.

Short hydration is a method to change partial intravenous hydration to oral to administer cisplatin (CDDP); however, the most suitable form of oral hydration is unknown. This study aimed to determine whether oral rehydration solution (ORS) affects CDDP-induced nephrotoxicity (CIN) and electrolyte imbalance. Lung cancer patients (n=200) who had received CDDP-including regimens (CDDP dosage ≥75 mg/m ) were retrospectively evaluated. We used logistic analysis to evaluate whether ORS intake could be a preventive factor for CIN (≥grade 2 serum creatinine elevation). Moreover, incidence of CIN and electrolyte imbalance and the variation in serum creatinine and electrolyte levels were compared between ORS and non-ORS (control) patients. CIN occurred in 9.8% of ORS patients, and 7.5% of non-ORS patients (p=0.79). The variation in serum creatinine level was also similar in both groups. Multivariate analysis suggested that ORS intake does not affect CIN, although CIN was associated with the coadministration of non-steroidal anti-inflammatory drugs and the presence of diabetes mellitus. The variations in serum electrolyte levels did not differ, and incidence of hyponatremia, hypokalemia, and hypochloremia was also similar between the groups. Moreover, patients in ORS group experienced significantly more anorexia compared to controls, and approximately 40% of the patients were unable to continue ORS intake. ORS intake in CDDP short hydration regimens does not affect CIN and CDDP-induced electrolyte imbalance; however, its intake is associated with the incidence of anorexia suggesting that ORS should not be used for oral hydration.

Background/Aim: Eribulin is an effective chemotherapeutic agent for the treatment of metastatic breast cancer and advanced or metastatic soft-tissue sarcomas. However, severe adverse effects (SAEs) occur in 30-40% of the patients, and significantly reduce the patients’ quality of life and disturb the recommended treatment schedules. Neutropenia is the main cause of treatment suspension, delay, and/or dose reductions, also leading to relative dose intensity reduction. This study aimed to examine the risk factors for SAE occurrence after eribulin treatment. Patients and Methods: Eighty patients with metastatic breast cancer or advanced or metastatic soft tissue sarcoma who received eribulin were retrospectively evaluated. Risk factors for SAE occurrence in the first cycle were primarily assessed. In addition, factors associated with SAE occurrence during all treatment cycles were evaluated. Results: SAEs in the first cycle occurred in 45% of patients. The primary SAE was neutropenia (91.7%). The incidence of SAEs during all treatment cycles was 61.3%. Multivariate analyses suggested that lower baseline neutrophil and hemoglobin levels were risk factors for SAE occurrence and severe neutropenia incidence in the first cycle. An independent factor associated with SAE occurrence during all cycles was age ≥65 years and a tendency was confirmed for baseline anemia. Conclusion: Baseline neutropenia and anemia were risk factors for SAE occurrence during the first eribulin treatment cycle. Age ≥65 years was also associated with SAE occurrence during all treatment cycles. Patients with these risk factors should be carefully monitored for assessment and prophylaxis.

BackgroundImmune checkpoint blockade (ICB) has been shown to elicit long-term, durable responses in patients with metastatic or unresectable lung cancer. Similar to immunity against pathogens, memory-like antitumor T cell response may be pivotal in these patients. Nonetheless, due to the absence of suitable clinic-to-bench preclinical animal models, the mechanisms behind the generation of beneficial T cells following ICB in lung cancer remain largely unexplored.MethodsSubclones were obtained from a syngeneic murine lung cancer cell line. Alongside confirming their genomic oncogenicity through whole exome sequencing, MHC class I and class II neoantigens within the subclones were computationally identified. The subclones were subsequently tested in vivo for their sensitivity to ICB, including anti-PD-1 monotherapy and a combination of anti-PD-1 and anti-CTLA-4, both of which are the standard of care for lung cancer. Additionally, we assessed the role of memory-like antitumor T cell response in wild-type and Batf3 knockout (KO) mice that had previously rejected the lung tumor cells post-ICB treatment.ResultsThree subclones, huL1, huL2, and huL3, were established. These retained oncogenic driver mutations, such as Kras, Nras, and Trp53, present in the parental cells, and also shared immunogenic MHC class I and class II neoantigens. Wild-type mice were subcutaneously challenged with 1x106 tumor cells, followed by ICB treatment on days 3, 6, and 9. Upon anti-PD-1 monotherapy, tumor rejection rates in mice bearing huL1, huL2, and huL3 were 30%, 0%, and 50%, respectively. Treatment with a combination of anti-PD-1 and anti-CTLA-4 improved rejection rates to 20% for huL1, 36% for huL2, and 100% for huL3. Following a minimum interval of three weeks after the rejection of huL3 tumors, mice were re-challenged with 5x106 huL3 tumor cells on the opposite flank. Despite remaining untreated, these mice spontaneously rejected the secondary-challenged tumor cells. The same approach was replicated with Batf3 KO mice, which also rejected huL3 tumor cells when treated with the ICB combination, albeit at a rate of 50%. Interestingly, these tumor-free Batf3 KO mice could not spontaneously reject re-challenged huL3 tumor cells, unlike their wild-type counterparts.ConclusionsWe have developed a novel preclinical lung cancer model that assesses antitumor immunological memory through tumor rejection. Our research findings suggest that Batf3 is crucial for the development of memory-like antitumor T cells following ICB.

Abstract Introduction: Peritoneal mesothelioma is an extremely rare malignancy of the peritoneum. It has a poor prognosis, and the optimal systemic chemotherapy remains controversial. Here, we report two cases of peritoneal mesothelioma with long-term survival and complete response to carboplatin, pemetrexed, and bevacizumab chemotherapy. Case Presentation: Both patients were treated with six cycles of carboplatin (AUC 5), pemetrexed (750 mg/m2), and bevacizumab (15 mg/kg) followed by pemetrexed and bevacizumab as maintenance therapy. Partial response continued for over 6 years in case 1, and complete response was obtained in case 2. The patient in case 1 died after 7 years due to accidental pneumonia, and the patient in case 2 remained disease-free for over 2 years after initiation of chemotherapy. Conclusion: Little information is available regarding angiogenesis in malignant peritoneal mesothelioma, and carboplatin/pemetrexed/bevacizumab are off-labeled chemotherapy by Japanese healthcare system as yet. However, our experience suggested that combined chemotherapy with bevacizumab is a feasible option for systemic chemotherapy in cases of peritoneal mesothelioma.

A 29-year-old woman with chronic, prolonged pustular psoriasis was admitted to our hospital because of high-grade fever and a systemic skin rash. General examination revealed a whole-body skin rash and superficial lymphadenopathy. Peripheral blood examination showed unclassified cells positive for CD3, CD4, and T-cell receptor αβ, and negative for CD20 and CD56. Soon after administration, she developed acute respiratory failure and required artificial ventilation. Bronchoalveolar lavage fluid showed increased numbers of eosinophils and abnormal lymphocytes of the same phenotype in peripheral blood and skin. She was diagnosed with eosinophilic pneumonia, and her respiratory failure was improved by corticosteroid therapy. Based on the histological findings of skin, lymph node, and bone marrow biopsies, a diagnosis of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), with positivity for CC chemokine receptor 4 was made. She received chemotherapy followed by allogeneic stem cell transplantation, which resulted in complete remission of her PTCL-NOS. She remained alive and disease-free 6 years later. This is the first reported case of PTCL-NOS developing during the clinical course of pustular psoriasis. The clinical manifestations of PTCL-NOS are complex, but an accurate diagnosis and appropriate therapy may produce a good clinical outcome in patients with PTCL-NOS.

Indian Ocean hydrothermal vents are believed to represent a novel biogeographic province, and are host to many novel genera and families of animals, potentially indigenous to Indian Ocean hydrothermal systems. In particular, since its discovery in 2001, much attention has been paid to a so-called 'scaly-foot' gastropod because of its unique iron-sulfide-coated dermal sclerites and the chemosynthetic symbioses in its various tissues. Despite increasing interest in the faunal assemblages at Indian Ocean hydrothermal vents, only two hydrothermal vent fields have been investigated in the Indian Ocean. Here we report two newly discovered hydrothermal vent fields, the Dodo and Solitaire fields, which are located in the Central Indian Ridge (CIR) segments 16 and 15, respectively. Chemosynthetic faunal communities at the Dodo field are emaciated in size and composition. In contrast, at the Solitaire field, we observed faunal communities that potentially contained almost all genera found at CIR hydrothermal environments to date, and even identified previously unreported taxa. Moreover, a new morphotype of 'scaly-foot' gastropod has been found at the Solitaire field. The newly discovered 'scaly-foot' gastropod has similar morphological and anatomical features to the previously reported type that inhabits the Kairei field, and both types of 'scaly-foot' gastropods genetically belong to the same species according to analyses of their COI gene and nuclear SSU rRNA gene sequences. However, the new morphotype completely lacks an iron-sulfide coating on the sclerites, which had been believed to be a novel feature restricted to 'scaly-foot' gastropods. Our new findings at the two newly discovered hydrothermal vent sites provide important insights into the biodiversity and biogeography of vent-endemic ecosystems in the Indian Ocean.

Purpose Small cell lung cancer (SCLC) is a highly aggressive disease associated with poor patient survival rates. The addition of an anti‐programmed death ligand 1 antibody to platinum combination chemotherapy can improve its prognosis. However, only a few patients achieve a long‐term response; thus, establishing new therapies for SCLC is crucial. Midkine (MDK) is a heparin‐binding growth factor involved in various biological processes, including cell proliferation and chemotherapeutic resistance, in diverse cancers. MDK has garnered attention as a therapeutic and diagnostic target for several cancers; however, only a few studies have evaluated its expression and function in SCLC. This study aimed to evaluate the MDK expression in human SCLC tissue and human SCLC cell lines, and to clarify its function in tumorigenesis. Methods MDK expression was analyzed in vitro and in vivo through ELISA, immunohistochemistry, and western blotting. Its effects on cell proliferation, as well as the effects of cisplatin, were evaluated using the MTT assay. Results MDK was pathologically expressed in human SCLC tumor tissues but not in normal lung tissues. Serum MDK concentrations in patients with SCLC reflected the SCLC tumor burden and were correlated with response to treatment. Moreover, MDK induced cell proliferation and attenuated the effects of cisplatin in SCLC cell lines. An MDK inhibitor and cisplatin exerted synergistic antitumor effects both in vitro and in vivo. Furthermore, MDK positively regulated the AKT pathway. Conclusion Our findings indicate that MDK promotes cell proliferation and chemotherapeutic resistance by activating the AKT pathway in SCLC cells. Therefore, MDK may be a potential therapeutic and diagnostic target for SCLC.

We describe a case of an anaplastic lymphoma kinase (ALK)‐rearranged non‐small cell lung cancer with development of uterine metastasis after crizotinib and alectinib treatment. Gene analysis from the tissue of uterine metastasis revealed the presence of 1151Tins, which was considered to be a crizotinib and alectinib resistance mutation. Subsequent therapy with the third‐generation ALK inhibitor lorlatinib, but not ceritinib, showed antitumor activity for 1 year. The uterus is an uncommon site for metastasis from lung cancer, and our case indicated that serial gene analysis could provide new information about ALK inhibitor resistance. A patient with ALK‐rearranged advanced non‐small cell lung cancer presented acquired resistance to alectinib and uterine metastasis. Gene analysis using the tissue from the uterine metastasis revealed the presence of 1151Tins. Lorlatinib showed antitumor activity on this disease for one year.