The present study was designed to examine the effect of d-amphetamine on CA release from the isolated perfused model of the rat adrenal gland, and to establish its mechanism of action. D- amphetamine (10~100microM), when perfused into an adrenal vein of the rat adrenal gland for 60 min, enhanced the CA secretory responses evoked by ACh (5.32x10-3 M), excess K+ (5.6x10-2 M, a membrane depolarizer), DMPP (10-4 M, a selective neuronal nicotinic Nn-receptor agonist) and McN-A-343 (10-4 M, a selective M1-muscarinic agonist) only for the first period (4 min), although it alone has weak effect on CA secretion. Moreover, d-amphetamine (30microM) in to an adrenal vein for 60 min also augmented the CA release evoked by BAY-K-8644, an activator of the dihydropyridine L-type Ca2+ channels, and cyclopiazonic acid, an inhibitor of cytoplasmic Ca2+ ATPase only for the first period (4 min). However, in the presence of high concentration (500microM), d-amphetamine rather inhibited the CA secretory responses evoked by the above all of secretagogues. Collectively, these experimental results suggest that d-amphetamine at low concentrations enhances the CA secretion from the rat adrenal medulla evoked by cholinergic stimulation (both nicotininc and muscarinic receptors) as well as by membrane depolarization, but at high concentration it rather inhibits them. It seems that d-amphetamine has dual effects as both agonist and antagonist at nicotinic receptors of the isolated perfused rat adrenal medulla, which might be dependent on the concentration. It is also thought that these actions of d-amphetamine are probably relevant to the Ca2+ mobilization through the dihydropyridine L-type Ca2+ channels located on the rat adrenomedullary chromaffin cell membrane and the release of Ca2+ from the cytoplasmic store.
(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride ; 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester ; Adrenal Glands ; Adrenal Medulla* ; Amphetamine ; Animals ; Calcium-Transporting ATPases ; Chromaffin Cells ; Cytoplasm ; Dextroamphetamine* ; Dimethylphenylpiperazinium Iodide ; Membranes ; Neurons ; Rats* ; Receptors, Nicotinic ; Veins

Paraneoplastic neutrophilia caused by a squamous cell carcinoma of the uterine cervix has been seen rarely. We report a case of relapsed squamous cell carcinoma of the uterine cervix with severe neutrophilia, rapid tumor growth and aggressive clinical course, possibly due to autocrine stimulation of cell growth by G-CSF and IL-6 without other possible causes of neutrophilia.
Carcinoma, Squamous Cell ; Cervix Uteri ; Female ; Granulocyte Colony-Stimulating Factor ; Interleukin-6 ; Paraneoplastic Syndromes

Purpose: Capmatinib, an oral MET kinase inhibitor, has demonstrated its efficacy against non–small cell lung cancer (NSCLC) with MET dysregulation. We investigated its clinical impact in advanced NSCLC with MET exon 14 skipping mutation (METex14) or gene amplification. Materials and Methods: Patients who participated in the screening of a phase II study of capmatinib for advanced NSCLC were enrolled in this study. MET gene copy number (GCN), protein expression, and METex14 were analyzed and the patients’ clinical outcome were retrospectively reviewed. Results: A total of 72 patients were included in this analysis (group A: GCN ≥ 10 or METex14, n=14; group B: others, n=58). Among them, 13 patients were treated with capmatinib (group A, n=8; group B, n=5), and the overall response rate was 50% for group A, and 0% for group B. In all patients, the median overall survival (OS) was 20.2 months (95% confidence interval [CI], 6.9 to not applicable [NA]) for group A, and 11.3 months (95% CI, 8.2 to 20.3) for group B (p=0.457). However, within group A, median OS was 21.5 months (95% CI, 20.8 to NA) for capmatinib-treated, and 7.5 months (95% CI, 3.2 to NA) for capmatinib-untreated patients (p=0.025). Among all capmatinib-untreated patients (n=59), group A showed a trend towards worse OS to group B (median OS, 7.5 months vs. 11.3 months; p=0.123). Conclusion Our data suggest that capmatinib is a new compelling treatment for NSCLC with MET GCN ≥ 10 or METex14 based on the improved survival within these patients.

Purpose: This study evaluated whether an addition of simvastatin to chemotherapy improves survival in ever-smokers with extensive disease (ED)–small cell lung cancer (SCLC). Materials and Methods: This is an open-label randomized phase II study conducted in National Cancer Center (Goyang, Korea). Chemonaive patients with ED-SCLC, smoking history (≥ 100 cigarettes lifetime), and Eastern Cooperative Oncology Group performance status of ≤ 2 were eligible. Patients were randomized to receive irinotecan plus cisplatin alone or with simvastatin (40 mg once daily orally) for a maximum of six cycles. Primary endpoint was the the 1-year survival rate. Results: Between September 16, 2011, and September 9, 2021, 125 patients were randomly assigned to the simvastatin (n=62) or control (n=63) groups. The median smoking pack year was 40 years. There was no significant difference in the 1-year survival rate between the simvastatin and control groups (53.2% vs. 58.7%, p=0.535). The median progression-free survival and overall survival between the simvastatin arm vs. the control groups were 6.3 months vs. 6.4 months (p=0.686), and 14.4 months vs. 15.2 months, respectively (p=0.749). The incidence of grade 3-4 adverse events was 62.9% in the simvastatin group and 61.9% in the control group. In the exploratory analysis of lipid profiles, patients with hypertriglyceridemia had significantly higher 1-year survival rates than those with normal triglyceride levels (80.0% vs. 52.7%, p=0.046). Conclusion Addition of simvastatin to chemotherapy provided no survival benefit in ever-smokers with ED-SCLC. Hypertriglyceridemia may be associated with better prognosis in these patient population.

BACKGROUND: It has been known that Ginseng extract causes the hypotensive action while it rather produces the hypertensive action. Some studies have suggested that Ginseng extract causes a biphasic response on blood pressure, namely, transient fall followed by prolonged elevation. It has been also shown that administration of Korean Red Ginseng powder has no effect on blood pressure in normotensive and hypertensive rats. The present study was designed to examine the effect of total Ginseng saponin on contractile responses of vasoconstrictors in the rat aorta and to establish the mechanism of its action. METHODS: The ring segment of aorta was mounted in a muscle bath filled with oxygenated Krebs solution for the measurement of isometric tension. After the equilibration period, under the presence of total Ginseng saponin, isometric tension induced by some vasoconstrictors were observed and compared to the control responses. The data were expressed as % of the control tension. RESULTS: Phenylephrine (an adrenergic alpha1-receptor agonist) and high potassium (a membrane depolarizing agent) caused greatly contractile responses in the rat aorta, respectively. However, in the presence of total ginseng saponin (600 g/ml), the contractile responses of phenylephrine (10(-6) and 10(-5) M) and high potassium (3.5 x 10(-2) and 5.6 x 10(-2) M) were markedly potentiated whereas prostglandin F2alpha(5 x 10(-6) M)-induced contractile responses was not affected. The contractile responses induced by phenylephrine (10(-5) M) and high potassium (3.5 x 10(-2) M) even under the presence of total ginseng saponin (600 g/ml) were greatly inhibited by the pretreatment of nicardipine (10(-6) M), a calcium channel blocker. CONCLUSION: Taken together, these experimental results suggest that total ginseng saponin can enhance the contractile responses evoked by stimulation of adrenergic alpha1-receptor and the membrane depolarization in the isolated rat aortic strips, which seems to be associated to calcium influx.
Animals ; Aorta* ; Baths ; Blood Pressure ; Calcium ; Calcium Channels ; Membranes ; Nicardipine ; Oxygen ; Panax* ; Phenylephrine ; Potassium ; Rats* ; Saponins* ; Vasoconstriction ; Vasoconstrictor Agents*

The present study was attempted to investigate the effect of vasoactive intestinal polypeptide (VIP) on secretion of catecholamines (CA) and to establish whether there is the existence of a noncholinergic mechanism in adrenomedullary CA secretion from the isolated perfused rat adrenal gland. The perfusion into an adrenal vein of VIP (3 X 10-6 M) for 5 min or the injection of acetylcholine (ACh, 5.32 X 10-3 M) resulted in great increases in CA secretion. Tachyphylaxis to releasing effect of CA evoked by VIP was not observed by the repeated perfusion. The net increase in adrenal CA secretion evoked by VIP still remained unaffected in the presence of atropine or chlorisondamine. However, the CA release in response to ACh was greatly inhibited by the pretreatment with atropine or chlorisondamine. The releasing effects of CA evoked by either VIP or ACh were depressed by pretreatment with nicardipine, TMB-8, and the perfusion of Ca2+-free medium. Moreover, VIP- as well as ACh-evoked CA secretory responses were markedly inhibited under the presence of (Lys1, Pro2.5, Arg3.4, Tyr6)-VIP or naloxone. CA secretory responses induced by ACh and high K+ (5.6 X 10-2 M) were potentiated by infusion of VIP (3 X 10-6 M for 5 min). Taken together, these experimental results indicate that VIP causes CA release in a fashion of calcium ion-dependence, suggesting strongly that there exists a noncholinergic mechanism that may be involved in the regulation of adrenomedullary CA secretion through VIP receptors in the rat adrenal gland, and that VIP may be the noncholinergic excitatory secretagogue present in the chromaffin cells.
Acetylcholine ; Adrenal Glands ; Adrenal Medulla* ; Animals ; Atropine ; Calcium ; Catecholamines ; Chlorisondamine ; Chromaffin Cells ; Naloxone ; Nicardipine ; Perfusion ; Rats* ; Receptors, Vasoactive Intestinal Peptide ; Tachyphylaxis ; Vasoactive Intestinal Peptide ; Veins

PURPOSE: This phase II study examined whether the addition of simvastatin to afatinib provides a clinical benefit compared with afatinib monotherapy in previously treated patients with nonadenocarcinomatous non-small cell lung cancer (NA-NSCLC). MATERIALS AND METHODS: Patients with advanced NA-NSCLC who progressed after one or two chemotherapy regimens were randomly assigned to a simvastatin (40 mg/day) plus afatinib (40 mg/day) (AS) arm or to an afatinib (A) arm. The primary endpoint was response rate (RR). RESULTS: Sixty-eight patients were enrolled (36 in the AS arm and 32 in the A arm). The RR was 5.7% (95% confidence interval [CI], 0.7 to 19.2) for AS and 9.4% (95% CI, 2.0 to 25.0) for A (p=0.440). In arms AS and A, the median progression-free survival (PFS) was 1.0 versus 3.6 months (p=0.240) and the overall survival was 10.0 months versus 7.0 months (p=0.930), respectively. Skin rash, stomatitis, and diarrhea were the most common adverse events in both arms. More grade 3 or 4 diarrhea was observed in arm A (18.8% vs. 5.6% in arm AS). In all patients, the median PFS for treatment including afatinib was not correlated with the status of epidermal growth factor receptor (EGFR) mutation (p=0.122), EGFR fluorescence in situ hybridization (p=0.944), or EGFR immunohistochemistry (p=0.976). However, skin rash severity was significantly related to the risk of progression for afatinib (hazard ratio for skin rash grade ≥ 2 vs. grade < 2, 0.44; 95% CI, 0.25 to 0.78; p=0.005). CONCLUSION: There were no significant differences in the efficacy between AS and A arms in patients with NA-NSCLC.
Arm ; Carcinoma, Non-Small-Cell Lung* ; Carcinoma, Squamous Cell ; Diarrhea ; Disease-Free Survival ; Drug Therapy ; Exanthema ; Fluorescence ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Immunohistochemistry ; In Situ Hybridization ; Receptor, Epidermal Growth Factor ; Simvastatin* ; Stomatitis

PURPOSE: Concurrent chemoradiotherapy (CCRT) is the standard care for stage III non-small cell lung cancer (NSCLC) patients; however, a more effective regimen is needed to improve the outcome by better controlling occult metastases. We conducted two parallel randomized phase II studies to incorporate erlotinib or irinotecan-cisplatin (IP) into CCRT for stage III NSCLC depending on epidermal growth factor receptor (EGFR) mutation status. MATERIALS AND METHODS: Patients with EGFR-mutant tumors were randomized to receive three cycles of erlotinib first and then either CCRT with erlotinib followed by erlotinib (arm A) or CCRT with IP only (arm B). Patients with EGFR unknown or wild-type tumors were randomized to receive either three cycles of IP before (arm C) or after CCRT with IP (arm D). RESULTS: Seventy-three patients were screened and the study was closed early because of slow accrual after 59 patients were randomized. Overall, there were seven patients in arm A, five in arm B, 22 in arm C, and 25 in arm D. The response rate was 71.4% and 80.0% for arm A and B, and 70.0% and 73.9% for arm C and D. The median overall survival (OS) was 39.3 months versus 31.2 months for arm A and B (p=0.442), and 16.3 months versus 25.3 months for arm C and D (p=0.050). Patients with sensitive EGFR mutations had significantly longer OS than EGFR-wild patients (74.8 months vs. 25.3 months, p=0.034). There were no unexpected toxicities. CONCLUSION: Combined-modality treatment by molecular diagnostics is feasible in stage III NSCLC. EGFR-mutant patients appear to be a distinct subset with longer survival.
Arm ; Carcinoma, Non-Small-Cell Lung* ; Chemoradiotherapy* ; Cisplatin* ; Erlotinib Hydrochloride* ; Humans ; Neoplasm Metastasis ; Pathology, Molecular ; Receptor, Epidermal Growth Factor

PURPOSE: We studied the voiding dysfunction after surgical treatment of female stress urinary incontinence and diagnosis and treatment. MATERIALS AND METHODS: Three hundred women with stress urinary incontinence underwent surgical procedure between January 1998 and December 2004. Ninety two patients(30.6%) experienced the postoperative voiding dysfunction. As the primary procedure for the management of postoperative voiding dysfunction alpha-blockers medication and clean intermittent catheterization(CIC) were performed. Then, hegar dilation and urethral pull-down procedure were performed as a secondary measure. For the patients who showed persistent obstructed symptoms, cutting of mesh or sling materials were performed. RESULTS: In 57 patients, symptoms improved by alpha-blockers medication and CIC. The others were received hegar dilation and urethral pull-down procedure, and 29 patients were improved. 6 patients were not controlled by conservative treatment, of which 3 patients underwent cutting of mesh or sling. De novo urgency was developed in 12 patients. Anticholinergics were taken, symptoms were diminished in 10 patients after 5 months of medication. CONCLUSION: Most voiding dysfunction after surgery may be effectively managed by conservative treatment. In cases of failure, hegar dilation and urethral pull-down procedure may be useful within postoperative first weak. Finally, cutting of mesh or sling must be considered in patient whose the secondary measure is failed.
Cholinergic Antagonists ; Diagnosis ; Female* ; Humans ; Urinary Incontinence*

Hepatitis B virus(HBV) infection has been suggested as the etiologic agent in membranoproliferative glomerulonephritis(MPGN), but the mechanism by which HBV infection leads to MPGN in human has not been established. To localize the HBV antigen and HBV-DNA in the kidney tissue, we examined paraffin sections of kidney biopsies which were positive for HBsAg by immunohistochemical study from 13 HBV carriers with MPGN (HBV-MPGN). Polymerase chain reaction(PCR) and in situ PCR(ISP) were used for the HBV DNA amplification and localization in kidney tissues. Primers used in PCR and ISP were from the S, C, and X HBV-DNA regions. Immunohistochemical study showed HBsAg deposits on the mesangium and glomerular capillaries. Arteriolar deposits were also occasionally observed. PCR for the S, C, and X regions were positive in 11 patients(85%), 11 patients(85%), and 9 patients (69%), respectively. The PCR findings were further confirmed by direct sequencing of PCR products and the amplification of HSP70 gene as a control. ISP showed the amplified HBV-DNA at the glomeruli and renal tubules. For S region, ISP was positive in 7 patients. For C and X regions, ISP was positive in 8 patients, respectively. 5 patients showed the positive signals for both the glomeruli and tubules, while 4 patients were positive at the tubules only. These 4 patients seemed to have the longer disease durations when compared to the other 5 patients (52.8 months vs. 11.8 months), but it was not statistically significant. In conclusion, the detection and the localization of HBV antigen and DNA in renal tissues indicate the presence of the complete virion in the kidney. These results suggest that HBV may infect the kidneys of HBV carriers with MPGN.
Biopsy ; Capillaries ; DNA ; Glomerulonephritis, Membranoproliferative* ; Hepatitis B Surface Antigens* ; Hepatitis B virus* ; Hepatitis B* ; Hepatitis* ; Humans ; Immunohistochemistry ; Kidney ; Paraffin ; Polymerase Chain Reaction ; Virion