This study explored the predictors of a histological aggressive component in ground glass opacity-containing lung adenocarcinoma.Of the 2388 patients who underwent resection for lung cancer at our institute between 2017 and 2020, we collected data on the 501 patients with ground glass opacity-containing adenocarcinoma with a total diameter of ≤2 cm. Using a historical cohort, we identified histological aggressive components that were related to a poor prognosis in early-stage adenocarcinoma. A multivariable analysis was conducted to identify predictors for the presence of a histological aggressive component.Lymphovascular invasion and predominant micropapillary or solid patterns were identified as histological aggressive components by a prognostic analysis using a historical cohort. Of the 501 patients included, 36 (7.2%) had at least one histological aggressive component. A multivariate analysis showed that a consolidation/tumour ratio > 0.5 (P < 0.01), maximum standardized uptake value on positron emission tomography ≥1.5 (P = 0.01) and smoking index >20 pack-years (P = 0.01) were predictors of the presence of a histological aggressive component. A total of 98% of cases without any of the above factors did not have a histological aggressive component.Approximately 7% of ground glass opacity-containing small adenocarcinomas contained histological aggressive component. A consolidation/tumour ratio > 0.5, maximum standardized uptake value ≥ 1.5 and smoking index >20 pack-years were predictors for such cases. These predictors may be useful for screening patients with a potentially high risk of a poor prognosis and for prioritizing resection without delay.
The time-dependence in diazepam kinetics after a single oral dose and after repeated oral doses was investigated in 5 healthy volunteers. Subjects took a single oral 5 mg dose of diazepam on two occasions, in the morning (09: 30) or in the evening (21: 30). Then they took repeated oral 5 mg doses once a day for 8 days every morning or every evening. After repeated oral doses as well as after a single oral dose, the mean peak total diazepam concentration in plasma (Cmax) tended to be higher in the morning trial. However, no difference was found in the mean elimination half-life.(t1/2), the area under the plasma concentration time-curve (AUC), the volume of distribution (Vd), or the total plasma clearance (CL) after repeated diazepam doses between morning and evening. The results found in the single dose study were essentially identical to the findings reported previously by our group.The time-dependence in diazepam kinetics was also found after repeated administrations. The mechanism of this time-dependency in the drug seems to be explained by the time-dependent variations in the rate of absorption from the gastro-intestinal tract and the rate of distribution of the drug. The plasma diazepam clearance significantly increased after repeated doses.
YM155, a novel molecular targeted agent, suppresses survivin, a member of the inhibitor of apoptosis protein family that is overexpressed in many tumor types. The aim of this study was to determine the maximum tolerated dose (MTD) and to assess the safety, pharmacokinetics, and antitumor activity of YM155 in patients with advanced refractory solid tumors.Patients with advanced refractory solid tumors were treated with escalating doses of YM155 administered by continuous i.v. infusion for 168 hours in 21-day cycles.Of the 34 patients enrolled, 33 (median age, 59 years) received at least 1 dose of YM155 (range, 1-19 cycles). The dose levels studied were 1.8, 3.6, 4.8, 6.0, 8.0, and 10.6 mg/m(2)/d. The MTD was determined to be 8.0 mg/m(2)/d, based on a dose-limiting toxicity of increased blood creatinine observed in 2 patients receiving 10.6 mg/m(2)/d. The most common adverse reactions judged to be related to YM155 were urine microalbumin present; fever; injection-site phlebitis; fatigue; and decreased hemoglobin/anemia, blood albumin, and lymphocyte count. The pharmacokinetic profile was almost linear over the dosing range and was similar between cycles 1 and 2. Urinary excretion of YM155 showed no definite difference among doses. Stable disease was achieved in nine patients.YM155 was safely administered to patients with advanced refractory solid tumors by 168-hour continuous i.v. infusion in 21-day cycles. The MTD was determined to be 8.0 mg/m(2)/d. The safety profile, plasma concentrations achieved, and antitumor activity observed merit further studies with this survivin suppressant, alone and in combination regimens.
Abstract: We have previously shown that human epidermal keratinocytes express macrophage migration inhibitory factor (MIF) mRNA, and immunohistochemical studies showed that MIF is expressed in human epidermis. To explore the possible pathophysiological roles of MIF in skin during rat fetal development, we examined the expression patterns of MIF during rat epidermal development using Northern blot analysis and in situ hybridization. Expression of MIF mRNA was first detected by in situ hybridization in the developing epidermis and hair germ cells from embryonic day (ED) 16. From ED 19, moderate levels of MIF expression were detected in the epidermis and epithelial sheath cells of growing hair follicles. In postnatal rat skin, higher MIF expression was detected in the epidermis and hair follicles on postnatal day 3. These observations were also confirmed by Northern blot analysis. Immunohistochemical analysis with an anti‐MIF antibody showed a similar distribution to that of the mRNA. Our results suggest that MIF is associated with epidermal and hair follicle development.
We aimed to visualize complicated patterns of lymph node metastases in surgically resected non-small cell lung cancer by applying a data mining technique.In this retrospective study, 783 patients underwent lobectomy or pneumonectomy with systematic mediastinal lymph node dissection for non-small cell lung cancer between January 2010 and December 2018. Surgically resected lymph nodes were classified according to the International Association for the Study of Lung Cancer lymph node map. Network analysis generated patterns of lymph node metastases from stations 1 to 14, and the degree of connection between 2 lymph node stations was assessed.The median number of lymph nodes examined per patient was 20, and the pathological N category was pN0 in 428 cases, pN1 in 132, pN2 in 221, and pN3 in 2. N1 lymph node stations had strong associations with superior mediastinal lymph node stations for patients with primary tumors in the upper lobes and with station 7 for the lower lobes. There was also a connection from the N1 lymph node stations to superior mediastinal lymph node stations in the lower lobes. In the right middle lobe, an even distribution from station 12m toward stations 2R, 4R, and 7 was noted. We released an interactive web application to visualize these data: http://www.canexapp.com.Lymph node metastasis patterns differed according to the lobe bearing the tumor. Our results support the need for clinical trials to further investigate selective mediastinal lymph node dissection.
We investigated the validity and inter‐criteria reproducibility between RECIST (Response Evaluation Criteria in Solid Tumors) guidelines and WHO (World Health Organization) criteria, considering the decrease in patient numbers resulting from inclusion of the minimum lesion size criterion introduced in RECIST guidelines. RECIST guidelines are based on unidimensional measurement and exclusion of small lesions from measurement. The aims of the study were to examine: (1) the effect of the minimum lesion size criterion, (2) the validity of unidimensional and bidimensional measurements, i.e., their relationship with tumor volume, (3) the inter‐criteria reproducibility between current RECIST guidelines and previous WHO criteria. One hundred and twenty patients with non‐small cell lung cancer (NSCLC) in clinical trials were evaluated. By applying the minimum lesion size criterion, six cases became ineligible without any influence on precision of tumor volume measurement. In the validity study, actual tumor volume was regarded as the gold standard. Although the unidimensional measurement had a lower correlation with tumor volume value than the bidimensional measurement, both the unidimensional measurement and bidimensional measurement correlated sufficiently well with tumor volume changes and the assessed tumor volume response. In the inter‐criteria reproducibility study between RECIST guidelines and WHO criteria, the response rate assessed by RECIST guidelines (19.3%) was almost the same as that assessed by WHO criteria (20.0%). In conclusion, RECIST guidelines are adequate for evaluating tumor response to chemotherapy in terms of both validity in relation to tumor volume and inter‐criteria reproducibility with the WHO criteria.
