FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium.

BACKGROUND: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. METHODS: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. RESULTS: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. CONCLUSION: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.

Ministry of health clinical practice guidelines: clinical blood transfusion.

The Health Sciences Authority (HSA) and the Ministry of Health (MOH) publish clinical practice guidelines on Clinical Blood Transfusion to provide doctors and patients in Singapore with evidence-based guidance for blood transfusion. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the HSA-MOH clinical practice guidelines on Clinical Blood Transfusion, for the information of readers of the Singapore Medical Journal. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website (http://www.moh.gov.sg/mohcorp/publications.aspx?id=25700). The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines.

Serial changes in the expression of breast cancer-related proteins in response to neoadjuvant chemotherapy.

BACKGROUND: Tumour expression of cyclooxygenase-2 (COX-2), epidermal growth factor receptor (EGFR), erythroblastic leukaemia viral oncogene homologue-2 (ErbB2), Ki-67 and p53 in breast cancer are associated with poorer outcomes. We investigated in vivo changes of these proteins with neoadjuvant chemotherapy. PATIENTS AND METHODS: Four core biopsies were taken from 100 breast cancer patients at baseline, during and upon completion of neoadjuvant chemotherapy. Immunohistochemical expression of these proteins were evaluated and correlated with clinicopathological features, clinical response and progression-free survival (PFS). RESULTS: There was a statistically significant change from positivity to negativity in COX-2 expression with chemotherapy (P = 0.002), predominantly in clinical responders (P = 0.002). COX-2-positive tumours that remained positive had shorter PFS than those that turned negative. Estrogen receptor (ER)+ and COX-2+ tumours at baseline that remained COX-2+ fared worse than those that became COX-2 negative (PFS 27 versus 52 months, P = 0.002). No significant changes in IHC expression were observed for ER, progesterone receptor, ErbB2, EGFR, p53 or Ki67. CONCLUSIONS: Chemotherapy induced change in COX-2 expression from positivity to negativity predominantly among clinical responders and is associated with longer PFS. Interaction between COX-2 and ER was observed, suggesting that some hormone receptor-positive patients may benefit from combining COX-2 inhibition with hormonal therapy.

Pharmacokinetics and pharmacodynamics of docetaxel with or without ketoconazole modulation in chemonaive breast cancer patients.

BACKGROUND: We previously found 70 mg flat-dose docetaxel coadministered with ketoconazole to modulate CYP3A4 to be the maximum tolerated dose that resulted in comparable docetaxel area under the plasma concentration-time curve (AUC) as 75-100 mg/m² docetaxel. PATIENTS AND METHODS: We compared cycle 1 docetaxel pharmacokinetics and pharmacodynamics between ketoconazole-modulated (70 mg flat-dose docetaxel, n = 31) and conventional-dosed docetaxel (75 mg/m², n = 51) in chemonaive breast cancer patients in two sequential phase II studies. RESULTS: Ketoconazole-modulated docetaxel resulted in reduced docetaxel clearance (22.05 ± 8.29 versus 36.52 ± 13.39 l/h, P < 0.001), similar docetaxel AUC (3.93 ± 2.77 versus 3.77 ± 2.70 mg/l·h, P = 0.794) and tumor efficacy (cycle 1 responder 52% versus 55%) and less day 8 neutrophil suppression (1.24 ± 1.02 × 109/l versus 0.47 ± 0.56 × 109/l, P < 0.001), grade 4 neutropenia (32.3% versus 72.0%, P < 0.001) and febrile neutropenia (3.2 versus 23.5%, P = 0.015), compared with conventional-dosed docetaxel. Chinese had the lowest docetaxel clearance, highest AUC and most myelosuppression, followed by Malays and Indians, in response to ketoconazole-modulated docetaxel, while no significant interethnic differences were observed with conventional-dosed docetaxel. CONCLUSIONS: Ketoconazole-modulated docetaxel achieved similar docetaxel AUC and tumor efficacy but reduced neutrophil suppression and febrile neutropenia at ∼40% reduced dose, representing a feasible alternative to conventional-dosed docetaxel. Interethnic differences in CYP3A4 inhibition by ketoconazole exist and are important when evaluating the impact of concomitant medications.

The founder mutation BRCA1c.2845insA identified in a fallopian tube cancer patient: a case report.

Fallopian tube carcinoma is a very rare tumor, comprising less than 1% of all gynecologic cancers and found primarily in postmenopausal women. With the disease being so uncommon, little is known about its causes and/or risk factors, and treatment approaches have been taken from experiences with ovarian cancer. We describe a case of a 42-year-old woman with fallopian tube cancer in which the founder mutation BRCA1c.2845insA was detected by mutational analysis. This same mutation was subsequently detected in four unaffected members of her family following genetic counseling. We report an association between this founder mutation and fallopian tube cancer as part of the hereditary breast cancer syndrome in an Asian population. A literature review of the association between this rare malignancy and BRCA mutation carriers and its implications to prophylactic surgery is discussed.

Changes in the local morphology of the rectus abdominis muscle following the DIEP flap: an ultrasonographic study.

This study was undertaken to assess the changes in the local morphology of the rectus abdominis muscle following intramuscular dissection of the deep inferior epigastric artery perforators after harvesting of the deep inferior epigastric perforator (DIEP) flap. While the DIEP provides the well-known advantage of use of the lower abdominal tissue with preservation of the integrity of the abdominal wall musculature, postoperative problems such as abdominal asymmetry, bulges and reduced flexion capacity have been found. These changes may be due to rectus abdominis muscle damage from ischemia or denervation. We used ultrasonography to assess the changes in rectus abdominis muscle thickness and contractility, preoperatively, 1-month and 1-year postoperatively. The study group consisted of 17 rectus abdominis muscles in 14 patients subjected to intramuscular dissection of perforators. The control group consisted of 11 intact rectus abdominis muscles in 11 patients who had undergone unilateral DIEP flap elevation, the dissected muscles being part of the study group. We found that the resting muscle thickness in the study group was, significantly increased at 1-month postoperatively, resolving by 1-year follow-up. As these changes were not seen in the control group, the increased muscle thickness is attributed to postoperative oedema that resolves with time. All muscles in the study and control groups retained contractility showing no evidence of muscle denervation. Our date demonstrates that intramuscular dissection of perforator vessels in the DIEP flap leads to minimal changes in the local morphology and contractility of the rectus abdominis muscle.

Are medullary breast cancers an indication for BRCA1 mutation screening? A mutation analysis of 42 cases of medullary breast cancer.

Recommended guidelines have limited breast cancer gene ( BRCA1 ) mutation testing to individuals with a personal or family history of early onset breast and/or ovarian cancer, and those with multiple affected close relatives. Such large breast cancer families are rare in the general population, limiting the clinical application of the BRCA1 discovery. Previous reports have suggested an association between medullary breast cancer and BRCA1 mutation carriers. To test the feasibility of using these rare histological subtypes as an alternative to epidemiological factors, 42 cases of medullary cancer unselected for family history were screened for BRCA1 point mutations and large exon rearrangements. The large majority (83%) of these patients did not have significant family of breast or ovarian cancer. Two deleterious mutations resulting in a premature stop codon, and one exon 13 duplication were found. All mutations were detected in patients with typical medullary cancer, who had family history of multiple breast and ovarian cancers. Our findings suggest that medullary breast cancers are not an indication for BRCA1 mutation screening in the absence of significant family risk factors.

The mastectomy clinical pathway: what has it achieved?

INTRODUCTION: The mastectomy clinical pathway was developed to optimise the clinical care and cost management of breast cancer patients. The aim of this study was to prospectively assess the effect of the mastectomy pathway at the National University Hospital, Singapore over a 7-month period. MATERIALS AND METHODS: A prospective study was carried out on all breast cancer patients admitted for elective mastectomy between March and October 2001. As surrogates of optimised cost and care management, the length of stay and hospital costs, as well as the incidence of complications and unscheduled readmissions, were analysed. Non-pathway mastectomy patients treated from March to October 2000 were used as controls. A total of 83 patients who underwent mastectomy formed the pathway group, while 69 non-pathway patients acted as controls. RESULTS: Compared to controls, the mean length of hospital stay decreased significantly from 4.91 days to 4.10 days (P = 0.018) and the mean cost per case decreased significantly from $5,050 to $4,406 (P = 0.014) for those in the pathway group. There were no significant differences in the complications and unscheduled hospital readmission rates between the two groups (P > 0.05). CONCLUSION: The implementation of mastectomy clinical pathway has improved consistency in patient's treatment, the quality of patient outcome, and has reduced the costs of care and length of hospital stay. In addition, variance analysis of the mastectomy pathway has shown to be valuable for problem identification to improve patient care.

Double omental hernia--case report on a very rare cause of intestinal obstruction.

INTRODUCTION: We report a case of transomental herniation of the ileum through a defect in the gastrocolic ligament with re-emergence through a defect in the gastrohepatic ligament. This type of herniation is extremely rare and a review of the literature is presented. CLINICAL PRESENTATION: A 41-year-old Chinese male presented with signs and symptoms of intestinal obstruction. TREATMENT: An urgent laparotomy was undertaken and he was found to have a rare form of intra-abdominal hernia. The hernia was reduced and the defects were closed. OUTCOME: Postoperative recovery was unremarkable. CONCLUSION: Urgent operation should not be delayed because of the high mortality associated with strangulation.

Germ line mutations associated with breast cancer susceptibility.

Laboratory-based research in germ line mutations associated with breast cancer susceptibility is rapidly being integrated into clinical practice with profound implications. A Medline search was performed for all relevant articles published since 1990. Where appropriate, historical articles referenced in those identified were also reviewed. The results suggested that while mutations in the BRCA1 and BRCA2 genes are the most clinically relevant, much of the data on which clinical decisions are based must be interpreted with wide confidence intervals. Between 1 in 152 and 1 in 833 individuals carry such mutations. They account for less than 5% of all breast cancer, but up to 10% of cancers in those under the age of 40 years. Founder mutations are responsible for a larger proportion of breast cancer cases within certain inbred communities. Phenotypic expression and penetrance of different mutations is not currently predictable and estimates of penetrance are largely based on highly selected populations. BRCA1 mutations are more commonly associated with ovarian cancer than BRCA2 mutations. BRCA1 cancers tend to have more distinct pathological features and are usually oestrogen receptor (ER)-negative. To conclude, the evidence in this review suggests that caution should be exercised when translating scientific progress in breast cancer germ line genetics into clinical practice. Most of the available data are derived from studies on highly selected populations. The importance of other less penetrant, but more prevalent, germ line mutations may be realised in the future.

Phyllodes tumour: an update of 40 cases.

This is a retrospective study of 40 cases of phyllodes tumour treated at the National University Hospital since 1985. The mean age of presentation was 37.8 years, with a range of 15 to 58 years [standard deviation (SD) 11.22 years]. Ninety per cent of the patients were premenopausal. The mean size of tumours was 52 mm, with a range of 10 to 220 mm. Preoperative diagnosis was correct in only five patients, the lesion most commonly being mistaken as a fibroadenoma. Initial surgical treatment was by simple excision in 80% of cases. Histologically, the ratio of benign, intermediate and malignant tumours was 82.5%, 12.5% and 5% respectively. Recurrences occurred in only four patients (10%), all of whom were initially treated by simple excision. The diagnosis of phyllodes tumour continues to be difficult even with newer modalities of preoperative investigations, resulting in simple excision as initial treatment of these tumours. Expectant follow-up should be continued for these patients, with wide excision of future recurrences.

Preventable trauma deaths in Singapore.

BACKGROUND: This study was undertaken to determine the incidence of preventable trauma death at a non-designated trauma centre in Singapore. METHODS: A retrospective audit was carried out on all trauma deaths that occurred between January 1993 and December 1994 at the National University Hospital, Singapore. Of the 138 deaths, 38.4% (53/138) of patients were dead on arrival and were omitted from the study. Data from the remaining 85 deaths were summarized and presented before a multidisciplinary review board and injuries were scored according to the Abbreviated Injury Scale (AIS). RESULTS: Except for one patient, all deaths had an AIS score of 16 or greater. Sixty-one per cent (52/85) of deaths were the result of severe head injuries, and the rest had severe injuries in more than one body region. Following the guidelines of the Trauma Research and Education Foundation of San Diego, the incidence of 'not preventable', 'potentially preventable' and 'frankly preventable' deaths were 77.6, 15.3 and 7.1%, respectively. The most common errors in management were caused by delays in inter-departmental transfer (25.9%) and missed initial diagnosis (16.5%). After assessment by the Coroner's Office, autopsies were carried out in 60% of the cases and yielded information that altered the assessment of preventable deaths, particularly in the group with multiple injuries. CONCLUSIONS: The present study concludes that the preventable death rates in the National University Hospital are comparable to those in non-trauma designated centres elsewhere. There can only be a decrease in the preventable death rate if an improved system of pre-hospital trauma care, improved interdisciplinary communication, closer supervision of the initial attending physicians and stricter protocols on clinical monitoring are established.

Morbidity and mortality for elderly patients with fractured neck of femur treated by hemiarthroplasty.

Patients above the age of 60 with displaced femoral neck fractures are treated by hemiarthroplasty in Singapore because of our low life expectancy. This study evaluates the morbidity and mortality of 110 such patients operated on in our department between January 1990 and December 1992. It has clinical significance because of the rapidly ageing population of Singapore. The mean age was 78 years with a female preponderance of 5:1. They were predominantly Chinese. None of the patients were Malay. This is the first study showing that such fractures are rare among Malays. Most fractures were due to trivial trauma. Fifty-eight per cent had co-existing illness(es). The mean hospitalization stay was 20 days. There were considerable and local complications in 15 patients. Twenty-five patients died. Of the remaining patients, 17 (20 per cent) were unable to regain independent ambulation. The mortality rate at 3, 6 and 12 months was 6.4 per cent, 9.1 per cent and 15 per cent respectively. Males showed a significantly higher mortality rate than females. Also, patients living in government-built high rise flats had a significantly higher mortality rate than those residing in privately owned homes.