Simplified 4-item criteria for polycystic ovary syndrome: A bridge too far?

OBJECTIVES: Although the Rotterdam 2003 polycystic ovarian syndrome (PCOS) diagnostic criteria is widely used, the need to consider multiple variables makes it unwieldy in clinical practice. We propose a simplified PCOS criteria wherein diagnosis is made if two of the following three items were present: (i) oligomenorrhoea, (ii) anti-mullerian hormone (AMH) above threshold and/or (iii) hyperandrogenism defined as either testosterone above threshold and/or the presence of hirsutism. DESIGN SETTING AND PARTICIPANTS: This prospective cross-sectional study consists of healthy women (n = 157) recruited at an annual hospital health screen for staff and volunteers from the university community, and a patient cohort (n = 174) comprising women referred for suspected PCOS. MAIN OUTCOME MEASURES: We used the healthy cohort to establish threshold values for serum testosterone, antral follicle counts (AFC), ovarian volume (OV) and AMH. Women from the patient cohort, classified as PCOS by simplified PCOS criteria, AMH alone and Rotterdam 2003, were compared with respect to prevalence of oligomenorrhoea, hyperandrogenism and metabolic indices. RESULTS: In healthy women, testosterone ≥1.89 nmol/L, AFC ≥22 follicles and OV ≥8.44 mL, best predicted oligomenorrhoea and were used as threshold values for PCOS criteria. An AMH level ≥37.0 pmol/L best predicted polycystic ovarian morphology. AMH alone as a single biomarker demonstrated poor specificity (58.9%) for PCOS compared to Rotterdam 2003. In contrast, there was a 94% overlap in women selected as PCOS by the simplified PCOS criteria and Rotterdam 2003. The population characteristics of these two groups of PCOS women showed no significant mean differences in androgenic, ovarian, AMH and metabolic (BMI, HOMA-IR) variables. CONCLUSIONS: Our data recommend the simplified PCOS criteria with population-specific thresholds for diagnosis of PCOS. Its ability to replace ovarian ultrasound biometry with the highly correlated variable AMH, and use of testosterone as a single marker for hyperandrogenaemia alongside the key symptoms of oligomenorrhoea and hirsutism confers significant clinical potential for the diagnosis of PCOS.

High expression of intratumoral stromal proteins is associated with chemotherapy resistance in breast cancer.

We studied the changes of intratumoral stromal proteins including THBS1, TNC, FN, SPARC and α-SMA, following neoadjuvant chemotherapy. The underlying mechanisms by which THBS1 and TNC regulated resistance to docetaxel were further studied using functional studies. 100 patients with newly diagnosed breast cancer were treated with alternating sequential doxorubicin and docetaxel. Immunohistochemistry (IHC) staining for stromal proteins was performed on pre- and post-treatment core biopsies respectively. THBS1 and TNC were further validated with IHC in an independent cohort of 31 patients. A high baseline combined expression score of the 5 stromal proteins predicted independently for poor progression-free (HRadjusted 2.22, 95% CI 1.06-4.64) and overall survival (HRadjusted 5.94, 95% CI 2.25-15.71). After 1-2 cycles of chemotherapy, increased expression of THBS1, TNC, FN, SPARC and α-SMA was seen in patients with subsequent pathological lymph node involvement at surgery. Increased expression of THBS1 and TNC compared to baseline was also seen in intrinsically resistant tumors, but not in sensitive ones. Both THBS1 and TNC-associated chemoresistance were confirmed in an independent validation cohort. Exogenous THBS1 and TNC protected MCF-7 cells against proliferation inhibition induced by docetaxel through activating integrin ß1/mTOR pathway. Thus, up-regulation of THBS1, TNC, FN, SPARC and α-SMA following neoadjuvant chemotherapy was associated with chemotherapy resistance in breast cancer patients. Functional studies showed THBS1 and TNC to mediate chemoresistance through the integrin ß1/mTOR pathway, suggesting that therapies targeting integrin ß1/mTOR pathway may be a promising strategy to overcome chemotherapy resistance.

HDAC1 and HDAC2 independently predict mortality in hepatocellular carcinoma by a competing risk regression model in a Southeast Asian population.

Histone deacetylases (HDACs) are enzymes involved in transcriptional repression. We aimed to examine the significance of HDAC1 and HDAC2 gene expression in the prediction of recurrence and survival in 156 patients with hepatocellular carcinoma (HCC) among a South East Asian population who underwent curative surgical resection in Singapore. We found that HDAC1 and HDAC2 were upregulated in the majority of HCC tissues. The presence of HDAC1 in tumor tissues was correlated with poor tumor differentiation. Notably, HDAC1 expression in adjacent non-tumor hepatic tissues was correlated with the presence of satellite nodules and multiple lesions, suggesting that HDAC1 upregulation within the field of HCC may contribute to tumor spread. Using competing risk regression analysis, we found that increased cancer-specific mortality was significantly associated with HDAC2 expression. Mortality was also increased with high HDAC1 expression. In the liver cancer cell lines, HEP3B, HEPG2, PLC5, and a colorectal cancer cell line, HCT116, the combined knockdown of HDAC1 and HDAC2 increased cell death and reduced cell proliferation as well as colony formation. In contrast, knockdown of either HDAC1 or HDAC2 alone had minimal effects on cell death and proliferation. Taken together, our study suggests that both HDAC1 and HDAC2 exert pro-survival effects in HCC cells, and the combination of isoform-specific HDAC inhibitors against both HDACs may be effective in targeting HCC to reduce mortality.

How do primary care physicians in Singapore keep healthy?

INTRODUCTION: Not much is known regarding how primary care physicians (PCPs) in Singapore keep themselves healthy and mitigate ill health. This study aims to determine the health-seeking behaviour of local PCPs and to identify the predictors of local PCPs attaining the recommended level of exercise. METHODS: This study was a cross-sectional questionnaire survey, which included questions on the demographic characteristics, practice profiles and health-seeking behaviour of PCPs. The sampling frame was the 1,400 listed members of the College of Family Physicians Singapore. The anonymised survey was executed in two phases: a postal survey, followed by a web-based survey on the College of Family Physicians Singapore website. The two data sets were collated; the categorical variables, summarised; and the differences between subgroups (based on exercise engagement), compared using Fisher's exact test. The effect of each risk factor on exercise duration was quantified using odds ratio (OR) estimate and 95% confidence interval (CI). Multivariate logistic regression analysis was performed to identify significant predictors of exercise engagement. RESULTS: A total of 631 PCPs participated in the survey--26% were ≤ 34 years old, 58% were male, 21% were single, 34% were singleton practitioners, and 56% were private practitioners. The percentage of PCPs who exercised ≥ 2.5 hours weekly was 29%, while 28% exercised < 0.5 hours weekly. Of the PCPs surveyed, 1% currently smoke, 0.8% drink more than 14 units of alcohol weekly, 60% undertook health screening, 65% had blood investigations done, and 64% had taken preventive measures such as getting influenza vaccination. CONCLUSION: While local PCPs generally did not have undesirable habits such as smoking and alcohol abuse, they could further increase their exercise intensity and undertake more preventive measures such as getting vaccinated against various diseases.

An elevated pro-inflammatory cytokine response is linked to development of amphotericin B-induced nephrotoxicity.

OBJECTIVES: The underlying mechanism for amphotericin B-induced acute kidney injury (AKI) remains poorly understood and may be immunologically mediated. We assessed whether the development of nephrotoxicity is linked to a distinct cytokine profile in patients receiving amphotericin B deoxycholate (AmBD). PATIENTS AND METHODS: In 58 patients who received AmBD, circulating serum interleukin (IL)-6, IL-8 and IL-10 were measured at baseline, week 1 and week 2 of antifungal treatment and correlated to the development of renal impairment. The Cox proportional hazards model approach was adopted for analysis. RESULTS: The P value was 0.026 for the overall effect of IL-6 on time to development of AKI. An increasing or non-receding IL-6 trend by week 1 of AmBD treatment (followed by a decreasing or non-receding IL-6 trend from week 1 to week 2) correlated with an increased likelihood of nephrotoxicity [hazard ratio (HR) 6.93, P value 0.005 and HR 3.46, P value 0.035, respectively]. Similarly, persistently increasing IL-8 levels were linked to a 3.84-fold increased likelihood of AKI. CONCLUSIONS: In patients receiving AmBD, persistence of an elevated pro-inflammatory cytokine milieu is associated with a predisposition to drug-related kidney injury.

Interest and attitudes of patients, cancer physicians, medical students and cancer researchers towards a spectrum of genetic tests relevant to breast cancer patients.

The perspectives of patients and healthcare professionals towards breast cancer genetic tests that are becoming increasingly available is unexplored in Asians. We surveyed the interest and attitudes of 200 breast cancer patients, 67 cancer physicians, 485 medical students and cancer researchers towards three genetic tests, BRCA1/2 mutation, CYP2D6 genotype and Oncotype DX testing, using hypothetical scenarios. Approximately 60% of patients expressed initial interest in each genetic test, although the majority reversed their decisions once test limitations were conveyed, with <15% maintaining interest in each test. Cancer physicians were most likely to recommend BRCA1/2 mutation testing (73%) and least likely to recommend CYP2D6 genotyping (12%), while patients were more likely to choose Oncotype DX testing (28%) over CYP2D6 (21%) and BRCA1/2 testing (15%). Cost concerns, low educational level and lack of prior awareness of genetic testing were the main barriers against breast cancer genetic testing among Asian patients.

Does the axillary lymph node ratio have any added prognostic value over pN staging for South East Asian breast cancer patients?

INTRODUCTION: Lymph node ratio (LNR, i.e. the ratio of the number of positive nodes to the total number of nodes excised) is reported to be superior to the absolute number of nodes involved (pN stage) in classifying patients at high versus low risk of death following breast cancer. The added prognostic value of LNR over pN in addition to other prognostic factors has never been assessed. METHODS: All patients diagnosed with lymph node positive, non-metastatic invasive breast cancer at the National University Hospital (Singapore) and University of Malaya Medical Center (Kuala Lumpur) between 1990-2007 were included (n = 1589). Overall survival of the patients was estimated by the Kaplan Meier method for LNR [categorized as low (>0 and <0.2), intermediate (0.2-0.65) and high (>0.65-1)] and pN staging [pN1, pN2 and pN3]. Adjusted overall relative mortality risks associated with LNR and pN were calculated by Cox regression. The added prognostic value of LNR over pN was evaluated by comparing the discriminating capacity (as indicated by the c statistic) of two multivariate models, one including pN and one including LNR. RESULTS: LNR was superior to pN in categorizing mortality risks for women ≥60 years, those with ER negative or grade 3 tumors. In combination with other factors (i.e. age, treatment, grade, tumor size and receptor status), substituting pN by LNR did not result in better discrimination of women at high versus low risk of death, neither for the entire cohort (c statistic 0.72 [0.70-0.75] and 0.73 [0.71-0.76] respectively for pN versus LNR), nor for the subgroups mentioned above. CONCLUSION: In combination with other prognosticators, substitution of pN by LNR did not provide any added prognostic value for South East Asian breast cancer patients.

The feasibility and accuracy of sentinel lymph node biopsy in clinically node-negative patients after neoadjuvant chemotherapy for breast cancer--a systematic review and meta-analysis.

The sentinel lymph node biopsy (SLNB) is now an accepted alternative to the axillary lymph node dissection for pathologic evaluation of the axilla in patients with early breast cancer. The use of SLNB after neoadjuvant chemotherapy (NAC) is controversial. This meta-analysis aims to determine the feasibility and the accuracy of SLNB in the population of patients who are clinically node-negative after NAC for breast cancer.

Plasma free hemoglobin: a novel diagnostic test for assessment of the depth of burn injury.

BACKGROUND: Accurate determination of the depth of burn injury is difficult, even for experienced surgeons. The authors hypothesized that the level of plasma free hemoglobin following burn injury is correlated to the depth of burn injury, and they evaluated this hypothesis in a murine model. METHODS: Full-thickness and partial-thickness burn injuries of varying sizes were inflicted on 38 and 36 male Wistar rats, respectively. Blood specimens were taken at 0, 15, 30, 45, and 60 minutes after burn injury, and the levels of plasma free hemoglobin were determined spectrophotometrically. RESULTS: Full-thickness burns cause two times more hemolysis than partial-thickness burns (p < 0.05). A linear correlation was demonstrated between plasma free hemoglobin levels and total body surface area burned in both the full-thickness (r = 0.91, p < 0.001) and partial-thickness burn groups (r = 0.94, p < 0.001). The correlation between the quantity of hemolysis and the total body surface area burned was strongest at 15 minutes after the onset of burn injury. The levels of free hemoglobin peaked rapidly between 15 and 30 minutes after thermal injury and declined thereafter. CONCLUSIONS: The authors' data suggest that the level of plasma free hemoglobin after burn injury is related to the size and depth of burn injury. This test can potentially be a valuable diagnostic adjunct in the assessment of burns.

Prognostic significance of peritoneal lavage cytology in gastric cancer in Singapore.

BACKGROUND: Peritoneal lavage cytology has been included as part of the staging process in the 13th edition of the Japanese Classification of Gastric Cancer. However, this procedure has neither been studied nor established in our population. We aimed to evaluate its prognostic relevance among our patients with gastric cancer. METHODS: A total of 142 consecutive patients with gastric carcinoma were recruited prospectively. All had histologically proven gastric carcinomas and had undergone laparotomy and intraoperative peritoneal lavage for cytological examination at Singapore General Hospital. The fluid recovered was centrifuged and stained by the Papanicolau method. All patients were followed up with endpoints of cancer recurrence and mortality. RESULTS: There were 91 men and 51 women; 36 patients (25.4%) had positive peritoneal lavage. Patients with advanced macroscopic features, presence of vascular invasion, nodal involvement, advanced depth of tumor invasion and metastatic disease tended to have positive lavage, by univariate logistic regression analysis. Despite curative resections, patients with positive cytology had a more dismal disease-free survival (mean, 27 months vs 53 months; P < 0.0001 by log rank test) and higher recurrence rate (54.5% vs 19.3%; P = 0.007 by log rank test). There was also a trend towards earlier recurrences (median, 8 months vs 11 months; P = 0.37). By multivariate Cox regression stepwise analysis, advanced depth of tumor invasion and positive lavage cytology were found to be independent poor prognostic factors for disease-free survival. CONCLUSION: Positive peritoneal lavage cytology correlated well with advanced features of gastric cancer. It is an independent poor prognostic factor and the procedure should be routinely performed. Integration of lavage status into our current staging systems may serve as a guide for adjuvant therapeutic options to improve the survival of gastric cancer in our population.

The age of menopause and the menopause transition in a multiracial population: a nation-wide Singapore study.

OBJECTIVE: To describe the prevalence of menopausal symptoms, define the mean age of menopause, and determine contributory factors, which influence the experience of symptoms among Singaporean women of different racial groups. DESIGN: Cross-sectional nation-wide study of a random sample of 1000 women drawn from the entire population of Singaporean female (Chinese, Malay, and Indian) citizens between 45 and 60 years of age. Face-to-face interviews using structured questionnaires were conducted. RESULTS: The response rate was 69.9%. The mean age of natural menopause was 49.0 years. This was not significantly different between the three ethnic groups. Increasing parity delayed the age of menopause (P=0.007). Muscle and joint ache was the most commonly reported symptom (52.6%). Although the prevalence of significant hot flushes in the general study population was low (3.9%), it was the most commonly reported complaint by peri-menopausal women (14.6%). Prevalence of significant hot flushes decreased with time from menopause (P=0.007) and completely disappeared beyond the fifth year of menopause. Recent unhappy events were associated with an increased risk of symptoms (P<0.001). Women of Chinese origin experienced a lower risk of menopausal symptoms when compared with other ethnic groups (P<0.05). CONCLUSION: The mean age of menopause was 49.0 years among Singaporean women. Ethnicity and recent unhappy events were two major factors, which influenced the risk of experiencing menopausal symptoms. Among the three ethnic groups studied, Chinese women were the least likely to experience disturbing menopausal symptoms. The overall prevalence of menopausal symptoms was low when compared to studies on women in western societies.

Postoperative endocrine function in patients with surgically treated thyrotoxicosis.

BACKGROUND: Endocrine function after surgery for thyrotoxicosis is difficult to predict. The operative morbidity and long-term thyroid function of patients surgically treated for thyrotoxicosis is presented, and factors postulated to affect long-term function are correlated with outcome. METHODS: The clinical records of 289 consecutive patients who underwent surgery for thyrotoxicosis were reviewed. Indications for surgery, intraoperative findings, postoperative complications, and endocrine status 1, 2, and 5 years after surgery were analyzed. Sex, age, duration of medical treatment, weight of thyroid removed and preserved, and antimicrosomal/antithyroglobulin antibody status were correlated with outcome 5 years after surgery. RESULTS: The incidence of permanent recurrent laryngeal nerve injury and hypocalcemia were 0.7% and 1.7%. The cumulative hypothyroid and hyperthyroid rates for the first, second, and fifth postoperative years were 13.8% and 3.5%, 14.5% and 4.8%, and 15.6% and 8.0%. All the prognostic variables analyzed did not achieve a significant correlation with outcome at 5 years by univariate and multivariate age- and sex-adjusted relative risk. CONCLUSIONS: Failure from hypothyroidism develops early; recurrent hyperthyroidism increases with the number of years of follow-up. Patients undergoing subtotal thyroidectomy warrant long-term follow-up because of the inability to accurately predict postoperative function with consistently reliable prognostic factors.

Knee dislocations-a retrospective study comparing operative versus closed immobilization treatment outcomes.

Controversies over operative versus closed immobilization of traumatic complex multiple ligamentous knee injury are still debated. The aim of our study is to evaluate the outcome of reconstructive vs non-reconstructive (closed immobilization) treatment outcomes. This is a retrospective review of cases seen at our institution. All cases admitted with a diagnosis of knee dislocation, defined as patients with multidirectional knee instability in the setting of trauma, were reviewed. Twenty-nine consecutive patients from January of 1996 to June of 2002 were reviewed. Twenty-six patients (89.7%) were successfully recalled and their functional outcome analyzed. Comparing the operated group (n=15, 57.7%) with closed immobilized patients (n=11, 42.3%), there was no statistical difference in the range of motion (mean difference 8.55 degrees , p=0.202). While the operated group had more flexion contracture (mean difference 3.9 degrees , p=0.002), they had better stability and better overall knee function as measured by the International Knee Documentation Committee (IKDC) score (the mean difference of IKDC score was 12.13, p=0.005). In the operated group of 15 patients, we compared partial repair (n=7) with complete repair of all torn ligaments (n=8). Superior results were noted in the group with complete repair of all structures, with comparable range of motion (mean difference 0.6 degrees , p=0.861) and flexion contractures (mean difference 1.0 degrees , p=0.795) but better stability and IKDC score (mean difference of IKDC score 13.6, p=0.003). Our conclusion is that operative treatment with complete repair of all torn structures produces the best overall knee function with better knee stability and patient satisfaction.

Clinical, biochemical and pathological features of initial and repeat transrectal ultrasonography prostate biopsy positive patients.

BACKGROUND: Using sextant biopsy, 16-41% of prostate cancers were diagnosed on repeat biopsy. The objective of the present study was to compare the differences in the clinical, biochemical and pathological features between patients with positive results on initial and repeat biopsies, with an aim to identify factors that can be used to improve the detection rate of transrectal ultrasound (TRUS) biopsy of the prostate. METHODS: Between February 2000 and April 2001, 222 patients with a mean age of 64 years (range 38-85) underwent TRUS-guided 10-core prostate biopsy for either abnormal prostate specific antigen (PSA) levels (>4 ng/mL) and/or abnormal digital rectal examination (DRE). Of this number, 165 patients underwent their first biopsy, whereas 45 and 12 patients had had one or two previous biopsies, respectively. RESULTS: Prostate cancer detection rates for the initial biopsy group (n = 165), second biopsy group (n = 45) and third biopsy group (n = 12) were 29.7, 23.0 and 41.7%, respectively. Six patients who had a negative first 10-core biopsy underwent a second 10-core biopsy and one patient (16%) was found to have cancer. Apart from total prostate volume, there were no significant statistical differences between the patient age, mean total PSA, PSA density, PSA-transition zone density, DRE and TRUS findings between the initial and repeat biopsy groups of subjects who had cancer. Those who had cancer detected only on repeat biopsies had larger prostate glands (P = 0.041). CONCLUSION: Patients who had cancer detected only on repeat biopsies had bigger prostate glands, supporting the hypothesis that TRUS sextant biopsy as a technique suffers the error of under-sampling in a bigger prostate.

Posterior perforation of peptic ulcers: presentation and outcome of an uncommon surgical emergency.

BACKGROUND: Posterior perforation of peptic ulcer is a distinct clinical entity not commonly encountered. This report evaluates the presentation, diagnosis, management, and outcome of this acute surgical condition. METHODS: We reviewed records of 9 patients with posterior perforations who were treated at our institution from January 1990 to June 2002. RESULTS: This condition was characterized by insidious onset of upper abdominal pain and delayed presentation. Abdominal examinations were equivocal in 7 patients on admission. Pneumoperitoneum on chest roentgenogram, when present, was a crucial diagnostic indicator of intra-abdominal pathology. The diagnosis was made intraoperatively in all cases; findings were sealed perforation, localized retroperitoneal abscess, or generalized contamination of the lesser sac and peritoneal cavity. Observed adverse operative risk factors included prolonged perforation (>24 hours), pre-existing chronic medical illnesses, and preoperative hypotension. In addition, significant peritoneal contamination at celiotomy, major resection (gastrectomy), and gastric perforations were noted to be associated with a poor outcome: 4 of the 9 patients died. CONCLUSION: A high index of suspicion is important. When a retroperitoneal collection is noted at celiotomy, posterior perforation of peptic ulcer should be actively excluded.

Necrotizing fasciitis: clinical presentation, microbiology, and determinants of mortality.

BACKGROUND: Necrotizing fasciitis is a life-threatening soft-tissue infection primarily involving the superficial fascia. The present report describes the clinical presentation and microbiological characteristics of this condition as well as the determinants of mortality associated with this uncommon surgical emergency. METHODS: The medical records of eighty-nine consecutive patients who had been admitted to our institution for necrotizing fasciitis from January 1997 to August 2002 were reviewed retrospectively. RESULTS: The paucity of cutaneous findings early in the course of the disease makes the diagnosis difficult, and only thirteen of the eighty-nine patients had a diagnosis of necrotizing fasciitis at the time of admission. Preadmission treatment with antibiotics modified the initial clinical picture and often masked the severity of the underlying infection. Polymicrobial synergistic infection was the most common cause (forty-eight patients; 53.9%), with streptococci and enterobacteriaceae being the most common isolates. Group-A streptococcus was the most common cause of monomicrobial necrotizing fasciitis. The most common associated comorbidity was diabetes mellitus (sixty-three patients; 70.8%). Advanced age, two or more associated comorbidities, and a delay in surgery of more than twenty-four hours adversely affected the outcome. Multivariate analysis showed that only a delay in surgery of more than twenty-four hours was correlated with increased mortality (p < 0.05; relative risk = 9.4). CONCLUSIONS: Early operative débridement was demonstrated to reduce mortality among patients with this condition. A high index of suspicion is important in view of the paucity of specific cutaneous findings early in the course of the disease.

Parotid gland surgery: 4-year review of 118 cases in an Asian population.

BACKGROUND: To determine the presentation and management of parotid lesions requiring excision in a largely Chinese Asian population. METHODS: Retrospective study of 118 consecutive parotidectomies. RESULTS: Thirty-seven percent were Warthin's tumor (WT), 33% pleomorphic adenoma (PA), 21% other benign disease (OBD), and 9% malignant tumor (MT). Mean age was significantly different between benign (51 years) and malignant (40 years) lesions. MT decreased above 50 years, but increased five times with pain and two times with a noninferior pole lesion. Sensitivity of fine-needle aspiration (FNA) for differentiating benign from MT = 78%, for WT =5 8%, for PA =82%, for OBD = 28%, and for MT = 38%. CT scans did not alter WT management. Facial nerve (FN) paresis was not associated with histology, tumor size, site, or parotidectomy type. CONCLUSIONS: This is the first report documenting that most benign parotid tumors are WT and not PA. MT risk is greater in those less than 50 with pain and a noninferior pole lesion. Cystic lesions such as WT require great care in the evaluation of FNA findings.