Molecular imaging probes derived from natural peptides.

Covering: up to the end of 2015.Peptides are naturally occurring compounds that play an important role in all living systems and are responsible for a range of essential functions. Peptide receptors have been implicated in disease states such as oncology, metabolic disorders and cardiovascular disease. Therefore, natural peptides have been exploited as diagnostic and therapeutic agents due to the unique target specificity for their endogenous receptors. This review discusses a variety of natural peptides highlighting their discovery, endogenous receptors, as well as their derivatization to create molecular imaging agents, with an emphasis on the design of radiolabelled peptides. This review also highlights methods for discovering new and novel peptides when knowledge of specific targets and endogenous ligands are not available.

A smoking cessation programme for current and recent ex-smokers following diagnosis of a potentially curable cancer.

BACKGROUND: Cancer patients who quit smoking have improved survival rates. The time of diagnosis provides a 'teachable moment' when healthcare providers can offer smoking-cessation treatment. AIMS: To assess the impact on quit rates of a tailored smoking-cessation intervention for patients diagnosed with a potentially curable cancer. METHODS: A prospective, one-arm cohort study of current smokers and recent quitters (<30 days) who had commenced treatment for a potentially curable cancer was performed. Intervention involved an initial motivational interview, regular follow up and pharmacotherapy when appropriate. Quit rates were measured at 1, 3, 6 and 12 months by self-reported abstinence and biochemical confirmation. The primary end point was prolonged abstinence at 12 months. Changes in quality of life parameters and distress were also assessed. RESULTS: Seventy-one patients were recruited, with a median age of 56 years. Forty-one patients (58%) had a smoking-related cancer. The prolonged abstinence rate at 12 months was 24% (95% confidence interval 14-36%). Factors associated with successful quitting included being in the preparation or action phase of readiness to change at study entry (P = 0.012) and having complications of treatment requiring hospitalisation (P = 0.024). Between baseline and 12 months, quitters reported improvement in self-control (P < 0.001) and reduced levels of distress (P = 0.03) compared to non-quitters. CONCLUSION: Patients who continue to smoke after being diagnosed with cancer require intensive support to quit. An individualised behavioural and pharmacological intervention can be successful in helping patients quit smoking, with quality of life improvements seen amongst successful quitters. Population measures to stop people starting smoking remain essential.

Total laparoscopic radical hysterectomy: a change in practice for the management of early stage cervical cancer in a U.K. cancer center.

In order to evaluate the safety, surgical, and oncological outcomes of the introduction of a total laparoscopic radical hysterectomy (TLRH) service, the authors conducted a retrospective review of all TLRHs performed in the present centre from the beginning of the service in August 2010. TLRH appears in this series to be safe. Complication rates were comparable to National Institute for Health and Clinical Excellence (NICE) and literature standards. Oncological outcomes, despite the short follow up period, appear acceptable. TLRH is a valuable alternative to open surgery for the treatment of early cervical cancer.

Risk of epithelial ovarian cancer in asymptomatic women with ultrasound-detected ovarian masses: a prospective cohort study within the UK collaborative trial of ovarian cancer screening (UKCTOCS).

OBJECTIVE: To estimate the risk of primary epithelial ovarian cancer (EOC) and slow growing borderline or Type I and aggressive Type II EOC in postmenopausal women with adnexal abnormalities on ultrasound. METHODS: This was a prospective cohort study in the ultrasound group of the UK Collaborative Trial of Ovarian Cancer Screening of postmenopausal women with ultrasound-detected abnormal adnexal (unilocular, multilocular, unilocular solid and multilocular solid, solid) morphology on their first scan. Women were followed up through the national cancer registries and by postal questionnaires. Absolute risks of EOC and borderline, Type I and Type II EOC within 3 years of initial scan were calculated. RESULTS: Of 48 053 women who underwent ultrasound examination and had complete scan data, 4367 (9.1% (95% CI, 8.8-9.3%)) had abnormal adnexal morphology. Median follow-up was 7.09 (25(th) -75(th) centiles, 6.03-7.92) years. Forty-seven (32 borderline or Type I, 15 Type II) were diagnosed with EOC. The overall absolute risk of EOC associated with abnormal adnexal morphology was 1.08% (95% CI, 0.79-1.43%); for borderline and Type I it was 0.73% (95% CI, 0.5-1.03%); and for Type II it was 0.34% (95% CI, 0.33-0.79%). In the subgroup (n = 741) with solid elements (unilocular solid, multilocular solid and solid) overall absolute risk was 4.45% (95% CI, 3.08-6.20%), for borderline and Type I it was 3.1% (95% CI, 1.9-4.6%) and for Type II it was 1.3% (95% CI, 0.6-2.4%). 11 982 women had both ovaries visualized and normal annual scans throughout the 3-year follow-up period. In this group, no borderline or Type I and eight Type II cancers were diagnosed. CONCLUSION: Asymptomatic postmenopausal women with ultrasound-detected adnexal abnormalities with solid elements have a 1 in 22 risk for EOC. Despite the higher prevalence of Type II EOC, the risk of borderline or Type I cancer in women with ultrasound abnormalities seems to be higher than does the risk of Type II cancer. This has important immediate implications for patients with incidental adnexal findings as well as for any future ultrasound-based screening.

Mature results of a randomized trial of two doses of cisplatin for the treatment of ovarian cancer. Scottish Gynecology Cancer Trials Group.

PURPOSE: In 1992, we reported the first results of a randomized study in ovarian cancer, comprising two doses of cisplatin and indicated a significant difference (P = .0008) in median survival. Four years later, we now describe the results of this trial. PATIENTS AND METHODS: After a median follow-up of 4 years and 9 months, 115 of 159 cases of advanced ovarian cancer, originally randomized to receive six cycles of cyclophosphamide 750 mg/m2 and either a high dose (HD) of 100 mg/m2 cisplatin or a low dose (LD) of 50 mg/m2 (LD) cisplatin, have now died. RESULTS: The overall survival for HD and LD patients is 32.4% and 26.6%, respectively, and the overall relative death rate is 0.68 (P = .043). This represents a reduction in overall benefit with longer follow-up compared with the first 2 years (relative death rate of 0.52). Toxicity, particularly neurotoxicity, is still evident in the fourth year (10/31 on HD compared with 1/24 on LD). CONCLUSION: Our recommended dose of cisplatin in combination schedule is therefore 75 mg/m2, representing the optimal balance between efficacy and toxicity.

Hypofractionation reduces the therapeutic ratio in early glottic carcinoma.

From 1969-1985 two types of fractionation schedules with similar time, dose, and fractionation factor (TDF) values were used to treat 197 patients with Tis, T1, and T2 squamous cell carcinoma of the vocal cord. One hundred and thirty-one patients were treated with conventional daily 2.0 Gy fractions, and 66 patients were treated once per week with large (5.5-6.6 Gy) fractions (hypofractionated group); both groups were treated over a period of approximately 6 weeks. The local failure and complication rates for patients completing treatment in the two groups were compared; a patient was regarded as having suffered a serious complication of treatment if laryngectomy or tracheostomy had to be performed in the absence of active disease, or if antibiotics and/or corticosteroids had to be prescribed for laryngeal oedema and/or necrosis. In patients with Tis and T1 disease, the failure rate was worse in the hypofractionated group than in the conventionally treated group (p = 0.06). In the smaller group of T2 patients, no significant difference was found in the failure rates between the hypo- and conventionally fractionated groups. Complication rates were similar in Tis/T1 and T2 patients, but significantly higher in the hypofractionated group (p less than 0.001). Neither stage nor fractionation schedule had an effect on survival, but laryngectomy/tracheostomy free survival was significantly worse in Tis/T1 patients receiving hypofractionated treatment, (p = 0.008) although not in T2 patients. These results indicate that in Tis/T1 glottic cancer, hypofractionation of radiotherapy produces a reduction in the therapeutic ratio.

Acute changes in iron metabolism following myocardial infarction.

Fifty six patients admitted consecutively to the coronary care unit with ischemic chest pain participated in a controlled prospective study of acute changes in iron metabolism. Following myocardial infarction there were significant reductions of plasma iron by 8.1 mumol/L (P = 0.002), total iron binding capacity by 12.9 mumol/L (P = 0.003), and plasma transferrin by 0.70 g/L (P = 0.007). In contrast, there was a significant elevation of serum ferritin by 218 micrograms/L (P = 0.0005). The magnitude and duration of these acute changes in iron metabolism was greater in patients with higher peak serum creating kinase levels, suggesting that these changes are influenced by the extent of tissue necrosis. Comparison with the control group showed that alteration in dietary iron intake was not a significant factor. The possible mechanisms of these acute changes and their similarity to those observed in the anemia of chronic disease are discussed.

The potential value of CA125 as a tumour marker in small volume, non-evaluable epithelial ovarian cancer.

Seventy four consecutive patients with epithelial ovarian cancer have been followed up longitudinally with serial serum CA125 for up to 48 months. From this database, the CA125 changes in small volume disease have been evaluated. For long term complete responders (n = 12), the mean plateau level of CA125 was 7.2 U/ml (95% confidence interval; 5.6 to 9.2 U/ml). The natural half-life of CA125 at 5.1 days (range 3.8 to 7 days) was calculated from five patients with Stage I and II disease who underwent complete surgical excision. A mean lead time of 99 days (range 14 to 255 days) was demonstrated between marker detection of disease progression and clinically apparent progressive disease in 12 out of 13 patients (92%) who relapsed after chemotherapy induced complete remission. The threshold of tumour volume detection with CA125 is unlikely to be determined by an arbitrary cut-off level. The kinetics of CA125 provide more useful information and the potential to define complete response or indeed cure with CA125 parameters requires further investigation.

Storage of platelet concentrates--an in vitro study of four types of plastic packs.

Four types of plastic blood collection packs were studied for their ability to preserve platelet function during a 5 d storage period. The platelet concentrates were stored in polyvinyl chloride (Tuta Laboratories), PL 1240 and PL 732 (Fenwal Laboratories) and CLX (Cutter Laboratories) packs, on a Fenwal elliptical rotator at 20 degrees-24 degrees C. Plasma pH, lactate concentration, hypotonic shock response (HSR), platelet aggregation in response to ADP, collagen and ristocetin and levels of the plasticisers, di-2-ethylhexyl phthalate (DEHP) and tri-ethylhexyl trimellitate (TEHTM), were measured. Morphological changes were assessed by electron microscopy. No significant fall in pH occurred in any type of pack but in vitro function and platelet morphology was generally better preserved in Tuta and CLX packs than in PL 732 and PL 1240. Very little TEHTM leached out of the PL 1240 and CLX packs whereas the mean concentration of DEHP in the platelet concentrates stored in Tuta packs was 27.4 mg/100 ml plasma after 5 d of storage. The results indicate that it is possible to prepare and store platelet concentrates in polyvinyl chloride plastic packs for a period of 5 d and maintain their function and viability.

Tolerability of transvaginal ultrasonography as an ovarian cancer screening test.

OBJECTIVE: To evaluate the acceptability of transvaginal ultrasonography as a screening tool. DESIGN: Prospective survey of women attending for screening within a randomised controlled trial. SETTING: University Hospital in Teesside. PARTICIPANTS AND METHODS: 54 women completed a questionnaire immediately after their first transvaginal ultrasound scan. RESULTS: 52 of 54 (96%) questionnaires were suitable for full analysis. The women were unlikely to find the scan was painful, 47 vs three (p<0.001), or embarrassing 45 vs five (p<0.001). Women were more likely to find both a smear, 42 vs eight (p<0.001) and a mammogram, 47 vs two (p<0.001) was more uncomfortable than transvaginal ultrasonography. CONCLUSIONS: Transvaginal ultrasonography is an acceptable tool for screening for ovarian cancer. It is better tolerated than other screening tools such as cervical smear and mammography.

Heterologous systems for expression of mammalian sulfotransferases.

This paper describes the use of both mammalian and bacterial expression systems as tools to study the structural and functional relationships of proteins encoded by cDNAs to both rat and human aryl sulfotransferases. In particular, we describe the use of the mammalian COS cell system for functional expression studies, and the use of Escherichia coli for the expression and purification of a sulfotransferase fusion protein suitable as an antigen for the generation of sulfotransferase antibodies.

The prognostic value of serum CA 125 in patients with advanced ovarian carcinoma: an analysis of 573 patients by the Medical Research Council Working Party on Gynaecological Cancer.

A number of studies have suggested that serum CA 125 levels may be an important prognostic factor for survival of patients with ovarian carcinoma. We investigated, in a large group of patients from 11 UK centers, which combination of CA 125 measurements provided the best prognostic index, and whether the predictive power could be improved by the addition of other factors. Analysis of the data from 248 patients showed that the absolute value of the third CA 125 sample was the single most important factor for predicting progression at 12 months, with the addition of residual bulk only slightly improving the predictive power. Seventy-four patients had CA 125> 70, and of these 57% were correctly predicted to progress or die within 12 months, but 43% remained alive and progression free. The best predictor for progression produced a false positive rate of 19%. We therefore conclude that prognostic information based upon CA 125 measurements up to the start of the third course of initial chemotherapy is not accurate enough to be used to manage individual patients.

The treatment of malignant mesothelioma of the pleura: review of a 5-year experience, with special reference to radiotherapy.

Thirty-eight patients with malignant mesothelioma of the pleura were seen at Peter MacCallum Cancer Institute between 1981 and 1985. In 35 patients presenting with disease confined to one hemithorax, the following treatments were given: radical surgery, 13 patients: radical radiotherapy, 12 patients; palliative radiotherapy, 20 patients; chemotherapy, 9 patients; observation only, 2 patients. Median survival from time of diagnosis for all 38 patients was 9 months, with an estimated 2-year survival rate of 16%. Treatment did not significantly affect survival, although there was an indication that patients having radical surgery did better (median survival 17 months) than those who did not (median survival 9 months) (p = 0.13). Fifteen patients were given radiotherapy with radical intent but only 12 completed treatment (50 Gy). The median survival of the 12 patients completing radiotherapy was 17 months, with an estimated 2-year survival rate of 17%. Two patient deaths were attributable to radical radiotherapy (one radiation hepatitis, one radiation myelopathy). Twenty-one patients received 31 courses of palliative radiotherapy for various symptoms, predominantly pain. The results were assessable for 26 courses, with 17 (65%) being at least partly successful. In conclusion, radiotherapy appears to be ineffective in prolonging survival in malignant mesothelioma of the pleura, but has a useful role in palliation.

Caesarean section audit by peer review.

OBJECTIVE: To provide activity audit data on 50 consecutive caesarean sections and assess the justification for the decision to perform each caesarean section. DESIGN: A retrospective audit with peer review. SETTING: Aberdeen Maternity Hospital. SUBJECTS: Fifty consecutive women undergoing caesarean section. The peer review was undertaken by four consultants and four registrars. MAIN OUTCOME MEASURES: The proportions of caesarean sections by indication stratified according to primiparae or multiparae and emergency or elective procedures. The auditors were asked 'do you think caesarean section was reasonable?' RESULTS: There were 18 (36%) elective caesarean sections and 32 (64%) emergency procedures. Of the 25 (50%) parous women, 14 (56%) had a previous caesarean section and of these 12 (86%) had an elective repeat caesarean section. Foetal distress was the principal indication for emergency caesarean section in 20 (63%) women, with foetal blood sampling performed in only four cases. For emergency caesarean sections the decision to delivery interval ranged from 13 to 160 min (mean 50 min). At least one auditor disagreed with the decision to perform caesarean section in 24 (48%) cases. Between observers the range of disagreement was from 2 to 18 of the decisions. In only 6 (33%) of the 18 elective procedures was there complete agreement. Four (67%) of these women had two previous caesarean sections. There was complete agreement with 20 (63%) of the 32 emergency caesarean sections. Conclusions--Interventions considered as a result of this audit include the introduction of structured diagnostic criteria for caesarean section indications and peer review by the on-call team of the caesarean sections performed in the preceding 24 h.

Does labetalol influence the development of proteinuria in pregnancy hypertension? A randomised controlled study.

It is the development of proteinuria in pregnancy-induced hypertension which is associated with an increased perinatal mortality. There is some evidence to suggest that labetalol may diminish the amount of proteinuria in patients who have already developed proteinuric pre-eclampsia. A randomised controlled study design was used to investigate whether labetalol treatment, started when a persistent diastolic blood pressure greater than 90 mmHg was observed, influenced the subsequent development of proteinuria. One hundred and fourteen women with singleton pregnancies and hypertension in the absence of proteinuria were randomised to receive either labetalol or no antihypertensive therapy. At recruitment maternal age, blood pressure and gestation were similar in both the labetalol and control groups. There was no difference in the frequency, quantity or timing of subsequent proteinuria between treatment and control groups. Overall 34% of primigravidae and 10% of parous women developed proteinuria. Labetalol did, however, control the blood pressure in 45 of the 51 treated women (88%) within 24 h. This effect was often shortlived requiring dose escalation after 3 to 5 days in the majority of cases. Labetalol was well tolerated and no significant maternal toxicity was noted.

Skin replacement by cultured keratinocyte grafts: an Australian experience.

We have prepared and supplied cultured epithelial autografts (CEA) to treat 37 burn patients around Australia. The method is a modification of the original methods of Green et al. The confluent 75 cm2 secondary cultures, obtained after less than 3 weeks, are 8-10 cell layers thick after detachment and have a shrinkage of only 7-14 per cent. The patients had full-thickness skin loss to 55-95 per cent of their total body surface area (TBSA) or deep partial-thickness burns to 3-50 per cent TBSA owing to scald injuries. In the case of full-thickness burns the CEA take in the 17 surviving patients for which data was available averaged 53 per cent (range 10-100 per cent). The take for seven patients with partial-thickness burns averaged 73 per cent (range 25-100 per cent). The variability and early graft failure is attributed largely to the presence of infection. The durability and percentage take of CEA grafts is discussed together with future developments in the replacement of both dermis and epidermis in burns injury.

Association between availability of non-prescription beta 2 agonist inhalers and undertreatment of asthma.

OBJECTIVE: To determine whether the availability of beta 2 agonist inhalers without prescription leads to undertreatment of asthma. DESIGN: Cross sectional study of adequacy of treatment in asthmatic subjects who purchased beta 2 agonist inhalers and subjects who obtained inhalers by prescription. SETTING: Community pharmacies in New South Wales, Australia. SUBJECTS: 403 eligible consecutive asthmatic subjects aged 13 to 55 purchasing salbutamol metered dose inhalers over the counter or by prescription; 197 attended for follow up and spirometry and 139 returned 14 day symptom, peak flow, and medication diaries. MAIN OUTCOME MEASURES: Severity of asthma assessed on frequency of day time and night time wheezing, frequency of inhaler use, and peak expiratory flow rates. Adequacy of treatment according to published guidelines. RESULTS: Of the 139 patients who completed the diary 83, (60%) purchased their inhalers without prescription and 83 were undertreated. The characteristics of patients in the prescription and purchasing groups were similar. Multiple logistic regression analysis identified use of non-prescribed salbutamol as being associated with a 2.9-fold increase in the odds of undertreatment (95% confidence interval 1.3 to 6.8). Smoking increased the odds of undertreatment (3.3, 1.2 to 9.5) and use of a peak flow meter reduced the odds (0.11, 0.04 to 0.34). Adjustment for frequency of consultation made use of non-prescription salbutamol insignificant (1.4, 0.55 to 3.8). Attitudes to services provided by doctors and pharmacists were favourable and not associated with undertreatment. CONCLUSION: Over the counter purchase of salbutamol is associated with infrequent consultation with doctors and undertreatment of asthma.

Perceived problems of occupational therapists: a subset of the professional curriculum.

Problem descriptions elicited from newly registered therapists were processed to produce 96 problem statements. These were clarified, assembled into a problem checklist, and mailed to 2,300 therapists registered subsequent to 1970 for the purpose of identifying the most frequent and bothersome problems encountered in practice. Factor analysis of the results revealed eight groups of problems, as well as four isolated problems, which were of statistical significance. This analysis suggested that basic skills of treatment planning and implementation are acquired by the new therapist before employment. Self-confidence and collaborative skills seem to be less well represented. It is suggested that these could be taught experientially by simulations within the classroom at several levels.

The 'art' of reflection: using drawing to uncover knowledge development in student nurses.

This paper describes how a nursing programme that is underpinned by the ideology of critical social theory used the medium of drawing to allow students to express learning that occurred on their clinical placement. The drawings were then examined to identify the different forms of knowing that the students depicted. It was found that students could demonstrate an awareness of different forms of knowledge.