Factors that influence the choice of seeking treatment at polyclinics.

INTRODUCTION: Patients in Singapore can choose their primary care provider on a per-episode basis and pay out-of-pocket for services rendered. The infrastructure of subsidised and private primary care sector facilities differs. Onsite ancillary services are available in subsidised facilities, allowing for convenience of routine investigations, while private clinics are usually standalone practices. This study sought to examine the factors influencing patients' choice of polyclinic. METHODS: This was a cross-sectional survey of a convenient sample of 484 random patients who sought treatment at a polyclinic located in a new housing estate from 24-27 June 2008. RESULTS: The response rate was 85.4% (n = 409). 38.1% of the patients were male. Mean age was 36.2 years. Only 13.8% had a regular private family physician, while 37.3% were followed up at polyclinics. Patients on regular polyclinic follow-up were more likely to be older (p < 0.001), unemployed, retirees or housewives (p < 0.001) and were seeking treatment for chronic diseases (p < 0.001). Geographical convenience (p = 0.002), low cost of consultation (p = 0.024), and onsite laboratory (p = 0.001) and imaging services (p = 0.018) significantly influenced those on regular polyclinic follow-up to attend the polyclinic. CONCLUSION: Affordability, convenience of travel and onsite laboratory facilities influence patients' choice of seeking treatment at polyclinics. Further research examining whether the overall convenience of onsite ancillary services influences patients' choice of primary care provider would be useful in redesigning private primary care infrastructure to enhance patient convenience and encourage more patients to have a regular private family physician.

Reversal of Hartmann's procedure: experience in an Asian population.

INTRODUCTION: With improvements in surgical techniques, instrumentation and perioperative care, Hartmann's procedure is now less frequently performed. Restoration of intestinal continuity after Hartmann's procedure has traditionally been viewed to be technically demanding and associated with significant morbidity and mortality. This is a study of outcomes after the reversal of Hartmann's procedure in an Asian population. METHODS: A prospectively collected database showed that 255 patients had undergone Hartmann's procedure from October 1989 to October 2005. Patients who subsequently underwent Hartmann's reversal were identified and their records reviewed retrospectively. RESULTS: Hartmann's reversal was attempted in 49 patients. The most common indication for Hartmann's procedure was colorectal carcinoma (49.0%). The median interval between resection and reversal was 23 weeks. Reversal was successful in 46 (93.9%) patients, with 79.6% experiencing no intraoperative complications. Failure of reversal was significantly associated with prior radiotherapy to the pelvis (p-value = 0.007). Anastomotic leak rates and re-bleeding rates were both 0.0%. 79.6% of patients made an uneventful recovery with no postoperative complications. There was no significant increase in the complication rate in older patients or patients with higher American Society of Anesthesiologists status. The overall incidence of 30-day morbidity and mortality was 20.4% and 0.0%, respectively. CONCLUSION: In our population, Hartmann's procedure is more commonly performed for colorectal cancer rather than for diverticular disease, resulting in lower rates of stoma reversal. Hartmann's reversal could be performed with acceptable morbidity and minimal mortality, although prior radiotherapy and shorter rectal stump may pose challenges during reversal surgery.

Anal canal malignancies: a review in an Asian population.

INTRODUCTION: Anal canal malignancies are rare tumours of the gastrointestinal tract that represent less than five percent of anorectal malignancies. METHODS: We retrospectively reviewed patients with anal canal malignancies who were treated from April 1989 to December 2008. Patients were identified from a prospective database and records were analysed for age, gender, presenting symptoms, duration of symptoms, mode of diagnosis, histological subtypes, stage of disease, treatment received, duration of follow-up, recurrence rates and survival. RESULTS: A total of 61 patients were treated for anal canal malignancies, comprising 2.1 percent of all anorectal malignancies treated during the same period. There were 31 male and 30 female patients, with a median age at diagnosis of 61 (range 38-83) years. The commonest presenting symptoms were per rectal bleeding (69.4 percent) and pain (33.9 percent). The commonest histology was adenocarcinoma (50.8 percent) and squamous cell carcinoma (SCC) (40.3 percent). Patients underwent either surgery, radiotherapy, chemoradiation or a combination of modalities. The median duration of follow-up was 28 (range 1-120) months. Five patients developed recurrences after a median of 23 (range 2-36) months. The five-year overall survival and disease-free survival was 65.5 percent and 63.7 percent, respectively, with SCC showing a trend toward a better prognosis. CONCLUSION: Anal canal tumours are a rare clinical entity. They are usually present in the elderly with per rectal bleeding. They are usually treated using a multimodality approach, after the accurate establishment of histological diagnosis, which can yield reasonable survival rates.

Solitary caecal ulcer syndrome: our experience with this benign condition.

AIM: Solitary caecal ulcer syndrome is rare. We describe our experience of 10 patients with the condition. METHOD: A prospectively collected database of patients undergoing colonoscopy or surgery with histology reporting a solitary caecal ulcer was reviewed from 1999 to 2008. Patients with known carcinoma of the colon, cytomegalovirus infection, amoebiasis, inflammatory bowel disease, immunosuppression and history of nonsteroidal anti-inflammatory drug use were excluded. RESULTS: Ten patients were found to have a solitary caecal ulcer. All were of Chinese ethnicity, of median age 61 years. The most common presenting symptoms were haematochezia and right-sided abdominal pain. Histological findings included ulceration sharing some features of solitary rectal ulcer syndrome, but with differences to suggest a different aetiology. CONCLUSION: Solitary caecal ulcer syndrome should be included in the differential diagnosis of lower gastrointestinal haemorrhage, right iliac fossa pain or when computed tomography imaging demonstrates caecal wall thickening. The diagnosis can only be made on histopathological examination.

418 cases of laparoscopic colorectal resections: a single-institution experience and literature review.

INTRODUCTION: Evidence from randomised controlled trials has shown that laparoscopic colon and rectal cancer resection not only confers short-term benefits but also does not differ considerably in terms of its long-term oncological outcomes, as compared with open surgery. METHODS: All laparoscopic colon and rectal resections performed between January 2005 and December 2007 were included. Patient records were reviewed from a prospective database and the relevant clinical data was obtained, with a subgroup analysis of cancer procedures performed. RESULTS: 418 patients (247 male), median age 63 years (range 24 to 88), underwent laparoscopic resection of the colon and rectum. The median Body Mass Index (BMI) was 22.5 (range 13.5 to 39.3). The majority of the procedures were performed for malignant disease (81.3 percent) and the most common procedure was anterior resection (79.4 percent). The median duration of surgery was 135 minutes (range 65 to 330), with conversions to open surgery in 44 patients (10.5 percent). Complications occurred in 78 patients (18.7 percent), including anastomotic leaks in five (1.20 percent). The median length of hospital stay was five days (range 3 to 90) and the median follow-up was 19 months (range 1 to 46). In the 340 patients with malignant disease, the median number of lymph nodes harvested was 13 (range 5 to 48), and at the latest review, 230 patients (67.6 percent) were disease-free, with locoregional recurrence in 2.9 percent and systemic recurrence in 10 percent. CONCLUSION: To date, this is the largest series of laparoscopic colorectal resections reported locally, and our results show that it is safe, feasible and produces favourable results.

Health insurance in Singapore: who's not included and why?

INTRODUCTION: Health insurance and the consequent risk pooling are believed to be essential components of a sustainable healthcare financing system. We sought to determine the profile of Singaporeans who had not procured health insurance over and above MediShield, the national government-spearheaded health insurance program and the factors associated with insurance procurement. METHODS: A total of 1,783 respondents were interviewed via telephone and asked to rank their agreement with statements pertaining to healthcare cost, quality and financing on a fivepoint Likert scale. RESULTS: Respondents were representative of the general population in terms of ethnicity and housing type, but lower income households were over-represented. Respondents also had a higher education level compared to the general population. Data on 1,510 respondents, with full information on household (HH) income, education and insurance status, was analysed. HH income below S$1,500 per month (odds ratio [OR] is 5.66, 95 percent confidence interval [CI] is 3.9-8.3, p is less than 0.0001) and a secondary education and below (OR is 2.05, 95 percent CI is 1.5-2.8, p is less than 0.0001) were associated with not procuring insurance over and above MediShield coverage. Respondents with insurance were less likely to agree that healthcare was affordable and that the "3M" framework was sufficient to meet healthcare needs. CONCLUSION: Singaporeans with a lower HH income and a lower education level were less likely to possess health insurance. This may be related to a stronger belief that healthcare is affordable even without insurance. Educational efforts to encourage the more widespread use of health insurance should be targeted toward lower income groups with less formal education and should be complemented by other interventions to address other aspects of insurance procurement considerations.

Radiation proctitis: a decade's experience.

INTRODUCTION: Pelvic radiotherapy is an essential component of potentially curative therapy for many pelvic malignancies; however, the rectum consequently often sustains collateral injury. METHODS: The researchers retrieved patient data that was prospectively gathered over a ten-year period between January 1995 and December 2004. The relevant details, including gender, age, pelvic pathology for which radiotherapy was administered, the presenting symptoms, the interval between radiotherapy and the onset of symptoms, the mode of diagnosis, treatments received, length of hospital stay and duration of follow-up, were analysed. RESULTS: During the period under review, 77 patients were admitted for the treatment of radiation proctitis, with a median follow-up period of 14 (range 1-61) months. There were 23 male and 54 female patients, with a median age of 63.9 (range 37-89) years. The most common underlying cancers were gynaecological (63.6 percent), prostate (18.2 percent) and colorectal (15.6 percent) cancer. The most common presenting symptom was bleeding per rectum (89.6 percent), with a change in bowel habits a distant second (10.4 percent). The median latent period between the completion of radiotherapy and the onset of symptoms was 24 (range 3-68) months. The majority of the patients (72.5 percent) received non-surgical treatment, most commonly using topical 4 percent formalin solution to arrest the bleeding, with more than half the patients requiring repeat treatments. 14 (18.2 percent) patients required colorectal resections for intractable bleeding, intestinal obstruction or intra-abdominal sepsis. CONCLUSION: Radiation proctitis can be a therapeutic challenge, even in the most experienced hands. The majority of patients who present with per rectal bleeding can be treated using topical modalities, while surgery may offer the only chance of relief from life-threatening symptoms.

Public perceptions of the factors that constitute a good healthcare system.

INTRODUCTION: In Singapore, few studies have been done on the factors that the general public considers to be most important in the healthcare system. We conducted this pilot study to determine the factor structure, reliability and validity of statements in a healthcare survey questionnaire as predictors of public perception of a good healthcare system. METHODS: Data on public perceptions of healthcare from a national survey of 1,434 adult Singaporeans was analysed using a principal component analysis and regression, to obtain the factors and predictors. The survey employed 31 statements on healthcare quality, cost, access and the role of the individual vis-à-vis society, which participants ranked on a five-point Likert scale. RESULTS: The exploratory factor analysis identified six critical factors (F): National healthcare financing framework (F1), Service at public institutions (F2), Service at private institutions (F3), Individual responsibility for health (F4), Affordability at public institutions (F5), and Affordability at private institutions (F6). These factors explained 54 percent of variance, and Cronbach's alpha ranged from 0.5 to 0.72, except for F1. Regression analysis showed an association of public perception of good healthcare in Singapore with the following factors: F2 (odds ratio [OR] 1.79, 95 percent confidence interval [CI] 1.48-2.16, p-value is less than 0.0001); F3 (OR 1.29, 95 percent CI 1.10-1.52, p-value is less than 0.0001); F5 (OR 1.52, 95 percent CI 1.27-1.83, p-value is less than 0.0001); F1 (OR 1.31, 95 percent CI 1.08-1.59, p-value is 0.01); F4 (OR 1.33, 95 percent CI 1.16-1.54, p-value is less than 0.0001); but not with F6. CONCLUSION: This pilot study provides a practical, reliable and valid first perception second level matrix to assess the Singapore healthcare system. Further snapshot surveys to assess perceptions of the healthcare system should be conducted with questionnaires abridged to include only these five identified critical factors.

Colorectal cancer mass screening event utilising quantitative faecal occult blood test.

INTRODUCTION: Colorectal cancer (CRC) is a leading cause of morbidity and mortality with human and financial costs. Screening by faecal occult blood test (FOBT) has proven to be effective in decreasing mortality from CRC in both randomised trials and case-control studies. We report on the results of a CRC screening event using quantitative FOBT (QFOBT) held in Singapore. METHODS: The mass screening event was held over two days, and participants 40 years or older without prior screening performed in the preceding year were eligible. Those with significant symptoms or medical comorbidities were excluded. Stool sampling was done with two issued immunochemical QFOBT kits, and participants with positive stool samples with equal or greater than 100 ng haemoglobin/ml sample solution in any two samples were advised to have a colonoscopy screening conducted. RESULTS: A total of 1,048 participants took part in the screening event. 222 (21 percent) of the participants claimed to have some abdominal symptoms prior to screening. 49 participants (26 males, 23 females) tested positive for QFOBT and 47 were evaluated. 10 (21 percent) had polyps and one case of colorectal cancer was detected. Seven of these cases had significant neoplasia (lesions 1 cm or larger) and were treated. Two patients required surgery. CONCLUSION: Our study demonstrates wide variation in the attitudes of participants who turned up for screening. In addition, the number of significant colorectal neoplasia patients (14 percent) in those with positive QFOBT provides further evidence of the importance of screening with a potential reduction in CRC mortality. Continuous education of the public in events such as this, is essential to improving attitudes towards screening.

Systematic review of intraoperative colonic irrigation vs. manual decompression in obstructed left-sided colorectal emergencies.

AIMS: A systematic review was conducted to determine if manual decompression is a safe alternative to intraoperative colonic irrigation prior to primary anastomosis in obstructed left-sided colorectal emergencies. METHODS: Search for relevant articles from 1980 to 2007 was conducted on Medline, Embase and the Cochrane Controlled Trials Register using the keywords "colonic lavage, irrigation, decompression, washout, obstructed and bowel preparation", either singularly or in combination. Trials in English publications with similar patient characteristics, inclusion criteria and outcome measures were selected for analysis. Thirty-day mortality, anastomotic leak rates and post-operative wound infection were studied as outcome variables. Analysis was performed with RevMan 4.2 software. RESULTS: Seven trials were identified for systematic review, with a total of 449 patients. Data from the single randomised controlled trial and one prospective comparative trial were analysed separately. Results from the remaining five studies were pooled into two arms of a composite series, one with colonic irrigation and one without. Results showed no significant difference in the anastomotic leak rates and mortality rates between the colonic irrigation and manual decompression arms in the randomised and comparative trials. The composite series, however, showed significantly better results with manual decompression (RR 6.18, 95% CI 1.67-22.86). The post-operative infection rate was similar in both groups. CONCLUSION: Manual decompression was comparable to colonic irrigation for primary anastomosis in obstructed left-sided colorectal emergencies, with no significant increase in mortality, leak or infection rates.

A prospective study assessing anal plug for containment of faecal soilage and incontinence.

OBJECTIVE: Faecal incontinence is a common and embarrassing problem for many individuals. Some patients remained symptomatic despite the availability of different treatments. There is a limited range of commercially available products designed to cope with faecal incontinence. The anal plug has been developed to contain the loss of stool. This study aimed to evaluate the use of anal plug in Asian patients with intractable faecal soilage and incontinence judged by clinical and functional outcomes. METHOD: A prospective study of consecutive patients with intractable faecal incontinence was carried out. Suitable patients tested the anal plug for 3 weeks. They completed a structured questionnaire on its use including the ASCRS quality of life questionnaire for faecal incontinence. RESULTS: Thirty patients, median age 63 (interquartile range 52-70) years, participated in the trial. Nineteen of 30 patients were comfortable wearing the plug, seven patients withdrew from the study because of discomfort, and four had tolerable discomfort and managed to complete the trial protocol. Patients who tolerated the plug found that it was highly successful in controlling faecal incontinence. Twenty-one of 30 patients wished to continue to use the plug regularly after the study. There was a trend toward improvement in quality of life scores during the study. CONCLUSION: The anal plug was effective in containing faecal incontinence and was well tolerated in the majority of patients selected for this treatment.

Rectogesic (glyceryl trinitrate 0.2%) ointment relieves symptoms of haemorrhoids associated with high resting anal canal pressures.

OBJECTIVE: Some haemorrhoids are associated with high resting anal canal pressures. The aim of this study was to assess if Rectogesic, a topical glyceryl trinitrate 0.2% ointment was effective in relieving symptoms of early grade haemorrhoids associated with high resting anal canal pressures. METHOD: This was a prospective, two-centre, open label study of 58 patients with persistent haemorrhoidal symptoms. Patients with first or second degree haemorrhoids and a maximum resting anal canal pressure > 70 mmHg were included. Rectogesic was applied three times a day for 14 days. Anorectal manometry was performed 30 min after the first application of Rectogesic. A 28-day diary was completed during 14 days of therapy and for 14 days after cessation of treatment. This recorded the incidence of rectal bleeding, and visual analogue scales for anal pain, throbbing, pruritus, irritation and difficulty in bowel movement. RESULTS: Maximum resting anal canal pressures were reduced after application of Rectogesic (115.0 +/- 40.4 mmHg vs 94.7 +/- 34.1 mmHg, P < 0.001). In the study period and at 14 days after cessation of Rectogesic, there was significant reduction in rectal bleeding (P = 0.0002), and significant improvement of anal pain (P = 0.0024), throbbing (P = 0.0355), pruritus (P = 0.0043), irritation (P = 0.0000) and difficulty in bowel movement (P = 0.001). The main adverse event was headache in 43.1% of patients. CONCLUSION: Rectogesic is a safe and feasible treatment for patients with early grade haemorrhoids associated with high resting anal canal pressures.

Prospective, randomized trial comparing intraoperative colonic irrigation with manual decompression only for obstructed left-sided colorectal cancer.

BACKGROUND: This is a prospective, randomized, controlled trial comparing the outcome of intraoperative colonic irrigation with that of manual decompression for acutely obstructing colorectal cancers distal to the splenic flexure. METHODS: All patients admitted to our department from June 1999 to August 2002 with obstructing left-sided colorectal cancers were recruited. Patients were randomized intraoperatively and were excluded if deemed unsuitable for segmental resection and primary anastomosis. Twenty-five patients were randomized to receive colonic irrigation and twenty-eight to receive manual decompression. Perioperative parameters and outcome including mortality and anastomotic leak were recorded. RESULTS: Both groups of patients were comparable in terms of gender and age. The time taken for mobilization, decompression, and irrigation in the colonic irrigation group (median, 31 minutes) was significantly longer than that for the manual decompression group (median, 13 minutes) (P; = 0.0005). However, the total time of the operation was similar for both groups. Times for recovery of bowel function, of wound infection, and until discharge from the hospital were also similar. In the manual decompression group there were two cases of anastomotic leak (8 percent, 2/25) requiring reoperation but none (0/24) in the colonic irrigation group. However, this difference was not statistically significant. CONCLUSION: Manual decompression of proximal colon without irrigation is as safe as colonic irrigation in one-stage surgical management of obstructing left-sided colorectal cancer.

Injectable silicone biomaterial for fecal incontinence caused by internal anal sphincter dysfunction is effective.

PURPOSE: Fecal incontinence caused by a weak or disrupted internal anal sphincter is common but there has been no effective treatment. This prospective study evaluates the medium-term clinical effects of an injectable silicone biomaterial, PTP (Bioplastique), used to augment the internal anal sphincter. METHOD: Eighty-two patients (64 females; median age, 66 years) with severe fecal incontinence and a low anal resting pressure caused by internal anal sphincter dysfunction (defect, n = 11; intact, n = 71) were randomized to PTP injection into intersphincteric space and internal anal sphincter with (Group A, n = 42) or without (Group B, n = 40) guidance by endoanal ultrasound. Both groups were similar in terms of age, gender, past anorectal surgery, duration of follow-up (median, 6 months; range, 1-12 months), and baseline continence score. Sixty-two percent of Group A and 55 percent of Group B had prolonged pudendal nerve terminal motor latency. RESULTS: There was no significant complication. Two patients in Group A and four patients in Group B noted minor discomfort at injection sites. At one month postprocedure, endoanal ultrasound confirmed retention of silicone biomaterial without migration. In both groups, fecal continence was significantly improved by PTP implants 1 month after injection, but continued to improve significantly for up to 12 months in Group A and 6 months in Group B (P < 0.001). Improvement in fecal continence and maximum anal resting pressure was significantly greater in Group A, in whom injection was guided by endoanal ultrasound, than in Group B. At three months after injection, significantly more Group A patients than Group B patients achieved >50 percent improvement in Wexner's continence score (69 percent vs. 40 percent; P = 0.014). Ninety-three percent of Group A and 92 percent of Group B had >50 percent improvement in global quality of life scores (visual analog scale). At a median follow-up of 6 months, all domains of the fecal incontinence quality of life scale improved significantly in both groups; however, the physical function and mental health scores of Short Form-12 only improved in Group A. A prolonged pudendal nerve terminal motor latency had no effect on functional outcome in either group. CONCLUSION: Injection of silicone biomaterial provided a marked improvement in fecal continence and quality of life in patients with internal sphincter dysfunction, despite the presence of pudendal neuropathy.

Total colectomy with ileorectal anastomosis leads to appreciable loss in quality of life irrespective of primary diagnosis.

Total colectomy with ileorectal anastomosis (TC) is a well-accepted procedure for many colonic pathologies but data on faecal incontinence and related quality of life after TC are lacking. The aims of this study were to assess the long-term bowel frequency, degree of incontinence and quality of life with respect to faecal incontinence and to compare them with the outcome for TC for different diagnostic groups. We identified 54 patients who had undergone TC at Singapore General Hospital and interviewed them using two questionnaires: the faecal incontinence quality of life (FIQL) scale and the Wexner faecal incontinence score (WS). The patients were allocated in 3 groups based on the primary diagnosis leading to operation, i. e. slow-transit constipation or megacolon (STC), colonic neoplasm (CA) and complicated pan-colonic diverticular disease (DD). Median bowel frequencies for STC and DD groups were 2.5/day; for CA, it was 3.5/day (p=0.042). There was no significant difference in the FIQL score and WS between the groups. Eleven patients had some degree of faecal incontinence based on WS. Many patients (20.4%) with perfect continence had fear of faecal leakage affecting their quality of life. In conclusion, patients with frequent stools do not need to have incontinence to suffer from the fear of it. The primary pathology leading to TC made no difference to the faecal incontinence or bowel urgency problems.

The Ewing tumor family of peripheral primitive neuroectodermal tumors expresses human gastrin-releasing peptide.

The Ewing tumor family of peripheral primitive neuroectodermal tumors (pPNETs) are characterized by chromosomal translocations leading to EWS-ETS gene fusions. These hybrid genes express chimeric proteins that are thought to act as aberrant transcription factors. We therefore used differential display-PCR to compare gene expression patterns in pPNET cell lines with those of other small round cell tumors (SRCTs) of childhood. This technique detected differential expression of sequences corresponding to human gastrin-releasing peptide (GRP) in pPNET cell lines but not in other SRCT cell lines. Subsequent Northern and reverse transcription-PCR analysis of SRCT cell lines confirmed GRP positivity in all pPNET lines tested. Of primary tumors tested by reverse transcription-PCR, GRP expression was found in 7 (44%) of 16 pPNETs but in no other primary SRCTs examined. Expression of the GRP receptor gene was demonstrable in 55% of pPNET cell lines and 25% of primary pPNET tumors but also in several other SRCTs. Radioimmunoassays and immunohistochemistry confirmed expression of bioactive GRP peptide in pPNET cell lines and primary tumors, respectively. Moreover, in vitro growth of a pPNET cell line was slowed by treatment with a GRP receptor antagonist and accelerated by a GRP receptor agonist. GRP is a known autocrine growth factor in small cell lung cancer and other neuroendocrine tumors. Its expression in pPNETs provides further evidence for a neuroectodermal histogenesis of these tumors and suggests that autocrine growth of this family of tumors may be at least partially regulated by GRP.

A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma.

Congenital (or infantile) fibrosarcoma (CFS) is a malignant tumour of fibroblasts that occurs in patients aged two years or younger. CFS is unique among human sarcomas in that it has an excellent prognosis and very low metastatic rate. CFS is histologically identical to adult-type fibrosarcoma (ATFS); however, ATFS is an aggressive malignancy of adults and older children that has a poor prognosis. We report a novel recurrent t(12;15)(p13;q25) rearrangement in CFS that may underlie the distinctive biological properties of this tumour. By cloning the chromosome breakpoints, we show that the rearrangement fuses the ETV6 (also known as TEL) gene from 12p13 with the 15q25 NTRK3 neurotrophin-3 receptor gene (also known as TRKC). Analysis of mRNA revealed the expression of ETV6-NTRK3 chimaeric transcripts in all three CFS tumours analysed. These were not detected in ATFS or infantile fibromatosis (IFB), a histologically similar but benign fibroblastic proliferation occurring in the same age-group as CFS. ETV6-NTRK3 fusion transcripts encode the helix-loop-helix (HLH) protein dimerization domain of ETV6 fused to the protein tyrosine kinase (PTK) domain of NTRK3. Our studies indicate that a chimaeric PTK is expressed in CFS and this may contribute to oncogenesis by dysregulation of NTRK3 signal transduction pathways. Moreover, ETV6-NTRK3 gene fusions provide a potential diagnostic marker for CFS.

Olfactory neuroblastoma is a peripheral primitive neuroectodermal tumor related to Ewing sarcoma.

Olfactory neuroblastoma (ONB) is a malignant tumor of the nasal mucosa whose histogenesis is unclear. A relationship to neuroblastoma (NB), a pediatric tumor of the sympathetic nervous system, is based on morphologic similarities and the expression of similar neural antigens. However, the clinical presentation of ONB differs from that of NB, and MYCN amplification characteristic of NB is not observed. We have therefore examined the relationship of this malignancy to other classes of neural tumors. In previous studies, two ONB cell lines demonstrated cytogenetic features and patterns of protooncogene expression suggestive of a relationship to the Ewing sarcoma family of childhood peripheral primitive neuroectodermal tumors (pPNETs). The pPNETs show t(11;22)(q24;q12) or t(21;22)(q22;q12) chromosomal translocations fusing the EWS gene from 22q12 with either the FL11 gene on 11q24 or the ERG gene on 21q22. We therefore analyzed ONBs for the presence of pPNET-associated gene fusions. Both cell lines showed rearrangement of the EWS gene, and fluorescence in situ hybridization (FISH) of each case demonstrated fusion of EWS and FL11 genomic sequences. Moreover, both lines expressed EWS/FL11 fusion transcripts with in-frame junctions between exon 7 of EWS and exon 6 of FL11 as described for pPNETs. We identified similar gene fusions in four of six primary ONB cases. None of the cases expressed tyrosine hydroxylase, a catecholamine biosynthetic enzyme widely expressed in NB. Our studies indicate that ONB is not a NB but is a member of the pPNET family.

Biphenotypic sarcomas with myogenic and neural differentiation express the Ewing's sarcoma EWS/FLI1 fusion gene.

Accurate diagnosis of primitive childhood sarcomas continues to be a formidable problem because these malignancies generally demonstrate very little morphological evidence of their tissue of origin. One of these tumor classes, the Ewing's sarcoma family of peripheral primitive neuroectodermal tumors (pPNETs), are thought to have a neural histogenesis based on evidence of neuroectodermal differentiation. Greater than 95% of pPNETs carry t(11;22) or t(21;22) chromosomal translocations which fuse the EWS gene from chromosome 22q12 in-frame with either FLI1 from chromosome 11q24 or ERG from chromosome 21q22. The pPNETs are considered to be histogenetically distinct from rhabdomyosarcomas, myogenic tumors lacking these EWS gene fusions and hypothesized to derive from immature skeletal muscle precursors. In the present study, we describe a unique set of childhood soft tissue sarcomas that show both neural and myogenic differentiation. These biphenotypic tumors express myogenic regulatory factors and muscle-specific antigens and also show neuroectodermal differentiation with ultrastructural evidence of neurosecretory granules and expression of neural-associated genes. Northern analysis and reverse transcriptase PCR reveal expression of EWS/FLI1 gene fusions in all biphenotypic sarcomas analyzed. Chimeric EWS/FLI1 transcripts and fusion proteins in these tumors are identical to those described for pPNETs. Our results provide evidence for a class of biphenotypic childhood sarcomas with myogenic and neural differentiation and suggest that these tumors may be related to the Ewing's sarcoma family of pPNETs.