Metformin dose increase versus added linagliptin in non-alcoholic fatty liver disease and type 2 diabetes: An analysis of the J-LINK study.

We validated the effect of linagliptin, an oral dipeptidyl peptidase-4 inhibitor, on nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). A total of 50 patients with NAFLD and T2DM treated with metformin were randomized (1:1) to metformin plus add-on linagliptin (linagliptin group) or to an increased dose of metformin (metformin group) for 52 weeks. The primary endpoint was change in hepatic steatosis from baseline to week 52 as quantified by unenhanced computed tomography imaging. Secondary endpoints included changes in the levels of anthropometric, biochemical and adipokinetic markers. The linagliptin group showed no statistically significant reduction in hepatic steatosis as compared to the metformin group (P = 0.97), although changes in hepatic steatosis were significantly correlated with decreased liver enzymes in both groups. Body weight was significantly reduced in the metformin group but not in the linagliptin group (P = 0.002). Serum leptin levels were significantly increased in the linagliptin group compared to the metformin group (P = 0.003), and were correlated with the changes body weight in whole samples. Adverse events were not different between the two groups (P = 0.78). Add-on linagliptin demonstrated a safe profile but was not superior to increased metformin in reducing hepatic steatosis.

Diagnosis of metachronous multiple lung adenocarcinoma at the cut-end by epidermal growth factor receptor mutation status discordance 4 years after sublobar resection for adenocarcinoma in situ: report of a case.

We report a case of metachronous multiple lung adenocarcinoma at the cut-end, diagnosed 4 years after sublobar resection for adenocarcinoma in situ (AIS), on the basis of discordance of epidermal growth factor receptor (EGFR) mutation status between the first and second tumor. The patient was an 81-year-old Japanese man, whose chest computer tomography (CT) scan showed mixed ground-glass opacity in the right upper lobe of the lung. Wedge resection was performed and a diagnosis of AIS, non-mucinous (18 × 14 mm), with a margin of 6 mm, was made. A tumor at the cut-end was seen on a CT scan 4 years later, and abnormal uptake was identified by fluorine-18 fluorodeoxyglucose-positron emission tomography. Right upper lobectomy and lymph node dissection were performed and the tumor was diagnosed as invasive adenocarcinoma, acinar predominant. Discordance of EGFR mutation status between the first tumor, harboring exon 19 deletion, and the second tumor, having an L858R point mutation in exon 21, revealed that the second tumor was metachronous multiple lung cancer. This case demonstrates the necessity of comparing EGFR mutation status between the first tumor and the second tumor at the cut-end.

Case of solitary pulmonary capillary hemangioma: pathological features based on frozen section analysis.

Solitary pulmonary capillary hemangioma (SPCH) is a rare benign lung tumor that must be distinguished from small and early lung cancers. Here, we report a case of SPCH for which we performed frozen section diagnosis. The patient was a 55-year-old Japanese woman. Five years before the operation, mixed ground-glass opacity was detected by computed tomography in the left posterior basal segment of the lower lobe (S10). Because the interior tumor density of the ground-glass opacity increased slightly, video-assisted thoracic surgery wedge resection was performed. Frozen section diagnosis revealed a benign tumor without proliferation of atypical epithelial cells. The tumor had narrow alveolar lumens, thickened alveolar septa and a clear boundary separating it from normal lung tissue. The proliferated lumens varied in size and were lined with single layers of flat cells. After the operation, immunohistochemical staining of a paraffin section revealed that the thickened alveolar septa resulted from the proliferation of capillary vessels, the flat cells of which were positive for CD31 and CD34 and negative for podoplanin; the tumor was diagnosed as SPCH. Here, we discuss the pathological features of SPCH on frozen sections with reference to this case and review previous related reports.

Transposition of pulmonary veins for mobilization of residual right middle and lower lobes after carinal right upper lobectomy: a unique pulmonary hilar mobilization technique for safe tension-free airway anastomosis.

Unique right hilar mobilization was performed by pulmonary venous transposition of the right middle and lower lobe veins to the opening of the right upper pulmonary vein to achieve tension-free airway anastomosis after carinal right upper lobectomy for a patient with adenoid cystic carcinoma. The right middle and lower lobes were reconstructed safely thereafter by side-to-end anastomosis between the side of the lower trachea and intermediate bronchus with acceptable suturing tension.

Long-term survival of thoracoscopic surgery compared with open surgery for clinical N0 adenocarcinoma.

BACKGROUND: Early stage non-small cell lung cancer (NSCLC) is good candidate for video-assisted thoracoscopic surgery (VATS). Long-term outcome compared between VATS and open surgery remains unclear. The aim of this study was to assess the long-term outcome of VATS in early stage adenocarcinoma. METHODS: A retrospective study was performed in 546 patients which were operated between January 2006 and December 2010 in our institute and of those, 240 (220 lobectomies, and 20 segmentectomies) were clinical N0 adenocarcinoma. One hundred and thirty-five patients underwent VATS and 105 patients for open surgery. Long-term oncological outcomes were compared in both groups. RESULTS: There were significant differences in age, gender, Blinkman index, clinical T factor and tumor size between two groups. VATS group showed statistically longer operation time (P=0.01), less blood loss (P=0.005), shorter length of stay (P=0.001), and less dissected number of lymph nodes (P<0.001) compared with open surgery. Disease-free survival in VATS was significantly better than open surgery (5- and 10-year survival; VATS, 91.4%, 79.0%; open, 85.1%, 73.6%; respectively, P=0.04). Overall survival in VATS was not different from open (P=0.58). Propensity matched disease-free and overall survival was not significantly different between two groups. Multivariate Cox regression analysis showed that age [P=0.04, 95% confidence interval (CI): (1.02-6.81)] in overall and T factor [P=0.01, 95% CI: (1.41-17.3)] in disease-free survival was prognostic significant after propensity matching. CONCLUSIONS: Our study demonstrated that long-term outcome in VATS for early stage adenocarcinoma was equivalent to open surgery. VATS may be a treatment of choice for promising long-term prognosis.

WHO Grade I Meningioma Metastasis to the Lung 26 Years after Initial Surgery: A Case Report and Literature Review.

Metastases from meningioma grade I are especially rare. We describe a case of a 65-year-old male with meningioma WHO grade I with a history of local recurrence and distant metastasis to the lung 26 years after the initial surgery. The original tumor was localized at the occipital low convex and invaded into the venous sinus and posterior cranial fossa; it was resected. About 15 years later, the tumor recurred in the posterior cranial fossa and γ-knife radiosurgery was performed. About 4 years later, the recurred tumor was resected at our hospital. Another 7 years later, the tumor recurred in the same area and right middle cranial fossa. All tumors except that inside the venous sinus were excised. All specimens obtained were classified as meningioma WHO grade I. Preoperative examination of the third operation revealed a nodule in the lower lobe of the right lung. The nodule grew gradually. Four months after the third surgery, partial resection of the right lung was performed. Histology indicated meningioma WHO grade I. The two lesions in the cranium and lung lesions were subjected to fluorescence in situ hybridization of the NF2 gene, and the three specimens had similar findings, genetically confirming them to be metastases of the intracranial meningioma. A literature review of past cases of meningioma progression revealed that the mean duration to metastasis is 12.5, 6.8, 3.7 years for grades I, II, and III, respectively. The current case therefore has an extended time frame.

Prognostic Significance of BMI-1 But Not MEL-18 Expression in Pulmonary Squamous Cell Carcinoma.

AIM: We investigated the possibility of BMI-1 and MEL-18 to predict survival in patients with pulmonary squamous cell carcinoma. MATERIALS AND METHODS: One hundred and ninety-nine patients underwent surgery in our Institute between 1995 and 2005. We used immunohistochemical (IHC) analysis to determine the expressions of BMI-1 and MEL-18 and compared them with clinicopathological factors and survival. RESULTS: Forty-one of 199 cases (21%) were BMI-1-positive. No correlation was found between BMI-1 and MEL-18 expression by IHC and clinicopathological factors. Five-year overall survival in the BMI-1-positive group (66.8%), but not MEL-18, was significantly better than that in the negative group (45.5%, p=0.04). In multivariate analysis, positive BMI-1 was a better prognostic factor of overall survival (hazard ratio (HR)=0.561, 95% confidence interval (CI)=0.271-1.16, p=0.12). CONCLUSION: BMI-1 expression, but not MEL-18, is associated with a favorable prognosis and is a possible prognostic factor of pulmonary squamous cell carcinoma.

Use of a titanium alloy (Chest Way) in the surgical stabilization of flail chest.

To avoid the complications of internal pneumatic stabilization for flail chest, we performed stabilization of the chest wall with a metal bar using the Nuss procedure. Here, we used a highly elastic lightweight biocompatible titanium alloy Chest Way (Solve Corporation, Kanagawa, Japan), enabling magnetic resonance imaging. The patient was a 37-year-old man who sustained injuries in a car crash. Gradually increasing subcutaneous emphysema was present. Bilateral pleural drainage and tracheal intubation were conducted on the scene, and a peripheral venous line was established. The patient was then transferred to our hospital by helicopter. A titanium alloy Chest Way was inserted to manage his flail chest accompanied by multiple rib fractures on the left side. Two days later, artificial respiration was no longer required.

Reduced Expression of Hugl 1 Contributes to the Progression of Lung Squamous Cell Carcinoma.

Cell polarity and cell-cell adhesion play a critical role in the regulation of normal tissue architecture and function. Disruption of cell adhesion and cell polarity is often associated with neoplastic tumors. Loss of apical-basal polarity in epithelial cells is one of the hallmarks of aggressive and invasive cancers. Several polarity proteins including atypical protein kinase C (aPKC), Par 6, Par 3, and Lethal giant larvae (Lgl, the human homologues of which are called Hugl 1 and Hugl 2) are localized at the leading edge of migrating cells, and play critical roles during directional migration. Herein, we investigated the expression of aPKC, Par 6, Par 3, Hugl 1, and Hugl 2 in lung squamous cell carcinoma (SqCC). An inverse correlation was observed between the expression of Hugl 1 and lung SqCC progression. Results of immunohistochemistry and real-time RT-PCR analyses showed that reduced expression of Hugl 1 predicts poor survival in lung SqCC patients. The expression of Hugl 1 was inversely correlated with both overall survival rate and tumor stage. On the other hand, no associations were observed between the expressions of Hugl 2, Par 6, and Par 3 and lung SqCC progression. These findings indicate that the reduced expression of Hugl 1 could be considered as a poor prognostic factor in human lung cancers.

Ki-67 labeling index affects tumor infiltration patterns of lung squamous cell carcinoma.

Ki-67 is a nuclear protein that is expressed during the G1, S, G2 and M phases of the mitotic cell cycle. A previous study categorized tumor infiltration patterns (INF), of which INFc indicated cancer nests exhibiting infiltrative growth and an unclear boundary between tumor tissue and surrounding healthy tissue. The present study used the Ki­67 labeling index (Ki­67 LI) as an indicator of cell proliferation, in order to examine the factors affecting INF in lung squamous cell carcinoma (SqCC). SqCC specimens (89) were classified into two groups: High­grade cell proliferation (Ki­67 LI ≥30%) and low­grade cell proliferation (Ki­67 LI <30%). However, a high Ki­67 LI was significantly associated with cases that had an INFc component [INFc(+); P=0.03]. Univariate analyses indicated that INFc(+) was a predictor of venous invasion [P=0.032; odds ratio (OR), 2.615; 95% confidence interval (95% CI), 1.085­6.305], scirrhous stromal type (P<0.001; OR, 6.462; 95% CI, 2.483­16.817) and high Ki­67 LI (P=0.018; OR, 12.543; 95% CI, 1.531­102.777). Multivariate logistic analyses indicated that high Ki­67 LI was the strongest predictor of INFc(+) (P=0.028; OR, 8.027; 95% CI, 1.248­51.624). In conclusion, high­grade cell proliferation activity may contribute to aggressive infiltrative growth of lung SqCC.

Successful treatment of penetrating chest injury caused by a crossbow.

A 67-year-old man presented with a crossbow injury sustained in a suicide attempt during which he fixed the crossbow to a table. Although he retired to bed without treatment on the day of the initial injury, his pain increased the following day, and he was admitted to our hospital. On arrival, his vital signs were stable and a 10-mm diameter crossbow arrow that had penetrated the right anterior chest remained in place. Chest computed tomography revealed suspected damage to the right middle lobe, diaphragm, and liver. A right anterior thoracotomy was performed with partial resection of the middle lobe, diaphragm repair, and arrest of hepatic bleeding. There were no complications, and his postoperative course was uneventful. On day 12 after surgery, he was transferred to the psychiatry department of another hospital for treatment of his depression.

Comparison between CT tumor size and pathological tumor size in frozen section examinations of lung adenocarcinoma.

OBJECTIVE: We examined the appropriate measurement for pathological tumor size by comparing radiological and pathological tumor size of resected lung adenocarcinoma in FSE. MATERIALS AND METHODS: We reviewed records of 59 resected specimens of lung adenocarcinoma for FSE from January to December 2008. Specimens were well-inflated with saline by using an injector before cutting into segments. After selecting the tumor segment of maximal diameter, we compared three ways of measuring pathological tumor size by using paired t-test: (I) macroscopic tumor size (MTS), measured with a metal straight ruler, (II) microscopic frozen section tumor size (FSTS), and (III) microscopic paraffin section tumor size (PSTS). We compared each discrepancy rate (DR) [DR=(CT tumor size-pathological tumor size)/CT tumor size×100] (%) between tumors that were air-containing type and solid-density type on CT scans, and also compared the tumors with lepidic component rates (LCR) ≥50% and LCR <50%, by using Mann-Whitney U-tests. RESULTS: FSE could diagnose malignancy with 100% accuracy. The mean CT tumor size was 18.36mm, and the mean pathological tumor sizes (MTS, FSTS, and PSTS) were 17.81, 14.29, and 14.23mm, respectively. FSTS and PSTS were significantly smaller than CT tumor size (p<0.001). The DR calculated with PSTS was significantly larger in air-containing than in solid-density tumors, and also larger in LCR ≥50% than in LCR <50% tumors. CONCLUSION: FSE with the inflation method diagnosed malignancy with 100% accuracy. The lung specimen must be sufficiently inflated to prevent tissue shrinking, and we propose MTS as the definition for pathological tumor size in FSE. The greater discordance observed between CT tumor size and microscopic tumor size was assumed to be due to shrinkage of the lepidic component in the tumor.

Localization of aPKC lambda/iota and its interacting protein, Lgl2, is significantly associated with lung adenocarcinoma progression.

Atypical protein kinase C lambda/iota (aPKC λ/ι) is expressed in several human cancers; however, the correlation between aPKC λ/ι localization and cancer progression in human lung adenocarcinoma (LAC) remains to be clarified. We found that patients with a high level of aPKC λ/ι expression in LAC had significantly shorter overall survival than those with a low level of aPKC λ/ι expression. In addition, localization of aPKC λ/ι in the apical membrane or at the cell-cell contact was associated with both lymphatic invasion and metastasis. The intercellular adhesion molecule, E-cadherin, was decreased in LACs with highly expressed aPKC λ/ι at the invasion site of tumor cells. This result suggested that the expression levels of aPKC λ/ι and E-cadherin reflect the progression of LAC. On double-immunohistochemical analysis, aPKC λ/ι and Lgl2, a protein that interacts with aPKC λ/ι, were co-localized within LACs. Furthermore, we found that Lgl2 bound the aPKC λ/ι-Par6 complex in tumor tissue by immune-cosedimentation analysis. Apical membrane localization of Lgl2 was correlated with lymphatic invasion and lymph node metastasis. These results thus indicate that aPKC λ/ι expression is altered upon the progression of LAC. This is also the first evidence to show aPKC λ/ι overexpression in LAC and demonstrates that aPKC λ/ι localization at the apical membrane or cell-cell contact is associated with lymphatic invasion and metastasis of the tumor.

Tumor budding is a significant indicator of a poor prognosis in lung squamous cell carcinoma patients.

Lung cancer is a leading cause of cancer mortality worldwide and patients occasionally develop local recurrence or distant metastasis soon after curative resection. Reports of new therapeutic strategies for lung squamous cell carcinoma (SqCC) are extremely rare, while selective anticancer therapy has been reported for lung adenocarcinoma. The aim of this study was to identify clinicopathological prognostic factors for SqCC. We analyzed tumor budding and infiltrative patterns (INF) in 103 cases of surgically-resected SqCC. Tumor infiltrative patterns were classified into three groups (INFa, b and c) and INFc was infiltrative growth at the tumor invasive front. The cases with an INFc component [INFc(+)]were significantly associated with venous invasion (P=0.014) and the scirrhous stromal type (P<0.001). The overall survival rate of patients with INFc(+) was significantly lower than that of patients without the INFc component [INFc(-); P=0.003]. Tumor budding was defined as a single cancer cell or a small nest of up to four cancer cells within stromal tissue. The cases with tumor budding [Bud(+)] were significantly associated with lymph node metastasis (P=0.001), lymphatic invasion (P=0.002), INFc(+) (P<0.001) and the scirrhous stromal type (P=0.014). Patients with the Bud(+) type had a lower overall survival rate than patients with the Bud(-) type (P<0.001). Multivariate analysis demonstrated that tumor budding [hazard ratio (HR), 2.766; 95% confidence interval (CI), 1.497-5.109] and lymph node metastasis (HR, 1.937; 95% CI, 1.097-3.419) were independent predictors of mortality. In conclusion, tumor budding is a significant indicator of a high malignant potential and poor prognosis in SqCC of the lung.

Laminin-5γ2 chain expression is associated with tumor cell invasiveness and prognosis of lung squamous cell carcinoma.

Our previous study showed that tumor budding is a significant indicator of a poor prognosis in lung squamous cell carcinoma patients. Tumor budding-positive (Bud(+)) cases of lung squamous cell carcinoma (SqCC) showed locally aggressive growth, and the positivity was a useful indicator of the lymph node status and prognosis. The present study focused on the clinicopathologic significance of laminin-5γ2 chain expression for local aggressiveness in lung SqCC. Laminin-5γ2 chain immunohistochemical stains in tissue samples were divided into three distinct types: basement membrane (B type; laminin-5γ2 present in basement membrane), cytoplasmic (C type; laminin- 5γ2 present in intracellular matrix), and invasive front (F type; laminin-5γ2 present in cytoplasm, and strongly in part of peripheral nest). The F type was more common in Bud(+) cases than tumor budding-negative (Bud(-)) cases; B and C types were less common in Bud(+) cases (P 〈 0.001). The F type was more closely associated with decreased overall survival than the B and C types (P 〈 0.001 for both). Univariate analysis showed that the F type could be used to predict tumor size, lymph node metastasis, lymphatic invasion, tumor infiltrative patterns, tumor budding, and laminin-5γ2 chain staining. Multivariate analysis showed that laminin-5γ2 chain staining and tumor budding could be used to predict patient mortality (P 〈 0.001 and P = 0.005, respectively). The overall survival rate after curative resection was lower in patients with the F/Bud(+) type than in those with B+C/Bud(-) and B+C/Bud(+) types (P < 0.001 for both, log-rank test), and also lower with the F/Bud(-) type than the B+C/Bud(-) type. On the other hand, there was no significant difference between the F/Bud(+) and F/Bud(-) types. In conclusion, both laminin- 5γ2 chain staining and tumor budding are associated with tumor cell invasiveness and are independent predictors of mortality in lung SqCC patients.

Comparison of the sizes of adenoidal tissues and upper airways of subjects with and without cleft lip and palate.

The purpose of this retrospective study was to compare 2-dimensionally the sizes of the adenoidal tissues and the upper airways in juvenile and adolescent males with and without cleft lip and palate (CLP). Two paired groups of age-matched boys were used: (1) 90 juveniles with CLP (CLP/j) and without CLP (control/j) and (2) 40 adolescents with CLP (CLP/a) and without CLP (control/a). Measurements of adenoidal tissues and upper airways were determined by using lateral cephalograms. The adenoidal tissue was significantly larger in the CLP/j group than in the control/j group, but there was no significant difference between the CLP/a and control/a groups. The adenoidal tissue was significantly smaller in the CLP/a group than in the CLP/j group. The upper airway in the CLP/j group was significantly smaller than that in the control/j group, and that in the CLP/a group was also significantly smaller than that in the control/a group. Moreover, the upper airway in the CLP/a group was significantly larger than that in the CLP/j group, and that in the control/a group was significantly larger than that in the control/j group. However, the upper airway in the CLP/a group was significantly smaller than that in the control/a group. These results suggest that the larger adenoidal tissues in the CLP/j group, compared with those in the control/j group, decreased to a similar size with aging. However, the more restricted upper airway in the CLP/j group, compared with that in the control/j group, appeared to persist until adolescence.