Cost-Consequence Analysis Alongside a Randomised Controlled Trial of Hospital Versus Telephone Follow-Up after Treatment for Endometrial Cancer

Background Regular outpatient follow-up programmes are usually offered to patients following treatment for gynaecological and other cancers. Despite the substantial resources involved in providing these programmes, there is evidence that routine follow-up programmes do not affect survival or the likelihood of detecting recurrence and may not meet patient needs. Alternative follow-up modalities may offer the same outcomes at lower cost. We examined the costs of using telephone-based routine follow-up of women treated for endometrial cancer undertaken by specialist gynaecology oncology nurses in comparison to routine hospital-based follow-up. Methods The ENDCAT trial randomised 259 women at five centres in the north west of England with a known diagnosis of Stage I endometrial cancer who had completed primary treatment on a 1:1 basis to receive either standard hospital outpatient follow-up or a telephone follow-up intervention administered by specialist nurses. A cost-consequence analysis was undertaken in which we compared costs to the health system and to individuals with the trial’s co-primary outcomes of psychological morbidity and participant satisfaction with information received. Results Psychological morbidity, psychosocial needs, patient satisfaction and quality of life did not differ between arms. Patients randomised to telephone follow-up underwent more and longer consultations. There was no difference in total health service mean per patient costs at 6 months (mean difference £8, 95% percentile confidence interval: − £147 to £141) or 12 months (mean difference: − £77, 95% percentile confidence interval: − £334 to £154). Estimated return journey costs per patient for hospital consultations were £11.47. Productivity costs were approximately twice as high under hospital follow-up. Conclusion Telephone follow-up was estimated to be cost-neutral for the NHS and may free up clinic time for other patients. There was some evidence that telephone follow-up may be more efficient for patients and wider society, and is not associated with additional psychological morbidity, lower patient satisfaction or reduced quality of life

Vibrational spectroscopy: a promising approach to discriminate neurodegenerative disorders

Neurodegenerative diseases are a growing burden in modern society, thus crucially calling for the development of accurate diagnostic strategies. These diseases are currently incurable, a fact which has been attributed to their late diagnosis, after brain damage has already become widespread. An earlier and improved diagnosis is necessary for the enrolment of patients into clinical trials and can pave the way for the development of therapeutic tactics. Novel analytical techniques, such as mass spectrometry and vibrational spectroscopy, have been able to successfully detect and characterise neurodegenerative disorders. It is critical to globally support and make use of innovative basic research and techniques, which could ultimately lead to the creation of a cost-effective diagnostic test. Minimally invasive samples, such as biological fluids, have also been shown to reveal information for these diseases; utilising them could simplify sample collection/analysis and be more preferable to patients

Underlying role of mitochondrial mutagenesis in the pathogenesis of a disease and current approaches for translational research

Mitochondrial diseases have been extensively investigated over the last three decades but many questions regarding their underlying aetiologies remain unanswered. Mitochondrial dysfunction is not only responsible for a range of neurological and myopathy diseases, but is also considered pivotal in a broader spectrum of common diseases such as epilepsy, autism and bipolar disorder. These disorders are a challenge to diagnose and treat as their aetiology might be multifactorial. In this review, the focus is placed on potential mechanisms capable of introducing defects in mitochondria resulting in disease. Special attention is given to the influence of xenobiotics on mitochondria; environmental factors inducing mutations or epigenetic changes in the mitochondrial genome can alter its expression and impair the whole cell’s functionality. Specifically, we suggest that environmental agents can cause damage by generating abasic sites in mitochondrial DNA, which consequently lead to mutagenesis. Abasic sites are observed in DNA after spontaneous loss of a nucleic base (e.g., “apurinic sites” after loss of purines, adenine or guanine) or through base excision repair; if left unrepaired, they can produce mutagenic DNA lesions. Moreover, we describe current approaches for handling mitochondrial diseases, as well as available prenatal diagnostic tests towards eliminating these maternally-inherited diseases. Undoubtedly, more research is required, as current therapeutic approaches mostly employ palliative therapies rather than targeting primary mechanisms or prophylactic approaches. More effort is needed into further unravelling the relationship between xenobiotics and mitochondria as the extent of influence in mitochondrial pathogenesis is increasingly recognised

An overview of early investigational drugs for the treatment of human papilloma virus infection and associated dysplasia

Introduction: High-risk HPV (HR-HPV) related invasive cervical cancer (ICC) causes >270,000 deaths per annum world-wide with over 85% of these occurring in low-resource countries. Ablative and excisional treatment modalities are restricted for use with high-grade pre-cancerous cervical disease with HPV infection and low-grade dysplasia mostly managed by a watch-and-wait policy.Areas Covered: Various pharmacological approaches have been investigated as non-destructive alternatives for the treatment of HR-HPV infection and associated dysplasia. These are discussed dealing with efficacy, ease-of-use (physician or self-applied), systemic or locally applied, side-effects, cost and risks. The main focus is the perceived impact on current clinical practice of a self-applied, effective and safe pharmacological anti-HPV treatment.Expert opinion: Current prophylactic HPV vaccines are expensive, HPV type restricted and have little effect in already infected women. Therapeutic vaccines are under development but are also HPV type-restricted. At present, the developed nations use national cytology screening and surgical procedures to treat only women identified with HPV-related high-grade dysplastic disease. However, since HPV testing is rapidly replacing cytology as the test-of-choice, a suitable topically-applied and low-cost antiviral treatment could be an ideal solution for treatment of HPV infection per se with test-of-cure carried out by repeat HPV testing. Cytology would only then be necessary for women who remained HPV positive. Although of significant benefit in the developed countries, combining such a treatment with self-sampled HPV testing could revolutionise the management of this disease in the developing world which lack both the infrastructure and resources to establish national cytology screening programs

Adiposity and cancer at major anatomical sites: umbrella review of the literature

Objective To evaluate the strength and validity of the evidence for the association between adiposity and risk of developing or dying from cancer. Design Umbrella review of systematic reviews and metaanalyses. Data sources PubMed, Embase, Cochrane Database of Systematic Reviews, and manual screening of retrieved references. Eligibility criteria Systematic reviews or meta-analyses of observational studies that evaluated the association between indices of adiposity and risk of developing or dying from cancer. Data synthesis Primary analysis focused on cohort studies exploring associations for continuous measures of adiposity. The evidence was graded into strong, highly suggestive, suggestive, or weak after applying criteria that included the statistical significance of the random effects summary estimate and of the largest study in a meta-analysis, the number of cancer cases, heterogeneity between studies, 95% prediction intervals, small study effects, excess significance bias, and sensitivity analysis with credibility ceilings. Results 204 meta-analyses investigated associations between seven indices of adiposity and developing or dying from 36 primary cancers and their subtypes. Of the 95 meta-analyses that included cohort studies and used a continuous scale to measure adiposity, only 12 (13%) associations for nine cancers were supported by strong evidence. An increase in body mass index was associated with a higher risk of developing oesophageal adenocarcinoma; colon and rectal cancer in men; biliary tract system and pancreatic cancer; endometrial cancer in premenopausal women; kidney cancer; and multiple myeloma. Weight gain and waist to hip circumference ratio were associated with higher risks of postmenopausal breast cancer in women who have never used hormone replacement therapy and endometrial cancer, respectively. The increase in the risk of developing cancer for every 5 kg/m2 increase in body mass index ranged from 9% (relative risk 1.09, 95% confidence interval 1.06 to 1.13) for rectal cancer among men to 56% (1.56, 1.34 to 1.81) for biliary tract system cancer. The risk of postmenopausal breast cancer among women who have never used HRT increased by 11% for each 5 kg of weight gain in adulthood (1.11, 1.09 to 1.13), and the risk of endometrial cancer increased by 21% for each 0.1 increase in waist to hip ratio (1.21, 1.13 to 1.29). Five additional associations were supported by strong evidence when categorical measures of adiposity were included: weight gain with colorectal cancer; body mass index with gallbladder, gastric cardia, and ovarian cancer; and multiple myeloma mortality. Conclusions Although the association of adiposity with cancer risk has been extensively studied, associations for only 11 cancers (oesophageal adenocarcinoma, multiple myeloma, and cancers of the gastric cardia, colon, rectum, biliary tract system, pancreas, breast, endometrium, ovary, and kidney) were supported by strong evidence. Other associations could be genuine, but substantial uncertainty remains. Obesity is becoming one of the biggest problems in public health; evidence on the strength of the associated risks may allow finer selection of those at higher risk of cancer, who could be targeted for personalised prevention strategies

Histology Verification Demonstrates That Biospectroscopy Analysis of Cervical Cytology Identifies Underlying Disease More Accurately than Conventional Screening:Removing the Confounder of Discordance

Background Subjective visual assessment of cervical cytology is flawed, and this can manifest itself by inter- and intra-observer variability resulting ultimately in the degree of discordance in the grading categorisation of samples in screening vs. representative histology. Biospectroscopy methods have been suggested as sensor-based tools that can deliver objective assessments of cytology. However, studies to date have been apparently flawed by a corresponding lack of diagnostic efficiency when samples have previously been classed using cytology screening. This raises the question as to whether categorisation of cervical cytology based on imperfect conventional screening reduces the diagnostic accuracy of biospectroscopy approaches; are these latter methods more accurate and diagnose underlying disease? The purpose of this study was to compare the objective accuracy of infrared (IR) spectroscopy of cervical cytology samples using conventional cytology vs. histology-based categorisation. Methods Within a typical clinical setting, a total of n = 322 liquid-based cytology samples were collected immediately before biopsy. Of these, it was possible to acquire subsequent histology for n = 154. Cytology samples were categorised according to conventional screening methods and subsequently interrogated employing attenuated total reflection Fourier-transform IR (ATR-FTIR) spectroscopy. IR spectra were pre-processed and analysed using linear discriminant analysis. Dunn?s test was applied to identify the differences in spectra. Within the diagnostic categories, histology allowed us to determine the comparative efficiency of conventional screening vs. biospectroscopy to correctly identify either true atypia or underlying disease. Results Conventional cytology-based screening results in poor sensitivity and specificity. IR spectra derived from cervical cytology do not appear to discriminate in a diagnostic fashion when categories were based on conventional screening. Scores plots of IR spectra exhibit marked crossover of spectral points between different cytological categories. Although, significant differences between spectral bands in different categories are noted, crossover samples point to the potential for poor specificity and hampers the development of biospectroscopy as a diagnostic tool. However, when histology-based categories are used to conduct analyses, the scores plot of IR spectra exhibit markedly better segregation. Conclusions Histology demonstrates that ATR-FTIR spectroscopy of liquid-based cytology identifies the presence of underlying atypia or disease missed in conventional cytology screening. This study points to an urgent need for a future biospectroscopy study where categories are based on such histology. It will allow for the validation of this approach as a screening tool

A Single-Arm, Proof-Of-Concept Trial of Lopimune (Lopinavir/Ritonavir) as a Treatment for HPV-Related Pre-Invasive Cervical Disease

BACKGROUND: Cervical cancer is the most common female malignancy in the developing nations and the third most common cancer in women globally. An effective, inexpensive and self-applied topical treatment would be an ideal solution for treatment of screen-detected, pre-invasive cervical disease in low resource settings. METHODS: Between 01/03/2013 and 01/08/2013, women attending Kenyatta National Hospital's Family Planning and Gynaecology Outpatients clinics were tested for HIV, HPV (Cervista®) and liquid based cervical cytology (LBC -ThinPrep®). HIV negative women diagnosed as high-risk HPV positive with high grade squamous intraepithelial lesions (HSIL) were examined by colposcopy and given a 2 week course of 1 capsule of Lopimune (CIPLA) twice daily, to be self-applied as a vaginal pessary. Colposcopy, HPV testing and LBC were repeated at 4 and 12 weeks post-start of treatment with a final punch biopsy at 3 months for histology. Primary outcome measures were acceptability of treatment with efficacy as a secondary consideration. RESULTS: A total of 23 women with HSIL were treated with Lopimune during which time no adverse reactions were reported. A maximum concentration of 10 ng/ml of lopinavir was detected in patient plasma 1 week after starting treatment. HPV was no longer detected in 12/23 (52.2%, 95%CI: 30.6-73.2%). Post-treatment cytology at 12 weeks on women with HSIL, showed 14/22 (63.6%, 95%CI: 40.6-82.8%) had no dysplasia and 4/22 (18.2%, 95%CI: 9.9-65.1%) were now low grade demonstrating a combined positive response in 81.8% of women of which 77.8% was confirmed by histology. These data are supported by colposcopic images, which show regression of cervical lesions. CONCLUSIONS: These results demonstrate the potential of Lopimune as a self-applied therapy for HPV infection and related cervical lesions. Since there were no serious adverse events or detectable post-treatment morbidity, this study indicates that further trials are clearly justified to define optimal regimes and the overall benefit of this therapy. TRIAL REGISTRATION: ISRCTN Registry 48776874

Aluminium foil as a potential substrate for ATR-FTIR, transflection FTIR or Raman spectrochemical analysis of biological specimens

The substantial cost of substrates is an enormous obstacle in the successful translation of biospectroscopy (IR or Raman) into routine clinical/laboratory practice (screening or diagnosis). As a cheap and versatile substrate, we compared the performance of readily available aluminium (Al) foil with low-E, Au-coated and glass slides for cytological and histological specimen analysis by attenuated total reflection Fourier-transform infrared (ATR-FTIR), transflection FTIR or Raman spectroscopy. The low and almost featureless background signal of Al foil enables the acquisition of IR or Raman spectra without substrate interference or sacrificing important fingerprint biochemical information of the specimen, even for very thin samples with thicknesses down to 2 \ensuremathμm. Al foil is shown to perform as well as, if not better than, low-E or Au-coated slide, irrespective of its relatively rough surface. Although transmission FTIR is not possible on Al foil, this work demonstrates Al foil is an inexpensive, readily available and versatile substrate suitable for ATR-FTIR, transflection FTIR or Raman spectrochemical measurements of diverse biological specimens. The features of Al foil demonstrated here could promote a transition towards accessible substrates that can be readily implemented in either research or clinical settings

A three-dimensional principal component analysis approach for exploratory analysis of hyperspectral data: identification of ovarian cancer samples based on Raman microspectroscopy imaging of blood plasma

Hyperspectral imaging is a powerful tool to obtain both chemical and spatial information of biological systems. However, few algorithms are capable of working with full three-dimensional images, in which reshaping or averaging procedures are often performed to reduce the data complexity. Herein, we propose a new algorithm of three-dimensional principal component analysis (3D-PCA) for exploratory analysis of complete 3D spectrochemical images obtained through Raman microspectroscopy. Blood plasma samples of ten patients (5 healthy controls, 5 diagnosed with ovarian cancer) were analysed by acquiring hyperspectral imaging in the fingerprint region (∼780–1858 cm−1). Results show that 3D-PCA can clearly differentiate both groups based on its scores plot, where higher loadings coefficients were observed in amino acids, lipids and DNA regions. 3D-PCA is a new methodology for exploratory analysis of hyperspectral imaging, providing fast information for class differentiation