Sublobar resection or lobectomy and postoperative respiratory complications in emphysematous lungs.

OBJECTIVES: Pulmonary resection in patients with severe emphysema may impact postoperative respiratory complications. Low-attenuation areas evaluated using three-dimensional computed tomography to assess emphysematous changes are strongly associated with postoperative respiratory complications. Herein, we investigated the relationship between low-attenuation area, the surgical procedure and resected lung volume, which has not been explored in previous studies. METHODS: We retrospectively evaluated patients with primary or metastatic lung cancer who underwent surgical resection. The low-attenuation area percentage (low-attenuation area/total lung area × 100) and resected lung volume were calculated using three-dimensional computed tomography software, and the relationship with postoperative respiratory complications was analysed. RESULTS: Postoperative respiratory complications occurred in 66 patients (17%) in the total cohort (n = 383). We set the median value of 1.1% as the cut-off value for low-attenuation area percentage to predict postoperative respiratory complications, which occurred in 24% and 10% of patients with low-attenuation area >1.1% and <1.1%, respectively (P < 0.001). Postoperative respiratory complications occurred in approximately one-third of the patients with low-attenuation area >1.1%, whose resected lung volume was ≥15.8% or ≥5 resected subsegments. Multivariable analysis revealed that sublobar resection was associated with a significantly lower risk of postoperative respiratory complications in patients with low-attenuation area >1.1% (odds ratio 0.4, 95% confidence interval 0.183-0.875). CONCLUSIONS: Emphysema is a risk factor for postoperative respiratory complications, and lobectomy is an independent predictive risk factor. Preserving more lung parenchyma may yield better short-term prognoses in patients with emphysematous lungs.

Segmentectomy-oriented anatomical model for enhanced precision surgery of the left upper lobe.

Objective: To optimize surgical outcomes and minimize complications in complex segmentectomy of the left upper lobe, we investigated the topographical anatomy of the left upper lobe and developed a segmentectomy-oriented anatomical model. Methods: A state-of-the-art 3-dimensional computed tomography workstation was used to visualize the intersegmental planes and associated veins to categorize the anatomical patterns influencing surgical procedures during left upper lobe segmentectomy. This included the central vein affecting S1+2 (apicoposterior segment) segmentectomy, the transverse S3 (anterior segment) affecting S3 segmentectomy, and other venous branching patterns in 395 patients who underwent thoracic surgery at our institution. Results: The central vein was observed in 32% of the patients, necessitating access from the interlobar area after segmental artery and bronchus division. Transverse S3 incidence was 27%, revealing that only one-third of the patients required complete left upper lobe transection between S4 and S3 during S3 segmentectomy. A significant negative correlation was observed between the presence of transverse S3 and the central vein (<10% of patients with the central vein had transverse S3 and vice versa). In 6% of patients, the lingular segmental veins partially or entirely drained into the inferior pulmonary vein, potentially causing excessive or insufficient resection during surgery. Conclusions: This study offers valuable insights into the topographic anatomy of the left upper lobe and presents a segmentectomy-oriented anatomical model for complex segmentectomies. Our approach enables a more precise and individualized surgical planning for patients undergoing segmentectomy based on their unique anatomy, which could thereby lead to improved patient outcomes.

Predicting 1-year non-cancer-related adverse events after lung resection.

OBJECTIVES: Assessing the risk for non-cancer-related outcomes following lung cancer surgery is crucial for high-risk patients. This study examined non-cancer-related adverse events within 1 year after lung resection, emphasizing the role of resected lung volume and postoperative atrial fibrillation (POAF). METHODS: We conducted a retrospective analysis of 460 patients who underwent anatomical lung resection for malignant lung tumours. We assessed perioperative factors, such as the number of resected subsegments and POAF, as potential predictors of 1-year non-cancer-related adverse events. Additionally, we validated a previously published nomogram for predicting POAF. RESULTS: One-year non-cancer-related adverse events occurred in 20% of patients. Multivariable analysis identified higher age, lower percentage-predicted forced expiratory volume in 1 second, greater number of resected subsegments and POAF as independent predictors of these adverse events. The incidence of POAF was 8.5%, with higher age, history of atrial fibrillation, and open thoracotomy as independent predictors. A temporal link between POAF and other severe postoperative complications was observed, as 71% of POAF cases preceded other complications. The nomogram's predicted risk for POAF was associated well with the actual incidence. CONCLUSIONS: Resected lung volume and POAF are statistically significant factors associated with non-cancer-related outcomes after lung resection. Minimizing resected lung volume when oncologically and technically feasible, along with identifying patients at risk for POAF, may contribute to improved postoperative outcomes. Our results have implications for risk stratification and preoperative decision-making in lung cancer surgery.

Erratum: Ligand-based, piggyBac-engineered CAR-T cells targeting EGFR are safe and effective against non-small cell lung cancers.

[This corrects the article DOI: 10.1016/j.omto.2023.100728.].

Ligand-based, piggyBac-engineered CAR-T cells targeting EGFR are safe and effective against non-small cell lung cancers.

Epidermal growth factor receptor (EGFR) is overexpressed in various cancers, including non-small cell lung cancer (NSCLC), and in some somatic cells at a limited level, rendering it an attractive antitumor target. In this study, we engineered chimeric antigen receptor (CAR)-T cells using the piggyBac transposon system, autologous artificial antigen-presenting cells, and natural ligands of EGFR. We showed that this approach yielded CAR-T cells with favorable phenotypes and CAR positivity. They exhibited potent antitumor activity against NSCLC both in vitro and in vivo. When administered to tumor-bearing mice and non-tumor-bearing cynomolgus macaques, they did not elicit toxicity despite their cross-reactivity to both murine and simian EGFRs. In total we tested three ligands and found that the CAR candidate with the highest affinity consistently displayed greater potency without adverse events. Taken together, our results demonstrate the feasibility and safety of targeting EGFR-expressing NSCLCs using ligand-based, piggyBac-engineered CAR-T cells. Our data also show that lowering the affinity of CAR molecules is not always beneficial.

Bronchial branching patterns and volumetry in the right upper lobe: impact on segmentectomy planning.

OBJECTIVES: The use of segmentectomy is expected to increase. However, understanding of the segmental bronchial branching is limited. Herein, we aimed to investigate bronchial branching pattern complexity and segmental volumetry of the right upper lung lobe to develop an accurate understanding of segmental anatomy and contribute to the advancement of safe and efficient lung segmentectomy. METHODS: We evaluated chest computed tomography scans of 303 patients and categorized the branching of segmental bronchi (segment 1, apical; segment 2, posterior; and segment 3, anterior) into 4 major types (typical trifurcated, bifurcated non-defective, bifurcated defective and atypical trifurcated) and 11 subtypes. Segmental volumetry was performed to determine the predominant segment in each case (volume difference <5% was considered equal). Branching complexity was evaluated separately for volumetry-predominant and volumetry-non-predominant segments. RESULTS: Trifurcated non-defective was the most frequent branching type (64.4%), followed by bifurcated non-defective (22.1%), bifurcated defective (8.6%) and trifurcated half-defective (4.0%). In terms of segmental volumetry, most cases had a one-segment-predominant distribution (71%) and only 5% of cases had equal distribution (segment 1 = segment 2 = segment 3). More than half of the cases had a segment 3-predominant distribution (52%). Branching complexity analysis revealed that the volumetry-non-predominant segment was associated with a higher risk of complex branching patterns compared with the volumetry-predominant segment (37% vs 19%, respectively; P < 0.005). CONCLUSIONS: Volumetric assessment of the right upper lobe showed a heterogeneous segmental volume distribution. Care should be taken during lung segmentectomy of the volumetry-non-predominant segments because of the high risk associated with complex bronchial branching patterns. CLINICAL TRIAL REGISTRATION: No. 4840.

Successful resection after first-line lenvatinib therapy in an advanced thymic carcinoma.

Thymic carcinoma is a highly malignant tumor and treatment options are limited. Lenvatinib, a novel multitargeted kinase inhibitor, has recently been approved for the treatment of unresectable thymic carcinoma. There are no reports of complete surgical resection after the administration of first-line lenvatinib in advanced thymic carcinoma. A 50-year-old man visited our hospital because a computed tomography (CT) scan of the chest showed a large thymic squamous cell carcinoma. We suspected malignant pericardial effusion, invasion of the left upper lobe of the lung, and left mediastinal lymph node metastases. The patient was diagnosed with WHO classification stage IVb disease. Lenvatinib therapy was started at 24 mg/day as first-line therapy. Gradual dose reduction to 16 mg/day was required because of hypertension, diarrhea, and palmar-plantar erythrodysesthesia syndrome as side effects. Chest CT findings after 6 months of lenvatinib therapy showed reduction of the main tumor, disappearance of the mediastinal lymph node metastases, and pericardial effusion. Complete salvage resection was successfully performed a month after discontinuation of lenvatinib. The patient has been disease-free for 1 year without adjuvant therapy. Lenvatinib therapy is one of the promising therapeutic options for thymic carcinoma and may make salvage surgery increasingly useful for advanced thymic carcinoma.

ATM-dependent phosphorylation of CHD7 regulates morphogenesis-coupled DSB stress response in fetal radiation exposure.

Following radiation exposure, unrepaired DNA double-strand breaks (DSBs) persist to some extent in a subset of cells as residual damage; they can exert adverse effects, including late-onset diseases. In search of the factor(s) that characterize(s) cells bearing such damage, we discovered ataxia-telangiectasia mutated (ATM)-dependent phosphorylation of the transcription factor chromodomain helicase DNA binding protein 7 (CHD7). CHD7 controls the morphogenesis of cell populations derived from neural crest cells during vertebrate early development. Indeed, malformations in various fetal bodies are attributable to CHD7 haploinsufficiency. Following radiation exposure, CHD7 becomes phosphorylated, ceases promoter/enhancer binding to target genes, and relocates to the DSB-repair protein complex, where it remains until the damage is repaired. Thus, ATM-dependent CHD7 phosphorylation appears to act as a functional switch. As such stress responses contribute to improved cell survival and canonical nonhomologous end joining, we conclude that CHD7 is involved in both morphogenetic and DSB-response functions. Thus, we propose that higher vertebrates have evolved intrinsic mechanisms underlying the morphogenesis-coupled DSB stress response. In fetal exposure, if the function of CHD7 becomes primarily shifted toward DNA repair, morphogenic activity is reduced, resulting in malformations.

Anatomical resection for right B3 downwards-shifting malformation.

The right B3 downwards-shifting malformation is rare. This malformation often leads to the following complications: abnormal pulmonary arteries that accompany the downward-displaced B3, and complete fusion of the upper and middle lobes into one lobe, with no horizonal fissure. When performing pulmonary anatomical resection in the right upper or middle lobes in patients with this malformation, careful preoperative planning and surgical technique are required, with which the surgeon should be familiar. Herein, we present the anatomical features necessary for anatomical resection of the right B3 downwards-shifting malformation based on our technical experiences with anatomic segmentectomy and lobectomy techniques.

Is using a consolidation tumor ratio 0.5 as criterion feasible in daily practice? Evaluation of interobserver measurement variability of consolidation tumor ratio of lung cancer less than 3 cm in size.

BACKGROUND: Consolidation tumor ratio (CTR) calculated as the ratio of the tumor consolidation diameter to the tumor maximum diameter on thin-section computed tomography (CT) of lung cancer has been reported as an important prognostic factor. It has also been used for treatment decision-making. This study aimed to investigate the interobserver variability of CTR measurements on preoperative CT and propose a clinically useful CTR-based classification criterion. METHODS: We enrolled 119 patients who underwent surgery for suspected or diagnosed small-sized lung cancer (≤3.0 cm in diameter). Nine doctors reviewed preoperative CT scans to measure CTR. Interobserver variability of CTR measurements was evaluated using the coefficient of variation (CV) and Fleiss' κ. The prognostic effect of the CTR-based classification was assessed using the Kaplan-Meier method. RESULTS: Interobserver variability of CTR measurement was the highest for tumors with the lowest CTR (CTR = 0); it decreased as CTR increased and reached a plateaued level of low variability (CV <0.5) at CTR of 0.5. We proposed a three-group classification based on the findings of CTR interobserver variability (CTR < 0.5, 0.5 ≤ CTR < 1, and CTR = 1). Interobserver agreement of the judgment of the CTR-based classification was excellent (Fleiss' κ = 0.81). The classification significantly stratified patient prognosis (p < 0.001, 5-year overall survival rates with CTR < 0.5, 0.5 ≤ CTR < 1, and CTR = 1 were 100, 88, and 73.8%, respectively). CONCLUSIONS: CTR 0.5 is a clinically relevant and helpful cutoff for treatment decision-making in patients with early-stage lung cancer based on high interobserver agreement and good prognostic stratification.

Epidemiological analysis of lung and mediastinal neuroendocrine neoplasms in Japan based on the national database.

BACKGROUND: Neuroendocrine neoplasms (NENs) are rare and can originate from any body part. However, there are only few epidemiological studies, especially on lung and mediastinal NENs. This study investigated the epidemiological trends and differences between lung and mediastinal NENs in Japan. METHODS: Patients with lung and mediastinal NENs were identified in a national hospital-based cancer registry between 2009 and 2015 in Japan. NENs were subclassified into neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). NECs were further subdivided into large neuroendocrine carcinomas (LCNECs) and small cell carcinomas (SCCs). We examined the patient characteristics: sex, age, histology, year of diagnosis, diagnostic opportunity, and initial treatment. RESULTS: We identified 48,433 patients with 47,888 lung (98.9%) and 545 mediastinal (1.1%) NENs. The commonest subtype of lung NENs was SCCs (87%), followed by LCNECs (10%) and NETs (3%). In the mediastinum, SCCs were also the commonest (48%), followed by NETs (38%) and LCNECs (14%). The number of lung NEN annually increased; however, that of mediastinal NENs did not change over time. The mean age of patients with lung NETs was lower than that of patients with lung LCNECs and SCCs (NETs, 62 ± 14 years; LCNECs, 70 ± 9 years; SCCs, 71 ± 9 years; p < .001). The lung and mediastinal NENs were mainly detected based on symptoms, except for lung NETs. Surgical intervention, including multimodal therapy, was performed for 89.3% of lung NETs (surgery alone: 83.6%), while only 15.6% of lung NECs were treated with surgery. For the mediastinum, 75.9% of NETs were treated with surgery, with 27.1% of cases treated with surgery plus multimodal therapy. Surgery was performed more frequently for mediastinal NECs (37%) than for lung NECs (15.6%). CONCLUSIONS: This study highlights differences in trends of lung and mediastinal NENs. This study's findings support the importance of epidemiological evaluations based on the primary sites and histological subtypes.

A Novel Strategy for the Diagnosis of Pulmonary High-Grade Neuroendocrine Tumor.

Correctly diagnosing a histologic type of lung cancer is important for selecting the appropriate treatment because the aggressiveness, chemotherapy regimen, surgical approach, and prognosis vary significantly among histologic types. Pulmonary NETs, which are characterized by neuroendocrine morphologies, represent approximately 20% of all lung cancers. In particular, high-grade neuroendocrine tumors (small cell lung cancer and large cell neuroendocrine tumor) are highly proliferative cancers that have a poorer prognosis than other non-small cell lung cancers. The combination of hematoxylin and eosin staining, Ki-67, and immunostaining of classic neuroendocrine markers, such as chromogranin A, CD56, and synaptophysin, are normally used to diagnose high-grade neuroendocrine tumors; however, they are frequently heterogeneous. This article reviews the diagnostic methods of lung cancer diagnosis focused on immunostaining. In particular, we describe the usefulness of immunostaining by Stathmin-1, which is a cytosolic phosphoprotein and a key regulator of cell division due to its microtubule depolymerization in a phosphorylation-dependent manner, for the diagnosis of high-grade neuroendocrine tumors.

Angiomatoid fibrosis histiocytoma in the pulmonary artery: A case report.

Angiomatoid fibrosis histiocytoma (AFH) is a rare neoplastic disease. Only one report has demonstrated an intraluminal tumor of the pulmonary artery (PA) corresponding to AFH to date. We describe the case of AFH with EWSR1-CREB1 fusion occurring in the ascending artery. A 42-year-old man exhibited an abnormal nodule on chest computed tomography (CT) during checkup. It revealed an intraluminal mass in the ascending artery with significant metabolic uptake in positron emission tomography (PET)/CT. Therefore, right upper lobectomy with wedge resection of the PA trunk was performed. Histologically, the tumor was multinodular and surrounded by a dense lymphoplasmacytic cuff. Each nodule was composed of myxoid stroma and comprised ovoid or spindle cell fascicles with mild atypia. Fluorescent in situ hybridization (FISH) analysis confirmed EWSR1-CREB1 fusion. A diagnosed as AFH was made. This report widens the spectrum of differential diagnoses of primary tumors occurring in the PA.

A case of giant enteric muco-submucosal elongated polyp detected by melena.

A 78-year-old woman was admitted for examination and treatment of melena. Although upper and lower gastrointestinal endoscopy and abdominal computed tomography showed no bleeding lesions, oral double-balloon endoscopy revealed a long, slender polyp covered with normal mucosa and accompanied with erosions in the proximal jejunum. Surgical resection was successful. Histopathologically, the polyp was 125 mm in length and composed of edematous mucosa with dilated blood vessels. The growth was diagnosed as a rare enteric muco-submucosal elongated polyp. Her melena improved postoperatively.

Differences in postoperative changes in pulmonary functions following segmentectomy compared with lobectomy.

OBJECTIVES: To clarify differences in postoperative changes in systemic and regional pulmonary functions between segmentectomy and lobectomy in patients with lung cancer, we compared the 2 procedures using lung perfusion scintigraphy with a fusion image of single-photon emission computed tomography and computed tomography. METHODS: This study is a retrospective matched cohort study of consecutively acquired data. Pulmonary function tests and perfusion single-photon emission computed tomography/computed tomography were conducted before surgery and 6 months after surgery to measure changes in forced expiratory volume in 1 s of a whole lung, contralateral lung and a lobe. After exactly matching the site of the resected lobe between the 2 procedures, propensity scores for age, sex, smoking status and pulmonary function were used to match them. RESULTS: Of the 184 patients treated with segmentectomy and the 208 patients treated with lobectomy between 2013 and 2016, 103 patients were selected from each group after the matching. Whole lung function was significantly more preserved after segmentectomy than after lobectomy (P < 0.001). Segmentectomy preserved the function of the operated lobe with 48 ± 21% of the preoperative function. The function of the ipsilateral non-operated lobe increased after segmentectomy (P = 0.003) but not after lobectomy (P = 0.97). Contralateral lung function increased after both procedures (P < 0.001). CONCLUSIONS: Our data suggest that segmentectomy preserved whole lung function better than lobectomy, because it not only preserved the lobe but also increased the function of the ipsilateral non-operated lobe. Lobectomy did not result in an increase of ipsilateral non-operated lobe function. Contralateral lung function increased after both procedures. The postoperative increase in regional functions could be the result of compensatory lung growth.

Progerin, the protein responsible for the Hutchinson-Gilford progeria syndrome, increases the unrepaired DNA damages following exposure to ionizing radiation.

INTRODUCTION: Progerin, the protein responsible for the Hutchinson-Gilford Progeria Syndrome (HGPS), is a partially deleted form of nuclear lamin A, and its expression has been suggested as a cause for dysfunctional nuclear membrane and premature senescence. To examine the role of nuclear envelop architecture in regulating cellular aging and DNA repair, we used ionizing radiation to increase the number of DNA double strand breaks (DSBs) in normal and HGPS cells, and analyzed possible relationship between unrepaired DSBs and cellular aging. RESULTS: We found that HGPS cells are normal in repairing a major fraction of radiation-induced double strand breaks (M-DSBs)but abnormal to show increased amount of residual unrepaired DSBs (R-DSBs). Such unrepaired DSBs were 2.6 times (CI 95 %: 2.2-3.2) higher than that in normal cells one week after the irradiation, and 1.6 times (CI 95 %: 1.3-1.9) higher even one month after the irradiation. These damages tend to increase as the nuclear envelope become abnormal, a characteristic of both HGPS and normal human cells which undergo replicative senescence. The artificial, enforced over-expression of progerin further impaired the repair of M-DSBs, implying lamin A-associated nuclear membrane has an important role for DNA DSB repair. Introduction of telomerase gene function in HGPS cells reversed such aging phenotypes along with upregulation of lamin B1 and downregulation of progerin, which is a hallmark of young cells. CONCLUSION: We suggest that lamin A- or progerin-associated nuclear envelope is involved in cellular aging associated with DNA damage repair.

Fetal irradiation of rats induces persistent translocations in mammary epithelial cells similar to the level after adult irradiation, but not in hematolymphoid cells.

In both humans and mice, fetal exposure to radiation fails to induce a persistent increase in the frequency of chromosome aberrations in blood lymphocytes. Such a low-level response to radiation exposure is counterintuitive in view of the generally accepted belief that a fetus is sensitive to radiation. To determine if this is a general phenomenon, both mammary epithelial cells and spleen cells were studied in rats. Fetuses of 17.5 days postcoitus were irradiated with 2 Gy of gamma rays, and mammary tissues were removed 6-45 weeks later. Subsequently, short-term cultures were established to detect translocations using the two-color FISH method. The results showed that translocation frequencies were not only elevated in rats irradiated as fetuses, but were also almost as high as those in rats that were irradiated as adults (12 weeks old, pregnant mothers or young virgins) and examined 6-45 weeks later. There was no evidence of higher sensitivity in fetal cells with respect to the induction of translocations. In contrast, translocation frequencies in spleen cells were not elevated in adult rats irradiated as fetuses but were increased after irradiation of adults as previously seen in mouse spleen cells and human T lymphocytes. In the case of irradiation of adult rats, the induced translocation frequencies were similar between spleen cells and mammary epithelial cells. If we take translocation frequency as a surrogate marker of potential carcinogenic effect of radiation, the current results suggest that fetal irradiation can induce persistent potential carcinogenic damage in mammary stem/progenitor cells but this does not contribute to the increased risk of cancer since it has been reported that irradiation of fetal rats of the SD strain does not increase the risk of mammary cancers. Possible reasons for this discrepancy are discussed.