Kensaku Ito

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.

Alterations of the RB1 gene in dedifferentiated liposarcoma

Dedifferentiated liposarcoma is a malignant adipocytic neoplasm containing a nonlipogenic sarcoma of variable histological grade that arises against the background of a pre-existing well-differentiated liposarcoma. The phenomenon of dedifferentiation is considered to be time-dependent, but the mechanism is not well known. The retinoblastoma protein, encoded by the RB1 gene located at 13q14, is a key regulator of proliferation, development, and differentiation of certain cell types, including adipocytes. In the current study, we investigated the genetic alterations of the RB1 gene, such as mutation (the essential promoter region and the protein-binding pocket domain; exons 20–24) and methylation of the promoter region, in addition to pRB expression and loss of heterozygosity (LOH) status, in two morphologically distinct areas (nonlipogenic dedifferentiated and well-differentiated components) in 27 patients. As a control, 11 undifferentiated high-grade pleomorphic sarcoma/pleomorphic malignant fibrous histiocytoma samples and 11 well-differentiated liposarcoma samples were also evaluated. Dedifferentiated components showed LOH (15/25; 60%) and abnormal retinoblastoma protein expression (18/27; 66.7%) more frequently than noted in the well-differentiated components (3/24; 12.5% and 9/27; 33.3%, respectively). Five and four out of the 27 dedifferentiated components harbored mutations and promoter methylation, respectively, whereas none of these alterations were seen in the well-differentiated components. These results suggest that retinoblastoma protein has a major role to play in dedifferentiation and that a ‘two-hit’ mechanism is involved in the altered retinoblastoma protein expression in dedifferentiated liposarcoma.

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.

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.

Biological significance of the maximum standardized uptake values on positron emission tomography in non-small cell lung cancer

The 2‐[18F]‐fluoro‐2‐deoxy‐d‐glucose positron emission tomography (FDG‐PET) has recently become an important non‐invasive tool for the diagnosis and staging in several cancers. The standardized uptake value (SUV) of primary tumor has been reported to relate to cancer progression and prognosis, however, biological mechanism is still unclear.

Assessing a clinical pathway to improve the quality of care in pulmonary resections

PurposeTo evaluate the efficacy of the current clinical pathway for pulmonary resections.MethodsThis study examined variances from expected clinical pathway outcomes for pulmonary resections performed between 2005 and 2009. Data on a total of 383 patients were retrospectively analyzed.ResultsThe median length of hospital stay (LOS) using the clinical pathway was 12 days (range: 1–188 days); the mean LOS was 15.5 days. The cost per day with use of the clinical pathway was 102 726 yen. Poor control of pain from intercostal neuralgia was the most frequently observed variance from expected outcomes. It affected 119 of 168 electronic clinical pathway patients (70.8%). The clinical pathway was terminated in 3.9% of patients (15/383) due to serious or life-threatening complications.ConclusionsThis study showed the single institutional experience of the clinical pathway for pulmonary resections. These findings indicate a need to revise certain aspects of the pathway, based on data from our analysis of variances.

Effectiveness of erlotinib against recurrent pulmonary adenocarcinoma unresponsive to gefitinib: report of a case.

We report a case of recurrent pulmonary adenocarcinoma, found 2 years after resection, which responded extremely well to erlotinib, after gefitinib treatment had failed to evoke any response. This case report provides useful information for thoracic oncologists and shows that we should consider giving erlotinib after gefitinib for recurrent pulmonary adenocarcinoma, even if the gefitinib treatment is ineffective.

Dedifferentiated Chondrosarcoma of the Lung : Report of a Case

This report presents a rare case of pulmonary sarcoma with regional anaplastic changes. A 73-year-old Japanese man with a hamartoma-like nodule of the left lung accompanied by interstitial pneumonia was followed up for 30 months. He underwent a surgical resection due to the rapid growth of the lung nodule. A pathological examination revealed a dedifferentiated sarcoma arising from the chondrosarcoma.

The influence of intracellular epidermal growth factor receptor (EGFR) signal activation on the outcome of EGFR tyrosine kinase inhibitor treatment for pulmonary adenocarcinoma

PurposeThe epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, exhibit up to a 70% response rate against non-small cell lung cancer (NSCLC) harboring somatic activating mutations of the EGFR gene (EGFR). The mechanism of intrinsic resistance of EGFR mutation-positive NSCLC against EGFR-TKIs is not known. The current study assesses the relationship between the molecular expression of EGFR signals and the response to gefitinib treatment in patients with pulmonary adenocarcinoma to elucidate the mechanism of intrinsic resistance to gefitinib.MethodsThe present study included 30 patients with pulmonary adenocarcinoma who were treated with gefitinib for a postoperative recurrence. The correlation between the response to gefitinib treatment and various clinical and molecular features was evaluated.ResultsEGFR mutations were detected in 20 (66.7%) of the 30 patients. The response to gefitinib treatment was a complete response in 1 case, partial response in 12 cases, stable disease in 4 cases, and progressive disease in 13 cases. Both univariate and multivariate analyses showed the presence of an EGFR mutation, and the expression of phospho-EGFR (p-EGFR) significantly correlated with a better response to gefitinib treatment. Ten of the 16 p-EGFR positive patients were disease controlled, but all 4 p-EGFR negative patients were intrinsically resistant to EGFR-TKIs (P = 0.025). Other factors including sex, smoking status, serum carcinoembryonic antigen and cytokeratin-19 fragment levels, EGFR, Met proto-oncogene, phospho-Met, and hepatocyte growth factor expression were not associated with the response to gefitinib treatment.ConclusionThese results suggest that, even if EGFR mutations were observed, a p-EGFR negative state might be a cause of intrinsic resistance to EGFR-TKIs.

The dynamics and clinical significance of alpha 2 plasmin inhibitor-plasmin complex and thrombin-antithrombin complex in postoperative pleural effusion following a pulmonary lobectomy.

PurposeThe overall incidence of postoperative alveolar air leakage (AAL) remains high; however, the mechanism regarding how to adequately heal such postoperative AAL remains to be elucidated. The aim of this study was to determine any correlations between the activity of the fibrinolytic and coagulation system in the postoperative pleural effusion and appearance or disappearance of postoperative AAL.MethodsThis study prospectively investigated 25 patients who underwent a pulmonary lobectomy from July 2005 to March 2006. Pleural effusion was collected through the chest tube. Alpha 2 plasmin inhibitor-plasmin complex (PIC), as a fibrinolytic marker, and thrombin-antithrombin complex (TAT), as a coagulation marker, were measured.ResultsThe activity of the coagulation system was higher than that of the fibrinolytic system. The concentration of TAT tended to increase (3rd vs 4th postoperative day [POD], P = 0.0907). The mean time of appearance and disappearance of postoperative AAL was 1.4 days and 3.2 days, respectively. The patients with postoperative AAL had a TAT level significantly below the average on the 3rd POD in comparison to the patients without postoperative AAL (P = 0.0163). Moreover, the concentration of TAT in patients with postoperative AAL was significantly lower than that in patients without postoperative AAL (1824.0 ± 137.3 ng/ml vs 3444.0 ± 287.6 ng/ml, P = 0.0113) on the 3rd POD. On the 4th POD, the concentration of TAT was almost same and there was no significance (P = 0.6759).ConclusionsThis study demonstrated for the first time the course of the fibrinolytic and coagulation activity in the pleural effusion after a pulmonary lobectomy, and showed that the delayed activity of the coagulation system is associated with the appearance of the postoperative AAL.