Dose-dense paclitaxel plus carboplatin as neoadjuvant chemotherapy for advanced ovarian, fallopian tube, or primary peritoneal carcinomas.

PURPOSE: Weekly dose-dense paclitaxel with carboplatin every 3 weeks (dose-dense TC) provides good efficacy, and neoadjuvant chemotherapy is common for advanced-stage disease. However, it is unclear the efficacy and safety of dose-dense TC as neoadjuvant chemotherapy. Therefore, we evaluated neoadjuvant dose-dense TC chemotherapy for advanced-stage ovarian carcinoma. METHODS: We retrospectively reviewed cases of ovarian carcinoma that were not suited for primary debulking surgery (2003-2014). The patients received neoadjuvant dose-dense TC chemotherapy, followed by interval debulking surgery and adjuvant chemotherapy. RESULTS: We identified 74 patients (mean age 60 years, range 39-85 years). The FIGO stages were IIIC (39/74, 52.7%) and IV (34/74, 45.9%). Fifty-six patients (75.6%) had a performance status of 0-1. The adverse events were grade 3/4 neutropenia (55.4%), anemia (44.6%), thrombocytopenia (21.6%), and peripheral neuropathy (8.1%); no treatment-related deaths were observed. Among the 66 patients who underwent debulking (89.2%), 55 patients (74.3%) achieved optimal debulking and 47 patients (63.5%) achieved complete resection. The median progression-free and overall survivals were 19.0 months (95% CI 16.2-23.7 months) and 55.1 months (95% CI 44.6 months to not estimable), respectively. A performance status of 2-3 was independently associated with poor prognosis (hazard ratio 3.84; p = 0.001). CONCLUSIONS: Neoadjuvant dose-dense TC chemotherapy was effective (complete resection in >60% of cases) and tolerable for advanced-stage ovarian carcinoma.

Construction of novel immune-related signature for prediction of pathological complete response to neoadjuvant chemotherapy in human breast cancer.

BACKGROUND: The aim of this study was to construct a novel prediction model for the pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) using immune-related gene expression data. PATIENTS AND METHODS: DNA microarray data were used to perform a gene expression analysis of tumor samples obtained before NAC from 117 primary breast cancer patients. The samples were randomly divided into the training (n = 58) and the internal validation (n = 59) sets that were used to construct the prediction model for pCR. The model was further validated using an external validation set consisting of 901 patients treated with NAC from six public datasets. RESULTS: The training set was used to construct an immune-related 23-gene signature for NAC (IRSN-23) that is capable of classifying the patients as either genomically predicted responders (Gp-R) or non-responders (Gp-NR). IRSN-23 was first validated using an internal validation set, and the results showed that the pCR rate for Gp-R was significantly higher than that obtained for Gp-NR (38 versus 0%, P = 1.04E-04). The model was then tested using an external validation set, and this analysis showed that the pCR rate for Gp-R was also significantly higher (40 versus 11%, P = 4.98E-23). IRSN-23 predicted pCR regardless of the intrinsic subtypes (PAM50) and chemotherapeutic regimens, and a multivariate analysis showed that IRSN-23 was the most important predictor of pCR (odds ratio = 4.6; 95% confidence interval = 2.7-7.7; P = 8.25E-09). CONCLUSION: The novel prediction model (IRSN-23) constructed with immune-related genes can predict pCR independently of the intrinsic subtypes and chemotherapeutic regimens.

Clinicopathological analysis of GATA3-positive breast cancers with special reference to response to neoadjuvant chemotherapy.

BACKGROUND: The aim of this study was to investigate the clinicopathological characteristics of GATA binding protein 3 (GATA3)-positive breast cancers as well as the association of GATA3 expression with response to chemotherapy. PATIENTS AND METHODS: Tumor specimens obtained before neoadjuvant chemotherapy [paclitaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide)] from breast cancer patients (n = 130) were subjected to immunohistochemical and mutational analysis of GATA3 and DNA microarray gene expression analysis for intrinsic subtyping. RESULTS: Seventy-four tumors (57%) were immunohistochemically positive for GATA3. GATA3-positive tumors were significantly more likely to be lobular cancer, estrogen receptor (ER)-positive, progesterone receptor (PgR)-positive, Ki67-negative, and luminal A tumors. Somatic mutations were found in only three tumors. Pathological complete response (pCR) was observed in 8 (11%) GATA3-positive tumors and in 22 (39%) GATA3-negative tumors. multivariate analysis showed that tumor size, human epidermal growth factor receptor 2 (her2), and gata3 were independent predictors of pcr. CONCLUSIONS: GATA3-positive breast cancers showed luminal differentiation characterized by high ER expression and were mostly classified as luminal-type tumors following intrinsic subtyping. Interestingly, GATA3 was an independent predictor of response to chemotherapy, suggesting that GATA3 might be clinically useful as a predictor of a poor response to chemotherapy.

Prognostic significance of Ki67 index after neoadjuvant chemotherapy in breast cancer.

PURPOSE: Recently, Ki67 index (cell proliferation marker) has been attracting a considerable attention as a prognostic factor in breast cancer but the prognostic significance of Ki67 after neoadjuvant chemotherapy (NAC) has rarely been examined. EXPERIMENTAL DESIGN: Primary breast cancer patients (n = 102) treated with NAC (sequential paclitaxel 12 cycles (q1w) and 5-FU/epirubicin/cyclophosphamide 4 cycles (q3w)) were recruited in the study. Ki67, estrogen receptor (ER) and progesterone receptor (PR) and breast cancer resistant protein (BCRP) and P-glycoprotein were determined by immunohistochemistry and HER2 was determined by FISH in tumor tissues obtained before and after NAC, and their association with patient prognosis (relapse-free survival) was examined. RESULTS: Of the 102 patients, pCR was achieved in 30 (29.4%). In the 72 non-pCR patients, Ki67 index significantly (P < 0.001) decreased after NAC. Ki67 index after NAC, but not Ki67 index before NAC, was significantly associated with a patient prognosis (P = 0.022). Multivariate analysis has shown that Ki67 index after NAC is a marginally significant (P = 0.05) prognostic factor and that other biomarkers including ER, PR, BCRP, and P-glycoprotein before and after NAC are not significant. CONCLUSIONS: Ki67 after NAC, but not before NAC, is prognostic in breast cancer patients, and might be clinically useful in the prognosis prediction of patients who do not achieve pCR after NAC. On the other hand, BCRP and P-glycoprotein before and after NAC are unlikely to be useful as prognostic factors in these patients.

Isolation and properties of the luciferase stored in the ovary of the scyphozoan medusa Periphylla periphylla.

Bioluminescence of the medusa Periphylla is based on the oxidation of coelenterazine catalyzed by luciferase. Periphylla has two types of luciferase: the soluble form luciferase L, which causes the exumbrellar bioluminescence display of the medusa, and the insoluble aggregated form, which is stored as particulate material in the ovary, in an amount over 100 times that of luciferase L. The eggs are especially rich in the insoluble luciferase, which drastically decreases upon fertilization. The insoluble form could be solubilized by 2-mercaptoethanol, yielding a mixture of luciferase oligomers with molecular masses in multiples of approximately 20 kDa. Those having the molecular masses of 20 kDa, 40 kDa, and 80 kDa were isolated and designated, respectively, as luciferase A, luciferase B, and luciferase C. The luminescence activities of Periphylla luciferases A, B, and C were 1.2 approximately 4.1 x 10(16) photon/mg. s, significantly higher than any coelenterazine luciferase known, and the quantum yields of coelenterazine catalyzed by these luciferases (about 0.30 at 24 degrees C) are comparable to that catalyzed by Oplophorus luciferase (0.34 at 22 degrees C), which has been considered the most efficient coelenterazine luciferase until now. Luciferase L (32 kDa) could also be split by 2-mercaptoethanol into luciferase A and an accessory protein (approx. 12 kDa), as yet uncharacterized. Luciferases A, B, and C are highly resistant to inactivation: their luminescence activities are only slightly diminished at pH 1 and pH 11 and are enhanced in the presence of 1 approximately 2 M guanidine hydrochloride; but they are less stable to heating than luciferase L, which is practically unaffected by boiling.

Direct imaging of phosphorylation-dependent conformational change and DNA binding of CREB by electron microscopy.

BACKGROUND: The second messenger cAMP stimulates the expression of numerous genes through the PKA-dependent phosphorylation of CREB. The cAMP-regulated transcription factor CREB undergoes conformational change in response to phosphorylation by PKA at Ser 133. The phosphorylation enables interaction between the kinase-inducible domain (KID) of CREB and KIX domain of CREB binding protein (CBP). RESULTS: To understand the activation mechanism of CREB-mediated gene expression, we performed the electron-microscope imaging of the transcription machinery. We improved the metal shadowing techniques to achieve higher resolution to detect phosphorylation-induced conformation change of the protein. Homodimer formation of CREB and the complex formation of phosphorylated CREB with CBP were observed under the electron microscope. The binding of the CREB dimer to CREs on the somatostatin and tyrosine hydroxylase promoters were also visualized directly and stereoscopically. CONCLUSIONS: Greatly improved resolution achieved by our modified metal shadowing techniques makes it possible to visualize that the shape of CREB homodimer was changed in phosphorylation-dependent manner and that the promoter DNA strands containing CREs appeared to be bent and twisted slightly by the holding in the crevice of the CREB homodimer. This method may be applicable to visualize transcriptional activation process of nuclear receptors or general transcription machinery.

Long-term follow-up of obstructive sleep apnea syndrome following surgery in children and adults.

Obstructive sleep apnea syndrome (OSAS) is characterized by recurrent apneas during sleep, resulting in repetitive hypoxemia. The present study retrospectively analyzed subjective and objective assessments of the patients with OSAS in a relatively long-term follow-up. From February 1986 to August 1996, 53 patients received surgical treatment for OSAS and snoring. Thirty-seven (27 males and 10 females) out of 53 patients completed the questionnaire and postoperative sleep study was obtained in 6 patients. In 20 children (<15 years), snoring, sleep apnea, and daytime sleepiness completely disappeared in 12, 19, and 16, and improved in 8, 1, and 4, respectively. These findings confirm that tonsillectomy and/or adenoidectomy in children may be the first selection for treatment. In 17 adults, snoring, sleep apnea, and daytime sleepiness completely disappeared in 2, 5, and 8, improved in 11, 8, and 7, and was unchanged in 4, 4, and 1, respectively. The apnea index in adults was significantly decreased in both early and late postoperative periods. These results suggest that surgery is a satisfactory alternative for adult patients if performed accurate preoperative diagnosis of the localization of the airway collapse and careful long-term follow-up.

Endoscopic sinus surgery improves pulmonary function in patients with asthma associated with chronic sinusitis.

We evaluated the clinical efficacy of endonasal endoscopic sinus surgery (ESS) in patients with asthma associated with chronic sinusitis. Twenty-one patients (13 men and 8 women) from 27 to 72 years old were enrolled in this study. All patients had had sinus-related symptoms for more than 3 months and had computed tomographic evidence of paranasal sinus opacification. Fifteen patients underwent bilateral endonasal ESS under local anesthesia, and 6 other patients without surgery were controls. The sinus-related symptoms of the preoperative and postoperative periods were assessed via a questionnaire. The period 6 months prior to surgery was compared with that 6 months postoperatively with regard to peak expiratory flow and total dosage of systemic glucocorticoids. Sinus-related symptoms in the ESS group were significantly improved 6 months postoperatively. The average peak expiratory flow 6 months following surgery was improved in the ESS patients, ranging from 40 to 190 L/min. Seven patients showed a reduction in the need for corticosteroids, whereas 2 patients were unchanged and 2 patients required larger dosages. The remaining 4 patients needed no corticosteroids before or after ESS. No significant changes in sinus-related symptoms or peak expiratory flow were obtained for the control group. Improvement of paranasal sinus disease by successful ESS can alleviate pulmonary dysfunction in asthma associated with chronic sinusitis. We believe that adequate and positive treatment for chronic sinusitis would reduce not only the nasal and sinus-related symptoms evoked by chronic sinusitis, but also some of the signs induced by asthma.

Nasal airway resistance and olfactory acuity following transsphenoidal pituitary surgery.

Rhinological problems after a transseptal transsphenoidal approach for pituitary tumors were prospectively investigated in 25 patients with special reference to nasal airway resistance and olfactory acuity. Five patients showed a significant increase in the unilateral and/or total nasal airway resistance. Endoscopic observation of the nasal cavity revealed the presence of crust formation, hypertrophy of the inferior turbinate, or synechiae. Three patients showed a significant deterioration in olfactory acuity. Coronal CT views with good visualization of the olfactory cleft were helpful in evaluating causes of hyposmia postoperatively.

Methacholine bronchial hyperresponsiveness in chronic sinusitis.

The coexistence of chronic sinusitis (CS) may deteriorate the clinical condition of lower airway diseases such as bronchial asthma (BA) or chronic bronchitis (CB). However, the bronchial hyperresponsiveness (BH) in CS without any apparent lower airway disease is not fully understood nor are the effects of treatment. We examined lower airway hyperresponsiveness to methacholine (MCh) in 42 subjects with CS but without allergic rhinitis (AR) who had normal lung functions without any pulmonary symptoms, comparing it with that of 50 subjects with stable BA, 50 subjects with simple CB and 40 subjects with AR, and further examined the effect of endoscopic sinus surgery in 7 CS subjects with BH. The BH to MCh was measured in terms of the minimum dose (Dmin), defined as the cumulative dose at the point where respiratory conductance began to decrease. A Dmin <50 units was defined as BH. Seventy-one percent of CS subjects showed BH without relation to the severity or duration of CS, or atopic status. BH in CS subjects, which was less than that in BA subjects, was similar to that in simple CB or AR in both its prevalence and degree. After the surgical treatment of CS, BH significantly decreased (p < 0.01) with improvements in both nasal symptoms and sinus lesions. These findings suggest that CS itself induces BH to a degree similar to simple CB and AR without any relationship to the clinical background, and that adequate treatment of CS reduces BH.

Expression of adhesion molecules in cultured human nasal mucosal microvascular endothelial cells activated by interleukin-1 beta or tumor necrosis factor-alpha: effects of dexamethasone.

Adhesion molecules of microvascular endothelial cells play a key role in the inflammatory processes involved in nonallergic sinusitis. We investigated the cytokine-regulated expression of intercellular adhesion molecule-1 (ICAM-1), E-selectin and vascular cell adhesion molecule-1 (VCAM-1), and the effect of dexamethasone on these expressions in cultured human nasal microvascular endothelial cells (HNMEC). ICAM-1 was enhanced, and E-selectin and VCAM-1 were induced in a dose-dependent fashion following stimulation with IL-1beta or TNF-alpha. HNMEC differed from human umbilical vein endothelila cells in that (1) maximal upregulation of ICAM-1 expression induced by IL-1beta or TNF-alpha required more time (2) TNF-alpha was more potent than IL-1beta in VCAM-1 expression, and (3) dexamethasone inhibited the upregulation of E-selectin expression alone. These findings contribute to a better understanding of the characteristic features of leukocyte infiltration into inflamed tissue and the effect of glucocorticoid in nonallergic chronic sinusitis.

Surgical criteria for obstructive sleep apnea syndrome based on localization of upper airway collapse during sleep: a preliminary study.

Obstructive sleep apnea syndrome (OSAS) is defined as intermittent complete or partial upper airway obstruction during sleep, causing mental and physical effects. Localization of obstructions in the upper airways in OSAS patients provides indispensable information for the selection of surgical procedures. We measured the pressure within the upper airways during sleep in 6 patients with OSAS in order to select the surgical procedure. Five patients were found to have the airway collapse in the velopharynx, and in three of them underwent uvulopalatopharyngoplasty (UPPP) with tonsillectomy was performed. The remaining one patient, having an obstruction in both the velopharynx and hypopharynx, underwent laser-assisted midline glossectomy as well as UPPP. The 4 patients receiving the operation showed improvements in the sleep apnea index and the lowest oxygen saturation postoperatively. These findings suggest that pressure measurement may be a reliable tool for localizing obstructions in OSAS patients and may be used for determined the surgical option.

Dominant negative ATF1 blocks cyclic AMP-induced neurite outgrowth in PC12D cells.

Extension of the neuronal process is a crucial step for establishment of the neuronal network. As CREB preferentially forms heterodimers with ATF1 in PC12D cells, we examined the roles of the CREB/ATF1 heterodimer on cyclic AMP (cAMP)-induced neurite extension, using originally constructed ATF1RL, which has a point mutation at the DNA binding domain of ATF1. Transient expression of ATF1RL suppressed the protein kinase A/CREB-induced expression of the CRE reporter gene as expected. Treatment with forskolin elicited a relatively poor mRNA induction for immediate early genes in PC12D-ATF1 RL cells, a PC12D cell line stably expressing ATF1RL, in comparison with the parental PC12D cells. Furthermore, the PC12D-ATF1RL cells were proved to be defective at cAMP-induced neurite outgrowth. In contrast, both the gene expression and the differentiation after nerve growth factor treatment noted in PC12D-ATF1RL cells were at the same levels as those in the parental cells. These data provide us the first evidence that links CREB/ATF1 to the cAMP-induced differentiation of PC12 cells.

Inhibitory effect of macrolides on interleukin-8 secretion from cultured human nasal epithelial cells.

The mechanism of macrolide therapy in chronic sinusitis patients is unclear. The authors studied the effect of macrolides on interleukin (IL)-8 secretion from cultured human nasal epithelial cells. Epithelial cells harvested from the nasal polyps of patients with chronic sinusitis were primary-cultured, and secreted IL-8 in culture media was measured by enzyme immunoassay. The cells secreted considerable amounts of IL-8 constitutively and in response to lipopolysaccharide. The secretion was significantly inhibited by 10(-5) M of erythromycin, clarithromycin, roxithromycin, and josamycin. 10(-6) M erythromycin still showed the inhibitory effect, whereas the same concentration of josamycin did not. These results indicate that macrolide antibiotics may act as an immunomodulator to reduce IL-8 in inflammatory sites and, at least partially, account for the clinically discrepant effects between 14- and 16-membered ring macrolides in long-term low-dose therapy for chronic sinusitis.

Expression of adhesion molecules in nonallergic chronic sinusitis.

Endothelial and epithelial adhesion molecules are important in the recruitment of leukocytes to inflammatory sites. To determine the relationship between recruited leukocytes and adhesion molecules in the paranasal sinus mucosa of nonallergic chronic sinusitis, we surgically obtained mucosa from 16 patients and identified the expression of intercellular adhesion molecules (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and P-selectin by immunohistochemistry. Neutrophils were significantly dominant in the nasal discharge as compared with eosinophils. The degree of neutrophil infiltration in the paranasal sinus mucosa was prominent in both intraepithelial and subepithelial areas as compared with the lamina propria. In each tissue site, the degree of infiltration of neutrophils was similar to that of eosinophils. These findings suggest that the tissue neutrophils actively and rapidly migrated into the lumen. All the adhesion molecules except VCAM-1 were expressed in the vascular endothelial cells. On the other hand, the surface epithelial cells showed the expression of only ICAM-1. The expression of ICAM-1 on the endothelial cells correlated with the degree of neutrophil infiltration in the mucosa The eosinophil infiltration was not dependent on any adhesion molecules examined here. It was concluded that ICAM-1 expression in the mucosa may be involved in neutrophil recruitment and may contribute to the establishment of the inflammatory cell distribution in the paranasal sinus of nonallergic chronic sinusitis.

A case of leiomyosarcoma of the sphenoid sinus.

A 43-year-old man with a primary leiomyosarcoma of the left sphenoid sinus is presented. To our knowledge, this is an unusual case of leiomyosarcoma, which has never been reported in the literature. Accurate and safe diagnosis was obtained by an endonasal endoscopic approach with minimal tissue invasion.

Effects of long-term low-dose macrolide administration on neutrophil recruitment and IL-8 in the nasal discharge of chronic sinusitis patients.

Effects of long-term low-dose macrolide administration were studied in patients with chronic sinusitis. Twelve patients with non-allergic chronic sinusitis were orally given 150 mg roxithromycin once a day without other treatments. The patients underwent computed tomography before and after the treatment, and paranasal sinus aeration was analyzed quantitatively. The number of neutrophils in the nasal smear was semiquantitatively assessed on a grading scale, and the IL-8 concentration in the nasal discharge was measured by enzyme immunoassay. The aeration of all four sinuses significantly improved, and recruited neutrophils and the IL-8 level in the nasal discharge were simultaneously reduced after the treatment. These findings suggest that long-term low-dose roxithromycin administration inhibits the positive feedback mechanism of neutrophil recruitment and IL-8 production by the recruited neutrophils, which is considered to be an essential cause of the prolongation of sinusitis.