Transforming tumoroids derived from ALK-positive pulmonary adenocarcinoma to squamous cell carcinoma in vivo.

Approximately 3-5% of non-small cell lung cancers (NSCLC) harbor ALK fusion genes and may be responsive to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors. There are only a few reports on cell lines with EML4-ALK variant 3 (v3) and tumoroids that can be subject to long-term culture (> 3 months). In this study, we established tumoroids (PDT-LUAD#119) from a patient with lung cancer harboring EML4-ALK that could be cultured for 12 months. Whole-exome sequencing and RNA sequencing analyses revealed TP53 mutations and an EML4-ALK v3 mutation. PDT-LUAD#119 lung tumoroids were sensitive to the ALK tyrosine kinase inhibitors (ALK TKIs) crizotinib, alectinib, entrectinib, and lorlatinib, similar to NCI-H3122 cells harboring EML4-ALK variant 1 (v1). Unexpectedly, clear squamous cell carcinoma and solid adenocarcinoma were observed in xenografts from PDT-LUAD#119 lung tumoroids, indicating adenosquamous carcinoma. Immunostaining revealed that the squamous cell carcinoma was ALK positive, suggesting a squamous transformation of the adenocarcinoma. Besides providing a novel cancer model to support basic research on ALK-positive lung cancer, PDT-LUAD#119 lung tumoroids will help elucidate the pathogenesis of adenosquamous carcinoma.

Establishment and characterization of novel high mucus-producing lung tumoroids derived from a patient with pulmonary solid adenocarcinoma.

Among mucus-producing lung cancers, invasive mucinous adenocarcinoma of the lung is a rare and unique subtype of pulmonary adenocarcinoma. Notably, mucus production may also be observed in the five subtypes of adenocarcinoma grouped under the higher-level diagnosis of Invasive Non-mucinous Adenocarcinomas (NMA). Overlapping pathologic features in mucus-producing tumors can cause diagnostic confusion with significant clinical consequences. In this study, we established lung tumoroids, PDT-LUAD#99, from a patient with NMA and mucus production. The tumoroids were derived from the malignant pleural effusion of a patient with lung cancer and have been successfully developed for long-term culture (> 11 months). Karyotyping by fluorescence in situ hybridization using an alpha-satellite probe showed that tumoroids harbored aneuploid karyotypes. Subcutaneous inoculation of PDT-LUAD#99 lung tumoroids into immunodeficient mice resulted in tumor formation, suggesting that the tumoroids were derived from cancer. Xenografts from PDT-LUAD#99 lung tumoroids reproduced the solid adenocarcinoma with mucin production that was observed in the patient's metastatic lymph nodes. Immunoblot analysis showed MUC5AC secretion into the culture supernatant of PDT-LUAD#99 lung tumoroids, which in contradistinction was barely detected in the culture supernatants of NCI-A549 and NCI-H2122 pulmonary adenocarcinoma cells known for their mucin-producing abilities. Here, we established a novel high-mucus-producing lung tumoroids from a solid adenocarcinoma. This preclinical model may be useful for elucidating the pathogenesis of mucus-producing lung cancer.

Endobronchial Ultrasonography With Guide Sheath for the Diagnosis of Peripheral Pulmonary Lesions in Japan: A Literature Review.

We evaluated the usefulness of endobronchial ultrasonography with guide sheath (EBUS-GS) for the diagnosis of peripheral pulmonary lesions (PPLs) in Japan. We searched the PubMed/Medline database using the keywords "EBUS guide sheath" for Japanese studies on EBUS-GS published between January 2004 and August 2023. We included 32 original articles that evaluated the diagnostic yield of EBUS-GS for PPLs. Case reports and conference abstracts were excluded due to limited information available for quality assessment. The diagnostic yield of EBUS-GS was 73.6% for 2996 malignant lesions, 65.4% for 752 ground-glass nodules, 59.4% for 414 benign lesions, 61.3% for 1114 lesions of size ≤2 cm, and 75.6% for 1246 lesions of size >2 cm; it was 69.4% for lesions located in the upper lobe (n=793), 71.9% for the middle lobe/lingula (n=121), and 62.5% for the lower lobe (n=334). None of the patients experienced severe complications. In this review, EBUS-GS is effective for the diagnosis of malignant and benign PPLs. A multimodality approach is needed to further enhance its diagnostic performance.

Patient-derived tumoroid models of pulmonary large-cell neuroendocrine carcinoma: a promising tool for personalized medicine and developing novel therapeutic strategies.

Pulmonary large-cell neuroendocrine carcinoma (LCNEC), a disease with poor prognosis, is classified as pulmonary high-grade neuroendocrine carcinoma, along with small-cell lung cancer. However, given its infrequent occurrence, only a limited number of preclinical models have been established. Here, we established three LCNEC tumoroids for long-term culture. Whole-exome sequencing revealed that these tumoroids inherited genetic mutations from their parental tumors; two were classified as small-cell carcinoma (S-LCNEC) and one as non-small cell carcinoma (N-LCNEC). Xenografts from these tumoroids in immunodeficient mice mimicked the pathology of the parent LCNEC, and one reproduced the mixed-tissue types of combined LCNEC with a component of adenocarcinoma. Drug sensitivity tests using these LCNEC tumoroids enabled the evaluation of therapeutic agent efficacy. Based on translational research, we found that a CDK4/6 inhibitor might be effective for N-LCNEC and that Aurora A kinase inhibitors might be suitable for S-LCNEC or LCNEC with MYC amplification. These results highlight the value of preclinical tumoroid models in understanding the pathogenesis of rare cancers and developing treatments. LCNEC showed a high success rate in tumoroid establishment, indicating its potential application in personalized medicine.

Pneumocystis jirovecii pneumonia mortality risk associated with preceding long-term steroid use for the underlying disease: A multicenter, retrospective cohort study.

OBJECTIVE: Long-term steroid use increases the risk of developing Pneumocystis pneumonia (PcP), but there are limited reports on the relation of long-term steroid and PcP mortality. METHODS: Retrospective multicenter study to identify risk factors for PcP mortality, including average steroid dose before the first visit for PcP in non-human immunodeficiency virus (HIV)-PcP patients. We generated receiver operating characteristic (ROC) curves for 90-day all-cause mortality and the mean daily steroid dose per unit body weight in the preceding 10 to 90 days in 10-day increments. Patients were dichotomized by 90-day mortality and propensity score-based stabilized inverse probability of treatment weighting (IPTW) adjusted covariates of age, sex, and underlying disease. Multivariate analysis with logistic regression assessed whether long-term corticosteroid use affected outcome. RESULTS: Of 133 patients with non-HIV-PcP, 37 died within 90 days of initial diagnosis. The area under the ROC curve for 1-40 days was highest, and the optimal cutoff point of median adjunctive corticosteroid dosage was 0.34 mg/kg/day. Past steroid dose, underlying interstitial lung disease and emphysema, lower serum albumin and lower lymphocyte count, higher lactate dehydrogenase, use of therapeutic pentamidine and therapeutic high-dose steroids were all significantly associated with mortality. Underlying autoimmune disease, past immunosuppressant use, and a longer time from onset to start of treatment, were associated lower mortality. Logistic regression analysis after adjusting for age, sex, and underlying disease with IPTW revealed that steroid dose 1-40 days before the first visit for PcP (per 0.1 mg/kg/day increment, odds ratio 1.36 [95% confidence interval = 1.16-1.66], P<0.001), low lymphocyte counts, and high lactate dehydrogenase revel were independent mortality risk factor, while respiratory failure, early steroid, and sulfamethoxazole/trimethoprim for PcP treatment did not. CONCLUSION: A steroid dose before PcP onset was strongly associated with 90-day mortality in non-HIV-PcP patients, emphasizing the importance of appropriate prophylaxis especially in this population.

Clinical characteristics of patients treated with immune checkpoint inhibitors in EGFR-mutant non-small cell lung cancer: CS-Lung-003 prospective observational registry study.

PURPOSE: Immune checkpoint inhibitors (ICIs) are ineffective against epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). This study aimed to investigate the clinical characteristics of patients who were treated or not treated with ICIs, and of those who benefit from immunotherapy in EGFR-mutant NSCLC. METHODS: We analyzed patients with unresectable stage III/IV or recurrent NSCLC harboring EGFR mutations using a prospective umbrella-type lung cancer registry (CS-Lung-003). RESULTS: A total of 303 patients who met the eligibility criteria were analyzed. The median age was 69 years; 116 patients were male, 289 had adenocarcinoma, 273 had major mutations, and 67 were treated with ICIs. The duration of EGFR-TKI treatment was longer in the Non-ICI group than in the ICI group (17.1 vs. 12.7 months, p < 0.001). Patients who received ICIs for more than 6 months were categorized into the durable clinical benefit (DCB) group (24 patients), and those who received ICIs for less than 6 months into the Non-DCB group (43 patients). The overall survival in the DCB group exhibited longer than the Non-DCB group (69.3 vs. 47.1 months), and an equivalent compared to that in the Non-ICI group (69.3 vs. 68.9 months). Multivariate analysis for time to next treatment (TTNT) of ICIs showed that a poor PS was associated with a shorter TTNT [hazard ratio (HR) 3.309; p < 0.001]. Patients who were treated with ICIs and chemotherapy combination were associated with a longer TTNT (HR 0.389; p = 0.003). In addition, minor EGFR mutation was associated with a long TTNT (HR 0.450; p = 0.046). CONCLUSION: ICIs were administered to only 22% of patients with EGFR-mutated lung cancer, and they had shorter TTNT of EGFR-TKI compared to other patients. ICI treatment should be avoided in EGFR mutated lung cancer with poor PS but can be considered for lung cancer with EGFR minor mutations. Pathological biomarker to predict long-term responders to ICI are needed.

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.

Prospective exosome-focused translational research for afatinib (EXTRA) study of patients with nonsmall cell lung cancer harboring EGFR mutation: an observational clinical study.

Background: The exosome-focused translational research for afatinib (EXTRA) study is the first trial to identify novel predictive biomarkers for longer treatment efficacy of afatinib in patients with epidermal growth factor receptor (EGFR) mutation-positive nonsmall cell lung cancer (NSCLC) via a comprehensive association study using genomic, proteomic, epigenomic, and metabolomic analyses. Objectives: We report details of the clinical portion prior to omics analyses. Design: A prospective, single-arm, observational study was conducted using afatinib 40 mg/day as an initial dose in untreated patients with EGFR mutation-positive NSCLC. Dose reduction to 20 mg every other day was allowed. Methods: Progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated. Results: A total of 103 patients (median age 70 years, range 42-88 years) were enrolled from 21 institutions in Japan between February 2017 and March 2018. After a median follow-up of 35.0 months, 21% remained on afatinib treatment, whereas 9% had discontinued treatment because of AEs. The median PFS was 18.4 months, with a 3-year PFS rate of 23.3%. The median afatinib treatment duration in patients with final doses of 40 (n = 27), 30 (n = 23), and 20 mg/day (n = 35), and 20 mg every other day (n = 18) were 13.4, 15.4, 18.8, and 18.3 months, respectively. The median OS was not reached, with a 3-year OS rate of 58.5%. The median OS in patients who did (n = 25) and did not (n = 78) receive osimertinib during the entire course of treatment were 42.4 months and not reached, respectively (p = 0.654). Conclusions: As the largest prospective study in Japan, this study confirmed favorable OS following first-line afatinib in patients with EGFR mutation-positive NSCLC in a real-world setting. Further analysis of the EXTRA study is expected to identify novel predictive biomarkers for afatinib. Trial registration: UMIN-CTR identifier (UMIN000024935, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_his_list.cgi?recptno=R000028688.

[Three Cases of Appendiceal Goblet Cell Adenocarcinoma in Our Institution].

Appendiceal goblet cell adenocarcinoma(AGCA)is a newly designated pathological term adopted in the 5th edition of the WHO classification. It is synonymous with goblet cell carcinoid, which was previously categorized as a part of appendiceal carcinoid. However, since 2018, it has been classified as a subtype of adenocarcinoma. We have experienced 3 cases of this relatively rare tumor, of which 2 were initially diagnosed with acute appendicitis and were diagnosed with AGCA by pathological examination after an emergency appendectomy. Each of them underwent additional ileocolic resection with lymph node dissection as the second surgery. In the 3rd case, an appendiceal tumor was detected during preoperative examinations for an ovarian tumor. Staging laparoscopy revealed comorbid peritoneal dissemination, and only the appendix and right ovary were removed in the consecutive surgery. The ovarian tumor was pathologically diagnosed as a metastasis of AGCA. In this case, the introduction of oxaliplatin-based systemic chemotherapy after surgery achieved a complete response after more than 2 years. Although no recurrence has been observed in all 3 cases to date, AGCA is considered highly malignant compared to conventional appendiceal carcinoids. Therefore, it is crucial to practice multidisciplinary treatments, including sufficient radical surgery based on a precise diagnosis of AGCA, as is performed for advanced colorectal cancer.

The complexity of EGFR exon 19 deletion and L858R mutant cells as assessed by proteomics, transcriptomics, and metabolomics.

Most lung adenocarcinoma-associated EGFR tyrosine kinase mutations are either an exon 19 deletion (19Del) or L858R point mutation in exon 21. Although patients whose tumors contain either of these mutations exhibit increased sensitivity to tyrosine kinase inhibitors, progression-free and overall survival appear to be longer in patients with 19Del than in those with L858R. In mutant-transfected Ba/F3 cells, 19Del and L858R were compared by multi-omics analyses including proteomics, transcriptomics, and metabolomics. Proteome analysis identified increased plastin-2, TKT, PDIA5, and ENO1 expression in L858R cells, and increased EEF1G expression in 19Del cells. RNA sequencing showed significant differences between 19Del and L858R cells in 112 genes. Metabolome analysis showed that amino acids, adenylate, guanylate, NADPH, lactic acid, pyruvic acid glucose 6-phosphate, and ribose 5-phosphate were significantly different between the two mutant cells. Because GSH was increased with L858R, we combined osimertinib with the GSH inhibitor buthionine sulfoximine in L858R cells and observed synergistic effects. The complexity of EGFR 19Del and L858R mutant cells was demonstrated by proteomics, transcriptomics, and metabolomics analyses. Therapeutic strategies for lung cancer with different EGFR mutations could be considered because of their different metabolic phenotypes.

Effect of a Cyclooxygenase-2 Inhibitor in Combination with (-)-Epigallocatechin Gallate or Polyphenon E on Cisplatin-Induced Lung Tumorigenesis in A/J Mice.

We investigated the effects of celecoxib combined with (-)-epigallocatechin-3-gallate (EGCG) or polyphenon E in a cisplatin-induced lung tumorigenesis model. Four-week-old female A/J mice were divided into seven groups: (i) Control, (ii) 150 mg/kg celecoxib (150Cel), (iii) 1,500 mg/kg celecoxib (1500Cel), (iv) EGCG+150 mg/kg celecoxib (EGCG+150Cel), (v) EGCG+1,500 mg/kg celecoxib (EGCG+1500Cel), (vi) polyphenon E+150 mg/kg celecoxib (PolyE+150Cel), and (vii) polyphenon E+1,500 mg/kg celecoxib (PolyE+1500Cel). All mice were administered cisplatin (1.62 mg/kg of body weight, i.p.) 1×/week for 10 weeks and sacrificed at week 30; the numbers of tumors on the lung surface were then determined. The tumor incidence and multiplicity (no. of tumors/mouse, mean±SD) were respectively 95% and 2.15±1.50 in Control, 95% and 2.10±1.29 in 150Cel, 86% and 1.67±1.20 in 1500Cel, 71% and 1.38±1.24 in EGCG+150Cel, 67% and 1.29±1.38 in EGCG+1500Cel, 80% and 1.95±1.36 in PolyE+150Cel, and 65% and 1.05±0.10 in PolyE+1500Cel. The combination of high-dose celecoxib with EGCG or polyphenon E significantly reduced multiplicity in cisplatin-induced lung tumors.

Safe sedation during diagnostic and therapeutic flexible bronchoscopy in Japan: A review of the literature.

We explored whether a combination of an opioid (fentanyl or pethidine) and midazolam could safely sedate Japanese patients undergoing bronchoscopic procedures. We searched the PubMed Medline and Igaku Chuo Zasshi (ICHUSHI) databases from 1980 to 2022 for papers on sedatives used during bronchoscopy, especially opioids (fentanyl and pethidine) and midazolam. The keywords were "bronchoscopy" and "sedation" ("kikanshikyo" and "chinsei", respectively, in Japanese). The results showed that midazolam was the preferred sedation agent during flexible bronchoscopy; with midazolam sedation is rapid, and the drug is associated with anterograde amnesia and decreased discomfort. A combination of an opioid (fentanyl or pethidine) and midazolam improved the patient tolerance and willingness to undergo a repeat procedure and also improved the working conditions for the physician. The British Thoracic Society guideline of 2013 suggested that a combination of an opioid (fentanyl or alfentanil) and midazolam should be considered to improve bronchoscopic tolerance. The American College of Chest Physicians Consensus Statement of 2011 suggested that fentanyl should be preferred; the onset of action and peak effect are rapid, and the effects are of relatively short duration. Emphasis has been placed on safety aspects, such as patient monitoring, the precautions that should be taken in patients with certain conditions, prevention and management of complications, adequate staffing, and optimal sedation and disinfection. In conclusion a combined opioid (fentanyl or pethidine) and midazolam sedation is optimal for diagnostic and therapeutic flexible bronchoscopy in Japanese patients.

Use of a highly sensitive lung cancer compact panel to detect KRAS G12D in the wash fluid from a lung tumor: A case report.

Here, we report a case of a pulmonary invasive mucinous adenocarcinoma harboring KRAS G12D, diagnosed from tumor samples containing a very small amount of tumor cells using next-generation sequencing (NGS) and the recently developed Lung Cancer Compact Panel. A 79-year-old woman without any respiratory symptoms underwent chest computed tomography, which revealed a tumor in the left lower lobe. During endobronchial ultrasound (EBUS)-guided transbronchial biopsy (TBB) using a guide sheath (GS), a sufficient specimen for pathological diagnosis could not be obtained because the patient had a severe cough and pulmonary bullae located adjacent to the tumor. In the absence of EBUS transbronchial biopsy findings using a guide sheath, brush cytology was used to categorize the tumor as class II (Papanicolaou classification). However, the wash fluid from the cytological examination contained enough cells to obtain sufficient nucleic acid for use in sequencing analysis. The latter revealed KRAS G12D expression. Although the patient underwent surgery without pathological evidence, the evaluation of the surgical specimen confirmed a diagnosis of pulmonary invasive mucinous adenocarcinoma. Use of the Lung Cancer Compact Panel enabled the detection of KRAS G12D in the wash fluid of a brush cytology sample and thus a diagnosis of pulmonary invasive mucinous adenocarcinoma.

First and repeat rebiopsy for detecting EGFR T790M mutation in non-small-cell lung cancer: CS-Lung-003 prospective observational registry study.

PURPOSE: Osimertinib is still essential for the treatment of epidermal growth factor receptor (EGFR)-T790M-positive non-small-cell lung cancer (NSCLC) even in a relapsed setting, which suggests the importance of rebiopsy. The clinical value of repeat rebiopsy in patients with NSCLC who are T790M-negative on a first rebiopsy remains unclear. In this study, we examined the status of the first rebiopsy and evaluated the frequency of repeat rebiopsy of T790M-negative tumors detected by the first rebiopsy. METHODS: We reviewed 144 patients with NSCLC with major EGFR mutations, but not T790M, who received first- or second-generation EGFR tyrosine kinase inhibitors (TKIs), registered in the prospective, umbrella-type lung cancer patient registry (CS-Lung-003). RESULTS: Overall, 63 patients (44%) underwent the first rebiopsy. In the first rebiopsy, 51 (81%) and 12 (19%) of 63 underwent histological/cytological rebiopsy and liquid biopsy with the blood sampling, respectively. In the repeat rebiopsy, 23 (85%) and 4 (15%) of 27 underwent histological/cytological rebiopsy and liquid biopsy, respectively. The most frequently rebiopsied site was a pulmonary lesion (n = 24, 38.7%). Overall, 29 (46.0%) of 63 patients harbored the T790M mutation. Interestingly, a high detection rate of cancer cells did not necessarily indicate a high detection rate of the T790M mutation (p < 0.01). Among 34 patients with T790M-negative tumors confirmed on the first rebiopsy, 20 (58.8%) underwent repeat rebiopsies following interval therapy, revealing that seven (36.8%) had T790M-positive tumors. Osimertinib yielded median progression-free survival of 11.8 and 16.2 months in patients with the 790M mutation detected by the first rebiopsy and repeat rebiopsy, respectively. CONCLUSION: In our prospective cohort, the T790M mutation was detected in 46% of patients who underwent the first rebiopsy. Repeat rebiopsy may increase the ability to detect the T790M mutation positivity rate.

Herpes zoster in lung cancer patients treated with PD-1/PD-L1 inhibitors.

Background: Herpes zoster (HZ) occurs mostly in elderly and immunocompromised individuals. Immune reconstitution may be associated with the pathogenesis of HZ. As immune checkpoint inhibitor (ICI) treatment amplifies the immune response, use of ICI may increase the incidence of HZ. There have been few studies of HZ in lung cancer patients treated with ICI. This study was performed to investigate the frequency of HZ in lung cancer patients who received ICI or cytotoxic chemotherapeutic agents. Methods: We searched the electronic medical records for lung cancer patients receiving anticancer drug therapy at our hospital, who developed HZ between April 2011 and June 2020. Results: The review identified 80 patients with a history of ICI treatment (ICI group) and 356 who had been treated with cytotoxic chemotherapeutic agents alone (non-ICI group). Among the 20 patients who developed HZ, 4 (5.0%) belonged to the ICI group and 16 (4.5%) to the non-ICI group (P=0.782). After exclusion of patients aged 65 years and older, to avoid effects of advanced age on the results, the ICI and non-ICI groups consisted of 24 and 81 patients, respectively. In total, 3 of the 24 patients (12.5%) in the ICI group and 1 of the 81 (1.2%) patients in the non-ICI group developed HZ (P=0.0365). Conclusions: There was no significant difference in the rate of HZ between lung cancer patients treated with ICI and those treated with cytotoxic chemotherapy alone. However, patients younger than 65 years treated with ICI might be at increased risk of HZ. Because this is a retrospective small study, further prospective observational studies are needed.

Oligoprogression in Non-Small Cell Lung Cancer.

We reviewed the literature on oligoprogressive disease (OPD) and local ablative therapy (LAT) in patients with advanced non-small cell lung cancer (NSCLC). The frequency of OPD varies depending on its definition and is estimated to be between 15-47%. The implications of the strategy of continuing the same anticancer agents beyond progressive disease after LAT with radiation therapy for OPD are based on the concept of progression in which only a small number of lesions, not more than about four, proliferate after chemotherapy. In the case of OPD harboring driver mutations such as EGFR, prospective studies are underway. However, evidence from retrospective studies support this strategy, which is currently recommended in some guidelines. The prognosis in OPD cases during the administration of an immune checkpoint inhibitor (ICI) is relatively promising. Additionally, LAT with radiation for OPD after the first-line treatment of ICI with cytotoxic chemotherapy may overcome the resistance to the combination drug therapy due to an abscopal effect. To achieve long-term survival in advanced-stage NSCLC, it is important to verify the optimal method and timing of the therapy through prospective comparative studies as well as patient selection based on patient characteristics and biomarker levels.

Targeting ROR1 in combination with osimertinib in EGFR mutant lung cancer cells.

Lung cancer that exhibits epidermal growth factor receptor (EGFR) gene mutation is sensitive to EGFR-tyrosine kinase inhibitors (TKIs), such as osimertinib. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) may be involved in overcoming EGFR-TKI resistance. Growth inhibition, colony formation, apoptosis, and mRNA/protein levels in four osimertinib-sensitive and resistant cell lines transfected with small interfering RNA (siRNA) targeting ROR1 (siROR1) were evaluated. Cell growth and colony formation were suppressed and apoptosis was increased in all cell lines treated with siROR1. Although EGFR, AKT, and ERK phosphorylation were not suppressed in all cell lines, TGF-ß2, AXL, CDH2, PARP1, PEG10, and TYMS mRNA expression levels were reduced. The combination of osimertinib with siROR1 was effective for the four cell lines, particularly in the two osimertinib-sensitive lines. In conclusion, targeting ROR1 in combination with osimertinib in EGFR mutant lung cancer may be a novel therapeutic option.

End-tidal capnographic monitoring during flexible bronchoscopy under fentanyl and midazolam sedation.

BACKGROUND: Bronchoscopic examination including endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is well established for lung cancer diagnosis and staging. Sedation using fentanyl and midazolam is recommended during bronchoscopic examinations. Meanwhile, inadvertent oversedation is a clinical problem. The objective of this research was to estimate the frequency of apnea episodes by end-tidal capnography under fentanyl and midazolam sedation during bronchoscopy. METHODS: Eighty-five patients were enrolled retrospectively between August 2017 and March 2018 at Okayama Medical Center. Apnea was defined as the cessation of airflow for more than 10 seconds. We reviewed medical records, including capnographic data, by cap-ONE YG-227T (NIHON KOHDEN, Tokyo, Japan) during flexible bronchoscopy under fentanyl and midazolam sedation. RESULTS: Patients received 49.4±20.6 µg of fentanyl [mean ± standard deviation (SD)] and 4.35±2.0 mg of midazolam (mean ± SD). The patients included 52 males and 33 females; the median age was 71 (range, 31-88) years were enrolled. Apnea episodes were recorded (median duration 18 seconds) in 85 patients (100%). Prolonged apnea episodes with more than 30 seconds occurred in 56 patients (65.8%). Furthermore, the median time was 32 (range, 5-102) seconds whose delay between the onset of an apnea episode and decline in the SpO2 level of ≥4% from baseline. CONCLUSIONS: End-tidal capnography, cap-ONE YG-227T was effective for detecting the occurrence of apnea in patients undergoing a bronchoscopic examination under fentanyl and midazolam sedation. Monitoring might be useful for preventing inadvertent oversedation.