A meta-analysis was conducted to assess the efficacy of transcatheter arterial embolization (TAE)... more A meta-analysis was conducted to assess the efficacy of transcatheter arterial embolization (TAE) compared with surgery in the management of patients with recurrent nonvariceal upper gastrointestinal bleeding (NVUGIB) after failure of endoscopic hemostasis. Publications in English and non-English literatures (OVID, MEDLINE, and EMBASE) and abstracts from major international conferences were searched for studies comparing TAE with surgery for treatment of NVUGIB after endoscopic hemostasis failure. Outcome measures included rebleeding rate, all-cause mortality rate, and need for additional interventions to secure hemostasis. From 1234 citations, 6 retrospective comparative studies were included that involved 423 patients (TAE, 182, 56 % male; surgery, 241, 68 % male). TAE patients were older (mean age, TAE 75, surgery, 68). The risk of rebleeding was significantly higher in TAE patients compared with surgically treated patients (relative risk [RR] 1.82, 95 % confidence interval [95 %...
Applied immunohistochemistry & molecular morphology : AIMM / official publication of the Society for Applied Immunohistochemistry, Jan 24, 2015
Primary neuroendocrine carcinoma of the breast is a rare variant, accounting for only 2% to 5% of... more Primary neuroendocrine carcinoma of the breast is a rare variant, accounting for only 2% to 5% of diagnosed breast cancers, and may have relatively aggressive behavior. Mutational profiling of invasive ductal breast cancers has yielded potential targets for directed cancer therapy, yet most studies have not included neuroendocrine carcinomas. In a tissue microarray screen, we found a 2.4% prevalence (9/372) of neuroendocrine breast carcinoma, including several with lobular morphology. We then screened primary or metastatic neuroendocrine breast carcinomas (excluding papillary and mucinous) for mutations in common cancer genes using polymerase chain reaction-mass spectroscopy (643 hotspot mutations across 53 genes), or semiconductor-based next-generation sequencing analysis (37 genes). Mutations were identified in 5 of 15 tumors, including 3 with PIK3CA exon 9 E542K mutations, 2 of which also harbored point mutations in FGFR family members (FGFR1 P126S, FGFR4 V550M). Single mutations...
Activating point mutations in the phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) are am... more Activating point mutations in the phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) are among the most common molecular defects in invasive breast cancer. Point mutations in the downstream kinase AKT1 are seen in a minority of carcinomas. These mutations are found preferentially in estrogen receptor-positive and Her2-positive breast carcinomas; however, special morphologic types of breast cancer have not been well studied. Twenty-nine cases of pure invasive mucinous carcinoma and 9 cases of ductal carcinoma with mucinous differentiation were screened for a panel of point mutations (>321 mutations in 30 genes) using a multiplex polymerase chain reaction panel with mass spectroscopy readout. In addition, associated ductal carcinoma in situ, hyperplasia, or columnar cell lesions were separately tested where available (25 lesions). In 3 invasive cases and 15 ductal carcinoma in situ/proliferative lesions, PIK3CA hotspot mutations were, instead, tested by direct sequencing. No point mutations were identified in invasive mucinous breast carcinoma. This contrasts with the 35% frequency of PIK3CA mutations in a comparative group of invasive ductal carcinomas of no special type. Interestingly, PIK3CA hotspot point mutations were identified in associated ductal carcinoma in situ (3/14) and hyperplasia (atypical ductal hyperplasia [2/3], usual ductal hyperplasia [2/3], columnar cell change [1/5]), suggesting that PIK3CA mutations may play a role in breast epithelial proliferation. This series represents the largest study, to date, of PIK3CA genotyping in mucinous carcinoma and supports the unique pathogenetics of invasive mucinous breast carcinoma.
Clarithromycin-based triple therapy (TT) is the first line treatment for H. pylori infection in S... more Clarithromycin-based triple therapy (TT) is the first line treatment for H. pylori infection in Singapore. There is awareness that TT may no longer be effective due to increased clarithromycin resistance rates. Sequential therapy (ST) and concomitant therapy (CT) are alternative treatment regimens. The study aimed to compare the efficacy of 10-day TT, ST and CT as first line treatment for H. pylori infection. A randomized study conducted in a teaching hospital. Patients aged 21 years and older with newly diagnosed H. pylori infection were randomized to 10-day TT, ST or CT. Treatment outcome was assessed by 13-carbon urea breath test at least 4 weeks after therapy. Intention to treat (ITT), modified ITT (MITT) and per protocol (PP) analysis of the eradication rates were performed. A total of 462 patients were enrolled (ST: 154; TT 155; CT 153). Patient demographics were similar. Eradication rates for ST vs. TT vs. CT: ITT analysis: 84.4% vs. 83.2% vs. 81.7% (p= NS); MITT analysis: 90.3% vs. 92.1% vs. 94.7% (p = NS); PP analysis: 94.1% vs. 92.8% vs. 95.4% (p = NS). Antibiotic resistance rates for amoxicillin, clarithromycin and metronidazole were 4.7%, 17.9% and 48.1% respectively. Dual clarithromycin and metronidazole resistance occurred in 7.5%. Dual resistance and lack of compliance were predictors of treatment failure. TT, ST and CT all achieved eradication rates above 80% on ITT and above 90% on MITT and PP analyses. Dual resistance and lack of compliance were predictors of treatment failure. ClinicalTrials.gov: NCT02092506.
Hunger is controlled by the brain, which receives input from signals of the GI tract (GIT). Durin... more Hunger is controlled by the brain, which receives input from signals of the GI tract (GIT). During fasting, GIT displays a cyclical motor pattern, the migrating motor complex (MMC), regulated by motilin. To study the relationship between hunger and MMC phases (I-III), focusing on spontaneous and pharmacologically induced phase III and the correlation with plasma motilin and ghrelin levels. The role of phase III was also studied in the return of hunger after a meal in healthy individuals and in patients with loss of appetite. In fasting healthy volunteers, mean hunger ratings during a gastric (62.5±7.5) but not a duodenal (40.4±5.4) phase III were higher (p<0.0005) than during phase I (27.4±4.7) and phase II (37±4.5). The motilin agonist erythromycin, but not the cholinesterase inhibitor neostigmine, induced a premature gastric phase III, which coincided with an increase in hunger scores from 29.2±7 to 61.7±8. The somatostatin analogue octreotide induced a premature intestinal phase III without a rise in hunger scores. Hunger ratings significantly correlated (β=0.05; p=0.01) with motilin plasma levels, and this relationship was lost after erythromycin administration. Motilin, but not ghrelin administration, induced a premature gastric phase III and a rise in hunger scores. In contrast to octreotide, postprandial administration of erythromycin induced a premature gastric phase III accompanied by an early rise in hunger ratings. In patients with unexplained loss of appetite, gastric phase III was absent and hunger ratings were lower. Motilin-induced gastric phase III is a hunger signal from GIT in man.
Micropapillary carcinoma of the breast is associated with increased rates of lymph node metastasi... more Micropapillary carcinoma of the breast is associated with increased rates of lymph node metastasis and lymphovascular invasion. While activating point mutations in PIK3CA (encoding phosphatidylinositol-3-kinase catalytic subunit) or AKT1 are found in 25% to 30% of invasive ductal carcinomas, the mutational profile of invasive micropapillary carcinomas has not been characterized in detail. Micropapillary carcinomas, concurrent metastatic and precursor breast lesions from 19 patients were identified. Lesional tissue was punched from paraffin-tissue blocks, and genomic DNA was extracted and screened for a large panel of known hotspot mutations using multiplex polymerase chain reaction and mass-spectroscopy analysis (643 mutations in 53 genes). Hotspot point mutations were identified in 35% (7/20) of micropapillary breast carcinomas, including PIK3CA exons 7, 9 and 20 hotspots, as well as the AKT1 plekstrin homology domain mutation (E17K); mutations in TP53 and KRAS were each found in a...
Diagnostic molecular pathology : the American journal of surgical pathology, part B, Jan 24, 2014
Primary neuroendocrine carcinoma of the breast is a rare variant, accounting for only 2% to 5% of... more Primary neuroendocrine carcinoma of the breast is a rare variant, accounting for only 2% to 5% of diagnosed breast cancers, and may have relatively aggressive behavior. Mutational profiling of invasive ductal breast cancers has yielded potential targets for directed cancer therapy, yet most studies have not included neuroendocrine carcinomas. In a tissue microarray screen, we found a 2.4% prevalence (9/372) of neuroendocrine breast carcinoma, including several with lobular morphology. We then screened primary or metastatic neuroendocrine breast carcinomas (excluding papillary and mucinous) for mutations in common cancer genes using polymerase chain reaction-mass spectroscopy (643 hotspot mutations across 53 genes), or semiconductor-based next-generation sequencing analysis (37 genes). Mutations were identified in 5 of 15 tumors, including 3 with PIK3CA exon 9 E542K mutations, 2 of which also harbored point mutations in FGFR family members (FGFR1 P126S, FGFR4 V550M). Single mutations...
Somatic mutations in PIK3CA are commonly seen in invasive breast cancer and several other carcino... more Somatic mutations in PIK3CA are commonly seen in invasive breast cancer and several other carcinomas, occurring in three hotspots: codons 542 and 545 of exon 9 and in codon 1047 of exon 20. We designed a locked nucleic acid (LNA)-PCR sequencing assay to detect low levels of mutant PIK3CA DNA with attention to avoiding amplification of a pseudogene on chromosome 22 that has >95% homology to exon 9 of PIK3CA. We tested 60 FFPE breast DNA samples with known PIK3CA mutation status (48 cases had one or more PIK3CA mutations, and 12 were wild type) as identified by PCR-mass spectrometry. PIK3CA exons 9 and 20 were amplified in the presence or absence of LNA-oligonucleotides designed to bind to the wild-type sequences for codons 542, 545, and 1047, and partially suppress their amplification. LNA-PCR sequencing confirmed all 51 PIK3CA mutations; however, the mutation detection rate by standard Sanger sequencing was only 69% (35 of 51). Of the 12 PIK3CA wild-type cases, LNA-PCR sequencing detected three additional H1047R mutations in "normal" breast tissue and one E545K in usual ductal hyperplasia. Histopathological review of these three normal breast specimens showed columnar cell change in two (both with known H1047R mutations) and apocrine metaplasia in one. The novel LNA-PCR shows higher sensitivity than standard Sanger sequencing and did not amplify the known pseudogene.
Substance P (SP) is a member of the neurokinin (NK) family and is one of the established neurotra... more Substance P (SP) is a member of the neurokinin (NK) family and is one of the established neurotransmitters in the mammalian central and enteric nervous system. It is unclear whether NK1 receptors are involved in the control of gastric sensorimotor function in man. We studied the effects of aprepitant, an NK1 receptor antagonist used in the treatment of chemotherapy-induced emesis, on gastric sensorimotor function in healthy volunteers. Sixteen healthy volunteers (six males, 32.4 ± 2.7 years) were studied on three separate occasions after placebo, aprepitant 80 or 125 mg in randomized double-blind study to assess gastric compliance, perception to isobaric distensions, and gastric accommodation with a gastric barostat. Compared to placebo, both doses of aprepitant did not influence gastric compliance or sensitivity to gastric distension. Aprepitant 80 and 125 mg did not have any significant effects on gastric accommodation compared with placebo (mean postprandial gastric volume increase, respectively, 83.4 ± 28.4 vs 35.3 ± 16.2 vs 83.9 ± 30.4 mL, NS). Postprandial gastric compliance and sensitivity to distention were also not altered. In health, NK1 receptors do not appear to be involved in the control of gastric compliance, accommodation or sensitivity to distention in man.
Nature Clinical Practice Gastroenterology & Hepatology, 2008
Heartburn is a typical symptom of GERD. The spectrum of diseases associated with GERD includes re... more Heartburn is a typical symptom of GERD. The spectrum of diseases associated with GERD includes reflux esophagitis, Barrett's esophagus and nonerosive reflux disease (NERD). Although acid reflux is the classic cause of heartburn in patients with erosive esophagitis, the relationship between acid and heartburn is far from clear, especially in patients with NERD. Strong evidence exists that weakly acidic reflux and/or non-acid-related events have a significant role in the generation of heartburn. In addition to the role of nonacidic refluxate components, activation of mechanoreceptors and chemoreceptors, and a possible role for central and peripheral sensitization, has been described. Although patients with erosive esophagitis respond well to acid-suppressive therapy, the same does not hold true for those with NERD. NERD represents a major clinical problem, and its management remains a challenge. Discussion of NERD focuses on the mechanisms that cause chest pain in this subgroup of patients. Improved understanding of the pathogenesis underlying heartburn in patients with GERD, in particular those with NERD, will shape our understanding of this condition. Such understanding will serve as a platform for further research and allow additional therapies to be developed for this increasingly encountered clinical condition.
The phosphatidylinositol-3-kinase pathway is one of the most commonly altered molecular pathways ... more The phosphatidylinositol-3-kinase pathway is one of the most commonly altered molecular pathways in invasive breast carcinoma, with phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) mutations in 25% of invasive carcinomas. Ductal carcinoma in situ (DCIS), benign papillomas, and small numbers of columnar cell lesions harbor an analogous spectrum of PIK3CA and AKT1 mutations, yet there is little data on usual ductal hyperplasia and atypical ductal and lobular neoplasias. We screened 192 formalin-fixed paraffin-embedded breast lesions from 75 patients for point mutations using a multiplexed panel encompassing 643 point mutations across 53 genes, including 58 PIK3CA substitutions. PIK3CA point mutations were identified in 31/62 (50%) proliferative lesions (usual ductal hyperplasia and columnar cell change), 10/14 (71%) atypical hyperplasias (atypical ductal hyperplasia and flat epithelial atypia), 7/16 (44%) lobular neoplasias (atypical lobular hyperplasia and lobular carcinoma in situ), 10/21 (48%) DCIS, and 13/37 (35%) invasive carcinomas. In genotyping multiple lesions of different stage from the same patient/specimen, we found considerable heterogeneity; most notably, in 12 specimens the proliferative lesion was PIK3CA mutant but the concurrent carcinoma was wild type. In 11 additional specimens, proliferative epithelium and cancer contained different point mutations. The frequently discordant genotypes of usual ductal hyperplasia/columnar cell change and concurrent carcinoma support a role for PIK3CA-activating point mutations in breast epithelial proliferation, perhaps more so than transformation. Further, these data suggest that proliferative breast lesions are heterogeneous and may represent non-obligate precursors of invasive carcinoma.
A meta-analysis was conducted to assess the efficacy of transcatheter arterial embolization (TAE)... more A meta-analysis was conducted to assess the efficacy of transcatheter arterial embolization (TAE) compared with surgery in the management of patients with recurrent nonvariceal upper gastrointestinal bleeding (NVUGIB) after failure of endoscopic hemostasis. Publications in English and non-English literatures (OVID, MEDLINE, and EMBASE) and abstracts from major international conferences were searched for studies comparing TAE with surgery for treatment of NVUGIB after endoscopic hemostasis failure. Outcome measures included rebleeding rate, all-cause mortality rate, and need for additional interventions to secure hemostasis. From 1234 citations, 6 retrospective comparative studies were included that involved 423 patients (TAE, 182, 56 % male; surgery, 241, 68 % male). TAE patients were older (mean age, TAE 75, surgery, 68). The risk of rebleeding was significantly higher in TAE patients compared with surgically treated patients (relative risk [RR] 1.82, 95 % confidence interval [95 %...
Applied immunohistochemistry & molecular morphology : AIMM / official publication of the Society for Applied Immunohistochemistry, Jan 24, 2015
Primary neuroendocrine carcinoma of the breast is a rare variant, accounting for only 2% to 5% of... more Primary neuroendocrine carcinoma of the breast is a rare variant, accounting for only 2% to 5% of diagnosed breast cancers, and may have relatively aggressive behavior. Mutational profiling of invasive ductal breast cancers has yielded potential targets for directed cancer therapy, yet most studies have not included neuroendocrine carcinomas. In a tissue microarray screen, we found a 2.4% prevalence (9/372) of neuroendocrine breast carcinoma, including several with lobular morphology. We then screened primary or metastatic neuroendocrine breast carcinomas (excluding papillary and mucinous) for mutations in common cancer genes using polymerase chain reaction-mass spectroscopy (643 hotspot mutations across 53 genes), or semiconductor-based next-generation sequencing analysis (37 genes). Mutations were identified in 5 of 15 tumors, including 3 with PIK3CA exon 9 E542K mutations, 2 of which also harbored point mutations in FGFR family members (FGFR1 P126S, FGFR4 V550M). Single mutations...
Activating point mutations in the phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) are am... more Activating point mutations in the phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) are among the most common molecular defects in invasive breast cancer. Point mutations in the downstream kinase AKT1 are seen in a minority of carcinomas. These mutations are found preferentially in estrogen receptor-positive and Her2-positive breast carcinomas; however, special morphologic types of breast cancer have not been well studied. Twenty-nine cases of pure invasive mucinous carcinoma and 9 cases of ductal carcinoma with mucinous differentiation were screened for a panel of point mutations (>321 mutations in 30 genes) using a multiplex polymerase chain reaction panel with mass spectroscopy readout. In addition, associated ductal carcinoma in situ, hyperplasia, or columnar cell lesions were separately tested where available (25 lesions). In 3 invasive cases and 15 ductal carcinoma in situ/proliferative lesions, PIK3CA hotspot mutations were, instead, tested by direct sequencing. No point mutations were identified in invasive mucinous breast carcinoma. This contrasts with the 35% frequency of PIK3CA mutations in a comparative group of invasive ductal carcinomas of no special type. Interestingly, PIK3CA hotspot point mutations were identified in associated ductal carcinoma in situ (3/14) and hyperplasia (atypical ductal hyperplasia [2/3], usual ductal hyperplasia [2/3], columnar cell change [1/5]), suggesting that PIK3CA mutations may play a role in breast epithelial proliferation. This series represents the largest study, to date, of PIK3CA genotyping in mucinous carcinoma and supports the unique pathogenetics of invasive mucinous breast carcinoma.
Clarithromycin-based triple therapy (TT) is the first line treatment for H. pylori infection in S... more Clarithromycin-based triple therapy (TT) is the first line treatment for H. pylori infection in Singapore. There is awareness that TT may no longer be effective due to increased clarithromycin resistance rates. Sequential therapy (ST) and concomitant therapy (CT) are alternative treatment regimens. The study aimed to compare the efficacy of 10-day TT, ST and CT as first line treatment for H. pylori infection. A randomized study conducted in a teaching hospital. Patients aged 21 years and older with newly diagnosed H. pylori infection were randomized to 10-day TT, ST or CT. Treatment outcome was assessed by 13-carbon urea breath test at least 4 weeks after therapy. Intention to treat (ITT), modified ITT (MITT) and per protocol (PP) analysis of the eradication rates were performed. A total of 462 patients were enrolled (ST: 154; TT 155; CT 153). Patient demographics were similar. Eradication rates for ST vs. TT vs. CT: ITT analysis: 84.4% vs. 83.2% vs. 81.7% (p= NS); MITT analysis: 90.3% vs. 92.1% vs. 94.7% (p = NS); PP analysis: 94.1% vs. 92.8% vs. 95.4% (p = NS). Antibiotic resistance rates for amoxicillin, clarithromycin and metronidazole were 4.7%, 17.9% and 48.1% respectively. Dual clarithromycin and metronidazole resistance occurred in 7.5%. Dual resistance and lack of compliance were predictors of treatment failure. TT, ST and CT all achieved eradication rates above 80% on ITT and above 90% on MITT and PP analyses. Dual resistance and lack of compliance were predictors of treatment failure. ClinicalTrials.gov: NCT02092506.
Hunger is controlled by the brain, which receives input from signals of the GI tract (GIT). Durin... more Hunger is controlled by the brain, which receives input from signals of the GI tract (GIT). During fasting, GIT displays a cyclical motor pattern, the migrating motor complex (MMC), regulated by motilin. To study the relationship between hunger and MMC phases (I-III), focusing on spontaneous and pharmacologically induced phase III and the correlation with plasma motilin and ghrelin levels. The role of phase III was also studied in the return of hunger after a meal in healthy individuals and in patients with loss of appetite. In fasting healthy volunteers, mean hunger ratings during a gastric (62.5±7.5) but not a duodenal (40.4±5.4) phase III were higher (p<0.0005) than during phase I (27.4±4.7) and phase II (37±4.5). The motilin agonist erythromycin, but not the cholinesterase inhibitor neostigmine, induced a premature gastric phase III, which coincided with an increase in hunger scores from 29.2±7 to 61.7±8. The somatostatin analogue octreotide induced a premature intestinal phase III without a rise in hunger scores. Hunger ratings significantly correlated (β=0.05; p=0.01) with motilin plasma levels, and this relationship was lost after erythromycin administration. Motilin, but not ghrelin administration, induced a premature gastric phase III and a rise in hunger scores. In contrast to octreotide, postprandial administration of erythromycin induced a premature gastric phase III accompanied by an early rise in hunger ratings. In patients with unexplained loss of appetite, gastric phase III was absent and hunger ratings were lower. Motilin-induced gastric phase III is a hunger signal from GIT in man.
Micropapillary carcinoma of the breast is associated with increased rates of lymph node metastasi... more Micropapillary carcinoma of the breast is associated with increased rates of lymph node metastasis and lymphovascular invasion. While activating point mutations in PIK3CA (encoding phosphatidylinositol-3-kinase catalytic subunit) or AKT1 are found in 25% to 30% of invasive ductal carcinomas, the mutational profile of invasive micropapillary carcinomas has not been characterized in detail. Micropapillary carcinomas, concurrent metastatic and precursor breast lesions from 19 patients were identified. Lesional tissue was punched from paraffin-tissue blocks, and genomic DNA was extracted and screened for a large panel of known hotspot mutations using multiplex polymerase chain reaction and mass-spectroscopy analysis (643 mutations in 53 genes). Hotspot point mutations were identified in 35% (7/20) of micropapillary breast carcinomas, including PIK3CA exons 7, 9 and 20 hotspots, as well as the AKT1 plekstrin homology domain mutation (E17K); mutations in TP53 and KRAS were each found in a...
Diagnostic molecular pathology : the American journal of surgical pathology, part B, Jan 24, 2014
Primary neuroendocrine carcinoma of the breast is a rare variant, accounting for only 2% to 5% of... more Primary neuroendocrine carcinoma of the breast is a rare variant, accounting for only 2% to 5% of diagnosed breast cancers, and may have relatively aggressive behavior. Mutational profiling of invasive ductal breast cancers has yielded potential targets for directed cancer therapy, yet most studies have not included neuroendocrine carcinomas. In a tissue microarray screen, we found a 2.4% prevalence (9/372) of neuroendocrine breast carcinoma, including several with lobular morphology. We then screened primary or metastatic neuroendocrine breast carcinomas (excluding papillary and mucinous) for mutations in common cancer genes using polymerase chain reaction-mass spectroscopy (643 hotspot mutations across 53 genes), or semiconductor-based next-generation sequencing analysis (37 genes). Mutations were identified in 5 of 15 tumors, including 3 with PIK3CA exon 9 E542K mutations, 2 of which also harbored point mutations in FGFR family members (FGFR1 P126S, FGFR4 V550M). Single mutations...
Somatic mutations in PIK3CA are commonly seen in invasive breast cancer and several other carcino... more Somatic mutations in PIK3CA are commonly seen in invasive breast cancer and several other carcinomas, occurring in three hotspots: codons 542 and 545 of exon 9 and in codon 1047 of exon 20. We designed a locked nucleic acid (LNA)-PCR sequencing assay to detect low levels of mutant PIK3CA DNA with attention to avoiding amplification of a pseudogene on chromosome 22 that has >95% homology to exon 9 of PIK3CA. We tested 60 FFPE breast DNA samples with known PIK3CA mutation status (48 cases had one or more PIK3CA mutations, and 12 were wild type) as identified by PCR-mass spectrometry. PIK3CA exons 9 and 20 were amplified in the presence or absence of LNA-oligonucleotides designed to bind to the wild-type sequences for codons 542, 545, and 1047, and partially suppress their amplification. LNA-PCR sequencing confirmed all 51 PIK3CA mutations; however, the mutation detection rate by standard Sanger sequencing was only 69% (35 of 51). Of the 12 PIK3CA wild-type cases, LNA-PCR sequencing detected three additional H1047R mutations in "normal" breast tissue and one E545K in usual ductal hyperplasia. Histopathological review of these three normal breast specimens showed columnar cell change in two (both with known H1047R mutations) and apocrine metaplasia in one. The novel LNA-PCR shows higher sensitivity than standard Sanger sequencing and did not amplify the known pseudogene.
Substance P (SP) is a member of the neurokinin (NK) family and is one of the established neurotra... more Substance P (SP) is a member of the neurokinin (NK) family and is one of the established neurotransmitters in the mammalian central and enteric nervous system. It is unclear whether NK1 receptors are involved in the control of gastric sensorimotor function in man. We studied the effects of aprepitant, an NK1 receptor antagonist used in the treatment of chemotherapy-induced emesis, on gastric sensorimotor function in healthy volunteers. Sixteen healthy volunteers (six males, 32.4 ± 2.7 years) were studied on three separate occasions after placebo, aprepitant 80 or 125 mg in randomized double-blind study to assess gastric compliance, perception to isobaric distensions, and gastric accommodation with a gastric barostat. Compared to placebo, both doses of aprepitant did not influence gastric compliance or sensitivity to gastric distension. Aprepitant 80 and 125 mg did not have any significant effects on gastric accommodation compared with placebo (mean postprandial gastric volume increase, respectively, 83.4 ± 28.4 vs 35.3 ± 16.2 vs 83.9 ± 30.4 mL, NS). Postprandial gastric compliance and sensitivity to distention were also not altered. In health, NK1 receptors do not appear to be involved in the control of gastric compliance, accommodation or sensitivity to distention in man.
Nature Clinical Practice Gastroenterology & Hepatology, 2008
Heartburn is a typical symptom of GERD. The spectrum of diseases associated with GERD includes re... more Heartburn is a typical symptom of GERD. The spectrum of diseases associated with GERD includes reflux esophagitis, Barrett's esophagus and nonerosive reflux disease (NERD). Although acid reflux is the classic cause of heartburn in patients with erosive esophagitis, the relationship between acid and heartburn is far from clear, especially in patients with NERD. Strong evidence exists that weakly acidic reflux and/or non-acid-related events have a significant role in the generation of heartburn. In addition to the role of nonacidic refluxate components, activation of mechanoreceptors and chemoreceptors, and a possible role for central and peripheral sensitization, has been described. Although patients with erosive esophagitis respond well to acid-suppressive therapy, the same does not hold true for those with NERD. NERD represents a major clinical problem, and its management remains a challenge. Discussion of NERD focuses on the mechanisms that cause chest pain in this subgroup of patients. Improved understanding of the pathogenesis underlying heartburn in patients with GERD, in particular those with NERD, will shape our understanding of this condition. Such understanding will serve as a platform for further research and allow additional therapies to be developed for this increasingly encountered clinical condition.
The phosphatidylinositol-3-kinase pathway is one of the most commonly altered molecular pathways ... more The phosphatidylinositol-3-kinase pathway is one of the most commonly altered molecular pathways in invasive breast carcinoma, with phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) mutations in 25% of invasive carcinomas. Ductal carcinoma in situ (DCIS), benign papillomas, and small numbers of columnar cell lesions harbor an analogous spectrum of PIK3CA and AKT1 mutations, yet there is little data on usual ductal hyperplasia and atypical ductal and lobular neoplasias. We screened 192 formalin-fixed paraffin-embedded breast lesions from 75 patients for point mutations using a multiplexed panel encompassing 643 point mutations across 53 genes, including 58 PIK3CA substitutions. PIK3CA point mutations were identified in 31/62 (50%) proliferative lesions (usual ductal hyperplasia and columnar cell change), 10/14 (71%) atypical hyperplasias (atypical ductal hyperplasia and flat epithelial atypia), 7/16 (44%) lobular neoplasias (atypical lobular hyperplasia and lobular carcinoma in situ), 10/21 (48%) DCIS, and 13/37 (35%) invasive carcinomas. In genotyping multiple lesions of different stage from the same patient/specimen, we found considerable heterogeneity; most notably, in 12 specimens the proliferative lesion was PIK3CA mutant but the concurrent carcinoma was wild type. In 11 additional specimens, proliferative epithelium and cancer contained different point mutations. The frequently discordant genotypes of usual ductal hyperplasia/columnar cell change and concurrent carcinoma support a role for PIK3CA-activating point mutations in breast epithelial proliferation, perhaps more so than transformation. Further, these data suggest that proliferative breast lesions are heterogeneous and may represent non-obligate precursors of invasive carcinoma.
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