A Diagnostic Program for Patients Suspected of Having Lung Cancer

BackgroundA standardized diagnostic program, initiated to reduce the length of the diagnostic track and to improve application of diagnostic tools for patients referred with suspicious abnormalities on standard chest radiographs, was evaluated.MethodsThe findings on integrated positron emission tomography/computed tomography (PET-CT) determined the choice of invasive investigations to be performed the same day. Diagnostic results, time courses, and number and sorts of applied invasive investigations were assessed.ResultsIn 297 eligible patients, malignant disease was diagnosed in 72% and benign disease was diagnosed in 26% of patients. One percent of the patients had no abnormalities at all. For 85% of patients with malignancy, investigations were completed in 1 day, resulting in a diagnosis and definitive clinical disease stage. The median time from start of the analysis to informing the patient about diagnosis and tumor stage was 7 days. One invasive investigation was performed in 53% of patients in the study group, and at least 2 investigations were performed in 33% of patients. Bronchoscopies formed a part of the diagnostic process in 59% of patients. Surgical diagnostic procedures were performed in 8% of patients.ConclusionThe diagnostic program resulted in a short time to diagnosis, with finalization of invasive investigations in 1 day in the majority of patients. The imaging-based choice of invasive investigations precluded bronchoscopies in a substantial portion of the patients.     

Economic analysis comparing induction of labour and expectant management for intrauterine growth restriction at term (DIGITAT trial)

Objective

Pregnancies complicated by intrauterine growth restriction (IUGR) are at increased risk for neonatal morbidity and mortality. The Dutch nationwide disproportionate intrauterine growth intervention trial at term (DIGITAT trial) showed that induction of labour and expectant monitoring were comparable with respect to composite adverse neonatal outcome and operative delivery. In this study we compare the costs of both strategies.

Study design

A cost analysis was performed alongside the DIGITAT trial, which was a randomized controlled trial in which 650 women with a singleton pregnancy with suspected IUGR beyond 36 weeks of pregnancy were allocated to induction or expectant management. Resource utilization was documented by specific items in the case report forms. Unit costs for clinical resources were calculated from the financial reports of participating hospitals. For primary care costs Dutch standardized prices were used. All costs are presented in Euros converted to the year 2009.

Results

Antepartum expectant monitoring generated more costs, mainly due to longer antepartum maternal stays in hospital. During delivery and the postpartum stage, induction generated more direct medical costs, due to longer stay in the labour room and longer duration of neonatal high care/medium care admissions. From a health care perspective, both strategies generated comparable costs: on average €7106 per patient for the induction group (N = 321) and €6995 for the expectant management group (N = 329) with a cost difference of €111 (95%CI: €−1296 to 1641).

Conclusion

Induction of labour and expectant monitoring in IUGR at term have comparable outcomes immediately after birth in terms of obstetrical outcomes, maternal quality of life and costs. Costs are lower, however, in the expectant monitoring group before 38 weeks of gestation and costs are lower in the induction of labour group after 38 weeks of gestation. So if induction of labour is considered to pre-empt possible stillbirth in suspected IUGR, it is reasonable to delay until 38 weeks, with watchful monitoring.     

DNA methylation analysis in self-sampled brush material as a triage test in hrHPV-positive women

Background:

Primary high-risk human papillomavirus (hrHPV) testing in cervical cancer screening shows relatively low specificity, which makes triage testing necessary. In this study, DNA methylation analysis was compared with cytology for triage testing in hrHPV-positive women. Moreover, feasibility of DNA methylation analysis directly on brush-based self-sampled specimens was assessed.

Methods:

Non-responding women from population-based screening were invited to self-collect a cervico-vaginal specimen for hrHPV testing; hrHPV-positive women were referred to a physician for triage liquid-based cytology. DNA methylation analysis was performed on 128 hrHPV-positive physician-collected triage samples and 50 matched brush self-samples with QMSP for C13ORF18, EPB41L3, JAM3 and TERT.

Results:

In physician-taken triage material, DNA methylation analysis of JAM3 showed the highest combined specificity (88%) and sensitivity (82%) for detection of CIN3+, whereas cytology showed a specificity of 48% and a sensitivity of 91%. Out of 39 women with abnormal cytology and normal histology (false-positive by cytology), 87% were negative for JAM3 and 90% for C13ORF18 methylation. Agreement between DNA methylation analysis performed directly on the matched self-sampled material and physician-taken samples was 88% for JAM3 (κ=0.75, P<0.001) and 90% for C13ORF18 (κ=0.77; P<0.001).

Conclusions:

DNA methylation analysis as a triage test in hrHPV-positive women is an attractive alternative to cytology. Furthermore, DNA methylation is feasible directly on brush-based self-samplers and showed good correlation with matched physician-taken samples. Direct molecular triage on self-collected specimens could optimise the screening program, especially for non-responders, as this would eliminate the need for an additional physician-taken scraping for triage testing.     

Intratumoral rhIL-12 administration in head and neck squamous cell carcinoma patients induces B cell activation

The objectives of this study were to investigate the effects of intratumorally (i.t.) administered recombinant human interleukin-12 (rhIL-12) on the distribution and function of B cells in the primary tumors, the locoregional lymph nodes and peripheral blood of head and neck squamous cell carcinoma (HNSCC) patients. The initial characterization of the patients participating in the phase Ib and phase II studies has previously been reported. After rhIL-12 treatment, fewer secondary follicles with a broader outer region of the mantle zones and an increase in interfollicular B-blasts were seen in the enlarged lymph nodes compared with control HNSCC patients. The size of the germinal center (GC) was diminished, partly due to a decrease in the number of CD57+ GC cells that have been associated with immune suppression. These changes did not correlate with signs of apoptosis or CXCR5 expression by B cells. Strikingly, in 3 out of 4 IL-12 treated patients, increased IFN-gamma mRNA expression by B cells was detected. In addition, a highly significant IgG subclass switch was seen in the plasma with more IgG1, less IgG2 and more IgG4, indicating a switch to T helper 1 phenotype. Finally, peritumoral B cell infiltration was a positive prognostic sign for overall survival in the 30 HNSCC patients investigated, irrespective of IL-12 treatment. In conclusion, these data indicate that after i.t. IL-12 treatment in HNSCC, significant activation of the B cell and the B cell compartment occurred and that the presence of tumor infiltrating B cells correlated with overall survival of HNSCC patients.     

Optic neuropathy in McCune-Albright syndrome: an indication for aggressive treatment

McCune-Albright syndrome consists of the triad polyostotic fibrous dysplasia, café-au-lait spots and autonomous hyperfunction of one or more endocrine systems. The most frequent neurological complication of craniofacial fibrous dysplasia is visual loss. We describe a 17-y-old boy with McCune-Albright syndrome and acute loss of vision in the left eye caused by encroachment of the left optic nerve by fibrous dysplastic lesions. Neurosurgical intervention improved left eye vision. Aggressive intervention is indicated in cases of acute visual loss in patients with craniofacial fibrous dysplasia. This is supported by a review of other reported cases.     

Hyperhomocysteinemia in premature arterial disease: examination of cystathionine {beta}-synthase alleles at the molecular level

Hyperhomocysteinemia occurs in approximately 30% of the patientswith premature occlusive arterial disease (POAD). Some of theseexhibit significantly reduced fibroblast cystathionine ß-synthase(CBS) activities, suggesting that they may be heterozygous forCBS deficiency. To test this possibility, we studied cDNA derivedfrom four well characterized patients with POAD, exhibitinghyperhomocysteinemia and reduced CBS activities, from four normalcontrols, and from four obligatory heterozygotes for CBS deficiency.Lysates of individual colonies of E.coli, containing full-lengthPCR-amplification products in the expression vector, pKK388.1,were tested for CBS activity. cDNA from at least seven of theeight possible independent POAD alleles encoded catalyticallyactive, stable CBS which exhibited normal response to both PLPand AdoMet. The sequences of all 3'-untranslated regions ofall seven isolated POAD alleles were identical to the normal,wild-type CBS sequences. The results of the expression studieswere confirmed for one POAD patient by determining the full-lengthcDNA sequences for both alleles; these were entirely normalover the complete length of the cDNA. In contrast, the screeningmethod correctly distinguished mutant from normal alleles inall four obligatory heterozygotes studied. We conclude thatCBS mRNAs from POAD individuals are free from inactivating mutations,including all 33 previously identified in heterozygous carriersand homocystinuric patients.     

Progress Towards Optimal Trial End-Points in Rheumatoid Arthritis

Trials in rheumatoid arthritis have been difficult to perform and interpret due to disagreement over what to measure. This paper reviews the most frequently used measures and their validity against the background of the Outcome Measures in Rheumatology (OMERACT) consensus conferences. These conferences have resulted in the adoption of a core set of end-points to be used as a minimum in all clinical trials in rheumatoid arthritis. These are known as the World Health Organization/International League of Associations for Rheumatology (WHO/ILAR) core set. This set of measures comprises: pain;patient global assessmentphysical disability;swollen joints;tender joints;acute phase reactants;physician (assessor) global assessment; and, in studies of 1 or more years duration,radiographs of joints. Other developments include a renewed interest in aggregate end-points (indices) such as response criteria, and in the measurement of adverse effects and economic costs. In sum, measurement methodology in rheumatoid arthritis has been improved in time to take advantage of expected important advances in treatment.     

Angiographic findings in homocystinuria

Homocystinuria (HC) is an inborn error of amino acid metabolism characterized by ectopia lentis, mental retardation, and skeletal abnormalities. Vascular disorders may also occur in HC, although they are less common. Arteriographic studies of two sisters with HC are described. The younger woman's renal arteries showed wall irregularities and aneurysms, narrowing of the celiac and superior mesenteric arteries, and some aneurysmatic changes. In the older patient, irregular right carotid and splenic arteries were seen and a splenic aneurysm was present.