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Abstract Background Based on the results of the PACIFIC trial, maintenance with durvalumab has emerged as the standard treatment following concurrent chemoradiotherapy in patients with unresectable locally advanced non‐small cell lung carcinoma (NSCLC). However, adverse events attributed to durvalumab, especially lung injuries, including immune‐related adverse events, and radiation pneumonitis, are concerning. This study retrospectively investigated the factors related to lung injury in patients receiving the PACIFIC regimen. Methods Patients with unresectable locally advanced NSCLC who received durvalumab maintenance therapy following concurrent chemoradiotherapy at Yokohama City University Medical Centre between July 2018 and March 2022 were included. Clinical data, volume of normal lung receiving 20 or 5 Gy or more (V20 or V5), planning target volume (PTV), and relative lung parenchyma volume in emphysematous lung receiving 20 or 5 Gy or more (RLPV20 or 5; V20 or V5/100‐percentage of low‐attenuation volume) were evaluated. Results Performance status (PS), V20, V5, PTV, RLPV20, and RLPV5 were significantly higher in the lung injury group in the univariate analysis. Furthermore, RLPV20 was the most significant factor in the lung injury group in the multivariate analysis comprising PS, PTV, V20, and RLPV20. Conclusion RLPV20 and RLPV5 are useful in estimating lung inflammation. RLPV20 could be considered the most reliable risk factor for maintenance therapy with durvalumab following concurrent chemoradiotherapy in patients with unresectable locally advanced NSCLC.

Abstract Thymic neuroendocrine tumors associated with multiple endocrine neoplasia are only defined as carcinoid and are not associated with large‐cell neuroendocrine carcinoma (LCNEC). We report the case of a multiple endocrine neoplasia type 1 patient with atypical carcinoid tumors with elevated mitotic counts (AC‐h), an intermediate condition between carcinoid and LCNEC. A 27‐year‐old man underwent surgery for an anterior mediastinal mass and was diagnosed with thymic LCNEC. Fifteen years later, a mass appeared at the same site, which was determined to be a postoperative recurrence based on the pathological results of a needle biopsy and the clinical course. The patient's disease remained stable for 10 months on anti‐programmed death‐ligand 1 antibody and platinum‐containing chemotherapy. The needle biopsy specimen was submitted for next‐generation sequencing, which revealed a MEN1 gene mutation, and after further examination, a diagnosis of multiple endocrine neoplasia type 1 was made. A re‐examination of the surgical specimen from 15 years prior showed that it corresponded to AC‐h. Although thymic AC‐h is classified as thymic LCNEC according to the current definition, our data suggests that a search for multiple endocrine neoplasia is warranted in such patients.

Abstract Primary tracheal small‐cell carcinoma is rare, and is often treated using small‐cell lung cancer guidelines given that no standard treatment has been established for it. We report a patient in whom nodules appeared in the trachea and left main bronchus 11 months after surgery for pulmonary large‐cell neuroendocrine carcinoma; a biopsy revealed small‐cell carcinoma. Given the absence of malignant lesions elsewhere in the body, the lesions were diagnosed as primary tracheal small‐cell carcinoma. Respiratory failure progressed rapidly owing to airway stenosis caused by the growing lesion, and the patient required nasal high‐flow therapy. However, the lesions shrank a few days after commencing first‐line chemotherapy, and his respiratory failure resolved. Accelerated hyperfractionated radiotherapy was administered in conjunction with the third course of chemotherapy, and the patient ultimately achieved a complete response. Although the lesions were initially suspected of being postoperative recurrence of pulmonary large‐cell neuroendocrine carcinoma, the fact that the biopsy revealed them to be primary tracheal small‐cell carcinoma indicates that intra‐airway nodules that appear after lung cancer surgery may possibly be primary tracheal tumors.

Abstract Background Pembrolizumab alone or in combination with chemotherapy is a standard treatment for patients with non‐small‐cell lung cancer (NSCLC) with high programmed death‐ligand 1 (PD‐L1) expression. However, no study has compared the efficacies of these two regimens. Therefore, we aimed to compare the efficacy of pembrolizumab alone and in combination with chemotherapy in NSCLC patients with high PD‐L1 expression. Methods We conducted a multicenter retrospective trial involving patients with diagnosed unresectable or recurrent NSCLCs who had received pembrolizumab with or without chemotherapy in the first‐line setting. Patients were divided into monotherapy and combination therapy groups. The progression‐free survival (PFS), overall survival (OS), and response rate (RR) were analyzed and compared between the groups. Clinical characteristics of patients were analyzed to assess their possible relationship with treatment outcomes. Results We enrolled 96 patients from five hospitals. Of these, 47 and 49 patients received monotherapy and combination therapy, respectively. The median PFS was 343 and 328 days in the monotherapy and combination therapy groups, respectively (hazard ratio 1.003, p = 0.99). No statistically significant differences were observed in the OS and RR between the two groups. However, in patients with metastases to the liver, lung, adrenal glands, bone, or lymph nodes, the PFS was longer in the monotherapy group than in the combination therapy group. Conclusion Although the PFS, OS, and RR were not significantly different between patients treated with pembrolizumab alone and or with pembrolizumab in combination with chemotherapy, patients with NSCLC having metastases to specific sites may benefit more from monotherapy.

Abstract Background Immune checkpoint inhibitors are a standard treatment for advanced lung cancer, although it remains important to identify biomarkers that can accurately predict treatment response. Immune checkpoint inhibitors enhance the antitumor T‐cell response, and interferon‐γ plays an important role in this process. Therefore, this study evaluated whether the number of interferon‐γ‐releasing peripheral T cells after phytohemagglutinin stimulation in the interferon‐γ release assay might act as a biomarker for the response of non‐small cell lung cancer to immune checkpoint inhibitor treatment. Methods Data were retrospectively collected regarding 74 patients with non‐small cell lung cancer who had received immune checkpoint inhibitors. Pretreatment screening tests had been performed using the T‐SPOT.TB assay, which quantifies the number of interferon‐γ‐releasing T cells (as immunospots) in response to phytohemagglutinin and tuberculosis‐specific antigen stimulation. Clinical factors and the number of spots in the T‐SPOT fields were evaluated for associations with patient outcomes. The median number of spots was used to categorize patients as having high or low values, and the two groups were compared. Results Relative to patients with a low ratio, patients with a high ratio of phytohemagglutinin/tuberculosis‐specific antigen spots (i.e. more responsive T cells) had significantly better progression‐free survival after immune checkpoint inhibitor treatment. When we only considered patients with negative T‐SPOT results, a high number of phytohemagglutinin‐stimulated spots corresponded to significantly longer progression‐free survival. Conclusion The T‐SPOT.TB assay can be used to quantify the number of immunospots in response to antigen stimulation, which may predict the response to immune checkpoint inhibitors in patients with non‐small cell lung cancer.

Background Advanced non‐small cell lung cancer (NSCLC) has a high mortality rate and poor prognosis. However, outcomes have gradually improved after the introduction of novel immunotherapies, including immune checkpoint inhibitors (ICIs). Although programmed death‐ligand 1 (PD‐L1) expression in tumor tissues is a known biomarker for guiding ICI treatment of NSCLC, challenges such as difficulty of liquid biopsy and heterogeneous results during treatment persist. This study evaluated the potential of miR200b as a surrogate biomarker for PD‐L1 expression. Methods We used the human lung cancer cell lines H226, H460, H520, A549, and H1975. miR200b expression in blood and bronchoscopy specimens of NSCLC patients was evaluated using reverse‐transcription‐quantitative PCR. Using flow cytometry, PD‐L1 expression in vitro, as well as in tumor tissues, was evaluated after transfection with a mimic miR200b or siRNA. Results miR200b expression negatively correlated with PD‐L1 expression in all cell lines. The induction or knockdown of miR200b also altered PD‐L1 expression in vitro. The patient group with a PD‐L1 tumor proportion score ≥ 50% had significantly lower miR200b expression in the bronchoscopy specimens (P = 0.025) and serum‐derived exosomes (P = 0.022) than that with PD‐L1 tumor proportion score

Introduction As most patients with epidermal growth factor receptor (EGFR)‐mutant non‐small cell lung cancer (NSCLC) develop progressive disease after treatment with osimertinib, it is important to develop more effective treatment options. Afatinib has been shown to be more effective in in vitro studies than osimertinib when used in cancer cell lines containing some specific EGFR mutations. Therefore, afatinib may be an effective solution, especially when used in combination with an anti‐VEGF agent such as bevacizumab. Methods A phase II multicenter, open‐label, single‐arm trial has been initiated to evaluate the efficacy and safety of afatinib and bevacizumab combination as salvage therapy for EGFR‐mutated lung cancer in patients previously treated with osimertinib. The primary endpoint will be the objective response rate (ORR) and secondary endpoints are progression‐free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs). Discussion A previous study indicated that afatinib inhibits lung cancer cells with specific EGFR mutations more effectively than other EGFR‐TKIs such as osimertinib. Therefore, we expect that combination therapy using afatinib and bevacizumab will be effective in patients previously treated with osimertinib (registration no. jRCTs031190077).

Abstract Background Currently, anticancer immunotherapy based on PD‐1/PD‐L1 blockade with immune checkpoint inhibitors (ICIs) is being used as a standard therapy for non‐small cell lung cancer (NSCLC). However, more effective treatments are required as these tumors are often resistant and refractory. Here, we aimed to determine the effects of immunomodulatory oligodeoxynucleotides (ODNs) in terms of the presence or absence of CpG motifs and the number of consecutive guanosines. Methods Western blots were used to measure the molecules which regulate the expression of PD‐L1 in human lung cancer cell lines after incubation with several cytokines and ODNs. The expression of PD‐L1 and β2‐microglobulin (β2‐MG) on A549 cells, and IFN‐γ‐induced apoptosis with ODNs were examined by flow cytometry. The relationship between IFN‐γ receptor and ODN was analyzed by ELISA and immunofluorescence chemistry. Results Our results verified that A‐CpG ODNs suppress the upregulation of IFN‐γ‐induced PD‐L1 and β2‐MG expression. In addition, we found that ODNs with six or more consecutive guanosines (ODNs with poly‐G sequences) may competitively inhibit the IFN‐γ receptor and abolish the effect of IFN‐γ, thereby suppressing apoptosis and indoleamine 2,3‐dioxygenase 1 expression in human lung cancer cells. The tumor microenvironment regulates whether this action will promote or suppress tumor immunity. Thus, in immunotherapy with CpG ODNs, it is essential to consider the effect of ODNs with poly‐G sequences. Conclusions This study suggests that ODNs containing six or more consecutive guanosines may inhibit the binding of IFN‐γ to IFN‐γ receptor. However, it does not directly show that ODNs containing six or more consecutive guanosines competitively inhibit the IFN‐γ receptor, and further studies are warranted to confirm this finding. Key points Significant findings of the study: Oligodeoxynucleotides with a contiguous sequence of six or more guanosines may competitively inhibit the IFN‐γ receptor and abolish the action of IFN‐γ. This may suppress IFN‐γ‐induced apoptosis and indoleamine‐2,3‐dioxygenase‐1 expression in human lung cancer cells. What this study adds: A‐CpG and poly‐G ODN may overcome tolerance if the cause of ICI tolerance is high IDO expression. However, IFN‐γ also has the effect of suppressing apoptosis of cancer cells, and it is necessary to identify the cause of resistance.

An 82‐year‐old man with chronic tuberculous empyema visited our hospital for an annual computed tomography (CT) scan. No differences were noted between the CT scan at presentation and a scan performed a year previously in August 2017. He began experiencing right chest, epigastrium, and back pain since the end of October 2017. A CT scan taken in November of 2017 to evaluate the pain in his right chest, epigastrium, and back showed an irregular thickening of the pleura adjacent to the empyema and an abnormal right seventh costal mass infiltrating the vertebral body. CT‐guided needle biopsy of the mass showed angiosarcoma. Positron emission tomography/CT revealed multiple metastases in his bones and liver. Chemotherapy was not recommended owing to his poor performance status, which was related to angiosarcoma. Therefore, he was offered palliative radiotherapy for the metastasis to the vertebral body.