Inflammatory Risk Factors for Early Recurrence of Non-Small Cell Lung Cancer Within One Year Following Curative Resection.

BACKGROUND: Several inflammation-based scoring systems and nutritional indicators have been shown to have relevance to survival of patients with non-small cell lung cancer (NSCLC).The present study examined preoperative and pathological factors in patients who underwent curative resection for non-small cell lung cancer, with the aim to elucidate risk factors for early recurrence within 1 year of surgery. METHODS: Patients with NSCLC who underwent surgery from January 2009 to December 2014 were retrospectively investigated. Routine laboratory measurements including carcinoembryonic antigen were performed before surgery, and pathological information was collected after surgery. Patients with recurrence within 1 year after surgery were considered as early recurrence group (ERG), those with recurrence after 1 year were as late recurrence group (LRG), and those without recurrence were as no recurrence group (NRG). RESULTS: Multivariate analysis between ERG and LRG revealed Glasgow prognostic score (GPS) and CRP-to-albumin ratio (CAR) as independent risk factors for early recurrence. Multivariate analysis between ERG and LRG + NRG confirmed CAR, vascular invasion, and pathological stage as risk factors for early recurrence. CONCLUSION: These findings indicated that CAR and GPS were confirmed to be risk factors for early recurrence, in addition to pathological factors.

Inflammation-Based Prognostic Score Predicts Postoperative Survival of Patients with Interstitial Pneumonia After Undergoing Lung Cancer Resection.

OBJECTIVES: Idiopathic interstitial pneumonias (IIPs) are associated with an increased risk of lung cancer. Glasgow prognostic score (GPS), which uses serum C-reactive protein (CRP) and albumin levels to indicate systemic inflammatory response and nutrition level, has been reported to be a predictor of overall survival in patients with various types of cancer. We evaluated the usefulness of GPS for prediction of survival of patients with both lung cancer and IIPs following a lung resection procedure. METHODS: Patients with IIPs who underwent lung cancer resection from January 2006 through December 2015 were investigated. Routine laboratory measurements, including serum CRP and albumin for determining GPS, were performed before the operation. Univariate and multivariate analyses with a COX proportional hazards regression model were used to identify independent risk factors for overall survival (OS), relapse-free survival (RFS), cancer-specific survival (CSS), and other disease-specific survival (ODSS). RESULTS: A total of 135 patients underwent lung resection during the study period. Multivariate analysis selected sublobar resection (p = 0.035), UIP pattern (p = 0.025), and GPS of 1-2 (p = 0.042) as predictive factors associated with OS, while GPS of 1-2 (p = 0.039) was shown to be a predictive factor associated with RFS. Multivariate analysis also revealed pTNM (p < 0.001), usual interstitial pneumonia pattern (p = 0.006), and GPS of 2 (p = 0.003) as predictive factors associated with CSS, while univariate analysis indicated pTNM (p = 0.042), GPS of 1 (p = 0.044), and %DLCO (p = 0.038) as predictive factors associated with ODSS. CONCLUSION: GPS is an independent prognostic factor of OS and RFS in lung cancer patients with IIPs undergoing a lung resection procedure. Furthermore, a GPS of 2 was found to be associated with CSS following lung cancer resection, while a score of 1 was associated with ODSS.

Mitosis count and number of cancer cells in cases of primary pulmonary adenocarcinoma: Correlations among phosphorylated histone 3, number of cancer cells, nuclear grade, pathologic features and prognosis.

Immunohistochemistry findings for the phosphorylated form of histone 3 (pHH3) have been shown to be a reliable mitosis-specific marker. We evaluated the correlation between pHH3-stained mitotic figures (PHMFs) and clinical outcome, and compared the results with findings for numbers of PHMFs and cancer cells. The primary tumor was obtained from 113 patients with pulmonary adenocarcinomas (≤2 cm maximum dimension). All specimens were stained with pHH3, then the number of cancer cells in each was determined. Cases with a cancer-cell index ≥1000 showed worse recurrence-free survival as compared to those with a value <1000 (P < 0.001). Also, cases with a pHH3 index ≥0.27 showed worse recurrence-free survival as compared to <0.27 (P = 0.001) and cases with a pHH3/cancer-cell index ≥0.001 showed worse recurrence-free survival as compared to <0.001 (P = 0.002). Multivariate analysis demonstrated that pHH3/cancer-cell index was significantly correlated with prognosis, but not Ki-67 index. The number of cancer cells was also strongly correlated with progression of Noguchi's classification and WHO pathologic type. pHH3/cancer-cell index was correlated with prognosis, and those were useful for prognostic evaluation of pulmonary adenocarcinoma patients. Furthermore, cancer cell number was correlated with Noguchi's classification and WHO pathologic type.

L-Type Amino Acid Transporter 1 Immunoreactivity as a Possible Diagnostic and Prognostic Marker of Thymic Carcinoma.

L-type amino acid transporter 1 (LAT1) functions to transport large neutral amino acids, such as leucine, isoleucine, valine, phenylalanine, tyrosine, tryptophan, methionine, and histidine. These amino acids are essential for cell growth and proliferation. Many studies have demonstrated LAT1 expression in various types of cancer, and its high expression level was associated with poor prognosis. However, the significance of LAT1 expression in thymic epithelial tumors is controversial. We conducted this retrospective study to investigate the LAT1 immunoreactivity in thymic epithelial tumors and its impact on prognosis. We analyzed 32 patients with thymoma and 14 patients with thymic carcinoma who underwent surgery at our institute. Immunohistochemical analysis was performed using formalin-fixed paraffin-embedded surgical tissues and an anti-LAT1 polyclonal antibody. We thus found that LAT1 immunoreactivity was undetectable in all of the thymoma specimens, regardless of the subtypes of thymoma. By contrast, LAT1 immunoreactivity was consistently detected in the cytosol of thymic carcinoma cells; namely, all 14 thymic carcinoma specimens demonstrated LAT1 immunoreactivity in the cytosol. Among these 14 thymic carcinoma specimens, four carcinoma specimens also showed LAT1 immunoreactivity in the cell membrane. Survival analysis indicated that the thymic carcinoma with the LAT1 membrane signal was associated with poor prognosis, compared with the specimens with the LAT1 cytosol signal. We therefore propose that LAT1 is expressed in the cytosol of thymic carcinoma cells, which could be a diagnostic marker of thymic carcinoma. Moreover, LAT1 expression in the cell membrane is a prognostic marker of thymic carcinoma.

[Salvage Surgery Following Chemoradiotherapy for Thymic Basaloid Cell Carcinoma].

We performed salvage surgery after chemoradiotherapy(CRT) in a patient with thymic basaloid cell carcinoma. A 46-year-old man with an abnormal chest shadow on X-ray findings was referred to our hospital. Computed tomography revealed a partially solid tumor along with a multilocular cyst in the anterior mediastinum with mediastinal lymph node swelling infiltrating to the superior vena cava(SVC). Positron emission tomography revealed FDG accumulation (SUVmax 7.94)in the tumor. Pathological findings of a tumor biopsy specimen obtained by thoracoscopy led to a diagnosis of thymic basaloid cell carcinoma. Following CRT (ADOC+RT:60 Gy), a complete resection (R0)with replacement of the SVC was performed. The postoperative course was uneventful, and the patient was alive at 20 months after surgery with metastasis to the cervical lymph nodes and bone.

Usefulness of Inflammation-Based Prognostic Score in Patients Undergoing Lung Metastasectomy for Colorectal Carcinoma.

OBJECTIVES: There is increasing evidence that Glasgow Prognostic Score (GPS), based on systemic inflammatory response and albumin level, is a useful predictor of overall survival in patients with various types of cancer. METHODS: Patients with lung metastasis from colorectal carcinoma who underwent a lung metastasectomy from 2000 to 2015 were retrospectively investigated. Routine laboratory measurements including serum C-reactive protein (CRP), albumin, and the tumor marker carcinoembryonic antigen were performed before the metastasectomy. RESULTS: Ninety-nine patients underwent 132 lung metastasectomy procedures during the study period. Kaplan-Meier analysis revealed that GPS (p = 0.017), number of metastases (p = 0.004), and the presence of liver metastasis (p = 0.010) were associated with overall survival, while univariate analysis selected GPS (p = 0.028), number of metastases (p = 0.005), and liver metastasis (p = 0.014) as predictive factors associated with overall survival. Multivariate analysis also indicated GPS (p = 0.004), number of metastases (p = 0.004), and liver metastasis (p = 0.013) as predictive factors associated with overall survival. CONCLUSION: In addition to number of metastases and liver metastasis, GPS is an important predictor of overall survival in colorectal cancer patients who undergo a lung metastasectomy.

[Anti-thymocyte Globulin Therapy for Cases of Acute Rejection Following Lung Transplantation].

A 58-year-old male underwent right lung transplantation from a brain-dead donor, after which acute rejection developed that was resistant to steroid pulse therapy. Rabbit-derived anti-thymocyte globulin (rATG) therapy was successful for controlling the rejection. However, following that therapy, the patient was affected by an opportunistic infection and suffered from repeated empyema. It is important to pay attention to immunosuppressive agent levels in blood following treatment, because ATG is a potent immunosuppressive drug and its effects can continue for more than 6 months after administration.

[Spindle Cell Sarcoma Originated in the Anterior Mediastinum;Report of a Case].

An anterior mediastinal sarcoma is a very rare type of mediastinal tumor. A 45-year-old female visited our hospital with swelling in the right anterior chest wall. Radiographically, the tumor was found to originate from the thymus and to infiltrate to the major pectoral muscle through the 1st intercostal space. Positron emission tomography revealed fluorodeoxyglucose accumulation at a standardized uptake maximum value of 16.1. Percutaneous needle biopsy showed the pathological findings of sarcoma. The tumor was resected along with the thymus and chest wall tissues including the right hemi-manubrium of the sternum, clavicle head, 1st and second ribs, and major pectoral muscle. After 4 months, tumor relapse occurred at the site of needle biopsy and additional resection was performed. At 10 months after the 2nd surgery, the patient was free from disease. From histologic and immunohistochemical findings, the tumor was diagnosed as spindle cell sarcoma.

[Pulmonary Clear Cell Type Squamous Cell Carcinoma that Required Differential Diagnosis from Metastatic Ureter Cancer;Report of a Case].

A 71-year-old woman was referred to our department for a nodular lesion in the left lung. She had been followed by urology department in our hospital for 6 years since right nephrectomy for ureter cancer. Chest X-ray and computed tomography (CT) scan demonstrated a small nodular shadow in the left lower lobe. The lung tumor was removed by wedge resection, and pathologically diagnosed during the operation as a metastasis from the ureter cancer. The lung tumor consisted of clear cells similar to the ureter cancer. However, the final pathological diagnosis changed to a primary lung cancer based on the findings of stratified differentiation and cancer cell nests in the tumor. Immunohistochemical staining for ureter epithelium-related antigens confirmed the diagnosis. Although we recommended left lower completion lobectomy, the patient refused additional surgery. She is suspected to have local recurrence in the left lower lobe 18 months after the surgery.

[Pulmonary mucosa-associated lymphoid tissue(MALT) lymphoma after occupational exposure to organic solvent].

A 68-year-old woman was referred to our hospital due to a left chest abnormal shadow on chest film. She had a history of occupational exposure to organic solvent for about 30 years until 10 years ago. Computed tomography (CT) scan demonstrated a nodular shadow 12 mm in diameter in the left lower lobe. As a lung cancer was suspected, partial resection of the lobe including the small lesion was performed. Since mucosa-associated lymphoid tissue(MALT) lymphoma was diagnosed by intraoperative pathological examination, we finished the operation without any more lung resection. The diagnosis was finally confirmed by histological finding of small lymphoid cell proliferation and positive staining for CD20. Chronic inflammation, such as Helicobacter pylori infection, is considered to be a cause of MALT lymphoma. We speculate that the long term exposure to organic solvent may develop the disease by continuous chemical stimulation to bronchus.

[Outcome of pulmonary resection for metastases from hepatocellular carcinoma].

Because pulmonary metastasis is considered to be systemic spread of hepatocellular carcinoma (HCC), indication of pulmonary resection as a treatment for it is not well-described. We retrospectively reviewed clinical records of the patients who underwent pulmonary resection for metastases from HCC in our hospital. Seven patients, 6 men, 1 woman, and the mean-age 65.4 year-old, underwent pulmonary resection from April in 2001 to March in 2010. During the same period, we carried out pulmonary resection for 122 patients with metastases from other malignant diseases. Therefore, pulmonary resection for HCC metastases accounted for 5.4% of the total pulmonary metastasectomy. One of the 7 patients, a 70 year-old man, survives for 69 months after right middle lobectomy for solitary HCC metastasis. Other 6 patients with multiple pulmonary metastases or with increased level of alpha-fetoprotein (AFP) before pulmonary resection died of systemic recurrence. The mean survival time of 7 patients was 20 months and was 11.8 months except the long-time survivor. From our results, patients with multiple pulmonary metastases from HCC or with increased serum level of AFP before surgery should be carefully selected as candidates for pulmonary metastasectomy.

[Radical resection following to concurrent chemoradiotherapy for eighty-five year-old patient with superior sulcus tumor].

An 85-year-old male with superior sulcus tumor was referred to our hospital complaining right brachial pain and omalgia. Chest computed tomography showed right apical lung tumor involving the 1st rib, and bronchoscopy established a diagnosis of squamous cell carcinoma, cT3NOM0. After concurrent chemoradiotherapy [cisplatin (CDDP) + 60 Gy], functional examination indicated him to be tolerable to lobectomy, and he underwent right upper lobectomy + chest wall resection (1st-3rd ribs) + lymph-node dissection. Pathological examination revealed that the effect of chemoradiotherapy was Ef. 3. The postoperative course was uneventful. He is free from recurrence for 7 years after the surgery.

[Diaphragmatic metastasis from uterine corpus cancer].

We report a case of metastatic diaphragm tumor from uterine corpus cancer. A 72-year-old female had a tumor on right diaphragm 4-years after operation for uterine corpus cancer. After chemotherapy, tumor resection was performed by right lung basal segmentectomy, partial liver resection, and partial diaphragm resection. The pathological examination revealed adenocarcinoma, compatible with uterine corpus cancer, metastasizing in diaphragm and involving lung and liver. After the operation, a local recurrence occurred at parasternal lymph node, which is considered to be present on the efferent route of lymph flow from diaphragm.

Comparison of 5-fluorouracil-related gene expression levels between adenocarcinomas and squamous cell carcinomas of the lung.

BACKGROUND: A recent meta-analysis study showed that post-operative adjuvant chemotherapy with UFT, an oral combination drug composed of tegafur [prodrug of 5-fluorouracil (5-FU)] and uracil [inhibitor of dihydropyrimidine dehydrogenase (DPD)] was associated with improved survival in patients with lung adenocarcinomas, but not in those with lung squamous cell carcinomas. METHODS: We investigated the 5-FU-related gene expression levels of thymidylate synthase (TS), DPD, thymidine phosphorylase (TP) and orotate phosphoribosyl transferase (OPRT) in resected tumor specimens from 51 patients with adenocarcinomas and 47 with squamous cell carcinomas using quantitative reverse transcription-PCR, and compared those levels between the two histological types. RESULTS: The relative gene expression values of TS, TP and OPRT were significantly lower in adenocarcinomas compared with squamous cell carcinomas, 1.60 +/- 0.86 versus 4.33 +/- 3.40 (P < 0.001), 0.84 +/- 0.52 versus 2.27 +/- 1.16 (P = 0.006) and 9.59 +/- 6.30 versus 16.94 +/- 12.04 (P < 0.001), respectively. The relative gene expression value of DPD was significantly greater in adenocarcinomas than those in squamous cell carcinomas, 2.33 +/- 1.22 versus 1.50 +/- 1.20 (P = 0.01). Lower expressions of TS and TP were observed more in adenocarcinomas (89.8%) than in squamous cell carcinomas (48.9%) (P < 0.001). CONCLUSION: These data may explain that post-operative adjuvant chemotherapy with UFT was associated with improved survival in stage I patients with adenocarcinoma, but less with squamous cell carcinoma.

Advanced Lung Cancer Inflammation Index Predicts Outcomes of Patients with Pathological Stage IA Lung Adenocarcinoma Following Surgical Resection.

PURPOSE: The correlation of advanced cancer with inflammation and/or nutrition factors is well known. Recently, the advanced lung cancer inflammation index (ALI) was developed as a new prognostic tool for patients with advanced lung cancer. In this study, we examined whether ALI results are correlated with prognosis of patients with early stage lung adenocarcinoma who undergo lung resection. METHODS: From January 2009 to December 2014, 544 patients underwent lung resection due to primary lung cancer at Dokkyo Medical University Hospital, of whom 166 with pathological stage IA lung adenocarcinoma were retrospectively investigated in this study. ALI was calculated as follows: Body Mass Index (BMI; kg/m2) × albumin (g/dL)/neutrophil-to-lymphocyte ratio (NLR). RESULTS: Multivariate analysis revealed that gender, red cell distribution width (RDW), NLR, and ALI were parameters significantly correlated with overall survival (OS). Patients with an ALI value less than 22.2 had an inferior 5-year OS rate as compared to those with a value of 22.2 or higher (p <0.001) as well as an inferior 5-year recurrence-free survival (RFS) rate (p <0.001). CONCLUSION: Low ALI was correlated with poor prognosis in patients with stage IA lung adenocarcinoma. Those with an ALI value less than 22.2 should be carefully followed regardless of cancer stage.

Impact of tumor infiltrating lymphocytes and lymphoid follicle formation on patient survival following surgery for lung squamous cell carcinoma.

BACKGROUND: Tumor infiltrating lymphocytes (TILs) are known to correlate with the prognosis of patients affected by a variety of cancer types. We evaluated TILs in patients who underwent surgery for lung squamous cell carcinoma (SCC). METHODS: Specimens obtained from patients during resection of lung SCC were examined for TIL density, lymphoid follicle formation, PD-L1 expression, and the appearance of regulatory T cells (Tregs). RESULTS: We enrolled 72 patients who underwent surgery for SCC (TIL grades 0, 1, and 2: 29, 18, and 25, respectively). Lymphoid follicles were observed in 13 (18.1%) patients and 8 were positive for Tregs, which were always observed in association with lymphoid follicles (P < 0.001). Multivariate analysis revealed that lymphoid follicle formation, the appearance of Tregs, pathological stage, and pleural invasion were independent prognostic factors related to overall survival, whereas TIL density and PD-L1 expression were not. CONCLUSION: SCC patients with lymphoid follicle formation accompanied by Tregs show poor survival following lung resection surgery.

Association of Perioperative Redox Balance on Long-Term Outcome in Patients Undergoing Lung Resection.

PURPOSE: We examined whether redox balance during the perioperative period is associated with long-term survival of patients after undergoing lung resection. METHODS: Patients who underwent surgery for lung cancer from January to June 2013 at our institution were investigated. Serum was collected during the operation, and on postoperative day (POD) 3 and 7, and the levels of derivatives of reactive oxygen metabolites (d-ROMs) and biologic antioxidant potential (BAP) were measured. RESULTS: In all, 21 patients (69 ± 7 years old) were enrolled, of whom 9 underwent video-assisted thoracoscopic surgery. Comorbidities in the patients included chronic obstructive pulmonary disease in eight and idiopathic pulmonary fibrosis in five. d-ROM values on POD 3 and 7 were significantly increased as compared to those obtained during the operation (p <0.001), whereas BAP did not change after surgery. Patients with a value below a d-ROM cutoff value of 327 during the operation showed significantly superior 3-year overall survival as compared to those with a value above the cutoff (87.5% vs. 20.0%, p <0.001). CONCLUSION: In the present patients, surgical stress caused an increase in d-ROM during the postoperative course. The d-ROM value obtained during the operation was correlated with long-term survival following resection for lung cancer.

Epidermal Growth Factor Receptor Gene Mutation in Pleural Lavage Cytology Findings of Primary Lung Adenocarcinoma Cases.

PURPOSE: In the present study, we examined the relationship between intraoperative pleural lavage cytology findings and presence of epidermal growth factor receptor (EGFR) gene mutations. METHODS: We investigated 160 patients who underwent surgical treatment for primary lung adenocarcinoma at our hospital from January 2011 to December 2013 to determine the presence of EGFR gene mutations and pleural lavage cytology. RESULTS: In all, 52 subjects (31.5%) were positive EGFR gene mutations, of whom 38 were found to possess the Exon 21 L858R mutation. Intraoperative pleural lavage cytology examinations were performed in 160 subjects and 12 had positive results, of whom 6 were positive for EGFR gene mutations, which was the Exon 21 L858R mutation in all. In a comparison between subjects possessing the Exon 21 L858R mutation and those negative for EGFR gene mutations, lavage cytology-positive (p = 0.02) and vascular infiltration-negative (p = 0.01) were characteristics of the Exon 21 L868R mutation-positive group. CONCLUSION: Subjects positive for the EGFR Exon 21 L858R mutation had a higher positive rate of intraoperative pleural lavage cytology than those not possessing EGFR mutations.

Prognostic significance of p21 protein expression in patients with pulmonary squamous cell carcinoma following induction chemotherapy.

BACKGROUND: The prognostic value of p21 protein expression in lung cancer patients has been assessed. However, its significance in those with pulmonary squamous cell carcinoma following induction chemotherapy (IC) remains unclear. We studied on patients who did or did not undergo IC (NIC) to elucidate the prognostic value of p21 protein expression. MATERIALS AND METHODS: p21 protein expression was assessed immunohistochemically and samples with greater than 10% positive tumor cells were considered positive. We then analyzed clinical-pathological features, including p53 protein expression and prognosis, in 43 patients who underwent IC group and 40 who did not IC (NIC) group. RESULTS: Positive nuclear p21 samples were obtained from 17 (41.5%) patients in the in IC group and 22 (55.0%) in the NIC group. In the IC group, there was no significant correlation between the histological effectiveness of chemotherapy and p53 protein expression, whereas a significant correlation was observed between that and p21 protein expression (p=0.048). Further, the prognosis for p21-positive patients tended to be better (p=0.0506) than for p21-negative patients, and was significant (p=0.048) in patients with pathological stage (p-stage) II or III disease. CONCLUSION: Our findings suggest that p21 protein expression is a prognostic factor for primary patients with pulmonary squamous cell carcinoma following IC.

Tumor-related gene expression levels in thymic carcinoma and Type B3 thymoma.

BACKGROUND: Thymic carcinoma (TC) is a rare type of malignant neoplasm that develops in the anterior mediastinum and associated with poor prognosis. Type B3 thymoma (B3) occasionally demonstrates malignant tumor characteristics, especially in the advanced stage. We investigated the expressions of tumor-related genes in resected TC and B3 specimens. METHODS: TC and B3 specimens resected from 1999 through 2012 were investigated. Tumor segments were collected from the specimens by micro-dissection to extract mRNA, then RT-PCR was performed according to Dannenberg's tumor profile method for semi-quantitation of tumor-related gene mRNA. To compare with other types of cancer, data from lung cancer (LC) cases in our database were also examined. RESULTS: The gene expression levels of thymidylate synthase were significantly higher in TC and B3 as compared to LC specimens (p < 0.02), while no difference were observed between TC and B3 tumors. The ratio of folypolyglutamyl synthase (FPGS) to gamma-glutamyl hydrolase (GGH) mRNA was significantly lower in TC than in B3 (p < 0.05), with lower FPGS/GGH in those tumors related to overall survival. Also, the gene expression of vascular endothelial growth factor (VEGF) was significantly higher in TC as compared to B3 (p = 0.04), with higher VEGF gene expression in TC and B3 specimens related to overall survival of affected patients. Epidermal growth factor receptor (EGFR) expression was significantly higher in B3 as compared to both TC and LC specimens (p < 0.01). However, there were no EGFR gene mutations detected in any of the specimens. CONCLUSIONS: These results indicate that elevated expressions of the tumor-related genes FPGS/GGH and VEGF are correlated with malignancy of TC and B3 tumors. Additional examinations will be necessary to investigate their chemosensitivity.