Prognostic value of perioperative changes in the prognostic nutritional index in patients with surgically resected non-small cell lung cancer.

PURPOSE: This single-institution retrospective cohort study was conducted to assess the prognostic significance of perioperative changes in the prognostic nutritional index (PNI) in patients who underwent surgery for non-small cell lung cancer (NSCLC). METHODS: Clinicopathological data were collected from 441 patients who underwent lobectomy for NSCLC between 2010 and 2016.The PNI ratio (postoperative PNI/preoperative PNI) was used as an indicator of perioperative PNI changes. Prognostic differences were investigated based on PNI ratios. RESULTS: The optimal cut-off value of the PNI ratio for overall survival (OS) was set at 0.88 using a receiver operating characteristic curve. The PNI ratio was inversely related to a high smoking index, interstitial lung disease, and postoperative pulmonary complications. The 5-year OS rates for the high vs. low PNI ratio groups were 88.2% vs. 68.5%, respectively (hazard ratio [HR]: 3.04, 95% confidence interval [CI]: 1.90-4.86). Multivariable analysis revealed that a low PNI ratio was significantly associated with poor prognosis (HR: 2.94, 95% CI: 1.77-4.87). The PNI ratio was a more sensitive indicator than postoperative PNI status alone for identifying patients at high risk of mortality, particularly those with non-lung cancer causes. CONCLUSION: The perioperative PNI change is a significant prognostic factor for patients with NSCLC.

Impact of central nervous system metastasis after complete resection of lung adenocarcinomas harboring common EGFR mutation - A real-world database study in Japan: The CReGYT-01 EGFR study.

OBJECTIVES: To clarify the impact of central nervous system (CNS) metastasis on performance status (PS) at relapse, on subsequent treatment(s), and on survival of patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutation. METHODS: We conducted the multicenter real-world database study for patients with radical resections for lung adenocarcinomas between 2015 and 2018 at 21 centers in Japan. EGFR mutational status was examined at each center. RESULTS: Of 4181 patients enrolled, 1431 underwent complete anatomical resection for lung adenocarcinoma harboring common EGFR mutations. Three-hundred-and-twenty patients experienced disease relapse, and 78 (24%) had CNS metastasis. CNS metastasis was significantly more frequent in patients with conventional adjuvant chemotherapy than those without (30% vs. 20%, P = 0.036). Adjuvant chemotherapy did not significantly improve relapse-free survival at any pathological stage (adjusted hazard ratio for stage IA2-3, IB, and II-III was 1.363, 1.287, and 1.004, respectively). CNS metastasis did not affect PS at relapse. Subsequent treatment, mainly consisting of EGFR-tyrosine kinase inhibitors (TKIs), could be equally given in patients with or without CNS metastasis (96% vs. 94%). Overall survival after relapse was equivalent between patients with and without CNS metastasis. CONCLUSION: The efficacy of conventional adjuvant chemotherapy may be limited in patients with lung adenocarcinoma harboring EGFR mutations. CNS metastasis is likely to be found in practice before deterioration in PS, and may have little negative impact on compliance with subsequent EGFR-TKIs and survival after relapse. In this era of adjuvant TKI therapy, further prospective observational studies are desirable to elucidate the optimal management of CNS metastasis.

Aging exacerbates murine lung ischemia-reperfusion injury by excessive inflammation and impaired tissue repair response.

Donor shortage is a major problem in lung transplantation (LTx), and the use of lungs from elderly donors is one of the possible solutions in a rapidly aging population. However, the utilization of organs from donors aged >65 years has remained infrequent and may be related to a poor outcome. To investigate the molecular events in grafts from elderly donors early after LTx, the left lungs of young and old mice were subjected to 1 hour of ischemia and subsequent reperfusion. The left lungs were collected at 1 hour, 1 day, and 3 days after reperfusion and subjected to wet-to-dry weight ratio measurement, histological analysis, and molecular biological analysis, including RNA sequencing. The lungs in old mice exhibited more severe and prolonged pulmonary edema than those in young mice after ischemia reperfusion, which was accompanied by upregulation of the genes associated with inflammation and impaired expression of cell cycle-related genes. Apoptotic cells increased and proliferating type 2 alveolar epithelial cells decreased in the lungs of old mice compared with young mice. These factors could become conceptual targets for developing interventions to ameliorate lung ischemia-reperfusion injury after LTx from elderly donors, which may serve to expand the old donor pool.

Clinical, Genomic, and Transcriptomic Featurses of Lung Adenocarcinoma With Uncommon EGFR Mutation.

PURPOSE: The purpose of this study is to identify the clinical, genomic, and transcriptomic features of patients with lung adenocarcinoma (LUAD) harboring uncommon epidermal growth factor receptor (EGFR) mutations (UCM) compared with common EGFR mutations (CM). MATERIALS AND METHODS: In this multicenter retrospective cohort study, clinicopathological data were collected from 1047 consecutive patients who underwent complete surgical resection for LUAD, as well as EGFR mutation analysis, between 2005 and 2012 at 4 institutions. Differences in postoperative overall survival (OS) and recurrence-free survival (RFS) according to EGFR mutation status were evaluated. For the genomic and transcriptomic analyses, 5 cohorts from public databases were evaluated. RESULTS: Of 466 eligible patients, 415 (89.1%) and 51 (10.9%) had CM and UCM, respectively. The 5-year OS and RFS rates in the CM/UCM groups were 86.8%/77.0% and 74.8%/59.0%, respectively. OS and RFS were significantly shorter in the UCM than CM group (both P < .01). Multivariable analysis of OS showed that UCM was an independent prognostic factor (hazard ratio 1.72, 95% confidential interval 1.01-2.93). According to the genomic analysis, tumors with UCM had a significantly higher tumor mutation burden and TP53 mutation frequency. Transcriptomic analysis showed that the T-cell-inflamed gene signature, a biomarker of the treatment for immunotherapy, was significantly associated with tumors with UCM. CONCLUSION: UCM were associated with a poor prognosis in patients with surgically resected EGFR-mutated LUAD. Tumors with UCM had unique genomic and transcriptomic features suggestive of a tumor microenvironment responsive to immunotherapy.

Long-term follow-up of a consecutive cohort validating an epidermal growth factor receptor mutation as an independent risk factor for postoperative recurrence in lung adenocarcinoma.

OBJECTIVES: Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors were recently reported to be effective as adjuvant therapy for resected lung adenocarcinoma (ADC) harbouring common EGFR mutations. However, whether the EGFR mutation is a direct risk factor for postoperative recurrence remains unknown. Therefore, we conducted a multi-institutional observational study to compare postoperative survival according to EGFR mutation status. METHODS: We collected the medical records of consecutive patients who underwent surgical resection for ADC between 2005 and 2012 at 4 participating institutions. Recurrence-free survival (RFS) and overall survival (OS) associated with EGFR mutation status were evaluated. We further analysed survival after pair-matching patients' clinicopathological characteristics. RESULTS: EGFR mutations were harboured by 401 of 840 (48%) enrolled patients. The number of patients with an EGFR mutation (M group) differed from that with the EGFR wild-type sequence (W group) in terms of sex, smoking history and pathological stage. The median follow-up period was 85 months. The five-year RFS/OS rates of the M and W groups were 70%/85% and 61%/75%, respectively (P < 0.001 for both groups). However, multivariable analysis revealed that EGFR mutation status was not independently related with both RFS and OS. In pair-matched analysis, the RFS and OS curves of the patients with an EGFR mutation and wild-type sequence were not statistically different, either. CONCLUSIONS: Long-term follow-up of consecutive patients did not show that a common EGFR mutation was an independent risk factor of recurrence or prognostic factor for completely resected lung ADC.

Efficacy of platinum-based adjuvant chemotherapy for epidermal growth factor receptor-mutant lung adenocarcinoma.

Background: The ADAURA trial reported that osimertinib improved overall survival (OS) as an adjuvant chemotherapy for pathological stage IB-IIIA epidermal growth factor receptor (EGFR) mutant lung cancer compared with a placebo. Currently, platinum-based adjuvant chemotherapy is the standard treatment for patients with or without EGFR mutations. This study aimed to evaluate the efficacy of platinum-based adjuvant chemotherapy in patient with stage II-IIIA EGFR mutant lung adenocarcinoma. Methods: We collected the medical records of consecutive patients who underwent surgical resection for lung adenocarcinoma between 2005 and 2012 at the four participating institutions. The data of 173 patients with different EGFR mutation status were retrospectively evaluated to determine the efficacy of platinum-based adjuvant chemotherapy for OS and recurrence-free survival (RFS). We further analyzed OS using the inverse probability of treatment weighting method with propensity scores. Results: The median age was 69 years (range, 45-85 years); 95 (54.9%) were male and 74 (42.8%) had EGFR mutations. A total of 43 patients with EGFR mutants (58.1%) and 43 patients with wild-type EGFR tumors (43.4%) received platinum-based adjuvant chemotherapy. No differences in RFS and OS were observed between EGFR mutant and wild-type EGFR in lung adenocarcinoma without adjuvant therapy. However, wild-type EGFR showed an improvement in OS with platinum-based adjuvant chemotherapy in inverse probability of treatment weighting analysis, whereas those with EGFR mutations showed no significant difference in OS between the surgery-only group and the adjuvant group. The deletion of exon 19 and exon 21 L858R point mutation showed no significant differences in OS between the surgery-only group and the adjuvant group, respectively. The hazard ratio (HR) exceeded 1 for uncommon EGFR mutations. Conclusions: Platinum-based adjuvant chemotherapy may be less effective for EGFR-mutant lung adenocarcinoma, regardless of the mutation type.

Successful Single-Lung Transplant for the Dominant Side: A Case Report.

Although single-lung transplant on the side with better lung function is challenging in patients with significantly asymmetrical lung function between the right and left sides, it sometimes can be a realistic option because of the recipient's condition and from the viewpoint of organ sharing. We report our experience with a successful case of single-lung transplant on the side with a pulmonary perfusion ratio of 89%. The transplant was performed with the patient under central venoarterial extracorporeal membrane oxygenation through a clamshell incision, and the patient had an acceptable short- and long-term outcome with a remarkable improvement of lung function.

Pneumonia With Scedosporium apiospermum and Lomentospora prolificans in a Patient After Bilateral Lung Transplantation for Pulmonary Hypertension: A Case Report.

Infections caused by the Scedosporium genus have become recognized as a fatal complication after lung transplantation in Europe and Australia, but the reports have been rare from Asian countries including Japan. We present a case of pneumonia caused by a mixed infection of Scedosporium apiospermum (SA) and Lomentospora prolificans (LP) that developed after augmentation of immunosuppression for chronic lung allograft dysfunction (CLAD) after lung transplantation. A 13-year-old man underwent bilateral lung transplantation for pulmonary hypertension. One year after surgery, he was treated with a series of augmented immunosuppressive therapy for severe acute rejection and subsequent CLAD. Three months following the first steroid pulse therapy, his serum ß-D-glucan elevated without any sign of fungal infection by other tests. The serum ß-D-glucan once returned to a normal level by empirical administration of micafungin; however, the patient's condition worsened again by discontinuation of it. He did not recover by restarting micafungin, and computed tomography (CT) scans eventually demonstrated new infiltrates in his lung field 6 weeks after the elevation of serum ß-D-glucan. Microscopic findings of transbronchial lung biopsy specimens showed filamentous fungi, and the culture of bronchoalveolar lavage fluid revealed the growth of SA and LP. Despite subsequent voriconazole administration, he died 14 days after the start of voriconazole. Early and aggressive inspection including bronchoscopy should be performed for the diagnosis of Scedosporium infection in immunocompromised patients, even if CT scans and sputum culture show no evidence of infection.

Prognostic significance of propofol-based intravenous anesthesia in early-stage lung cancer surgery.

PURPOSE: The purpose of this study was to assess whether the anesthetic type is associated with the prognosis of pathological stage I non-small cell lung cancer (NSCLC). METHODS: Clinicopathological data from 431 consecutive patients who underwent lobectomy for NSCLC between 2010 and 2016 were collected. Patients were classified into groups according to the type of anesthesia: propofol-based total intravenous anesthesia (TIVA) or inhalation anesthesia (INHA). We investigated the prognostic differences between these two groups. RESULTS: A total of 72 patients in the TIVA group and 158 patients in the INHA group were eligible for the analysis. Recurrence was observed in 4 (5.6%) patients in the TIVA group and 19 (12.0%) patients in the INHA group (P = 0.159), and all-cause death occurred in 4 (5.6%) patients in the TIVA group and 24 (15.2%) patients in the INHA group (P = 0.049). The 5-year recurrence-free survival (RFS) and overall survival rates of the TIVA/INHA groups were 91.7%/77.4% and 94.4%/83.5%, respectively. TIVA was associated with a significantly better prognosis. A multivariable analysis of factors associated with RFS revealed that the type of anesthesia as a significant prognostic factor (P = 0.047). CONCLUSION: Propofol-based TIVA was associated with a better prognosis in comparison to INHA in patients with surgically resected pathological stage I NSCLC.

[Aspergillus Empyema with Bronchopleural Fistula due to Destroyed Lung after Postoperative Radiotherapy for Thymoma].

A 35-year-old man underwent adjuvant chemoradiation therapy to the surgical margin of the thymoma. Five years after the therapy, an area of the right upper lung lobe, which was included in the irradiation field, developed destroyed lung, resulting in Aspergillus empyema with bronchopleural fistula. To control the infection, an open window thoracostomy was performed. As the bronchopleural fistula resulted in pneumonia, bronchial embolization was performed with an Endobronchial Watanabe Spigot. After the empyema cavity was cleaned, the empyema space was closed with omental and muscular flap, thoracoplasty. Negative pressure wound therapy was carried out because of poor wound healing. The patient is doing well without relapse 15 months after the thoracoplasty.

Enhancer remodeling promotes tumor-initiating activity in NRF2-activated non-small cell lung cancers.

Transcriptional dysregulation, which can be caused by genetic and epigenetic alterations, is a fundamental feature of many cancers. A key cytoprotective transcriptional activator, NRF2, is often aberrantly activated in non-small cell lung cancers (NSCLCs) and supports both aggressive tumorigenesis and therapeutic resistance. Herein, we find that persistently activated NRF2 in NSCLCs generates enhancers at gene loci that are not normally regulated by transiently activated NRF2 under physiological conditions. Elevated accumulation of CEBPB in NRF2-activated NSCLCs is found to be one of the prerequisites for establishment of the unique NRF2-dependent enhancers, among which the NOTCH3 enhancer is shown to be critical for promotion of tumor-initiating activity. Enhancer remodeling mediated by NRF2-CEBPB cooperativity promotes tumor-initiating activity and drives malignancy of NRF2-activated NSCLCs via establishment of the NRF2-NOTCH3 regulatory axis.

Postoperative prognostic nutritional index as a prognostic factor after non-small cell lung cancer surgery.

OBJECTIVE: The prognostic nutritional index (PNI) is an immunonutrition index. Although preoperative PNI (pre-PNI) has been reported as a prognostic factor for patients with surgically resected non-small cell lung cancer (NSCLC), it is unclear whether postoperative PNI (post-PNI) and perioperative PNI change is a prognostic factor. METHODS: Clinicopathological data from 262 consecutive patients who underwent lobectomy for NSCLC were collected. Pre-PNI and post-PNI were calculated within 1 month before surgery and at 1 month after surgery, respectively. We investigated which clinicopathological factors contributed to the post-PNI, the differences in prognosis according to the post-PNI status, and the impact of perioperative PNI change on prognosis. RESULTS: We set 50 and 45 as an optimal cutoff value of pre-PNI and post-PNI for OS using a receiver operating characteristic curve. Patients who were older and male and who had lower pre-PNI, larger thoracotomy size, longer operative duration, larger blood loss during surgery, and postoperative pulmonary complications showed significantly lower post-PNI. The 5-year overall survival (OS), lung cancer-specific survival, and recurrence-free survival rates for the high/low post-PNI groups were 87.4%/58.4% (P < 0.001), 92.0%/74.8% (P = 0.001), and 80.5%/55.3% (P < 0.001). respectively. Multivariate analysis showed that the post-PNI was a significant prognostic factor (P < 0.001). We further revealed the equivalent OS with "low pre-PNI and high post-PNI" patients or "high pre-PNI and high post-PNI" patients. CONCLUSIONS: Post-PNI status was a significant prognostic factor and perioperative PNI changes could play a significant role in the survival of patients with NSCLC after surgery.

A surgical case of mediastinal hematoma caused by a minor traffic injury.

BACKGROUND: Mediastinal hematoma rarely occurs after a minor traffic injury. CASE PRESENTATION: A woman in her forties was transferred to the emergency room by ambulance due to a traffic accident. Computed tomography (CT) revealed no abnormal findings, and she went home. Two days after the accident, the contrast-enhanced CT was repeated, which revealed cervical and mediastinal hematomas. Because it was possible that there was active bleeding from the right inferior thyroid artery, embolization of the right inferior thyroid artery was performed; however, her condition further deteriorated, so we performed emergency surgery to achieve hemostasis and remove the hematoma. Because of oozing from the right thyroid lobe, we performed right hemithyroidectomy and drainage of mediastinal space and right thoracic cavity. Since there was no bleeding site in the mediastinum, we thought that the mediastinal hematoma was due to bleeding from the thyroid gland. Her postoperative course was uneventful, and she is doing well at 9 months of follow-up after surgery. CONCLUSIONS: It is possible that mediastinal hematoma might be caused by a minor traffic injury.

Thymic Small Cell Carcinoma Associated With Lambert-Eaton Myasthenic Syndrome.

Thymic small cell cancer is a very rare type of thymic epithelial tumor. Lambert-Eaton myasthenic syndrome is a rare paraneoplastic syndrome associated with thymic epithelial tumors. We report an extremely rare case of Lambert-Eaton myasthenic syndrome associated with thymic small cell carcinoma. A 71-year-old man was referred to our institution for a mediastinal tumor and a 2-month history of ptosis, fatigue, and gait disorder. Based on radiologic findings thymoma associated with Lambert-Eaton myasthenic syndrome was diagnosed, and extended thymectomy was performed. After surgery the patient's symptoms had not improved. Anticholinesterase treatment alleviated his symptoms.

[Long-term Outcome of Pulmonary Segmentectomy for Lung Cancer].

OBJECTIVE: Pulmonary segmentectomy has been performed for patients with radiographic early-stage lung cancer. This retrospective study investigated the validity of choice of procedures at our institute by examining the survival outcomes of lung cancer patients who underwent surgery. METHOD: Data from 354 consecutive patients with pT1a~c N0 M0 stages I A1~3 non-small cell lung cancer who underwent surgery between 2004 and 2014 were extracted (segmentectomy group:84 patients, lobectomy group:270 patients). Overall, recurrence-free and cancer-specific survival of patients operated by segmentectomy and lobectomy was compared using the Cox proportional hazard model. RESULT: The segmentectomy group had a higher average age and frequency of history of another cancer and smaller lung cancers and its diameter and solid components than the lobectomy group. By univariate and multivariate analyses, surgical procedures were not identified as independent risk factors for overall, recurrence-free and cancer-specific survival. CONCLUSION: In this study cohort, the mode of surgical procedure between segmentectomy and lobectomy did not affect relapse and prognosis in pathological stages I A1~3 lung cancer. The choice of procedures at our institute seemed to be appropriate in this study period.

Impact of enhanced recovery after surgery on outcomes of elderly patients undergoing open thoracic surgery.

OBJECTIVE: An enhanced recovery after surgery (ERAS) program might be effective for postoperative recovery in elderly patients undergoing thoracic surgery. This study aimed to clarify the impact of ERAS on the post-operative recovery of elderly patients, with regard to shortening hospital stay and reducing complications after open thoracic surgery. METHODS: We used a prospectively collected database and retrospectively accessed the data of patients who underwent lobectomies or segmentectomies for pulmonary malignancies from April 2013 to March 2018 and evaluated outcomes after implementation of ERAS. ERAS patients were those who completed an ERAS program. The control patients were those who underwent surgery before June 2015 and later operated patients who did not receive ERAS. Propensity score matching was performed to balance the characteristics of patients in both groups. Patients were also divided into the following three groups for evaluating the efficacy of ERAS: patients aged < 65 years, 65-74 years of age, and ≥ 75 years of age. RESULTS: Before propensity score matching, the ERAS patients had shorter postoperative stay, shorter duration of chest tube drainage, and lower rate of postoperative complications than the patients without ERAS. The difference between readmission rates was not significant. After matching, the ERAS patients had shorter postoperative stay. The difference between readmission rates was not significant. After matching, the postoperative hospital stay was shorter in the patients aged ≥ 65 years. CONCLUSIONS: ERAS shortened the length of postoperative hospital stay in patients aged ≥ 65 years and did not increase readmission rates.

[Postoperative Analgesia with Regular Acetaminophen Drip Infusion after Surgery for Lung Cancer].

BACKGROUND: Only a few studies have examined the effects of regular acetaminophen drip infusion as postoperative analgesia in lung cancer surgery. METHODS: We consecutively collected the medical data of 282 patients who underwent complete resection for lung cancer and divided them into 2 groups according to their postoperative analgesia;248 patients with conventional analgesia( group C) and 34 who received acetaminophen( group A). RESULTS: There was no significant difference in the surgical approach, length of surgical incision, or postoperative pain scale between the 2 groups. Postoperative vital signs and laboratory data were also not significantly different. CONCLUSION: Postoperative analgesia with acetaminophen was conducted safely, but its effect on postoperative pain did not differ from the conventional analgesia.

Spread through air spaces in lung cancer patients is a risk factor for pulmonary metastasis after surgery.

BACKGROUND: Spread through air spaces (STAS) is regarded as a significant risk factor for lung cancer recurrence. STAS consists of micropapillary clusters, solid nests, or single cells beyond the edge of the tumor into air spaces in the surrounding lung parenchyma. However, the patterns of lung cancer recurrence have not been clarified in patients with STAS. The aim of this study was to explore STAS and recurrence patterns in patients who underwent lung cancer surgery. METHODS: Between January 2000 and December 2017, a total of 1,426 patients underwent complete resection of lung cancer. We studied 848 patients with pathological stage I disease who underwent surgery. Recurrence patterns and recurrence-free rates were determined from pathological findings, particularly the presence of STAS. Locoregional recurrences included surgical margin recurrences, hilar and mediastinal lymph node metastases, ipsilateral lobe metastases, and pleural dissemination, whereas distant recurrences included extrathoracic organ and contralateral lobe metastases. RESULTS: STAS was observed in 139 of 848 (16.4%) cases. Recurrences developed in 108 (12.7%) cases: locoregional recurrences in 76 (9.0%), distant metastases in 27 (3.2%), and both in 5 (0.6%) cases. Among recurrences, pleural dissemination developed in 12 (1.4%) and pulmonary metastases in 46 (5.4%) cases. Five-year recurrence-free rates were 65.4% among patients with STAS and 89.0% among patients without STAS. Univariate and multivariate analyses revealed that STAS was a significant risk factor for recurrence (P<0.001), particularly locoregional recurrence (P=0.005). In addition, STAS was a significant risk factor for pulmonary metastasis (P=0.009). CONCLUSIONS: Among pathological stage I patients who undergo complete resection of lung cancer, patients with STAS tend to develop locoregional recurrence and pulmonary metastases.

[Long-term Results of Sublobar Resection for Lung Cancer;a 10-year Follow-up Study].

As a treatment for lung cancer, sublobar resection has been performed not only for high-risk patients but also for patients with radiographic early stage lung cancer. Although many studies revealed the short-term results of sublobar resection, long-term outcomes are still unclear. Here, we examined the 10-year follow-up results of sublobar resection for lung cancer, especially in overall survival(OS), cause-specific survival(CSS)and recurrence or death dynamics. Data from 48 consecutive patients who underwent sublobar resection for lung cancer between 2004 to 2008 were collected(21 patients:segmentectomy, 27:wedge resection). The median length of follow-up was 10 years. During follow-up, recurrences developed in 12 patients(25%)and 19 patients(40%)died, including 9(19%)patient deaths due to lung cancer. The 3-/5-/10-year OS and CSS rates for all patients were 81/77/61% and 87/85/80%, respectively. In terms of recurrence or death, 11 out of 12 patients with recurrences were diagnosed within the 3rd year. The peak of death due to lung cancer was shown to be years after surgery to which wedge resection contributed. On contrast, small peaks of non-cancer death were shown to be 8-10 years after surgery without relation to surgical procedure.