Management of overactive bladder: consensus statements from the Hong Kong Urological Association and the Hong Kong Geriatrics Society.

Overactive bladder (OAB) is a common urological disease with a high prevalence in older adult populations. Antimuscarinic drugs have been the most common treatment for OAB for more than a decade, but their anticholinergic side-effects and potential impact on cognitive function among older patients are usually underestimated. This consensus aimed to provide practical recommendations concerning OAB management, with a particular emphasis on older patients. A joint consensus panel was formed by representatives of the Hong Kong Urological Association and the Hong Kong Geriatrics Society. Literature searches regarding OAB and its management were performed in PubMed and Ovid. Several working meetings were held to present and discuss available evidence, develop consensus statements, and vote for the statements. A modified Delphi method was used in this consensus process. To address questions regarding various aspects of OAB, 29 consensus statements were proposed covering the following areas: diagnosis, initial assessment, non-pharmacological treatments, considerations before administration of pharmacological treatments, various pharmacological treatments, combination therapy, and surgical treatment. Twenty-five consensus statements were accepted.

Glycaemic control and microvascular complications among paediatric type 2 diabetes mellitus patients in Hong Kong at 2 years after diagnosis.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is becoming increasingly common among children and adolescents worldwide, including those in Hong Kong. This study analysed the characteristics and prevalence of microvascular complications among paediatric T2DM patients in Hong Kong at diagnosis and 2 years after diagnosis. METHODS: All patients aged <18 years who had been diagnosed with DM at public hospitals in Hong Kong were recruited into the Hong Kong Childhood Diabetes Registry. Data collected at diagnosis and 2 years after diagnosis were retrospectively retrieved from the Registry for patients diagnosed from 2014 to 2018. RESULTS: Median haemoglobin A1c (HbA1c) levels were 7.5% (n=203) at diagnosis and 6.5% (n=135) 2 years after diagnosis; 59.3% of patients achieved optimal glycaemic control (HbA1c level <7%) at 2 years. A higher HbA1c level at diagnosis was associated with worse glycaemic control at 2 years (correlation coefficient=0.39; P<0.001). The presence of dyslipidaemia (adjusted odds ratio [aOR]=3.19; P=0.033) and fatty liver (aOR=2.50; P=0.021) at 2 years were associated with suboptimal glycaemic control. Diabetic neuropathy and retinopathy were rare in our cohort, but 18.6% of patients developed microalbuminuria (MA) within 2 years after diagnosis. Patients with MA had a higher HbA1c level at 2 years (median: 7.2% vs 6.4%; P=0.037). Hypertension was a risk factor for MA at 2 years, independent of glycaemic control (aOR=4.61; P=0.008). CONCLUSION: These results highlight the importance of early diagnosis and holistic management (including co-morbidity management) for paediatric T2DM patients.

Preoperative considerations and benefits of neoadjuvant chemotherapy: insights from a 12-year review of the Hong Kong Breast Cancer Registry.

INTRODUCTION: Neoadjuvant chemotherapy (NAC) was initially used for locally advanced or inoperable breast cancers. Its extension to early disease has facilitated breast-conserving surgery (BCS). This study investigated the use of NAC in patients registered with the Hong Kong Breast Cancer Registry (HKBCR); it also assessed NAC effectiveness according to rates of pathological complete response (pCR) and BCS. METHODS: Records were retrieved from the HKBCR regarding 13 435 women who had been diagnosed with invasive breast cancer during the period of 2006 to 2017, including 1084 patients who received NAC. RESULTS: The proportion of patients treated with NAC nearly doubled from 5.6% in 2006-2011 to 10.3% in 2012-2017. The increase was most pronounced among patients with stage II or III disease. In terms of biological subtype, substantial increases in the receipt of NAC were evident among patients with triple-negative and human epidermal growth factor receptor 2 (HER2)-positive (non-luminal) tumours. The best rates of pCR were observed in patients with HER2-positive (non-luminal) [46.0%] tumours, followed by patients with luminal B (HER2-positive) [29.4%] and triple-negative (29.3%) tumours. After NAC, the rate of BCS was 53.9% in patients with clinical stage IIA disease, compared with 38.2% in patients with pathological stage IIA disease who did not receive NAC. CONCLUSION: The use of NAC in Hong Kong increased from 2006 to 2017. The findings regarding rates of pCR and BCS indicate that NAC is an effective treatment; it should be considered in patients with stage ≥II disease, as well as patients with HER2- positive (non-luminal) or triple-negative breast cancers.

Guidance on the management of familial hypercholesterolaemia in Hong Kong: an expert panel consensus viewpoin.

In 2016, meetings of groups of physicians and paediatricians with a special interest in lipid disorders and familial hypercholesterolaemia were held to discuss several domains of management of familial hypercholesterolaemia in adults and children in Hong Kong. After reviewing the evidence and guidelines for the diagnosis, screening, and management of familial hypercholesterolaemia, consensus was reached on the following aspects: clinical features, diagnostic criteria, screening in adults, screening in children, management in relation to target plasma low-density lipoprotein cholesterol levels, detection of atherosclerosis, lifestyle and behaviour modification, and pharmacotherapy.

Neoadjuvant chemotherapy increases rates of breast-conserving surgery in early operable breast cancer.

INTRODUCTION: Neoadjuvant chemotherapy is commonly used in stage III breast cancer for disease down-staging. Its use has now been extended to early breast cancer to increase the rate of breast-conserving surgery. This study aimed to evaluate the effectiveness of neoadjuvant chemotherapy in early operable cancers. METHODS: A retrospective study was carried out at the Hong Kong Sanatorium & Hospital of 102 patients with stage I to III primary breast cancer. All patients who underwent neoadjuvant chemotherapy followed by definitive breast surgery between January 2004 and July 2013 were included. Their pathological complete response and rate of breast-conserving surgery were studied. Data were compared using Chi squared test and Student's t test. RESULTS: After neoadjuvant chemotherapy, 23% of patients achieved a pathological complete response, of whom 80% had human epidermal growth factor receptor 2 (HER2)-positive disease or triple-negative disease. Hormonal receptor negativity was associated with a higher pathological complete response rate (P<0.05) that was in turn associated with a higher likelihood of breast-conserving surgery (P=0.028). Patients with stage II disease were more likely to convert from mastectomy to breast-conserving surgery following neoadjuvant chemotherapy. CONCLUSIONS: Neoadjuvant chemotherapy is a useful treatment to downsize tumour in early breast cancer, thereby increasing the rate of breast-conserving surgery. It is especially effective in patients with HER2-positive/oestrogen receptor-negative disease or triple-negative disease.

Ductal carcinoma in situ of breast: detection and treatment pattern in Hong Kong.

INTRODUCTION: The treatment of ductal carcinoma in situ has been widely reported in the western and other Asian countries, but the relevant data in Hong Kong are relatively limited. This study aimed to evaluate the latest detection and treatment pattern for ductal carcinoma in situ in Hong Kong so as to guide planning of future service provision. METHODS: This was a retrospective case series study. A total of 573 patients who registered with the Hong Kong Breast Cancer Registry, and were diagnosed and treated in Hong Kong from January 2001 to December 2011 were reviewed. RESULTS: Compared with invasive breast cancer patients, patients with ductal carcinoma in situ were younger (median, 48.6 vs 50.3 years; P<0.001), had a higher education level (P<0.001), had a higher total monthly family income (P<0.001), and more common breast-screening habits (P<0.001). Significantly more patients with ductal carcinoma in situ underwent breast-conserving surgery than their invasive cancer counterparts (55.8% vs 36.7%; P<0.001). The percentage of screen-detected ductal carcinoma in situ was relatively lower than that reported in other studies, but was still much higher than that in invasive breast cancer patients (29.0% vs 4.7%; P<0.001). Screen-detected patients with ductal carcinoma in situ tended to choose a private hospital instead of a public hospital for treatment (P=0.05) and to undergo breast-conserving surgery (P=0.02). With a median follow-up of 3 years, the crude local recurrence rate after mastectomy and breast-conserving surgery was 0.4% and 3.3%, respectively; 44% of recurrent tumours had developed invasive components. No regional recurrence, distant recurrence, or cancer-related deaths were recorded. CONCLUSIONS: In the absence of a population-based breast screening programme in Hong Kong, ductal carcinoma in situ is more frequently found in the higher social classes and managed in the private sector. The clinical outcome of ductal carcinoma in situ is excellent and more than half of the patients can be successfully managed with breast-conserving surgery.

Factors associated with multidisciplinary case conference outcomes in children admitted to a regional hospital in Hong Kong with suspected child abuse: a retrospective case series with internal comparison.

INTRODUCTION: In all cases of suspected child abuse, accurate risk assessment is vital to guide further management. This study examined the relationship between risk factors in a risk assessment matrix and child abuse case conference outcomes. METHODS: Records of all children hospitalised at United Christian Hospital in Hong Kong for suspected child abuse from January 2012 to December 2014 were reviewed. Outcomes of the hospital abuse work-up as concluded in the Multi-Disciplinary Case Conference were categorised as 'established', 'high risk', or 'not established'. All cases of 'established' and 'high risk' were included in the positive case conference outcome group and all cases of 'not established' formed the comparison group. On the other hand, using the Risk Assessment Matrix developed by the California State University, Fresno in 1990, each case was allotted a matrix score of low, intermediate, or high risk in each of 15 matrix domains, and an aggregate matrix score was derived. The effect of individual matrix domain on case conference outcome was analysed. Receiver operating characteristic curve analysis was used to examine the relationship between case conference outcome and aggregate matrix score. RESULTS: In this study, 265 children suspected of being abused were included, with 198 in the positive case conference outcome group and 67 in the comparison group. Three matrix domains (severity and frequency of abuse, location of injuries, and strength of family support systems) were significantly associated with case conference outcome. An aggregate cut-off score of 23 yielded a sensitivity of 91.4% and specificity of 38.2% in relation to outcome of abuse categorisation. CONCLUSIONS: Risk assessment should be performed when handling suspected child abuse cases. A high aggregate score should arouse suspicion in all disciplines managing child abuse cases.

Current management of pregnancy-associated breast cancer.

Pregnancy-associated breast cancer is the most common malignancy during pregnancy with an expected rise in incidence. The belief in the need for termination of pregnancy and that chemotherapy is contra-indicated during pregnancy is challenged by recent evidence. Patients can consider breast-conserving surgery and sentinel lymph node biopsy with acceptably low fetal risk from radiation exposure. A range of chemotherapeutics is possible in the second trimester in terms of drug class and frequency. Hormonal therapy and monoclonal antibody therapy are contra-indicated during pregnancy and lactation. Fetal outcome after in-utero exposure to chemotherapy appears similar to that in a non-pregnant population. Future pregnancy, in most situations, does not appear to be contra-indicated but a multidisciplinary and patient-centred approach is recommended. Fertility preservation techniques are also being developed with reported success and consequent pregnancies.

Is pain from mammography reduced by the use of a radiolucent MammoPad? Local experience in Hong Kong.

INTRODUCTION: Screening mammogram can decrease the mortality of breast cancer. Studies show that women avoid mammogram because of fear of pain, diagnosis, and radiation. This study aimed to evaluate the effectiveness of a radiolucent pad (MammoPad; Hologic Inc, Bedford [MA], US) during screening mammogram to reduce pain in Chinese patients and the possibility of glandular dose reduction. METHODS: This case series was conducted in a private hospital in Hong Kong. Between November 2011 and January 2012, a total of 100 Chinese patients were recruited to our study. Left mammogram was performed without MammoPad and served as a control. Right mammogram was performed with the radiolucent MammoPad. All patients were then requested to complete a simple questionnaire. The degree of pain and discomfort was rated on a 0-10 numeric analogue scale. Significant reduction in discomfort was defined as a decrease of 10% or more. RESULTS: Of the 100 patients enrolled in this study, 66.3% of women reported at least a 10% reduction in the level of discomfort with the use of MammoPad. No statistical differences between age, breast size, and the level of discomfort were found. CONCLUSION: The use of MammoPad significantly reduced the level of discomfort experienced during mammography. Radiation dose was also reduced.

Comparison of clinical and pathological characteristics between screen-detected and self-detected breast cancers: a Hong Kong study.

INTRODUCTION: Breast cancer is the leading cause of death of Hong Kong women with increasing incidence. This study aimed to determine any prognostic differences between screen-detected and self-detected cases of breast cancer in a cohort of Hong Kong patients. METHODS: This was a case series with internal comparison carried out in a private hospital in Hong Kong. Approximately 3000 cases of Chinese patients diagnosed with ductal carcinoma in situ or invasive breast cancer were reviewed. RESULTS: The screen-detected group showed better pathological characteristics than the self-detected group. Number of lymph nodes involved, invasive tumour size, and tumour grade were more favourable in the screen-detected group. There was also a lower proportion of patients with pure invasive ductal carcinoma and mastectomy in the screen-detected group. CONCLUSION: This study provides indirect evidence that women in the local population may gain clinical benefit from regular breast cancer screening. The findings need to be validated in a representative population of Hong Kong women.

Canadian consensus: inhibition of ALK-positive tumours in advanced non-small-cell lung cancer.

Anaplastic lymphoma kinase (alk) is an oncogenic driver in non-small-cell lung cancer (nsclc). Chromosomal rearrangements involving the ALK gene occur in up to 4% of nonsquamous nsclc patients and lead to constitutive activation of the alk signalling pathway. ALK-positive nsclc is found in relatively young patients, with a median age of 50 years. Patients frequently have brain metastasis. Targeted inhibition of the alk pathway prolongs progression-free survival in patients with ALK-positive advanced nsclc. The results of several recent clinical trials confirm the efficacy and safety benefit of crizotinib and ceritinib in this population. Canadian oncologists support the following consensus statement: All patients with advanced nonsquamous nsclc (excluding pure neuroendocrine carcinoma) should be tested for the presence of an ALK rearrangement. If an ALK rearrangement is present, treatment with a targeted alk inhibitor in the first-line setting is recommended. As patients become resistant to first-generation alk inhibitors, other treatments, including second-generation alk inhibitors can be considered.

Complications following surgery with or without radiotherapy or radiotherapy alone for prostate cancer.

BACKGROUND: Men undergoing treatment of clinically localised prostate cancer may experience a number of treatment-related complications, which affect their quality of life. METHODS: On the basis of population-based retrospective cohort of men undergoing surgery, with or without subsequent radiotherapy, or radiotherapy alone for prostate cancer in Ontario, Canada, we measured the incidence of treatment-related complications using administrative and billing data. RESULTS: Of 36 984 patients, 15 870 (42.9%) underwent surgery alone, 4519 (12.2%) underwent surgery followed by radiotherapy, and 16 595 (44.9%) underwent radiotherapy alone. For all end points except urologic procedures, the 5-year cumulative incidence rates were lowest in the surgery only group and highest in the radiotherapy only group. Intermediary rates were seen in the surgery followed by radiotherapy group, except for urologic procedures where rates were the highest in this group. Although age and comorbidity were important predictors, radiotherapy as the primary treatment modality was associated with higher rates for all complications (adjusted hazard ratios 1.6-4.7, P=0.002 to <0.0001). CONCLUSIONS: In patients treated for prostate cancer, radiation after surgery increases the rate of complications compared with surgery alone, though these rates remain lower than patients treated with radiation alone. This information may inform patient and physician decision making in the treatment of prostate cancer.

Screening for dysglycaemia by oral glucose tolerance test should be recommended in all women with polycystic ovary syndrome.

STUDY QUESTION: Should fasting glucose (FG) or an oral glucose tolerance test (OGTT) be used to screen for dysglycaemia in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: A full OGTT should be recommended as the screening method for dysglycaemia in women with PCOS, regardless of BMI or family history of diabetes mellitus (DM). STUDY DESIGN, SIZE, DURATION: A cross-sectional study on 467 Chinese women diagnosed with PCOS by the Rotterdam criteria between January 2010 to December 2013. PARTICIPANTS, SETTING, METHODS: The study was done at a university hospital in Hong Kong. All subjects underwent a 75 g OGTT after overnight fasting. We evaluated the performance of FG alone, when compared with the full OGTT, in identifying subjects with dysglycaemia (prediabetes or DM, according to the 2010 diagnostic criteria of the American Diabetes Association). MAIN RESULTS AND THE ROLE OF CHANCE: Of the 467 subjects, 58 (12.4%) had dysglycaemia, among which 46 (9.8%) had prediabetes and 12 (2.6%) had DM, including 4 with known DM. Of the 46 subjects with prediabetes, 25 (54.3%) had normal FG and of the 8 subjects with screened DM in this study, 1 (12.5%) had normal FG. The sensitivity of FG alone in screening for prediabetes, DM and overall dysglycaemia were 45.7, 87.5 and 48.1%, respectively, i.e. missing 54.3% of prediabetes and 12.5% of DM cases as defined by the OGTT. Among the 54 subjects with screened dysglycaemia, 20 (37.0%) had BMI < 25 kg/m(2) and 35 (64.8%) had no family history of DM. LIMITATIONS, REASONS FOR CAUTION: We only reported on the biochemical diagnosis of DM based on a single time point. In clinical practice, confirmatory results at another time point is required for definitive diagnosis in asymptomatic subjects. WIDER IMPLICATIONS OF THE FINDINGS: There is an ongoing debate as to whether FG or an OGTT should be used as a screening method for dysglycaemia in women with PCOS. Some guidelines also recommend glucose screening only in those who are overweight and/or having family history of diabetes (DM). There have been scarce data on this issue in the Chinese population, which the current study aims at addressing. STUDY FUNDING/COMPETING INTERESTS: The study was supported by a research grant from the Hong Kong Obstetrical and Gynaecological Trust Fund, as well as internal research funding of the Department of Obstetrics and Gynaecology, The University of Hong Kong. All authors have no competing interests.

Active disease is independently associated with more severe anxiety rather than depressive symptoms in patients with systemic lupus erythematosus.

OBJECTIVE: The inter-correlation between and co-existence of depression and anxiety may engender inconsistency in addressing the relationship between the severity of depression and disease activity of systemic lupus erythematosus (SLE). We aimed at identifying whether lupus disease activity is independently associated with depression and anxiety in lupus patients. METHODS: Adult lupus patients were assessed for the severity of depressive and anxiety symptoms and lupus disease activity by using the Hospital Anxiety and Depression Scale (HADS) and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), respectively. Age- and gender-matched healthy controls (HCs) were recruited for comparison. Prevalence and severity of depressive and anxiety symptoms were compared between lupus patients and HCs. Independent relationships between the severity of anxiety (HADS-Anxiety) and depressive (HADS-Depression) symptoms, and SLEDAI were studied with regression models. RESULTS: In total, 110 lupus patients and 110 HCs were studied. Lupus patients had significantly higher HADS scores than HCs (10.82 ± 6.5 vs. 7.34 ± 4.9, p < 0.001). Significantly more lupus patients had anxiety (40.9 vs. 21.8%, p = 0.002) and depressive symptoms (15.5 vs. 6.4%, p = 0.025) than HCs. Multiple linear regression analyses revealed that SLEDAI (ß = 0.160, p = 0.016), calcineurin inhibitor non-use (ß = -1.929, p = 0.041) and past cyclophosphamide non-use (ß = -1.603, p = 0.039) independently predicted HADS-Anxiety amongst lupus patients even after adjusting for HADS-Depression. Conversely, SLEDAI (ß = 0.014, p = 0.834) lost its significant univariate correlation with HADS-Depression after controlling for HADS-Anxiety and other covariates. CONCLUSION: Anxiety is more common in lupus patients than in HCs, and its severity is independently associated with more active SLE regardless of the presence or absence of concomitant depression.

Improving outcomes in breast cancer for low and middle income countries.

Breast cancer is the most common cancer in women world-wide. Incidence rates in low- and middle-income countries (LMICs) are lower than in high income countries; however, the rates are increasing very rapidly in LMICs due to social changes that increase the risk of breast cancer. Breast cancer mortality rates in LMICs remain high due to late presentation and inadequate access to optimal care. Breast Surgery International brought together a group of breast surgeons from different parts of the world to address strategies for improving outcomes in breast cancer for LMICs at a symposium during International Surgical Week in Helsinki, Finland in August 2013. A key strategy for early detection is public health education and breast awareness. Sociocultural barriers to early detection and treatment need to be addressed. Optimal management of breast cancer requires a multidisciplinary team. Surgical treatment is often the only modality of treatment available in low-resource settings where modified radical mastectomy is the most common operation performed. Chemotherapy and radiotherapy require more resources. Endocrine therapy is available but requires accurate assessment of estrogen receptors status. Targeted therapy with trastuzumab is generally unavailable due to cost. The Breast Health Global Initiative guidelines for the early detection and appropriate treatment of breast cancer in LMICs have been specifically designed to improve breast cancer outcomes in these regions. Closing the cancer divide between rich and poor countries is a moral imperative and there is an urgent need to prevent breast cancer deaths with early detection and optimal access to treatment.

An integrative review of experiences of patients with rheumatoid arthritis.

AIM: To provide an overview of evidence on the experiences and needs of adults living with rheumatoid arthritis (RA). BACKGROUND: Many research have studied the impact of RA on one's quality of life, but no reviews have examined the overall experiences of patients living with RA. METHODS: An integrative review was performed to synthesize the experiences and/or needs of adult patients with RA based on articles retrieved from databases of CINAHL, Scopus, PubMed, PsycINFO and Web of Science, and published between January 2003 and March 2014 in English. RESULTS: A total of 38 studies were reviewed. RA has adverse effects on patients' quality of life due to its negative impacts in their physical and psychosocial aspects of health. Patients with RA cope with these impacts using various methods and are frequent users of healthcare services. However, few studies have evaluated patients' further needs in coping or the effectiveness of their coping mechanisms, and patients' experiences with health care. CONCLUSION: This review provides evidence for healthcare professionals to gain a better understanding of RA patients' experiences and needs. Future studies can explore interventions that will enhance the quality of current healthcare practices and ultimately improve patients' quality of life. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Establishing a positive healthcare professional-patient relationship is crucial and healthcare professionals are in a position to provide greater informational and emotional support to patients. Policy makers and healthcare organizations need to look into ways to enhance the healthcare services to better suit RA patients' needs.

Brachytherapy for high grade prostate cancer induces distinct changes in circulating CD4 and CD8 T cells - Implications for systemic control.

This exploratory study is a follow up to our previous investigation of immune response in the circulation of high-grade Gleason 9 prostate cancer patients treated with EBRT + BT compared to EBRT alone. Notably, EBRT + BT demonstrates the potential to elicit an effect on CD4/CD8 ratio which may have attributed to improved clinical response to therapy. Our findings show promise for leveraging circulating immune cells as predictive biomarkers for radiotherapy response.

Uncovering the armpit of SBRT: An institutional experience with stereotactic radiation of axillary metastases.

Purpose/objectives: The growing use of stereotactic body radiotherapy (SBRT) in metastatic cancer has led to its use in varying anatomic locations. The objective of this study was to review our institutional SBRT experience for axillary metastases (AM), focusing on outcomes and process. Materials/methods: Patients treated with SBRT to AM from 2014 to 2022 were reviewed. Cumulative incidence functions were used to estimate the incidence of local failure (LF), with death as competing risk. Kaplan-Meier method was used to estimate progression-free (PFS) and overall survival (OS). Univariate regression analysis examined predictors of LF. Results: We analyzed 37 patients with 39 AM who received SBRT. Patients were predominantly female (60 %) and elderly (median age: 72). Median follow-up was 14.6 months. Common primary cancers included breast (43 %), skin (19 %), and lung (14 %). Treatment indication included oligoprogression (46 %), oligometastases (35 %) and symptomatic progression (19 %). A minority had prior overlapping radiation (18 %) or surgery (11 %). Most had prior systemic therapy (70 %).Significant heterogeneity in planning technique was identified; a minority of patient received 4-D CT scans (46 %), MR-simulation (21 %), or contrast (10 %). Median dose was 40 Gy (interquartile range (IQR): 35-40) in 5 fractions, (BED10 = 72 Gy). Seventeen cases (44 %) utilized a low-dose elective volume to cover remaining axilla.At first assessment, 87 % had partial or complete response, with a single progression. Of symptomatic patients (n = 14), 57 % had complete resolution and 21 % had improvement. One and 2-year LF rate were 16 % and 20 %, respectively. Univariable analysis showed increasing BED reduced risk of LF. Median OS was 21.0 months (95 % [Confidence Interval (CI)] 17.3-not reached) and median PFS was 7.0 months (95 % [CI] 4.3-11.3). Two grade 3 events were identified, and no grade 4/5. Conclusion: Using SBRT for AM demonstrated low rates of toxicity and LF, and respectable symptom improvement. Variation in treatment delivery has prompted development of an institutional protocol to standardize technique and increase efficiency. Limited followup may limit detection of local failure and late toxicity.

Novel mRNA isoforms and mutations of uridine monophosphate synthetase and 5-fluorouracil resistance in colorectal cancer.

The drug fluorouracil (5-FU) is a widely used antimetabolite chemotherapy in the treatment of colorectal cancer. The gene uridine monophosphate synthetase (UMPS) is thought to be primarily responsible for conversion of 5-FU to active anticancer metabolites in tumor cells. Mutation or aberrant expression of UMPS may contribute to 5-FU resistance during treatment. We undertook a characterization of UMPS mRNA isoform expression and sequence variation in 5-FU-resistant cell lines and drug-naive or -exposed primary and metastatic tumors. We observed reciprocal differential expression of two UMPS isoforms in a colorectal cancer cell line with acquired 5-FU resistance relative to the 5-FU-sensitive cell line from which it was derived. A novel isoform arising as a consequence of exon skipping was increased in abundance in resistant cells. The underlying mechanism responsible for this shift in isoform expression was determined to be a heterozygous splice site mutation acquired in the resistant cell line. We developed sequencing and expression assays to specifically detect alternative UMPS isoforms and used these to determine that UMPS was recurrently disrupted by mutations and aberrant splicing in additional 5-FU-resistant colorectal cancer cell lines and colorectal tumors. The observed mutations, aberrant splicing and downregulation of UMPS represent novel mechanisms for acquired 5-FU resistance in colorectal cancer.