A phase III randomized study of gemcitabine and cisplatin with or without PF-3512676 (TLR9 agonist) as first-line treatment of advanced non-small-cell lung cancer.

BACKGROUND: This open-label phase III study assessed the addition of Toll-like receptor 9-activating oligodeoxynucleotide PF-3512676 to gemcitabine/cisplatin chemotherapy in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naive patients with stage IIIB or IV NSCLC were randomized (1:1) to receive six or fewer 3-week cycles of i.v. gemcitabine (1250 mg/m2 on days 1 and 8) and cisplatin alone (75 mg/m2 on day 1, control arm) or combined with s.c. PF-3512676 0.2 mg/kg on days 8 and 15 of each chemotherapy cycle and weekly thereafter until progression or unacceptable toxicity (experimental arm). No crossover was planned. The primary end point was overall survival (OS). RESULTS: A total of 839 patients were randomized. Baseline demographics were well balanced. Median OS (11.0 versus 10.7 months; P=0.98) and median progression-free survival (PFS) (both 5.1 months) were similar between groups. Grade≥3 hematologic adverse events (AEs), injection-site reactions, and influenza-like symptoms were more frequently reported among patients receiving PF-3512676. At the first-interim analysis, the Data Safety Monitoring Committee recommended study discontinuation. Administration of PF-3512676 was halted based on efficacy futility and increased grade≥3 AEs (experimental arm). CONCLUSIONS: Addition of PF-3512676 to gemcitabine/cisplatin chemotherapy did not improve OS or PFS but did increase toxicity.

Trisomy 21 associated transient neonatal myeloproliferation in the absence of Down's syndrome.

Although usually associated with Down's syndrome, transient neonatal myeloproliferation (TMD) can occur in the absence of a constitutional trisomy 21. This report describes two such cases, both of whom had a trisomy 21 restricted to clonal cells. Unlike in previous such reported cases, spontaneous morphological, cytogenetic, and molecular remission in both cases was followed by re-emergence, in one case, of an evolved clone with a more malignant phenotype which required pharmacological intervention. Awareness that trisomy 21 bearing leukaemia in the neonatal period can be transient even in the absence of Down's syndrome is important to prevent unnecessary treatment. Equally, such cases require indefinite follow up as a proportion may have a recurrence which may require treatment.

Hepatitis C virus infection in multi-transfused children with haematological malignancy.

Transmission of hepatitis C virus (HCV) is an important hazard of blood transfusion and may result in chronic liver disease. 98 children from Nottingham and Sheffield with haematological malignancies were studied to determine the prevalence of HCV infection by enzyme immunoassay and RT/PCR techniques. The children had been exposed to up to 184 donors through red cell and platelet transfusion, the majority prior to routine testing for HCV infection in blood donors. Only one sample showed evidence of HCV infection being both ELISA and RT/PCR positive. None of the samples taken since donor screening were positive. This provides reassurance as to the low rate of HCV acquisition in multi-transfused patients in this part of the U.K. compared to other parts of the world.

Nocturnal enuresis in normal Jamaican children. Implications for therapy.

The prevalence of nocturnal enuresis has been investigated in 477 children (243 boys, 234 girls) attending government Basic Schools in Kingston, Jamaica. Enuresis, defined as wet at least 2 nights a week, occurred in 62%, 48%, 42% and 40% at 2, 3, 4 and 5 years of age, respectively. Enuresis, defined as wet at least one night a month, occurred in 68%, 58%, 53% and 52%, respectively. There was no significant difference between the sexes. Children with a family history of enuresis (first degree relatives wet beyond 8 years of age) were more likely to be enuretic than those with no family history, the difference reaching statistical significance for girls (less than 0.001) and for the sexes combined (p less than 0.001) but not for boys alone (p = 0.06). The prevalence of nocturnal enuresis in Jamaican children is higher than reported for Black children elsewhere, which in turn is higher than in their White counterparts. Cultural attitudes to bedwetting contribute to this variation and have implications for choice of therapy, both in Jamaica and elsewhere.

Nocturnal enuresis in normal Jamaican children: implications for therapy

The prevalence of nocturnal enuresis has been investigated in 477 children (243 boys, 234 girls) attending government Basic Schools in Kingston, Jamaica. Enuresis, defined as wet at least 2 nights a week, occurred in 62%, 48%, 42%and 40%at 2, 3, 4 and 5 years of age, respectively. Enuresis, defined as wet at least one night a month, occurred in 68%, 58%, 53%and 52%, respectively. There was no significant difference between the sexes. Children with a family history of enuresis (first degree relatives wet beyound 8 years of age) were more likely to be enuretic than those with no family history, the difference reaching statistical significance for girls (<0.001) and for the sexes combined (p <0.001) but not for boys alone (p=0.06). The prevalence of nocturnal enuresis in Jamaican children is higher than reported for Black children elsewhere, which in turn is higher than in their White counterparts. Cultural attitudes to bed-wetting contribute to this variation and have implications for choice of therapy, both in Jamaica and elsewhere.

Determinants of nocturnal enuresis in homozygous sickle cell disease.

The determinants of nocturnal enuresis in homozygous sickle cell (SS) disease have been investigated in 16 enuretic and 16 age and sex matched non-enuretic children. Overnight fluid deprivation tests (8pm-8am) demonstrated no significant difference in maximum urine osmolality or urine volumes, although the latter tended to be higher in the enuretic children. Maximum functional bladder capacity, estimated by maximum voided volume during oral fluid loading, was lower and the ratio of overnight urine volume to maximum functional bladder capacity higher in the enuretic than the non-enuretic group. Enuretic children were more likely than non-enuretics to be considered deep sleepers by their family. High urine volumes may contribute to nocturnal enuresis in SS disease, although the similar values in enuretic and non-enuretic children implies that additional factors determine the presence of enuresis. Low maximum functional bladder capacity, and a high ratio of overnight urine volume to maximum functional bladder capacity, appear to be important determinants.

Nocturnal enuresis in sickle cell haemoglobinopathies.

The prevalence of nocturnal enuresis (wet at least two nights a week) was investigated in children, aged 8, who were being followed up as part of a prospective cohort study. There were 175 children with homozygous sickle cell disease, 106 with sickle cell haemoglobin C disease, and 150 controls with a normal haemoglobin genotype. In homozygous sickle cell disease, 48 boys (52%) and 31 girls (38%) were enuretic, a significantly higher prevalence than in those with sickle cell haemoglobin C disease--five boys (10%) and 11 girls (20%)--or in normal children--16 boys (22%) and 13 girls (17%). There was no significant difference between children with sickle cell haemoglobin C disease and the normal genotype. Boys with homozygous sickle cell disease were significantly more likely to be enuretic if they came from large families; there was a similar trend for girls with homozygous sickle cell disease, although it did not reach significance. Enuresis was more common in boys with homozygous sickle cell disease who had low concentrations of fetal haemoglobin and in girls with sickle cell haemoglobin C disease who had high mean corpuscular haemoglobin concentrations. Similar associations were not shown for girls with homozygous sickle cell disease or boys with sickle cell haemoglobin C disease.

Dilemmas associated with antenatally detected urinary tract abnormalities.

Over a five year period 55 fetuses had abnormalities of the urinary tract detected by antenatal ultrasound scan. The incidence was 1:935 total births during a one year prospective study. Intrauterine intervention was undertaken in five for suspected obstructive uropathy, which was confirmed in only two. Of 51 live born infants, five died (two with renal failure), and only 18 (35%) had a clinically detectable abnormality at birth. Twenty seven patients underwent postnatal operations, the remainder being treated conservatively. Antenatal counseling was seldom undertaken by those responsible for the postnatal care. There were many instances of prospective parents receiving little or inappropriate information. Greater cooperation is required between all the staff concerned particularly as the natural history and appropriate postnatal management of some urinary tract abnormalities are still not known.