The spread of metastatic lymph nodes to the mediastinum from left upper lobe cancer: results of superior mediastinal nodal dissection through a median sternotomy.

BACKGROUND: This study endeavored to clarify the location, frequency, and prognostic value of metastatic lymph nodes in the mediastinum among patients with left upper lung cancer who underwent complete dissection of the superior mediastinal lymph node through a median sternotomy. METHODS: Forty-four patients with left upper lobe cancer underwent extended radical mediastinal nodal dissection (ERD), all of whom were analyzed in this retrospective study. The group comprised 12 females and 32 males, with ages ranging from 28 to 70 years (median age, 60 years). Mediastinal nodal status was assessed according to the systems of Mountain/Dresler 7 and Naruke 8. The clinicopathological records of each patient were examined for prognostic factors, including age, sex, histology, tumor size, c-N number, preoperative serum CEA level, metastatic stations and distribution of metastatic nodes according to Naruke's system 8. The superior mediastinal lymph nodes which cannot be dissected through a left thoracotomy (bilateral #1 and #2, #3, right #3a, and right #4 according to Naruke's map 8 were defined as extra-superior mediastinal nodes for left lung cancer (ESMD). RESULTS: Fourteen patients had one or more metastases to mediastinal lymph nodes, among whom the most common metastatic station was the aortic nodes: 71.4% had metastasis to #5 or #6 (57.1% to #5 and 50% to #6). The next most common metastatic station was the left tracheobronchial nodes (42.8%). Metastasis to the ESMD occurred in 7 of the 44 study subjects (16%), representing a 50% rate of occurrence (7/14) among those with mediastinal nodal involvement. Univariate analysis found that CN factor and aortic nodal involvement (#5, #6) were significant predictive factors for ESMD metastasis. Multivariate analysis determined that only aortic nodal involvement was significant (p = 0.008). Furthermore, ESMD metastasis was rare (5.8%) in the absence of aortic node metastasis. The overall survival rate at 5 years was 50% among the patients without ESMD metastasis. However, the survival rate was 32% at 3 years and 0% at 5 years among the seven patients with ESMD metastasis. CONCLUSIONS: The aortic lymph node is the most common site of metastasis from left upper lobe cancer. Multivariate analysis demonstrated that aortic nodal involvement was a significant predictive factor for ESMD metastasis. Based upon the rates of metastasis and the post-operative prognosis in our study patients, dissection of aortic nodes and left tracheobronchial nodes may be important for patients with left upper lobe cancer. Whether ESMD dissection has a beneficial effect on prognosis remains controversial.     

Reevaluation of the unilateral pulmonary artery occlusion test--hemodynamics after lobectomy and pneumonectomy for lung cancer

After lobectomy, it is recognized that functional as well as absolute reduction occurs in residual lobes of the operated side. So whether lobectomy is indicated or not is determined by the same criteria as those for pneumonectomy, namely, by the unilateral pulmonary artery occlusion (UPAO) test. However, is it really appropriate to use the same criteria for both lobectomy and pneumonectomy? To answer to this question, in patients with lung cancer we compared the hemodynamics after lobectomy (13 cases) and pneumonectomy (14 cases) with that at the UPAO test. After pneumonectomy, the mean pulmonary arterial wedge pressure (mPWP) was significantly lower than that on the preoperative day and at the test. It seemed that hypovolemic change occurred in the hemodynamics after pneumonectomy. After pneumonectomy, the pulmonary arteriolar resistance index (PARI) was significantly higher than the preoperative value. It was the same as that as at the time of the UPAO test. The total pulmonary vascular resistance index (TPVRI) at the time of the test was significantly higher than the preoperative value, but the TPVRI after pneumonectomy was not significantly higher. The TPVRI tended to decrease after pneumonectomy, compared to the value predicated by the test. These results indicated that some of the cases judged inoperable on the basis of the UPAO test might be operable. On the day of lobectomy, the PARI was significantly higher than the preoperative value, but significantly lower than that at the time of the test. The cardiac index (CI) was significantly higher and the mPWP was significantly lower than each preoperative value.(ABSTRACT TRUNCATED AT 250 WORDS)     

A study of the right ventricular load at the unilateral pulmonary artery occlusion test after pneumonectomy

After pneumonectomy, it is recognized that the absolute reduction of the pulmonary vascular bed makes the right ventricular afterload increase and can cause right heart failure in patients with low cardiopulmonary reserve. Therefore, we investigated how the right ventricular load was predicted by UPAO test, comparing hemodynamics at the time of the test with those after pneumonectomy in patients with lung cancer. At the test, the absolute reduction of the pulmonary vascular bed made the right ventricular afterload increase but the right ventricular pump function was maintained at the preoperative level by the increase of the right ventricular work load, namely, by the contraction of the right ventricle. After pneumonectomy, the absolute reduction of the vascular bed did not always make the afterload increase and in spite of the decreased preload the pump function was maintained at the preoperative level by increased heart rate. Additionally, the increase of the right ventricular work load improved during early postoperative days. It was concluded that UPAO test was apt to overestimate the right ventricular load of the postoperative day because it was done under the condition of the different compensatory function from the postoperative hypovolemic change.     

Interaction between cytochrome P450 gene polymorphisms and serum organochlorine TEQ levels in the risk of endometriosis

Exposure to dioxins and polychlorinated biphenyls (PCBs) has been suggested as a possible etiologic factor for endometriosis, but the association remains highly controversial. To assess whether cytochrome P450 (CYP) gene polymorphisms modulate the effect of dioxins and/or PCBs in endometriosis risk, we conducted a case-control study among infertile Japanese women. A total of 138 eligible women aged 20-45 were diagnosed laparoscopically and classified into three subgroups: control (no endometriosis), early endometriosis (stages I-II) and advanced endometriosis (stages III-IV). Neither CYP1A1 Ile462Val and CYP1B1 Leu432Val polymorphisms (genotypes with versus genotypes without the minor allele) nor serum dioxin and PCB toxic equivalency (TEQ) levels (low versus high) were independently associated with either early or advanced endometriosis risk. However, genotypes with the CYP1A1 462Val allele showed a statistically significant reduced risk of advanced endometriosis in combination with high serum dioxin TEQ levels (adjusted odds ratio = 0.13, 95% confidence interval: 0.02-0.76) (P for interaction = 0.08). Although no association was found between serum PCB TEQ level and advanced endometriosis in any stratum of CYP1B1 Leu432Val polymorphism, a statistically significant interaction was found (P for interaction = 0.05). CYP1A1 and CYP1B1 polymorphisms may modify the relation between environmental exposure to organochlorine and advanced endometriosis risk.     

Prospective study showing that dietary vitamin C reduced the risk of age-related cataracts in a middle-aged Japanese population

Background In Western countries, many epidemiological studies have demonstrated that specific dietary nutrients are associated with the risk of developing age-related cataracts. These reports have suggested that dietary antioxidant vitamins, in particular vitamin C, can play a role in preventing the onset or progression of age-related visual impairment. However, few prospective studies have examined this relationship in a general Asian population. Therefore, in this study, we investigated whether dietary vitamin C was associated with a lower incidence of age-related cataracts by performing a 5-year prospective population-based analysis using data from a cohort of over 30,000 Japanese residents recruited to the Japan Public Health Center-based Prospective Study (JPHC Study) cohort I. Aim of the study We carried out a prospective analysis of the association between vitamin C intake and age-related cataracts among middle-aged Japanese, to study the effects of dietary antioxidants in an Asian population. Methods This 5-year population-based study included 16,415 men and 18,771 women (aged 45–64 years), who were recruited onto the JPHC Study and had not reported cataracts in baseline surveys. Vitamin C was calculated from the nutrient intake assessed by self-administered food-frequency questionnaires (FFQ). Self-reported questionnaires were used to assess two endpoints: diagnosis or extraction of cataracts. Results At follow-up, 216 men and 551 women reported new diagnoses, and 110 men and 187 women reported extractions of cataracts. For both endpoints, a higher vitamin C intake was associated with a reduced incidence of cataracts in both sexes. After adjusting for potential confounding factors, the multivariate odds ratios (ORs) for men and women in the highest quintiles of energy-adjusted vitamin C intake, relative to the lowest quintiles, were 0.65 (95% CI, 0.42–0.97) and 0.59 (95% CI, 0.43–0.89) for cataract diagnoses, and 0.70 (95% CI, 0.44–1.20) and 0.64 (95% CI, 0.41–0.94) for cataract extractions, respectively. Conclusions Dietary vitamin C intake might lower the risk of age-related cataracts among middle-aged Japanese. Study Group Members: Members of the Japan Public Health Center-based Prospective Study Group are: S. Tsugane, M. Inoue, T. Sobue, T. Hanaoka, National Cancer Center, Tokyo; J. Ogata, S. Baba, T. Mannami, A. Okayama, National Cardiovascular Center, Suita; K. Miyakawa, F. Saito, A. Koizumi, Y. Sano, I. Hashimoto, Iwate Prefectural Ninohe Public Health Center, Ninohe; Y. Miyajima, N. Suzuki, S. Nagasawa, Y. Furusugi, Akita Prefectural Yokote Public Health Center, Yokote; H. Sanada, Y. Hatayama, F. Kobayashi, H. Uchino, Y. Shirai, T. Kondo, R. Sasaki, Y. Watanabe, Y. Miyagawa, Nagano Prefectural Saku Public Health Center, Saku; Y. Kishimoto, E. Takara, T. Fukuyama, M. Kinjo, M. Irei, H. Sakiyama, Okinawa Prefectural Chubu Public Health Center, Okinawa; K. Imoto, H. Yazawa, T. Seo, A. Seiko, F. Ito, F. Shoji, Katsushika Public Health Center, Tokyo; A. Murata, K. Minato, K. Motegi, T. Fujieda, Ibaraki Prefectural Mito Public Health Center, Mito; K. Matsui, T. Abe, M. Katagiri, M. Suzuki, Niigata Prefectural Kashiwazki and Nagaoka Public Health Center, Kashiwazaki and Nagaoka; M. Doi, A. Terao, Y. Ishikawa, Kochi Prefectural Chuo-higashi Public Health Center, Tosayamada; H. Sueta, H. Doi, M. Urata, N. Okamoto, F. Ide, Nagasaki Prefectural Kamigoto Public Health Center, Arikawa; H. Sakiyama, N. Onga, H. Takaesu, Okinawa Prefectural Miyako Public Health Center, Hirara; F. Horii, I. Asano, H. Yamaguchi, K. Aoki, S. Maruyama, M. Ichii, Osaka Prefectural Suita Public Health Center, Suita; S. Matsushima, S. Natsukawa, Saku General Hospital, Usuda; M. Akabane, Tokyo University of Agriculture, Tokyo; M. Konishi, K. Okada, Ehime University, Matsuyama; H. Iso, Y. Honda, Tsukuba University, Tsukuba; H. Sugimura, Hamamatsu University, Hamamatsu; Y. Tsubono, Tohoku University, Sendai; M. Kabuto, National Institute for Environmental Studies, Tsukuba; S. Tominaga, Aichi Cancer Center Research Institute, Nagoya; M. Iida, W. Ajiki, Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka; S. Sato, Osaka Medical Center for Health Science and Promotion, Osaka; N. Yasuda, Kochi Medical School, Nankoku; S. Kono, Kyushu University, Fukuoka; K. Suzuki, Research Institute for Brain and Blood Vessels Akita, Akita; Y. Takashima, Kyorin University, Mitaka; E. Maruyama, Kobe University, Kobe; the late M. Yamaguchi, Y. Matsumura, S. Sasaki, S. Watanabe, National Institute of Health and Nutrition, Tokyo; and T. Kadowaki, Tokyo University, Tokyo.     

Long-term antihypertensive drug use and risk of cancer: The Japan Public Health Center-based prospective study

Antihypertensive drugs have been reported as both promotors and suppressors of cancers and this relationship has been known for several decades. We examined a large-scale prospective cohort study in Japan to assess the relationship between long-term antihypertensive drug use, for 10 y, and carcinogenesis. We divided participants into 4 categories according to the period of antihypertensive drug use, and calculated the hazard ratios (HRs), 95% confidence intervals (CIs), and P trends using the Cox proportional hazard model. In all cancers, there was a significant difference in the medication period and the adjusted HR, as well as a significant difference in the P trend. Furthermore, more than 10 y use of antihypertensive drugs significantly increased the adjusted HR in colorectal cancer (multivariable HR: 1.18, 95% CI: 1.01-1.37 in the >10 y use group; P for trend = .033) and renal cancer (multivariable HR: 3.76, 95% CI: 2.32-6.10 in the 5-10 y use group; multivariable HR: 2.14, 95% CI: 1.29-3.56 in the >10 y use group; P for trend < .001). The highest adjusted HR in renal cancer among antihypertensive drug users was observed in the analysis performed on patients in which the outcomes were calculated from 3 y after the 10-y follow-up survey and by sex. A large-scale cohort study in Japan suggested that long-term use of antihypertensive drugs may be associated with an increased incidence of colorectal and renal cancer.     

Histological sequence of the development of rat mesothelioma by MWCNT,with the involvement of apolipoproteins

A rat model of mesothelioma development by peritoneal injection of multiwalled carbon nanotube (MWCNT) has been established and found to be useful to understand the mechanisms underlying fibrous particles-associated carcinogenesis. Its detailed histological sequence, however, remains largely obscure. We therefore aimed to assess the time-course of mesothelioma development by MWCNT and evaluate a set of lipoprotein-related molecules as potential mechanism-based biomarkers for the phenomenon. Male Fischer 344 rats were injected intraperitoneally (ip) with MWCNT (MWNT-7) at 1 mg/kg body weight, and necropsied at 8, 16, 24, 32, or 42 wk after injection. For biochemical analyses of the lipoprotein-related molecules, more samples, including severe mesothelioma cases, were obtained from 2 other carcinogenicity tests. Histologically, in association with chronic inflammation, mesothelial proliferative lesions appeared at c. Wk-24. Before and at the beginning of the tumor development, a prominent infiltration of CD163-positive cells was seen near mesothelial cells. The histological pattern of early mesothelioma was not a papillary structure, but was a characteristic structure with a spherical appearance, composed of the mesothelioma cells in the surface area that were underlain by connective tissue-like cells. Along with the progression, mesotheliomas started to show versatile histological subtypes. Serum levels of apolipoprotein A-I and A-IV, and a ratio of HDL cholesterol to total cholesterol were inversely correlated with mesothelioma severity. Overall, the detailed histological sequence of mesotheliomagenesis by MWCNT is demonstrated, and indicated that the altered profile of apolipoproteins may be involved in its underlying mechanisms.     

Development of a novel 6-DOF parallel mechanism moving platform for investigating the effects of multimodal sensory feedback information regarding postural stability in humans

The purpose of this study was to develop a six-degree-of-freedom parallel mechanism moving platform to investigate the effects of multimodal sensory feedback information while standing upright. We constructed a custom-designed disturbance-applying instrument (DAI) consisting of a support surface suspended from eight pneumatic artificial muscles. The posture of the support surface was controlled with a proportional–integral–derivative (PID) feedback system using an infra-red camera-based real-time 3D motion capture system, and was estimated by step and frequency responses. Head trajectories of two healthy subjects were recorded to evaluate the effect of the differences in the impedance of the support surface during upright standing with their eyes opened/closed. The results demonstrated that the step and frequency responses of the DAI were good enough to enhance the bodily oscillation and head motion relative to the support surface. Indeed, the head-swaying space, using the DAI in a 0.2-Hz air-supplying condition during upright standing with their eyes closed, was larger than in the other standing condition. These results suggest that the specific medio-lateral head swaying was caused by the effects of the multimodal sensory feedback information using the DAI. In conclusion, we developed a novel moving platform to investigate the effects of multimodal sensory feedback information upon upright postural control. The DAI would be particularly valuable to enhance the head-swaying space during upright standing by changing the impedance of the support surface or stimulating the translational and/or rotational sensory feedback integration.     

Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer: PEGASUS‐PC Study

Gemcitabine is a key drug for the treatment of pancreatic cancer; however, with its limitation in clinical benefits, the development of another potent therapeutic is necessary. Vascular endothelial growth factor receptor 2 is an essential target for tumor angiogenesis, and we have conducted a phase I clinical trial using gemcitabine and vascular endothelial growth factor receptor 2 peptide (elpamotide). Based on the promising results of this phase I trial, a multicenter, randomized, placebo‐controlled, double‐blind phase II/III clinical trial has been carried out for pancreatic cancer. The eligibility criteria included locally advanced or metastatic pancreatic cancer. Patients were assigned to either the Active group (elpamotide + gemcitabine) or Placebo group (placebo + gemcitabine) in a 2:1 ratio by the dynamic allocation method. The primary endpoint was overall survival. The Harrington–Fleming test was applied to the statistical analysis in this study to evaluate the time‐lagged effect of immunotherapy appropriately. A total of 153 patients (Active group, n = 100; Placebo group, n = 53) were included in the analysis. No statistically significant differences were found between the two groups in the prolongation of overall survival (Harrington–Fleming P‐value, 0.918; log–rank P‐value, 0.897; hazard ratio, 0.87, 95% confidence interval [CI], 0.486–1.557). Median survival time was 8.36 months (95% CI, 7.46–10.18) for the Active group and 8.54 months (95% CI, 7.33–10.84) for the Placebo group. The toxicity observed in both groups was manageable. Combination therapy of elpamotide with gemcitabine was well tolerated. Despite the lack of benefit in overall survival, subgroup analysis suggested that the patients who experienced severe injection site reaction, such as ulceration and erosion, might have better survival.