Retrospective review of diagnostic performance of intracranial translucency in detection of open spina bifida at the 11-13-week scan.

OBJECTIVES: To evaluate diagnostic performance of intracranial translucency (IT) for detection of open spina bifida and interobserver agreement for visualization of IT during the 11-13-week scan. METHODS: A retrospective study was undertaken in a tertiary referral center. Two hundred 11-13-week scans for nuchal translucency, performed by sonographers certified by The Fetal Medicine Foundation, U.K., were reviewed independently for IT by two expert observers. When IT was not seen, the observers determined whether this was due to poor IT image quality or the presence of spina bifida. Discordant cases were reviewed by a third observer and the majority decision was used for analysis. All observers were blinded to individual pregnancy outcome and the number of cases with spina bifida. RESULTS: There were 191 normal fetuses, eight fetuses with open spina bifida and one with closed spina bifida (this case was excluded from analysis). IT was seen in 150 fetuses and all were normal. In six of the 49 cases in which IT was not seen, IT non-visibility was attributed to open spina bifida; among these cases, four fetuses had open spina bifida and two were normal. In the remaining 43 cases (including 39 normal fetuses), IT non-visibility was attributed to inadequate image quality. Sensitivity was 50% (4/8) and specificity was 99% (150/152). Concordance between the two observers concerning IT visibility was 79%, (κ = 0.47, representing moderate agreement). CONCLUSION: There was moderate interobserver agreement for visualization of IT on images obtained for nuchal translucency measurement at 11-13 weeks. When IT was confidently seen, open spina bifida could be excluded. However, non-visibility of IT correctly diagnosed only 50% of fetuses with open spina bifida.

Cochlear implantation in postirradiated ears: outcomes and challenges.

OBJECTIVES: Radiotherapy to head and neck tumors can potentially damage the auditory pathways. This has relevance in cochlear implants and there is a need for clinical studies to confirm the feasibility of cochlear implantation in these patients. METHODS: The records of all patients who had received cochlear implants at our institution were reviewed in this retrospective study and those who had prior irradiation for head and neck tumors were further studied. Case controls consisted of comparable cochlear implant recipients who did not have prior radiotherapy. RESULTS: Four of 230 patients met the criteria for further study. They had received radiotherapy for nasopharyngeal carcinoma 11 to 28 years ago and the postimplant follow-up period ranged from 9 to 46 months. The implanted ear of each patient had favorable preoperative promontory stimulation results. Postimplant, all patients were satisfied with their hearing outcomes and the improvement in speech discrimination scores was comparable to the controls. These cases also illustrated specific clinical concerns, including 1) radiation-induced endocrine dysfunction was common and, if overlooked, could result in increased anesthetic risks, and 2) irreversible eustachian tube dysfunction led to chronic middle ear problems, which complicated surgery; the use of modified surgical techniques overcame these difficulties. CONCLUSIONS: Deafened postirradiated patients with nasopharyngeal carcinoma were able to achieve good postimplant hearing outcomes comparable to those of nonirradiated patients. Should cochlear implantation be indicated in patients who have had prior radiation to the head and neck, specific preoperative, intraoperative, and postoperative issues have to be addressed.

FOXA1 acts upstream of GATA2 and AR in hormonal regulation of gene expression.

Hormonal regulation of gene expression by androgen receptor (AR) is tightly controlled by many transcriptional cofactors, including pioneer factors FOXA1 and GATA2, which, however, exhibit distinct expression patterns and functional roles in prostate cancer. Here, we examined how FOXA1, GATA2 and AR crosstalk and regulate hormone-dependent gene expression in prostate cancer cells. Chromatin immunoprecipitation sequencing analysis revealed that FOXA1 reprograms both AR and GATA2 cistrome by preferably recruiting them to FKHD-containing genomic sites. By contrast, GATA2 is unable to shift AR or FOXA1 to GATA motifs. Rather, GATA2 co-occupancy enhances AR and FOXA1 binding to nearby ARE and FKHD sites, respectively. Similarly, AR increases, but not reprograms, GATA2 and FOXA1 cistromes. Concordantly, GATA2 and AR strongly enhance the transcriptional program of each other, whereas FOXA1 regulates GATA2- and AR-mediated gene expression in a context-dependent manner due to its reprogramming effects. Taken together, our data delineated for the first time the distinct mechanisms by which GATA2 and FOXA1 regulate AR cistrome and suggest that FOXA1 acts upstream of GATA2 and AR in determining hormone-dependent gene expression in prostate cancer.

LncRNA HOTAIR enhances ER signaling and confers tamoxifen resistance in breast cancer.

Tamoxifen, an estrogen receptor (ER) antagonist, is the mainstay treatment of breast cancer and the development of resistance represents a major obstacle for a cure. Although long non-coding RNAs such as HOTAIR have been implicated in breast tumorigenesis, their roles in chemotherapy resistance remain largely unknown. In this study, we report that HOTAIR (HOX antisense intergenic RNA) is upregulated in tamoxifen-resistant breast cancer tissues compared to their primary counterparts. Mechanistically, HOTAIR is a direct target of ER-mediated transcriptional repression and is thus restored upon the blockade of ER signaling, either by hormone deprivation or by tamoxifen treatment. Interestingly, this elevated HOTAIR increases ER protein level and thus enhances ER occupancy on the chromatin and potentiates its downstream gene regulation. HOTAIR overexpression is sufficient to activate the ER transcriptional program even under hormone-deprived conditions. Functionally, we found that HOTAIR overexpression increases breast cancer cell proliferation, whereas its depletion significantly impairs cell survival and abolishes tamoxifen-resistant cell growth. In conclusion, the long non-coding RNA HOTAIR is directly repressed by ER and its upregulation promotes ligand-independent ER activities and contributes to tamoxifen resistance.

Effect of radiotherapy on retro-cochlear auditory pathways.

OBJECTIVES: The cochlea may be damaged by modern conventional radiotherapy (RT) for head and neck cancers when the ear is included in the radiation field. It is unclear however, if the retro-cochlear auditory pathways are affected as well, which has clinical significance in cochlear implantation. This study aims to investigate the integrity of the retro-cochlear auditory pathways in patients who had received RT for nasopharyngeal carcinoma. STUDY DESIGN: Prospective study. METHODS: Patients who were newly diagnosed with nasopharyngeal carcinoma and treated by RT alone were studied. Evoked response audiometry and PTAs were carried out prior to and after RT (at 3, 18, and 48 months postRT). In addition, evoked response audiometry was also performed during the 3rd, 5th, and 7th week of RT. Waves 1 to 5, 1 to 3, and 3 to 5 latencies were measured. The values recorded during and postRT were compared with those recorded before RT. In addition, a subset of ears that demonstrated postRT sensorineural hearing loss were identified so that their respective wave 1 to 5 interwave latencies could be similarly compared. Wilcoxon signed ranks test was used in the statistical analysis. To confirm that the cochlea and internal auditory meatus receive significant doses of radiation, the RT treatment plans of nine other nasopharyngeal carcinoma patients treated by the same RT technique were analyzed to derive dose-volume histograms of these structures. RESULTS: Twenty-seven patients (20 males and 7 females) with a mean age of 51.2 (range 36-75) years participated in the study. There was no statistically significant difference in waves 1 to 5, 1 to 3, and 3 to 5 interwave latencies recorded during RT and postRT as compared with those recorded before RT (P > .05). Pre- and postRT wave 1 to 5 latencies of the 16 ears that had postRT hearing deterioration were also not statistically significant (P = .366). The mean radiation doses delivered to the cochlea and internal auditory meatus ranged from 24.1 to 62.2 Gy and 14.4 to 43.4 Gy, respectively. CONCLUSION: This study suggests in patients who have had RT for nasopharyngeal carcinoma, the retro-cochlear auditory pathways are functionally intact even in the longer term.

Design of a prognostic index score for metastatic nasopharyngeal carcinoma.

The survival outcome of patients with systemic cancer differs significantly between individuals even within the same tumour type. We set out to illustrate this by analysing the factors determining survival in patients with metastatic disease from nasopharyngeal carcinoma (NPC) and to design a scoring system based on these prognostic factors. Patients referred between January 1994 and December 1999 were retrospectively analysed. Factors analysed included patient (age group, gender, performance status (BS) at diagnosis of metastases), disease (number of metastatic sites, specific metastatic sites, disease-free interval (DFI), metastases at presentation, presence of locoregional recurrence), and laboratory factors (leucocyte count, haemoglobin level, albumin level). Univariate and multivariable analyses were performed using the Cox proportion hazards model. A numerical score was derived from the regression coefficients of each independent prognostic variable. The prognostic index score (PIS) of each patient was calculated by totalling up the scores of each independent variable. Independently significant, negative prognostic factors were liver metastasis, lung metastasis, anaemia, poor PS, distant metastasis at initial diagnosis, and a DFI of <6 months. Three prognostic groups based on the PIS were obtained: (i) good risk (PIS=0-6); (ii) intermediate risk (7-10); (iii) poor risk (>or=11). The median survivals for these groups were 19.5, 10, and 5.8, months, respectively, (log rank test: P<0.0001). The variable prognosis of patients with disseminated NPC can be assessed by using easily available clinical information (patient, disease and laboratory factors). The PIS system will need to be validated on prospectively collected data of another cohort of patients.

Concurrent chemoradiotherapy followed by adjuvant chemotherapy in Asian patients with nasopharyngeal carcinoma: toxicities and preliminary results.

PURPOSE: Nasopharyngeal carcinoma (NPC) is endemic in Singapore. Nearly 60% of the patients diagnosed with NPC will present with locally advanced disease. The North American Intergroup study 0099 reported improved survival outcome in patients with locally advanced NPC who received combined chemoradiotherapy when compared to radiotherapy alone. Hence we explored the feasibility and efficacy of a similar protocol in our patients. METHODS AND MATERIALS: Between June 1996 and December 1997, 57 patients were treated with the following schedule as described. Radical radiotherapy (RT) of 66-70 Gy to the primary and neck with cisplatin (CDDP) 25 mg/m2 on days 1-4 given by infusion over 6-8 hours daily on weeks 1, 4, and 7 of the RT. This is followed by a further 3 cycles of adjuvant chemotherapy starting from week 11 from the first dose of radiation (CDDP 20 mg/m2/d and 5-fluorouracil [5-FU] 1 gm/m2/d on days 1-4 every 28 days). RESULTS: The majority of patients (68%) had Stage IV disease. About 54% of patients received all the intended treatment; 75% received all 3 cycles of CDDP during the RT phase and 63% received all three cycles of adjuvant chemotherapy. The received dose intensity of CDDP and 5-FU of greater than 0.8 was achieved in 58% and 60% of the patients respectively. Two treatment-related deaths due to reactivation of hepatitis B and neutropenic sepsis respectively, were encountered. At median follow-up of 16 months, 14 patients had relapsed, 12 systemically and 2 loco-regionally. CONCLUSION: Due to the acceptable tolerability of such a protocol in our cohort of patients, we have embarked on a Phase III study to confirm the results of the 0099 Intergroup study in the Asian context.

Incidence, severity, and timing of subependymal and intraventricular hemorrhages in preterm infants born in a perinatal unit as detected by serial real-time ultrasound.

Real-time ultrasound scans were performed on 66 low-birth-weight infants within the first six hours of life (mean, two hours), and then at 12, 24, 48, and 72 hours, and thereafter at weekly intervals. All of the infants were born in a perinatal unit. The incidence of intraventricular hemorrhage and subependymal hemorrhage was 31%. Eight of 20 infants had small hemorrhages (Papile, grades I and II); seven infants sustained grade III hemorrhages, and five infants sustained grade IV hemorrhages. All hemorrhages occurred in the first 72 hours of life; 25% were diagnosed with the first scan (ie, within the first six hours of life). The infants especially at risk were those less than 29 weeks' gestation. Five infants developed progressive posthemorrhagic ventriculomegaly that subsided spontaneously by age 8 weeks. The mortality in the study group was only 4.5%.

A novel nonmetallized tip for electrospray mass spectrometry at nanoliter flow rate.

We report the fabrication of a durable nonmetallized nanospray tip. This nanospray tip does not require complex preparation procedures such as chemical treatment, deposition of gold or SiOx vapor. It was fabricated by pulling a heated glass capillary of 1.1 mm internal diameter to produce a fine tip with an orifice of 10-15 microns in diameter. A 10 microns gold-plated tungsten wire was inserted through the capillary tip. This tungsten wire played a central role in the operation of this durable nanospray tip by providing electrical contact. This type of nanospray tip could withstand electrical discharges and sustained spraying of solution at nanoliter flow rate for more than 3 h. Using insulin (35 microM) and myoglobin (1 microM) solutions, useful mass spectrum could be acquired with low fmol sensitivity.

Prenatal sonographic diagnosis of Pena-Shokeir syndrome type I, or fetal akinesia deformation sequence.

We report on a familial case of Pena-Shokeir syndrome type I (fetal akinesia deformation sequence) born to healthy parents. The antenatal ultrasound diagnosis was based on hydramnios, restricted limb movements, decreased fetal chest movements, small chest, arthrogryposis, clubfoot, fixed extension of knees, fixed flexion of elbows, camptodactyly, kyphosis of thoracic spine, cryptorchidism, and small muscle bulk. Thymic hyperplasia was noted at autopsy.

Diagnosis and evolution of periventricular leukomalacia: a study with real-time ultrasound.

Periventricular leukomalacia is an ischemic lesion in periventricular white matter of premature infants. Hemorrhage into the ischemic area occurs in up to 25% of cases. We report two cases in which the diagnosis of periventricular leukomalacia was made during life with real-time ultrasound scanning. In one case, serial scans demonstrated the evolution of echodense regions, observed in the first 3 days of life, to cystic echolucent areas at 4 weeks. In the second case, periventricular echodense areas did not precede the occurrence of cystic echolucent lesions. This may reflect a more chronic ischemic cerebral insult (consistent with recurrent apnea and bradycardia) rather than a presumed acute episode of cerebral ischemia (with or without secondary hemorrhage) sustained by the first case. Real-time ultrasound scanning is a simple, non-invasive technique with which to document the evolution of periventricular leukomalacia, and thus to define the clinical neurological correlates in the neonatal period.

Diagnostic value of Epstein-Barr viral serology in nasopharyngeal carcinoma.

Although Epstein-Barr virus (EBV) IgA serology has been established as an effective marker for nasopharyngeal carcinoma (NPC), it remains unclear how useful or cost-effective it is as a screening test. This article is aimed at establishing how these tests could be used most effectively in the diagnosis of NPC in an otolaryngology outpatient clinic. A total of 111 consecutive patients with NPC and an equal number of control subjects were studied. Forty-seven patients with NPC had early (AJCC stages 1 and 2) and 64 had advanced (stages 3 and 4) disease. A positive early antigen (EA) serology result was found in 81.2% of NPC patients and in none of the controls. Negative EA and viral capsid antigen (VCA) serology results were present in 2.7% of NPC patients and in 46.8% of controls. Negative EA and positive VCA serology results were found in 30.0% of NPC patients with early disease, 7.8% of NPC patients with advanced disease, and 53.2% of controls. Given its high specificity, serology for EA is recommended as a clinically useful screening test. Serology for VCA, although highly sensitive, has an unacceptably high false-positive rate, and its cost-effectiveness as a universal screening test is questionable.

Long-term hearing status after radiotherapy for nasopharyngeal carcinoma.

This paper evaluates the hearing status in the long-term, of patients who have had radiotherapy for nasopharyngeal carcinoma (NPC) and also discusses the hearing losses from a disability point of view, which takes into account binaural hearing. Forty patients who have had NPC successfully treated by a single radical course of radiotherapy of 70-80 Gy were studied at 2-12 years (mean 6.2 years) after radiotherapy. Each patient was examined clinically and with a pure-tone audiogram. Averaged hearing thresholds over 0.5, 1.0, 2.0 and 4.0 kHz were evaluated and a value > 30 dB was considered abnormal. The findings were compared with age-matched controls. The median hearing threshold for each ear in NPC patients was found to be 31.9 dB (range 10.0-86.3 dB) and that for controls 17.5 dB (7.5-38.8 dB) (P < 0.0005, Wilcoxon's matched pairs test). In NPC patients, 44 ears (55.0%) had abnormal hearing, of which 17 (21.3%), 5 (6.3%) and 22 (27.5%) ears had predominantly sensori-neural, conductive and mixed hearing losses, respectively. Nineteen ears had middle ear effusions, accounting for the majority of mixed and conductive hearing losses. In terms of individual patients, 8 (20.0%) and 18 (45.0%) patients had abnormal hearing in one year (monaural hearing disability) and both ears (binaural hearing disability), respectively. In conclusion, a substantial proportion of patients who have had radiotherapy for NPC, have hearing disability in the long-term, as compared to normal controls.

Long-term post-irradiation middle ear effusion in nasopharyngeal carcinoma.

This study aimed to find out if there were factors which influenced the development of long-term middle ear effusion (MEE) in patients irradiated for nasopharyngeal carcinoma. Thirty-five patients (70 ears) were studied for 2-8 years (mean 5.5 years) post-radiotherapy. The factors studied were (a) sex (b) age (c) tumour size and (d) presence of pre-radiotherapy MEE. Only the presence of pre-radiotherapy MEE was found to be statistically significant (P = 0.004, Fisher's exact test). Stepwise multiple regression analysis showed the presence of pre-radiotherapy MEE was a predictor of post-radiotherapy MEE with an odds ratio of 0.67. It is postulated that irreversible Eustachian tube dysfunction occurs when the tube which has been damaged by tumour is further damaged by irradiation. This may explain the frequent persistent otorrhea when ventilation tubes are used to treat post-radiotherapy MEE in patients with nasopharyngeal carcinoma. In conclusion, an ear with pre-irradiation MEE was almost seven times more likely to have long-term post-irradiation MEE than an ear without pre-irradiation MEE.

Hearing disability before and after radiotherapy for nasopharyngeal carcinoma.

This paper evaluates post-irradiation hearing changes in patients with nasopharyngeal carcinoma (NPC) from a disability orientated approach, which takes into account binaural hearing. Newly diagnosed patients with NPC were studied before radiotherapy, and at four to 12 months (mean 9.2 months) after radiotherapy, provided they remained disease-free. Each patient was examined clinically and with pure tone audiograms. Tympanometry was used to confirm middle ear effusion. Averaged hearing thresholds over 0.5, 1 and 2 kHz were evaluated. If abnormal (> 30 dB), the resultant hearing disability was illustrated by a modified Glasgow Plot. Twenty-three males and 10 females completed the study. Middle ear effusions resulted in 39.3 per cent (binaural in two patients) and 33.3 per cent (binaural in five patients) of patients having hearing disability pre- and post-irradiation respectively. No patient had hearing disability as a result of a sensorineural loss. It is recommended that future reporting of post-irradiation hearing changes in patients with NPC, as in middle ear surgery, be considered from a disability-orientated approach.

Factors contributing to delayed diagnosis in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) can be difficult to diagnose. Not only is the post-nasal space (PNS) inaccessible to examination, it is frequently occupied by normal lympho-epithelium which can make differentiation from NPC difficult. Together with its frequent atypical presentation, it is not surprising that the diagnosis is missed or delayed. This is undesirable as the treatment of early NPC carries an excellent prognosis. The aim of this study is to ascertain the extent of the problem of missed or delayed diagnosis and to study the factors responsible. This was a retrospective study of all newly diagnosed patients with NPC from the Singapore General Hospital and treated in the Department of Therapeutic Radiology in the year 1996 (1 January-31 December). A total of 126 patients were studied. Eighteen patients (14.3 per cent) were found to have delayed diagnosis of more than a month. The delay ranged from 1.2 to 25 months (mean 7.2 months). Factors identified which contributed to delayed diagnosis included i) Clinicians not considering a diagnosis of NPC ii) Clinicians suspecting NPC but misled by the results of investigations iii) Patients refusing investigation or defaulting follow-up. Nearly a fifth of patients with NPC had delayed diagnosis. Many of the factors responsible for the delays appear to be preventable by better patient education and counselling, doctors having sharper clinical acumen and skills in NPC diagnosis and the hospital administration having a system of tracking down high risk patients who default.

Lip and intraoral tumours: a local perspective.

Lip and intra-oral cancer is an uncommon disease in Singapore among the local population. The incidence is less than 1.5% of all cancers reported to the Singapore Cancer Registry which recorded a total of 18,049 cases of all types of cancer in a 5-year period from 1978 to 1982. The Department of Plastic Surgery at Singapore General Hospital has been conducting a multidisciplinary clinic for the management of head and neck tumours since 1984. The results of the distribution, age, sex and racial differences, risk factors and modalities of treatment of the various types of cancer affecting the lip and intraoral region were analysed in a prospective study. A total of 69 cases were analysed and of these 59 (85.5%) were squamous cell carcinoma (SCC) of varying grades of malignancy, the remaining comprising adenoidcystic and mucoepidermoid carcinoma, malignant melanoma and a single case of ameloblastoma. A number of predisposing factors such as smoking, alcohol and the chewing of betel nuts could be identified in the history of patients suffering from cancers involving the buccal mucosa and tongue. As the numbers involved in non-SCC are small in this study, the discussion will be confined to patients presenting with squamous cell carcinoma only.

Localised nodal non-Hodgkin's lymphoma--a study of 42 cases treated by radiotherapy.

The records of 42 patients with stage I and II nodal non-Hodgkin's lymphoma treated by radiotherapy with and without chemotherapy were analysed with regards to clinical presentation, investigations, treatment, radiotherapy techniques and results. The 5-year overall survival rates for all, low grade, intermediate grade and high grade histology types are 69.5%, 100%, 64.4% and 46.9% respectively. The 5-year relapse-free survival rates of those treated by initial radiotherapy alone for all, low grade and intermediate-high grade histology types are 54.8%, 46.9% and 59.4% respectively.

Concurrent chemoradiotherapy in patients with locally advanced nasopharyngeal carcinoma of the undifferentiated type.

The result with radiotherapy alone in patients with locally advanced nasopharyngeal carcinoma (NPC) was disappointing. Encouraging results have been reported with the use of concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck. Hence, we decided to explore the use of this treatment schedule in patients who presented with locally advanced disease (UICC/AJCC classification system). Between July 1995 and March 1996, 14 patients with locally advanced NPC were treated with the following schedule: radiation therapy was given conventionally to a total of 66 to 70 Gy to both the nasopharynx and neck with or without parapharyngeal/intracavitary boost; chemotherapy consisted of intravenous cisplatin at 20 mg/m2/day and intravenous 5-flurouracil 1000 mg/m2/day, infused over 8 hours on days 1 to 4 during the first and fifth week of radiation therapy. Depending on the patient's tolerability and clinical assessment of toxicity, a third cycle of chemotherapy was planned 4 to 5 weeks after the second cycle, upon the completion of the radiotherapy. Twelve patients completed all intended treatment. Two patients failed to do so due to treatment-related mortality. The median follow-up duration was 30 months. Limiting toxicities were myelosuppression and oropharyngeal mucositis. The overall response rate was a 100% at both the primary and nodal sites of disease. The median disease-free survival was 21 months. Forty per cent of the patients were alive at 3 years. This treatment schedule was associated with an unacceptable treatment-related death rate. As a result, this protocol was terminated.

Patient profile and survival in 270 computer tomography-staged patients with nasopharyngeal cancer treated at the Singapore General Hospital.

This is a report analysing the patient profile and survival results in 270 patients with nasopharyngeal carcinoma treated with radiation therapy between July 1987 and December 1988. The patients had a median age of 52.6 months, and a male-female ratio of 2.5:1. Ninety-four percent of patients were Chinese. The commonest presentation was that of a neck mass (found in approximately 65% of patients). Approximately two-thirds presented with disease more advanced than Ho's stage II. At a median follow-up of 52.6 months, the 5-year actuarial survival rate was 53% and the freedom from relapse rate was 57%. One hundred and seven patients died within the observation period. Of these, 46 patients had disease in the post nasal space, 41 in the neck and 60 in sites outside the head and neck.