Masami Abiko

New IASLC/ATS/ERS Classification and Invasive Tumor Size are Predictive of Disease Recurrence in Stage I Lung Adenocarcinoma

Introduction: The purpose of this study is to analyze and validate the prognostic impact of the new lung adenocarcinoma (ADC) classification proposed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society and invasive tumor size in stage I lung ADC of Japanese patients. Methods: We reclassified 191 stage I ADCs according to the new classification. The percentage of each histological subtype and the predominant type were determined. In addition, both total tumor size and invasive tumor size were examined. The relationship between these results and clinicopathological backgrounds was investigated statistically. Results: The 5-year disease-free survival (DFS) of adenocarcinoma in situ and minimally invasive adenocarcinoma was 100%; lepidic-predominant ADCs, 94.9%; papillary-predominant ADCs, 85.4%; acinar-predominant ADCs, 89.7%; and solid-predominant ADCs, 54%. The predominant growth pattern was significantly correlated with DFS (p < 0.001, overall). With regard to tumor size, total tumor size was not correlated with DFS (p = 0.475, overall), however, invasive tumor size was significantly correlated with DFS (⩽0.5 cm/ > 0.5cm, ⩽1cm/ >1 cm, ⩽2 cm/>2 cm, ⩽3 cm/ >3cm, 100%/91.5%/85.9%/80.8%/66.7%% in 5-year DFS) (p = 0.006, overall). A multivariate analysis showed solid-predominant and invasive tumor size were independent predictors of increased risk of recurrence (solid versus nonsolid: hazard ratio = 4.08, 95% confidence interval:1.59–10.5, p = 0.003; invasive tumor size: hazard ratio = 2.04, 95% confidence interval:1.14–3.63, p = 0.016). Conclusion: The new International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society ADC classification and invasive tumor size are very useful predictors of recurrence of stage I ADCs in Japanese patients.

The Correlation of the International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) Classification With Prognosis and EGFR Mutation in Lung Adenocarcinoma

BACKGROUND The purpose of this study was to validate the prognostic effect and the frequency of mutations in the gene expressing epidermal growth factor receptor (EGFR) in lung adenocarcinoma of Japanese patients, on the basis of the new adenocarcinoma classification proposed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. METHODS The new classification was used to reclassify 486 adenocarcinomas. The percentage of each histopathologic subtype and the predominant pattern were determined. EGFR mutation was also investigated. The relationship between these results and clinicopathologic backgrounds was investigated statistically. RESULTS No patients with adenocarcinoma in situ or minimally invasive adenocarcinoma died within the follow-up periods, followed by patients with lepidic predominant. Patients with papillary or acinar predominant, or invasive mucinous adenocarcinoma, showed almost similar overall survival (OS). The patients with solid predominant and micropapillary predominant showed the worst OS. Multivariate analysis showed that the new classification was an independent predictor of OS. The frequency of EGFR mutation was adenocarcinoma in situ (62%), minimally invasive adenocarcinoma (60%), lepidic (77%), acinar (49%), papillary (50%), solid (28%), micropapillary (43%), and invasive mucinous adenocarcinoma (0%). CONCLUSIONS This new adenocarcinoma classification is a very useful predictive marker to plan and determine a therapeutic strategy for lung adenocarcinoma.

Acceleration of dermal tissue repair by angiotensin II

Angiotensin II is a naturally occurring peptide which has been shown to possess angiogenic properties. In the studies reported here, angiotensin II was shown to increase the proliferation of cultured bovine aortic arch endothelial cells in a concentration‐dependent manner. Acute administration of angiotensin II in Hydron accelerated the repair of dermal injuries in a full‐thickness excisional rat model. Additional studies were done to determine the best vehicle for delivery of angiotensin II to a dermal injury. Several vehicles, including 10% low‐viscosity carboxymethyl cellulose, 4% medium‐viscosity carboxymethyl cellulose, and 3% high‐viscosity carboxymethyl cellulose, were found to be effective in this regard. Daily administration of angiotensin II for days 0 to 4 after injury (day 0 being the time of surgery) was determined to provide the optimal dosage for acceleration of wound repair by angiotensin II. In addition, dose‐response studies indicated that angiotensin II accelerated wound repair in a dose‐dependent fashion with 0.03 and 0.01 µg/rat/day of angiotensin II administered on days 0 to 4 being the minimally effective and no‐effect doses, respectively. Administration of 100 µg/day of angiotensin II in 10% carboxymethyl cellulose for 5 days after injury to animals with impaired healing (steroid‐ and adriamycin‐treated rats and diabetic mice) was also found to accelerate the rate of repair. In conclusion, angiotensin II accelerated the closure of full‐thickness skin injuries in a dose‐dependent manner in normal and impaired animal models.

Positron Emission Tomography/Computed Tomography and Lymphovascular Invasion Predict Recurrence in Stage I Lung Cancers

Background: Although pathologic stage I lung cancers generally have a favorable prognosis, approximately 20% of patients experience recurrence after surgery. Therefore, a method of selecting patients who need adjuvant therapy is necessary. The goal of this study was to evaluate the significance of positron emission tomography (PET)/computed tomography (CT) results after lung cancer surgery and to identify the predictive factors for recurrence in cases of pathologic stage I lung cancer. Methods: From January 2004 to December 2008, 356 patients with lung cancer underwent surgery at our institution. Of these, 282 patients received F-18 fluorodeoxyglucose PET/CT, and the maximum standardized uptake value (max SUV) was measured. There were 201 patients with pathologic stages IA and IB evaluated. The associations between disease-free survival (DFS) and the following clinicopathological factors were analyzed: age, gender, smoking history, carcinoembryonic antigen level, tumor size, max SUV values, histology, and lymphovascular and pleural invasion. Results: The 4-year DFS rate was 86.3%. Multivariate analysis revealed lymphovascular invasion (LVI; p < 0.01) and max SUV ≥4.7 (p < 0.01) to be independent predictive factors. Patients with a max SUV more than 4.7 had a significantly high risk of recurrence. DFS of patients with high max SUVs and LVI (n = 18) was significantly reduced compared with other patients (n = 183, p < 0.01). Conclusions: The PET-CT results significantly correlated with recurrence in pathologic stage I lung cancers. Patients with high max SUVs and LVI were more likely to have recurrence and should be candidates for adjuvant chemotherapy.

Alterations of angiotensin II Receptor levels in sutured wounds in rat skin.

Angiotensin II receptor levels have been shown to vary with postoperative time in tissue harvested from full-thickness dermal excisional wounds on adult rats. This study examined the expression of AII receptors in a sutured wound model. Two full-thickness incisional wounds were made in the dorsal skin of adult Sprague-Dawley rats and sutured immediately under general anesthesia. The wound tissues were harvested at 0, 0.5, 1, 2, 4, 24 h and on days 2, 3, 4, 5, 7, and 10 after the wounding. The levels of 125I-Sar1.Ile8-AII bound to membrane preparations of the wound tissues decreased at early time points (from 0.5 to 4 h), increased from day 1 to day 7, and returned to nonsurgical levels by day 10. Competitive binding studies showed that the receptors were predominantly of the AT1 receptor subtype. These results suggest that an immediate and transient reduction in AII receptor expression occurred after wounding, followed by an increase in the number of AII receptors that was maintained for 5 to 7 days postoperatively. Because these data are consistent with those observed after excisional wounding, temporal changes in AII receptor expression may be integral to the process of wound healing.

Positron emission tomography for predicting recurrence in stage I lung adenocarcinoma: standardized uptake value corrected by mean liver standardized uptake value

OBJECTIVE F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) has become an important staging tool for patients with lung cancer, and determination of the standardized uptake value (SUV) is probably the most widely used method for evaluating patients. Although SUV is recognized as a powerful surrogate marker for lung cancer outcomes, SUV standardization and reproducibility in clinical practice remain major concerns. The aim of this study was to evaluate the corrected SUV as a universal marker for lung cancer recurrence. METHODS We conducted a case-control study in our institute. From May 2004 to February 2010, 141 patients with pathological stage IA and IB adenocarcinomas underwent PET-computed tomography scanning and SUV determination. The corrected SUV was defined as the SUV index, which was calculated as the ratio of tumor SUV(max) to liver SUV(mean). We examined the association between disease-free survival and several clinicopathological factors, including the SUV index. RESULTS The 3-year overall survival rate after surgery was 94.3% and the 3-year disease-free survival rate was 90.4%. Univariate analysis showed that male gender (p=0.04), smoking (p=0.02), and SUV index (p<0.01) were independent predictive factors for recurrence. Multivariate analysis showed that the SUV index was significantly associated with a high risk for recurrence (p=0.03). No patient with an SUV index <1.0 experienced a recurrence. CONCLUSIONS The SUV index is a significantly predictive and reproducible factor for recurrence in pathological stage I lung cancers. Patients with an SUV index <1.0 were more likely to have a good prognosis. Additional multi-institutional studies are needed to confirm these study results.

The Clinical Impact of Solid and Micropapillary Patterns in Resected Lung Adenocarcinoma

Introduction Since the new adenocarcinoma (ADC) classification was presented in 2011, several authors have reported that patients with solid (S) and/or micropapillary (MP) predominant patterns showed a worse prognosis. On the other hand, there are several patients who have S and/or MP patterns even if their patterns are not predominant. However, the evaluation of these patients is uncertain. Methods A total of 531 ADCs were examined. We classified the patients into five subgroups according to the proportion of S and/or MP patterns: (1) both patterns absent (S–/MP–), (2) S predominant (S pre), (3) MP predominant (MP pre), (4) S pattern present although not predominant and MP pattern absent (S+ not pre/MP–), and (5) MP pattern present although not predominant (MP+ not pre). Results Of the 531 ADCs, 384 (72.3%) were classified as S–/MP–, 55 (10.4%) as S pre, 11 (2.1%) as MP pre, 42 (7.9%) as S+ not pre/MP–, and 39 (7.3%) as MP+ not pre. In a univariate analysis, the recurrence‐free survival (RFS) and overall survival differed significantly among the five subgroups (p < 0.01 and p < 0.01, respectively). In a multivariate analysis, patients with S–/MP– had significantly higher RFS rates than did those with other subgroups. On the other hand, patients with MP pre had lower RFS rates than did those with other subgroups. Conclusion Patients with S and/or MP patterns have a poorer prognosis even if their patterns are not predominant. The S and/or MP patterns must be treated at the time of diagnosis.

Prognostic impact and initial recurrence site of lymphovascular and visceral pleural invasion in surgically resected stage I non-small-cell lung carcinoma

OBJECTIVES This study aimed to analyse and validate the prognostic impact and effect of the initial recurrence site of lymphovascular and visceral pleural invasion (VPI) on survival outcomes for Stage I non-small-cell lung carcinoma (NSCLC). METHODS We retrospectively reviewed 433 patients undergoing resection of Stage I NSCLC. The relationship between the clinicopathological background and the pathological variables, lymphovascular invasion (LVI) and VPI, was evaluated by univariate and multivariate analyses. RESULTS Lymphovascular and VPI was observed in 41 and 45 patients, respectively. On univariate analysis, the presence of LVI was associated with a significant decrease in relapse-free survival (RFS) (P < 0.001) and overall survival (OS) (P < 0.001). The RFS of the patients of Stage IB with LVI was worse than the RFS of those of Stage IIA (T2aN1 and T2bN0)/IIB (T3N0), and similar to the RFS of those of Stage IIB (T2bN1). The presence of VPI was also associated with a significant decrease in RFS (P < 0.001) and OS (P = 0.01). On multivariate analysis, LVI was found to be an independent predictor of both decreased RFS and decreased OS. However, VPI was not an independent predictor of both. Recurrence was seen in 68 patients. As an initial recurrence site, distant recurrence was seen in 32 patients and local recurrence, in 36. The proportion of local recurrence was significantly higher in the patients with VPI than in those without VPI compared with between the patients with LVI and those without LVI. CONCLUSIONS We propose that LVI and/or VPI may be a candidate marker to determine adjuvant therapy or a more careful follow-up for these patients.

Removal of cartilage rings of the graft and omentopexy for extended tracheal autotransplantation

BACKGROUND One of the serious problems in longer-size tracheal transplantation is infection or severe stenosis of the graft, probably caused by an inadequate blood supply even with omentopexy. For obtaining an appropriate blood supply, we experimentally developed a new technique that included removal of some cartilage rings of the graft and omentopexy. METHODS Twenty-one adult mongrel dogs were used. In group A (n = 11), a nine-cartilage ring length of the trachea in which six of nine rings were removed, leaving one cartilage ring at each end of the graft and another in the center, was autotransplanted with omentopexy. Two artificial tracheal rings outside the graft were used for maintaining the lumen. In group B (n = 10), a nine-cartilage ring length of the trachea was autotransplanted with omentopexy. RESULTS In group A, all dogs survived until being sacrificed, whereas 5 group B dogs died of graft infection and mediastinitis (p<0.05 versus group A). Mucosal blood flow of the graft in group A was normal and higher than in group B (p<0.05). Grade of the graft stenosis at death or sacrifice was 14%+/-1% in group A and 58%+/-25% in group B (p<0.05). CONCLUSIONS Removal of some cartilage rings improved blood supply to the graft and resulted in satisfactory survival and nonsignificant tracheal stenosis in extended tracheal autotransplantation.

Malignant solitary fibrous tumor with superior vena cava syndrome

Mediastinal solitary fibrous tumors, particularly those that are malignant, are rare. We report a case of malignant solitary fibrous tumor with superior vena cava syndrome and highly aggressive behavior. Postoperative radiotherapy was performed due to incomplete resection, but the tumor relapsed within 4 months. Gemcitabine-based chemotherapy was ineffective.