Background: Several risk factors for the immune-related adverse events (irAEs) during treatment with immune checkpoint inhibitors (ICIs) have been reported, of which include high levels of C-reactive protein (CRP). In this study, we aim to evaluate CRP levels before ICIs treatments as potential predictive biomarkers of irAEs incidence rate and overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC). Methods: Between December 1, 2015 to December 31, 2019, we retrospectively collected all adult patients with NSCLC who received at least one dose of an ICI targeting the PD-1/PD-L1 axis at the Iwate Medical University Hospital in Japan. In this study the patients were categorized into low and high groups with a cut-off value of 10 mg/L as the baseline level of CRP before the ICI treatment. The primary endpoint was relationship between CRP levels at baseline and incidence of irAEs. The secondary endpoints were the relationship of progression-free survival (PFS) and OS. Results: A total of 101 irAEs, and 25 severe irAEs were observed. The incidence of the most irAEs was higher in the high CRP group compared to the low CRP group (54.4% vs. 34.5%, respectively, P=0.003). The most frequent irAEs were skin rush (28.8%), followed by pneumonitis (19.2%), hypothyroidism (15.4%), and hepatotoxicity (9.6%). The most common grade 3 or 4 irAEs was pneumonitis (7.9%), which tended to be more frequent in the high CRP group. In multivariate analysis, patients with high CRP levels had an adjusted OR of 2.41 and were associated with an increased risk of developing irAEs (95% CI: 1.16-4.43, P=0.020). The high CRP group was related with shorter PFS compared to the low CRP group (2.2 vs. 3.3 months, respectively, P=0.006). The high CRP group were also related with shorter OS compared to the low CRP group (8.9 vs. 39.1 months, respectively, P<0.001). Conclusions: The results suggest that higher level of pretreatment CRP is involved in the development of irAE and poor prognosis. Identification of patients at high risk of irAEs would be of great help. Future multicenter prospective studies are needed to expand on this study.

Background: Kirsten rat sarcoma virus (KRAS) gene mutations are a type of driver mutation discovered in the 1980s, but for a long time no molecular targeted drugs were available for them. Recently, sotorasib was developed as a molecular targeted drug for KRAS mutations. It is therefore necessary to identify the characteristics of patients with KRAS mutations.Methods: This was the single-institution retrospective study. Surgically resected tumors from lung adenocarcinoma patients were collected at a single institution from June 2016 to September 2019. Peptide nucleic acid-locked nucleic acid polymerase chain reaction (PNA-LNA PCR) clamp analysis of KRAS G12X mutations was compared with analysis by therascreen KRAS RGQ kit. The association between KRAS mutation status and patient characteristics and prognosis was assessed.Results: Among 499 lung adenocarcinomas, KRAS mutations were evaluated in 197 cases, excluding stage IV lung cancer and tumors with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations. KRAS G12X mutations were detected in 59 cases (29.9%). The highest frequency by gene mutation subtype was G12V in 23 cases (39.0%), followed by G12C in 16 cases (27.1%), G12D in 12 cases (20.3%), G12S in 4 cases (6.8%) and G12A in 2 cases. For the G12C mutation, the PNA-LNA PCR clamp and therascreen methods were consistent, but for the G12D and G12S mutations, the PNA-LNA PCR clamp method showed higher detection rates. In operable tumors, G12C mutations were more frequent in males, smokers, and patients with high expression of programmed death-ligand 1 (PD-L1), and had no correlation with prognosis.Conclusions: By the PNA-LNA PCR clamp method, G12C mutation of surgical specimens was detected successfully. The PNA-LNA PCR clamp method is expected to be applied to the detection of druggable G12C mutations.

BACKGROUND:Chemotherapy-induced peripheral neuropathy (CIPN) has a significant impact on the therapeutic efficacy of chemotherapy and patients' quality of life. The aim of this study was to assess the preventive effect of lafutidine on CIPN.METHODS:Patients were randomly assigned (1:1) to carboplatin and paclitaxel chemotherapy with lafutidine 10 mg twice daily (lafutidine group) or without lafutidine (control group). Peripheral neuropathy in both groups was assessed with the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and two patient-based questionnaires, the Patient Neurotoxicity Questionnaire (PNQ) and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx). The primary outcome was the incidence of grade 2 or higher peripheral neuropathy in CTCAE version 5.0. The target number of cases was set at approximately 40.RESULTS:In total, 18 patients were screened, and 16 patients were assigned to the lafutidine group (n=9) or control group (n=7) between January 2021 and January 2023. Due to poor recruitment, the target number of cases was not reached. Grade 2 or higher neuralgia was 22.2% in the lafutidine group and 14.3% in the control group. Grade 2 or higher peripheral sensory neuropathy was 100% in the lafutidine group and 71.4% in the control group (P=0.175). Grade 3 or higher peripheral neuropathy was not detected in either group. There was no significant difference in PNQ scores between the two groups. Median FACT/GOG-Ntx scores after the fourth cycle tended to be lower in the lafutidine group than in the control group. There was no statistically significant difference in progression free survival (PFS) between the two groups. There were no adverse events due to lafutidine administration.CONCLUSIONS:Although the preventive effect of lafutidine on CIPN could not be demonstrated statistically, lafutidine FACT/GOG-Ntx scores showed a trend toward decreased neurotoxicity as chemotherapy proceeded. More reliable studies using lafutidine on the prevention of CIPN should be conducted.TRIAL REGISTRATION:Japan Registry of Clinical Trials, identifier: jRCTs021200031.

Background: COVID-19 has caused a large number of deaths, in the elderly. In this situation, vaccines have been considered the main strategy to combat COVID-19 and were developed worldwide in 2020. One problem with COVID-19 vaccination is side effects after vaccination. In this report, we identify the relationship between side effects and elevation of antibodies as determined by monitoring several kinds of antibodies against COVID-19. Objective: We investigated whether the antibody level changed depending on side effects after COVID-19 vaccination. Methods: Healthy volunteers, who received two vaccinations between 10 March and 7 May 2021, were collected for this study. Information including age, gender, smoking history, medical history including allergies and side reactions after vaccination was obtained by questionnaire. Serum levels of antibodies of IgG and IgM against each S1, SP, and NP antigens of COVID-19 were evaluated frequently for 3 - 4 months after the first vaccination. Result: Ten employees working at Iwate Medical University were evaluated in this study. Side effects were observed in 7 of 10 patients, and grade 2 side effects in all 3 patients with a history of allergic disease. Serum S1 and SP IgG were elevated sufficiently in all patients. In all patients, IgG antibody titers fell below the cutoff point in approximately 3 months. No cases had elevated NP antibodies. SP IgM was elevated in three cases; all three cases with elevated IgM had allergic disease and the degree of side effects was relatively higher. Subjects with long-lasting elevated SPIgM were observed. Conclusion: S1 IgG and SP IgG exceeded the cutoff in all subjects after vaccination but decreased below the cutoff in all subjects within 4 months, regardless of side effects or allergic history. On the other hand, elevated SPIgM was suspected to be related to side effects and history of allergies, and cases with persistent elevation of SPIgM were observed.

31歳，男性．左眼の違和感，左視野の歪みを主訴に眼科を受診し，精査の結果，右下葉肺腺癌cT2aN0M1b cStage IVA，転移性網膜腫瘍の診断となった．CTガイド下肺生検の検体を用いたPNA LNA PCR-Clamp法やオンコマインDx Target TestマルチCDxシステムⓇではEGFR遺伝子変異は検出されなかったが，胸膜播種病変を用いてOncomine Comprehensive Assay v3Ⓡで解析を行ったところ，EGFR遺伝子変異exon19 L747Pを検出しOsimertinib治療で約4カ月病変を制御する治療効果を得た．次世代シークエンス検査の普及に伴って遭遇する稀なEGFR遺伝子変異に対しては，更なる知見の蓄積が必要である．

A 54-year-old woman on dialysis due to chronic renal failure had a fever lasting 2 weeks and was referred to a hospital. Non-enhanced CT and blood tests showed no remarkable findings. She was hospitalized and received an antibacterial drug. Although she was discharged after the fever subsided, she was hospitalized again due to a fever a few days later. A contrast-enhanced CT revealed mediastinal lymphadenopathy, and she was transferred to our hospital for a bronchoscopy. Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration (EBUS-TBNA) for subcarinal lymph nodes was performed in our hospital. The Polymerase Chain Reaction (PCR) test of the obtained specimen was positive for mycobacterium tuberculosis, and histologically, caseous granulomas were found in the specimen. She was diagnosed with mediastinal tuberculous lymphadenitis, and HREZ (isoniazid, rifampicin, ethambutol, and pyrazinamide) treatment was started. The fever subsided immediately, and she was discharged from our hospital 2 weeks after the initiation of treatment. Thereafter, she received treatment as an outpatient. Since the use of a contrast medium was complicated by dialysis, a non-enhanced CT was performed at first, and it was difficult to make a diagnosis from this. We report this as an informative case that could be diagnosed with EBUS-TBNA, which was easily performed on a patient weakened by prolonged fever and dialysis.

Abstract Background Epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) have become the gold standard for EGFR‐mutated non‐small cell lung cancer (NSCLC) treatment. Immune checkpoint inhibitors (ICIs) have been developed for the treatment of several malignancies, including lung cancer. However, it is known that ICIs have poorer efficacy in EGFR‐mutated NSCLC. Methods We collected data for patients with EGFR‐mutated NSCLC receiving monotherapy with ICIs after EGFR‐TKIs between December 2015 and March 2020 in three institutions, and retrospectively analyzed the association between patient characteristics and efficacy of ICIs. Results A total of 25 patients were included in this study. We defined responders as patients undergoing 90 days or longer of ICI treatment. Comparing characteristics between responders and non‐responders, more tumors with L858R EGFR mutation were observed in responders than in non‐responders (L858R: 66.7% and 25.0%, respectively, p < 0.05). There was no difference in incidence of T790M resistance mutation before ICI treatment. The PD‐L1 positive rate was slightly higher in responders but not statistically significant (22.2% and 12.5%, respectively). Median duration of EGFR‐TKI pretreatment was shorter in ICI responders compared with nonresponders (13.3 and 19.9 months, respectively). The survival of patients with L858R tumors was significantly longer than that of patients with exon 19 deletion (HR: 0.35, 95% CI: 0.13–0.93, p = 0.026). Conclusions ICI treatment tends to have better efficacy in patients with L858R‐mutated tumors. This study suggests that patients with L858R‐mutated NSCLC are candidates for ICI treatment after EGFR‐TKI treatment.

The Oncomine Dx Target Test(Oncomine) is one of next generation sequence tests simultaneously analyze 46 genetic abnormalities including 4 genes approved for companion diagnostic tests for non-small cell lung cancer (NSCLC). The success rates of Oncomine in clinical practice has become an issue. In this report, we evaluated implementation status of Oncomine in our hospital and its usefulness in clinical practice.

Meningeal carcinomatosis in lung cancer is known to have a very poor prognosis. Here we report a case in which bevacizumab plus erlotinib (BE) was effective against meningeal carcinomatosis from afatinib-resistant EGFR mutation-positive lung cancer. A 61-year-old man started afatinib, a 2nd generation molecular targeting drug, as first-line treatment for lung adenocarcinoma cT1bN0M1a stage IVA harboring EGFR exon19 deletion mutation. This treatment shrank the tumor and allowed sustained control of tumor growth. After 19 months from the start of treatment, head MRI revealed brain metastasis in the cerebellum and meningeal carcinomatosis with loss of appetite and slurred speech, in response to which whole-brain irradiation was performed. Head MRI 1 month after whole-brain irradiation showed no change in the disseminated lesions of the cerebellum. In Japan, osimertinib treatment after failure of EGFR-TKI treatments requires the T790M mutation in the tumor, blood or body fluid, so BE treatment was started as second-line treatment. Brain MRI showed improvement in cerebellar disseminated lesions 1 month after the start of BE treatment. BE treatment controlled intrapulmonary metastases, pleural disseminated lesions and meningeal carcinomatosis for 6 months. BE treatment as second-line treatment should be considered as an option for meningeal carcinomatosis of EGFR tyrosine kinase inhibitor (TKI) -resistant EGFR mutated lung cancer.

pembrolizumab in the recurrent group was similar to that in the advanced group (38.2 vs. 42.4%, p = 0.997).In contrast, progression-free survival (PFS; median 13.0 vs. 5.3 months, p = 0.031) and overall survival (OS; median 38.1 vs. 18.2 months, p = 0.025) were significantly longer in the recurrent group.In addition, recurrent disease after curative intent treatment, smoking history (ex-smoker) and performance status (0-1) were independent favorable prognostic factors in the multivariate analysis of PFS, and recurrent disease after definitive treatment, sex (female) and performance status (0-1) were independent favorable prognostic factors in the multivariate analysis of OS.These results suggest that recurrent disease after curative intent treatment may be considered a favorable prognostic factor for PD-L1-positive NSCLC patients treated with pembrolizumab as first line treatment.

•Extra-thoracic metastases from non-small cell lung cancer are seen frequently in order of bone, brain, and liver.•Cases with liver metastases have the worse prognosis compared to bone and brain metastases.•Treatment including bevacizumab might ameliorate worse prognosis of patients with distal metastases.

Background: The optimal regimen for concurrent chemoradiotherapy (CCRT) of locally advanced non-squamous non-small cell lung cancer (NSCLC) was not definitive. We conducted randomized phase II study, NJLCG0601, and chemoradiotherapy with uracil/tegafur (UFT) and cisplatin achieved promising efficacy without severe toxicities. Here, we evaluated between this regimen and pemetrexed plus cisplatin in chemoradiotherapy for stage III non-squamous NSCLC. Methods: Patients with inoperable stage III non-squamous NSCLC were randomly assigned in a 1:1 ratio to UFT 400 mg/m(2) on days 1-14 and 29-42, and cisplatin 80 mg/m(2) on days 8 and 36 (UP), or cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on days 1, 22, and 43 (PP). Involved-field radiotherapy (IFRT) underwent from day 1 to a total dose of 66 Gy in 33 fractions. Consolidation chemotherapy after CCRT was prohibited for this study. The primary endpoint was defined as 2-year overall survival (OS). This trial was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000003948). Results: From November 2010 to June 2017, 86 patients were entered from 11 institutions. Median followup was 54 months. Of the 85 eligible patients, the 2-year OS rate was 78.6% (95% CI, 62.8-88.3%) in UP and 85.5% (95% CI, 70.5-93.2%) in PP. Median PFS and OS was 12.3 and 64.2 months in UP, 26.2 months and not reached in PP, respectively. Grade 3/4 febrile neutropenia was more frequent in the UP group (14.0% vs. 2.0%). Conclusions: Both UP and PP with IFRT achieved the expected 2-year OS. PP engendered more favorable OS and PFS compared to UP in terms.

Introduction: Dyspnea is the cardinal symptom of COPD. Localization of dyspnea sensation in the brain has been studied by a small number of investigators. However little is known about transmission and activation of dyspnea sensation in CNS. Objectives: We analyzed pathway and localization of dyspnea sensation in the brain of normal subjects and COPD patients using functional magnetic resonance imaging (fMRI). Methods: Six normal subjects (M/F; 5/1, 53.7±5.9 yr: mean ± SEM) and 4 COPD patients (M/F; 4/0, 68.5±1.7 yr) were recruited. After informed consent, these subjects were requested to breathe through resistive loads ranging from 5 to 50 cm H2O/L/sec adjusted by the Borg CR10 Scale. The subjects received 1minute of repetitive resistive-loaded breathing three times with 1minute interval. During these process, brain activity was analyzed by 3 Tesla scanner (Signa Excite HD; GE Healthcare). Results: Activation of bilateral sensory cortices was recorded among 6 normal subjects and 4 COPD patients. In addition, VPM in bilateral thalami was also activated in all subjects when subjects breathed with the resistive load. There was no difference of the localization of activated portions during resistive-loaded breathing between in normal subjects and in COPD patients. Values of the resistive load to induce thalamic and cortical activation were significantly lower in COPD patients than those in normal subjects. Conclusion: Activation of thalamus and sensory cortex was dependent on the resistive load among normal subjects and COPD patients. The resistive loads on COPD patients to induce the thalamic activation were significantly lower than those on the normal subjects.

Background: Nuclear factor of activated T cells (NFAT) is required for the differentiation of Th2 responses, so we examined its role in mouse experimental asthma and tested the hypothesis that an NFAT blockade with a decoy against NFAT can prevent asthma progression. Objective: To determine the effects of the NFAT decoy oligodeoxynucleotides (ODNs) on the development of airway inflammation, we designed a novel ribbon-type ODN containing two binding sites for NFAT in a single decoy molecule without an open end, which is more stable than a conventional decoy, and largely preserved its structural integrity in the presence of nucleases. Methods: Ribbon-type NFAT decoy ODNs were transfected into ovalbumin (OVA)-sensitized CD3+ T cells in vitro. OVA-immunized mice received these cells by intraperitoneal injection. Airway hyperreactivity (AHR) was measured and the transfected CD3+ T cells’ responses to the airways were characterized. Results: Development of AHR after OVA challenge was effectively abolished after adoptive transfer of ribbon-type NFAT decoy ODN transfected CD3+ T cells. Transfer of ribbon-type decoy significantly reduced the number of inflammatory cells and the concentrations of IL-4, IL-5 and IL-13, but not IFN-γ, in the bronchoalveolar lavage of the recipient mice. Conclusion: These results suggest the inhibitory effect of ribbon-type decoy ODNs against NFAT on the induction of bronchial asthma. Adoptively transferred CD3+ T cells, which are transfected with NFAT decoy, may be an effective strategy for the treatment of asthma.