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Abstract Background Immune-related pneumonitis (irP) is one of the most important immune-related adverse events caused by immune checkpoint inhibitors (ICIs). After corticosteroid therapy irP frequently relapses, which can interfere with cancer therapy. However, risk factors for irP relapse are unknown. Methods This study was a follow-up analysis of a phase II study that evaluated 56 patients with grade ≥ 2 irP treated with oral prednisolone, 1 mg/kg/day, tapered over 6 weeks. Clinical factors including patient characteristics, blood test findings, and response to prednisolone therapy were assessed to identify risk factors for irP relapse using the Fine–Gray test. Results Among 56 patients with irP, 22 (39.3%) experienced irP relapse after 6 weeks of prednisolone therapy during the follow-up observation period. Radiographic organising pneumonia (OP) pattern and duration to irP onset ≥ 100 days from ICI initiation were determined to be significant risk factors for irP relapse in a multivariate Fine–Gray test (hazard ratio [HR] = 3.17, 95% CI 1.37–7.32, p = 0.007, and HR = 2.61, 95% CI 1.01–6.74, p = 0.048, respectively). Other patient characteristics, blood test findings, irP severity, and response to prednisolone therapy were not associated with irP relapse. Conclusions In irP patients treated with 6-week prednisolone tapering therapy, OP pattern and duration to irP onset ≥ 100 days were associated with relapse risk. Assessment of the risk factors for irP relapse will be helpful for irP management.

AbstractBackground Adjuvant durvalumab after chemoradiation has become the standard of care for patients with stage III NSCLC, according to the PACIFIC trial. Whether biomarkers before durvalumab for patients with stage III NSCLC showed predictive and prognostic effects remains unknown.Methods This is a retrospective study in the Fujieda Municipal General Hospital between October 2018 and March 2022. We assessed the predictive value of the Prognostic Nutritional Index (PNI) in stage III non-small cell lung cancer (NSCLC) patients treated with durvalumab after chemoradiation.Results After applying the inclusion and exclusion criteria, the study included 56 patients for further analysis. The median follow-up period was 17.6 months (range, 3.0–45.4 months). According to receiver operating characteristic curve results, the PNI cutoff value to predict overall survival (OS) was 37.9, with sensitivity and specificity at 67.9% and 67.9%. Accordingly, the patients were divided into low- and high-PNI groups. Patients with the low-PNI group had a significantly shorter progression-free survival compared to the high-PNI group (median, 9.1 vs. 21.3 months, p = 0.032). OS was also shorter in the low-PNI group (median, 19.0 months vs. not reached, p

Abstract Background Recently, deaths due to mucormycosis in immunocompromised hosts have increased; however, the clinical and pathological features of mucormycosis are not fully understood, especially in view of the associated high mortality and rare incidence in immunocompetent patients. Case presentation We have described a rare autopsy case of a 67-year-old Japanese man with chronic obstructive pulmonary disease who contracted mucormycosis. He had not been on any immunosuppressants, and his immune functions were intact. Since 3 days prior to admission to our hospital, he had experienced progressive dyspnea, productive cough, and fever. Chest computed tomography revealed pleural effusion in the left lower hemithorax and consolidation in the right lung field. Although he was administered with tazobactam-piperacillin hydrate (13.5 g/day), renal dysfunction occurred on the ninth disease day. Therefore, it was switched to cefepime (2 g/day). However, his general condition and lung-field abnormality worsened gradually. Cytological analysis of the sputum sample at admission mainly revealed sporangiophores and unicellular sporangioles, while repeated sputum culture yielded Cunninghamella species. Therefore, he was diagnosed with pulmonary mucormycosis. Liposomal amphotericin B (5 mg/kg/day) was initiated on the 28th disease day. However, chest radiography and electrocardiography detected cardiomegaly and atrial fibrillation, respectively, and he died on the 37th disease day. A postmortem examination revealed clusters of fungal hyphae within the arteries of the right pulmonary cavity wall, the subpericardial artery, intramyocardial capillary blood vessels, and the esophageal subserosa vein. Direct sequencing revealed that all fungal culture samples were positive for Cunninghamella bertholletiae. Conclusions Cunninghamella bertholletiae could rapidly progress from colonizing the bronchi to infecting the surrounding organs via vascular invasion even in immunocompetent patients.

ABSTRACT Aims/Introduction Diabetes and sarcopenia have a two‐way relationship with each other with advanced age. Additionally, malnutrition is correlated with a higher risk of sarcopenia in elderly patients. This study evaluated the association between sarcopenia and geriatric nutritional risk index (GNRI) in elderly patients with type 2 diabetes mellitus. Materials and Methods Patients with type 2 diabetes mellitus aged ≥60 years were recruited from June 2018 to August 2020. This study analyzed 234 patients, who completed a physical performance test required for the diagnosis of sarcopenia. To investigate the effect of GNRI on sarcopenia, logistic regression analyses was used. Results Patients with sarcopenia were significantly older with a lower body mass index (BMI) and GNRI compared with normal patients. The GNRI showed a positive correlation with the skeletal muscle index (SMI) and handgrip strength (SMI: R = 0.486, P

Background There has been no prospective trial for treatment of immune-related pneumonitis (irP) occurred after immune checkpoint inhibitors (ICIs).Methods In this single-arm phase II study, patients with cancer with grade ≥2 irP received oral prednisolone (1 mg/kg/day), tapered over 6 weeks. The primary endpoint was a pneumonitis control rate at 6 weeks from the start of the study treatment, defined as complete disappearance or partial improvement of irP in high-resolution CT of the chest.Results Among 57 patients enrolled, 56 were included in the final analysis. The most frequent cause of irP was single ICI therapy (51.8%), followed by combination with chemotherapy plus ICI (39.3%). Thirty-five (62.5%) patients had grade 2 irP and 21 (37.5%) had grade ≥3. Fifty-one (91.1%) patients completed the study treatment while 5 discontinued the study treatment because of relapse of irP (n=1), death from cancer (n=1), occurrence of immune-related hepatitis (n=1), extension of the treatment duration more than 6 weeks (n=1), and attending physician’s decision (n=1). Six weeks after the start of the study treatment, 16 (28.5%) patients demonstrated complete recovery from irP, 35 (62.5%) had a partial improvement in irP, 1 (1.8%) had a relapse of irP, and 4 (7.1%) were not evaluable. The pneumonitis control rate at 6 weeks was 91.1% (95% CI, 80.7% to 96.1%). Twelve weeks after the start of the study treatment, 5 (8.9%), 27 (48.2%), and 15 (26.8%) patients demonstrated complete recovery, partial improvement, and relapse, respectively, and 9 (16.1%) were not evaluable. The pneumonitis control rate at 12 weeks was 57.1% (95% CI, 44.1% to 69.2%). During the observation period, 18 (32.1%) patients experienced a relapse of irP, and of those, 17 received re-treatment with corticosteroids. Grade ≥3 adverse events occurred in 10 (17.9%) patients, in which hyperglycemia was most frequent (n=6). There was no treatment-related death.Conclusions In this first prospective study for irP, prednisolone at 1 mg/kg/day, tapered over 6 weeks, demonstrated a promising clinical benefit and manageable toxicity, suggesting a potential treatment option for irP.Trial registration number jRCT: 1041190029.

Abstract Background Clinical efficacy of immune checkpoint inhibitors (ICIs) for non-small cell lung cancer (NSCLC) with uncommon histology (uNSCLC) is unknown. Methods Patients with NSCLC treated with ICI monotherapy between January 2014 and December 2018 in 10 Japanese hospitals were retrospectively evaluated. The patients were divided into: (1) NSCLC with common histology (cNSCLC), defined as adenocarcinoma and squamous cell carcinoma; and (2) uNSCLC, defined as incompatibility with morphological and immunohistochemical criteria for adenocarcinoma or squamous cell carcinoma. Propensity score matching was performed to balance the two groups. Results Among a total of 175 patients included, 44 with uNSCLC (10 pleomorphic carcinomas, 9 large cell neuroendocrine carcinomas, 2 large cell carcinomas, and 23 not otherwise specified) and 44 with matched cNSCLC (32 adenocarcinomas and 12 squamous cell carcinomas) were selected for analyses. Median progression-free survival (PFS) (4.4 months, 95% confidence interval [CI] 1.8–7.7 months) and overall survival (OS) (11.4 months, 95% CI 7.4–27.4 months) in the uNSCLC patients were not significantly different from those in matched cNSCLC patients (5.4 months, 95% CI 3.1–7.6 months, p = 0.761; and 14.1 months, 95% CI 10.6–29.6 months, p = 0.381). In multivariate analysis, Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0–1 and programmed death ligand-1 (PD-L1) expression were predictive for PFS and OS in uNSCLC. Conclusions ICIs had similar clinical efficacy for treatment of uNSCLC and cNSCLC. Good ECOG-PS and PD-L1 expression were predictive for efficacy of ICIs in uNSCLC.

Introduction: Although recent advances in chemotherapy for lung cancer are remarkable, most clinical trials have excluded patients with interstitial lung disease (ILD) due to the concern of developing acute exacerbation (AE) of ILD. Hence, accumulating original evidence of cancer treatment for this population is important. Methods: Between 2016 and 2020, a prospective observational study was conducted across 11 Japanese hospitals. Patients with chemotherapy- naïve , inoperable, advanced lung cancer with ILD were included. The primary outcome was the frequency of AE-ILD after registration; the secondary outcomes were the risk factor of AE-ILD and the efficacy of chemotherapy. Results: Among 124 patients enrolled, 109 patients who received chemotherapy were analyzed. The median age was 72 years, and the majority showed usual interstitial pneumonia (UIP)/probable UIP pattern upon chest computed tomography. The median percent-predicted forced vital capacity (%FVC) was 81% (interquartile range: 66–95%). After registration, 23 patients (21.1%; 95% confidence interval [CI]: 14.4–29.7%) developed AE-ILD. The logistic analysis revealed that lower %FVC slightly but significantly increased the risk of AE-ILD (odds ratio per 10% decrease: 1.27; 95% CI: > 1.00–1.62). Overall response rates/median overall survival times in non-small-cell lung cancer and small-cell lung cancer for the first-line chemotherapy were 41% (95% CI: 31–53)/8.9 months (95% CI: 7.6–11.8) and 91% (95% CI: 76–98)/12.2 months (95% CI: 9.2–14.5), respectively. Conclusion: AE-ILD during chemotherapy is a frequent complication among patients with lung cancer with ILD, particularly those with lower %FVC. Conversely, even in this population, passable treatment response can be expected.

Abstract Background Immune checkpoint inhibitors have potential applications in treating various cancers but are associated with immune-related adverse events, such as inflammation, in a wide range of organs; however, allergic inflammation caused by these agents has not been extensively studied. Case presentation A 65-year-old man was diagnosed with a kidney neuroendocrine carcinoma. Three months after kidney resection surgery, the tumor cells had metastasized to his liver and lymph nodes. Subsequently, the patient started chemotherapy; however, regardless of treatment, the tumor grew, and the patient experienced a series of adverse effects, such as taste disorder, anorexia, and general fatigue. Finally, he was administered a programmed cell death (PD)-1 inhibitor, nivolumab (biweekly, toal 200 mg/body), which was effective against kidney carcinoma. However, the patient had a bronchial asthma attack at 22 cycles of nivolumab treatment and chest computed tomography (CT) revealed an abnormal bilateral shadow after 37 cycles of nivolumab treatment. Bronchoscopy findings revealed eosinophil infiltration in the lungs along with severe alveolar hemorrhage. Paranasal sinus CT scanning indicated sinusitis and nerve conduction analysis indicated a decrease in his right ulnar nerve conduction velocity. Based on these findings, the patient was diagnosed with eosinophilic granulomatosis with polyangiitis; he was treated with prednisolone, which alleviated his bronchial asthma. To restart nivolumab treatment, the dose of prednisolone was gradually tapered, and the patient was administered a monthly dose of mepolizumab and biweekly dose of nivolumab. To date, there have been no bronchial attacks or CT scan abnormalities upon follow up. Conclusions We present a rare case in which a patient with cancer was diagnosed with eosinophilic granulomatosis with polyangiitis following treatment with a PD-1 inhibitor. Blockade of PD-1 and the programmed cell death ligand (PD-L) 1/PD-1 and PD-L2/PD-1 signaling cascade may cause allergic inflammation. Further studies are needed to identify the specific mechanisms underlying allergic inflammation after PD-1 blockade.

Abstract Background Allergic bronchopulmonary aspergillosis (ABPA) and allergic fungal rhinosinusitis (AFRS) are characterized by hyper-responsiveness of the respiratory tract and the nasal cavity and paranasal sinuses, respectively to Aspergillus species and AFRS causes chronic rhinosinusitis. Herein, we report the first case of sinobronchial allergic mycosis (SAM) syndrome, defined as ABPA with concomitant AFRS, caused by Aspergillus fumigatus patient > 80 years. Case presentation An 82-year-old male with interstitial pneumonia who returned for follow-up exhibited high-attenuation mucus plug in the right intermediate bronchial trunk, infiltration in the right lung field, and right pleural effusion on regular chest computed tomography (CT). We found unilateral central bronchiectasis in the right upper lobe. Similarly, CT scan of the paranasal sinuses revealed high-attenuation mucus plugs in left ethmoid sinuses. Biopsy specimens from the plugs in the right intermediate bronchial trunk and the left ethmoid sinuses revealed allergic mucin with layers of mucus eosinophils, eosinophil-predominant mixed inflammatory cell infiltrate and Aspergillus hyphae. The patient fulfilled all the major criteria for ABPA and AFRS, and was diagnosed with SAM syndrome. CT scan of the lung and paranasal sinuses revealed apparent amelioration after oral steroid therapy. Conclusion Despite mostly reported in relatively young patients, SAM syndrome can occur in elderly individuals as well.

Immunoglobulin type G4 -related disease (IgG4-RD) is known as a chronic systemic inflammatory disease, which is sometimes associated with lung cancer. However, the detailed association between IgG4-RD and lung cancer in clinical settings is still poorly understood. An 80-year-old man was diagnosed with progressive lung adenocarcinoma carrying an EGFR point mutation at L858R, and osimertinib treatment was administered. Two months later, although osimertinib treatment showed good response to the primary tumor, fever and anorexia appeared, and multiple lymph nodes, in particular in the left axillary, became swollen. Ultrasonography-guided biopsy of the axillary lymph node revealed infiltration of lymphocytes with IgG4-positive plasma cells and fibrosis. Serum IgG4 levels were also increased. These results suggested that the multiple swollen lymph nodes were not metastasis, but IgG4-related disease. Based on these results, therapy using prednisolone was initiated. Multiple lymphadenopathy gradually decreased, and his symptoms improved. Currently, his good responses to osimertinib treatment have been maintained. Like in our case, multiple lymphadenopathy with IgG4-positive plasma cell infiltration during successful anti-cancer treatment is quite rare. In this case, it was hypothesized that anti-cancer treatment with osimertinib induced IgG4-positive plasma cell infiltration in multiple lymph nodes. When lymphadenopathy occurs during lung cancer treatment, IgG4-RD has to be considered other than lung cancer metastasis.

Epidermal growth factor receptor (EGFR) exon 20 insertion is not associated with sensitivity to EGFR tyrosine kinase inhibitors and chemotherapy. Here, we report the case of a 41-year-old man who presented a right lower lobe nodule and mediastinal lymph node enlargement diagnosed as EGFR exon 20 insertion adenocarcinoma with high-expression programmed cell death ligand 1 (PD-L1). He showed stable disease to chemoradiation treatment at the primary tumor site. However, durvalumab treatment has good response. Non-small cell lung cancer with EGFR exon 20 insertion and high PD-L1 expression may be treated with immunotherapy exposure.

Abstract Background There are few reports about the factor influencing the prognosis of high-grade neuroendocrine carcinoma. In this study, we evaluated surgical outcome of clinical stage I high-grade neuroendocrine carcinoma. Methods Patients who underwent curative surgery for high-grade neuroendocrine tumors of the lung in clinical stage I were included in this study. We retrospectively analyzed 27 consecutive patients. The aim of this study was to clarify the clinical course of the disease after surgery and what factors influence the prognosis. Results Twenty-two patients have small cell carcinoma, and 5 patients have large cell neuroendocrine carcinoma. Patients who could undergo surgery within 60 days after the first visit (p

Mitosis is the most conspicuous cell cycle phase and Shugoshin-like 1 (SGOL1) is a key protein in protecting sister chromatids from precocious separation during mitosis. We studied the role of SGOL1 and its splice variants in non-small cell lung cancer (NSCLC) using 82 frozen NSCLC tissue samples. SGOL1-B expression was prevalent in smokers, in cases with a wild-type (WT) EGFR status, and in cases with the focal copy number amplification of genes that are known to be important for defining the biological behaviors of NSCLC. The overexpression of SGOL1-B1 in an NSCLC cell line induced aberrant chromosome missegregation, precociously separated chromatids, and delayed mitotic progression. A higher level of SGOL1-B mRNA was related to taxane resistance, while the forced down-regulation of SGOL1-B increased the sensitivity to taxane. These results suggest that the expression of SGOL1-B causes abnormal mitosis and taxane resistance in NSCLC cells. [ABSTRACT FROM AUTHOR]