Mariko Fukui

Tumour standardized uptake value on positron emission tomography is a novel predictor of adenocarcinoma in situ for c-Stage IA lung cancer patients with a part-solid nodule on thin-section computed tomography scan†

OBJECTIVES Adenocarcinoma in situ (AIS), which is considered to be pathologically non-invasive in the new International Association for the Study of Lung Cancer/the American Thoracic Society/the European Respiratory Society classification, might be present in patients who show a part-solid nodule on thin-section computed tomography (CT) scan. METHODS Between 2008 and 2011, 556 clinical Stage IA (c-Stage IA) lung cancer patients underwent pulmonary resection. For all the patients, the findings obtained by preoperative thin-section CT were reviewed and categorized as pure ground-glass nodule (GGN), part-solid nodule or pure-solid nodule based on the findings on thin-section CT, i.e. based on the consolidation/tumour ratio (CTR). A part-solid nodule was defined as a tumour with 0 < CTR < 1.0, which indicated focal nodular opacity that contained both solid and GGN components. All the patients were evaluated by positron emission tomography (PET), and the maximum standardized uptake value (SUVmax) was recorded. Several clinicopathological features were investigated to identify predictors of AIS in clinical Stage IA lung cancer patients with a part-solid nodule radiologically, using multivariate analyses. RESULTS One-hundred and twelve c-Stage IA lung cancer patients showed a part-solid appearance on thin-section CT. Among them, AIS was found in 10 (32%) of the tumours with 0 < CTR ≤ 0.5, in contrast to 3 (5%) with 0.5 < CTR < 1.0. According to multivariate analyses, SUVmax and CTR significantly predicted AIS in patients with a part-solid nodule (P = 0.04, 0.02). The mean SUVmax of the patients with AIS was 0.57 (0-1.6). Moreover, in the subgroup of part-solid nodule with a SUVmax of ≤1.0 and a CTR of ≤0.40, which were calculated as cut-off values for AIS based on the results for a receiver operating characteristic curve, 6 (40%) patients with these criteria showed a pathological non-invasive nature, even patients with a part-solid nodule. CONCLUSIONS Among c-Stage IA adenocarcinoma with a part-solid nodule on thin-section CT scan, an extremely low level of SUVmax could reflect a pure GGN equivalent radiologically and AIS pathologically. The preoperative tumour SUVmax on PET could yield important information for predicting non-invasiveness in patients with a part-solid nodule.

Lung cancer with scattered consolidation: detection of new independent radiological category of peripheral lung cancer on thin-section computed tomography

OBJECTIVES Ground glass opacity (GGO) on thin-section computed tomography (CT) has been reported to be a favourable prognostic marker in lung cancer, and the size or area of GGO is commonly used for preoperative evaluation. However, it can sometimes be difficult to evaluate the status of GGO. METHODS A retrospective study was conducted on 572 consecutive patients with resected lung cancer of clinical stage IA between 2004 and 2011. All patients underwent preoperative CT and their radiological findings were reviewed. The areas of consolidation and GGO were evaluated for all lung cancers. Lung cancers were divided into three categories on the basis of the status of GGO: GGO, part solid and pure solid. Lung cancers in which it was difficult to measure GGO were selected and their clinicopathological features were investigated. RESULTS Seventy-one (12.4%) patients had lung cancer in whom it was difficult to measure GGO. In all these cases, consolidation and GGO were not easily measured because of their scattered distribution. In this cohort, nodal metastases were not observed at all. The frequency of other pathological factors, such as lymphatic and/or vascular invasion, was significantly lower (P < 0.0001). CONCLUSIONS This new category of lung cancer with scattered consolidation on thin-section CT scan tended to be pathologically less invasive. When lung cancer has GGO and is difficult to measure because of a scattered distribution, its prognosis could be favourable regardless of the area of GGO. This new category could be useful for the preoperative evaluation of lung cancer.

The presence of air bronchogram is a novel predictor of negative nodal involvement in radiologically pure-solid lung cancer.

OBJECTIVES Phase III trials regarding the feasibility of segmentectomy for lung cancer ≤ 2 cm in size are now underway in Japan and the USA. However, despite their small size, lung cancers that show a pure-solid appearance on thin-section computed tomography (CT) are considered to be invasive with a high frequency of nodal involvement. METHODS Between 2008 and 2011, 556 clinical Stage IA lung cancer patients underwent pulmonary resection. For all patients, the findings obtained by preoperative thin-section CT were reviewed and the maximum standardized uptake value (SUVmax) on positron emission tomography was recorded. Several clinicopathological features were investigated to identify predictors of nodal metastasis using multivariate analyses. RESULTS One hundred and eighty-four clinical Stage IA lung cancer patients showed a pure-solid appearance on thin-section CT. Among them, air bronchogram was found radiologically in 58 (32%) patients. Nodal involvement was observed in 10 (17%) patients with air bronchogram, compared with 43 (34%) without air bronchogram, in clinical Stage IA pure-solid lung cancer. A multivariate analysis revealed that air bronchogram, clinical T1a and SUVmax were significant predictors of postoperative nodal involvement (P < 0.01, <0.01, and 0.03, respectively). Furthermore, nodal metastasis was never seen in patients with clinical T1a pure-solid lung cancers who had both air bronchogram and low SUVmax. CONCLUSIONS The presence of air bronchogram was a novel predictor of negative nodal involvement in clinical Stage IA pure-solid lung cancer. Segmentectomy with thorough lymph node dissection is a feasible option for these patients despite a pure-solid appearance.

Correlation of EGFR or KRAS mutation status with 18F-FDG uptake on PET-CT scan in lung adenocarcinoma

Background 18F-fluoro-2-deoxy-glucose (18F-FDG) positron emission tomography (PET) is a functional imaging modality based on glucose metabolism. The correlation between EGFR or KRAS mutation status and the standardized uptake value (SUV) of 18F-FDG PET scanning has not been fully elucidated. Methods Correlations between EGFR or KRAS mutation status and clinicopathological factors including SUVmax were statistically analyzed in 734 surgically resected lung adenocarcinoma patients. Molecular causal relationships between EGFR or KRAS mutation status and glucose metabolism were then elucidated in 62 lung adenocarcinomas using cap analysis of gene expression (CAGE), a method to determine and quantify the transcription initiation activities of mRNA across the genome. Results EGFR and KRAS mutations were detected in 334 (46%) and 83 (11%) of the 734 lung adenocarcinomas, respectively. The remaining 317 (43%) patients had wild-type tumors for both genes. EGFR mutations were more frequent in tumors with lower SUVmax. In contrast, no relationship was noted between KRAS mutation status and SUVmax. CAGE revealed that 4 genes associated with glucose metabolism (GPI, G6PD, PKM2, and GAPDH) and 5 associated with the cell cycle (ANLN, PTTG1, CIT, KPNA2, and CDC25A) were positively correlated with SUVmax, although expression levels were lower in EGFR-mutated than in wild-type tumors. No similar relationships were noted with KRAS mutations. Conclusions EGFR-mutated adenocarcinomas are biologically indolent with potentially lower levels of glucose metabolism than wild-type tumors. Several genes associated with glucose metabolism and the cell cycle were specifically down-regulated in EGFR-mutated adenocarcinomas.

Lipoprotein-X in cholestatic patients causes xanthomas and promotes foam cell formation in human macrophages

BACKGROUND Lipoprotein-X (Lp-X) is an abnormal phospholipid-rich lipoprotein found in patients with cholestatic liver disease. Some patients exhibit skin xanthomas and severe hyperlipidemia. OBJECTIVE We investigated whether Lp-X induces foam cell formation in human-derived macrophages. METHODS To compare the atherogenic properties of Lp-X and modified LDL, we isolated Lp-X from 2 patients who had drug-induced cholestasis and xanthoma striata in the interphalangeal folds. We prepared oxidized LDL and acetylated LDL from healthy volunteers for the positive control experiments. RESULTS When human monocyte-derived macrophages were incubated with these lipoproteins, the isolated Lp-X induced more prominent lipid accumulation than oxidized LDL or acetylated LDL. One case underwent liver biopsy, with the bile ducts showing marked damage, fulfilling the criteria for vanishing bile duct syndrome. The other case was clinically diagnosed as drug-induced hypersensitivity syndrome. In both cases, Lp-X levels decreased markedly and the xanthomas disappeared completely after the improvement of cholestasis. CONCLUSION This study indicates that Lp-X induces foam cell formation in human-derived macrophages. Our findings strongly suggest that persistently elevated Lp-X may cause xanthomas.

Prospective randomized trial comparing buttressed versus nonbuttressed stapling in patients undergoing pulmonary lobectomy.

BACKGROUND The aim of this study was to evaluate the efficacy of buttressed stapling using a stapler with an attached polyglycolic acid sheet in reducing the rate of air leak associated with pulmonary lobectomy. Materials and METHODS A prospective, randomized, phase III study was conducted to confirm the superiority of a buttressed stapler in a test treatment group to a conventional nonbuttressed stapler in a current international standard of care group among patients undergoing pulmonary lobectomy. The primary end point was the frequency of intraoperative air leaks. RESULTS Although no fatal postoperative bleeding occurred in the present study, this trial closed early with 100 patients because the manufacturer recalled the buttressed stapler based on reports of 13 serious injuries and 3 fatalities following pulmonary resection in routine clinical practice. A total of 76 patients treated with a stapler (35 in the non-B group and 41 in the B group) were included as subjects in the analysis. No statistical differences were observed between the groups in the frequency of intraoperative air leaks (22 [63%] vs. 26 [63%]) or the postoperative duration of air leaks (mean: 3.5 vs. 2.9 days). The frequency of air leak from stapler holes was significantly lower in the B group than in the non-B group (2% [1/41] vs. 20% [7/35]; p=0.016). CONCLUSIONS The efficacy of buttressed stapling in reducing the rate of air leak in patients undergoing pulmonary lobectomy could not be clearly demonstrated. However, air leak from stapler holes can be prevented with buttressed stapling.

Comparison of digital and traditional thoracic drainage systems for postoperative chest tube management after pulmonary resection: A prospective randomized trial

Objective: The objective of this study was to evaluate whether a digital thoracic drainage system (group D) is clinically useful compared with a traditional thoracic drainage system (group T) in chest tube management following anatomic lung resection. Methods: Patients scheduled to undergo segmentectomy or lobectomy were prospectively randomized before surgery to group D or T. A stratification randomization was performed according to the following air leak risk factors: age, sex, smoking status, and presence of emphysema and/or chronic obstructive pulmonary disease. The primary end point was the duration of chest tube placement. Results: No statistically significant differences were found between groups D (n = 135) and T (n = 164) with regard to the duration of chest tube placement (median, 2.0 vs 3.0 days; P = .149), duration of hospitalization (median, 6.0 vs 7.0 days; P = .548), or frequency of postoperative adverse events (25.1% vs 20.7%; P = .361). In subgroup analyses of the 64 patients with postoperative air leak (20 in group D and 44 in group T), the duration of chest tube placement (median, 4.5 vs 4.0 days; P = .225) and duration of postoperative air leak (median, 3.0 vs 3.0 days; P = .226) were not significantly different between subgroups. Conclusions: The use of a digital thoracic drainage system did not shorten the duration of chest tube placement in comparison to a traditional thoracic drainage system after anatomic lung resection.

Limb-Shaking Transient Ischemic Attack Induced by Middle Cerebral Artery Dissection after Lung Surgery

We report a case of limb-shaking transient ischemic attack (TIA) caused by a dissection of the middle cerebral artery (MCA) following lung surgery under general anesthesia. An 81-year-old male patient who underwent lobectomy for lung cancer suddenly developed transient shaking movements of the neck and the left upper distal limb on postoperative day 1. On the basis of the double-barrel appearance of the right M1 segment of the MCA, a diagnosis of MCA dissection was made. Physicians should be aware that limb-shaking TIA is sometimes caused by MCA dissection and could be precipitated by any condition, including lung surgery under general anesthesia.

Surgical intervention for ground glass dominant lesions: observation or outright resection?

Background The management of ground glass opacity (GGO) on computed tomography (CT) remains controversial. Information of the relationship between clinical behavior and pathological invasiveness of GGO is valuable for management. We conducted this retrospective study to establish differences in the pathological invasiveness between GGO with and without changes. Methods Among 1762 patients, the following criteria was used: (1) maximum tumor diameter of 3 cm or less, (2) tumor having 50% or more GGO and (3) resection after at least three months of follow up. A change of CT findings was defined as an increase in the diameter or consolidation compared with the initial CT. The relationship between preoperative changes and ratio of invasive adenocarcinoma was investigated. Predictors of GGO growth were also examined. Results There were 250 patients: pure GGO without changes (G-N group; n = 118), pure GGO with changes (G-C group; n = 35), part-solid GGO without changes (S-N group; n = 78), and part-solid GGO with changes (S-C group; n = 20). The ratio of invasive adenocarcinoma in each group was 0.54, 0.89, 0.8, and 0.90. There was a significant difference between the G-N and G-C group (P < 0.001). However, there was no significant difference between the G-C, S-N and S-C group. Multivariate analysis indicated age was a predictor of preoperative changes (OR = 1.953, P = 0.049). Conclusions The pathological results of part-solid GGO with changes were not different from those without changes. Therefore surgery can be deferred until those lesions demonstrate changes. The pathological results of pure GGO with changes were equivalent to those of part-solid GGO. Therefore, even for pure GGO, follow up is necessary especially in elderly patients.

Risk of the preoperative underestimation of tumour size of lung cancer in patients with idiopathic interstitial pneumonias.

OBJECTIVES Sublobar resection of lung cancer (LC) is a valuable procedure in patients with idiopathic interstitial pneumonias (IIPs). Having adequate surgical margins is the key to successful sublobar resection, and evaluation of the precise extent of LC is mandatory. However, tumour extent in IIPs is difficult to evaluate. This study assessed the risk of underestimating tumour size by preoperative computed axial tomography (CAT) scan in LC patients with IIPs. METHODS A retrospective study was performed on 1221 patients who underwent surgical resection of primary LC at our institute between 2009 and 2013. Review of CAT findings revealed that 136 (11.1%) patients were complicated with IIPs. The discrepancy between radiological and pathological tumour dimensions was measured and underestimation was defined as 10 mm or more in pathological tumour dimension. The rate and cause of preoperative underestimation were also compared between patients with and without IIPs. Univariate and multivariate analyses were performed using a logistic regression model to predict underestimation of the preoperative tumour size. RESULTS Maximum tumour dimension was underestimated in 14 (10.3%) patients with IIPs and 35 (3.2%) patients without IIPs. A multivariable analysis revealed that IIP was the only predictive factor for tumour size underestimation identified in this study (hazard ratio = 3.52, P = 0.017). Underestimation of tumour size in patients with IIPs was mainly due to extension of tumour cells in the honeycomb lung. CONCLUSIONS IIPs pose a high risk for underestimating tumour size of LCs in preoperative measurements. Thus, tumour extent should be assessed carefully in order to maintain adequate surgical margins.