Adaptive Radiotherapy in the Management of Cervical Cancer: Review of Strategies and Clinical Implementation.

The complex and varied motion of the cervix-uterus target during external beam radiotherapy (EBRT) underscores the clinical benefits afforded by adaptive radiotherapy (ART) techniques. These gains have already been realised in the implementation of image-guided adaptive brachytherapy, where adapting to anatomy at each fraction has seen improvements in clinical outcomes and a reduction in treatment toxicity. With regards to EBRT, multiple adaptive strategies have been implemented, including a personalised internal target volume, offline replanning and a plan of the day approach. With technological advances, there is now the ability for real-time online ART using both magnetic resonance imaging and computed tomography-guided imaging. However, multiple challenges remain in the widespread dissemination of ART. This review investigates the ART strategies and their clinical implementation in EBRT delivery for cervical cancer.

Podiatry as a career in the UK - what attracts Generation Z? A qualitative exploration with university and college students.

BACKGROUND: Training for a career in podiatry is reported to provide graduates with excellent employability, alongside professional autonomy and suitable renumeration. Yet, there has been an ongoing decline in the number of those applying to study the subject. There is limited literature associated with this topic and we sought to explore the factors that attract 'generation Z' (those born 1995-2010) to a potential career in podiatry. METHOD: A qualitative design framework underpinned by phenomenological principles used four focus groups over a two-year period to generate data from participants at University and in Further Education. Focus group conversations were led by external facilitator, recorded, independently transcribed verbatim and anonymised prior to thematic analysis. This was followed by external, independent verification of themes. RESULTS: Four main themes were determined from the analysis i) a lack of awareness of podiatry; ii) podiatry: accessible course, accessible career; iii) career status; iv) breadth/opportunity of the scope of practice. Both positive and negative experiences were reported and highlighted key gaps in how the attractiveness of a career in podiatry is portrayed. CONCLUSION: The chronic lack of awareness of podiatry as a career clearly needs to be addressed, ideally with more positive role modelling in mainstream and popular media. The career status offered together with the breadth of, and opportunity associated with, the scope of practice should continue to be celebrated.

Prediction of postnatal outcome in fetuses with congenital lung malformation: 2-year follow-up study.

OBJECTIVES: To identify, in fetuses with a congenital lung malformation (CLM), prenatal predictors of the need for postnatal respiratory support and the need for surgery by calculating the CLM volume ratio (CVR), and to evaluate the concordance between the prenatal appearance and the postnatal type of CLM. METHODS: This was an analysis of prenatal, perinatal and postnatal data from fetuses diagnosed with a CLM at the Erasmus University Medical Center - Sophia Children's Hospital in Rotterdam, The Netherlands, between January 2007 and December 2016. For all included fetuses, CVR was measured retrospectively on stored ultrasound images obtained at 18 + 1 to 24 + 6 weeks (US1), 25 + 0 to 29 + 6 weeks (US2) and/or 30 + 0 to 35 + 6 weeks' gestation (US3). Postnatal diagnosis of CLM was based on computed tomography or histology. Primary outcomes were the need for respiratory support within 24 h and surgery within 2 years after birth. RESULTS: Of the 80 fetuses with a CLM included in this study, 14 (18%) required respiratory support on the first postnatal day, and 17 (21%) required surgery within 2 years. Only the CVR at US2 was predictive of the need for respiratory support, with a cut-off value of 0.39. Four of 16 (25%) fetuses which showed full regression of the CLM prenatally required respiratory support within 24 h after birth. The CVR at US1, US2 and US3 was predictive of surgery within 2 years. Overall, the prenatal appearance of the CLM showed low concordance with the postnatal type. Prenatally suspected microcystic congenital pulmonary airway malformation (CPAM) was shown on computed tomography after birth to be congenital lobar overinflation in 15/35 (43%) cases. Respiratory support within 24 h after birth and surgical resection within 28 days after birth were needed in all cases of macrocystic CPAM. CONCLUSIONS: CVR can predict the need for respiratory support within 24 h after birth and for surgery within 2 years. Regression of a CLM prenatally does not rule out respiratory problems after birth. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. - Legal Statement: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

The Role of Biomarkers for the Prediction of Response to Checkpoint Immunotherapy and the Rationale for the Use of Checkpoint Immunotherapy in Cervical Cancer.

Checkpoint immunotherapy has revolutionised the way that melanoma is treated and has also shown significant effectiveness in lung, bladder, renal, and head and neck cancers. At the present time, trials of checkpoint immunotherapy in cervical cancer are at early phases, but there is very good rationale for pursuing this as a treatment option, especially as cervical cancer is a virally driven cancer and therefore should be recognised by the immune system as being foreign. This review explores the biomarkers for the selection of patients for immunotherapy in other cancers, such as programmed death ligand 1 (PD-L1) expression, tumour infiltrating lymphocytes and total mutational burden, and relates these biomarkers to cervical cancer. A PubMed search was carried out for publications published in English with the terms 'immunotherapy' OR 'cervical cancer' OR 'checkpoint blockade' OR 'tumour infiltrating lymphocytes' OR 'total mutational burden'. Articles that met these criteria and were available on PubMed before 8 October 2018 were included. The results showed that PD-L1 is positive in up to 90% of cervical cancers and that the total mutational burden is moderately high, with 5-6 mutations per megabase. In addition, the tumour microenvironment in cervical cancer has an impact on prognosis, with higher ratios of CD8+ tumour infiltrating lymphocytes to CD4+ T regulatory cells being associated with improved survival. Clinical studies to date have shown the response rate of cervical cancer to checkpoint immunotherapy to be in the region to 10-25%. Cervical cancer exhibits many of the features that have been shown to be correlated with response to checkpoint immunotherapy in other tumour sites. However, response rates to date are in the region of 10-25%. Therefore, combinations of immunotherapeutic agents or checkpoint inhibitors with radiotherapy may be required to maximise the therapeutic benefit of harnessing the host immune system to fight cancer.

Diagnosing and treating antiphospholipid syndrome: a consensus paper.

INTRODUCTION: The antiphospholipid syndrome (APS) is defined by the occurrence of venous and/or arterial thrombosis and/or pregnancy-related morbidity, combined with the presence of antiphospholipid antibodies (aPL) and/or a lupus anticoagulant (LAC). Large, controlled, intervention trials in APS are limited. This paper aims to provide clinicians with an expert consensus on the management of APS. METHODS: Relevant papers were identified by literature search. Statements on diagnostics and treatment were extracted. During two consensus meetings, statements were discussed, followed by a Delphi procedure. Subsequently, a final paper was written. RESULTS: Diagnosis of APS includes the combination of thrombotic events and presence of aPL. Risk stratification on an individual base remains challenging. 'Triple positive' patients have highest risk of recurrent thrombosis. aPL titres > 99th percentile should be considered positive. No gold standard exists for aPL testing; guidance on assay characteristics as formulated by the International Society on Thrombosis and Haemostasis should be followed. Treatment with vitamin K-antagonists (VKA) with INR 2.0-3.0 is first-line treatment for a first or recurrent APS-related venous thrombotic event. Patients with first arterial thrombosis should be treated with clopidogrel or VKA with target INR 2.0-3.0. Treatment with direct oral anticoagulants is not recommended. Patients with catastrophic APS, recurrent thrombotic events or recurrent pregnancy morbidity should be referred to an expert centre. CONCLUSION: This consensus paper fills the gap between evidence-based medicine and daily clinical practice for the care of APS patients.

The Human Papillomavirus as a Common Pathogen in Oropharyngeal, Anal and Cervical Cancers.

The burden of human papillomavirus (HPV)-related cancers worldwide is significant. Although the incidence of cervical cancer is decreasing due to cervical screening programmes, the incidences of oropharyngeal, anal and vulval cancers are increasing. The introduction of HPV vaccination programmes in many countries has had an impact on HPV infection rates but due to the time-lag from initial HPV infection to the development of invasive carcinoma, the impact on the incidence of HPV-related cancer will take more time to become evident. This review explores the common aspects of HPV-related cancers and how they differ from their HPV-negative counterparts, both clinically and molecularly. It also covers the implications this has on future treatment strategies, including the possible role of immunotherapy.

Pharmacodynamic considerations in the treatment of pulmonary hypertension in infants: challenges and future perspectives.

INTRODUCTION: Pulmonary hypertension (PH) in infants is a life-threatening disease with a high mortality. It is treated with different drugs that act upon the three different pathways involved in its development. Studies on the drug pharmacodynamics are sparse, however. AREAS COVERED: This review reports a search on the currently available literature in English on drug pharmacodynamics in infants with PH. The search yielded 2499 citations in the EMBASE, MEDLINE, COCHRANE, Web of Science, PubMed Publisher and Google Scholar databases since 1961. Of these, 1691 did not meet the research question. Eventually, 655 articles were of interest, including 44 randomized controlled trials on PH in infants. These articles cover all PH medications used in infancy. EXPERT OPINION: Mortality of PH in infancy has dropped considerably over the past years. iNO is widely used, followed by sildenafil - both orally and intravenously in contrast to the exclusively oral use in adults. In adults, the pharmacodynamic effects of the different medications are tested using the 6-minute walking test, changes in the NYHA classification, or by invasive measurement of pulmonary pressure. Reliable data of pharmacodynamics tested in adequate series or in randomized controlled trials in children are lacking, however, for most of these medications.

Effects of dextromethorphan as add-on to sitagliptin on blood glucose and serum insulin concentrations in individuals with type 2 diabetes mellitus: a randomized, placebo-controlled, double-blinded, multiple crossover, single-dose clinical trial.

In this clinical trial, we investigated the blood glucose (BG)-lowering effects of 30, 60 and 90 mg dextromethorphan (DXM) as well as 100 mg sitagliptin alone versus combinations of DXM and sitagliptin during an oral glucose tolerance test (OGTT) in 20 men with T2DM. The combination of 60 mg DXM plus 100 mg sitagliptin was observed to have the strongest effect in the OGTT. It lowered maximum BG concentrations and increased the baseline-adjusted area under the curve for serum insulin concentrations in the first 30 min of the OGTT (mean ± standard deviation 240 ± 47 mg/dl and 8.1 ± 6.1 mU/l/h, respectively) to a significantly larger extent than did 100 mg sitagliptin alone (254 ± 50 mg/dl and 5.8 ± 2.5 mU/l/h, respectively; p < 0.05) and placebo (272 ± 49 mg/dl and 3.9 ± 3.0 mU/l/h, respectively; p < 0.001). All study drugs were well tolerated, alone and in combination, without serious adverse events or hypoglycaemia. Long-term clinical trials are now warranted to investigate the potential of the combination of 30 or 60 mg DXM and dipeptidyl peptidase-4 inhibitors in the treatment of individuals with T2DM, in particular as preclinical studies have identified the ß-cell protective properties of DXM.

Evaluating a standardised tool to explore the nature and extent of foot and ankle injuries in amateur and semi-professional footballers.

BACKGROUND: Most studies of football injuries include professional players and data have been collected in without a single validated, standardised tool. We aimed to develop a new standardised questionnaire for assessing injuries among non-professional footballers and pilot its use. METHOD: A questionnaire was developed using input from footballers, healthcare professionals and triangulation from the literature. The new tool was piloted among players representing amateurs and semi-professionals. Their comments were used iteratively to improve the instrument. RESULTS: The development phase produced a 33-item questionnaire collecting quantitative and qualitative data. In the pilot phase, 42 questionnaires were distributed, 34 (81%) returned. Respondents reported total of 273 football-related injuries, 114 affecting the foot/ankle (70 at the ankle and 44 at the foot). In total, 44% of respondents had suffered one or more foot/ankle injuries in the past 12 months. CONCLUSION: We developed a new standardised tool which we found to be well-completed by young male footballers in semi-professional and amateur settings with an excellent response rate. Our results suggested that foot/ankle injuries were common, larger studies in non-professionals are needed to identify risk factors for injury and develop pragmatic advice for prevention.

Association of exercise-induced hyperinsulinaemic hypoglycaemia with MCT1-expressing insulinoma.

AIMS/HYPOTHESIS: Exercise-induced hyperinsulinism (EIHI) is a hypoglycaemic disorder characterised by inappropriate insulin secretion following anaerobic exercise or pyruvate load. Activating promoter mutations in the MCT1 gene (also known as SCLA16A1), coding for monocarboxylate transporter 1 (MCT1), were shown to associate with EIHI. Recently, transgenic Mct1 expression in pancreatic beta cells was shown to introduce EIHI symptoms in mice. To date, MCT1 has not been demonstrated in insulin-producing cells from an EIHI patient. METHODS: In vivo insulin secretion was studied during an exercise test before and after the resection of an insulinoma. The presence of MCT1 was analysed using immunohistochemistry followed by laser scanning microscopy, western blot analysis and real-time RT-PCR of MCT1. The presence of MCT1 protein was analysed in four additional insulinoma patients. RESULTS: Clinical testing revealed massive insulin secretion induced by anaerobic exercise preoperatively, but not postoperatively. MCT1 protein was not detected in the patient's normal islets. In contrast, immunoreactivity was clearly observed in the insulinoma tissue. Western blot analysis and real-time RT-PCR showed a four- to fivefold increase in MCT1 in the insulinoma tissue of the EIHI patient compared with human pancreatic islets. MCT1 protein was detected in three of four additional insulinomas. CONCLUSIONS/INTERPRETATION: We show for the first time that an MCT1-expressing insulinoma was associated with EIHI and that MCT1 might be present in most insulinomas. Our data suggest that MCT1 expression in human insulin-producing cells can lead to EIHI and warrant further studies on the role of MCT1 in human insulinoma patients.

Identifying patient-reported outcomes in rheumatoid arthritis: the impact of foot symptoms on self-perceived quality of life.

BACKGROUND: The importance of patient-reported outcome measures in healthcare is increasingly recognized but these need to be patient generated. Given that foot symptoms are very common in rheumatoid arthritis (RA), we chose a patient-centred model with which to investigate the patients' perspective on how their foot symptoms affected them as individuals and impacted on their self-perceived quality of life, rather than using the traditional approaches of clinical examination (e.g. prevalence of deformities) or radiological assessments. METHODS: A 33-item self-administered postal questionnaire was sent to all people with RA attending outpatient clinics in three hospitals over the course of one month (n=390). The questionnaire used both quantitative and qualitative approaches to enquire about the nature and extent of foot complaints and how respondents believed this affected their quality of life. RESULTS: In total, 190 usable replies were received (49%). Nearly all respondents (n=177; 93.2%) reported that their quality of life was adversely affected by their foot complaint(s), with over half describing their quality of life as being badly or very badly affected. When asked to rate how severely foot complaints affected their quality of life using a 10 cm visual analogue scale, the mean score was 5.36 (range 0-10 ± SD 3), indicating that foot complaints have a moderate-to-severe effect on quality of life. Those aspects of daily living most significantly affected were: the ability to walk and the ability to wear a variety of shoes. CONCLUSION: This study demonstrated that people with RA focus on different aspects of the impact of their disease to doctors. Rather than foot deformity or ulceration, disease activity score or health assessment questionnaire score, patients were easily able to pinpoint the key negativities of living with RA in their feet and indicated choice of footwear and ability to walk as crucial. This study and similar ones are key to identifying appropriate patient-reported outcome measures.

Comparison of foot pain and foot care among rheumatoid arthritis patients taking and not taking anti-TNFα therapy: an epidemiological study.

Epidemiological studies report foot pain affects more than 90% of people with rheumatoid arthritis (RA). Most data about foot involvement in RA were collected prior to the availability of novel treatments such as biologics. The objective of this study is to compare the prevalence of foot symptoms, frequency of foot examination, and access to foot care services among RA patients currently treated with anti-TNFα to those not receiving biologics. This study is a cross-sectional epidemiological study: a 28-item self-administered questionnaire was posted to 1,040 people with RA throughout the UK. Overall, 585 (55%) useable replies were received, and 120 (20.5%) respondents were currently taking anti-TNFα medication. Prevalence of current foot pain was 99% among the biologics group compared with 76% not treated with biologics. Stiffness, swelling, and numbness in the feet were all significantly more common in the anti-TNFα group (P < 0.05). Most respondents (90%) taking biologics discussed their foot pain with their rheumatologist, but only 70% were receiving podiatry (compared to 78% not taking anti-TNFα). Subjects reported that their feet were examined significantly less frequently (P < 0.001) than their hands. Foot complaints are common in this group, and allied health professions could enhance rheumatological care by undertaking foot assessment.

An amelanotic malignant melanoma masquerading as hypergranulation tissue.

We report a case of amelanotic malignant melanoma occurring in the nail sulcus of the hallux, which on initial presentation was mistaken for hypergranulation tissue due to an in-growing toenail. We highlight the importance of this differential diagnosis as such lesions can have serious sequelae.

Major sacrococcygeal teratoma in an extreme premature infant: a multidisciplinary approach.

Antenatally diagnosed, large sacrococcygeal teratomas in very premature infants are associated with a very poor outcome. We present an extreme premature infant with cardiac decompensation, diagnosed at 27 weeks and 1 day of gestational age. A positive outcome could be achieved with intensive multidisciplinary planning of the delivery, postnatal stabilization and surgical resection, as demonstrated in this case report.

Biologic agents used to treat rheumatoid arthritis and their relevance to podiatrists: a practice update.

This review considers the pharmacological management of rheumatoid arthritis including the role of anti-tumour necrosis factor alpha (TNFalpha) agents, as a precursor to highlighting some of the issues for podiatrists involved in the care of patients on this particular medication.

Intravenous drug abuse and one academic health center.

Increasing reports of management problems involving intravenous drug abuse patients prompted our study. From 1983 to 1988, the recorded inpatient prevalence of diagnoses consistent with drug abuse/dependence, other than alcohol or nicotine, rose hospitalwide from 0.6% to 3.5%. Disruptive behavior was documented in the records of 38 of 71 active cocaine or heroin users admitted during 1988 vs 12 of 64 matched control subjects. Care and teaching focused principally on secondary complications of intravenous drug use. Study recommendations included (1) establishment of a comprehensive substance abuse treatment education, and research program with a dedicated inpatient unit; (2) use of an explicit social contract between patients and care givers; and (3) staff education about legal limits in managing disruptive patients and searching for illegal substances. Primary and secondary prevention, including combating societal enabling of substance abuse, should be the institution's long-term goals.

Inappropriate use of the cerebrospinal fluid Venereal Disease Research Laboratory (VDRL) test to exclude neurosyphilis.

Only 3 of 2536 cerebrospinal fluid (CSF) VDRL tests ordered at the Johns Hopkins Hospital in 1980 were positive. Of patients on whom the test was ordered, 226 had a positive or borderline serum fluorescent treponemal antibody absorption test. Records from 156 (69%) of these patients, including all 3 with positive CSF-VDRL tests, were reviewed and showed that the diagnosis of neurosyphilis had been considered only in 44 (28%). One third of records lacked notations of historical and physical findings characteristic of neurosyphilis. Forty seropositive patients who had lumbar puncture to rule out asymptomatic neurosyphilis had negative CSF-VDRL tests; none had neurosyphilis diagnosed. Use of the CSF-VDRL test seemed to represent predominantly "box-checking" on the requisition to rule out neurosyphilis. Yet the test performs better when "ruling in" rather than ruling out neurosyphilis. The Centers for Disease Control should reevaluate its recommendation to rule out neurosyphilis in asymptomatic patients with untreated syphilis of greater than 1 year's duration, given the costs, risks, and dubious benefits.

Peer review organizations. Promises and potential pitfalls.

The Health Care Financing Administration has contracted with 54 peer review organizations (PROs) to monitor hospital use and quality of care for Medicare patients. PROs promised reductions in readmissions, in "unnecessary" admissions or invasive procedures, and in "avoidable" mortality and morbidity. A review of contract summaries for 49 PROs revealed wide variations in reduction targets. In attempting to meet their goals, PROs will encounter numerous potential pitfalls, including inaccurate and incomplete discharge data, inadequate descriptors for the variety of patients and physicians' management plans, honest differences in judgments about patient care, and limited research on the criteria used to set their reduction targets as well as the means to accomplish them. Despite having more explicit quality-of-care objectives, PROs, like PSROs (professional standards review organizations) before them, are more likely to be seen as agents of cost containment than of quality assurance. Both their credibility and their effectiveness might be enhanced if an expert panel of clinicians and health services researchers were established to help them set and achieve reasonable objectives for quality of care.