Role of definitive chemoradiotherapy using docetaxel and 5-fluorouracil in patients with unresectable locally advanced esophageal squamous cell carcinoma: a phase II study.

Definitive chemoradiotherapy (CRT) with docetaxel (DOC) and 5-fluorouracil (5-FU) is a unique regimen for esophageal cancer. In this prospective phase II study, antitumor effect and safety of CRT using DOC and 5-FU for inoperable locally advanced esophageal cancer were evaluated. DOC 7.5 mg/m2 was infused on days 1, 8, 22, and 29. 5-FU 250 mg/m2 /day was infused continuously on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, and 43-45. Radiotherapy was given to 66 Gy in 33 fractions. Eleven patients with thoracic and five with cervical esophageal cancer were eligible. All patients had esophageal squamous cell carcinoma (ESCC). The response rate was 94%, with complete response in five patients (31%) and partial response in 10 (63%). Hematologic toxicity was mild; only one patient (6%) had Grade 1 leukopenia. Nonhematologic Grade 3 or higher adverse events were esophagitis (31%), anorexia (6%), and esophago-bronchial fistula (6%). No treatment-related deaths occurred. The median time to progression was 20 months and overall 3-year and 5-year survival were 44% and 31%, respectively. Definitive CRT using DOC and 5-FU could be performed safely, and it demonstrated a favorable antitumor effect for ESCC. This regimen might be indicated in patients in whom it is desirable to avoid myelosuppression and progression of renal impairment.

Effects of neoadjuvant chemoradiotherapy on postoperative morbidity and mortality associated with esophageal cancer.

We compared the surgical outcomes between 114 patients who did not receive neoadjuvant therapy (group 1) and 92 others who received neoadjuvant chemoradiotherapy (nCRT) (group 2), and assessed the preoperative and surgical factors that influence postoperative morbidity to determine the impact of nCRT on morbidity and mortality after esophagectomy via cervical, right transthoracic, and abdominal approaches. The overall postoperative morbidity rates were 44.7% and 55.4% in groups 1 and 2, respectively (P = 0.13). Rates of anastomotic leak (8.8% vs. 16.3%; P = 0.10), pneumonia (9.6% vs. 13.0%; P = 0.44), recurrent nerve palsy (15.8% vs. 10.9%; P = 0.31), and all other complications did not significantly differ between the groups. Multivariable analysis revealed cervical lymph node dissection (odds ratio [OR], 1.97; 95% confidence interval [CI], 1.01-3.84; P = 0.047) as the sole independent covariate for overall morbidity. Furthermore, a history of cardiovascular disease (OR, 2.90; 95% CI, 1.03-8.24; P = 0.045), the retrosternal reconstruction route (OR, 15.15; 95% CI, 3.56-62.50; P = 0.0002), and a longer surgical duration (OR, 1.01; 95% CI, 1.002-1.02; P = 0.01) were independent covariates for anastomotic leakage, and advanced age (OR, 1.08; 95% CI, 1.01-1.15; P = 0.02) and lower body mass index (OR, 1.16; 95% CI, 1.01-1.33; P = 0.04) were independent covariates for pneumonia. However, whether or not patients received nCRT was irrelevant. We found that nCRT is safe for three-incision esophagectomy and it does not increase the incidence of postoperative morbidity and mortality relative to esophagectomy alone.

Effects of an elemental diet to reduce adverse events in patients with esophageal cancer receiving docetaxel/cisplatin/5-fluorouracil: a phase III randomized controlled trial-EPOC 2 (JFMC49-1601-C5).

BACKGROUND: Oral mucositis (OM) is an unpleasant adverse event in patients receiving chemotherapy. A prospective feasibility study showed that elemental diet (ED), an oral supplement that does not require digestion, may prevent OM. Based on this, we established a central review system for oral cavity assessment by dental oncology specialists blinded to background data. We used this system to elucidate the preventive effect of an ED against OM in patients with esophageal cancer receiving docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy. PATIENTS AND METHODS: In this phase III, multicenter, parallel-group, controlled trial, patients consuming a normal diet orally were randomly assigned (1 : 1) to receive two cycles of DCF with (group A) or without (group B) an ED (Elental® 160 g/day). We assessed the incidence of grade ≥2 OM evaluated by two reviewers, changes in body weight, prealbumin, C-reactive protein, and DCF completion rate based on ED compliance. RESULTS: Of the 117 patients randomly assigned to treatment, four failed to start treatment and were excluded from the primary analysis; thus, groups A and B comprised 55 and 58 patients, respectively. There were no significant differences in background characteristics. Grade ≥2 OM was observed in eight (15%) and 20 (34%) patients in groups A and B, respectively (P = 0.0141). Changes in body weight and prealbumin during the two DCF cycles were significantly higher in group A than B (P = 0.0022 and 0.0203, respectively). During the first cycle, changes in C-reactive protein were significantly lower in group A than B (P = 0.0338). In group A (receiving ED), the DCF completion rate was 100% in patients with 100% ED compliance and 70% in patients failing ED completion (P = 0.0046). CONCLUSIONS: The study findings demonstrate that an ED can prevent OM in patients with esophageal cancer receiving chemotherapy.

[Intrabronchial leiomyoma treated with endoscopic resection; report of a case].

A 63-year-old female presented with an abnormal shadow on a chest X-ray. A serial chest computed tomography (CT) showed ground-glass attenuation, which measured 2 cm on S1+2 of the left lung. When bronchofiberscopy was performed to make a diagnosis, a tumor with a smooth surface was revealed which obstructed the right middle bronchus. Leiomyoma was thus diagnosed. At first, a wide wedge resection of left lung tumor was performed. Secondly, a bronchus tumor was successively removed using a high frequency snare and a laser by a bronchofiberscopy. Her postoperative course was uneventful. Leiomyoma of the bronchus is rare benign tumor. This report describes the performance of a resection using bronchofiberscopy with good results.

Evidence for basic fibroblast growth factor as a crucial angiogenic growth factor, released from human trophoblasts during early gestation.

The objective of this study was to clarify the possible angiogenesis-promoting factors from human trophoblasts in early stage gestation. The existence of angiogenic growth factors such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in the condition medium from human villous trophoblasts was determined. Biological activity of angiogenic growth factors released by trophoblasts was examined using vascular endothelial cell lines. The condition medium from trophoblasts enhanced the growth of endothelial cells. Although cultured trophoblasts exhibited immunoreactive products for both bFGF and VEGF in the cytoplasm, only bFGF was detected in the condition medium by ELISA. The growth-enhancing activity of the condition medium was eliminated completely by the addition of anti-bFGF antibody but not with anti-VEGF antibody. Thus, trophoblastic cells seem to play an important role in extensive angiogenesis occurring in early gestation, mainly by releasing bFGF but not VEGF.

Novel aspect of cyclic 3',5'-adenosine monophosphate synthesis in Escherichia coli 3000A1.

A kinetic analysis of cyclic 3',5'-adenosine monophosphate (cAMP) synthesis in an adenine auxotroph of Escherichia coli 3000 was made by assaying the incorporation of [3H]adenine into cAMP during exponential growth. The rate of increase in intracellular [3H]cAMP was very slow (0.1-0.2 pmol/min/DU660). The steady state level was attained at about 40-min incubation after the addition of [3H]adenine, and was estimated to be 5 to 7 pmol/DU660. The rate and level of intracellular cAMP were scarcely affected by growth conditions, such as change of carbon source, whereas the excretion of cAMP into the medium began immediately after the addition of [3H]adenine, and continued at a rate of 5 to 7 pmol/min/DU660 in the glycerol medium. The excretion rate decreased to 1.4 pmol/min/DU660 in the presence of glucose. These results are inconsistent with the view that the excretion rate is dependent on the intracellular concentration of cAMP. Although the decreased rate of cAMP synthesis in the presence of glucose accounts for the permanent catabolite repression of inducible enzyme systems, no immediate depression in cAMP synthesis, which might account for the transient repression, was found after the addition of glucose.

Localization of nitric oxide synthase-immunoreactive neurons in the solitary nucleus and ventrolateral medulla oblongata of the rat: their relation to catecholaminergic neurons.

The morphological relationship between nitric oxide (NO) and catecholamines in the solitary nucleus (SOL) and ventrolateral medulla oblongata (VLM) was studied by a double immunostaining method with antibodies against NO synthase (NOS), an NO-synthesizing enzyme, and tyrosine hydroxylase (TH), a catecholamine-synthesizing enzyme. Although NOS- and TH-immunoreactive neurons were widely distributed in the SOL and VLM, these immunoreactivities did not coexist in any single neurons. NOS-immunoreactive neurons formed clusters in some restricted regions, i.e. in the medial subnucleus of the SOL, where both NOS- and TH-immunoreactive neurons showed a complementary distribution. These findings suggest that NO-producing neurons constitute a subclass that is distinct from that of catecholaminergic neurons.

Early axonal and glial pathology in fetal sheep brains with leukomalacia induced by repeated umbilical cord occlusion.

We conducted a chronic preparation experiment involving near term fetal sheep to evaluate the contribution of umbilical cord occlusion to fetal brain injury. In experimental groups (n = 11), complete cord occlusion for 3 min followed by 5 min release, repeated 5 times were performed at 3 days after initial surgery. Instrumental cases without cord occlusion (n = 3) and uninstrumental twins (n = 6) were also examined as controls. Multiple necrotic foci predominantly in the periventricular white matter were found in the fetal brains examined at 1-3 days after cord occlusion. To estimate the contribution of early axonal and glial reaction to brain injury the following immunohistochemical study was performed. In the lesions, coagulation necrosis, axonal swelling and microglial activation were demonstrated with amyloid precursor protein or ionized calcium binding adapter molecule 1 immunohistochemistry. The induction of tumor necrosis factor alpha and inducible nitric oxide synthase were also detected immunohistochemically in the microglia at 1 and 3 days after cord occlusion. In contrast, the reaction of glial fibrillary acidic protein positive astrocytes was faint at 1 day after occlusion, but the induction of cyclooxygenase-2 was observed. These findings suggest the glial reaction of cytokines and free radicals induced by fetal hypoxia may contribute to the occurrence of brain injury.

[Percutaneous subacute toxicity study of 10% nitroglycerin (NT-1 ointment) in rabbits].

NT-1 ointment is a compound containing 10% nitroglycerin which is topically applied to the skin for angina pectoris. The subacute toxicity of this compound was examined by the continuous application for 5 weeks to the shaven skin of rabbit back at dose levels of 240, 120 and 60 mg/kg, and the recovery was examined 3 weeks after withdrawal of the drug. No special skin response to the NT-1 ointment was observed other than an erythema of the grading 2-3 Draize points, while the control ointment, which was the base ointment without nitroglycerin, showed a higher grade of erythema equivalent to 4 Draize point with crusta formation. No relationship between the dose level of NT-1 ointment and the skin response was observed, and skin response was thought to be caused mainly by the base ointment. The skin response gradually reduced even during the application period, and the skin response disappeared within a few days after withdrawal of the ointment. Histological examination of the treated skin at the respective ends of the application and recovery periods showed thickening of the corneum and epithelial layer, round cell infiltration and fibrosis in the corium, and development of hair folliculi in the subdermis. No systemic effect of the topically applied NT-1 ointment was observed in the majority of the animals, either in behavior, hematologic and electrocardiographic examination, food consumption, body weight change or urinalysis.

Effects of sairei-to and tokishakuyaku-san on cytokine release from peripheral blood mononuclear cells upon recognition of HLA-G protein in the treatment of recurrent abortion.

Human leukocyte antigen (HLA)-G has been shown to play a role in establishing pregnancy through the mechanism of modulating cytokine secretion from maternal lymphocytes. To elucidate the mechanisms of actions of the herbal medicines, Sairei-to and Tokishakuyaku-san, in the treatment of recurrent abortion, we investigated whether these medicines modulate cytokine secretion from peripheral blood mononuclear cells (PBMCs) upon recognition of HLA-G protein on trophoblasts. Sairei-to and Tokishakuyaku-san increased the interleukin (IL)-1 beta and tumor necrosis factor (TNF)-alpha secretion and decreased the IL-3 secretion from PBMCs regardless of whether these cells recognized HLA-G protein or not. Accordingly, Sairei-to nullified the effects of HLA-G to reduce the secretion of IL-1 beta and TNF-alpha and to enhance the secretion of IL-3. Tokishakuyaku-san also abolished the effect of HLA-G to reduce IL-1 beta and TNF-alpha secretion but did not affect the increase in IL-3 secretion. Thus, it is conceivable that Sairei-to may normalize Th1/Th2 balance by enhancing Th1 polarization in autoimmunity-related recurrent abortion in which Th1/Th2 balance might be shifted towards Th2 polarization. However, the mechanisms of action of Tokishakuyaku-san when used in treating unexplained recurrent abortion, cannot be explained only by the Th1/Th2.

[BrdU immunohistochemical observation on regeneration of tracheal epithelia using tissue culture method].

The growth process of tracheal epithelia was observed by primary cell culture method using BrdU. Cells stained with BrdU, that showed mitotic activity, were nonciliary cells and BrdU was not found in ciliated (differentiated) cells. The dividing cells and the mature cells could be distinguished by BrdU. Thus, it was demonstrated that BrdU could be used as an index for investigating the growth process of basal cells. Tissue culture of the tracheal rings after mucosal injury was performed. On the third day post-injury, the cells stained with BrdU and the migrating epithelia were observed in the border region between the non-injury and injury site. On the seventh day post-injury, healing was completed. The tissue culture method using BrdU is useful for observing the healing process of the tracheal mucous membrane.

[Electron microscopic observation on intracellular connective structures during healing of the tracheal mucous epithelia of guinea pigs--by means of tissue culture].

Healing processes of the tracheal epithelia after minor mechanical injury in vitro were morphologically investigated by electron microscopy. Actin filaments in the epithelia, at the injured site, were observed by phalliodin. The results are as follows: 1) The injured area was covered with one layer of epithelium within 48 hours and there were no mitotic figures. 2) The epithelial cells at the healing site were squamous and well developed. 3) Actin-filaments could be observed with well developed interdigitation. In conclusion these findings suggest that areas of minor injury heal by sliding of cells surrounding the injured area. The development of interdigitation is considered to play an important role in this process. It seems that actin observed at the site of interdigitation development plays some role in this healing process.

[Tissue culture of guinea pig middle ear epithelium--morphological characterization and proliferative activities of cultured cells on fibroblast-reorganized collagen gels].

Long-term culture of the middle ear epithelium of guinea pigs was carried out on reconstituted floating collagen matrix. Fibroblasts established from the abdominal skin dermis of allogenic animals were used to reorganize hydrated collagen gels into a dermal-like matrix. The explants placed on the surface of these matrices were composed of pseudostratified columnar cells with polygonal flat outgrowth sheets, which could be maintained for up to one month. In contrast, with simple hydrated collagen gel, no lysis of the substrate was observed regarding this reorganized collagen gel. In order to examine the growth pattern of these culture cells, 5-bromodeoxyuridine (BrdU) was added to the medium during the entire culture period. The specimens were immunohistologically stained using monoclonal antibodies. Noticeable changes were observed in the marginal portion of the explant where the cell shape changed from cuboidal to squamous. In this transitional area, most cells showed positive staining and consequently high proliferative activity. In the central area of the explants, however, the number of positive cells decreased and the main observation was a few labeled basal cell nuclei. It was suggested that the same regenerative process which usually occurs in normal respiratory epithelia after mechanical injury or other insults, was replayed in this culture system.