The genetics of gastroesophageal adenocarcinoma and the use of circulating cell free DNA for disease detection and monitoring

Introduction: Gastroesophageal adenocarcinoma (GOA) is a frequently occurring cancer worldwide with a poor clinical outcome. Adenocarcinomas of the esophagus and gastroesophageal junction have shown a recent increase in frequency, therefore there is need to increase our understanding of GOA in order to improve our ability to detect, monitor and treat the disease.

Areas covered: The authors discuss the current classification of GOA in the context of recent changes in incidence. The authors also discuss developments in the understanding of disease biology and recent discoveries from whole genome and whole exome sequencing, and studies in immunotherapy. Finally, the authors discuss the recent developments in the use of circulating tumour DNA (ctDNA). PubMed search terms were in English including ‘esophageal/gastric adenocarcinoma’, ‘gastroesophageal junctional tumour’, ‘whole genome/exome sequencing’, ‘immunotherapy’ and ‘circulating tumour DNA’.

Expert commentary: Shared biological and genetic changes in GOA suggest it can be investigated as a single disease entity with different molecular subtypes. A number of genes are recurrently mutated including TP53, SMAD4, PIK3CA and there are frequent somatic copy number alterations and high levels of chromosomal instability. A subset of these genetic alterations have been detected in ctDNA and may provide an important avenue of research for detecting minimal residual disease and response to chemo- and immunotherapies.     

Classifying circulating tumor cells to monitor cancer progression

Introduction: The term ‘liquid biopsy’ refers to molecular analysis of a tumor’s genetic features based on circulating genetic material in the peripheral blood derived from circulating tumor cells (CTCs), circulating tumor DNA (ctDNA) and circulating miRNAs, and has emerged as a minimally invasive tool in early cancer diagnosis and disease monitoring. CTCs are believed to originate from the primary tumor and obtain genetic heterogeneity during evolution.

Areas covered: The presence of CTCs has been associated with poor clinical outcome in patients with metastatic breast cancer, lung cancer, colorectal cancer and prostate cancer. In addition, the detection of CTCs in patients with early breast cancer has been shown to represent an independent prognostic factor associated with an unfavorable clinical outcome. Moreover, the longitudinal evaluation of CTCs in patients with early breast cancer may reveal the presence of chemo- and hormone-therapy resistant CTCs which are associated with an increased risk for disease relapse and disease-related death.

Expert commentary: The molecular characterization of CTCs may provide an important tool for the monitoring and the evaluation of treatment efficacy in patients with different tumor types such as breast, prostate, colon, and non-small cell lung cancer.     

An update on liquid biopsy analysis for diagnostic and monitoring applications in non-small cell lung cancer

Introduction: Collection of tumor samples is not always feasible in non-small cell lung cancer (NSCLC) patients, and circulating free DNA (cfDNA) extracted from blood represents a viable alternative. Different sensitive platforms have been developed for genetic cfDNA testing, some of which are already in clinical use. However, several difficulties remain, particularly the lack of standardization of these methodologies.

Areas covered: Here, the authors present a review of the literature to update the applicability of cfDNA for diagnosis and monitoring of NSCLC patients.

Expert commentary: Detection of somatic alterations in cfDNA is already in use in clinical practice and provides valuable information for patient management. Monitoring baseline alterations and emergence of resistance mutations is one of the most important clinical applications and can be used to non-invasively track disease evolution. Today, different technologies are available for cfDNA analysis, including whole-genome or exome sequencing and targeted methods that focus on a selection of genes of interest in a specific disease. In the case of Next Generation Sequencing (NGS) approaches, in depth coverage of candidate mutation loci can be achieved by selecting a limited number of targeted genes.     

The potential use of urine cell free DNA as a marker for cancer

Introduction: Although the role of circulating cell free DNA in cancer has been widely demonstrated, less is known about the role of urine cell free DNA (UcfDNA). UcfDNA can serve as a ‘liquid biopsy’ for urological and non-urological tumors, as it carries information on DNA from cells exfoliated in urine and from circulation.

Areas covered: We review the studies on UcfDNA as a source of biomarkers for cancer, focusing on the new techniques and the differences between urological and non-urological tumors. We searched Pubmed for articles published between 1998 and 2016 with the following key words and phrases: ‘urine’ and ‘cell free DNA’ or ‘liquid biopsy’ or ‘cancer’.

Expert commentary: Despite the few papers published on this topic, UcfDNA is an important component of ‘liquid biopsy’, a useful and non-invasive tool for cancer diagnosis, prognosis and treatment monitoring, containing a wide range of genetic information.     

Identification of the affected ear in lateral canal benign paroxysmal positional vertigo

Background:

The effective management of lateral canal benign paroxysmal positional vertigo (LC-BPPV) is dependent upon the accurate identification of the affected ear. The supine roll test is the gold standard for diagnosing LC-BPPV. However, in some cases, the elicited nystagmus has a similar intensity when the head is rolled to the right or to the left.

Objectives:

The purpose of this systematic review was to determine the effectiveness of accessory diagnostic procedures, used in conjunction with the supine roll test, at accurately identifying the affected ear in individuals with LC-BPPV.

Methods:

The following databases were searched: (1) CINAHL Plus with Full Text, (2) ProQuest Medical Library, and (3) MEDLINE. The following search terms were used: (1) ‘lateral canal’ OR ‘horizontal canal’ AND (2) ‘positional vertigo’ OR ‘positioning vertigo’ OR ‘positional nystagmus’ OR ‘positioning nystagmus’. Evidence level was examined with the Oxford Centre for Evidence-Based Medicine 2011 levels of evidence method, and methodological rigour was examined with the QUADAS method.

Results:

A database search originally identified 1348 records, and nine studies were ultimately included in the qualitative synthesis. This systematic review revealed four index tests that, when used in conjunction with the supine roll test, were able to accurately identify the affected ear in a majority of individuals with LC-BPPV.

Conclusions:

The pseudo-spontaneous test was found to be slightly superior to the other three index tests in terms of eliciting nystagmus during its administration and identifying the same affected ear as the supine roll test.     

Parent-based diagnosis of ADHD is as accurate as a teacher-based diagnosis of ADHD

Objective: To review the literature evaluating the psychometric properties of parent and teacher informants relative to a gold-standard ADHD diagnosis in pediatric populations.

Method: We included studies that included both a parent and teacher informant, a gold-standard diagnosis, and diagnostic accuracy metrics. Potential confounds were evaluated. We also assessed the ‘OR’ and the ‘AND’ rules for combining informant reports.

Results: Eight articles met inclusion criteria. The diagnostic accuracy for predicting gold standard ADHD diagnoses did not differ between parents and teachers. Sample size, sample type, participant drop-out, participant age, participant gender, geographic area of the study, and date of study publication were assessed as potential confounds.

Conclusion: Parent and teachers both yielded moderate to good diagnostic accuracy for ADHD diagnoses. Parent reports were statistically indistinguishable from those of teachers. The predictive features of the ‘OR’ and ‘AND’ rules are useful in evaluating approaches to better integrating information from these informants.     

Liquid biopsy for brain tumors

Introduction: Minimally invasive methods will augment the clinical approach for establishing the diagnosis or monitoring treatment response of central nervous system tumors. Liquid biopsy by blood or cerebrospinal fluid sampling holds promise in this regard.

Areas covered: In this literature review, the authors highlight recent studies describing the analysis of circulating tumor cells, cell free nucleic acids, and extracellular vesicles as strategies to accomplish liquid biopsy in glioblastoma and metastatic tumors. The authors then discuss the continued efforts to improve signal detection, standardize the liquid biopsy handling and preparation, develop platforms for clinical application, and establish a role for liquid biopsies in personalized medicine.

Expert commentary: As the technologies used to analyze these biomarkers continue to evolve, we propose that there is a future potential to precisely diagnose and monitor treatment response with liquid biopsies.     

The effect on the patient flow in a local health care after implementing reverse triage in a primary care emergency department: a longitudinal follow-up study

Objective: Reverse triage means that patients who are not considered to be in need of medical services are not placed on the doctor’s list in an emergency department (ED) but are sent, after face-to-face evaluation by a triage nurse, to a more appropriate health care unit. It is not known how an abrupt application of such reverse triage in a combined primary care ED alters the demand for doctors’ services in collaborative parts of the health care system.

Design: An observational study.

Setting: Register-based retrospective quasi-experimental longitudinal follow-up study based on a before–after setting in a Finnish city.

Subjects: Patients who consulted different doctors in a local health care unit.

Main outcome measures: Numbers of monthly visits to different doctor groups in public and private primary care, and numbers of monthly referrals to secondary care ED from different sources of primary care were recorded before and after abrupt implementation of the reverse triage.

Results: The beginning of reverse triage decreased the number of patient visits to a primary ED doctor without increasing mortality. Simultaneously, there was an increase in doctor visits in the adjacent secondary care ED and local private sector. The number of patients who came to secondary care ED without a referral or with a referral from the private sector increased.

Conclusions: The data suggested that the reverse triage causes redistribution of the use of doctors’ services rather than a true decrease in the use of these services.     

Droplet-based digital PCR and next generation sequencing for monitoring circulating tumor DNA: a cancer diagnostic perspective

Introduction: Early detection of cancers through the analysis of ctDNA could have a significant impact on morbidity and mortality of cancer patients. However, using ctDNA for early cancer diagnosis is challenging partly due to the low amount of tumor DNA released in the circulation and its dilution within DNA originating from non-tumor cells. Development of new technologies such as droplet-based digital PCR (ddPCR) or optimized next generation sequencing (NGS) has greatly improved the sensitivity, specificity and precision for the detection of rare sequences.

Areas covered: This paper will focus on the potential application of ddPCR and optimized NGS to detect ctDNA for detection of cancer recurrence and minimal residual disease as well as early diagnosis of cancer patients.

Expert commentary: Compared to tumor tissue biopsies, blood-based ctDNA analyses are minimally invasive and accessible for regular follow-up of cancer patients. They are also described as a better picture of patients’ pathology allowing to highlight both tumor heterogeneity and multiple tumor sites. After a brief introduction on the application of the follow-up of ctDNA using genetic or epigenetic biomarkers for prognosis and surveillance of cancer patients, potential perspectives of using ctDNA for early diagnosis of cancers will be presented.     

Improving the CellSearch® system

Introduction: The CellSearch® CTC test enumerates tumor cells present in 7.5 ml blood of cancer patients. improvements, extensions and different utilities of the cellsearch system are discussed in this paper.

Areas covered: This paper describes work performed with the CellSearch system, which go beyond the normal scope of the test. All results from searches with the search term ‘CellSearch’ from Web of Science and PubMed were categorized and discussed.

Expert commentary: The CellSearch Circulating Tumor Cell test captures and identifies tumor cells in blood that are associated with poor clinical outcome. How to best use CTC in clinical practice is being explored in many clinical trials. The ability to extract information from the CTC to guide therapy will expand the potential clinical utility of CTC.     

Point-of-care diagnostics for respiratory viral infections

Introduction: Successful treatment outcomes for viral respiratory tract infections presenting from primary health care to quaternary hospitals will only be achieved with rapid, sensitive and specific identification of pathogens to allow effective pathogen-specific antiviral therapy and infection control measures.

Areas covered: This review aims to explore the different point-of-care tests currently available to diagnose viral respiratory tract infections, discuss the advantages and limitations of point-of-care testing, and provide insights into the future of point-of-care tests. The following databases were searched: Medline (January 1996 to 30 September 2017) and Embase (1988 to 30 September 2017), using the following keywords: ‘point of care’, ‘respiratory virus’, ‘influenza’, ‘RSV’, ‘diagnostics’, ‘nucleic acid test’ and ‘PCR’.

Expert commentary: Viral respiratory tract infections cause significant morbidity and mortality worldwide, and point-of-care tests are facilitating the rapid identification of the pathogen responsible given the similarities in clinical presentation.     

Peripheral response to cervical or thoracic spinal manual therapy: an evidence-based review with meta analysis

Objectives:

Spinal manual therapy (SMT) is commonly used for treatment of musculoskeletal pain in the neck, upper back, or upper extremity. Some authors report a multi-system effect of SMT, including peripheral alterations in skin conductance and skin temperature, suggesting that SMT may initiate a sympathetic nervous system (SNS) response. The focus of this evidence-based review and meta-analysis is to evaluate the evidence of SNS responses and clinically relevant outcomes following SMT to the cervical or thoracic spine.

Methods:

A systematic search used the terms: ‘manual therapy’, ‘SMT’, ‘spinal manipulation’, ‘mobilization’, ‘SNS’, ‘autonomic nervous system’, ‘neurophysiology’, ‘hypoalgesia’, ‘pain pathophysiology’, ‘cervical vertebrae’, ‘thoracic vertebrae’, ‘upper extremity’, and ‘neurodynamic test’. Data were extracted and within-group and between-group effect sizes were calculated for outcomes of skin conductance, skin temperature, pain, and upper extremity range of motion (ROM) during upper limb neurodynamic tests (ULNTs).

Results:

Eleven studies were identified. Statistically significant changes were seen with increased skin conductance, decreased skin temperature, decreased pain, and increased upper extremity ROM during ULNT.

Discussion:

A mechanical stimulus at the cervical or thoracic spine can produce a SNS excitatory response (increased skin conductance and decreased skin temperature). Findings of reduced pain and increased ROM during ULNT provide support to the clinical relevance of SMT. This evidence points toward additional mechanisms underlying the therapeutic effect of SMT. The effect sizes are small to moderate and no long-term effects post-SMT were collected. Future research is needed to associate peripheral effects with a possible centrally-mediated response to SMT.     

The rise of genomic profiling in ovarian cancer

Introduction: Next-generation sequencing and advances in ‘omics technology have rapidly increased our understanding of the molecular landscape of epithelial ovarian cancers.

Areas covered: Once characterized only by histologic appearance and clinical behavior, we now understand many of the molecular phenotypes that underlie the different ovarian cancer subtypes. While the current approach to treatment involves standard cytotoxic therapies after cytoreductive surgery for all ovarian cancers regardless of histologic or molecular characteristics, focus has shifted beyond a ‘one size fits all’ approach to ovarian cancer.

Expert commentary: Genomic profiling offers potentially ‘actionable’ opportunities for development of targeted therapies and a more individualized approach to treatment with concomitant improved outcomes and decreased toxicity.     

Factors associated with self-rated health in primary care

Background: Self-rated health (SRH) measures one’s current general health and is a widely used health indicator. Sleep problems, somatic health complaints, and unmet needs in interpersonal relationships are suspected to influence SRH, but studies in primary health care settings are sparse.

Objective: To examine the associations between patients’ self-rated health and their sleep problems, somatic health complaints, and unmet needs in interpersonal relationships.

Design: We collected data via questionnaires for this cross-sectional study from general practice.

Setting: Primary health care in Norway.

Subjects: 1302 consecutive patients participated.

Main outcome measures: The questionnaire included a single question about SRH, the Bergen Insomnia Scale (BIS), five questions on somatic health complaints, and three questions from the Basic Psychological Needs Scale (BPNS) pertaining to the relationships domain. We analyzed our data using ordinal logistic regression models.

Results: Our response rate was 74%. The prevalence of fair/poor SRH was 26%, with no gender differences. We revealed a significant association between increasing age and reduced SRH. The study showed that sleep problems and somatic health complaints were strongly associated with SRH, and unmet needs in relationships were also significantly and independently associated with reduced SRH in a full model analysis.

Conclusion: Sleep problems, somatic health complaints, and unmet needs in interpersonal relationships were all associated with reduced SRH. These factors are all modifiable and could be managed both within and outside a primary care setting in order to improve SRH.

• Key Points

• There was a high prevalence of reduced SRH in clinical general practice

• Sleep problems, somatic health complaints, and unmet needs in interpersonal relationships were all associated with reduced SRH

• These predictors are all modifiable with a potential to improve SRH

     

Non-pharmacological management of phantom limb pain in lower limb amputation: a systematic review

Background: The incidence and severity of phantom limb pain (PLP) does not differ much between the extremities of amputation. However, its impact on functional ability and quality of life in lower limb amputation may be different, as prosthetic weight bearing is a key component in the movement and functional rehabilitation of individuals with a lower limb amputation.

Objective: To evaluate the evidence for effectiveness or efficacy of non-pharmacological interventions in the management of PLP in adults with lower limb amputation.

Methods: A comprehensive literature search conducted on 11 electronic databases, from their inception to 25 March 2016 identified 626 potentially relevant articles. Full-text randomised controlled trials in English which examined any form of non-pharmacologic intervention for managing PLP in lower limb amputees were included. The data with regard to characteristics of the studies, participants, intervention and outcome measures and overall statistical result were extracted. The Cochrane ‘Risk of bias assessment tool’ was used to assess the bias of all included articles.

Results: Four studies met the final criteria to be included in the review. Four treatment techniques had been used in the treatment of 204 patients with lower limb amputation. Two trials showed a positive impact of intervention on PLP compared to control group. Risk of bias varied across studies, and only one included study was assessed as having a low risk of bias.

Conclusion: The review identified lack of evidence to support non-pharmacological interventions in the management of PLP. Adequately powered high-quality trials are needed in this area to inform rehabilitation.     

Optimising the quality and outcomes of treatments for diabetic foot infections

Introduction: Infection is the commonest foot complication that arises in people with diabetes and may lead to amputation and even death. The emergence of multidrug resistant bacteria, especially in Gram negative rods, may have a negative impact on the chances of cure in these patients.

Areas covered: We searched the Medline and Pubmed databases for studies using the keywords ‘diabetic foot infection’ and ‘diabetic foot osteomyelits’ from 1980 to 2016.

Expert commentary: Much has been done in the field of diabetic foot infection regarding pathophysiology, diagnosis and treatment. The construction of multidisciplinary teams is probably the most efficient way to improve the patients’ outcome. The rational use of antibiotics and surgical skills are essential in these potentially severe infections. Each case of diabetic infection deserves to be discussed in the light of the current guidelines and the local resources. Because of the overal poor outcome of these infections, prevention remains a priority.     

A systematic review to determine the optimal type and dosage of land-based exercises for treating knee osteoarthritis

Background: Exercise has been acknowledged as an effective non-pharmacological intervention for osteoarthritis. Consensus regarding the type of exercise i.e., aerobic or resistance, weight bearing or non-weight bearing, and dosage i.e., frequency, loading, duration, or intensity, is yet to be reached.

Objective: The purpose of this review was to address two questions: (1) is there a difference in clinical outcomes between different exercise programmes; and (2) what is the optimal dosage of exercises for people with knee osteoarthritis.

Methods: A systematic review was conducted. A study of published (AMED, CINAHL, MEDLINE, EMBASE, PubMed, and the Cochrane Library) and unpublished literature (WHO International Clinical Trials Registry Platform, current controlled trials and the United States National Institute of Health Trials Registry, and Open Grey) was undertaken in January 2013. Studies assessing the clinical outcomes of different types and dosages of exercise for people with osteoarthritis of the knee were included. Methodological quality was assessed using the critical appraisal skills programme (CASP) randomized controlled trial (RCT) appraisal tool.

Results: Ten studies assessing 958 knees from 916 participants were included. Exercise significantly improved pain and function for people with knee osteoarthritis. There was no significant difference in outcomes for different types of exercise i.e., aerobic versus resistance, weight bearing versus non-weight bearing. There was no significant difference in respect to the intensity of exercise i.e., high- versus lower-intensity resistance or aerobic exercises. The quality of the literature was moderate to high.

Conclusions: While exercise appears to improve symptoms and optimize function for people with knee osteoarthritis, the optimal form and dosage of exercise remains unknown.

Funding: None.

PROSPERO Registration Number: CRD42012002811.     

Resolution of cannabis hyperemesis syndrome with topical capsaicin in the emergency department: a case series

Background: Cannabinoid hyperemesis syndrome (CHS) is characterized by symptoms of cyclic abdominal pain, nausea, and vomiting in the setting of prolonged cannabis use. The transient receptor potential vanilloid 1 (TRPV1) receptor may be involved in this syndrome. Topical capsaicin is a proposed treatment for CHS; it binds TRPV1 with high specificity, impairing substance P signaling in the area postrema and nucleus tractus solitarius via overstimulation of TRPV1. This may explain its apparent antiemetic effect in this syndrome.

Purpose: We describe a series of thirteen cases of suspected cannabis hyperemesis syndrome treated with capsaicin in the emergency departments of two academic medical centers.

Methods: A query of the electronic health record at both centers identified thirteen patients with documented daily cannabis use and symptoms consistent with CHS who were administered topical capsaicin cream for symptom management.

Results: All 13 patients experienced symptom relief after administration of capsaicin cream.

Conclusion: Topical capsaicin was associated with improvement in symptoms of CHS after other treatments failed.     

What happens when the doctor denies a patient’s request? A qualitative interview study among general practitioners in Norway

Objective: To explore general practitioners (GPs’) experiences from consultations when a patient’s request is denied, and outcomes of such incidents.

Design and participants: We conducted a qualitative study with semi-structured individual interviews with six GPs in Norway. We asked them to tell about experiences from specific encounters where they had refused a patient’s request. The texts were analysed with Systematic Text Condensation, a method for thematic cross-case analysis.

Main outcome measures: Accounts of experiences from consultations when GPs refused their patients’ requests.

Results: Subjects of dispute included clinical topics like investigation and treatment, certification regarding welfare benefits and medico-legal issues, and administrative matters. The arguments took different paths, sometimes settled by reaching common ground but more often as unresolved disagreement with anger or irritation from the patient, sometimes with open hostility and violence. The aftermath and outcomes of these disputes lead to strong emotional impact where the doctors reflected upon the incidents and sometimes regretted their handling of the consultation. Some long-standing and close patient–doctor relationships were injured or came to an end.

Conclusions: The price for denying a patient’s request may be high, and GPs find themselves uncomfortable in such encounters. Skills pertaining to this particular challenge could be improved though education and training, drawing attention to negotiation of potential conflicts. Also, the notion that doctors have a professional commitment to his or her own autonomy and to society should be restored, through increased emphasis on core professional ethics in medical education at all levels.