We encountered a family of Japanese descent in which multiple members developed lung cancer. Using whole-exome sequencing, we identified a novel germline mutation in the transmembrane domain of the ...human epidermal growth factor receptor 2 (HER2) gene (G660D). A novel somatic mutation (V659E) was also detected in the transmembrane domain of HER2 in one of 253 sporadic lung adenocarcinomas. Because the transmembrane domain of HER2 is considered to be responsible for the dimerization and subsequent activation of the HER family and downstream signaling pathways, we performed functional analyses of these HER2 mutants. Mutant HER2 G660D and V659E proteins were more stable than wild-type protein. Both the G660D and V659E mutants activated Akt. In addition, they activated p38, which is thought to promote cell proliferation in lung adenocarcinoma. Our findings strongly suggest that mutations in the transmembrane domain of HER2 may be oncogenic, causing hereditary and sporadic lung adenocarcinomas.
Children with influenza virus infections are prone to complications and are common sources of influenza transmission. Baloxavir marboxil inhibits cap-dependent endonuclease and was approved for ...influenza treatment in adolescent, adult, and pediatric patients in Japan. The miniSTONE-2 study included pediatric patients with influenza (1 to < 12 years) and demonstrated similar median times to alleviation of signs and symptoms of influenza with a single dose of baloxavir granules (weight < 20 kg: 2 mg/kg, greater than or equai to 20 kg: 40 mg) and oseltamivir. Although the baloxavir dose in miniSTONE-2 was higher than the Japanese-approved dose, baloxavir exposure in miniSTONE-2 was similar to Japanese pediatric patients who receive the Japanese-approved dose. This study will be the first randomized active-controlled study in pediatric patients with influenza using the Japanese-approved dose of baloxavir. This is a multicenter, open-label, randomized, active-controlled trial in which 200 Japanese subjects aged 6 to < 12 years with influenza virus infection are randomly allocated (2:1) to a single dose of baloxavir at the approved dose in Japan (weight greater than or equai to 10 to < 20 kg: 10 mg, greater than or equai to 20 to < 40 kg: 20 mg, greater than or equai to 40 kg: 40 mg) or oseltamivir twice daily for 5 days. The primary clinical endpoint is the time to illness alleviation of influenza, from administration of baloxavir or oseltamivir until the following criteria were met and sustained for at least 21.5 h (24 h--10%): cough and nasal discharge/nasal congestion rated as absent or mild axillary body temperature < 37.5 degreesC. The primary analysis population is the intention-to-treat infected population, which includes all pediatric subjects who receive at least one dose of study drug and have confirmed influenza virus infection by reverse transcription-polymerase chain reaction. The safety population includes all subjects who receive at least one dose of study drug. No comparative studies have been conducted to confirm the efficacy and safety of baloxavir versus a comparator in pediatric patients with influenza infection in Japan. The outcomes from this trial will provide evidence on the efficacy and safety of baloxavir as an antiviral treatment option for Japanese pediatric patients with influenza infection. Trial registration Japan Registry of Clinical Trials: jRCTs011200011. Registered November 2020. (https://rctportal.niph.go.jp/en/).
Abstract Small-cell lung cancer (SCLC) is an aggressive tumor with a dismal prognosis among primary lung cancers. MicroRNAs (miRNAs) can act as oncogenes or tumor-suppressor genes in human ...malignancy. The miR-34 family is comprised of tumor-suppressive miRNAs, and its reduced expression by methylation has been reported in various cancers, including non-small cell lung cancer (NSCLC). In this study, we investigated the alteration and tumor-suppressive impact of miR-34s in SCLC. The methylation of miR-34a and miR-34b/c was observed in 4 (36%) and 7 (64%) of 11 SCLC cell lines, respectively. Among the 27 SCLC clinical specimens, miR-34a and miR-34b/c were methylated in 4 (15%) and 18 (67%), respectively. In contrast, 13 (28%) miR-34a methylated cases and 12 (26%) miR-34b/c methylated cases were found in 47 NSCLC primary tumors. The frequency of miR-34b/c methylation was significantly higher in SCLC than in NSCLC ( p < 0.001). The expressions of miR-34s were reduced in methylated cell lines and tumors and restored after 5-aza-2′-deoxycytidine treatment, indicating that methylation was responsible for the reduced expression of miR-34s. Because the frequency of methylation was higher in miR-34b/c, we focused on miR-34b/c for a functional analysis. We examined the effect of miR-34b/c introduction on cell proliferation, migration and invasion. The transfection of miR-34b/c to two SCLC cell lines (H1048 and SBC5) resulted in the significant inhibition of cell growth, migration, and invasion, compared with control transfectants. Our results indicate that the aberrant methylation of miR-34b/c plays an important role in the pathogenesis of SCLC, implying that miR-34b/c may be a useful therapeutic target for SCLC.
The lung is one of the most common sites of breast cancer metastasis. While metastatic seeding is often accompanied by a dormancy-promoting mesenchymal to epithelial reverting transitions (MErT), we ...aimed to determine whether lung epithelial cells can impart this phenotype on aggressive breast cancer cells.
Co-culture experiments of normal lung epithelial cell lines (SAEC, NHBE or BEAS-2B) and breast cancer cell lines (MCF-7 or MDA-MB-231) were conducted. Flow cytometry analysis, immunofluorescence staining for E-cadherin or Ki-67 and senescence associated beta-galactosidase assays assessed breast cancer cell outgrowth and phenotype.
Co-culture of the breast cancer cells with the normal lung cells had different effects on the epithelial and mesenchymal carcinoma cells. The epithelial MCF-7 cells were increased in number but still clustered even if in a slightly more mesenchymal-spindle morphology. On the other hand, the mesenchymal MDA-MB-231 cells survived but did not progressively grow out in co-culture. These aggressive carcinoma cells underwent an epithelial shift as indicated by cuboidal morphology and increased E-cadherin. Disruption of E-cadherin expressed in MDA-MB-231 using shRNA prevented this phenotypic reversion in co-culture. Lung cells limited cancer cell growth kinetics as noted by both (1) some of the cells becoming larger and positive for senescence markers/negative for proliferation marker Ki-67, and (2) Ki-67 positive cells significantly decreasing in MDA-MB-231 and MCF-7 cells after co-culture.
Our data indicate that normal lung epithelial cells can drive an epithelial phenotype and suppress the growth kinetics of breast cancer cells coincident with changing their phenotypes.
Objectives
We previously reported that the use of a stapler to divide intersegmental planes did not decrease preserved pulmonary volume or function relative to electrocautery. However, preservation ...of pulmonary volume or function can be compromised when a stapler is used with larger intersegmental planes. Here, we assessed the correlations between preserved lung volume and pulmonary function after segmentectomy and the size of the intersegmental planes, based on the division method.
Methods
Intersegmental plane sizes in 56 patients were semi-automatically calculated using image analysis software on computed tomography images. The ratios of the remnant segment and ipsilateral lung volumes to their preoperative values (R-seg and R-ips) and the ratio of the postoperative pulmonary function relative to the predicted value were calculated based on three-dimensional volumetry. Correlations between preserved lung volume and pulmonary function and the intersegmental plane sizes were analyzed according to the division method.
Results
Intersegmental planes were divided by either electrocautery or with a stapler (EC/Mixed) in 21 patients and by stapler alone (ST) in 35 patients. There was no difference in the average size of the intersegmental planes between the two groups. The intersegmental plane size negatively correlated with R-seg in the ST group.
Conclusions
Using the stapler method, as the size of the intersegmental planes increased, the preserved remnant segmental volume decreased; however, relation between the plane size and preserved pulmonary function was unclear. These findings indicate that stapler use is acceptable even for large intersegmental planes.
Poly(p-phenylene benzobisoxazole) (PBO) has excellent thermal stability and mechanical properties because of its rod-like rigid structure. Preparing nanofibers of PBO using ordinary methods is ...difficult (e.g., electrospinning) because PBO is not soluble in organic solvents. Herein, we report the preparation of PBO nanofibers with an average diameter of approximately 50 nm via crystallization from a dilute solution in sulfuric acid. In addition, a PBO nanofiber mat was prepared that exhibited extremely high thermal stability and high thermal diffusivity, etc.
Background
Induction therapy is used in about 80% of lung transplant centers and is increasing globally. Currently, there are no standards or guidelines for the use of induction therapy. At our ...institution, we have two induction strategies, basiliximab, and alemtuzumab. The goal of this manuscript is to share our experience and practice since this is an area of controversy.
Methods
We retrospectively reviewed 807 lung transplants performed at our institution between 2011 and 2020. Indications for the use of the basiliximab protocol were as follows: patients over the age of 70 years, history of cancer, hepatitis C virus or human immunodeficiency virus infection history, and cytomegalovirus or Epstein-Barr virus (donor positive/ recipient negative). In the absence of these clinical factors, the alemtuzumab protocol was used.
Results
453 patients underwent alemtuzumab induction and 354 patients underwent basiliximab. There were significant differences in delayed chest closure (24.7% alemtuzumab vs 31.4% basiliximab, p = 0.037), grade 3 primary graft dysfunction observed within 72 hours (19.9% alemtuzumab vs 29.9% basiliximab, p = 0.002), postoperative hepatic dysfunction (8.8% alemtuzumab vs 14.7% basiliximab, p = 0.009), acute cellular rejection in first year (39.1% alemtuzumab vs 53.4% basiliximab, p < 0.001). The overall survival rate of the patients with alemtuzumab induction was significantly higher than those of the patients with basiliximab induction (5 years survival rate: 64.1% alemtuzumab vs 52.3%, basiliximab, p < 0.001). Multivariate Cox regression analysis confirmed lower 5-year survival for basiliximab induction (HR = 1.41, p = 0.02), recipient cytomegalovirus positive (HR = 1.49, p = 0.01), postoperative hepatic dysfunction (HR = 2.20, p < 0.001), and acute kidney injury requiring renal replacement therapy (HR = 2.27, p < 0.001).
Conclusions
In this single center retrospective review, there was a significant difference in survival rates between induction strategies. This outcome may be attributable to differences in recipient characteristics between the groups. However, the Alemtuzumab group experienced less episodes of acute cellular rejection within the first year.
Air leakage is a common complication after pulmonary resection, which is usually caused by direct lung damage during surgery. Herein, we describe a case in which a pulmonary cyst developed rapidly in ...the right lower lobe and ruptured 10 days after right upper lobectomy. A 49‐year‐old man, who was a heavy smoker, underwent thoracoscopic right upper lobectomy for primary lung cancer. No air leakage was observed postoperatively, and the chest drain tube was removed on postoperative day 1. Although his postoperative course was uneventful for more than a week, extensive subcutaneous emphysema developed unexpectedly on postoperative day 10. Computed tomography (CT) scan revealed a large pulmonary cyst in the right lower lobe that was not present before the right upper lobectomy. Surgery was performed on postoperative day 13, and it revealed a large thick‐walled pulmonary cyst in the right lower lobe. The cyst was filled with blood clots, and air leaks were observed inside it, suggesting that the dissection of the pulmonary parenchyma caused its development. The cyst wall was sutured together with the pulmonary parenchyma, and no air leakage was subsequently observed.
Key points
Significant findings of the study
In patients with fragile pulmonary tissue, the pulmonary parenchyma may become dissociated after pulmonary resection and induce rapid development of a pulmonary cyst.
Risk factors for pulmonary cyst development include upper lobectomy and emphysema. Pulmonary cysts are often formed in the lower lobe.
What this study adds
In patients with pulmonary emphysema post‐upper lobectomy, the fragility of the pulmonary parenchyma and hyperinflation of the remaining lung may cause dissection of the pulmonary parenchyma, resulting in massive air leakage.
Objective: To evaluate trends and outcomes of lung transplants (LTx) in recipients ≥ 70 years. Methods: We performed a retrospective analysis of the UNOS database identifying all patients undergoing ...LTx (May 2005–December 2022). Baseline characteristics and postoperative outcomes were compared by age (<70 years, ≥70 years) and center volume. Kaplan–Meier analyses were performed with pairwise comparisons between subgroups. Results: 34,957 patients underwent LTx, of which 3236 (9.3%) were ≥70 years. The rate of LTx in recipients ≥ 70 has increased over time, particularly in low-volume centers (LVCs); consequently, high-volume centers (HVCs) and LVCs perform similar rates of LTx for recipients ≥ 70. Recipients ≥ 70 had higher rates of receiving from donor after circulatory death lungs and of extended donor criteria. Recipients ≥ 70 were more likely to die of cardiovascular diseases or malignancy, while recipients < 70 of chronic primary graft failure. Survival time was shorter for recipients ≥ 70 compared to recipients < 70 old (hazard ratio (HR): 1.36, 95% confidence interval (CI): 1.28–1.44, p < 0.001). HVCs were associated with a survival advantage in recipients < 70 (HR: 0.91, 95% CI: 0.88–0.94, p < 0.001); however, in recipients ≥ 70, survival was similar between HVCs and LVCs (HR: 1.11, 95% CI: 0.99–1.25, p < 0.08). HVCs were more likely to perform a bilateral LTx (BLT) for obstructive lung diseases compared to LVCs, but there was no difference in BLT and single LTx likelihood for restrictive lung diseases. Conclusions: Careful consideration is needed for recipient ≥ 70 selection, donor assessment, and post-transplant care to improve outcomes. Further research should explore strategies that advance perioperative care in centers with low long-term survival for recipients ≥ 70.
Background: With new variants challenging the effectiveness of preventive measures, we are beginning to recognize the reality that COVID-19 will continue to pose an endemic threat. The manifestations ...of COVID-19 in lung transplant recipients during index admission are poorly understood with very few cases reported in recent lung transplant recipients. Optimal management of immunosuppression and antiviral therapy in recent transplant recipients is challenging. Methods: We performed a retrospective analysis identifying lung transplant recipients at our institution who contracted COVID-19 in the immediate postoperative period (within index admission). In addition, we performed a systematic review from January 2020 to August 2023 identifying all publications on the PUBMED database regarding COVID-19 infection in lung transplant recipients during index admission. Results: We report four cases of COVID-19 pneumonia in lung transplant recipients in the immediate postoperative period and we describe the clinical course, treatment options, and immunosuppression changes to manage this unique clinical problem. All patients made a full recovery and were eventually discharged home. Within our review of the literature, the most prevalent presenting symptoms were cough, dyspnea, and fatigue. Six (75%) patients decreased or held their antimetabolite. The two most common treatments were monoclonal antibodies (38%) and remdesivir (63%). Conclusion: Although previous literature demonstrates that COVID-19 can be deadly in recent lung transplant recipients, rapid treatment with anti-viral therapy/immunotherapy, deescalating immunosuppression, and treatment of respiratory decompensation with Decadron was effective in our patients.
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