CDK4/6 signaling attenuates the effect of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer.

Background: Epidermal growth factor receptor (EGFR) mutations, such as exon 19 deletion and exon 21 L858R, are driver oncogenes of non-small cell lung cancer (NSCLC), with EGFR tyrosine kinase inhibitors (TKIs) being effective against EGFR-mutant NSCLC. However, the efficacy of EGFR-TKIs is transient and eventually leads to acquired resistance. Herein, we focused on the significance of cell cycle factors as a mechanism to attenuate the effect of EGFR-TKIs in EGFR-mutant NSCLC before the emergence of acquired resistance. Methods: Using several EGFR-mutant cell lines, we investigated the significance of cell cycle factors to attenuate the effect of EGFR-TKIs in EGFR-mutant NSCLC. Results: In several EGFR-mutant cell lines, certain cancer cells continued to proliferate without EGFR signaling, and the cell cycle regulator retinoblastoma protein (RB) was not completely dephosphorylated. Further inhibition of phosphorylated RB with cyclin-dependent kinase (CDK) 4/6 inhibitors, combined with the EGFR-TKI osimertinib, enhanced G0/G1 cell cycle accumulation and growth inhibition of the EGFR-mutant NSCLC in both in vitro and in vivo models. Furthermore, residual RB phosphorylation without EGFR signaling was maintained by extracellular signal-regulated kinase (ERK) signaling, and the ERK inhibition pathway showed further RB dephosphorylation. Conclusions: Our study demonstrated that the CDK4/6-RB signal axis, maintained by the MAPK pathway, attenuates the efficacy of EGFR-TKIs in EGFR-mutant NSCLC, and targeting CDK4/6 enhances this efficacy. Thus, combining CDK4/6 inhibitors and EGFR-TKI could be a novel treatment strategy for TKI-naïve EGFR-mutant NSCLC.

Efficacy of gilteritinib in comparison with alectinib for the treatment of ALK-rearranged non-small cell lung cancer.

Gilteritinib is a multitarget tyrosine kinase inhibitor (TKI), approved for the treatment of FLT3-mutant acute myeloid leukemia, with a broad range of activity against several tyrosine kinases including anaplastic lymphoma kinase (ALK). This study investigated the efficacy of gilteritinib against ALK-rearranged non-small cell lung cancers (NSCLC). To this end, we assessed the effects of gilteritinib on cell proliferation, apoptosis, and acquired resistance responses in several ALK-rearranged NSCLC cell lines and mouse xenograft tumor models and compared its efficacy to alectinib, a standard ALK inhibitor. Gilteritinib was significantly more potent than alectinib, as it inhibited cell proliferation at a lower dose, with complete attenuation of growth observed in several ALK-rearranged NSCLC cell lines and no development of drug tolerance. Immunoblotting showed that gilteritinib strongly suppressed phosphorylated ALK and its downstream effectors, as well as mesenchymal-epithelial transition factor (MET) signaling. By comparison, MET signaling was enhanced in alectinib-treated cells. Furthermore, gilteritinib was found to more effectively abolish growth of ALK-rearranged NSCLC xenograft tumors, many of which completely receded. Interleukin-15 (IL-15) mRNA levels were elevated in gilteritinib-treated cells, together with a concomitant increase in the infiltration of tumors by natural killer (NK) cells, as assessed by immunohistochemistry. This suggests that IL-15 production along with NK cell infiltration may constitute components of the gilteritinib-mediated antitumor responses in ALK-rearranged NSCLCs. In conclusion, gilteritinib demonstrated significantly improved antitumor efficacy compared with alectinib against ALK-rearranged NSCLC cells, which can warrant its candidacy for use in anticancer regimens, after further examination in clinical trial settings.

Cone-Beam Computed Tomography-Guided Marking of Small Pulmonary Nodules with Surgical Clips.

BACKGROUND: Preoperative computed tomography-guided marking can help identify small non-palpable pulmonary nodules during surgery. However, this technique is associated with the risk of air embolism. We retrospectively evaluated whether small pulmonary nodules could be intraoperatively localized using cone-beam computed tomography (CBCT). METHODS: A hybrid operating room permitting stable lateral positioning and scanning from the pulmonary apex to the base was used in all patients. CBCT images were obtained using a 10-s protocol with 180º rotation of the C-arm flat panel detector around the patient. Clips were placed on the visceral pleura to help guide pulmonary nodule localization. Partial pulmonary resection was performed using video-assisted thoracoscopic surgery at the predicted nodule site. RESULTS: Between July 2013 and June 2019, 132 patients with 145 lesions underwent this procedure at our center. The detection rate of lesions on CBCT was 100%. The pathological diagnoses were primary lung cancer, metastatic pulmonary tumors, and benign lesions. The average consolidation-to-tumor ratio was 0.65 for all nodules, with ratios of 0.33, 0.96, and 0.70 for primary lung cancer, metastatic pulmonary tumors, and benign lesions, respectively. No complications related to this localization method were observed. CONCLUSIONS: CBCT-guided intraoperative localization is safe and feasible for non-palpable small pulmonary nodules. This technique may eliminate the risk of serious complications such as air embolism.

Transformed diffuse large B-cell lymphoma from marginal zone lymphoma in the anterior mediastinum: A case report and review of the literature.

Marginal zone lymphoma (MZL) arising from the anterior mediastinum is rare. In the majority of reported cases, the tumor was incidentally discovered, reflecting its indolent clinical features. We present a 38-year-old woman who had no medical history, and presented with a bulky anterior mediastinal tumor complicated by life-threatening compression of the vasculature and bronchi. Biopsy specimens of the neoplasm suggested transformed diffuse large B-cell lymphoma (DLBCL) from MZL. To our best knowledge, this is the first case report of anterior mediastinum MZL associated with an aggressive clinical course and life-threatening complications likely due to transformation to DLBCL.

An immortalized porcine macrophage cell line competent for the isolation of African swine fever virus.

African swine fever virus (ASFV) is the etiological agent of African swine fever (ASF), a fatal hemorrhagic disease of domestic pigs and wild boar. The virus primarily infects macrophage and monocyte host cells, these do not grow in vitro. Many attempts have been made to establish sustainable ASFV-sensitive cell lines, but which supported only low viral replication levels of limited, mostly artificially attenuated strains of ASFV. Here, we examined the competence of a novel cell line of immortalized porcine kidney macrophages (IPKM) for ASFV infection. We demonstrated that IPKM cells can facilitate high levels (> 107.0 TCID50/mL) of viral replication of ASFV, and hemadsorption reactions and cytopathic effects were observed as with porcine alveolar macrophages when inoculated with virulent field isolates: Armenia07, Kenya05/Tk-1, and Espana75. These results suggested that IPKM may be a valuable tool for the isolation, replication, and genetic manipulation of ASFV in both basic and applied ASF research.

Successful Desensitization Treatment with Osimertinib after the Development of Osimertinib-induced Urticaria in a Patient Undergoing Treatment for Non-small Cell Lung Cancer Harboring the EGFR T790M Mutation.

Some patients discontinue receiving osimertinib for non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) Thr790Met (T790M) mutation due to adverse its effects. We report a case of successful desensitization therapy after osimertinib-induced urticaria. An 85-year-old Japanese woman received osimertinib as third-line therapy for NSCLC with the EGFR T790M mutation. After two days, she developed urticaria of the lower extremities. We started osimertinib desensitization therapy at 0.1 mg/day, which was gradually increased to 40 mg/day. She continued osimertinib for >12 months without adverse effects. Desensitization therapy with osimertinib could be useful for patients experiencing osimertinib-induced urticaria.

Dramatic Response of Brain Metastasis from EGFR-mutation-positive NSCLC to Dacomitinib.

The central nervous system efficacy of dacomitinib, a key agent used in the treatment of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC), is unclear. We herein present our experience in the use of dacomitinib for the treatment of multiple brain metastatic lesions from EGFR-mutation-positive NSCLC in an elderly patient. This case report demonstrates that dacomitinib can be an essential treatment option for patients with brain metastases.

Temporary airway stenting for giant anterior mediastinal tumor biopsy: Two case reports.

INTRODUCTION: When the management of an anterior mediastinal tumor requires general anesthesia, airway narrowing and obstruction may occur secondary to muscle relaxation. PRESENTATION OF CASES: Two men (ages, 15 and 36 years) presented with a giant anterior mediastinal tumor and central airway obstruction. We used Dumon stents to effectively secure the airway in both patients. After chemotherapy, stent removal was safely performed in each case because the tumor was substantially smaller. DISCUSSION: Dumon stents effectively secured the airway. These stents were easily removed after chemotherapy without severe complications. CONCLUSION: Temporary stenting is useful in patients with a giant anterior mediastinal tumor who require general anesthesia.

Lung function in the late postoperative phase and influencing factors in patients undergoing pulmonary lobectomy.

BACKGROUND: Lung function in the late postoperative phase after pulmonary lobectomy is insufficiently characterized. This study aimed to appraise lung function in the late postoperative phase according to vital capacity (VC) and forced expiratory volume in 1 second (FEV1) in patients who underwent pulmonary lobectomy. METHODS: Pre- and postoperative VC and FEV1 were reviewed in 112 patients who underwent pulmonary lobectomy. Postoperative lung volume was assessed >1 year after surgery. Postoperative decreases in VC and FEV1 were compared with preoperative predicted values among patients who underwent resection of specific lobe. Determinants effecting a decrease in lung function were also investigated. RESULTS: A mean postoperative decreased VC of 10.5%±1.8% was recorded in patients who underwent right upper lobectomy (RU), 7.2%±1.5% for right middle lobectomy (RM), 14.3%±2.3% for right lower lobectomy (RL), 16.6%±3.0% for left upper lobectomy (LU), and 14.7%±2.5% for left lower lobectomy (LL). Corresponding FEV1 values were 14.8%±1.8% for RU, 11.9%±4.0% for RM, 14.9%±2.3% for RL, 17.9%±2.9% for LU, and 15.1%±2.4% for LL. The actual decreasing rate of VC was overestimated in patients who underwent RU, RL, LU, and LL. In contrast, FEV1 was overestimated only in patients who underwent RL and LL. Patients with chronic obstructive pulmonary disease (COPD) exhibited significantly better preservation of FEV1. CONCLUSIONS: Patients scheduled for RL and LL, or those with COPD, appeared to exhibit preserved lung function in the late postoperative phase after pulmonary lobectomy.

Survival after initial lung metastasectomy for metastatic colorectal cancer in the modern chemotherapeutic era.

BACKGROUND: A clear survival benefit has been reported for lung metastasectomy for colorectal cancer, and several clinicopathological prognostic factors have been proposed in the past. However, clinical advances, such as chemotherapy and radiographic imaging, should have improved patient outcome and may have altered prognosticators. This study aimed to assess patient survival and determine prognostic factors for survival and recurrence in patients who underwent initial lung metastasectomy for colorectal cancer in the modern clinical era. METHODS: Clinicopathological data and outcomes of 59 patients who underwent curative initial lung metastasectomy for colorectal cancer from 2004 to 2012 at a single institution in Japan were retrospectively investigated. Survival was estimated using the Kaplan - Meier method, and Cox proportional hazards regression models were used to estimate the prognostic impacts of each variable in univariate and multivariate analysis. RESULTS: The 5-years overall and disease-free survival rates were 54.3 and 40.6%, respectively. A disease-free interval < 24 months after colorectal cancer resection (P = 0.004) and a serum carcinoembryonic antigen ≥ 5.0 ng/mL before initial lung metastasectomy (P = 0.015) were independent predictors for poor overall survival. Moreover, the disease-free interval after colorectal cancer resection < 24 months (P = 0.010) and a colorectal cancer with N2 stage disease (P = 0.018) were independently associated with poor disease-free survival. On the other hand, the number of lung metastasis was not identified as a poor prognostic factor for both overall and disease-free survival. CONCLUSIONS: Our findings demonstrated similar or slightly better overall survival, and substantially favorable disease-free survival as compared with past reports. Poor prognostic factors for overall survival appeared not to differ from those of past studies, although this modern series did not determine the number of lung metastasis as a poor prognostic factor, which should be investigated in future studies. Moreover, initial lung metastasectomy is not expected to be a curable treatment for patients with both a short disease-free survival after colorectal cancer resection and colorectal cancers with N2 stage disease.

Experimental validation of talc pleurodesis for carcinomatous pleuritis in an animal model.

OBJECTIVE: This study was performed to evaluate the change of pleural cavity by talc pleurodesis for carcinomatous pleuritis in an animal model. METHODS: Models of malignant pleuritis were produced by an intra-venous injection of lung adenocarcinoma cells to male BALB/c nude mice at 6 weeks of age. Two weeks after the injection, either talc or saline was injected into the left thoracic cavity and the mice were further observed for 4 weeks. Six weeks after the injection, they were killed and the occurrence of lung cancer, amount of pleural effusion, and histological change of the pleural cavity were examined and compared between the two groups with or without talc administration. RESULTS: Talc administration caused a significant reduction in pleural effusion with no increase of pleural adhesion. Talc administration resulted in marked pleural thickening compared to saline treatment. The vascular architecture and its area did not differ between the two groups. CONCLUSION: Talc pleurodesis to reduce pleural effusion is valid for carcinomatous pleuritis, potentially through an acceleration of pleural thickening.

Clinicopathologic and Prognostic Implications of Programmed Death Ligand 1 Expression in Thymoma.

BACKGROUND: Programmed death ligand 1 (PD-L1) has been reported to be expressed in various malignancies and is considered to be a prognostic factor and an immunotherapeutic target. The aim of this study was to characterize PD-L1 expression in thymoma and determine statistical associations between this expression and clinical features. METHODS: We reviewed formalin-fixed, paraffin-embedded tissue specimens from 82 thymoma cases accumulated at Kurume University, the majority of which achieved surgical complete resection. Expression of PD-L1 was evaluated by immunohistochemistry. Statistical associations between PD-L1 expression and clinicopathologic features were evaluated by using χ(2) test and Fisher's exact test. Disease-free survival and overall survival curves were established by the Kaplan-Meier method and compared using a log-rank test. Predictive factors for disease-free survival after complete resection were analyzed by using a Cox proportional hazards model in univariate and multivariate analysis. RESULTS: Overall, 44 thymoma cases (54%) revealed high PD-L1 expression. High PD-L1 expression was statistically associated with Masaoka stage III/IV disease (p = 0.043) and World Health Organization type B2 or B3 thymoma (p = 0.044). Disease-free survival after complete resection in high PD-L1 expression was significantly worse than that in low PD-L1 expression (p = 0.021), although there was no significant difference in overall survival (p = 0.957). Multivariate analysis also revealed high PD-L1 expression as an independent risk factor for recurrence (p = 0.008). CONCLUSIONS: Characterization of PD-L1 expression in thymoma should enable more effective clinical approaches, including prognostic stratification of patients and potential use of anti-PD-L1 antibody immunotherapy.

Thymoma in Patient with Myasthenia Gravis Has Significantly Fewer Forkhead Box P3 Positive Lymphocytes than that without One.

Forkhead box P3 (FoxP3) is known as a pivotal and specific transcriptional factor of regulatory T cells, and are implicated in various immune diseases including myasthenia gravis (MG). The aim of this study was to investigate the relationships between FoxP3 expression of lymphocytes in thymoma and clinicopathological characteristics, particularly MG status in thymoma patients. We reviewed 83 thymoma specimens, including 22 from MG patients, and evaluated the FoxP3 expression of lymphocytes in thymoma using immunohistochemistry (IHC). Statistical association was evaluated using chi-square test and Fisher's exact test. Thirty-four cases (41.0%) were classified as FoxP3 positive. There were no statistical differences in sex (P=0.289), age (P=0.536), Masaoka stage (P=0.086), WHO histological classification (P=0.097), or Myasthenia Gravis Foundation of America (MGFA) Clinical Classification (P=0.117) between FoxP3 positive and negative cases. In contrast, thymoma in cases with MG showed significantly fewer FoxP3 positive lymphocytes than those in cases without MG (P=0.037). Moreover, cases with anti-acetylcholine receptor antibody titer equal to or greater than the normal limit also showed significantly fewer FoxP3 positive lymphocytes than cases within the normal limit (P<0.001). Our result indicated the possibility that the decrease of FoxP3 positive lymphocytes in thymoma may lead to the development of MG and to an increase in anti-acetylcholine receptor antibodies. In addition, FoxP3 positive lymphocytes might be a useful biomarker for evaluation of the risk of MG onset, and could open the way to more effective therapeutic strategies in thymoma patients.

FilGAP, a Rac-specific Rho GTPase-activating protein, is a novel prognostic factor for follicular lymphoma.

FilGAP, a Rho GTPase-activating protein (GAP), acts as a mediator of Rho/ROCK (Rho-associated protein kinase)-dependent amoeboid movement, and its knockdown results in Rac-driven mesenchymal morphology. Herein, we focus on the possible roles of FilGAP expression in normal and malignant lymphocytes. Eighty-three cases of follicular lymphoma (FL), 84 of diffuse large B-cell lymphoma (DLBCL), and 25 of peripheral T-cell lymphoma (PTCL), as well as 10 of normal lymph nodes, were immunohistochemically investigated. In normal lymph nodes, FilGAP immunoreactivity was significantly higher in lymphocytes in the mantle zone as compared to those in the germinal center and paracortical areas. In contrast, the expression levels of both cytoplasmic and perinuclear Rac1 were significantly lower in the germinal center as compared to paracortical regions, suggesting that changes in the FilGAP/Rac axis may occur in B-cell lineages. In malignant lymphomas, FilGAP expression was significantly higher in B-cell lymphomas than PTCL, and the immunohistochemical scores were positively correlated with cytoplasmic Rac1 scores in FL and DLBCL, but not in PTCL. Patients with FL and germinal center B-cell-like (GCB)-type DLBCL showing high FilGAP scores had poor overall survival rates as compared to the low-score patients. Moreover, multivariate Cox regression analysis showed that a high FilGAP score was a significant and independent unfavorable prognostic factor in FL, but not in DLBCL. In conclusion, FilGAP may contribute to change in cell motility of B-lymphocytes. In addition, its expression appears to be useful for predicting the behavior of B-cell lymphoma, in particular FL.

[A Case of Rectal Cancer with Lymphangiosis Carcinomatosa Successfully Treated with Chemotherapy Despite Anaphylactic Reaction to Oxaliplatin].

A 64-year-old man was admitted because of dyspnea. He was diagnosed with rectal cancer with lymphangiosis carcinomatosa and metastases in the liver and lymph nodes. The patient was treated with cetuximab and modified FOLFOX6 (mFOLFOX6). After treatment, the primary rectal cancer and metastases were considered to have achieved a partial response (PR) and the lymphangiosis carcinomatosa remarkably improved. However, anaphylactic shock occurred in the 6 courses of treatment, 5 minutes after the infusion of oxaliplatin, and the patient was treated.

Neutrophil elastase activity in pulmonary venous blood during lung resection.

OBJECTIVES: Neutrophil elastase has been reported to play an important role in acute lung injury, which is a major cause of postoperative mortality after pulmonary resection. Neutrophil elastase released in the lungs reaches the peripheral circulation via the pulmonary veins. This study was performed to compare neutrophil elastase activity in pulmonary venous blood (collected during lobectomy) with that in the peripheral blood, and to determine the perioperative changes of neutrophil elastase activity. METHODS: In 34 patients undergoing lobectomy with mediastinal lymph node dissection, the leucocyte count, neutrophil count, neutrophil elastase activity and levels of tumour necrosis factor-α, interleukin-6 and interleukin-8 were measured in the pulmonary venous blood and peripheral arterial blood before and after surgery. Then, these parameters were compared between before and after surgery with peripheral and pulmonary blood. RESULTS: Neutrophil elastase activity was found to be significantly higher in pulmonary venous blood at the completion of surgery than at the start (during thoracotomy), while the neutrophil elastase activity of peripheral arterial blood showed no significant change between the start and completion of surgery. CONCLUSIONS: In conclusion, measurement of neutrophil elastase activity in pulmonary venous blood revealed changes associated with lobectomy.

Factors related to an early restoration of exercise capacity after major lung resection.

PURPOSE: We attempted to identify the factors related to an early restoration of the exercise capacity after lung resection. METHODS: Major lung resection was performed in 164 patients. Exercise testing and spirometry were performed before surgery, and 2 weeks and 1 month afterward. During exercise, the maximum oxygen uptake per minute per m(2) of body surface area (VO(2)max/m(2)) was measured. The percent change of VO(2)max/m(2) at 2 weeks and 1 month after surgery was calculated by setting the preoperative VO(2)max/m(2) value as 100%. Patients were then assigned to the early restoration group or late restoration group according to their VO(2)max/m(2) measured 2 weeks after surgery. Preoperative cardiopulmonary function, as well as various preoperative and intraoperative factors were compared between the two groups. RESULTS: At 2 weeks after surgery, the mean VO(2)max/m(2) was 80.9% compared with that before surgery, and was 88.1% at 1 month. A multivariate analysis showed that the surgical method used (thoracotomy and mediastinal lymph node dissection) had a significant effect on the postoperative restoration of the VO(2)max/m(2). CONCLUSION: An early restoration of exercise capacity after lung resection is possible in patients without mediastinal lymph node dissection and in those who have a small thoracotomy wound.

Selection of pulmonary resection procedures to reduce postoperative complications in 200 patients.

PURPOSE: We previously demonstrated in a pilot study that postoperative cardiopulmonary complications could be reduced by selecting pulmonary resection procedures based on the results of a combination of specific preoperative cardiopulmonary function tests. The present study reports a re-examination of the criteria for preoperative screening and prospectively assessed whether the selected surgical procedures were appropriate in 200 patients who underwent the planned extent of pulmonary resection. METHODS: In 200 patients requiring lung tumor resection, five preoperative parameters (forced expiratory volume in 1 s on the intact side, maximal oxygen uptake, ejection fraction, occluded pulmonary artery pressure, and occluded total pulmonary vascular resistance index) were used to assign each patient to one of five risk categories in order to select the optimal resection procedure. Thereafter, the postoperative course was investigated to determine the value of this selection method. RESULTS: Thoracotomy was performed in 195 of the 200 patients (97.5%). Two patients (1%) died; one patient succumbed to acute exacerbation of interstitial pneumonia and the other patient died from pulmonary embolism. Six patients (3.1%) developed major complications after surgery and 12 patients (6.2%) had mild complications, while 175 (89.7%) showed a good postoperative course. CONCLUSION: The use of five preoperative parameters to select the pulmonary resection procedure minimized postoperative death and major complications.

Giant liposarcoma occupying most of the hemi-thorax and resected in the supine position: report of a rare case.

Liposarcoma originating in the thoracic cavity is not common. It has been reported that neither chemotherapy nor radiotherapy is effective, and that surgical resection is the only therapeutic option. There have been several cases reported of a large liposarcoma compressing adjacent organs such as the lung and the heart. In such cases, careful management is required to prevent adverse cardiopulmonary events during resection. Here we report a rare case of a 52-year-old male who had a giant liposarcoma occupying the majority of the right thorax. The patient was placed in the supine position, and the tumor was resected through an anterior thoracotomy. Percutaneous cardiopulmonary support (PCPS) was prepared in case of need. However, we succeeded in resecting the huge tumor without use of PCPS. We were unable to completely resect the tumor because it originated from the posterior mediastinum and extended into the left thorax. The resected tumor weighed 3,500 g and was 28 cm in largest diameter. The postoperative course was uneventful, except for hypoxemia lasting a few days caused by re-expansion edema in the lung. The patient was discharged and is alive at five years to date.

Nonmalignant pericardial effusion associated with thymic cancer.

We report a case of thymic carcinoma with massive pericardial effusion in a 74-year-old man. This patient with dyspnea was referred to our hospital because of pericardial effusion detected by echocardiography. A chest computed tomography and magnetic resonance imaging showed an anterior mediastinal mass measuring 8.0 x 5.0 cm with massive pericardial effusion. The mass lesion was suggestive of thymic carcinoma or invasive thymoma. Initially, he underwent pericardial drainage. The collected fluid was serous and yellow, and cytological examination found no malignant cells. The tumor with partial pericardium was resected. Histopathological findings confirmed the lesion to be squamous cell carcinoma of the thymus. The etiology of a massive nonmalignant pericardial effusion associated with thymic carcinoma warrants further studies. The patient is alive without recurrence and without pericardial effusion at 3 years to date after the operation. Not all pericardial effusion associated with thymic cancer involves malignant effusion.