Redundancy in the International Anorectal Physiology Working Group Manometry Protocol: A Diagnostic Accuracy Study in Fecal Incontinence.

BACKGROUND: Anorectal manometry (ARM) is essential for identifying sphincteric dysfunction. The International Anorectal Physiology Working Group (IAPWG) protocol and London Classification provide a standardized format for performing and interpreting ARM. However, there is scant evidence to support timing and number of constituent maneuvers. AIMS: To assess the impact of protocol modification on diagnostic accuracy in patients with fecal incontinence. METHODS: Retrospective analysis of high-resolution ARM recordings from consecutive patients based on the current IAPWG protocol and modifications thereof: (1) baseline rest period (60 vs. 30 vs. 10 s); (2) number of abnormal short squeezes (SS) out of 3 (SS1/SS2/SS3) based on maximal incremental squeeze pressures over 5 s; (3) resting anal pressures (reflecting recovery) at 25-30 versus 15-20 s after SS1. RESULTS: One hundred patients (86 F, median age 55 [IQR: 39-65]; median St. Mark's incontinence score 14 [10-17]) were studied. 26% and 8% had anal hypotonia and hypertonia, respectively. Compared with 60-s resting pressure, measurements had perfect correlation (κ = 1.0) over 30 s, and substantial correlation (κ = 0.85) over 10 s. After SS1, SS2, and SS3, 43%, 49%, and 46% had anal hypocontractility, respectively. Correlation was substantial between SS1 and SS2 (κ = 0.799) and almost perfect between SS2 and SS3 (κ = 0.9). Compared to resting pressure of 5 s before SS1, pressure recordings at 25-30 and 15-20 s after SS1 were significantly correlated. CONCLUSIONS: A 30-s resting anal pressure, analysis of 2 short-squeezes with a 20-s between-maneuver recovery optimizes study duration without compromising diagnostic accuracy. These findings indicate the IAPWG protocol has redundancy.

Altered anal slow-wave pressure activity in low anterior resection syndrome: short case series in two independent specialist centres provide new mechanistic insights.

AIM: Conventional parameters (anal resting and squeeze pressures) measured with anorectal manometry (ARM) fail to identify anal sphincter dysfunction in many patients with low anterior resection syndrome (LARS). We aimed to assess whether there are differences in anal canal slow-wave pressure activity in LARS patients and healthy individuals. METHOD: High-resolution ARM (HR-ARM) traces of 21 consecutive male LARS patients referred to the Royal London Hospital, UK (n = 12) and Aarhus University Hospital, Denmark (n = 9) were compared with HR-ARM data from 37 healthy men. RESULTS: Qualitatively (by visual inspection of HR-ARM recordings), the frequency of slow-wave pressure activity was strikingly different in 11/21 (52.4%) LARS patients from that observed in all the healthy individuals. Quantitative analysis showed that peaks of the mean spectrum in these 11 LARS patients occurred at approximately 6-7 cycles per minute (cpm), without activity at higher frequencies. An equivalent pattern was found in only 2/37 (5.4%) healthy individuals (P < 0.0001). Peaks of the mean spectrum in healthy individuals were concentrated at 16 cpm and 3-4 cpm. CONCLUSION: Over half of the male LARS patients studied had altered anal slow-wave pressure activity based on analysis of HR-ARM recordings. Further studies could investigate the relative contributions of sex, human baseline variance and neoadjuvant/surgical therapies on anal slow waves, and correlate the presence of abnormal activity with symptom severity.

The Changing Profile of Helicobacter pylori Antibiotic Resistance in Singapore: A 15-Year Study.

BACKGROUND: Antibiotic resistance is an important cause of H. pylori treatment failure. This study aimed to examine the change in H. pylori antibiotic resistance profile in Singapore over the course of 15 years. MATERIALS AND METHODS: The study period was from 2000 to 2014. Gastric mucosal biopsies obtained from H. pylori-positive patients were cultured. Antibiotic susceptibility to metronidazole, clarithromycin, levofloxacin, tetracycline, and amoxicillin was tested. The change in resistance rates over time was analyzed. RESULTS: A total of 708 H. pylori isolates were cultured. There was a significant increase in resistance rates for metronidazole (2000-2002: 24.8%; 2012-2014: 48.2%; p < .001), clarithromycin (2000-2002: 7.9%; 2012-2014: 17.1%; p = .022), and levofloxacin (2000-2002: 5%; 2012-2014: 14.7%; p = .007). The resistance rates for tetracycline (2000-2002: 5%; 2012-2014: 7.6%) and amoxicillin (2000-2002: 3%; 2012-2014: 4.4%) remained stable. Increase in dual (2000-2002: 6.9%; 2012-2014: 9.4%; p = .479) and triple antibiotic resistance rates (2000-2002: 0; 2012-2014: 7.6%; p < .001) were observed. Overall, the most common dual and triple resistance patterns were metronidazole/clarithromycin (4.4%) and metronidazole/clarithromycin/levofloxacin (1.8%), respectively. CONCLUSIONS: Over 15 years, H. pylori resistance rates to metronidazole, clarithromycin and levofloxacin had increased. There was increased resistance to multiple antibiotics.

Ten-day triple therapy versus sequential therapy versus concomitant therapy as first-line treatment for Helicobacter pylori infection.

BACKGROUND AND AIM: Clarithromycin-based triple therapy (TT) is the first-line treatment for Helicobacter 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. This study aimed to compare the efficacy of 10-day TT, ST, and CT as first-line treatment for H. pylori infection. METHODS: 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) analyses of the eradication rates were performed. RESULTS: A total of 462 patients were enrolled (ST: 154; TT 155; CT 153). Patient demographics were similar. Eradication rates for ST versus TT versus CT: ITT analysis: 84.4% versus 83.2% versus 81.7% (P = not significant [NS]); MITT analysis: 90.3% versus 92.1% versus 94.7% (P = NS); PP analysis: 94.1% versus 92.8% versus 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. CONCLUSIONS: 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).

Frequent phosphatidylinositol-3-kinase mutations in proliferative breast lesions.

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.

Prevalence of Potentially Pathogenic Germline Variants Among Adult Patients in the Philippines With Solid Malignancies Who Underwent Tumor Genomic Profiling.

PURPOSE: In high-income countries, 2%-10% of tumor genomic profiling (TGP) reports reveal incidental pathogenic germline variants. A third of these patients would not qualify for genetic testing on the basis of current guidelines. Our study determined the prevalence of potentially pathogenic germline variants (PPGVs) in TGP results of adult patients with solid malignancies in the Philippines. METHODS: Annotated reports of patients with solid cancers who underwent TGP using FoundationOne or FoundationOne Heme between January 2021 and July 2023 were reviewed. PPGV criteria include having a variant allele frequency of >30% and were categorized as (1) high penetrance gene (HP), founder variant (FV), or variant associated with clinical presentation (VA). Pathogenicity was crosschecked through the ClinVar database. RESULTS: Of 446 patients, 13 PPGV variants were found in 50 (11.2%) patients at a median age of 60.5 years. Of them, 28 (56%) had HP (BRCA1, BRCA2, MSH2, MSH6, MLH1, RAD51C, RAD51D), 25 (50%) patients had VA (APC, SMAD4, CDH1, CDKN2A, PTEN), and two patients with lung cancer had a FV (EGFR p.Thr790Met). Six patients had more than one PPGV. PPGVs were primarily found in patients with colorectal (42% of 50 patients with PPGVs), breast (16%), ovarian (6%), and lung (6%) cancer (P < .001). HP genes were mostly found in female patients (71.4%; P = .03). CONCLUSION: With a PPGV prevalence of 11% in this study, it is important to recognize PPGVs as it can prompt genetic counseling and confirmatory germline testing.

KRAS mutations are associated with solid growth pattern and tumor-infiltrating leukocytes in lung adenocarcinoma.

KRAS mutations define a clinically distinct subgroup of lung adenocarcinoma patients, characterized by smoking history, resistance to EGFR-targeted therapies, and adverse prognosis. Whether KRAS-mutated lung adenocarcinomas also have distinct histopathological features is not well established. We tested 180 resected lung adenocarcinomas for KRAS and EGFR mutations by high-sensitivity mass spectrometry-based genotyping (Sequenom) and PCR-based sizing assays. All tumors were assessed for the proportion of standard histological patterns (lepidic, acinar, papillary, micropapillary, solid, and mucinous), several other histological and clinical parameters, and TTF-1 expression by immunohistochemistry. Among 180 carcinomas, 63 (35%) had KRAS mutations (KRAS+), 35 (19%) had EGFR mutations (EGFR+), and 82 (46%) had neither mutation (KRAS-/EGFR-). Solid growth pattern was significantly over-represented in KRAS+ carcinomas: the mean±s.d. for the amount of solid pattern in KRAS+ carcinomas was 27±34% compared with 3±10% in EGFR+ (P<0.001) and 15±27% in KRAS-/EGFR- (P=0.033) tumors. Furthermore, at least focal (≥20%) solid component was more common in KRAS+ (28/63; 44%) compared with EGFR+ (2/35; 6%; P<0.001) and KRAS-/EGFR- (21/82; 26%; P=0.022) carcinomas. KRAS mutations were also over-represented in mucinous carcinomas and were significantly associated with the presence of tumor-infiltrating leukocytes and heavier smoking history. EGFR mutations were associated with non-mucinous non-solid patterns, particularly lepidic and papillary, lack of necrosis, lack of cytological atypia, hobnail cytology, TTF-1 expression, and never/light smoking history. In conclusion, extended molecular and clinicopathological analysis of lung adenocarcinomas reveals a novel association of KRAS mutations with solid histology and tumor-infiltrating inflammatory cells and expands on several previously recognized morphological and clinical associations of KRAS and EGFR mutations. Solid growth pattern was recently shown to be a strong predictor of aggressive behavior in lung adenocarcinomas, which may underlie the unfavorable prognosis associated with KRAS mutations in these tumors.

Driver mutations determine survival in smokers and never-smokers with stage IIIB/IV lung adenocarcinomas.

BACKGROUND: The authors previously demonstrated that never-smokers with stage IIIB/IV nonsmall cell lung cancer (NSCLC) lived 50% longer than former/current smokers. This observation persisted after adjusting for age, performance status, and sex. In this study, the authors hypothesized that smoking-dependent differences in the distribution of driver mutations may explain differences in prognosis between these subgroups. METHODS: In total, 293 never-smokers and 382 former/current smokers with lung adenocarcinoma who underwent testing for epidermal growth factor receptor (EGFR) mutations and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and rearrangements in anaplastic lymphoma kinase (ALK) between 2009 and 2010 were investigated. Clinical outcomes and patient characteristics were collected. Survival probabilities were estimated using the Kaplan-Meier method. Group comparison was performed with log-rank tests and Cox proportional hazards methods. RESULTS: Although the overall incidence of these mutations was nearly identical (55% never-smokers vs 57% current/former smokers; P = .48), there were significant differences in the distribution of mutations between these groups for EGFR mutations (37% never-smokers vs 14% former/current smokers; P < .0001), KRAS mutations (4% never-smokers vs 43% former/current smokers; P < .0001), and ALK rearrangements (12% never-smokers vs 2% former/current smokers; P < .0001). Among never-smokers and former/current smokers, the prognosis differed significantly by genotype. Patients who had KRAS mutations had the poorest survival. Smoking status, however, had no influence on survival within each genotype. CONCLUSIONS: Never-smokers and former/current smokers with lung adenocarcinomas were not homogeneous subgroups. Each was made up of individuals whose tumors had a unique distribution of driver mutations, which were associated with different prognoses, irrespective of smoking history.

Myelodysplastic Syndrome: Diagnosis and Screening.

Myelodysplastic syndromes (MDS) are heterogeneous groups of clonal myeloid disorders characterized by unexplained persistent peripheral blood (PB) cytopenia(s) of one or more of the hematopoietic lineages, or bone marrow (BM) morphologic dysplasia in hematopoietic cells, recurrent genetic abnormalities, and an increased risk of progression to acute myeloid leukemia (AML). In the past several years, diagnostic, prognostic, and therapeutic approaches have substantially improved with the development of Next Generation Sequencing (NGS) diagnostic testing and new medications. However, there is no single diagnostic parameter specific for MDS, and correlations with clinical information, and laboratory test findings are needed to reach the diagnosis.

Evaluation of a six-probe cocktail (caffeine, tolbutamide, omeprazole, dextromethorphan, midazolam, and digoxin) approach to estimate hepatic drug detoxification capability and dosage requirements after a single oral dosing in healthy Chinese volunteers.

The primary objectives of this study were to investigate the suitability of a 6-probe cocktail (caffeine, tolbutamide, omeprazole, dextromethorphan, midazolam, and digoxin) to be used as a tool for assessing the activity of drug metabolizing enzymes and transporters, and examine differences in the way drugs are handled among groups with different genetic regulation of these processes. This was a single-center, open-label, phase I clinical study involving 20 young, healthy Chinese volunteers (equal gender distribution). The subjects were administered a single, oral dose of the 6-probe cocktail and serum samples were collected to assess the disposition of the different probe substrates and produced metabolites. The serum samples were analyzed using ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry technology. The DNA samples were subjected to whole exome sequencing. Nineteen healthy volunteers completed the study. The 6-probe cocktail was safe and well-tolerated by all the subjects. The parent substrates and metabolites-caffeine (paraxanthine), dextromethorphan (dextrorphan), digoxin, midazolam (1-hydroxy-midazolam), omeprazole (5-hydroxy-omeprazole), and tolbutamide (4-hydroxy-tolbutamide)-were within the detectable window. Genetic variations known to alter drug metabolism (CYP2D6*10, CYP2C19*2, CYP2C19*3, and CYP2C9*3) were identified and generally correlated with phenotypic status. The 6-probe cocktail appeared to be suitable for assessing drug metabolizing activities. This, in conjunction with individual genetics, will pave the way for the implementation of personalized medicine in clinical practice. This will hopefully improve efficacy and reduce the incidence of adverse drug reactions.

Clinical audit of current Helicobacter pylori treatment outcomes in Singapore.

Introduction: H. pylori eradication reduces the risk of gastric malignancies and peptic ulcer disease. First-line therapies include 14-day PAC (proton pump inhibitor [PPI], amoxicillin, clarithromycin) and PBMT (PPI, bismuth, metronidazole, tetracycline). Second-line therapies include 14-day PBMT and PAL (PPI, amoxicillin, levofloxacin). This clinical audit examined current treatment outcomes in Singapore. Methods: Clinical data of H. pylori-positive patientswho underwent empirical first- and second-line eradication therapies from 1 January 2017 to 31 December 2018 were reviewed. Treatment success was determined by 13C urea breath test performed at least 4 weeks after treatment and 2 weeks off PPI. Results: A total of 963 patients (862 PAC, 36 PMC [PPI, metronidazole, clarithromycin], 18 PBMT, 13 PBAC [PAC with bismuth], 34 others) and 98 patients (62 PMBT, 15 PAL, 21 others) received first-and second-line therapies respectively. A 14-day treatment duration was appropriately prescribed for first- and second-line therapies in 65.2% and 82.7% of patients, respectively. First-line treatment success rates were noted for PAC (seven-day: 76.9%, ten-day: 88.3%, 14-day: 92.0%), PMC (seven-day: 0, ten-day: 75.0%, 14-day: 69.8%), PBMT (ten-day: 100%, 14-day: 87.5%) and PBAC (14-day: 100%). 14-day treatment was superior to seven-day treatment (90.8% vs. 71.4%; P = 0.028). PAC was superior to PMC (P < 0.001) but similar to PBMT (P = 0.518) and PBAC (P = 0.288) in 14-day therapies. 14-day second-line PAL and PBMT had similar efficacy (90.9% vs. 82.4%; P = 0.674). Conclusion: First-line empirical treatment using PAC, PBMT and PBAC for 14 days had similar efficacy. Success rates for second-line PBMT and PAL were similar.

Clinical trial: seven-day vonoprazan- versus 14-day proton pump inhibitor-based triple therapy for first-line Helicobacter pylori eradication.

BACKGROUND: One-week triple therapy with vonoprazan is endorsed by Japanese guidelines as an alternative to proton pump inhibitor (PPI)-based triple therapy for first-line Helicobacter pylori eradication. This contrasts with Western guidelines recommending 2-week PPI-based triple therapy. AIM: To verify the non-inferiority of 1-week vonoprazan-based triple therapy versus 2-week PPI-based triple therapy as first-line H. pylori eradication in a multiracial Asian cohort. METHODS: Randomised controlled trial of treatment-naïve patients with H. pylori infection assigned 1:1 to either 7 days amoxicillin 1 g + clarithromycin 500 mg + vonoprazan 20 mg twice per day or 14 days amoxicillin 1 g + clarithromycin 500 mg + omeprazole OR esomeprazole OR rabeprazole 20 mg twice/day. Subjects were randomly assigned to each PPI 1:1:1 Demographics, H. pylori resistance, CYP 2C19 genotype, eradication success and safety profiles were compared between groups. RESULTS: Between June 2019 and June 2021, 252 of 1097 subjects screened were randomised. 244 (age [SD] 51.7 [14.6]) received vonoprazan- (n = 119) or PPI-based (n = 125) triple therapy. Eradication rates by intention-to-treat analysis were 87.4% (vonoprazan-based triple therapy) versus 88.0% (PPI-based triple therapy. By per protocol analysis: 96.3% (vonoprazan-based triple therapy) versus 94.0% (PPI-based triple therapy). Clarithromycin resistance predicted treatment failure on multivariate analysis: RR 11.4; 95% CI [1.4-96.3], p = 0.025. No significant differences in CYP 2C19 genotypes or adverse events occurred between groups. CONCLUSION: One-week vonoprazan-based triple therapy achieved comparable efficacy to 2-week PPI-based triple therapy and was well tolerated.

The present and future of gastroenterology and hepatology: an international SWOT analysis (the GASTROSWOT project).

GASTROSWOT is a strategic analysis of the current and projected states of the different subspecialties in gastroenterology that aims to provide guidance for research, clinical, and financial planning in gastroenterology. We executed a consensus-based international strengths, weaknesses, opportunities, and threats (SWOT) analysis. Four general coordinators, six field coordinators, and 12 experts participated in the study. SWOTs were provided for the following fields: neurogastroenterology, functional gastrointestinal disorders, and upper gastrointestinal diseases; inflammatory bowel disease; pancreatology and biliary diseases; endoscopy; gastrointestinal oncology; and hepatology. The GASTROSWOT analysis highlights the following in the current state of the field of gastroenterology: the incidence and complexity of several gastrointestinal diseases, including malignancies, are increasing; the COVID-19 pandemic has affected patient care on several levels; and with the advent of technical innovations in gastroenterology, a well trained workforce and strategic planning are required to optimise health-care utilisation. The analysis calls attention to the following in the future of gastroenterology: artificial intelligence and the use of big data will speed up discovery and smarter health-care provision in the field; the growth and diversification of gastroenterological specialties will improve specialised care for patients, but could promote fragmentation of care and health system inefficiencies; and furthermore, thoughtful planning is needed to reach an effective balance between the need for subspecialists and the value of general gastroenterology services.

Immunohistochemical algorithm for differentiation of lung adenocarcinoma and squamous cell carcinoma based on large series of whole-tissue sections with validation in small specimens.

Immunohistochemistry is increasingly utilized to differentiate lung adenocarcinoma and squamous cell carcinoma. However, detailed analysis of coexpression profiles of commonly used markers in large series of whole-tissue sections is lacking. Furthermore, the optimal diagnostic algorithm, particularly the minimal-marker combination, is not firmly established. We therefore studied whole-tissue sections of resected adenocarcinoma and squamous cell carcinoma (n=315) with markers commonly used to identify adenocarcinoma (TTF-1) and squamous cell carcinoma (p63, CK5/6, 34ßE12), and prospectively validated the devised algorithm in morphologically unclassifiable small biopsy/cytology specimens (n=38). Analysis of whole-tissue sections showed that squamous cell carcinoma had a highly consistent immunoprofile (TTF-1-negative and p63/CK5/6/34ßE12-diffuse) with only rare variation. In contrast, adenocarcinoma showed significant immunoheterogenetity for all 'squamous markers' (p63 (32%), CK5/6 (18%), 34ßE12 (82%)) and TTF-1 (89%). As a single marker, only diffuse TTF-1 was specific for adenocarcinoma whereas none of the 'squamous markers,' even if diffuse, were entirely specific for squamous cell carcinoma. In contrast, coexpression profiles of TTF-1/p63 had only minimal overlap between adenocarcinoma and squamous cell carcinoma, and there was no overlap if CK5/6 was added as a third marker. An algorithm was devised in which TTF-1/p63 were used as the first-line panel, and CK5/6 was added for rare indeterminate cases. Prospective validation of this algorithm in small specimens showed 100% accuracy of adenocarcinoma vs squamous cell carcinoma prediction as determined by subsequent resection. In conclusion, although reactivity for 'squamous markers' is common in lung adenocarcinoma, a two-marker panel of TTF-1/p63 is sufficient for subtyping of the majority of tumors as adenocarcinomas vs squamous cell carcinoma, and addition of CK5/6 is needed in only a small subset of cases. This simple algorithm achieves excellent accuracy in small specimens while conserving the tissue for potential predictive marker testing, which is now an essential consideration in advanced lung cancer specimens.

Helicobacter pylori Treatment Strategies in Singapore.

The management of Helicobacter pylori infection in Singapore remains a clinical challenge. Similar to other regions, there has been an increase in antibiotic resistance rates through the years. Nonetheless, over the past two decades, clarithromycin-based triple therapy has continued to be used as the first line treatment option, with an eradication rate exceeding 90%, although the accepted treatment duration must now be lengthened from 1 to 2 weeks to maintain efficacy. Concomitant and sequential therapies did not demonstrate superiority over standard triple therapy. Current empiric second line treatment utilizes either bismuth-based quadruple therapy or levofloxacin-based triple therapy, but outcomes remain less than ideal. Identifying options to further improve treatment success rates is challenging. Strategies being considered include the use of potent acid suppressants, such as vonoprazan, and H. pylori culture and antibiotic susceptibility testing-guided therapy.

Guidance on performance and reporting of high-resolution oesophageal manometry and ambulatory pH monitoring in Singapore.

INTRODUCTION: We aimed to provide a practical and evidence-based guide on the indications, performance and reporting of high-resolution oesophageal manometry (HRM) and ambulatory pH monitoring (PHM) in adult patients in Singapore. METHODS: The guideline committee comprised local gastroenterologists from public and private sectors with particular expertise in aspects of HRM and PHM, and it was tasked to produce evidence-based statements on the indications, performance and reporting of these tests. Each committee member performed literature searches to retrieve relevant articles within the context of domains to which they were assigned. RESULTS: Twelve recommendation statements were created and summarised. CONCLUSION: Standardising key aspects of HRM and PHM is imperative to ensure the delivery of high-quality care. We reported the development of recommendations for the performance and interpretation of HRM and ambulatory reflux monitoring in Singapore.

Prospective serial diagnostic study: the effects of position and provocative tests on the diagnosis of oesophageal motility disorders by high-resolution manometry.

BACKGROUND: Standard high-resolution manometry (HRM) protocols are based on 10 single water swallows acquired in the supine position. AIMS: To assess the impact of position, rapid drink challenge and solid test meal on the diagnosis of oesophageal motility disorders. METHODS: Seventy-two healthy volunteers (20-76 years) and 366 consecutive patients (18-90 years) completed HRM with 10 single water swallows in the supine and upright positions. Rapid drink challenge was performed twice, before and after the solid test meal. Diagnosis based on single water swallows in the supine position (Chicago Classification v3.0) was compared with results in the upright position and with provocative tests. RESULTS: Overall, diagnostic agreement in the supine and upright positions was present in 296/438 (67.6%) subjects. This increased to 90.0% when ineffective oesophageal motility was considered with normal motility. Integrated relaxation pressure was 4 mm Hg higher in the supine position. There was a higher prevalence of inconsistent, likely false positive, diagnoses of outlet obstruction in the supine compared to the upright position (16/20 vs 1/4 patients, P = 0.0007). Similarly, the difference in concordance for the diagnosis of oesophago-gastric junction obstruction or achalasia between single water swallows in the supine and upright positions with solid test meal was significant (12/29 (41.4%) vs 12/14 (85.7%), P = 0.0087). CONCLUSION: Diagnostic agreement for oesophageal motility disorders based on single water swallows in the upright and supine positions was moderate, with frequent discordant findings for ineffective motility and outlet obstruction. HRM studies can be performed in either position, using appropriate reference values. Rapid drink challenge or solid test meal can resolve diagnostic discrepancies.

Diagnosis of gastroesophageal reflux: an update on current and emerging modalities.

Gastroesophageal reflux disease (GERD) is a common condition characterized by troublesome symptoms or esophageal mucosal lesions attributed to excessive esophageal acid exposure. Various pathophysiological mechanisms account for GERD, including impaired esophageal peristalsis and anatomical or physiological defects at the esophagogastric junction (EGJ). Endoscopy identifies GERD complications and detects potential alternative diagnoses. However, if symptoms persist despite proton pump inhibitor therapy, functional esophageal tests are useful to characterize reflux burden and define the symptom association profile. Ambulatory pH or pH-impedance monitoring measures the 24-h acid exposure time, which remains the most reproducible reflux metric and predicts response to antireflux therapy. Apart from identifying peristaltic dysfunction, esophageal high-resolution manometry defines the morphology and contractile vigor (EGJ-CI) of the EGJ. Novel metrics obtained from pH-impedance monitoring include the postreflux swallow-induced peristaltic wave index and mean nocturnal baseline impedance, which augment the diagnostic value of pH-impedance testing. Mucosal impedance can also be recorded using a probe inserted through a gastroscope, or a novel balloon catheter with arrays of impedance electrodes inserted following sedated endoscopy. The latest developments in functional esophageal tests define the GERD phenotype based on pathogenesis, reflux exposure, structural or motility disorders, and symptom burden, facilitating appropriate treatment.

Placental mesenchymal dysplasia: a potential misdiagnosed entity.

Placental mesenchymal dysplasia is a rare condition characterized by enlarged multicystic placenta with anechoic regions on ultrasound. Gross examination shows grapelike vesicles which mimics molar pregnancy. Microscopic findings shows large edematous villi with cistern formation interspersed with normal villi. The absence of trophoblastic proliferation and trophobastic inclusions differentiates it from molar pregnancy. We report a new case of placental mesenchymal dysplasia. A 31-year-old G2P1 presented with preterm vaginal bleeding at 24 5/7 weeks of gestation. Ultrasound findings show cystic placenta and placenta previa. She went into preterm labor and delivered a female baby with no dysmorphic features but later suffered from complications of prematurity. Pathologically, the placenta showed multiple grapelike cystic vesicles with unremarkable chorionic vessels. Microscopically, enlarged edematous villi with cistern formation were noted. Trophoblastic proliferation or inclusions were not seen.

High Preponderance of BRAF V600E Mutation in Papillary Thyroid Carcinoma Among Filipinos: A Clinicopathologic Study.

PURPOSE: BRAF mutation in papillary thyroid carcinoma (PTC) is associated with an aggressive phenotype, with varying incidence. We evaluated the prevalence of BRAF mutations in PTC among Filipino patients and their correlation with clinicopathologic characteristics. PATIENTS AND METHODS: Clinicopathologic data were retrieved from 64 sequential patients who underwent thyroidectomy from June 2016 to December 2016. BRAF mutation testing was performed using Sanger sequencing. RESULTS: Eighteen (28%) of 64 patients were diagnosed with PTC; 12 (70.59%) of 17 harbored a BRAF V600E mutation (no amplification in one patient). Demographics of patients with PTC were as follows: 13 women and five men, with median age of 46 years (range, 25 to 74 years). Fourteen patients had conventional subtype PTC; two, follicular variant; one, oncocytic variant; and one, tall-cell features. Tumor size ranged from 0.8 to 7.0 cm (median, 2.4 cm); extrathyroidal extension was present in seven (38.9%) of 18 patients, multifocality in six (33.33%) of eight, and lymph node involvement in eight (44.4%) of 18. Significant association between presence of a BRAF mutation and presence of extrathyroidal extension or lymph node involvement was not determined due to the limited sample size. CONCLUSION: The high preponderance of BRAF mutation (70.59%) suggests some correlation with the previously reported lower 5-year survival among Filipinos. This warrants further investigation in a larger-cohort prospective study.