Ayuko Takahashi

A disintegrin and metalloprotease 12 (ADAM12) is a prognostic factor in resected pathological stage I lung adenocarcinoma

A disintegrin and metalloprotease 12 (ADAM12) has multiple domains and functions, and it plays important roles in the development of cancer. We conducted a retrospective study to determine whether the expression of the membrane type of ADAM12 (ADAM12‐L) could be a prognostic factor in resected pathological (p‐) stage I lung adenocarcinoma.

Proteoglycans maintain lung stability in an elastase-treated mouse model of emphysema.

Extracellular matrix remodeling and tissue rupture contribute to the progression of emphysema. Lung tissue elasticity is governed by the tensile stiffness of fibers and the compressive stiffness of proteoglycans. It is not known how proteoglycan remodeling affects tissue stability and destruction in emphysema. The objective of this study was to characterize the role of remodeled proteoglycans in alveolar stability and tissue destruction in emphysema. At 30 days after treatment with porcine pancreatic elastase, mouse lung tissue stiffness and alveolar deformation were evaluated under varying tonicity conditions that affect the stiffness of proteoglycans. Proteoglycans were stained and measured in the alveolar walls. Computational models of alveolar stability and rupture incorporating the mechanical properties of fibers and proteoglycans were developed. Although absolute tissue stiffness was only 24% of normal, changes in relative stiffness and alveolar shape distortion due to changes in tonicity were increased in emphysema (P < 0.01 and P < 0.001). Glycosaminoglycan amount per unit alveolar wall length, which is responsible for proteoglycan stiffness, was higher in emphysema (P < 0.001). Versican expression increased in the tissue, but decorin decreased. Our network model predicted that the rate of tissue deterioration locally governed by mechanical forces was reduced when proteoglycan stiffness was increased. Consequently, this general network model explains why increasing proteoglycan deposition protects the alveolar walls from rupture in emphysema. Our results suggest that the loss of proteoglycans observed in human emphysema contributes to disease progression, whereas treatments that promote proteoglycan deposition in the extracellular matrix should slow the progression of emphysema.

Value of FOXP3 expression in peripheral blood as rejection marker after miniature swine lung transplantation.

BACKGROUND Outcome for highly immunogenic lung transplantation remains unsatisfactory despite the development of potent immunosuppressants. The poor outcome may be the result of a lack of minimally invasive methods to detect early rejection. There is emerging clinical evidence that, paradoxically, expression of forkhead box P3 (FOXP3, a specific marker for the regulatory T cells) is upregulated within rejecting grafts. METHODS Orthotopic lung transplantation was performed using miniature swine without immunosuppression. Rejection was monitored by chest radiography and open lung biopsy. Expressions levels of FOXP3, perforin, Fas-L and IP-10 mRNA were quantified in the peripheral blood. In addition, rescue immunosuppressive therapy (steroid plus tacrolimus) was administered on post-operative day (POD) 4 or 6. RESULTS Early rejection was detected by open lung biopsy, but misdiagnosed by chest radiography on POD 4. Expression of FOXP3 in the peripheral blood reached its highest value as early as POD 4, followed by a decline. Such an increase of FOXP3 was not observed in recipients given high-dose tacrolimus. Neither perforin, Fas-L or IP-10 in the peripheral blood exhibited significant fluctuations in the early phase of rejection. Rescue immunosuppressive therapy from POD 4, when peak FOXP3 was seen, prolonged graft survival (27.2 days, versus 9.1 days without immunosuppression, p < 0.001), in contrast to POD 6, when rejection was suspected by chest radiography (11.5 days, p = not statistically significant [NS]). CONCLUSIONS In a miniature swine lung transplantation model, the FOXP3 mRNA level in the peripheral blood was upregulated at an early phase of rejection. The clinical implication of this finding remains to be elucidated.

Forced Oscillation Technique as a Non-Invasive Assessment for Lung Transplant Recipients

We usually use spirometry for the medical follow-up of respiratory mechanics after lung transplantation. However, especially in the first few post-operative weeks, it is easily affected by postoperative pain and the patients co-operation during forced breathing effort. To avoid missing out on assessing pulmonary function, we perform non-invasive forced oscillation techniques on the patients who cannot perform forced breathing maneuvers. In this paper, we discuss the application of forced oscillation techniques on a patient with suspicion of acute lung rejection, whose spirometry could not be correctly performed and seemed to be unreliable. The respiratory impedance measurements had good correlation with the patients clinical symptoms before and after steroid therapy. Thus, postoperative pulmonary function follow-up using forced oscillation technique was useful in assessing peripheral airway condition in critically ill patients, and may be able to detect acute rejection.

Noninvasive assessment for acute allograft rejection in a rat lung transplantation model

After lung transplantation, early detection of acute allograft rejection is important not only for timely and optimal treatment, but also for the prediction of chronic rejection which is a major cause of late death. Many biological and immunological approaches have been developed to detect acute rejection; however, it is not well known whether lung mechanics correlate with disease severity, especially with pathological rejection grade. In this study, we examined the relationship between lung mechanics and rejection grade development in a rat acute rejection model using the forced oscillation technique, which provides noninvasive assessment of lung function. To this end, we assessed lung resistance and elastance (RL and EL) from implanted left lung of these animals. The perivascular/interstitial component of rejection severity grade (A‐grade) was also quantified from histological images using tissue fraction (TF; tissue + cell infiltration area/total area). We found that TF, RL, and EL increased according to A‐grade. There was a strong positive correlation between EL at the lowest frequency (Elow; EL at 0.5 Hz) and TF (r2 = 0.930). Furthermore, the absolute difference between maximum value of EL (Emax) and Elow (Ehet; Emax − Elow) showed the strong relationship with standard deviation of TF (r2 = 0.709), and A‐grade (Spearmans correlation coefficients; rs = 0.964, P < 0.0001). Our results suggest that the dynamic elastance as well as its frequency dependence have the ability to predict A‐grade. These indexes should prove useful for noninvasive detection and monitoring the progression of disease in acute rejection.

En bloc total vertebrectomy for lung cancer invading the spine

Introduction of spinal surgery into lung cancer operations has made extensive operations feasible with an acceptable long-term survival. We report our successful experience of en bloc total vertebrectomy for lung cancer invading the spine. A 49-year-old man was found to have squamous cell carcinoma of the posterior apex of the right lung with an invasion of the body of the second and third thoracic vertebra. After induction chemoradiotherapy, we performed en bloc resection through thoracotomy and posterior median approach. Vertebral stabilization was achieved with a rod fixation and a placement of titanium mesh cage packed with autogenous bone chips.

Age-Related Changes in the Trachea in Healthy Adults

To investigate age-related changes in the shape of trachea, normal male volunteers (n = 83, mean +/- SD: 47.7 +/- 20.2 years old) underwent inspiratory CT scans at full inspiration and lung function tests. Subjects who showed VC < 80% predicted or FEV1 < 80% predicted on lung function tests were excluded. The CT data, which is located at 2.0 cm above the aortic arch, were transferred to a personal computer. The tracheal area (St) and two parameters, Tracheal index (Ti) and Circularity (Ci) indicating the shape of the trachea, were automatically calculated. Ti was defined the ratio of the coronal to the sagittal diameter of the trachea, and the Ci (Ci = 4piS/L2, S: tracheal area, L: tracheal perimeter) was used to indicate the roundness of the trachea. A Ci value of less than 1 indicated the distortion of the roundness. Both St and St/BSA (body surface area) showed a significant correlation with age (r = 0.37, r = 0.52; p = 0.0006, p < 0.0001). Ti was not correlated with age (r = -0.20; p = 0.0697), whereas Ci was significantly correlated with age (r = -0.32; p = 0.00364). There were measurable age related changes of the trachea both in the area and the shape. Aging results in the increased tracheal area and a distortion of the roundness.

Interlobar lymph node metastases according to primary tumor location in lung cancer

Interlobar lymph node metastases were analyzed in consecutive 284 lung cancer patients with lobar-hilar and mediastinal lymph node dissection. Interlobar lymph node metastases were observed in 46 (16.2%) patients with no difference between right and left cases. On the right side, there was a significant difference in the frequency of inferior interlobar lymph node metastases between upper lobe and middle/lower lobe tumors (P=0.0004), but no difference in the frequencies of superior ones according to primary site. On the left, there was a significant difference in the frequency of interlobar lymph node metastases between upper lobe and lower lobe tumors (P=0.0021). In per-segment analyses, the frequency of inferior interlobar lymph node metastases in segments 1-3 and 6 was significantly lower than in the other total segments (P<0.0001) on the right, and that of interlobar lymph node metastases in the upper division segments (S1-3) was significantly lower than in the other total segments (P=0.0008) on the left. Even limited to one lobe, the patterns of interlobar lymph node metastases were different among the segments in the right lower lobe and the left upper lobe.

Comparing Part-Solid and Pure-Solid Tumors in the TNM Classification of Lung Cancer (Eighth Edition)

BACKGROUND  In the eighth edition of the TNM classification, the lung tumors that have the same solid components are categorized either as part-solid or pure-solid tumors. However, this is debatable since the tumors in the same T component categories were evaluated without considering this categorization, and was based on a more malignant behavior and a poorer prognosis of pure-solid tumors. The aim of this study was to investigate and compare the prognosis between part-solid and pure-solid tumors. METHODS  We retrospectively analyzed 530 patients who were diagnosed with clinical-T1a-cN0M0 non-small-cell lung cancer (NSCLC) and were treated surgically. The subjects were divided into part-solid and pure-solid tumor groups using thin-section computed tomography. The prognosis was compared between the groups. RESULTS  Although relapse-free survival (RFS) was significantly shorter in the pure-solid tumor group (p = 0.016), no significant differences were observed in the overall survival (OS) between the two groups (p = 0.247). In 137 propensity score-matched pairs, including variables such as age, gender, Brinkman index, body mass index, forced expiratory volume in 1 second/forced vital capacity, Charlson comorbidity index, carcinoembryonic antigen levels, clinical-T status, surgical procedure, and extent of surgery, no significant differences were seen in the RFS and OS between the two groups (p = 0.709 and p = 0.517, respectively). CONCLUSION  In the eighth edition of the TNM classification of clinical-T1a-cN0M0 NSCLC, the prognosis of part-solid and pure-solid tumors showed no significant differences. Solid component size of the tumor is considered important prognostic factor in early-stage NSCLC.

Adjuvant chemotherapy for elderly patients with non-small-cell lung cancer

Background Adjuvant chemotherapy after complete surgical resection is currently the standard of care for patients with stage IB, II, or IIIA non-small-cell lung cancer. However, the generalizability of this treatment to elderly patients is controversial. We investigated the effects of adjuvant chemotherapy in patients aged over 75 years with stage IB-IIIA non-small-cell lung cancer. Methods We retrospectively analyzed 246 consecutive patients aged over 75 years with stage IB-IIIA non-small-cell lung cancer who underwent standard lung cancer surgery between January 2001 and December 2015. They were divided into 102 who had adjuvant chemotherapy and 144 who had none (control group). The outcomes were compared between the two groups, and prognostic factors were evaluated. Results Relapse-free survival and overall survival were significantly shorter in the control group than the chemotherapy group (p = 0.006 and p = 0.008, respectively). In multivariable analyses, adjuvant chemotherapy was found to be an independent prognostic factor for relapse-free survival and overall survival (hazard ratio = 0.594, 95% confidence interval: 0.396–0.893, p = 0.012; and hazard ratio = 0.616, 95% confidence interval: 0.397–0.957, p = 0.031, respectively). After inverse-probability-of-treatment weighting adjustment using the propensity score for baseline characteristics, chemotherapy almost improved relapse-free survival and overall survival (hazard ratio = 0.652, 95% confidence interval: 0.433–0.981, p = 0.040; and hazard ratio = 0.657, 95% confidence interval: 0.429–1.004, p = 0.052, respectively). Conclusions Adjuvant chemotherapy improved the prognosis after standard lung cancer surgery in patients aged over 75 years with stage IB-IIIA non-small-cell lung cancer.