Initial management of low‐risk localized prostate cancer in the UK: analysis of the British Association of Urological Surgeons Cancer Registry

Study Type – Therapy (outcomes research)
Level of Evidence 2c

OBJECTIVE

To assess the patterns of care for low‐risk localized prostate cancer. Management of this condition is highly controversial, with a range of treatment options, but there are no published UK data.

METHODS

Data from the British Association of Urological Surgeons (BAUS) Cancer Registry were linked to the UK Association of Cancer registries postcode directory. The demographic and clinical characteristics, and the initial management of men diagnosed with low‐risk localized prostate cancer in the UK between 2000 and 2006 were analysed.

RESULTS

In all, 43 322 cases of localized prostate cancer were recorded in the BAUS Registry between 2000 and 2006, of which 8861 (20%) met the criteria for low‐risk disease. The proportion classified as low risk ranged from 16% in 2000 to 21% in 2006. The proportion of men with low‐risk disease opting for ‘watchful waiting’ increased from 0% to 39% over the same period. Treatment choice was associated with socio‐economic status. For example, radical prostatectomy was chosen by 34% of patients in the most affluent quintile, compared with 19% in the most deprived quintile (P= 0.01).

CONCLUSION

The management of low‐risk localized prostate cancer in the UK has changed markedly in recent years, and contrasts with that in the USA. The association observed between socio‐economic status and choice of treatment deserves further study.     

Indomethacin inhibits bone formation in inductive allografts but not in autografts: studies in rat

Background Non-steroidal anti-inflammatory drugs (NSAIDs) are known to have inhibitory effects on new bone formation. We wanted to analyze some effects of the NSAID indomethacin on different inductive stimuli for bone formation.

Methods We experimentally induced heterotopic new bone with demineralized allogeneic bone matrix (DABM) and with bone autografts in rats, in order to study the effects of indomethacin on new bone formation at 3 and 6 weeks.

Results Indomethacin inhibited net bone formation in DABMs by 30% at 6 weeks. At 6 weeks, the mineral accretion rate was unaffected, indicating that it is at the early phase of the inductive process that mineral accretion is sensitive to inhibition by indomethacin, but not at the later stages.

In traumatized skeletal bone, the ⁴⁵Ca-specific activity was higher than in non-traumatized bone, while indomethacin significantly reduced the ⁴⁵Ca uptake at 3 weeks, but not at 6 weeks.

In the autografts, a net mineral loss occurred, but neither mineral content nor ⁴⁵Ca incorporation was affected by Indomethacin treatment.

Interpretation Indomethacin inhibited the early phase of new bone formation in heterotopic DABMs and the early bone healing process in traumatized skeletal bone, but did not affect resorption or bone formation in heterotopic autografts. ▪     

A new source for cardiovascular tissue engineering: human bone marrow stromal cells

Objective: Vascular-derived cells represent an established cell source for tissue engineering of cardiovascular constructs. Previously, cell isolation was performed by harvesting of vascular structures prior to scaffold seeding. Marrow stromal cells (MSC) demonstrate the ability to differentiate into multiple mesenchymal cell lineages and would offer an alternative cell source for tissue engineering involving a less invasive harvesting technique. We studied the feasibility of using MSC as an alternative cell source for cardiovascular tissue engineering. Methods: Human MSC were isolated from bone marrow and expanded in culture. Subsequently MSC were seeded on bioabsorbable polymers and grown in vitro. Cultivated cells and seeded polymers were studied for cell characterization and tissue formation including extracellular matrix production. Applied methods comprised flow cytometry, histology, immunohistochemistry, transmission (TEM) and scanning electron microscopy (SEM), and biochemical assays. Results: Isolated MSC demonstrated fibroblast-like morphology. Phenotype analysis revealed positive signals for alpha-smooth muscle actin and vimentin. Histology and SEM of seeded polymers showed layered tissue formation. TEM demonstrated formation of extracellular matrix with deposition of collagen fibrils. Matrix protein analysis showed production of collagen I and III. In comparison to vascular-derived cell constructs quantitative analysis demonstrated comparable amounts of extracellular matrix proteins in the tissue engineered constructs. Conclusions: Isolated MSC demonstrated myofibroblast-like characteristics. Tissue formation on bioabsorbable scaffolds was feasible with extracellular matrix production comparable to vascular-cell derived tissue engineered constructs. It appears that MSC represent a promising cell source for cardiovascular tissue engineering.     

In vivo real-time monitoring system of electroporation mediated control of transdermal and topical drug delivery

Electroporation (EP) is a physical method for the delivery of molecules into cells and tissues, including the skin. In this study, in order to control the degree of transdermal and topical drug delivery, EP at different amplitudes of electric pulses was evaluated. A new in vivo real-time monitoring system based on fluorescently labeled molecules was developed, for the quantification of transdermal and topical drug delivery. EP of the mouse skin was performed with new non-invasive multi-array electrodes, delivering different amplitudes of electric pulses ranging from 70 to 570 V, between the electrode pin pairs. Patches, soaked with 4 kDa fluorescein-isothiocyanate labeled dextran (FD), doxorubicin (DOX) or fentanyl (FEN), were applied to the skin before and after EP. The new monitoring system was developed based on the delivery of FD to and through the skin. FD relative quantity was determined with fluorescence microscopy imaging, in the treated region of the skin for topical delivery and in a segment of the mouse tail for transdermal delivery. The application of electric pulses for FD delivery resulted in enhanced transdermal delivery. Depending on the amplitude of electric pulses, it increased up to the amplitude of 360 V, and decreased at higher amplitudes (460 and 570 V). Topical delivery steadily enhanced with increasing the amplitude of the delivered electric pulses, being even higher than after tape stripping used as a positive control. The non-invasive monitoring of the delivery of DOX, a fluorescent chemotherapeutic drug, qualitatively and quantitatively confirmed the effects of EP at 360 and 570 V pulse amplitudes on topical and transdermal drug delivery. Delivery of FEN at 360 and 570 V pulse amplitudes verified the observed effects as obtained with FD and DOX, by the measured physiological responses of the mice as well as FEN plasma concentration. This study demonstrates that with the newly developed non-invasive multi-array electrodes and with the varying electric pulse amplitude, the amount of topical and transdermal drug delivery to the skin can be controlled. Furthermore, the newly developed monitoring system provides a tool for rapid real-time determination of both, transdermal and topical delivery, when the delivered molecule is fluorescent.     

Ultrasound-guided Fine Needle Aspiration Cytology prior to Sentinel Lymph Node Biopsy in Melanoma Patients

Background Sentinel lymph node biopsy (SLNB) allows early detection of metastases, thereby enabling early treatment in melanoma patients likely to benefit from adjuvant therapies. This prospective study analyzes the possible benefits of additional ultrasound (US) and fine needle aspiration cytology (FNAC) of sentinel nodes (SN) prior to SLNB.Method Over a 2-year period 127 melanoma patients with 151 SN were scheduled for SLNB. All SN were initially identified with lymphoscintigraphy, then identified and evaluated by US and the cells aspirated for cytology (FNAC). US findings and FNAC results were compared to surgical findings.Results Of 127 patients, 114 had one SN each, 12 had two, and one had three. In vivo US achieved a sensitivity of 79% (95% CI: 62–91%) and a specificity of 72% (95% CI: 62–81%). FNAC showed a sensitivity of 59% (95% CI: 41–76%) and a specificity of 100% (95% CI: 95–100%). The combination of these two in vivo methods achieved an overall sensitivity of 82% (95% CI: 65–93%) and an overall specificity of 72% [95% CI: 62–81%].Conclusion Combined US and FNAC provides important information prior to SLNB in that both procedures identify metastases in the lymph nodes (sensitivity > 80%). Patients with positive FNAC may proceed directly to complete lymph node dissection (cLND) instead of having initial SLNB. Thus, combined US and FNAC may prevent unnecessary anesthesia and surgical management as well reduce costs. In our study 16% (19/121) fewer SLNB procedures were carried out, subsequently replaced by cLND. For patients with a negative combination of in vivo US and FNAC, SLNB remains the best diagnostic option.Part of this work was presented in May 2003 at the Melanoma session of the 39^th Annual Meeting of the American Society of Clinical Oncology in Chicago, Illinois, and at the Oral Melanoma Poster Discussion session of the 40^th Annual Meeting of the American Society of Clinical Oncology in New Orleans, Louisiana.     

Beta-trace protein in pediatric otitis media with effusion

Objectives

The middle ear cleft connects by membranes to the inner ear and the subarachnoid space particularly in infants. In order to gain more insight about the permeability between the two compartments we quantified the concentration of beta-trace protein – a highly specific marker for CSF and perilymph but not for serum and mucosal effusion – in middle ear secretions from children with otitis media with effusion.

Methods

One-hundred and three patients were included and 93 samples from secretory otitis media were collected during myringotomy or explorative tympanotomy. Thirty-eight patients of 103 had to be excluded (36.9%). Of the 93 collected samples from 65 subjects, 82 viscous samples were pre-diluted 1:1 with tyloxapol. In spite of the attempt to pre-dilute the viscous samples, 30 glue-like samples of 93 were not applicable for nephelometry. The final analysis was made on 63 samples of 52 subjects (median age 3 years) which were quantified for beta-trace protein using immunonephelometry.

Results

In 3/63 samples the beta-trace protein values were below the detection range (<0.2 mg/L) and in 1/63 it was beyond with 18.3 mg/L. The median beta-trace protein value for 59 samples within the measuring range was 2.4 mg/L, range 0.2–14.2.

Conclusion

In pediatric middle ear effusions, the beta-trace protein concentration was found to have a high range compared to other body fluids from other studies. In other studies, the values for serum (0.59 mg/L) or mucosal secretion (0.003–0.12 mg/L) were lower and the values in CSF (18.4 mg/L) or perilymphatic fluid (23.5 mg/L) were highest. This finding might indicate a weak barrier between the cerebrospinal fluid space or inner ear fluid compartments on the one side and the tympanic cavity on the other side given the condition of otitis media with effusion. The detection of beta-trace protein might be important to assess the risk of impending complications.     

Hereditary hemorrhagic telangiectasia: an update on clinical manifestations and diagnostic measures

Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber disease, is an autosomal dominant disorder of the fibrovascular tissue. It is characterized by the classic triad of (muco-)cutaneous telangiectases, arteriovenous malformations with recurrent epistaxis and hemorrhages, and inheritance. A wide variety of clinical manifestations in HHT have been described. In more than 90% of the patients, nosebleeds are the first predominant symptom, therefore ENT physicians often play a key role as far as diagnosis and management of the disease are concerned. In spite of recent diagnostic and therapeutic progress, a cure for this often burdening and handicapping disease is still not available. Apart from affecting the nose, arteriovenous malformations (AVMs) may also affect the skin, lungs, brain, liver and gastrointestinal tract. The two known genes that are implicated in HHT are endoglin (ENG) located on chromosome 9q33-q34 and activin-receptor-like kinase (ALK1) located on chromosome 12q13. Mutations of ENG are observed in HHT type 1 with an incidence up to 40% for pulmonary AVMs, whereas mutations of ALK1 are observed in HHT type 2 with an incidence of only 14% for pulmonary AVMs, which clinically distinguishes these two types of mutation. The emphasis of this paper is mainly on the clinical manifestation, molecular genetics and diagnosis of HHT, taking account of current literature on HHT in order to better understand the complexity of the disease. Recent therapeutic options in the treatment of HHT have been omitted from this paper as they are subject of a following paper. HHT is more common than previously thought and shows a broad range of different clinical organ manifestations that can be sources of substantial morbidity and mortality, making HHT a continuing challenge for many sub-specialties where interdisciplinary diagnostic screening is mandatory in the management of the disease.     

DPPIV (CD26) as a novel stem cell marker in Ph+ chronic myeloid leukaemia

The concept of leukaemic stem cells (LSCs) has been developed to explain the complex cellular hierarchy and biology of leukaemias and to screen for pivotal targets that can be employed to improve drug therapies through LSC eradication in these patients. Some of the newly discovered LSC markers seem to be expressed in a disease‐specific manner and may thus serve as major research tools and diagnostic parameters. A useful LSC marker in chronic myeloid leukaemia (CML) appears to be CD26, also known as dipeptidylpeptidase IV. Expression of CD26 is largely restricted to CD34⁺/CD38^? LSCs in BCR/ABL1⁺ CML, but is not found on LSCs in other myeloid or lymphoid neoplasms, with the exception of lymphoid blast crisis of CML, BCR/ABL1_p210+ acute lymphoblastic leukaemia, and a very few cases of acute myeloid leukaemia. Moreover, CD26 usually is not expressed on normal bone marrow (BM) stem cells. Functionally, CD26 is a cytokine‐targeting surface enzyme that may facilitate the mobilization of LSCs from the BM niche. In this article, we review our current knowledge about the biology and function of CD26 on CML LSCs and discuss the diagnostic potential of this new LSC marker in clinical haematology.     

Is herniography useful and safe?

117 consecutive herniograms were reviewed for patients who had symptoms suggestive of hernia but with no evidence or inconclusive findings on physical examination. The traditional approach has been to explore patients with suspected occult hernias. The aim of this study was to assess the impact of herniography in minimizing needless groin exploration and to evaluate its safety. Thirty-three herniograms were positive and showed unilateral and bilateral inguinal hernias. There were no false positive examinations and two false negative examinations. No complications were present. Patients with positive herniograms were explored, and operative findings correlated well with herniographic findings. Twenty-four patients were referred to other specialities. Follow-up in clinic and telephone interviews showed symptomatic improvement in the majority of patients. Herniography is useful in evaluating obscure groin pain and occult hernias. It is a safe procedure and more cost effective than a negative exploration or diagnostic laparoscopy.