Optimisation of irinotecan dose in the treatment of patients with metastatic colorectal cancer after 5-FU failure: results from a multinational, randomised phase II study

Although irinotecan 350 mg m(-2) is a standard option for relapsed/refractory advanced colorectal cancer, there is some evidence that suggests that a higher dose may be more effective, with acceptable tolerability, following 5-fluorouracil (5-FU). This study assessed the optimal dosing strategy for irinotecan, along with treatment efficacy and safety. A total of 164 patients with metastatic colorectal cancer progressing after failure on 5-FU or raltitrexed received either 350 mg m(-2) irinotecan (Group A; n=36) or 250, 350 or 500 mg m(-2), according to individual patient tolerance (Group B; n=62) or based on risk factor optimisation (Group C; n=66). There were no complete responses. There was a trend towards a higher overall response rate in Group B (13%) than in Groups A (8%) and C (9%). Tumour control growth rate was high in all three groups: 58% in group A, 60% in Group B and 50% in Group C. A total of 34% of patients in Group B and 9% in Group C were able to receive a dose of 500 mg m(-2). Median duration of response and time to progression were significantly longer in Groups A and B compared with Group C. No significant between-group differences for any adverse events were seen, although there was a small trend towards better tolerability in Group B. Individual dose escalation based on patient tolerance may allow more patients to receive a higher irinotecan dose without causing additional toxicity and can be an appropriate patient management strategy.     

Three cases of hypotension and syncope with ventricular pacing: Possible role of atrial reflexes

Hypotension with lightheadedness and near syncope occurred in three patients during effective ventricular pacing. Hemodynamic studies demonstrated a decrease in cardiac output ranging from almost no decrease to 15 percent, presumably related to the loss of effective atrial contraction. The decrease in output was too small to explain by itself the reduced blood pressure, which resulted from paradoxic reduction of total peripheral resistance in one patient and from failure of resistance to increase in two. Baroceptor reflexes (Valsalva response) were normal in all three patients; hence it is suggested that the failure of compensatory increases in total peripheral resistance may be due to a reflex from the sudden atrial distension that occurs during atrioventricular (A-V) dissociation. The fluctuations in arterial pressure during ventricular pacing were synchronous with the appearance of cannon waves in the right atrial pressure tracing.Arterial pressure during A-V dissociation thus appears to be balanced by two opposite reflexes: the baroceptor reflex, which attempts to compensate for reduction in output, and atrial distension, which reduces peripheral resistance.     

Auditory neuropathy in patients carrying mutations in the otoferlin gene (OTOF)

Inherited hearing impairment affects one in 2,000 newborns. Nonsyndromic prelingual forms are inherited mainly as autosomal recessive traits, for which 16 genes are currently known. Mutations in the genes encoding connexins 26 and 30 account for up to 50% of these cases. However, the individual contribution of the remaining genes to the whole remains undetermined. In addition, for most of the genes there is a need for studies on genotype-phenotype correlations, to identify distinctive clinical features which may direct the molecular diagnosis to specific genes. Here we present a mutation analysis and a genotype-phenotype correlation study on the gene encoding otoferlin (OTOF), responsible for the DFNB9 subtype of prelingual hearing impairment. Four novel mutations were identified: c.2122C>T (p.Arg708Ter), c.4275G>A (p.Trp1425Ter), c.4362+2T>G, and c.5860_5862delATC (p.Ile1954del). A total of 37 subjects with mutations in OTOF were studied clinically. They were phenotypically homogeneous, having profound hearing impairment with very early onset, as shown by pure-tone audiometry and auditory brainstem responses. Magnetic resonance imaging and computed tomography did not reveal any inner ear malformation. Unexpectedly, transient evoked otoacoustic emissions (TEOAEs) were present, either bilaterally or unilaterally in 11 subjects. Altogether, clinical data of these subjects met the diagnostic criteria of auditory neuropathy. A total of 10 subjects had been successfully provided with cochlear implants. The results of our study indicate that genetic diagnosis of subjects with auditory neuropathy and profound hearing impairment should be directed to the otoferlin gene. Our data are of concern to universal screening programs which use TEOAEs as the first detection test for hearing impairment in newborns, since this technique may overlook a nonnegligible proportion of cases.     

Prevalence and treatment of isolated and concurrent hypertension and hypercholesterolaemia in the United Kingdom

AIMS

To determine the prevalence and treatment of hypertension, dyslipidaemia and both together in the UK between 1998 and 2006.

METHODS

We used The Health Improvement Network (THIN) a general practice-based database from 1998 to 2006 and we compared the 1998 and 2003 data to that taken from the Health Survey for England (HSE) in 1998 and 2003.

RESULTS

The prevalence (treatment) of hypertension was 25.3% (11.4%) in 1998, 27.8% (15.1%) in 2003 and 26.9% (16.2%) in 2006 in THIN. In HSE it was 37.3% (9.6%) in 1998 and 32.9% (13.8%) in 2003. For dyslipidaemia the figures were 8.6% (1.9%), 18.5% (6.5%) and 24.4% (9.8%) for THIN and 67.8% (2.3%) and 74.9% (7.0%) for HSE. Concurrent hypertension and dyslipidaemia in THIN increased from 5.5% (1.1%) in 1998 to 13.5% (4.5%) in 2003 and 17.4% (7.1%) in 2006. The prevalence of both conditions was 30.6% (0.7%) in HSE in 1998 and 28.7% (3.1%) in 2003.

CONCLUSIONS

There has been a progressive improvement in the detection and treatment of hypertension, dyslipidaemia and both conditions together between 1998 and 2006. However, much still needs to be done to improve the diagnosis and treatment of hypertension, hypercholesterolaemia and concurrent hypertension and hypercholesterolaemia in the United Kingdom.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The 1998 and 2003 Health Survey for England revealed a high prevalence of hypertension and hypercholesterolaemia in the population of England.
• Major changes in the reimbursement of primary care for the management of both hypertension and hypercholesterolaemia have occurred in the UK.

WHAT THIS STUDY ADDS

• Using a GP database we have examined the proportion of subjects diagnosed and treated for hypertension and hypercholesterolaemia over time. To examine the true population rates and primary care data we compared the results of the Health survey for England in both 1998 and 2003 with the recorded data on GP computers.
• Despite current guidelines, many patients with hypertension and/or hypercholesterolaemia are under-treated and, even amongst those who are treated, many do not achieve their blood pressure and/or lipid targets.
• Although treatment rates in the UK have improved recently, particularly for lipid-lowering therapies, they remain suboptimal.

     

High dose etretinate and interferon-alpha--a phase I study in squamous cell carcinomas and transitional cell carcinomas.

Simultaneous exposure to retinoids and interferons can result in enhanced antiproliferative and differentiating effects on malignant lesions. We studied the toxicity and the potential efficacy of an association of high dose etretinate and Interferon-alpha (IFN-alpha) in squamous cell carcinomas of the lung, head and neck, the esophagus, cervix and the penis, as well as in transitional carcinomas of the bladder. The treatment consisted of etretinate (Tigason) 4 mg/kg/d on 2, 3, 4 and finally 5 consecutive days every other week and IFN-alpha (Roferon) 6 Mio IU sc. q.d. for 5 days every week. Of 24 patients enrolled, 23 were assessable for toxicity and 20 for response. With two occurrences of grade 3 cutaneous toxicity, the administration of etretinate (Tigason) 4 mg/kg/d on 5 consecutive days every other week and IFN-alpha (Roferon) 6 Mio IU sc. q.d. for 5 days every week was considered to be the MTD. Toxicity was mild otherwise, mostly at grades 1 and 2 level, causing fatigue, skin peeling and erythema, mucositis and cheilitis; 3 PR (partial response) and 8 SD (stable disease) were recorded. Of the responders, one patient had become resistant to cisplatin-based chemotherapy and the other two had at no time ever received systemic therapy. We conclude that the association of high doses of etretinate and IFN-alpha has moderate activity in squamous cell carcinomas, is well tolerated, and that IFN-alpha plays a role in the improved tolerance of the retinoid.     

Pamidronate for pain control in patients with malignant osteolytic bone disease: a prospective dose-effect study

In a prospective dose-escalation study tolerability and effectiveness of repeated infusions with intravenous pamidronate were investigated. A total of 80 patients with proven malignancy and pain due to osteolytic bone disease were enrolled. Doses of 30 mg, 45 mg, 60 mg and 90 mg pamidronate, given every 4 weeks, 3 weeks or 2 weeks were tested. Thus dose intensity was increased by giving higher doses and/or by shortening the intervals. A combined palliation score on the bases of pain score (WHO), analgesic score (WHO) and improvement of performance status (SAKK/ECOG) was rated by the physician on a six-point scale. Regression analysis showed a close correlation between dose intensity and effect (Pearson's R=0.7: P<0.0001). A statistically significantly different palliative score for patients treated with low (below 15 mg/week), medium (16–30 mg/week) and high doses (above 31 mg/week) of pamidronate was found (P=<0.01). A dose intensity below 10 mg pamidronate/week and single doses of 30 mg had no clinically relevant benefit, whereas dose intensities of 25–45 mg/week showed a significant palliative effect. We conclude that pamidronate should be given in a close intensity of 20 mg per week or more in patients with far advanced osteolytic bone disease. Best results are obtained with high doses of 60 mg or 90 mg pamidronate. Further investigations by prospective randomized trials are needed to determine the optimal dose and schedule of pamidronate infusions.     

Impact of Non-routine Vaccination on the Incidence of Invasive Haemophilus influenzae Type b (Hib) Disease: Experience in the Autonomous Region of Valencia, Spain

OBJECTIVE: This study assessed the impact of non-routine vaccination against invasive Haemophilus influenzae (Hib)disease before the introduction of universal childhood Hib vaccination. METHODS: Data were obtained from a prospective surveillance program for invasive bacterial diseases in children <15 years of age that was begun in the Autonomous Region of Valencia on 1 December 1995. RESULTS: An incidence of 15.5 cases of invasive Hib disease per 100,000 children <5 years of age was reported in the first year of the surveillance program (from 1 December 1995 to 30 November 1996), when Hib vaccination coverage was estimated to be 32.5%. An increase in vaccination coverage to 44% in the second year (1 December 1996 to 30 November 1997) was associated with a reduction in disease incidence to 3.3 cases per 100,000. After the initiation of universal vaccination in December 1998, only two cases were reported. The effectiveness of non-routine vaccination was 71% in 1997. CONCLUSIONS: These results show that before the introduction of routine childhood Hib vaccination, widespread use of the vaccine can dramatically reduce the occurrence of invasive Hib disease.