Weekly paclitaxel with trastuzumab and pertuzumab in patients with HER2-overexpressing metastatic breast cancer: overall survival and updated progression-free survival results from a phase II study.

We previously reported progression-free survival (PFS) results on a phase II trial of weekly paclitaxel, trastuzumab, and pertuzumab in patients with human epidermal growth factor receptor 2(HER2)-positive metastatic breast cancer (MBC) treated in the first- and second-line setting. Here, we report results for overall survival (OS) and updated PFS after an additional year of follow-up. Patients with HER2-positive MBC with 0-1 prior treatment were eligible. Treatment consisted of paclitaxel (80 mg/m(2)) weekly, and trastuzumab (loading dose 8 mg/kg â†’ 6 mg/kg) and pertuzumab (loading dose 840 mg â†’ 420 mg) every 3 weeks, all given intravenously. Primary endpoint was 6-month PFS. Secondary endpoints included median PFS, 6-month and median OS. Evaluable patients received at least one full dose of treatment. From January 2011 to December 2013, 69 patients were enrolled: 51 (74 %) and 18 (26 %) treated in first- and second-line metastatic settings, respectively. As of July 1, 2015, the median follow-up was 33 months (range 3-49 months; 67 patients were evaluable for efficacy). The median OS was 44 months (95 % CI 37.5-NR) overall and 44 months (95 % CI 38.3-NR) and 37.5 months (95 % CI 30.3-NR) for patients with 0 and 1 prior metastatic treatment, respectively; 6-month OS was 98 % (95 % CI 90-1). The 6-month PFS was 86 % (95 % CI 75-93) overall and 89 % (95 % CI 76-95) and 78 % (95 % CI 51-91) for patients with 0 and 1 prior therapy, respectively; and median PFS was 21.4 months (95 % CI 14.1-NR) overall and 25.7 months (95 % CI 14.1-NR) and 16.9 months (95 % CI 8.5-NR) for patients with 0-1 prior treatment, respectively. Treatment was well tolerated. Updated analysis demonstrates that weekly paclitaxel, when added to trastuzumab and pertuzumab, is associated with a favorable OS and PFS and offers an alternative to docetaxel-based therapy. http://www.ClinicalTrials.gov NCT0127604.

HER2-positive advanced breast cancer: optimizing patient outcomes and opportunities for drug development.

Effective targeting of the human epidermal growth factor receptor 2 (HER2) has changed the natural history of HER2 overexpressing (HER2+) metastatic breast cancer. The initial success of trastuzumab improving time to progression and survival rates led to the clinical development of pertuzumab, ado-trastuzumab emtansine and lapatinib. These biologic therapies represent significant additions to the breast medical oncology armamentarium. However, drug resistance ultimately develops and most tumours progress within 1 year. Ongoing studies are evaluating novel therapeutic approaches to overcome primary and secondary drug resistance in tumours, including inhibition of PI3K/TOR, HSP90, IGF-IR and angiogenesis. Mounting experimental data support the clinical testing of immune checkpoint modulators and vaccines. The central nervous system remains a sanctuary site for HER2+ breast cancer and further studies are needed for the prevention and treatment of brain metastases in this population. Despite efforts to identify predictors of preferential benefit from HER2-targeted therapies (e.g., truncated HER2, PTEN loss and SRC activation), HER2 protein overexpression and/or gene amplification remains the most important predictive factor of response to HER2-targeted therapies. In this article, we review the optimal sequence of HER2-targeted therapies and describe ongoing efforts to improve the outcome of HER2+ advanced breast cancer through rational drug development.

Influence of risk factors on the safety of ileocolic anastomosis in Crohn's disease surgery.

BACKGROUND: Ileocecal resection is the most commonly performed operation in patients with Crohn's disease. Anastomotic-associated complications, with their associated morbidity, are the most feared risks of surgery. OBJECTIVE: This study aimed to assess the influence of a variety of putative risk factors in a homogenous group of patients undergoing first or subsequent surgery for Crohn's disease to quantify the cumulative risk for anastomotic-associated complications. DESIGN AND PATIENTS: All patients undergoing ileocecal or ileocolic resections for Crohn's disease from 2000 to 2010 were studied with the use of a prospective database. Demographics, operative details, possible risk factors, and anastomotic-associated complications were recorded. Patients having strictureplasties, multiple resections, or subtotal colonic resections were excluded from analysis. Statistical analysis was by univariate analysis (Mann-Whitney U test) and binary logistic regression. OUTCOMES: An anastomotic-associated complication was defined as a proven anastomotic leak, postoperative fistulation, or intra-abdominal abscess formation. RESULTS: Two hundred seven patients (109 female) with a median age of 35 years (range, 13-75 years) were identified. One hundred seventy-three underwent primary anastomosis, 94 as an emergency procedure. Fifty-three had laparoscopic (5 converted) procedures. Nineteen of 173 anastomotic complication events (11%) were recorded. Steroid usage (OR 2.67, 95% CI 1.0-7.2) and the presence of preoperative abscess formation (OR 3.4, 95% CI 1.2-9.8) were identified as independent predictors of anastomotic-associated complications. In the absence of both steroids and intra-abdominal abscess, the risk of anastomotic complications was 6%, which increased to 14% if either risk factor was present. When both risk factors were present, complication rates reached 40%. CONCLUSION: Steroid usage and preoperative abscess were associated with higher rates of anastomotic complications following ileocolic resection for Cohn's disease. When both risk factors are present, it is best to avoid primary anastomosis.

Neurotransmitter metabolic enzymes and antioxidant status on Alzheimer's disease induced mice treated with Alpinia galanga (L.) Willd.

Amyloid ß25₋35 (Aß) peptide may be neurotoxic during the progression of Alzheimer's disease by eliciting reactive oxygen species. The use of folklore medicine is prevalent and plants which possess a rejuvenating property are a large source of natural antioxidants that might afford leads for the development of novel drugs in neurodegenerative disorders. The study was designed to investigate the effect of an ethanol extract of Alpinia galanga (L.) Willd (EAG) on oxidative stress induced Alzheimer's type amnesia in mice. Mice were treated with an experimental extract at 200 mg/kg and 400 mg/kg dose for 14 days and injected with neurotoxic Aß and the doses were continued for 21 days. Behavioural studies with open field, step-down inhibitory avoidance and a water maze after treatment indicated the acceleration in cognitive function. The elevated levels of acetylcholinesterase and monoamine oxidase enzymes in amnesia induced mice were attenuated by treatment with EAG. The generation of free radicals was decreased due increased activity of antioxidant enzymes after treatment with EAG. These findings suggested that EAG exerts an antiamnesiac effect in Aß induced neurodegeneration through an antioxidant property.

Neuroprotective potential of ethanolic extract of Pseudarthria viscida (L) Wight and Arn against beta-amyloid(25-35)-induced amnesia in mice.

The neuroprotective potential of ethanolic extract of roots of Pseudarthria viscida (L) Wight and Arn (EEPV) was investigated against beta-amyloid(25-35)-induced amnesia in mice which is a suitable animal model for Alzheimer's disease (AD). The senile plaques of beta-amyloid (Abeta) are major constituents accumulated during the progression of AD as a potent neurotoxicant. In our investigation, intracerebroventricular injection of Abeta(25-35) in mice induced the neurodegeneration, exhibited the increased time of escape latency in behavioral pattern using water maze and decreased the levels of antioxidants namley superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) and vitamin C with elevated level of acetylcholinesterase enzyme (AChE). The neuroprotective potential of EEPV was determined by behavioral pattern using water maze and biochemical parameters such as SOD, CAT and GPx and vitamin C content as well as AChE. Mice were treated with EEPV at 200 and 400 mg/kg doses for 21 days. Except control, all animals received a single injection of neurotoxicant Abeta(25-35) on 14th day. In behavioural assessment, treatment with ethanolic extract improved the cognitive function in the water maze and attenuated the elevated levels of AChE with increase in antioxidant enzymes, indicating the neuroprotection with increased levels of vitamin C. These findings suggest that ethanolic extract of P. viscida exerts anti-amnesiac effects and enhances cognitive function.

Prevalence and risk factors for female sexual dysfunction in women attending a medical clinic in south India.

BACKGROUND: Reports from India on the prevalence and determinants of female sexual dysfunction (FSD) are scant. AIMS: To determine the prevalence and risk factors for FSD. SETTINGS AND DESIGN: A cross-sectional survey in a medical outpatient clinic of a tertiary care hospital. MATERIALS AND METHODS: We administered a Tamil version of the Female Sexual Function Index (FSFI) to 149 married women. We evaluated putative risk factors for FSD. We elicited participant's attributions for their sexual difficulties. STATISTICAL ANALYSIS: We estimated the prevalence of possible FSD and sexual difficulties from published FSFI total and domain cut-off scores. We used logistic regression to identify risk factors for possible FSD. RESULTS: FSFI total scores suggested FSD in two-thirds of the 149 women (73.2%; 95% confidence intervals [CI] 65.5% to 79.6%). FSFI domain scores suggested difficulties with desire in 77.2%; arousal in 91.3%; lubrication in 96.6%; orgasm in 86.6%, satisfaction in 81.2%, and pain in 64.4%. Age above 40 years (odds ratios [OR] 11.7; 95% CI 3.4 to 40.1) and fewer years of education (OR 1.2; 95% CI 1.0 to 1.3) were identified by logistic regression as contributory. Women attributed FSD to physical illness in participant or partner, relationship problems, and cultural taboos but none had sought professional help. CONCLUSIONS: Sexual problems suggestive of dysfunction, as suggested by FSFI total and domain scores, are highly prevalent in the clinic setting, particularly among women above 40 and those less educated, but confirmation using locally validated cut-off scores of the FSFI is needed.

4-(3-Methoxyphenyl)-1-substituted-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones: new class of H1-antihistaminic agents.

A series of 1-substituted-4-(3-methoxyphenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones were synthesized by the cyclization of 2-hydrazino-3-(3-methoxyphenyl)-3H-quinazolin-4-one with various electrophile. The starting material 2-hydrazino-3-(3-methoxyphenyl)-3H-quinazolin-4-one was synthesized from 3-methoxy aniline by an innovative route. Title compounds were tested for their in vivo H1-antihistaminic activity on guinea pigs; all the tested compounds protected the animals from histamine induced bronchospasm significantly. Compound 1-methyl-4-(3-methoxyphenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (II) emerged as the most active compound of the series and was more potent (72.76%) than the reference standard chlorpheniramine maleate (71%). Compound II showed negligible sedation (10%) when compared to chlorpheniramine maleate (25%). Hence it could serve as prototype molecule for further development as a new class of H1-antihistaminic agents.

Nitric oxide inhibition of cAMP synthesis in parotid acini: regulation of type 5/6 adenylyl cyclase.

The nitric oxide (NO) donor, GEA 3162, inhibited isoproterenol-induced cyclic AMP (cAMP) accumulation in a concentration- and time-dependent manner in mouse parotid acini; SIN-1 mimicked these effects. Inhibition of stimulated cAMP accumulation was independent of phosphodiesterase activity. GEA 3162 also inhibited forskolin-induced cAMP accumulation. Removal of extracellular Ca(2+), addition of La(3+), or the calmodulin (CaM) inhibitor, calmidazolium, did not prevent the NO-mediated response, and addition of the soluble guanylyl inhibitor, ODQ, did not reverse GEA 3162-induced inhibition of cAMP accumulation. GEA 3162 also inhibited adenylyl cyclase in vitro independently of Ca(2+)/CaM. Further studies revealed that the NO synthase (NOS) inhibitor, 7-nitroindazole (7-NI), reduced significantly thapsigargin-induced Ca(2+) release and capacitative Ca(2+) entry and reversed thapsigargin inhibition of the AC Type 5/6 isoform (AC5/6). Data suggest that NO produced endogenously has dual effects on cAMP accumulation in mouse parotid acini, an inhibitory effect on AC activity and a modulatory effect on capacitative Ca(2+) entry resulting in AC5/6 inhibition.

Monovalent ion enhancement of beta-adrenergic-stimulated adenylate cyclase activity in mouse parotid gland.

Sodium activated basal adenylate cyclase at all concentrations of sodium examined (5-100 mM) and independently of GTP. Stimulation of adenhylate cyclase by the beta-adrenergic agonist, isoproterenol, was enhanced at all concentrations (5-100 mM) of sodium ions tested in the presence of GTP. Maximal enzyme activation under all conditions occurred between 25 and 50 mM NaCl. Enhancement of forskolin-activated adenylate cyclase by sodium did not require GTP nor was it affected by guanosine-5'-O-(2-thiodiphosphate) (GDP beta S), a competitive inhibitor of GTP. The selectivity of adenylate cyclase for monovalent cations was Na+ congruent to K+. Lithium chloride produced an inhibition of hormone-activated adenylate cyclase. Sodium ions also enhanced isoproterenol- and forskolin-activated adenylate cyclase of submandibular gland membranes. In contrast to mouse parotid and submandibular glands, activation of mouse liver and brain adenylate cyclase activities by forskolin and isoproterenol was not enhanced by sodium ions. The tissue differences were not related to differences in potency of the agonists. These results suggest (1) that sodium ions may have a selective and positive regulatory role in hormonal activation of adenylate cyclase in mouse exocrine tissue, and (2) that sodium ions enhance hormonal activation of enzyme by interacting at a site on the adenylate cyclase complex which is independent of the hormone receptor (Rs) and the stimulatory guanine nucleotide binding protein (Ns).

Augmentation of cholinergic-mediated amylase release by forskolin in mouse parotid gland.

Cholinergic-mediated amylase release in mouse parotid acini was augmented by forskolin; the potency but not the maximal response to carbachol was altered. Amylase released by carbachol plus forskolin was dependent on extracellular calcium and was mimicked by the calcium ionophore, A23187 plus forskolin. Forskolin was also shown to enhance carbachol-stimulated 45Ca2+ uptake into isolated acini. Hydroxylamine, nitroprusside, and 8-bromo-c-GMP each in combination with forskolin mimicked the effects of carbachol plus forskolin on amylase release. In the presence of carbachol (10(-8)M) forskolin did not augment c-AMP levels. However, in the presence of carbachol (5 X 10(-7) M) or hydroxylamine (50 microM) forskolin did significantly augment c-AMP accumulation. These results suggest that calcium and c-GMP may mediate the augmentation of cholinergic-mediated amylase release by effects on c-AMP metabolism.

Peritoneal mesothelioma masquerading as an inguinal hernia.

We report a case of an 80-year-old man who presented with a right inguinal hernia that appeared incarcerated. On exploration a sausage shaped mass was found in the sac, which was debulked and histologically shown to be a well differentiated malignant peritoneal mesothelioma. Rare tumours may present as inguinal hernias and palliative debulking may be effective when they present in inguinal hernia sacs.

Peritoneal mesothelioma masquerading as an inguinal hernia.

We report a case of an 80-year-old man who presented with a right inguinal hernia that appeared incarcerated. On exploration a sausage shaped mass was found in the sac, which was debulked and histologically shown to be a well differentiated malignant peritoneal mesothelioma. Rare tumours may present as inguinal hernias and palliative debulking may be effective when they present in inguinal hernia sacs.

Neuroprotective effect of Alpinia galanga (L.) fractions on Aß(25-35) induced amnesia in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The rhizomes of Alpinia galanga (L.) Willd (Zingiberaceae), a ginger substitute for flavouring food was traditionally used as nervine tonic and stimulant. AIM OF THE STUDY: This investigation is designed to screen cognitive improvement of Alpinia galanga (AG) fractions in Alzheimer's type of amnesia in mice induced by Aß((25-35)). MATERIALS AND METHODS: Alzheimer's disease induced mice treated with fractions (n-hexane, chloroform and ethyl acetate) of AG in 200 and 400mg/kg. Neurotoxicity was induced by intracerebroventricular injection of Aß((25-35)) on the 14th day of 21 days drug treatment. Open field and water maze were carried to determine habituation memory and hippocampal memory. Na(+)/K(+)-ATPase, acetylcholinesterase (AChE) and antioxidant enzymes (SOD, GPx, catalase and vitamin C) were determined in brain tissue homogenate to estimate the brain biochemical changes and its anti-amnesic potential with intensity of oxidative stress signaling. Further bioactive (chloroform) fraction was eluted through column chromatography to identify the lead molecules. RESULTS: Increased habituation memory and decreased escape latency in behavioral parameter are the indicative of the cognitive enhancement after treatment with Alpinia galanga fractions. Increment in Na(+)/K(+)-ATPase and antioxidant activity depicts brain membrane integrity improvement and free radical scavenging property. AChE level was decreased to improve the cognition by enhancing cholinergic transmission. CONCLUSION: Anti-amnesic effect was exerted by various fractions of Alpinia galanga. Among all fractions, preeminent neuroprotection was exerted by chloroform fraction, which has compound, 1'δ-1'-acetoxyeugenol acetate and it may be a potential therapeutic agent for Alzheimer's type of amnesia. These results further motivate us to explore the activity of lead compound's anti-amnesic effect on transgenic mice model of AD.

Regulation of cAMP metabolism in mouse parotid gland by cGMP and calcium.

The interaction of hormones acting via the mobilization of calcium and stimulation of cAMP levels in cells was examined by determining the effects of carbachol and forskolin on cAMP and cGMP accumulation in mouse parotid gland. Treatment of isolated acini with either carbachol (0.01 to 20 microM) or forskolin (1 microM) alone produced little or no increase in cAMP levels; carbachol, however, augmented the effect of forskolin on cAMP accumulation approximately 3- to 4-fold. The effects of carbachol on forskolin-stimulated cAMP levels were further augmented approximately 10-fold in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (MIX) but not in the presence of "low Km" cGMP-inhibited phosphodiesterase inhibitor milrinone. Augmentation of cAMP levels also occurred in the presence of carbachol plus the beta-adrenergic agonist isoproterenol (0.01 microM). In either the presence or absence of forskolin, carbachol increased cGMP levels independently of the inclusion of MIX and in a fashion parallel to that observed for cAMP accumulation. In the presence of forskolin (1 microM), the concentration of carbachol that produced half-maximal effects on cAMP and cGMP levels was 0.62 and 0.72 microM, respectively. Similar values were obtained in the presence of MIX. Cyclic GMP levels were also enhanced by carbachol plus isoproterenol. Hydroxylamine, as well as dibutyryl-cGMP and 8-bromo-cGMP in combination with forskolin, mimicked the effects of carbachol plus forskolin on cAMP levels. LY83583 (6-anillino-5,8-quinolinedione), an agent that lowers cGMP by inhibiting guanylate cyclase, reduced basal levels of cGMP and also completely prevented the increase in cGMP caused by carbachol plus forskolin. In these experiments, however, the augmentation of forskolin-stimulated cAMP levels by carbachol was reduced by approximately 50%. Additional studies suggest that calcium is also required for carbachol augmentation of forskolin-stimulated cAMP accumulation by effects on the adenylate cyclase complex. Augmentation of cAMP levels by carbachol did not involve effects on cAMP degradation. The results suggest that, when cAMP synthesis is stimulated by forskolin or isoproterenol, the muscarinic agonist carbachol augments cAMP accumulation by mechanisms involving cGMP and calcium in mouse parotid gland.

A mouth opening index for patients with temporomandibular disorders.

Limitation of mouth opening is an important sign of temporomandibular disorders. It is usually measured linearly from the incisal edge of the maxillary incisors to the incisal edge of the mandibular incisors. This measurement has been queried. A new measure of mouth opening, the opening index is suggested. It was shown that the mean opening index differs for groups of patients with a myogenous or arthrogenous temporomandibular joint problem.