Circulating tumor DNA association with residual cancer burden after neoadjuvant chemotherapy in triple-negative breast cancer in TBCRC 030.

BACKGROUND: We aimed to examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy. PATIENTS AND METHODS: We identified responders (RCB 0/1) and matched non-responders (RCB 2/3) from the phase II TBCRC 030 prospective study of neoadjuvant paclitaxel versus cisplatin in TNBC. We collected plasma samples at baseline, 3 weeks and 12 weeks (end of therapy). We created personalized ctDNA assays utilizing MAESTRO mutation enrichment sequencing. We explored associations between ctDNA and RCB status and disease recurrence. RESULTS: Of 139 patients, 68 had complete samples and no additional neoadjuvant chemotherapy. Twenty-two were responders and 19 of those had sufficient tissue for whole-genome sequencing. We identified an additional 19 non-responders for a matched case-control analysis of 38 patients using a MAESTRO ctDNA assay tracking 319-1000 variants (median 1000 variants) to 114 plasma samples from 3 timepoints. Overall, ctDNA positivity was 100% at baseline, 79% at week 3 and 55% at week 12. Median tumor fraction (TFx) was 3.7 × 10-4 (range 7.9 × 10-7-4.9 × 10-1). TFx decreased 285-fold from baseline to week 3 in responders and 24-fold in non-responders. Week 12 ctDNA clearance correlated with RCB: clearance was observed in 10 of 11 patients with RCB 0, 3 of 8 with RCB 1, 4 of 15 with RCB 2 and 0 of 4 with RCB 3. Among six patients with known recurrence, five had persistent ctDNA at week 12. CONCLUSIONS: Neoadjuvant chemotherapy for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders. In 58% (22/38) of patients, ctDNA TFx dropped below the detection level of a commercially available test, emphasizing the need for sensitive tests. Additional studies will determine whether ctDNA-guided approaches can improve outcomes.

Olanzapine as an add-on, pre-operative anti-emetic drug for postoperative nausea or vomiting: a randomised controlled trial.

Postoperative nausea or vomiting occurs in up to 40% in patients with multiple risk factors, despite prophylaxis. Olanzapine is an antipsychotic drug that is used to prevent nausea and vomiting in palliative care and to treat chemotherapy-induced nausea and vomiting. This study aimed to examine whether pre-operative olanzapine, as a prophylactic anti-emetic added to intra-operative dexamethasone, ondansetron and total intravenous anaesthesia, reduced the incidence of postoperative nausea or vomiting. We performed a multiply-blinded randomised controlled trial in patients aged 18-60 years with cancer at high risk of postoperative nausea or vomiting (three or four risk factors according to the Apfel criteria) plus a previous history of chemotherapy-induced nausea and vomiting. Patients were allocated at random to receive 10 mg olanzapine or placebo orally 1 h before surgery in addition to a two-drug regimen (dexamethasone and ondansetron) and propofol anaesthesia to prevent postoperative nausea or vomiting. The primary outcome was the incidence of postoperative nausea or vomiting in the first 24 h after surgery. In total, 100 patients were enrolled; 47 in the olanzapine group and 49 in the control group completed the study. The baseline characteristics of the groups were similar. The incidence of postoperative nausea or vomiting in the first 24 h after surgery was lower in the olanzapine group (12/47, 26%) than in the control group (31/49, 63%) (p = 0.008, RR 0.40 (95%CI 0.21-0.79)). Adding pre-operative oral olanzapine to intra-operative dexamethasone and ondansetron was highly effective in reducing the risk of postoperative nausea or vomiting in the first 24 hours after surgery in patients with a previous history of chemotherapy-induced nausea and vomiting and at least three Apfel risk factors for postoperative nausea or vomiting.

ESMO expert consensus statements (ECS) on the definition, diagnosis, and management of HER2-low breast cancer.

Human epidermal growth factor receptor 2 (HER2)-low breast cancer has recently emerged as a targetable subset of breast tumors, based on the evidence from clinical trials of novel anti-HER2 antibody-drug conjugates. This evolution has raised several biological and clinical questions, warranting the establishment of consensus to optimally treat patients with HER2-low breast tumors. Between 2022 and 2023, the European Society for Medical Oncology (ESMO) held a virtual consensus-building process focused on HER2-low breast cancer. The consensus included a multidisciplinary panel of 32 leading experts in the management of breast cancer from nine different countries. The aim of the consensus was to develop statements on topics that are not covered in detail in the current ESMO Clinical Practice Guideline. The main topics identified for discussion were (i) biology of HER2-low breast cancer; (ii) pathologic diagnosis of HER2-low breast cancer; (iii) clinical management of HER2-low metastatic breast cancer; and (iv) clinical trial design for HER2-low breast cancer. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. A review of the relevant scientific literature was conducted in advance. Consensus statements were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This article presents the developed statements, including findings from the expert panel discussions, expert opinion, and a summary of evidence supporting each statement.

Association of HER2DX with pathological complete response and survival outcomes in HER2-positive breast cancer.

BACKGROUND: The HER2DX genomic test predicts pathological complete response (pCR) and survival outcome in early-stage HER2-positive (HER2+) breast cancer. Here, we evaluated the association of HER2DX scores with (i) pCR according to hormone receptor status and various treatment regimens, and (ii) survival outcome according to pCR status. MATERIALS AND METHODS: Seven neoadjuvant cohorts with HER2DX and clinical individual patient data were evaluated (DAPHNe, GOM-HGUGM-2018-05, CALGB-40601, ISPY-2, BiOnHER, NEOHER and PAMELA). All patients were treated with neoadjuvant trastuzumab (n = 765) in combination with pertuzumab (n = 328), lapatinib (n = 187) or without a second anti-HER2 drug (n = 250). Event-free survival (EFS) and overall survival (OS) outcomes were available in a combined series of 268 patients (i.e. NEOHER and PAMELA) with a pCR (n = 118) and without a pCR (n = 150). Cox models were adjusted to evaluate whether HER2DX can identify patients with low or high risk beyond pCR status. RESULTS: HER2DX pCR score was significantly associated with pCR in all patients [odds ratio (OR) per 10-unit increase = 1.59, 95% confidence interval 1.43-1.77; area under the ROC curve = 0.75], with or without dual HER2 blockade. A statistically significant increase in pCR rate due to dual HER2 blockade over trastuzumab-only was observed in HER2DX pCR-high tumors treated with chemotherapy (OR = 2.36 (1.09-5.42). A statistically significant increase in pCR rate due to multi-agent chemotherapy over a single taxane was observed in HER2DX pCR-medium tumors treated with dual HER2 blockade (OR = 3.11, 1.54-6.49). The pCR rates in HER2DX pCR-low tumors were ≤30.0% regardless of treatment administered. After adjusting by pCR status, patients identified as HER2DX low-risk had better EFS (P < 0.001) and OS (P = 0.006) compared with patients with HER2DX high-risk. CONCLUSIONS: HER2DX pCR score and risk score might help identify ideal candidates to receive neoadjuvant dual HER2 blockade in combination with a single taxane in early-stage HER2+ breast cancer.

[The neuro-urological expert opinion in statutory accident insurance : Consensual recommendations for diagnostics and for the assessment of reduction of earning capacity]. / Das neurourologische Gutachten in der gesetzlichen Unfallversicherung : Konsentierte Empfehlungen zur Diagnostik und zur Bewertung der Minderung der Erwerbsfähigkeit.

BACKGROUND: Previous assessment guidelines from standard sources for urologic expert opinions show considerable differences in the recommended percentages for the assessment of reduction of earning capacity (MdE) for accident sequelae in the neuro-urological specialty. OBJECTIVES: To develop a "revised and standardized version of the MdE assessments of neuro-urological accident sequelae (in tabular form) as a guideline/manual" for expert opinions in the legal area of the German and Austrian Statutory Accident Insurance ( www.dguv.de , www.auva.at ). MATERIALS AND METHODS: A working group of neuro-urologists from spinal cord injury centers of different BG ("Berufsgenossenschaft") clinics was formed within the working group Neuro-Urology of DMGP (German-speaking Medical Society for Paraplegiology; www.dmgp.de ). Between January 2017 and September 2022, a total of 7 working meetings and 2 video conferences were held. The consensus of the developed documents was reached by formal consensus finding in a nominal group process and in a final consensus conference. RESULTS: The necessary bases for a targeted, legally sound diagnosis of accident consequences in the neuro-urological field were elaborated and, based on the experience of many years of expert opinion activity, a "matrix" for a uniform, graduated assessment of the level of reduction of earning capacity in the (neuro-)urological field in the case of confirmed neuro-urological accident consequences was created. CONCLUSION: In the interest of equal treatment of all insured persons, it is of great importance to make a uniform and comprehensible assessment of the amount of the MdE on the basis of "table values" that reflect the available empirical values.

Prediction of successful hearing aid treatment in first-time and experienced hearing aid users: Using the International Outcome Inventory for Hearing Aids.

OBJECTIVE: Primarily to understand whether clinically relevant factors affect the International Outcome Inventory (IOI-HA) scores and to examine if IOI-HA scores improve when renewing the hearing aids (HA) for experienced users. Secondly, to estimate the overall HA effectiveness using the IOI-HA. DESIGN: A prospective observational study. STUDY SAMPLE: In total, 1961 patients with hearing loss were included. All patients underwent a hearing examination, were fitted with HAs, and answered the IOI-HA. Factor analysis of IOI-HA separated the items into a Factor 1 (use of HA, perceived benefits, satisfaction, and quality of life) and Factor 2 (residual activity limitation, residual participation restriction and impact on others) score. RESULTS: Degree of hearing loss, word recognition score, motivation, HA usage time, tinnitus, asymmetry, and sex were significantly associated with total IOI-HA, Factor 1, or Factor 2 scores. The seven IOI-HA items increased on average by 0.4 (p < 0.001) when renewing HAs. The total median IOI-HA score at follow-up was 29 (7) for experienced (n = 460) and first-time users (n = 1189), respectively. CONCLUSIONS: Degree of hearing loss, word recognition score, motivation, tinnitus, asymmetry, and sex may be used to identify patients who require special attention to become successful HA users.

Hip Labral Reconstruction: Techniques and Outcomes.

PURPOSE OF REVIEW: With increased understanding of the biomechanical function of the acetabular labrum, more attention has been directed towards surgical techniques that preserve or restore normal joint anatomy. While labral repair has been shown to produce superior outcomes to labral debridement, repair is not always possible in the setting of severe labral intrasubstance tearing or deficiency. These patients were previously left without suitable arthroscopic treatment options. RECENT FINDINGS: Labral reconstruction is an emerging procedure that has been shown to offer promising outcomes for traditionally difficult-to-treat hip pathology. Short- and mid-term follow-up studies have consistently demonstrated significant improvement in patient-reported outcomes, function, and patient satisfaction postoperatively, often despite less favorable preoperative characteristics. Labral reconstruction is a viable arthroscopic treatment option that has been shown to reliably produce clinically meaningful results in patients with severe labral pathology that is not amenable to repair/refixation or augmentation.

A musician-centered approach to management of performance-related upper musculoskeletal injuries.

STUDY DESIGN: Invited Clinical Commentary BACKGROUND: Performance related musculoskeletal disorders (PRMD) are common in instrumental musicians and often affect the upper extremities. These overuse injuries typically result from inadequate attention to the musculoskeletal demands required for the high-level performance of musician-students and experienced instrumentalists.1 PRMDs often interfere with career trajectory, and in extreme cases, can be career ending. Many clinicians and healthcare practitioners treating upper extremity injuries are not familiar with the specific demands faced by instrumental musicians and how to tailor treatment and prevention strategies to the specific risks and occupational needs of each instrumental group. PURPOSE OF THE STUDY: This paper describes an evidenced-based framework for the assessment, prevention, and treatment of musculoskeletal musician injuries to provide clinicians with an instrument-specific, and musician-centered guide for practice. We synthesized available literature on instrumental ergonomics, biomechanical demands, and upper extremity injuries to highlight the risks and common upper-extremity pathologies, focusing on the specific demands of instrumental groups: piano, high strings (violin and viola), low strings (cello and bass), percussion, woodwinds, and brass. Targeted assessment, prevention, and treatment strategies are reviewed in this context to provide healthcare providers with an evidence-based framework to approach the treatment of PRMD to mitigate incidence of injury during practice and performance. METHODS: A comprehensive search of electronic databases was conducted including all study designs. RESULTS: This review describes risk factors for PRMD in instrumental musicians, strategies to prevent misuse and performance injury, and musician-centered interventions to allow playing while reducing risk of misuse. CONCLUSION: The suggested assessment and treatment framework can assist clinicians with a customized patient-centered approach to prevention and treatment by addressing the gap in clinical knowledge with the goal of ultimately reducing the incidence and severity of PRMD in musicians.

Stability of hepatitis E virus at high hydrostatic pressure processing.

Hepatitis E virus (HEV) is the causative agent of acute and chronic hepatitis in humans. The zoonotic HEV genotype 3 is the main genotype in Europe. The foodborne transmission via consumption of meat and meat products prepared from infected pigs or wild boars is considered the major transmission route of this genotype. High hydrostatic pressure processing (HPP) is a technique, which can be used for inactivation of pathogens in food. Here, preparations of a cell culture-adapted HEV genotype 3 strain in phosphate-buffered saline (PBS) were subjected to HPP and the remaining infectivity was titrated in cell culture by counting fluorescent foci of replicating virus. A gradual decrease in infectivity was found by application of 100 to 600 MPa for 2 min. At 20 °C, infectivity reduction of 0.5 log10 at 200 MPa and 1 log10 at 400 MPa were observed. Slightly higher infectivity reduction of 1 log10 at 200 MPa and 2 log10 at 400 MPa were found by application of the pressure at 4 °C. At both temperatures, the virus was nearly completely inactivated (>3.5 log10 infectivity decrease) at 600 MPa; however, low amounts of remaining infectious virus were observed in one of three replicates in both cases. Transmission electron microscopy showed disassembled and distorted particles in the preparations treated with 600 MPa. Time-course experiments at 400 MPa showed a continuous decline of infectivity from 30 s to 10 min, leading to a 2 log10 infectivity decrease at 20 °C and to a 2.5 log10 infectivity decrease at 4 °C for a 10 min pressure application each. Predictive models for inactivation of HEV by HPP were generated on the basis of the generated data. The results show that HPP treatment can reduce HEV infectivity, which is mainly dependent on pressure height and duration of the HPP treatment. Compared to other viruses, HEV appears to be relatively stable against HPP and high pressure/long time combinations have to be applied for significant reduction of infectivity.

TBCRC 030: a phase II study of preoperative cisplatin versus paclitaxel in triple-negative breast cancer: evaluating the homologous recombination deficiency (HRD) biomarker.

BACKGROUND: Cisplatin and paclitaxel are active in triple-negative breast cancer (TNBC). Despite different mechanisms of action, effective predictive biomarkers to preferentially inform drug selection have not been identified. The homologous recombination deficiency (HRD) assay (Myriad Genetics, Inc.) detects impaired double-strand DNA break repair and may identify patients with BRCA1/2-proficient tumors that are sensitive to DNA-targeting therapy. The primary objective of TBCRC 030 was to detect an association of HRD with pathologic response [residual cancer burden (RCB)-0/1] to single-agent cisplatin or paclitaxel. PATIENTS AND METHODS: This prospective phase II study enrolled patients with germline BRCA1/2 wild-type/unknown stage I-III TNBC in a 12-week randomized study of preoperative cisplatin or paclitaxel. The HRD assay was carried out on baseline tissue; positive HRD was defined as a score ≥33. Crossover to an alternative chemotherapy was offered if there was inadequate response. RESULTS: One hundred and thirty-nine patients were evaluable for response, including 88 (63.3%) who had surgery at 12 weeks and 51 (36.7%) who crossed over to an alternative provider-selected preoperative chemotherapy regimen due to inadequate clinical response. HRD results were available for 104 tumors (74.8%) and 74 (71.1%) were HRD positive. The RCB-0/1 rate was 26.4% with cisplatin and 22.3% with paclitaxel. No significant association was observed between HRD score and RCB response to either cisplatin [odds ratio (OR) for RCB-0/1 if HRD positive 2.22 (95% CI: 0.39-23.68)] or paclitaxel [OR for RCB-0/1 if HRD positive 0.90 (95% CI: 0.19-4.95)]. There was no evidence of an interaction between HRD and pathologic response to chemotherapy. CONCLUSIONS: In this prospective preoperative trial in TNBC, HRD was not predictive of pathologic response. Tumors were similarly responsive to preoperative paclitaxel or cisplatin chemotherapy.

Stability of hepatitis E virus at different pH values.

Infection with the hepatitis E virus (HEV) can cause acute and chronic hepatitis in humans. The zoonotic HEV genotype 3 is mainly transmitted by consumption of raw and fermented meat products prepared from infected pigs or wild boars. Lowering of pH during fermentation is one of the microbiological hurdles considered to inhibit growth of certain pathogens. However, no data are currently available on pH stability of HEV. As a reliable and reproducible measurement of HEV infectivity in meat products is not established so far, the stability of the cell culture-adapted HEV genotype 3 strain 47832c was analyzed here in phosphate-buffered saline (PBS) at different pH values. Only a minimal decrease of infectivity (up to 0.6 log10 focus forming units) was found after treatment at pH 2 to 9 for 3 h at room temperature. At pH 10, a decrease of about 3 log10 was evident, whereas no remaining virus (>3.5 log10 decrease) was detected at pH 1. The conditions usually achieved during curing of raw sausages were simulated using D/L-lactic acid added to PBS resulting in pH 4.5 to 6.5. After incubation at 4 °C for 7 days at these conditions, no significant differences as compared to a standard PBS solution at pH 7.7 were evident. At room temperature, a 0.8 log10 decrease was found at pH 4.7 after 7 days incubation compared to pH 7.7, but less at the other pH values. In conclusion, only minimal inactivating effects were found at pH conditions commonly occurring during food processing. Therefore, remaining infectious virus might be present in fermented meat products if HEV-contaminated starting material was used. Additional effects of other factors like high salt concentrations and low aw values should be investigated in future studies.

Prospective methods for identifying perioperative risk-assessment methods for patient safety over 20 years: a systematic review.

BACKGROUND: Serious preventable surgical events still occur despite considerable efforts to improve patient safety. In addition to learning from retrospective analyses, prospective risk-assessment methods may help to decrease preventable events further by targeting perioperative hazards. The aim of this systematic review was to assess the methods used to identify perioperative patient safety risks prospectively, and to describe the risk areas targeted, the quality characteristics and feasibility of methods. METHODS: MEDLINE, Embase, CINAHL and Cochrane databases were searched, adhering to PRISMA guidelines. All studies describing the development and results of prospective methods to identify perioperative patient safety risks were included and assessed on methodological quality. Exclusion criteria were interventional studies, studies targeting one specific issue, studies reporting on structural factors relating to fundamental hospital items, and non-original or case studies. RESULTS: The electronic search resulted in 16 708 publications, but only 20 were included for final analysis, describing five prospective risk-assessment methods. Direct observation was used in most studies, often in combination. Direct (16 studies) and indirect (4 studies) observations identified (potential) adverse events (P)AEs, process flow disruptions, poor protocol compliance and poor practice performance. (Modified) Healthcare Failure Mode and Effect Analysis (HFMEA™) (5 studies) targeted potential process flow disruption failures, and direct (P)AE surveillance (3 studies) identified (P)AEs prospectively. Questionnaires (3 studies) identified poor protocol compliance, surgical flow disturbances and patients' willingness to ask questions about their care. Overall, quality characteristics and feasibility of the methods were poorly reported. CONCLUSION: The direct (in-person) observation appears to be the primary prospective risk-assessment method that currently may best help to target perioperative hazards. This is a reliable method and covers a broad spectrum of perioperative risk areas.

ANTECEDENTES: A pesar de los esfuerzos considerables para mejorar la seguridad del paciente, aún se producen complicaciones quirúrgicas graves prevenibles. Además de adquirir conocimientos a través de los análisis retrospectivos, los métodos de evaluación de riesgos prospectivos por su enfoque en los riesgos perioperatorios, pueden ayudar a disminuir aún más los efectos adversos prevenibles. Esta revisión sistemática tiene como objetivo evaluar los métodos utilizados para identificar de forma prospectiva los riesgos perioperatorios de seguridad del paciente, describiendo las áreas de riesgo y las características de calidad y viabilidad de los métodos. MÉTODOS: Se realizaron búsquedas en las bases de datos MEDLINE, EMBASE, CINAHL y Cochrane siguiendo las recomendaciones PRISMA. Se incluyeron todos los estudios que describían el desarrollo y los resultados de métodos prospectivos para identificar los riesgos perioperatorios de seguridad del paciente y se evaluó su calidad metodológica. Se excluyeron los estudios de intervención, aquellos estudios dirigidos a un tema específico, los estudios enfocados a factores estructurales relacionados con elementos hospitalarios clave, y los estudios no originales o series de casos. RESULTADOS: La búsqueda electrónica identificó 16.708 publicaciones, pero solamente se incluyeron 20 publicaciones en las que se describían 5 métodos prospectivos de evaluación de riesgos. La observación directa fue el método utilizado en la mayoría de los estudios, a menudo en combinación con métodos indirectos. Las observaciones directas (80%) e indirectas (20%) identificaron efectos adversos potenciales (potential adverse events, (P)AEs), disrupciones en el flujo de los procesos, baja adherencia a los protocolos y prácticas deficientes. El análisis (modificado) de fallo de la atención sanitaria por modo y efecto (Healthcare-Failure-Mode-and-Effect Analysis) (25%) enfocado a fallos potenciales de disrupción de los procesos y la vigilancia directa de los (P)AEs (16%) identificaron (P)AEs de forma prospectiva. Los cuestionarios (15%) identificaron una baja adherencia a los protocolos, alteraciones en el flujo del proceso quirúrgico y la disposición de los pacientes para hacer preguntas sobre su atención. En general, las características de calidad y la viabilidad de los métodos se describían de manera deficiente. CONCLUSIÓN: La observación directa (en persona) es el principal método prospectivo de evaluación de riesgos que actualmente podría ser el mejor método para el enfoque en los riesgos perioperatorios. Es un método confiable y cubre un amplio espectro de áreas de riesgo perioperatorio.

A combinatorial biomarker predicts pathologic complete response to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast cancer.

BACKGROUND: HER2-positive (+) breast cancers, defined by HER2 overexpression and/or amplification, are often addicted to HER2 to maintain their malignant phenotype. Yet, some HER2+ tumors do not benefit from anti-HER2 therapy. We hypothesize that HER2 amplification levels and PI3K pathway activation are key determinants of response to HER2-targeted treatments without chemotherapy. PATIENTS AND METHODS: Baseline HER2+ tumors from patients treated with neoadjuvant lapatinib plus trastuzumab [with endocrine therapy for estrogen receptor (ER)+ tumors] in TBCRC006 (NCT00548184) were evaluated in a central laboratory for HER2 amplification by fluorescence in situ hybridization (FISH) (n = 56). HER2 copy number (CN) and FISH ratios, and PI3K pathway status, defined by PIK3CA mutations or PTEN levels by immunohistochemistry were available for 41 tumors. Results were correlated with pathologic complete response (pCR; no residual invasive tumor in breast). RESULTS: Thirteen of the 56 patients (23%) achieved pCR. None of the 11 patients with HER2 ratio <4 and/or CN <10 achieved pCR, whereas 13/45 patients (29%) with HER2 ratio ≥4 and/or CN ≥10 attained pCR (P = 0.0513). Of the 18 patients with tumors expressing high PTEN or wild-type (WT) PIK3CA (intact PI3K pathway), 7 (39%) achieved pCR, compared with 1/23 (4%) with PI3K pathway alterations (P = 0.0133). Seven of the 16 patients (44%) with HER2 ratio ≥4 and intact PI3K pathway achieved pCR, whereas only 1/25 (4%) patients not meeting these criteria achieved pCR (P = 0.0031). CONCLUSIONS: Our findings suggest that there is a clinical subtype in breast cancer with high HER2 amplification and intact PI3K pathway that is especially sensitive to HER2-targeted therapies without chemotherapy. A combination of HER2 FISH ratio and PI3K pathway status warrants validation to identify patients who may be treated with HER2-targeted therapy without chemotherapy.

Combined tetrahydrocannabinol and cannabidiol to treat pain in epidermolysis bullosa: a report of three cases.

Epidermolysis bullosa (EB) is a genetic blistering disorder characterized by intense pain related to disease pathology and care-based interventions. Opioid-based therapies underpin pain care in EB; however, they are unable to provide adequate analgesia in a significant proportion of patients. Cannabinoid-based medicines (CBMs) have been studied increasingly for pain conditions of various aetiologies and pose as a novel dimension for pain care in EB. We present three patients with EB who were prescribed pharmaceutical-grade sublingually administered CBMs comprising tetrahydrocannabinol and cannabidiol. All three patients reported improved pain scores, reduced pruritus and reduction in overall analgesic drug intake.

Altered hypothalamus-pituitary-adrenal axis function: A relevant factor in the comorbidity of atopic eczema and attention deficit/hyperactivity disorder?

Epidemiological data show a significant association between childhood atopic eczema (AE) and an increased risk to develop attention deficit/hyperactivity disorder (ADHD). However, the underlying mechanisms of the comorbidity of AE and ADHD are mostly unknown. We investigated whether alterations of hypothalamus-pituitary-adrenal (HPA) axis function represent a shared feature of AE and ADHD potentiating AE-ADHD comorbidity. Children aged 6-12 years with AE, ADHD, or comorbid AE + ADHD and healthy control (HC) children were examined cross-sectionally (N = 145). To evaluate HPA axis function, salivary cortisol in response to psychosocial stress (Trier Social Stress Test for Children, TSST-C), after awakening (cortisol awakening response, CAR), and throughout the day (short diurnal profile) and hair cortisol capturing long-term HPA axis activity were assessed. Quantile regression analyses showed an attenuated cortisol response (% maximum change) to the TSST-C in children with ADHD compared to HC. A diminished cortisol response to acute stress was also observed in the comorbid AE + ADHD group, in which the reduction was numerically even more pronounced. Contrary to our previous findings, no alteration of the cortisol response to the TSST-C was observed in children with AE. However, in children with AE, increased ADHD-like behavior (i.e., inattention, impulsivity, and overall ADHD symptom severity) was associated with a reduced HPA axis response to acute stress. No such associations were observed in children without AE. Groups did not differ in CAR, short diurnal profile, and hair cortisol. These findings underscore the potential relevance of HPA axis function in the pathophysiology of AE and ADHD with emphasis on stress reactivity. Additional studies are required to further explore the separate and joint role of the HPA axis in the pathophysiology of AE and ADHD.

Development and validation of a Self-assessment Instrument for Perioperative Patient Safety (SIPPS).

BACKGROUND: Patient safety is a fundamental value of healthcare to avoid patient harm. Non-compliance with patient safety standards may result in patient harm and is therefore a global concern. A Self-assessment Instrument for Perioperative Patient Safety (SIPPS) monitoring and benchmarking compliance to safety standards was validated in a multicentre pilot study. METHODS: A preliminary questionnaire, based on the Dutch perioperative patient safety guidelines and covering international patient safety goals, was evaluated in a first digital RAND Delphi round. The results were used to optimize the questionnaire and design the SIPPS. For measurement and benchmarking purposes, SIPPS was categorized into seven main patient safety domains concerning all care episode phases of the perioperative trajectory. After consensus was reached in a face-to-face Delphi round, SIPPS was pilot-tested in five hospitals for five characteristics: measurability, applicability, improvement potential, discriminatory capacity and feasibility. RESULTS: The results of the first Delphi round showed moderate feasibility for the preliminary questionnaire (81·6 per cent). The pilot test showed good measurability for SIPPS: 99·8 per cent of requested information was assessable. Some 99·9 per cent of SIPPS questions were applicable to the selected respondents. With SIPPS, room for improvement in perioperative patient safety compliance was demonstrated for all hospitals, concerning all safety domains and all care episode phases of the perioperative trajectory (compliance 76·1 per cent). SIPPS showed mixed results for discriminatory capacity. SIPPS showed good feasibility for all items (range 91·9-95·7 per cent). CONCLUSION: A self-assessment instrument for measuring perioperative patient safety (SIPPS) compliance meeting international standards was validated. With SIPPS, improvement areas for perioperative patient safety and best practices across hospitals could be identified.

Decision making process for amputation in case of therapy resistant complex regional pain syndrome type-I in a Dutch specialist centre.

Deciding for an amputation in case of complex regional pain syndrome type I (CRPS-I) is controversial. Evidence for favorable or adverse effects of an amputation is weak. We therefore follow a careful and well-structured decision making process. After referral of the patient with the request to amputate the affected limb, it is checked if the diagnosis CRPS-I is correct, duration of complaints is more than 1 year, all treatments described in the Dutch guidelines have been tried and if consequences of an amputation have been well considered by the patient. Thereafter the patient is assessed by a multidisciplinary team (psychologist, physical therapist, anesthesiologist-pain specialist, physiatrist and vascular surgeon). During a multidisciplinary meeting professionals summarize their assessment. Pros and cons of an amputation are discussed, taking into account level of amputation and expectations about post amputation functioning of patient and team. Based on assessments and discussion a consensus based decision is formulated and the patient is informed. If it is decided that an amputation is to be performed, the amputation will follow shortly. If it is decided not to amputate, the decision is extensively explained to the patient. Incidence of patients suffering from therapy resistant CRPS-I referred for amputation is low and because referred patients are strongly in favor of an amputation, a randomized controlled trial will be difficult to perform. Hence level of evidence in favor or against an amputation will remain low. We therefore report our decision making process to facilitate discussion about this difficult and delicate matter.

[Medicaments and oral healthcare. Systematic review of the -literature assessing the effect of drugs on the salivary glands]. / Serie: Medicamenten en mondzorg.Systematisch literatuuronderzoek naar effect van medicatie op de speekselklieren.

Evidence-based reviews of drugs causing medication-induced salivary gland dysfunction, such as xerostomia (sensation of oral dryness) and subjective sialorrhea are lacking. To compile a list of medicaments that influence salivary gland function, electronic databases were searched for relevant articles published up to June 2013. A total of 269 papers out of 3,867 records located satisfied the inclusion criteria (relevance, quality of methodology, strength of evidence). A total of 56 active substances with a higher level of evidence and 50 active substances with a moderate level of evidence of causing salivary gland dysfunction are described in this article. While xerostomia was a commonly reported outcome, the objective effect on salivary secretion was rarely measured. Xerostomia was, moreover, mostly reported as a negative side effect instead of the intended effect of that drug. A comprehensive list of medications having documented effects on salivary gland function or symptoms was compiled, which may assist practitioners in assessing patients who complain of dry mouth while taking medications.

Electrostimulation of the lingual nerve by an intraoral device may lead to salivary gland regeneration: A case series study.

BACKGROUND: Salivary gland function is controlled by the salivary reflex, whose efferent arm is composed by the parasympathetic and the sympathetic divisions of the autonomic nervous system. Parenchymal injury is the main salivary gland involvement of Sjögren's syndrome and head and neck radiotherapy, but neural damage has been reported as well. Recently an intraoral device for electrostimulation of the lingual nerve in vicinity to the lower third molar has been introduced. At this point this nerve carries efferent fibers for the innervation of the submandibular, sublingual and several minor salivary glands and afferent fibers of the salivary reflex. Therefore, excitation of these fibers potentially leads to increased secretion of all salivary glands. Thus, the study objective was to assess whether comprehensive neural activation by electrostimulation of the lingual nerve carries the potential to induce the regeneration of damaged salivary glands. MATERIAL AND METHODS: The device was tested on three patients with no collectable resting and stimulated secretion of saliva during a double blind, sham controlled period of two months and nine open-label months. RESULTS: All three subjects developed the capacity to spit saliva, not only in direct response to the electrostimulation but also after free intervals without electrostimulation. In addition, their symptoms of dry mouth severity and frequency improved. CONCLUSIONS: This recovery is probably due to the combined effect of increase in secretory functional gland mass and regain of nervous control of the secretory elements and blood vessels. Both are phenomena that would contribute to gland regeneration.