Physical activity in patients with non-small cell lung cancer after lung resection.

BACKGROUND: Lung resection is the standard of care for patients with clinical stage I/II non-small cell lung cancer. This surgery reduces both the duration and quality of patients' daily ambulatory activities 1 month after surgery. However, little is known about physical activity after lung resection in patients with lung cancer. To evaluate the recovery process of physical activity with pulmonary rehabilitation in patients after lung resection and examine whether physical activity is affected by age. METHODS: In this prospective, observational study, we measured and analysed participants' postoperative physical activity using a uniaxial accelerometer daily from postoperative day 1 to 30. FINDINGS: We analysed 99 patients who underwent thoracic surgery. The number of walking steps significantly increased until day 4 and then reached a plateau thereafter. The duration of exercise at <3 metabolic equivalents significantly increased until day 3, and no significant difference was observed thereafter. Exercise at >3 metabolic equivalents significantly increased until day 4 and reached a plateau thereafter. A significant correlation was observed between age and number of steps after day 4. Compared with video-assisted thoracoscopic surgery, thoracotomy significantly decreased the number of steps from day 3 to 4. INTERPRETATION: We found that the level of physical activity varied by index in patients with non-small cell lung cancer who underwent lung resection. Age and surgical procedure affect different periods with the increase in post-operative walking steps.

NOTCH1 and CREBBP co-mutations negatively affect the benefit of adjuvant therapy in completely resected EGFR-mutated NSCLC: translational research of phase III IMPACT study.

The phase III IMPACT study (UMIN000044738) compared adjuvant gefitinib with cisplatin plus vinorelbine (cis/vin) in completely resected epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Although the primary endpoint of disease-free survival (DFS) was not met, we searched for molecular predictors of adjuvant gefitinib efficacy. Of 234 patients enrolled in the IMPACT study, 202 patients were analyzed for 409 cancer-related gene mutations and tumor mutation burden using resected lung cancer specimens. Frequent somatic mutations included tumor protein p53 (TP53; 58.4%), CUB and Sushi multiple domains 3 (CSMD3; 11.8%), and NOTCH1 (9.9%). Multivariate analysis showed that NOTCH1 co-mutation was a significant poor prognostic factor for overall survival (OS) in the gefitinib group and cAMP response element binding protein (CREBBP) co-mutation for DFS and OS in the cis/vin group. In patients with NOTCH1 co-mutations, gefitinib group had a shorter OS than cis/vin group (Hazard ratio 5.49, 95% CI 1.07-28.00), with a significant interaction (P for interaction = 0.039). In patients with CREBBP co-mutations, the gefitinib group had a longer DFS than the cis/vin group, with a significant interaction (P for interaction = 0.058). In completely resected EGFR-mutated NSCLC, NOTCH1 and CREBBP mutations might predict poor outcome in patients treated with gefitinib and cis/vin, respectively.

Impact of ground glass opacity in a three-dimensional analysis for pathological findings and prognosis in stage IA pure solid lung cancer.

Background: We investigated whether a three-dimensional (3D) analysis could correct the discrepancy between conventional computed tomography findings and pathological findings and contribute to prognostic stratification in early pure solid lung cancer. Methods: A total of 370 patients with two-dimensional (2D) pure solid, clinical stage IA non-small cell lung cancer (NSCLC) who underwent complete resection at our hospital between January 2010 and March 2021 were included in the present study. We classified the patients into the 3D solid group and the 3D ground glass opacity (GGO) group according to the consolidation volume/tumor volume ratio (C/T volume ratio) measured using a Synapse Vincent 3D analysis workstation, and compared the pathological findings and prognosis between the two groups. Results: There were 142 (38.4%) patients in the 3D GGO group. Lepidic lesions were significantly more frequent in the 3D GGO group (27.6% vs. 59.2%, P<0.001). Lymphatic invasion, vascular invasion and lymph node metastasis were significantly more frequent in the 3D solid group (52.2% vs. 27.5%, P<0.001; 67.5% vs. 43.0%, P<0.001; 22.3% vs. 11.2%, P=0.04). A Cox proportional hazards multivariate analysis for overall survival (OS) and recurrence-free survival (RFS) showed that 3D solid was an independent poor prognostic factor [hazard ratio (HR): 1.981, P=0.02; HR: 1.815, P=0.02]. Kaplan-Meier curves for 5-year OS (74.1% vs. 87.8%, P<0.001) and 5-year RFS (65.6% vs. 84.9%, P<0.001) showed significant differences between the two groups. Conclusions: The C/T volume ratio determined by a 3D analysis detects GGO and reflects the pathological findings, and further prognostic stratification is possible in early 2D pure solid lung cancer.

Multiple solitary fibrous tumors of the pleura with multicentric and unilateral involvement: a case report.

BACKGROUND: Solitary fibrous tumor of the pleura (SFTP) is a mesenchymal tumor. Patients with SFTP generally have only one lesion. We herein report an extremely rare case of multiple SFTPs that were multicentric and unilateral. CASE PRESENTATION: The patient was a 21-year-old asymptomatic young man who was referred to our hospital due to abnormal shadows on a chest X-ray. Computed tomography showed 6 tumors of heterogeneous sizes in the left thoracic cavity. The tumors were suspected to be multiple benign or low-grade malignant thoracic tumors, and tumor resection was performed. The tumors had almost the same appearance, with uniform fibroblastic spindle cell proliferation, and arose from the pleura in microscopy. Immunohistochemical staining revealed that the tumor cells were positive for CD34, CD99, Bcl-2, and STAT6. Based on these findings, the tumors were diagnosed as multiple SFTPs with multicentricity. At 1 year and 6 months after the first surgery, 2 new lesions were found above the diaphragm, and these were resected. These tumors were arose from the pleura with a fibrous capsule structure. Their pathological findings were identical to the initial tumor without evidence of malignant transformation. CONCLUSION: We experienced an extremely rare case of multiple SFTPs with multicentric and unilateral lesions.

Preoperative detection of pleural adhesions using dynamic chest radiography: prospective analysis.

Background: To plan a surgical approach and predict the operative time or bleeding volume, it is important to determine the presence of pleural adhesions before surgery. Dynamic chest radiography (DCR) is a new modality that can dynamically capture X-rays, and we assessed the utility of DCR for detecting pleural adhesions preoperatively. Methods: The subjects of this study were those who underwent DCR before surgery from January 2020 to May 2022. The preoperative evaluation was performed by three imaging analysis modes, and pleural adhesion was defined as the that spreading to more than 20% of the thoracic cavity and/or taking more than 5 minutes to dissect. Results: Of the 120 total patients, DCR was performed properly for 119 (99.2%). Accurate preoperative evaluations of pleural adhesions were confirmed in 101 patients (84.9%), with a sensitivity of 64.5%, specificity of 91.0%, positive predictive value of 74.1%, and negative predictive value of 88.0%. Conclusions: DCR was very easy to perform in all preoperative patients with all manner of thoracic disease. We demonstrated the utility of DCR, showing its high specificity and negative predictive value. DCR has the potential to become a common preoperative examination for detecting pleural adhesions with further improvements in software programs.

Bronchiolar adenoma/ciliated muconodular papillary tumor mixed with adenocarcinoma in situ in the same tumor.

Bronchiolar adenoma (BA)/ciliated muconodular papillary tumor (CMPT) is defined as a benign tumor composed of epithelial and basal cells. Recently, some cases with driver mutations or malignant transformation have been observed. Thus, whether BA/CMPT is benign or malignant remains controversial. We herein report an extremely rare case of a 68-year-old woman with a CMPT accompanied by adenocarcinoma in situ (AIS). BA/CMPT existed inside the AIS. The BA/CMPT component did not show any driver mutations; however, the AIS component had an EGFR driver mutation in exon 19. The accumulation of cases and further studies are needed to discuss the malignant potential of BA/CMPT.

Pathologically noninvasive cancer predictors and surgical procedure for peripheral lung cancer.

BACKGROUND: In this retrospective study, based on recent studies reporting the superiority of sublobar resection to lobectomy for peripheral small size non-small cell lung cancer (NSCLC), we investigated the optimal pathological factors for predicting noninvasive cancer and the selection of operative procedure. METHODS: Patients with peripheral NSCLC of ≤2 cm who underwent surgery at our hospital between January 2010 and June 2020 were included in this study. We evaluated the relationship between pathologically noninvasive cancer and predictive factors according to the area under the curve (AUC) and accuracy, and the cutoff value was set to investigate indications for sublobar resection. RESULTS: The comparison of the AUCs revealed that the maximum standardized uptake value and consolidation to tumor (C/T) volume ratio were better predictors than the C/T ratio. Among the three factors, the C/T volume ratio showed the best accuracy. The patients were divided into two groups (low and high) using the cutoff value of the C/T volume ratio and compared according to the surgical procedure (lobectomy vs. segmentectomy). In the low-group, there was no significant difference in the prognosis. In the high-group, the 5-year recurrence-free survival rate of the patients who received lobectomy was 87.8%, while that of patients who received segmentectomy was 75.8% (p = 0.08). CONCLUSIONS: The C/T volume ratio was the best preoperative pathologically noninvasive predictive factor. Sublobar resection should be performed with caution in cases with significant solid components on three-dimensional images.

Real-World Data Analysis of Pembrolizumab Monotherapy for NSCLC Using Japanese Postmarketing All-Case Surveillance Data.

Introduction: Pembrolizumab is a programmed death-ligand 1 inhibitor that was initially indicated for monotherapy in patients with advanced lung cancer. The Japanese Lung Cancer Society conducted an observational study on pembrolizumab using confirmative data obtained through postmarketing all-case surveillance (PMACS), which was performed by a pharmaceutical company under the Japanese law in 2017. Methods: This multicenter observational study was conducted by the Japanese Lung Cancer Society using PMACS data with the newly created central registration system regarding patients with NSCLC who received pembrolizumab monotherapy between February 1, 2017 and June 30, 2017; a new database was created by adding the clinical information regarding prognosis for 3 years after therapy to the existing data collected by PMACS. Results: A total of 300 patients from 43 facilities were enrolled in this study. The median overall survival and progression-free survival after pembrolizumab initiation were 558 and 188 days, respectively. Moreover, the 1- and 3-year survival rates were 58.9% and 33.7%, respectively. Results of multivariate analysis revealed performance status (p < 0.0001), histology (p = 0.0118), previous chemotherapy (p = 0.0007), programmed death-ligand 1 expression status (p = 0.0195), and previous steroid use (p = 0.0460) as significant factors that affected overall survival. The toxicity profile was similar to that previously reported. Conclusions: In this first attempt to use PMACS data, we successfully collected clinical information and found the real-world efficacy and safety of pembrolizumab.

[Tracheobronchial Foreign Body].

Foreign body aspiration is most common in infants of <3 years of age and the elderly. Peanuts and plant seeds account for approximately 70~80% of airway foreign bodies in children, while dental materials( e.g., dentures and crowns) are common in adults. Tracheobronchial foreign bodies are diagnosed by detailed history taking, careful auscultation, chest radiography, and computed tomography (CT). Chest radiography should be performed in frontal and lateral views. CT is useful for assessing the presence of a foreign body, the site of involvement, and secondary changes (e.g., pneumonia or atelectasis). In urgent cases with severe dyspnea, life-saving measures, including endotracheal intubation, administration of oxygen, and securing an intravenous line should be performed first, followed by immediate removal. Removal is often performed with a rigid bronchoscope in children, and a flexible bronchoscope under local anesthesia in adults. When removal by flexible bronchoscope is difficult, a rigid bronchoscope is used. Surgical removal is considered when bronchoscopic removal is difficult or associated with a high risk of complications( e.g., major bleeding or bronchial perforation). After removal, pneumonia is likely to occur, so antibiotic agents should be administered. For airway foreign bodies, appropriate and immediate treatment is required from the diagnosis to removal and post-removal management.

Treatment of secondary pneumothorax with interstitial lung disease: the surgical indications at the start of treatment is important.

Background: Secondary pneumothorax with interstitial lung disease (ILD) is often difficult to treat in comparison to primary pneumothorax. The purpose of this study was to analyze the actual management and outcome, and to find the most effective treatment. Methods: Among 180 patients with pneumothorax caused by ILD, who were managed between January 2000 and April 2021, 129 patients were included. Fifty-one patients with observation only were excluded. In the present study, a patient was considered to be cured if their chest tube could be removed. Results: The managements included chest tube drainage alone (n=41), pleurodesis (n=67), bronchoscopic treatment (n=14), and surgery (include overlapping cases) (n=25). The mean number of pleurodesis treatments was 2.4 (range, 1-9), and the most frequently used agent was blood-patch. All patients who received bronchoscopic treatment underwent bronchial occlusion with silicon spigots. The surgical procedures included bullectomy (n=20), lung cyst ligation (n=3), pleural covering with oxidized cellulose sheet (n=1), and spraying of fibrin glue alone (n=1). One hundred patients (77.5%) were curatively treated, 27 patients (20.9%) died, and 2 patients were transferred without chest tube removal. Among 25 patients who received surgery [including 6 patients with performance status (PS) ≥2], 24 patients (96.0%) were cured, and 1 patient died due to an acute exacerbation of ILD after surgery. The univariate analysis revealed that PS ≥2 and >3 pleurodesis treatments were significant non-curative factors, while steroid treatment before the development of pneumothorax was not. Conclusions: The outcomes of surgery for pneumothorax in patients with ILD were good, and it is desirable to consider the surgical indications.

Role of fluorodeoxyglucose-positron emission tomography in predicting the pathological response and prognosis after neoadjuvant chemoradiotherapy for locally advanced non-small-cell lung cancer.

OBJECTIVES: The present study compared the utility of fluorodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT) for predicting the pathological response and prognosis following neoadjuvant therapy for locally advanced non-small-cell lung cancer (NSCLC). METHODS: This retrospective analysis included 72 patients in whom adjacent structures showed involvement and/or cN2 NSCLC who received induction chemoradiotherapy (ICRT) and subsequent surgery at our hospital from 2008 to 2019. FDG-PET and CT were performed in all patients before and after ICRT using the same scanner with similar techniques. We calculated the reduction in the maximum standardized uptake value in FDG-PET (ΔSUVmax) and tumour size on CT (ΔCT-size) before and after ICRT and investigated the relationship between the pathological response and prognosis. RESULTS: The disease response was classified as a major pathological response in 43 patients, and a minor response in 29 patients. ΔSUVmax 60% and ΔCT-size 30% were identified as the optimal cut-off values for predicting a major pathological response. ΔSUVmax was superior to ΔCT-size in terms of sensitivity, specificity, positive predictive value and negative predictive value. Furthermore, ΔSUVmax was superior to ΔCT-size for predicting the prognosis. CONCLUSIONS: Based on the results of the present study, FDG-PET appeared to have greater utility than CT in predicting the pathological response following ICRT and the postoperative prognosis in patients with locally advanced NSCLC.

m6A demethylase ALKBH5 promotes tumor cell proliferation by destabilizing IGF2BPs target genes and worsens the prognosis of patients with non-small-cell lung cancer.

The modification of N6-methyladenosine (m6A) in RNA and its eraser ALKBH5, an m6A demethylase, play an important role across various steps of human carcinogenesis. However, the involvement of ALKBH5 in non-small-cell lung cancer (NSCLC) development remains to be completely elucidated. The current study revealed that the expression of ALKBH5 was increased in NSCLC and increased expression of ALKBH5 worsened the prognosis of patients with NSCLC. In vitro study revealed that ALKBH5 knockdown suppressed cell proliferation ability of PC9 and A549 cells and promoted G1 arrest and increased the number of apoptotic cells. Furthermore, ALKBH5 overexpression increased the cell proliferation ability of the immortalized cell lines. Microarray analysis and western blotting revealed that the expression of CDKN1A (p21) or TIMP3 was increased by ALKBH5 knockdown. These alterations were offset by a double knockdown of both ALKBH5 and one of the IGF2BPs. The decline of mRNAs was, at least partly, owing to the destabilization of these mRNAs by one of the IGF2BPs. In conclusions, the ALKBH5-IGF2BPs axis promotes cell proliferation and tumorigenicity, which in turn causes the unfavorable prognosis of NSCLC.

Surgical treatment for synchronous multiple primary lung cancer: Is it possible to achieve both curability and preservation of the pulmonary function?

BACKGROUND: With the advent of high-resolution chest imaging, the number of patients diagnosed with multiple primary lung cancers is increasing. For the treatment of multiple lung cancers, a surgical procedure that preserves pulmonary function while ensuring curability is required. METHODS: The study population included 85 patients with synchronous multiple primary lung cancer who received surgical resection between January 2010 and September 2020. Patients with synchronous lung cancer within the same lobe were excluded, and only patients with ≥2 involved lobes were included. The postoperative pulmonary function was examined at 3-6 months after the surgery. RESULTS: Sixty-seven patients had cancers within the ipsilateral lobe, and 18 patients had cancers in bilateral lobes. Seventy-six patients (89.4%) underwent combination surgery with limited resection (e.g., segmentectomy and wedge resection). The preoperative pulmonary functions (mean VC/%VC, mean FEV1 /%FEV1 , and mean %DLCO) were 3.06 L/100.2%, 2.23 L/96.1%, and 117.2%, respectively, and the postoperative pulmonary functions were 2.45 L/81.4%, 1.87 L/81.2%, and 102.6%. In each parameter, the predicted reductions of pulmonary function were almost the same as the predicted values. The 5-year survival rate was 85.0%. The 5-year survival rate according to the most advanced pathological stage was 94.9% for stage I disease, and 62.6% for stage ≥II, which was a significant difference (p < 0.001). CONCLUSIONS: Surgical treatment including limited resection, especially segmentectomy and wedge resection, for synchronous multiple primary lung cancer can preserve pulmonary function while ensuring curability.

[Reoperation for Secondary Cancer Following the Excision of Pulmonary Cancer].

There has been an increase in cases in which complete recovery is possible through surgery thanks to improvements in multimodal therapy along with increased early-stage pulmonary cancer in conjunction with the spread of pulmonary cancer computed tomography (CT) examinations and advancements in image diagnostic technologies. Moreover, post-operative follow-ups are now conducted for a relatively longer period of time, so there are now more opportunities to treat secondary cancer. It is difficult to determine if nodules that occur following pulmonary cancer surgery are cases of secondary cancer or cases of relapse. In the case of a solitary nodule, it cannot be assumed that there has been a complete recovery from cancer, so reoperation should be actively considered. In the event of reoperation, not only should the expected post-operative pulmonary function be considered, but whether the location is the same lung or the other lung, the blood flow distribution of the remaining lung, as well as other factors, should also be considered. Reoperation on the same lung is extremely difficult because it assumes a high degree of accretion in the cavum thoracis. Even if reduction surgery or lobectomy of the remaining lung is planned, separation is difficult, with potential unforeseen conditions such as hemorrhaging. Therefore, this assumes unavoidable total extirpation of the remaining lung. Regarding reoperation on the other lung, attention must be paid to management of the respiratory system during surgery. Further, blood circulation relies on the lung in which the reoperation is to be performed more than expected, with cases existing in which complications such as pulmonary edema may occur due to a rapid reduction of the pulmonary vascular bed as a result of a pulmonary resection. In particular, attention must be paid to respiratory failure and heart failure in the event of a lobectomy in both lungs. Prior to surgery, it is beneficial to evaluate the blood distribution with a pulmonary blood flow scintigram. As suggested above, reoperation on secondary cancer following pulmonary cancer excision requires a detailed treatment plan before the operation.

YTHDF1 and YTHDF2 are associated with better patient survival and an inflamed tumor-immune microenvironment in non-small-cell lung cancer.

The human YTH domain family (YTHDF) proteins are RNA-binding proteins that recognize N6-methyladenosine (m6A), facilitating various biological processes via m6A RNA modification. How these molecules associate with non-small-cell lung cancer (NSCLC) molecular mechanisms remain unclear. The protein expression levels of YTHDF1 and YTHDF2 in 603 cases of resected NSCLC were evaluated using immunohistochemistry. We analyzed the associations of these attributes with patient characteristics and survival. We also assessed four subsets of lymphocytes (PD-1+, CD8+, Foxp3+, and CD45RO+) as tumor-infiltrating lymphocytes (TILs) in the tumor nest and in the surrounding stroma separately. In addition, we investigated differentially expressed genes and the expression of PD-L1 in YTHDF1- and YTHDF2-deprived lung cancer cells. The expressions of both YTHDF1 and YTHDF2 were less in the advanced-stage tumors than in the early-stage tumors. The expressions of both YTHDF1 and YTHDF2 were also independent favorable prognostic factors for recurrence-free survival (HR, 0.745; 95% CI, 0.562-0.984 for YTHDF1; HR, 0.683; 95% CI, 0.503-0.928 for YTHDF2). The TIL densities of almost all four lymphocyte subsets in the stroma were significantly higher in the tumors with high YTHDF1 and YTHDF2 expression. In vitro, YTHDF1 and YTHDF2 knockdown in cells upregulated tumor PD-L1 expression and altered multiple immune-related genes. High expressions of both YTHDF1 and YTHDF2 are associated with a favorable prognostic outcome of NSCLC patients, a greater amount of TILs, and downregulation of PD-L1. YTHDF1 and YTHDF2 could be novel prognostic and druggable targets related to the tumor-immune microenvironment in lung cancers.

Survival benefits of salvage surgery for primary lung cancer based on routine clinical practice.

BACKGROUND: Premeditated induction chemotherapy followed by surgical resection is accepted as safe and effective. Studies on salvage surgery in patients with incompletely cured lung cancer are lacking. This study aimed to demonstrate the safety and efficacy of salvage surgery. METHODS: We conducted a retrospective multi-institutional cohort study on patients who underwent salvage surgery for advanced (stage III and IV) non-small cell lung cancer (NSCLC) between January 2005 and December 2016 at the 14 hospitals of the Chubu Lung Cancer Surgery Study Group. A total of 37 patients were assigned to the salvage surgery group; a lobectomy with mediastinal lymph node dissection was performed. The survival benefit was assessed using the Kaplan-Meier method and the Cox proportional hazard model. RESULTS: Although postoperative complications were observed in 11 patients (29.7%), surgery-related death occurred in only one patient (mortality rate: 2.7%) resulting from respiratory failure caused by interstitial pneumonia exacerbation. Postoperative recurrence was observed in 22 patients (61.1%), the incidence of brain metastasis being high (nine patients: 40.9%). The five-year survival rate from the first day of treatment was 60%. The survival of the postoperative pathological stage (s'-stage) I group was significantly better (five-year survival rate: 80.9%) than that of the other groups (p < 0.05). S'-stage was the most significant factor (p < 0.01) associated with long-term survival. CONCLUSIONS: Salvage surgery is a feasible therapeutic modality for advanced lung cancer. Downstaging to s'-stage I with previous treatment was most important for survival. Complete resection (R0) should be the goal because surgical procedures were tolerated despite intense treatment.

Phase II Study of Neoadjuvant Concurrent Chemo-immuno-radiation Therapy Followed by Surgery and Adjuvant Immunotherapy for Resectable Stage IIIA-B (Discrete N2) Non-small-cell Lung Cancer: SQUAT trial (WJOG 12119L).

INTRODUCTION: We describe our ongoing multicenter, prospective, single-arm, phase II trial of neoadjuvant concurrent chemo-immuno-radiation therapy followed by surgical resection and adjuvant immunotherapy for resectable stage IIIA-B (discrete N2) non-small-cell lung cancer (NSCLC) (registered at the Japan Pharmaceutical Information Center, Clinical Trials Information-195069). PATIENTS AND METHODS: Key inclusion criteria include (1) clinical T1-3/T4 (tumor size) N2 stage IIIA-B NSCLC, and (2) pathologically confirmed N2 without extranodal invasion (based on diagnostic imaging). Patients will receive concurrent chemoradiotherapy (carboplatin [area under the curve = 2] and paclitaxel [40 mg/m2] on days 1, 8, 15, 22, and 29, with involved-field radiation therapy [RT] [dose 50 Gy] on days 1-25) and neoadjuvant immunotherapy (durvalumab [1500 mg] on days 1 and 29). Surgical resection with mediastinal lymph node dissection is performed within 2 to 6 weeks after RT. Consolidation therapy with durvalumab is administered for up to 1 year after surgery. The primary endpoint is major pathologic response (MPR) (≤10% residual viable tumor) according to the central pathological assessment. Secondary endpoints are progression-free survival, overall survival, and safety. The sample size is planned to be 31 patients based on the exact binomial distribution with a 1-sided significance level of 5% and a power of 80%, and assuming a threshold MPR rate of 40% and an expected MPR rate of 65%. CONCLUSION: This trial will help establish a novel treatment strategy for resectable N2-positive NSCLC.

[Surgical Treatment and Outcomes for Synchronous Multiple Lung Cancer].

OBJECTIVES: With the advent of high-resolution chest imaging systems and lung cancer screening programs, the number of patients diagnosed with multiple primary lung cancers is increasing. For the treatment of multiple lung cancers, a surgical procedure that preserves the lung function while ensuring curability is required. We herein report the surgical strategy and outcomes of synchronous multiple lung cancer. SUBJECTS: The subjects were 83 patients with synchronous multiple lung cancer who received surgical resection between January 2010 and March 2020. Cases within the same lobe were excluded, and only cases with two or more lobes involved were included in this study. RESULTS: The study enrolled 39 male and 44 female patients, and the mean age was 67.8 years old. Sixty-five patients had cancers within a unilateral lobe, and all had undergone surgery for one term. Eighteen patients had cancers in bilateral lobes, and 17 of them received secondary surgery for more advanced cancer. Bilobectomy was performed in 9 patients( 10.8%), consisting of 5 upper-middle lobectomies, 3 middle-lower lobectomies, and 1 right middle lobectomy with left lower lobectomy. Seventy-four patients (89.2%) underwent combination surgery with sublobar resection, such as segmentectomy and partial resection. Pneumonectomy was not performed in any patients. The histologic type was adenocarcinoma in 78 patients (94.0%), and 37 patients (47.4%) had adenocarcinoma in situ. Regarding the most advanced pathological stage, 57 patients( 68.7%) were stage≤Ⅰ, and 26( 31.3%) were stage≥Ⅱ. Postoperative complications were observed in 29 patients( 34.9%), and persistent pulmonary fistula of ≥7 days after the surgery was the most common, being observed in 16 patients. Operative death within 30 days after surgery occurred in 2 patients( 2.4%)[ due to pneumonia in 1 and cerebral infarction in 1]. None of the patients required home oxygen therapy after surgery. Recurrence occurred in 20 patients;14 of these had pathological stage ≥Ⅱ, 11 had lymph node metastases, and 2 had pleural dissemination. The recurrence patterns were metastasis to other organs, pleural dissemination, or lymph node metastasis;no local recurrence was observed. The mean recurrence-free survival was 32.4 months, and the five-year survival rate was 84.8%. On comparing outcomes according to the most advanced pathological stage, the five-year survival rate for stage ≤Ⅰdisease was 94.9%, and that for stage ≥Ⅱ disease was 61.7%, showing a significantly better prognosis for stage ≤Ⅰdisease (p<0.001). CONCLUSIONS: Selecting an appropriate operative procedure for synchronous multiple lung cancer renders the prognosis equivalent to that of single cancer. Surgical treatments, including sublobar resection, are thus deemed important.

Evaluation of FGFR inhibitor ASP5878 as a drug candidate for achondroplasia.

Achondroplasia is caused by gain-of-function mutations in FGFR3 gene and leads to short-limb dwarfism. A stabilized analogue of C-type natriuretic peptide (CNP) is known to elongate bone by interacting with FGFR3 signals and thus is a promising drug candidate. However, it needs daily administration by percutaneous injection. FGFR inhibitor compounds are other drug candidates for achondroplasia because they directly fix the mutant protein malfunction. Although FGFR inhibitors elongate the bone of model mice, their adverse effects are not well studied. In this study, we found that a new FGFR inhibitor, ASP5878, which was originally developed as an anti-cancer drug, elongated the bone of achondroplasia model male mice at the dose of 300 µg/kg, which confers an AUC of 275 ng·h/ml in juvenile mice. Although ASP5878 was less effective in bone elongation than a CNP analogue, it is advantageous in that ASP5878 can be administered orally. The AUC at which minimal adverse effects were observed (very slight atrophy of the corneal epithelium) was 459 ng·h/ml in juvenile rats. The positive discrepancy between AUCs that brought efficacy and minimal adverse effect suggests the applicability of ASP5878 to achondroplasia in the clinical setting. We also analyzed effects of ASP5878 in a patient-specific induced pluripotent stem cell (iPSC) model for achondroplasia and found the effects on patient chondrocyte equivalents. Nevertheless, cautious consideration is needed when referring to safety data obtained from its application to adult patients with cancer in clinical tests.