Yosuke Morodomi

Clinical Significance of PD-L1 Protein Expression in Surgically Resected Primary Lung Adenocarcinoma.

Introduction The clinicopathological features of carcinomas expressing programmed death ligand 1 (PD‐L1) and their associations with common driver mutations, such as mutations in the EGFR gene, in lung adenocarcinoma are not clearly understood. Here, we examined PD‐L1 protein expression in surgically resected primary lung adenocarcinoma and the association of PD‐L1 protein expression with clinicopathological features, EGFR mutation status, and patient outcomes. Methods The expression of PD‐L1 protein in 417 surgically resected primary lung adenocarcinomas was evaluated by immunohistochemical analysis. The cutoff value for defining PD‐L1 positivity was determined according to the histogram of proportions of PD‐L1–positive cancer cells. Results Samples from 85 patients (20.4%) and 144 patients (34.5%) were positive for PD‐L1 protein expression according to 5% and 1% PD‐L1 cutoff values, respectively. Fisher’s exact tests showed that PD‐L1 positivity was significantly associated with male sex, smoking, higher tumor grade, advanced T status, advanced N status, advanced stage, the presence of pleural and vessel invasions, micropapillary or solid predominant histological subtypes, and wild‐type EGFR. Univariate and multivariate survival analyses revealed that patients with PD‐L1 positivity had poorer prognoses than those without PD‐L1 protein expression at the 1% cutoff value (disease‐free survival p < 0.0001, overall survival p < 0.0001). Conclusions PD‐L1 protein expression was significantly higher in smoking‐associated adenocarcinoma and in EGFR mutation–negative adenocarcinoma. PD‐L1 protein expression was associated with poor survival in patients with lung adenocarcinoma. The PD‐L1/programmed cell death 1 pathway may contribute to the progression of smoking‐associated tumors in lung adenocarcinoma.

Prognostic significance of intratumoral blood vessel invasion in pathologic stage IA non-small cell lung cancer.

BACKGROUND The 5-year survival rate of pathologic stage IA non-small cell lung cancer (NSCLC) is excellent; however, up to 10% of patients with pathologic stage IA NSCLC still relapse postoperatively and die. This study retrospectively analyzed the clinicopathologic features of patients with pathologic stage IA NSCLC to identify the prognostic factors and investigate the effect of a combination of intratumoral vessel invasion and tumor size. METHODS From December 1991 to December 2003, 217 consecutive patients with stage IA NSCLC were selected, and disease-free survival (DFS) was analyzed. RESULTS Intratumoral blood vessel invasion (BVI) was identified as an independent poor prognostic factor (p = 0.0006). The relative risk for patients with BVI was 4.599 times higher than that for patients without BVI (95% confidence interval, 1.913 to 11.056). According to the new T N M system, the difference in DFS between the patients with and without BVI was statistically significant, not only in tumors exceeding 2 cm (T1b with BVI vs T1b without BVI, p = 0.0020) but also in tumors smaller than 2 cm (T1a with BVI vs T1a without BVI, p < 0.0001). The survival curve of T1b patients without BVI was similar to that of T1a patients without BVI (p = 0.0892). Distant recurrence was frequently observed in both T1a and T1b patients with BVI. CONCLUSIONS BVI is an independent poor prognostic factor in patients with pathologic stage IA NSCLC. These T1a and T1b patients with BVI both might benefit from adjuvant chemotherapy.

PD-L1 Is Upregulated by Simultaneous Amplification of the PD-L1 and JAK2 Genes in Non–Small Cell Lung Cancer

Objectives The programmed death ligand 1(PD‐L1)/programmed cell death protein 1 (PD‐1) pathway is one of the most important checkpoint pathways for mediating tumor‐induced immune suppression through T‐cell exhaustion. Recently, targeted therapies using monoclonal antibodies against components of this pathway have been shown to reduce tumor burden in patients with non–small cell lung cancer (NSCLC). However, the prognostic significance of PD‐L1 expression is controversial and the precise mechanisms of PD‐L1 gene activation in lung cancer have yet to be clarified. Methods We investigated copy number alterations (CNAs) in the PD‐L1 gene by real‐time PCR in 94 surgically resected lung cancer samples to find possible associations between PD‐L1 CNA and lung cancer biology. Janus kinase 2 gene (JAK2) CNA and its influence on the PD‐L1/PD‐1 pathway were also assessed. Results Five samples were shown to have PD‐L1 gene amplification, whereas 89 samples did not. The patients with PD‐L1 amplification had worse prognoses than did those without PD‐L1 amplification. Genetic amplification of the PD‐L1 gene was correlated with JAK2 gene amplification. The lung cancer cell line HCC4006 was found to harbor both JAK2 and PD‐L1 amplification. Flow cytometry analyses revealed the level of PD‐L1 protein expression to be higher in HCC4006 cells than in other NSCLC cell lines. Expression of the PD‐L1 protein was significantly reduced by the JAK2 inhibitor TG‐101348 and the signal transducer and activator of transcription 3 (STAT‐3) inhibitor BP‐1‐102, but not by the STAT1 inhibitor fludarabine. Conclusions Our data suggest that expression of PD‐L1 protein is upregulated by the simultaneous amplification of the PD‐L1 and JAK2 genes through JAK‐STAT signaling in NCSLC.

Predictive impact for postoperative recurrence using the preoperative prognostic nutritional index in pathological stage I non-small cell lung cancer

BACKGROUND The most effective treatment for early-stage non-small cell lung cancer (NSCLC) is surgical resection. Nevertheless, up to 20% of patients, even those with stage I NSCLC, relapse after surgery and die. The prognostic nutritional index (PNI) is used to assess immunonutritional conditions or is a predictor of postoperative recurrence in patients with digestive malignancies. However, the usefulness of the PNI for lung cancer is still unknown. We retrospectively analyzed clinicopathological features of stage I NSCLC patients to identify predictors of recurrence and to investigate effects of preoperative PNI levels. METHODS We selected 141 consecutive stage I NSCLC patients who were treated from August 2005 to August 2010. We measured their preoperative PNI levels in uni- and multivariate Cox regression analyses of recurrence-free survival. RESULTS A low PNI was significantly associated with sex (P=0.0117), preoperative serum carcino embryonic antigen levels (P=0.0228), and postoperative recurrence (P<0.0001). In multivariate analysis, PNI (RR: 9.243; 95% CI: 3.662-25.823; P<0.0001), pleural invasion (RR: 8.664; 95% CI: 2.510-38.056; P=0.0005), and intratumoral blood vessel invasion (RR: 3.151; 95% CI: 1.259-7.681; P=0.0152) were independent prognostic factors. The low-PNI group had a significantly shorter recurrence-free survival than the high-PNI group, regardless of pathological T factors (T1a, P=0.0422; T1b, P<0.0001; T2a, P=0.0098). CONCLUSIONS The preoperative PNI level is a simple and novel predictor of recurrence in stage I NSCLC patients, and might help identify patients who will need multimodality therapy such as induction or adjuvant therapy.

An extremely rare case of small-cell lung cancer harboring variant 2 of the EML4-ALK fusion gene

Anaplastic lymphoma kinase (ALK) fuses echinoderm microtubule-associated protein-like 4 (EML4) to acquire a transforming activity in lung adenocarcinomas. However, the presence of an EML4-ALK fusion gene in other lung cancer histologies is an extremely rare phenomenon. A 43-year-old female was referred to our department due to dyspnea on effort and left back pain. Computed tomography (CT) showed a large mass in the upper lobe of the left lung and a massive left pleural effusion, while a CT-guided needle biopsy confirmed a diagnosis of small-cell lung cancer (SCLC). Surprisingly, the tumor was genetically considered to harbor the EML4-ALK fusion gene (variant 2). Although the patient underwent two regimens of cytotoxic chemotherapy for SCLC, she died approximately seven months after the administration of first-line chemotherapy. Our analysis of 30 consecutive patients with SCLC for EML4-ALK revealed that two patients, including the current patient and a patient we previously reported, harbored the EML4-ALK fusion gene.

Verification of the Newly Proposed T Category (Seventh Edition of the Tumor, Node, and Metastasis Classification) from a Clinicopathological Viewpoint in Non-small Cell Lung Cancer—Special Reference to Tumor Size

Introduction: This study first verified the T classification, which is the major point of the revision regarding the seventh Tumor, Node, and Metastasis classification, from a viewpoint of the clinicopathological findings at the primary tumor site in non-small cell lung cancer. Methods: The medical records of 1393 patients with non-small cell lung cancer who underwent a complete resection at this hospital from 1974 to 2003 were thoroughly reviewed for pathologic findings and survival. Results: According to greatest dimension of the primary tumors, the 5-year postoperative survival was 77.8% for T1a (≤2 cm), 63.3% for T1b (≤3 cm), 46.4% for T2a (≤5 cm), 38.8% for T2b (<7 cm), and 21.4% for T3 (>7 cm). The differences among those new T categories were all statistically significant. The incidence of lymphatic permeation within the primary tumor was 17.2% for T1b and 29.8% for T2a (T1b versus T2a, p < 0.05). The incidence of vascular invasion within the primary tumor was 24.9% for T1b, 35.3% for T2a, and 54.2% for T2b (T1b versus T2a and T2a versus T2b, p < 0.05). On the other hand, the incidence of pleural invasion of the primary tumor was 18.1% for T1a, 29.4% for T1b, 49.3% for T2a, 47.3% for T2b, and 87.5% for T3 (T1a versus T1b, T1b versus T2a, T2b versus T3, p < 0.05). Significant differences were observed among the newly revised T subsets in at least one incidence of lymphatic, vascular, or pleural invasion. Conclusion: The new T classification, which is based mainly on the tumor size, is therefore considered to be appropriate for the pathologic findings of the primary tumor.

Clinical implications of sarcopenia in patients undergoing complete resection for early non-small cell lung cancer

OBJECTIVES Sarcopenia is characterized by progressive and generalized loss of skeletal muscle mass and strength. We aimed to investigate sarcopenia in patients with stage I non-small cell lung cancer (NSCLC) who underwent complete resection, and the relationship of sarcopenia with clinicopathological factors. METHODS All consecutive patients who underwent lung resection between January 2005 and December 2008 were enrolled in this retrospective study. Eligible patients were assigned to one of 2 groups according to the presence or absence of sarcopenia, as assessed by the sum of cross-sectional areas of skeletal muscles in the region of the third lumbar vertebra (L3) on preoperative computed tomography (CT). RESULTS Sixteen of 52 male (30.8%) and 22 of 38 female (57.9%) patients were identified with sarcopenia (p=0.01). Patients with sarcopenia were more likely to have a low body mass index (BMI) (p<0.0001). Kaplan-Meier analysis showed that patients with sarcopenia had a significantly worse outcome than patients without sarcopenia (5-year-survival: 72.8% vs 85.8%, respectively, p=0.028). Multivariate analysis found that sarcopenia was a significant independent prognostic factor (hazard ratio: 7.09, p=0.0008). CONCLUSIONS Sarcopenia identified on a cross-sectional CT image of the L3 level was associated with poor outcome with completely resected early-stage NSCLC.

Nanomedicines Eradicating Cancer Stem-like Cells in Vivo by pH-Triggered Intracellular Cooperative Action of Loaded Drugs

Nanomedicines capable of control over drug functions have potential for developing resilient therapies, even against tumors harboring recalcitrant cancer stem cells (CSCs). By coordinating drug interactions within the confined inner compartment of core-shell nanomedicines, we conceived multicomponent nanomedicines directed to achieve synchronized and synergistic drug cooperation within tumor cells as a strategy for enhancing efficacy, overcoming drug resistance, and eradicating CSCs. The approach was validated by using polymeric micellar nanomedicines co-incorporating the pan-kinase inhibitor staurosporine (STS), which was identified as the most potent CSC inhibitor from a panel of signaling-pathway inhibitors, and the cytotoxic agent epirubicin (Epi), through rationally contriving the affinity between the drugs. The micelles released both drugs simultaneously, triggered by acidic endosomal pH, attaining concurrent intracellular delivery, with STS working as a companion for Epi, down-regulating efflux transporters and resistance mechanisms induced by Epi. These features prompted the nanomedicines to eradicate orthotopic xenografts of Epi-resistant mesothelioma bearing a CSC subpopulation.

Results of a surgical resection of pulmonary metastasis from malignant head and neck tumor

There have been only a few reports about a surgical resection of pulmonary metastasis from malignant head and neck tumor. Here we investigate the survival after a pulmonary metastasectomy, and discuss the prognostic factors. We retrospectively reviewed 25 patients who underwent a pulmonary metastasectomy from malignant head and neck tumor at Kyushu University Hospital from 1981 through 2008. We assessed the five year overall survival by the Kaplan-Meier method and the log-rank (Mantel-Cox) test using the Stat View software program. The three- or five-year overall survival after a metastasectomy was 53.3% and 50.0%, respectively. We investigated the clinico-pathological prognostic factors including gender, age, histology, disease free interval, number or size of pulmonary metastatic tumors, and the operative procedure. Both age (older than 60 years) (P=0.0189) and pulmonary metastases from squamous cell carcinomas in either oral cavity or pharyngeal region (P=0.0002) were identified to be adverse prognostic factors. To obtain a long survival, a positive surgical resection is considered to be an effective and standard treatment for pulmonary metastasis from malignant head and neck tumor. It is also necessary, however, to elucidate fully the primary site and histology of such pulmonary metastasis.

Antagonism of VEGF by genetically engineered dendritic cells is essential to induce antitumor immunity against malignant ascites

Malignant ascitis (MA) is a highly intractable and immunotherapy-resistant state of advanced gastrointestinal and ovarian cancers. Using a murine model of MA with CT26 colon cancer cells, we here determined that the imbalance between the VEGF-A/vascular permeability factor and its decoy receptor, soluble fms-like tryrosine kinase receptor-1 (sFLT-1), was a major cause of MA resistance to dendritic cell (DC)-based immunotherapy. We found that the ratio of VEGF-A/sFLT-1 was increased not only in murine but also in human MA, and F-gene–deleted recombinant Sendai virus (rSeV/dF)-mediated secretion of human sFLT-1 by DCs augmented not only the activity of DCs themselves, but also dramatically improved the survival of tumor-bearing animals associated with enhanced CTL activity and its infiltration to peritoneal tumors. These findings were not seen in immunodeficient mice, indicating that a VEGF-A/sFLT-1 imbalance is critical for determining the antitumor immune response by DC-vaccination therapy against MA. Mol Cancer Ther; 10(3); 540–9. ©2011 AACR.