Tomonari Kinoshita

Forkhead box P3 regulatory T cells coexisting with cancer associated fibroblasts are correlated with a poor outcome in lung adenocarcinoma

Recently, an association between tumor infiltrating Forkhead box P3 regulatory T cells (Treg) and an unfavorable prognosis has been clinically shown in some cancers, but the mechanism of Treg induction in the tumor microenvironment remains uncertain. The aims of the present study were to examine the relationship between Treg and patient outcome and to investigate whether Treg induction is influenced by the characteristics of cancer‐associated fibroblasts (CAF) in lung adenocarcinoma. The numbers of Treg in both the tumor stroma and the tumor nest were counted in 200 consecutive pathological stage I lung invasive adenocarcinoma specimens. To examine whether the characteristics of CAF influence Treg induction, we selected and cultured CAF from low Treg and high Treg adenocarcinoma. The number of Treg was much higher in the stroma than in the nest (P < 0.01). Patients with high Treg had a significantly poorer prognosis than those with low Treg (overall survival: P = 0.03; recurrence‐free survival: P = 0.02; 5‐year overall survival: 85.4% vs 93.0%). Compared with the CAF from low Treg adenocarcinoma, culture supernatant of the CAF from high Treg adenocarcinoma induced more Treg (P = 0.01). Also, CAF from high Treg adenocarcinoma expressed significantly higher mRNA levels of transforming growth factor‐β (P = 0.01) and vascular endothelial growth factor (P = 0.01), both of which are involved in Treg induction. Our studies suggest the possibility that CAF expressing immunoregulatory cytokines may induce Treg in the stroma, creating a tumor‐promoting microenvironment in lung adenocarcinoma that leads to a poor outcome.

Prognostic significance of hypoxic PET using 18 F-FAZA and 62 Cu-ATSM in non-small-cell lung cancer

OBJECTIVES Tumor hypoxia is believed to have a strong correlation with the resistance to chemoradiotherapy. Noninvasive evaluation of hypoxic status in tumors using molecular imaging has the potential to characterize the tumor aggressiveness. We evaluated the clinical usefulness of newly-developed tumor hypoxic positron emission tomography (PET) tracers in localized non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Forty-seven patients with localized NSCLC received either or both hypoxic PETs using the tracers: (18)F-fluoroazomycin arabinoside ((18)F-FAZA) (n=45) and/or (62)Cu-diacetyl-bis (N4)-methylsemithiocarbazone ((62)Cu-ATSM) (n=22). All received (18)F-fluorodeoxyglucose ((18)F-FDG) PET tracer (n=47). We examined the correlation between uptake of three PET tracers and clinicopathological factors, and evaluated their impacts on survival after treatment retrospectively. RESULTS A couple of commonly-identified unfavorable factors such as presence of vascular invasion and pleural invasion was significantly correlated with higher uptake of these hypoxic agents as well as that of (18)F-FDG. Larger tumor diameter, high neutrophil-to-lymphocyte ratio and advanced pathological stage were also associated with accumulation of hypoxic PETs ((18)F-FAZA, p<0.01; (62)Cu-ATSM, p<0.04), but not with that of (18)F-FDG. The patients with a higher accumulation had significantly poorer overall survival [(18)F-FAZA, HR (hazard ratio), 9.50, p<0.01; (62)Cu-ATSM, HR, 4.06, p<0.05] and progression free survival ((18)F-FAZA, HR, 5.28, p<0.01, (62)Cu-ATSM, HR, 2.72, p<0.05). CONCLUSION Both (18)F-FAZA and (62)Cu-ATSM PET provide useful information regarding tumor aggressiveness and prediction of survival among NSCLC patients. We believe these hypoxic PETs could contribute to the establishment of the optimally individualized treatment of NSCLC.

Prognostic Factors Based on Clinicopathological Data Among the Patients with Resected Peripheral Squamous Cell Carcinomas of the Lung

Introduction: Although the incidence of peripheral squamous cell carcinomas (p-SqCCs) of the lung has increased over recent years, clinicopathological factors influencing prognosis of resected p-SqCCs remain unclear. Methods: We examined 280 patients who underwent complete resection of SqCCs and analyzed the clinicopathological features in relation to their overall survival (OS) and recurrence-free survival (RFS) according to the primary location. Results: Multivariate analysis of all stages of p-SqCCs patients revealed that high serum squamous cell carcinoma antigen (SCC) level (OS; p < 0.01, RFS; p < 0.01), vascular invasion (OS; p < 0.01, RFS; p < 0.01), pleural invasion (OS; p = 0.03, RFS; p = 0.01), nodal metastasis (OS; p = 0.02) and complication with lung disease (OS; p < 0.01) were independently unfavorable prognostic factors. Among stage I p-SqCCs patients, high serum SCC level (OS; p < 0.01, RFS; p < 0.01), vascular invasion (RFS; p < 0.01) and pleural invasion (RFS; p = 0.01) were also strongly correlated with poor prognosis independently. When we reevaluated the survival rate, T1 p-SqCCs with high serum SCC level or vascular invasion can be upgraded to T2a. Patients with stage IB had a significantly poorer prognosis than stage IA (5-year RFS; 61.4 % versus 76.6 %, p < 0.05). Conclusion: High serum SCC level, pleural and vascular invasions were independent poor prognostic factors for completely resected p-SqCCs. T1 p-SqCCs with high serum SCC level or vascular invasion should be upgraded to T2a, which accurately reflect survival status among patients with p-SqCCs.

The differences of biological behavior based on the clinicopathological data between resectable large-cell neuroendocrine carcinoma and small-cell lung carcinoma

INTRODUCTION Large cell neuroendocrine carcinoma of the lung and SCLC are collectively classified as high-grade NECs. However, there have been few reports focusing on the differences of clinicopathological prognostic factors between resectable LCNEC and SCLC. PATIENTS AND METHODS We reviewed the clinical data of 140 patients who underwent complete resection of high grade NEC in our institute and analyzed the clinicopathological features in relation to their survival. RESULTS There were no statistically significant differences in overall and recurrence-free survival between pure and combined subtypes in either LCNEC or SCLC. In LCNEC, larger tumor diameter (P = .01), nodal metastasis (P < .01), lymphatic permeation (P < .01), and vascular invasion (P = .01) were unfavorable prognostic factors. However, in SCLC, tumor diameter and vascular invasion were not prognostic factors, but nodal metastasis (P < .01) and lymphatic permeation (P = .03) were strongly correlated with poor prognosis. CONCLUSION There were no apparent differences in biological behavior between pure and combined subtypes in either LCNEC or SCLC. Lymphatic involvement was an important unfavorable prognostic factor in SCLC, whereas tumor diameter, vascular invasion, and lymphatic involvement had a poor prognostic effect in LCNEC.

Prognostic Impact of Preoperative Tumor Marker Levels and Lymphovascular Invasion in Pathological Stage I Adenocarcinoma and Squamous Cell Carcinoma of the Lung

Introduction: Some unfavorable prognostic factors for stage I non–small-cell lung cancers have been reported; however, they are not reflected in the current Tumor–Node–Metastasis classification. Methods: We retrospectively reviewed 629 patients who underwent complete resection of pathological stage I adenocarcinomas (ADs) or squamous cell carcinomas (SQs) at two institutes between 1996 and 2011. The correlation between clinicopathological characteristics and survival rates was analyzed to identify prognostic factors. Results: Multivariate analysis indicated that among ADs, high serum carcinoembryonic antigen levels (p = 0.04 for overall survival [OS]; p < 0.01 for recurrence-free survival [RFS]; p = 0.02 for disease-specific survival [DSS]), lymphatic permeation (p < 0.01 for RFS and DSS), and vascular invasion (p < 0.01 for OS and RFS; p = 0.03 for DSS) were independent prognostic factors. Among SQs, high squamous cell carcinoma antigen (SCC) (p < 0.05 for OS), and vascular invasion (p < 0.05 for RFS and DSS) were independently prognostic. We suggest that among completely resected tumors less than or equal to 5 cm without lymph node metastasis, the current stages IA and IB AD with high serum carcinoembryonic antigen levels, lymphatic permeation, or vascular invasion should be upgraded to stage IB and IIA, respectively. The current stage IA SQ with high SCC antigen levels or vascular invasion should be upgraded to stage IB. These reclassifications accurately reflect survival status (p < 0.04 in all comparisons). Conclusions: Some important differences in prognostic factors were observed between AD and SQ. High preoperative serum tumor marker levels and lymphovascular invasion should be included as additional criteria in the forthcoming Tumor–Node–Metastasis staging.

Pulmonary metastasis from encapsulated cervical ectopic type a thymoma.

A 39-year-old woman underwent tumor resection for an encapsulated cervical ectopic thymoma (type A). However 7 years after complete resection, computed tomography (CT) screening detected a 9-mm pulmonary nodule, which was completely resected and was diagnosed as a metastasis from the ectopic thymoma. There have been few reports on cervical ectopic thymoma metastasizing to a distant site and, to the best of our knowledge, this is the first case report of a cervical ectopic type A thymoma with distant metastasis.

Survival predictors after resection of lung metastases of head or neck cancers

Pulmonary metastasectomies are performed for a variety of cancers, though few reports have examined their merit for head and neck cancers. This study examined the relationship between clinical and pathological characteristics and survival after resection of lung metastases of these cancers.

Spontaneous regression of metastatic extraskeletal myxoid chondrosarcoma

Spontaneous regression of tumors is very unusual and is defined as a partial or complete disappearance of metastatic tumors without any treatment. This phenomenon has been reported in almost all types of cancer. The patient was a 25-year-old woman who presented with multiple pulmonary nodules on her bilateral lungs on the annual chest roentgenograph. Simultaneously, a swelling mass on her subcutaneous inguinal region was observed. The diagnosis of the inguinal mass was extraskeletal myxoid chondrosarcoma. The inguinal mass and pulmonary nodules spontaneously regressed without any treatment after biopsy. The patient was doing well without evidence of recurrence at 1 year after the operation without any additional therapy. Our case is the first clinical one that indicated a possibility of histologic regression of extraskeletal myxoid chondrosarcoma.

Tumor associated macrophages support the growth of FGF9-induced lung adenocarcinoma by multiple mechanisms

OBJECTIVES Tumor-associated macrophages (TAMs) are known to promote tumorigenesis but the mechanism(s) remain elusive. We have developed a mouse model of lung cancer that is initiated through an inducible overexpression of fibroblast growth factor 9 (FGF9) in type-2 pneumocytes. Expression of FGF9 in adult lungs resulted in a rapid development of multiple adenocarcinoma-like tumor nodules, and is associated with an intense immunological reaction. The purpose of this study is to characterize the immune response to the FGF9-induced lung adenocarcinoma and to determine the contribution of TAMs to growth and survival of these tumors. MATERIALS AND METHODS We used flow cytometry, immunostaining, RT-PCR and in vitro culture system on various cell populations isolated from the FGF9-induced adenocarcinoma mouse lungs. RESULTS Immunostaining demonstrated that the majority of the inflammatory cells recruited to FGF9-induced lung tumors were macrophages. These TAMs were enriched for the alternatively activated (M2) macrophage subtype. TAMs performed a significantly high immune suppressive function on T-cells and displayed high levels of arginase-1 expression and activity. The growth and colony forming potential of tumor cells was induced by co-culture with TAMs. Additionally, TAMs were shown to promote fibroblast proliferation and angiogenesis. TAMs had high expression of Tgf-β, Vegf, Fgf2, Fgf10, Fgfr2 and several matrix metalloproteinases; factors that play multiple roles in supporting tumor growth, immune protection, fibroblast activation and angiogenesis. CONCLUSION Our results provide evidence that the Fgf9-induced lung adenocarcinoma is associated with recruitment and activation of M2-biased TAMs, which provided multiple means of support to the tumor. This model represents an excellent means to further study the complex interactions between TAMs, their related chemokines, and progression of lung adenocarcinoma, and adds further evidence to support the importance of TAMs in tumorigenesis.

The Availability of Pre- and Intraoperative Evaluation of a Solitary Pulmonary Nodule in Breast Cancer Patients

PURPOSE It is clinically difficult to differentiate between primary lung cancer (PLC) and metastasis from breast cancer (MBC) in the diagnosis of a solitary pulmonary nodule (SPN) observed in a patient with past history of breast cancer. We evaluated several clinical, radiological and pathological variables in patients with SPN in an attempt to identify reliable markers to differentiate them. METHODS Retrospectively we reviewed the clinical, radiological and pathological characteristics of 64 patients with a history of breast cancer resection who subsequently underwent surgical resection of an indeterminate SPN in our institute. RESULTS The patients with MBC were significantly younger (p = 0.01). Among CT findings, presence of a solid opacity (p <0.01), well-defined tumor (p <0.01) and absence of an air bronchogram (p <0.01) were significantly associated with MBC. Among the intraoperative frozen section pathologic findings, the absence of lepidic or papillary patterns (p <0.01) and the presence of strong fibrosis in the tumor (p <0.01) were significantly correlated with MBC. CONCLUSION Although some cases are difficult to confirm the definitive diagnoses of SPN, combining CT and intraoperative pathological findings might enable us to distinguish SPN between MBC and PLC prior to postoperative examinations.