Activating point mutations in the MET kinase domain represent a unique molecular subset of lung cancer and other malignancies targetable with MET inhibitors.

Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas (PRCC). Here, using comprehensive genomic profiling among >600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of ~0.5%. The most common mutations in the MET TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others. Preclinical modeling of these alterations confirmed their oncogenic potential, and also demonstrated differential patterns of sensitivity to type I and type II MET inhibitors. Two patients with metastatic lung adenocarcinoma harboring MET TKD mutations (H1094Y, F1200I) and no other known oncogenic drivers achieved confirmed partial responses to a type I MET inhibitor. Activating MET TKD mutations occur in multiple malignancies and may confer clinical sensitivity to currently available MET inhibitors.

Prognosis of non-small cell lung cancer with postoperative regional lymph node recurrence.

BACKGROUND: Regional lymph node recurrence after radical surgery for non-small cell lung cancer (NSCLC) is an oligo-recurrent disease; however, no treatment strategy has been established. In the present study we aimed to determine the clinical outcomes of postoperative regional lymph node recurrence and identify prognostic predictors in the era of molecular-targeted therapy. METHODS: We retrospectively analyzed data on clinical characteristics and outcomes of patients with regional lymph node recurrence after surgery who underwent treatment for NSCLC between 2002 and 2022. RESULTS: A total of 53 patients were included in this study. The median time between surgery and detection of recurrence was 1.21 years. Radiotherapy (RT) alone and chemoradiotherapy (CRT) were performed in 38 and six patients, respectively. Driver gene alterations were detected in eight patients (EGFR: 6, ROS1:1, and BRAF: 1) and programmed death-ligand 1 (PD-L1) expression was examined in 22 patients after 2016. Median progression-free survival (PFS) and overall survival (OS) after lymph node recurrences were 1.32 and 4.34 years, respectively. Multiple lymph node recurrence was an independent prognostic factor for PFS, whereas driver gene alteration was the only prognostic factor for OS. There was no significant difference in the OS between patients stratified according to the initial treatment modality for lymph node recurrence. CONCLUSION: Our results suggest that the number of tumor recurrences may correlate with PFS, while detection of driver gene alterations could guide decision-making for the appropriate molecular-targeted therapy to achieve longer OS.

RNF31 promotes proliferation and invasion of hepatocellular carcinoma via nuclear factor kappaB activation.

RNF31 is a multifunctional RING finger protein implicated in various inflammatory diseases and cancers. It functions as a core component of the linear ubiquitin chain assembly complex (LUBAC), which activates the nuclear factor kappaB (NF-κB) pathway via the generation of the Met1-linked linear ubiquitin chain. We aimed to clarify the role of RNF31 in the pathogenesis of hepatocellular carcinoma (HCC) and its relevance as a therapeutic target. High RNF31 expression in HCC, assessed by both immunohistochemistry and mRNA levels, was related to worse survival rates among patients with HCC. In vitro experiments showed that RNF31 knockdown in HCC cell lines led to decreased cell proliferation and invasion, as well as suppression of tumor necrosis factor (TNF)-α-induced NF-κB activation. Treatment with HOIPIN-8, a specific LUBAC inhibitor that suppresses RNF31 ubiquitin ligase (E3) activity, showed similar effects, resulting in decreased cell proliferation and invasion. Our clinical and in vitro data showed that RNF31 is a prognostic factor for HCC that promotes tumor aggressiveness via NF-κB activation.

The oncogenic role of LGR6 overexpression induced by aberrant Wnt/ß-catenin signaling in lung cancer.

BACKGROUND: Molecular abnormalities in the Wnt/ß-catenin pathway confer malignant phenotypes in lung cancer. Previously, we identified the association of leucine-rich repeat-containing G protein-coupled receptor 6 (LGR6) with oncogenic Wnt signaling, and its downregulation upon ß-catenin knockdown in non-small cell lung cancer (NSCLC) cells carrying CTNNB1 mutations. The aim of this study was to explore the mechanisms underlying this association and the accompanying phenotypes. METHODS: LGR6 expression in lung cancer cell lines and surgical specimens was analyzed using quantitative RT-PCR and immunohistochemistry. Cell growth was assessed using colony formation assay. Additionally, mRNA sequencing was performed to compare the expression profiles of cells subjected to different treatments. RESULTS: LGR6 was overexpressed in small cell lung cancer (SCLC) and NSCLC cell lines, including the CTNNB1-mutated NSCLC cell lines HCC15 and A427. In both cell lines, LGR6 knockdown inhibited cell growth. LGR6 expression was upregulated in spheroids compared to adherent cultures of A427 cells, suggesting that LGR6 participates in the acquisition of cancer stem cell properties. Immunohistochemical analysis of lung cancer specimens revealed that the LGR6 protein was predominantly overexpressed in SCLCs, large cell neuroendocrine carcinomas, and lung adenocarcinomas, wherein LGR6 overexpression was associated with vascular invasion, the wild-type EGFR genotype, and an unfavorable prognosis. Integrated mRNA sequencing analysis of HCC15 and A427 cells with or without LGR6 knockdown revealed LGR6-related pathways and genes associated with cancer development and stemness properties. CONCLUSIONS: Our findings highlight the oncogenic roles of LGR6 overexpression induced by aberrant Wnt/ß-catenin signaling in lung cancer.

Anatomy of the lung revisited by 3D-CT imaging.

The anatomy of the lung was originally described based on data acquired from cadaveric studies and surgical findings. Over time, computed tomography (CT) and three-dimensional (3D) imaging techniques have been developed, allowing for reconstruction and understanding of lung anatomy in a more intuitive way. The wide adoption of 3D-CT imaging technology has led to a variety of anatomical studies performed not only by anatomists but also by surgeons and radiologists. Such studies have led to new or modified classification systems, shed light on lung anatomy from a useful surgical viewpoint, and enabled us to analyze lung anatomy with a focus on particular anatomical features. 3D images also allow for enhanced pre- and intra-operative simulation, improved surgical safety, enhanced educational utility, and the capacity to perform large-scale anatomical studies in shorter time frames. We will review here the key features of 3D-CT imaging of the lung, along with representative anatomical studies regarding (I) general lung anatomy, (II) anatomy of the right and left lobes, and (III) features of interlobar vessels. The current surge of 3D imaging analysis shows that the field is growing, with the technology continuing to improve. Future studies using these new and innovative methodologies will continue to refine our understanding of lung anatomy while enhancing our ability to perform safe and effective surgical resections.

Risk factors for late-onset pulmonary fistula after pulmonary segmentectomy.

Background: Late-onset pulmonary fistula (LOPF) is a well-described complication after segmentectomy, but the precise incidence and risk factors are still unclear. We aimed to determine the incidence of, and risk factors for, LOPF development after segmentectomy. Methods: A single-institution retrospective study was performed. A total of 396 patients who underwent segmentectomy were enrolled. Perioperative data were analyzed to identify the risk factors for LOPF requiring readmission according to univariate and multivariate analyses. Results: The overall morbidity rate was 19.4%. The incidence rates of prolonged air leak (PAL) in the early phase and LOPF in the late phase were 6.3% (25/396) and 4.5% (18/396), respectively. The most common surgical procedures with LOPF development were segmentectomy of the upper-division (n=6) and S6 (n=5). With a univariate analysis, presence of smoking-related diseases did not affect LOPF development (P=0.139). Conversely, segmentectomy with cranial side free space (CSFS) in the intersegmental plane and use of electrocautery to divide the intersegmental plane were associated with a high risk of LOPF development (P=0.006 and 0.009, respectively). A multivariate logistic regression analysis showed that segmentectomy with CSFS in the intersegmental plane and use of electrocautery were independent risk factors for LOPF development. Approximately 80% of patients who developed LOPF recovered by prompt drainage and pleurodesis without reoperation, whereas the remaining patients developed empyema due to delayed drainage. Conclusions: Segmentectomy with CSFS is an independent risk factor for LOPF development. Careful postoperative follow up and rapid treatment are necessary to avoid empyema.

Clinicopathological features and surgical outcomes of lobectomy combined with segmentectomy: a cohort study.

Background: Segmentectomy is a standard procedure, and there is considerable data on routine segmentectomies. However, there are only few reports on lobectomy performed in combination with segmentectomy (lobectomy + segmentectomy). Thus, we aimed to clarify the clinicopathological features and surgical outcomes of lobectomy + segmentectomy. Methods: We reviewed patients who underwent lobectomy + segmentectomy between January 2010 and July 2021 at Gunma University Hospital, Japan. We comparatively analyzed clinicopathological data of patients who underwent lobectomy + segmentectomy and those who underwent lobectomy in combination with wedge resection (lobectomy + wedge resection). Results: We collected data from 22 patients who underwent lobectomy + segmentectomy and 72 who underwent lobectomy + wedge resection. Lobectomy + segmentectomy was mainly performed to treat lung cancer, and the median number of resected segments was 4.5 and the median number of lesions was 2. Lobectomy + segmentectomy was associated with a higher rate of thoracotomy and a longer operation time. Incidence of overall complications, including pulmonary fistula and pneumonia was higher in the lobectomy + segmentectomy group. However, there were no significant differences in the length of drainage, major complications, and mortality. For lobectomy + segmentectomy, the only left-sided procedure was a left lower lobectomy + lingulectomy, whereas procedures were diverse on the right side, mostly combining a right upper or middle lobectomy with atypical segmentectomies. Conclusions: Lobectomy + segmentectomy was performed for (I) multiple lung lesions, (II) lesions invading an adjacent lobe, or (III) lesions with a metastatic lymph node invading the bronchial bifurcation. Although lobectomy + segmentectomy is a lung-preserving procedure that can benefit patients with multiple or advanced diseases involving two lobes, this procedure should still be performed following a careful patient selection process.

Identification and molecular analysis of RNF31 Q622H germline polymorphism.

The linear ubiquitin chain assembly complex (LUBAC), which is composed of RING finger protein 31 (RNF31), RANBP2-type and C3HC4-type zinc finger containing 1 and SHANK-associated RH domain interactor subunits, is the only ubiquitin ligase to generate Met1-linked linear ubiquitin chains. Linear ubiquitin chains regulate canonical NF-κB activation and cell death. Single nucleotide polymorphisms in RNF31, such as Q584H and Q622L, are known to cause the activated B cell-like subtype of diffuse large B cell lymphoma (ABC-DLBCL) because of enhanced LUBAC-mediated NF-κB activation. The present study identified a novel Q622H polymorphism of RNF31 in two patients with lung cancer, one of whom had concurrent ABC-DLBCL. Immunohistochemical analyses revealed that although the expression of RNF31 was elevated in both patients, only the ABC-DLBCL specimen showed increased NF-κB activation. Cancer panel analysis showed that the Q622H-related ABC-DLBCL did not harbor co-mutations that were previously reported in Q584H-/Q622L-related ABC-DLBCL. Furthermore, in contrast to Q584H and Q622L, Q622H showed no enhancement effects on LUBAC and NF-κB activity in vitro compared with wild-type RNF31. The present study's structural prediction suggested that the electrostatic interaction related to the Q622 residue may not have had an important role in LUBAC formation. In conclusion, the molecular mechanism and mutational background of RNF31 Q622H differed from that of RNF31 Q584H or Q622L. Furthermore, RNF31 Q622H appeared not to induce NF-κB activation in lung cancer.

Video-assisted thoracoscopic segmentectomy with combined chest wall resection: A case report.

BACKGROUND: Resection of lung cancer with chest wall involvement is an invasive procedure. CASE PRESENTATION: We report a case of pulmonary adenocarcinoma with chest wall involvement that was resected through video-assisted thoracoscopic segmentectomy and combined en bloc resection of the chest wall (2nd to 4th ribs). Surgical stress was decreased by reducing the extent of lung parenchymal resection and applying a video-assisted technique with an additional posterior paravertebral incision. CONCLUSION: A thoracoscopic surgical approach involving incisions in areas requiring resection of the proximal, lateral, and posterior sides of the involved ribs can be applied to tumors invading the chest wall.

Molecular and expressional characterization of tumor heterogeneity in pulmonary carcinosarcoma.

The genetic concordance and heterogeneity of the two components of pulmonary carcinosarcoma (PCS), carcinoma, and sarcoma, have not been fully elucidated because of its rare occurrence. We performed targeted sequencing of the carcinoma and sarcoma components of four PCSs to identify genetic similarities and differences. Formalin-fixed paraffin-embedded tissue samples were macroscopically or microscopically dissected. DNA was extracted from each component, and genetic alterations were analyzed separately. Moreover, we performed RNA-seq analysis on both components of one PCS to compare differences in gene expression profiles. The carcinoma part consisted of adenocarcinoma in two cases, squamous cell carcinoma in one, and adenosquamous carcinoma in the last. TP53 mutation was observed in three samples from the trunk, although it was detected only in the sarcoma part in one case. No specific driver gene mutation was observed; however, KRAS mutations were observed in one case in the trunk. RNA-seq analysis revealed that the rhabdomyosarcoma component expressed various genes related to muscle development, whereas the carcinoma component did not; and that gene expression overall was completely different between the two components. Our study revealed that the two different components of PCS shared common gene mutations in most cases. Although gene expression was different among components, if driver genes such as KRAS were detected in PCS, molecular targeted therapy could be beneficial even when the tumor contains a sarcoma component.

RAB11A Expression Is Associated With Cancer Aggressiveness Through Regulation of FGFR-Signaling in Lung Squamous Cell Carcinoma.

BACKGROUND: Fibroblast growth factor receptor (FGFR)-signaling in lung squamous cell carcinoma (LSCC) is associated with cancer aggressiveness and poor prognosis. Small GTPase RAB11A regulates the recycling of membrane proteins such as FGFR. This study evaluated the potential of RAB11A as a new therapeutic target for LSCC through its regulation of FGFR-signaling. METHODS: Immunohistochemical analysis of 84 LSCC samples was performed to determine the correlation between RAB11A expression, clinicopathologic features, and prognosis. Alterations in FGFR-signaling were assessed in RAB11A-suppressed and RAB11A-overexpressed LSCC cells both in vitro and in vivo. RESULTS: The study identified RAB11A as a strong predictor of poor prognosis in the LSCC cohort. Cell proliferation and invasion were promoted and inhibited respectively in RAB11A-overexpressed and RAB11A -suppressed LSCC cells. In RAB11A-overexpressed and RAB11A-suppressed LSCC cells, FGFR-signaling was respectively up- and downregulated. The viability of the cells treated with nintedanib and lenvatinib was greater in RAB11A-overexpressing cells than in control cells. The in vivo tumor growth and micro-vessel density of RAB11A-overexpressing tumors were significantly higher than in the control cells. CONCLUSION: As a potentially valuable prognostic marker, RAB11A is a promising therapeutic target for LSCC. Evaluation of RAB11A may be useful for identification of LSCC in patients whose cancer is refractory to FGFR inhibitors.

Clinical and anatomical features of the lateral costal artery and vein.

The lateral costal artery and vein are under recognized yet potentially important vessels for physicians, especially cardiothoracic surgeons. This study sought to determine the prevalence and clinical, anatomical, and radiological features of lateral costal vessels. We retrospectively analyzed lateral costal vessels based on intraoperative images in patients who underwent thoracic surgery at our institute between January 2016 and March 2020. Clinical data and surgical videos were analyzed for patient characteristics, prevalence, length, laterality, and additional anatomical and radiological features. The overall prevalence of lateral costal vessels was 19% and was significantly higher in males than females (22% vs. 14%, p = 0.003). The lateral costal vessels extended beyond the 2nd intercostal space in 74% of the cases, with differing length between the right and left sides in bilateral cases. Lateral costal vessels could be identified intraoperatively using indocyanine green or preoperatively through three-dimensional computed tomography. The prevalence of lateral costal vessels is relatively high and should be acknowledged by physicians prior to procedures involving the vessels.

A "Catlike Cry" as a Symptom of Congenital Tracheoesophageal Fistula.

Congenital tracheoesophageal fistula is usually diagnosed at an early age, but may remain undetected into adulthood if atresia is absent and if the fistula is small. A tracheoesophageal fistula should be suspected in patients with unexplained episodes of respiratory distress or pneumonia; however, more subtle signs can be an important symptom for early recognition of the disease. Ono's sign is a well-known symptom of tracheoesophageal fistula, characterized by paroxysmal coughing triggered by swallowing of fluids. In the present case, air movement between the esophagus and the trachea through the fistula caused a high-pitched sound, which the patient described as a "catlike cry." The high-pitched sound ceased after surgical closure of the fistula. We report here the symptom of "catlike cry" as one manifestation of tracheoesophageal fistula.

Complex vs. simple segmentectomy: comparing surgical outcomes in the left upper division.

BACKGROUND: Lung segmentectomy is an option for the treatment of noninvasive or minimally invasive lung cancer. For tumors located in the left upper division (LUD), LUD trisegmentectomy (S1+2 + S3) is frequently performed as a sublobar resection because of its technical simplicity. However, the differences in surgical outcomes between simple and complex segmentectomies remain unclear. METHODS: We compared the surgical outcomes and frequency of postoperative complications of LUD trisegmentectomy (simple group) with those of complex segmentectomy (other than LUD trisegmentectomy; complex group) for pulmonary lesions using three-dimensional computed tomography between 2010 and 2021. RESULTS: In total, 118 patients were included: 65 in the simple group and 53 in the complex group (S1+2: 25, S3: 15, others: 13). There were no significant differences in surgical time or duration of postoperative chest drainage. However, the blood loss volume was significantly smaller in the complex group than in the simple group (12 vs. 36 mL, p = 0.023), and major complications tended to occur less frequently in the complex group than in the simple group (3.8 vs. 13.8%, p = 0.061). Among patients who underwent intentional segmentectomy for primary lung cancer (n = 61), major complications were significantly less common in the complex group (p = 0.006). CONCLUSIONS: Complex segmentectomy can be performed safely under the guidance of three-dimensional CT. Complex segmentectomy itself is not a risk factor for postoperative complications when the intersegmental planes are sufficiently recognized and accurately cut.

Surgical outcomes after multiple segmentectomy: a cohort study.

BACKGROUND: Segmentectomy is now a common treatment option for both lung cancer and metastatic lung tumors with increasing data and evidence. However, data on multiple segmentectomy of different lobes are scarce. Our objective was to clarify the clinicopathological features of multiple segmentectomy. METHODS: We reviewed patients who underwent segmentectomy between January 2010 and December 2019 at Gunma University Hospital. Multiple segmentectomy was defined as segmentectomy of different lobes during the same operation, in contrast to single segmentectomy, which was defined as segmentectomy of a single lobe. Clinicopathologic, operative, and postoperative results were compared between multiple segmentectomy and single segmentectomy. RESULTS: There were 324 patients who underwent single segmentectomy and 11 patients (12 cases) who underwent multiple segmentectomy. Multiple segmentectomy was mostly performed for treatment of metastatic lesions rather than lung cancer. The median number of resected segments was 1 (range, 1-5) in the single segmentectomy group and 3 (range, 2-4) in the multiple segmentectomy group. The median number of resected lung lesions was 3.5 in the multiple segmentectomy group. Multiple segmentectomy was associated with longer operative time, more bleeding, and longer drainage period and postoperative stay than the single segmentectomy group. There were no significant differences in severe complications as well as 30- and 90-day mortality. CONCLUSIONS: Multiple segmentectomy is a lung-preserving procedure that can be considered for patients with multiple lung lesions and has feasible postoperative outcomes.

Taste disorder in a patient with invasive thymoma without myasthenia gravis: a rare case report.

Taste disorder has been reported as a non-motor symptom caused by myasthenia gravis (MG)-related autoimmune mechanism. Taste disorder in some cases recovered along with MG treatment, such as thymothymectomy or immunosuppressive treatment. However, symptom of taste disorder in thymoma patients without MG is very rare. Here, we reported a case of invasive thymoma without MG which had concurrent taste disorder. The taste disorder was successfully treated with cyclosporine. A female in her seventies had an anterior mediastinal tumor of 78-mm in diameter and pleural dissemination. She also had taste disorder, limited to sweet taste, and pure red cell aplasia (PRCA). Symptoms and physical findings showed no feature of MG. Pre-operative blood examination revealed no elevation of anti-acetylcholine receptor antibody . Extended total thymothymectomy and resection of all detectable pleural disseminations was performed. Pathological examination showed type B3 thymoma. Clinical stage was Masaoka stage IVa. After operation, there was no improvement in taste disorder and PRCA. Six months after operation, cyclosporine was administered for PRCA. In parallel with gradual improvement of anemia, taste disorder also gradually improved. Three months after the first administration of cyclosporine, taste disorder had completely recovered. This is the first case of taste disorder without any myasthenic status, which recovered with immunosuppressive drug. Our case suggested the potency of immunosuppressive treatment for taste disorder associate with thymoma without MG.

Superior Lingular S4 Segmentectomy.

Although segmentectomy has become a routine procedure, atypical segmentectomies are less popular than their typical counterparts, probably because anatomic and surgical data are lacking. The left superior lingular S4 segment is considered relatively small, usually resected along with other segments. However S4 segment size varies among patients, and resection of this single segment can be a valuable lung-preserving procedure in carefully selected patients with tumors located at the border of the upper division and lingular segments. We present here the anatomic and surgical features required for a methodologic left S4 segmentectomy based on our experience and the literature.

Comprehensive expressional analysis of chemosensitivity-related markers in large cell neuroendocrine carcinoma of the lung.

OBJECTIVES: Various drug-sensitivity markers have been reported to be associated with tumor progression and chemotherapy resistance. Detailed expression profiles of sensitivity markers for cytotoxic chemotherapy in pulmonary large cell neuroendocrine carcinoma (LCNEC) remain unclear. Herein, we aimed to clarify the correlation between the expression of drug-sensitivity markers and clinicopathological features, prognostic impact, and status of tumor immunity in patients with LCNEC. METHODS: We retrospectively analyzed the correlation between clinicopathological features and the expression of drug-sensitivity-related markers, including vascular endothelial growth factor 2 (VEGFR2), thymidylate synthase (TS), tubulin beta 3 class III (TUBB3), topoisomerase I (Topo-I), and Topo-II in 92 surgically resected LCNEC samples. Furthermore, we examined the prognostic significance of expression of these and their correlation with the immune cell status. RESULTS: Overall, high expression of TS, TUBB3, VEGFR2, Topo-I, and Topo-II was detected in 50 (54%), 31 (34%), 23 (25%), 65 (71%), and 36 (39%) samples, respectively. Univariate and multivariate analyses revealed that advanced pathological T and N factors, positive lymphatic permeation, and Topo-II expression were independent unfavorable prognosticators for recurrence-free survival, and advanced pathological T and N factors, Topo-II positive expression, and TS positive expression were independent unfavorable prognosticators for overall survival. In terms of correlation with immune cell status, higher expression of VEGFR2 was closely linked to negative PD-L1 expression. CONCLUSIONS: These findings suggest that elevated Topo-II and TS expression may contribute to poor outcomes through protumoral biology in patients with LCNEC, and elevated VEGFR2 expression might negatively impact tumor immune reactions in LCNEC.