Effect of BRCA1 and XPG mutations on treatment response to trabectedin and pegylated liposomal doxorubicin in patients with advanced ovarian cancer: exploratory analysis of the phase 3 OVA-301 study.

BACKGROUND: We investigated the association of BRCA1 and XPG mutations with response rate (RR), progression-free survival (PFS) and overall survival (OS) in a subset of patients from a phase 3 clinical trial comparing the efficacy and safety of trabectedin + pegylated liposomal doxorubicin (PLD) versus PLD alone in patients with recurrent ovarian cancer. PATIENTS AND METHODS: A candidate array was designed based on the Breast Cancer Information Core database for BRCA mutation analyses. An exploratory analysis of BRCA1/XPG mutation status was conducted using a two-sided log-rank test and 0.05 significance in germline DNA samples from 264 women with failed first-line platinum-based chemotherapy, randomized (1 : 1) to trabectedin + PLD or PLD alone. RESULTS: Overall, 41 (16%) of the 264 women had BRCA1(mut) (trabectedin + PLD: n = 24/135, 18%; PLD: n = 17/129; 13%) and 17 (6%) had XPG(mut) (trabectedin + PLD: n = 8/135, 6%; PLD: n = 9/129, 7%). A higher RR was observed in BRCA1(mut) patients (20/41; 49%) versus BRCA1(wt) patients (62/223; 28%). Within the BRCA1(mut) group, trabectedin + PLD-treated patients had longer PFS and longer OS than PLD-treated patients (median PFS 13.5 versus 5.5 months, P = 0.0002; median OS 23.8 versus 12.5 months, P = 0.0086), whereas in BRCA1(wt) patients, OS was not significantly different (median OS: 19.1 versus 19.3 months; P = 0.9377). There were no differences in OS or PFS of patients with XPG(mut) between the two treatment arms. However, trabectedin + PLD-treated patients with XPG(mut) had a trend toward shorter PFS (median PFS: 1.9 versus 7.5 months; P = 0.1666) and OS (median OS: 14.5 versus 20.7 months; P = 0.1774) than those with XPG(wt). CONCLUSIONS: In this exploratory analysis, patients with recurrent ovarian cancer carrying the BRCA1(mut) had improved outcomes with trabectedin + PLD treatment compared with PLD alone. Prospective evaluation of BRCA status is likely an important evaluation for DNA-damaging agents and may significantly impact interpretation of clinical studies. XPG may be a biomarker of poor outcome in these patients.

Antenatal use of a novel vaginal birth training device by term primiparous women in Singapore.

INTRODUCTION: To study the use, safety and effectiveness of a novel antenatal vaginal birth training device (EPI-NO) in primiparous women. METHODS: Antenatal use of the EPI-NO vaginal birth trainer was prospectively studied in 31 primiparous booked patients who were delivered by obstetricians from July to December 2002 at the KK Women's and Children's Hospital. This was studied in relation to episiotomy rate, perineal trauma and analgesic requirements during the postpartum period. A patient questionnaire form was used to assess their perception of pain and how well they coped with its use. For comparison, perineal trauma was also studied retrospectively in 60 consecutive obstetrician-booked primiparous term patients who had normal vaginal delivery (NVD) and who did not use EPI-NO during the same study period. RESULTS: The mean length of usage was for 2.1 weeks (standard deviation [sd] 1.2 weeks). The mean frequency of use was 5.3 episodes per week (sd 2.1, range 1 to 7). There was no laceration and vaginal infection arising from its usage. There was a case of minimal bleeding post-usage. There were 20 (64.5 percent) NVDs, four (12.9 percent) forceps deliveries, five vacuum deliveries (16.1 percent) and two (6.5 percent) Caesarean sections. Of the 29 vaginal delivery cases, 19 (65.5 percent) had episiotomy, eight (27.6 percent) had lacerations, and two (6.9 percent) did not sustain laceration. The reasons for episiotomy in the 19 cases were nine cases of pending tearing of vagina/perineum, nine cases of instrumental vaginal deliveries, and one to shorten second stage. There was no third degree tear. 21 (67.7 percent) out of 30 required a painkiller. The majority of patients (17; 54.8 percent) appeared to be comfortable with the use of EPI-NO. All coped well with vaginal examination after using EPI-NO perineal training. Comparing among term primiparous NVD cases with (n value equals 20) and without (n value equals 60) EPI-NO, the perineal trauma rate (90.0 percent vs 96.6 percent, p value equals 0.24) was slightly but not significantly lower in the EPI-NO group. The episiotomy rate was significantly lower (50.0 percent vs 93.3 percent, p value is less than 0.0001) and the extent of perineal trauma in the patient appeared to be less severe in cases using EPI-NO. CONCLUSION: EPI-NO appeared to be safe and acceptable to the majority of users. Although birth training with EPI-NO significantly decreases the rate of episiotomies in term primiparous patients, and the degree of perineal tissue injury appeared to be less in the EPI-NO group especially among those with lacerations, the overall perineal trauma rate was slightly but not significantly lower, in view of the higher spontaneous laceration rate in the EPI-NO group.

CTLA-4 gene A-G polymorphism and childhood Graves' disease.

OBJECTIVE: Graves' disease is associated with a polymorphism at position 49 in exon 1 of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene in Caucasians and Japanese. A high incidence of childhood Graves' disease has been documented in Hong Kong Chinese. The aims of this study were to investigate the CTLA-4 gene A-G polymorphism association in Chinese children with Graves' disease. PATIENTS AND DESIGN: One hundred and twenty-three Chinese children with Graves' disease (104 girls and 19 boys) and 158 racially matched healthy controls were recruited for the study. Genomic DNA was extracted from venous blood samples. The dimorphism at position 49 A-G was analysed by polymerase chain reaction, single-strand conformation polymorphism and restriction fragment-length polymorphism analysis. RESULTS: The genotype distribution and allele frequencies of children with Graves' disease differed significantly from those of the controls (P = 0.0023 and P = 0.022, respectively). The presence of at least one G allele (GG or AG) was associated with an increased risk of Graves' disease (OR = 6.8, 95% CI = 2.0-36.1; P = 0.001). CONCLUSIONS: This study confirms that CTLA-4 49 A-G polymorphism is associated with Graves' disease in Chinese children. The CTLA-4 49 G allele confers an increased risk of childhood Graves' disease.

Changes in markers of bone metabolism during dexamethasone treatment for chronic lung disease in preterm infants.

AIM: To characterise the change in serum and urinary bone markers in the early postnatal period, and to assess the effect of systemic corticosteroid on bone metabolism in preterm infants. METHODS: Bone formation was quantified by measurement of serum concentrations of bone specific alkaline phosphatase (BALP) and osteocalcin. Bone resorption was measured by monitoring creatinine adjusted urinary deoxypyridinoline (Dpd) concentration. Blood and urinary samples were collected from corticosteroid treated infants (n = 19) immediately before the start (T(d-pre)), three weeks after the start (T(d-end)), and two (T(d-post2)) and four weeks (T(d-post4)) after the end of the dexamethasone course. Untreated patients (n = 30) had specimens taken at week 3 (T(wk-3)), 6 (T(wk-6)), 8 (T(wk-8)), and 10 (T(wk-10)) of postnatal age. RESULTS: Serum concentrations of BALP and osteocalcin at T(d-end) were significantly lower than pretreatment levels and the levels at the corresponding time point (T(wk-6)) of the non-treatment group. In contrast, urinary Dpd concentration at T(d-end) was not significantly decreased compared with the pretreatment level. However, it was significantly lower than the urinary Dpd concentration at T(wk-6) of the non-treatment group. The rate of increase in lower leg length was significantly higher in the non-treatment group between weeks 3 and 6 than in the corresponding period during dexamethasone treatment in the corticosteroid group. CONCLUSION: Systemic corticosteroid causes appreciable suppression of serum BALP and osteocalcin and, to a lesser extent, urinary Dpd. The results suggest that corticosteroid inhibits bone growth mainly by decreasing bone formation.

Increasing incidence of childhood Graves' disease in Hong Kong: a follow-up study.

OBJECTIVE: Childhood Graves' disease has been reported to be rare but preliminary epidemiological data on its incidence appeared to be high in Hong Kong Chinese children. The aim of this study is to determine the incidence of childhood Graves' disease in Hong Kong and to analyse whether there is an increasing trend of the incidence. PATIENTS AND DESIGN: We established a registry of childhood Graves' disease at our centre to collect cases from four districts in Hong Kong. The diagnosis of Graves' disease was based on clinical features, diffused enlargement of thyroid gland, raised free thyroxine or triiodothyronine levels, suppressed TSH levels, and the presence of thyroid receptor antibodies. Confirmed cases of Graves' disease who resided in any of the four districts were used to calculate the incidence for the study period between 1989 and 1998. RESULTS: One hundred and eighteen Chinese children under 15 years of age had a confirmed diagnosis of Graves' disease during the study period from January 1989 to December 1998. There were 11 boys and 107 girls giving a male to female ratio of 1 : 9.7. The overall incidence rates were 3.2/100 000/year and 6.5/100 000/year for the two periods 1989-93 and 1994-98, respectively. The incidence rates for girls have increased significantly (P < 0.001) from 3.8/100 000/year in 1989 to 14.1/100 000/year in 1998. The current incidence of childhood Graves' disease in our population is about eight times that reported in Danish children. CONCLUSIONS: This study confirms the high incidence of childhood Graves' disease in Hong Kong and documents an increasing trend for girls. Further studies are required to reveal possible genetic or environmental factors responsible for such epidemiology in Hong Kong Chinese children.

Sex differences in the growth of diabetic children.

To investigate the effect of diabetes on the growth of children and to detect possible impairment of their final height, 58 Chinese subjects (22 boys; 36 girls) with childhood diabetes were studied longitudinally from diagnosis. Mean onset age at presentation was 8. 70 years. All patients were measured and weighed at diagnosis and every 3-4 months during the follow up period. Their height and weight measurements were converted to standard deviation scores (S.D. S.) using normal height and weight-for-height reference standards for Chinese children established in Hong Kong. The mean height S.D.S. for boys and girls at diagnosis were +0.76 and -0.07 (P=0.015). The mean final height S.D.S. for boys and girls were +0.14 and -0.57. The final heights of girls were significantly shorter than their target heights. At attainment of final height for diabetic girls, their mean weight-for-height S.D.S. was +0.76 indicating that they tended to become overweight. This study demonstrates the sex differences in the growth of diabetic children. Diabetic boys were tall for age at presentation but they achieved average final heights while diabetic girls attained below average adult stature and they tended to become obese.

Directional line detectors in correlated noisy environments.

In this research, we present a methodology for extracting very narrow lines in correlated noisy environments. The approach is a generalization of the analysis of variance applied to the symmetrically balanced incomplete-blocks design. It encompasses many well-known algorithms when subjected to more restrictive conditions. The detector is robust and superior to the polynomial-approximation-based detector and the classical Prewitt detector. The procedure detects narrow lines embedded in nonuniform background without compromising resolution, and performs satisfactorily in severe corruptive noise. Extensive computer simulations demonstrate the practicality of the detector on real imaging environments.

Growth in childhood thyrotoxicosis.

UNLABELLED: Childhood thyrotoxicosis is an uncommon condition. To investigate the effect of thyrotoxicosis on the growth of children and to detect possible influence of the disease on their final height, 105 Chinese children (90 girls; 15 boys) with thyrotoxicosis were studied longitudinally from diagnosis. At presentation their mean age was 11. 57 years. Their height and weight measurements were converted to standard deviation scores (SDS) using normal height and weight-for-height reference standards for Chinese children established in Hong Kong. Their mean height SDS at diagnosis was +0. 73. Bone age assessment at diagnosis was done in 48 girls and 8 boys and their mean +/- S.D. bone development quotient was 1.16 +/- 0.11. A total of 53 girls have reached adult height and their mean height was 161.3 cm, corresponding to a SDS of +0.63. Their final heights significantly exceeded their target heights. CONCLUSION: This study demonstrates that children with thyrotoxicosis were tall for age and their bone ages were advanced at presentation. They continued to be tall for age after starting treatment and they achieved final heights exceeding their target height.

[Peripheral T-lymphocyte subsets changes in patients with endocrine and metabolic diseases].

In this study the authors utilized the OKT monoclonal anti-human T lymphocyte antibodies to determine the normal level of T lymphocyte subsets in the peripheral blood of 30 healthy volunteers, 36 patients with Graves' disease (GD), 4 with hypothyroidism and 30 with diabetes mellitus (DM). It is shown that OKT+3, OKT+4 OKT+8 and OKT+4/OKT+8 ratio of T-lymphocyte subsets in the peripheral blood of 30 healthy volunteers were 72.4 +/- 5.1%, 38.9 +/- 5.2%, 26.8 +/- 4.3% and 1.5 +/- 0.3. In 36 patients with GD OKT+3 was 67.6 +/- 5.8%, OKT+4 was 33.8 +/- 6.6% and OKT+8 was 17.9 +/- 6.1%. These were all significantly lower than those of normal controls (P less than 0.001). OKT+4/OKT+8 ratio was 2.1 +/- 0.6, which was significantly higher (P less than 0.001). The value of OKT+4 and OKT+8 in 10 patients with GD after treatment were markedly elevated. However, the ratio of OKT+4/OKT+8 was significantly decreased (P less than 0.05). OKT+3 of 4 cases of hypothyroidism was 69.7 +/- 3.35%, being similar to that of normal controls (P greater than 0.2). OKT+4 and OKT+8 were 31.73 +/- 4.99% and 18 +/- 2.94% respectively, both of which being markedly decreased (P less than 0.01). The ratio of OKT+4/OKT+8 was 1.97 +/- 0.22, being not significantly elevated (P greater than 0.05). OKT+3, OKT+4 and OKT+8 of 23 cases with DM were 68.8 +/- 7.2% (P less than 0.05), 33 +/- 8.1% (P less than 0.005), and 21.2 +/- 6.5% (P less than 0.001) respectively. All of these were significantly decreased. The ratio of OKT+4/OKT+8 was 1.6 +/- 0.5, being not significantly changed.