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Brain metastases (BM) present a common cause of mortality and morbidity in several metastatic cancer entities. New therapeutic developments during the last decades, including targeted and immune-related therapies, have shown considerable extra- and intracranial response rates in specific subgroups of BM patients. However, differences in the molecular alteration in the BM tumor tissue compared to extracranial tumors leads to heterogeneous therapeutic responses. Therefore, an accurate molecular analyzation of BM tissue, if possible, has become an essential part in therapeutic decision making in BM patients. The concordance of predictive molecular biomarkers between multiple sites including extracranial and intracranial tumor tissue have been analyzed for some but not all biomarkers routinely applied in modern precision medicine approaches. In the present review, we summarize the current evidence of predictive biomarkers for personalized therapy approaches in the treatment of parenchymal BM.

Modern hyperacute reperfusion therapies including intravenous thrombolysis and mechanical thrombectomy have transformed the management of arterial ischemic stroke (AIS) in adults. Multiple randomized clinical trials have demonstrated that these therapies enable remarkable improvements in clinical outcome for properly selected patients with AIS. Because pediatric patients were excluded from predicate clinical trials, there is a conspicuous lack of data to guide selection of therapies and inform age-adjusted and pathology-oriented treatment modifications for children. Specifically, technical guidance concerning treatment eligibility, drug dosing, and device implementation is lacking. This review aims to outline important features that differentiate pediatric AIS from adult AIS and provide practical strategies that will assist the stroke specialist with therapeutic decision making.

The frontline treatment paradigm for patients with advanced or metastatic non-small cell lung cancer (NSCLC) has changed dramatically in the past decade amid efforts to tackle this leading cause of cancer-related mortality. Immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1 (PD-1) receptor and its ligand PD-L1 are an important therapeutic option for patients whose tumors lack genetic alterations that dictate response to molecularly targeted therapies. With a growing number of FDA-approved ICI monotherapy and combination therapy options for first-line therapy, the use of biomarkers such as PD-L1 expression has become increasingly important in guiding therapeutic decision making. Presently, PD-L1 expression remains a key biomarker in this setting, in spite of its limitations. This article will evaluate the current and evolving clinical trends in the use of ICIs in the frontline management of metastatic NSCLC, as well as the challenges associated with PD-L1 expression analysis and biomarker implementation.

BACKGROUND AND AIMS Therapeutic, clinical trial entry and stratification decisions for hepatocellular carcinoma (HCC) are made based on prognostic assessments, using clinical staging systems based on small numbers of empirically selected variables that insufficiently account for differences in biological characteristics of individual patients' disease. APPROACH AND RESULTS We propose an approach for constructing risk scores from circulating biomarkers that produce a global biological characterization of individual patient's disease. Plasma samples were collected prospectively from 767 patients with HCC and 200 controls, and 317 proteins were quantified in a Clinical Laboratory Improvement Amendments-certified biomarker testing laboratory. We constructed a circulating biomarker aberration score for each patient, a score between 0 and 1 that measures the degree of aberration of his or her biomarker panel relative to normal, which we call HepatoScore. We used log-rank tests to assess its ability to substratify patients within existing staging systems/prognostic factors. To enhance clinical application, we constructed a single-sample score, HepatoScore-14, which requires only a subset of 14 representative proteins encompassing the global biological effects. Patients with HCC were split into three distinct groups (low, medium, and high HepatoScore) with vastly different prognoses (medial overall survival 38.2/18.3/7.1 months; P

Relapsing multiple sclerosis (RMS) presents a highly variable clinical evolution among patients, and its management should be personalized. Although there is no cure at present, effective disease-modifying therapies (DMTs) are available. Selection of the most appropriate DMT for each patient is influenced by several clinical, radiological and demographic aspects as well as personal preferences that, at times, are not covered in the regulatory criteria. This may be a source of difficulty, especially in certain situations where so-called ‘high-efficacy DMTs’ (usually considered second-line) could be of greater benefit to the patient. In this narrative review, we discuss evidence and experience, and propose a pragmatic guidance on decision-making with respect to the indication and management of high-efficacy DMT in adult patients with RMS based on expert opinion.

These recommendations, produced by a group of Canadian retina experts, have been developed to assist both retina specialists and general ophthalmologists in the management of vision-threatening neovascular age-related macular degeneration (nAMD). The recommendations are based on published evidence as well as collective experience and expertise in routine clinical practice. We provide an update on practice principles for optimal patient care, focusing on identified imaging biomarkers, in particular retinal fluid, as well as current and emerging therapeutic approaches. Algorithms for delivering high-quality care and improving long-term patient outcomes are provided, with an emphasis on timely and appropriate treatment to preserve and maintain vision. In the context of nAMD, increasing macular fluid or leakage on fluorescein angiography (FA) may indicate disease activity regardless of its location. Early elimination of intraretinal fluid (IRF) is of particular relevance as it is a prognostic indicator of worse visual outcomes. Robust referral pathways for second opinion and peer-to-peer consultations must be in place for cases not responding to intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy.

Background Implementation of personalized medicine requires the accessibility of tumor molecular profiling in order to allow prioritization of appropriate targeted therapies for individual patients. Our aim was to study the role of comprehensive genomic profiling assays that may inform treatment recommendations for patients with solid tumors. Materials and Methods We performed a prospective study to evaluate the feasibility of application of the FoundationOne CDx panel—which detects substitutions, insertions and deletions, and copy number alterations in 324 genes, select gene rearrangements, and genomic signatures including microsatellite instability and tumor mutation burden (TMB)—to patients with advanced or recurrent solid tumors before its approval in Japan. Results A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%. The median turnaround time was 41 days (range, 21–126 days). The most common known or likely pathogenic variants were TP53 mutations (n = 113), PIK3CA mutations (n = 33), APC mutations (n = 32), and KRAS mutations (n = 29). Among the 153 patients assessed for TMB, the median TMB was 4 mutations/Mb, and tumors with a high TMB (≥10 mutations/Mb) were more prevalent for lung cancer (11/32) than for other solid tumor types (9/121, Fisher's exact test p < .01). No clear trend toward increased efficacy for immune checkpoint inhibitor (ICI) monotherapy or ICI combination chemotherapy in patients with a high programmed cell death–ligand 1 tumor proportion score or a high TMB was apparent. Among the 174 patients found to harbor known or likely pathogenic actionable alterations, 24 individuals (14%) received matched targeted therapy. Conclusion The FoundationOne CDx assay was performed with formalin‐fixed, paraffin‐embedded tumor specimens with a success rate of >95%. Such testing may inform the matching of patients with cancer with investigational or approved targeted drugs. Implications for Practice This prospective cohort study was initiated to investigate the feasibility and utility of clinical application of FoundationOne CDx. A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%, and 24 individuals (14%) received matched targeted therapy., Comprehensive genomic profiling assays can identify multiple actionable genetic alterations that may inform treatment recommendations for patients with solid tumors. This article evaluates the feasibility of the application of the FoundationOne CDx panel to patients with advanced or recurrent solid tumors.

Purpose: The primary origin of neuroendocrine tumor metastases can be difficult to determine by histopathology alone, but is critical for therapeutic decision making. DNA methylation–based profiling is now routinely used in the diagnostic workup of brain tumors. This has been enabled by the availability of cost-efficient array-based platforms. We have extended these efforts to augment histopathologic diagnosis in neuroendocrine tumors. Experimental Design: Methylation data was compiled for 69 small intestinal, pulmonary, and pancreatic neuroendocrine tumors. These data were used to build a ridge regression calibrated random forest classification algorithm (neuroendocrine neoplasm identifier, NEN-ID). The model was validated during 3 × 3 nested cross-validation and tested in a local and an external cohort (n = 198 cases). Results: NEN-ID predicted the origin of tumor samples with high accuracy (>95%). In addition, the diagnostic approach was determined to be robust across a range of possible confounding experimental parameters, such as tumor purity and array quality. A software infrastructure and online user interface were built to make the model available to the scientific community. Conclusions: This DNA methylation–based prediction model can be used in the workup for patients with neuroendocrine tumors of unknown primary. To facilitate validation and clinical implementation, we provide a user-friendly, publicly available web-based version of NEN-ID.

Venous thromboembolism associated with COVID-19, particularly acute pulmonary embolism, may represent a challenging and complex clinical scenario. The benefits of having a multidisciplinary pulmonary embolism response team (PERT) can be important during such a pandemic. The aim of PERT in the care of such patients is to provide fast, appropriate, multidisciplinary, team-based approach, with the common goal to tailor the best therapeutic decision making, prioritizing always optimal patient care, especially given lack of evidence-based clinical practice guidelines in the setting of COVID-19, which potentially confers a significant prothrombotic state. Herein, we would like to briefly emphasize the importance and potential critical role of PERT in the care of patients in which these two devastating illnesses are present together.

Bladder cancer is a heterogenous disease that is associated with tangible mortality in muscle invasive disease. The WHO 2016 classification of urothelial tumours reflects the contemporary approach towards histological variants in bladder cancer, including variants of urothelial carcinoma (UC) and non-urothelial variants. This review focuses on variant histology in UC, and discusses the importance of accurate histological diagnosis, and subsequent risk stratification and therapeutic decision making based on proper variant recognition. Most urothelial variants are associated with poorer outcomes compared to conventional UC, although some perform reasonably better. However, high quality evidence detailing optimal treatment and survival outcomes are still lacking in literature, due to the rarity of these cases.

The recent changes in curricula in veterinary medicine have changed the delivery and focus on veterinary pharmacology and therapeutics, resulting in a perceived lack of knowledge of pharmacology and therapeutic decision making in recent graduates. To aid veterinary pharmacologists and clinicians teaching clinical pharmacology, core competencies were drafted by a working group. Following this process, a Delphi study was performed to come to a consensus on day-1 competencies in veterinary pharmacology and therapeutics. The described competencies could be useful to a variety of stakeholders in veterinary pharmacology, including those teaching veterinary pharmacology worldwide. Secondly, they could form the basis of vertical alignment of the subject within schools and across the world, as well as serving to frame the integration of veterinary pharmacology and therapeutics into competency-based veterinary education.

Introduction To improve therapeutic decision making, it is crucial that information regarding adverse drug reactions reaches patients. It is not enough to disseminate such findings through regulatory and scientific channels; targeted efforts to reach patients are necessary. One possible avenue is to collaborate with patient organizations. Objectives The aim of this pilot study was to explore how adverse drug reactions can be communicated through patient organizations. Methods A text describing a signal of levothyroxine and panic attacks was tailored to patients’ needs, in terms of language, style and content, with emphasis placed on what to do when experiencing the symptoms described. The signal was communicated via the Dutch thyroid organization’s digital newsletter, social media channels, website and print magazine. Results The digital newsletter was distributed to around 5000 subscribers. On Facebook, 13,820 people viewed the message, with 2346 clicks in the message, indicating an intention to read the whole post. The interactions on social media were positive, and the tone was respectful. Conclusion Patient organizations can help enable effective communication of adverse drug reactions to a relevant audience. The social media post generated more engagement than other communications from the patient organization, indicating a strong interest in this information. The additional patient experiences that were shared in the comments on social media further strengthened the original signal and its relevance to patients, creating an interesting feedback loop. The favourable experiences in this study support further consideration and exploration of this approach to communicate adverse drug reactions to patients.

Introduction Regular physical activity (PA) is recommended by all type 2 diabetes mellitus (T2DM) management guidelines. The OPADIA study aimed to determine whether using a specific patient questionnaire (Optima-PA©) could help T2DM patients increase their PA by leading to better physician-patient communication and improved levels of shared decision making concerning Specific, Measurable, Acceptable, Realistic, Timely (SMART)-PA micro-objectives. Methods Physicians participating in this multicentre, prospective, randomised, real-life study were allocated to a standard group (T2DM patients managed according to usual clinical practice, n = 24) or the OPTIMA-PA group (additional use of the questionnaire, n = 30). The main outcome was the percentage of inclusion visits ending with the setting up of at least one SMART-PA micro-objective. Other outcomes were the impact of the OPTIMA-PA questionnaire on patient perceptions of shared decision making (ENTRED questionnaire) and the impact of the OPTIMA-PA questionnaire and establishing SMART-PA micro-objectives as well as patient-perceived physician empathy (ENTRED questionnaire) and GP aptitude for patient-centredness (SEPCQ scores) on patient PA levels over a 3-month period (IPAQ-SF scores). Results One hundred twenty-two patients were included in the standard group and 134 in the OPTIMA-PA group. Unexpectedly, more inclusion visits ended with SMART-PA micro-objectives being set up in the standard group (p

Objective To evaluate the use of WhatsApp as a clinical tool and determine the perception of orthopaedic surgeons of its usefulness. Material and methods Orthopaedic surgeons attending a scientific meeting were invited to complete an anonymous and structured survey on the use of the application in the clinical setting. Results A total of 41 (38%) surveys were correctly completed. Of the respondents, 100% had been either senders or receivers of clinical information via the application. Ninety-three per-cent had used the application to consult in relation to a clinical case. Of the respondents, 78% belonged to a WhatsApp group in which clinical information is shared: 71% agreed that communication between clinicians through WhatsApp is a useful tool for making therapeutic decisions. Conclusion The use of WhatsApp for clinical purposes by orthopaedic surgeons is widespread. Most consider it a useful tool in therapeutic decision making.

Summary In recent decades, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis has transformed from an almost uniformly fatal disease to a treatable form of primary systemic vasculitis. Substantial disease heterogeneity exists within ANCA-associated vasculitis and the increasing understanding of this heterogeneity has implications for guiding treatment decisions. Approaches to induction and maintenance therapy vary depending on disease severity, clinical manifestations, and patient-specific factors. In this narrative Review, we examine how disease heterogeneity in ANCA-associated vasculitis, with respect to disease severity, clinical presentations, and ANCA specificity, influences therapeutic decision making. Many questions regarding therapeutic strategies in ANCA-associated vasculitis remain unanswered, and these should guide future research in this complex group of diseases.

Since its introduction to the diagnostic pathway for prostate cancer management, prostate-specific membrane antigen (PSMA)–ligand PET has demonstrated great potential. PSMA-ligand imaging is increasingly influencing therapeutic decision making, although its impact on patient outcomes still needs to be defined. One relatively new application, enabled through chemical and engineering efforts, is PSMA-guided surgery. This review highlights the potential of PSMA-guided surgery and discusses its implications in lymph node dissection in primary and recurrent prostate cancer.

Therapeutic options for metastatic CRC (mCRC) have changed significantly in recent years, greatly increasing the complexity of therapeutic decision-making. Although oncology guidelines have helped improve the care process, guidelines may also limit the flexibility to individualize in-clinic decision-making. This consensus paper addresses specific gaps in the current international guidelines to assist Taiwanese colon and rectal experts make specific therapeutic choices. Over 3 years and three meetings with selected experts on “real-world” Taiwanese practice patterns for mCRC, consensus was achieved. The experts also discussed specific questions during in-depth one-on-one consultation. Outcomes of the discussion were then correlated with published evidence by an independent medical writer. The final consensus includes clinically implementable recommendations to provide guidance in treating Taiwanese mCRC patients. The consensus includes criteria for defining fit and unfit intensive treatment patients, treatment goals, treatment considerations of molecular profiles, treatment consideration, and optimal treatment choices between different patient archetypes, including optimal treatment options based on RAS, BRAF, and microsatellite instability (MSI) status. This consensus paper is the second in the Taiwan Society of Colon and Rectal Surgeons (TSCRS) Consensus series to address unmet gaps in guideline recommendations in lieu of Taiwanese mCRC management. Meticulous discussions with experts, the multidisciplinary nature of the working group, and the final drafting of the consensus by independent medical professionals have contributed to the strong scientific value of this consensus.

Background: Despite clear indications for intervention, therapeutic decision-making for elderly patients with severe symptomatic aortic stenosis (AS) remains a complex issue due to the wide variation in individual risk profiles and the involvement of patients' subjective preferences. We aimed to investigate the reasons leading to the decisions against intervention and the consequences thereof on survival.Methods: Data were derived from the China Elderly Valve Disease (China-DVD) Cohort Study on patients aged ≥60-year-old with severe symptomatic AS consecutively enrolled between September to December 2016. Patients were analyzed according to the initial therapeutic decisions made by consensus between patients and physicians at the time of the index evaluation: intervention group (patients who were evaluated as suitable for intervention and accepted the treatment proposal); patient-refusal group (patients who were evaluated as suitable for intervention but refused due to subjective preferences); physician-deny group (patients who were denied intervention by physicians after evaluation). The least absolute shrinkage and selection operator (LASSO)-penalized logistic regression model was used to identify the factors associated with physicians' decisions against intervention. Twelve-month survival was analyzed using Cox proportional hazards models, with multivariate adjustment using inverse probability weighting (IPW).Results: Among the enrolled 456 elderly patients with severe symptomatic AS, 52 (11.4%) patients refused intervention and 49 (10.7%) patients were denied intervention by their physicians. LASSO-penalized logistic regression model identified that reduced left ventricular ejection fraction and increased EuroSCORE-II were strongly associated with physicians' decisions against intervention. At 12-month follow-up, only 8 (15.4%) patients who initially refused the intervention proposal underwent the subsequent intervention, with an average delay of 195 days. Patients' initial decisions against intervention were significantly associated with 12-month mortality, even after IPW adjustment (Hazard ratio: 2.61; 95% confidence interval: 1.09–6.20; P = 0.031).Conclusions: The decision against intervention was taken in about one-fifth of elderly patients with symptomatic severe AS, half of which were due to patients' subjective preferences. Surgical risk remains the primary concern for physicians when making therapeutic decisions. Elderly patients' initial decisions against intervention have a profound impact on subsequent intervention rates and prognosis, and therefore should be treated as a “risk factor” at the subjective level.Clinical Trial Registration:clinicaltrials.gov/ct2/show/NCT02865798, China elDerly Valve Disease (China-DVD) cohort study (NCT02865798).

Infection-induced acute encephalopathy 3 (IIAE3) is an autosomal dominant disease resulting from a pathogenic variant in the RANBP2 gene. IIAE3 results in the susceptibility to the recurrence of acute necrotizing encephalopathy (ANE1) which presents as bilateral symmetric thalamic, midbrain and/or hindbrain lesions that typically develops within 1-4 days post-acute viral infection, commonly occurring before age 6.1-6 These case reports highlight a retrospective analysis of clinical data and radiographic studies on 2 ANE1 cases from our institution. The novel p.Leu450Phe variant of the RANBP2 gene was analyzed using in silico algorithms (PolyPhen-2, SIFT, Mutationtaster) which suggests the p.Leu450Phe variant is probably deleterious.7 An expansion of documented ANE1 case presentations and clinically significant RANBP2 gene mutations has the potential to improve long term outcomes if more informed therapeutic decision making can be achieved.

Objective: To evaluate the impact of cone-beam computed tomography (CBCT) in endodontic therapeutic decision-making of immature traumatized teeth with suspected pulp necrosis. Methods: Over two years, consecutive patients with a dental trauma in their front teeth (apex >0.5 mm) and with suspected pulp necrosis based on clinical and radiographic findings were referred to a specialist clinic in Sweden. Fifteen patients aged 6–13 (18 teeth) were included and clinically examined by an endodontist. Intraoral radiographs and CBCT examinations were obtained. Five practitioners, three endodontists and two residents in endodontics, used these examinations to determine the most appropriate treatment for the 18 cases (all central incisors) on two occasions scheduled 19 weeks apart. On the first occasion, the practitioners had access to clinical information and the intraoral radiographs (‘before’ CBCT); on the second occasion, the practitioners had also access to a radiologist report and the CBCT images (‘after’ CBCT). Their treatment plans – no treatment, watchful waiting, endodontic orthograde treatment, or extraction – were made anonymously and independently. Results were analysed using descriptive statistics and Wilcoxon signed-rank test. Results: ‘After’ CBCT, practitioners changed treatment plans in 30% of the 90 assessments, 74% of which were more aggressive (p = 0.028). In 49% of the assessments, practitioners who chose the watchful and waiting treatment plan ‘before’ CBCT changed to a more aggressive therapy such as endodontic orthograde treatment and extraction ‘after’ CBCT (p = 0.005). Conclusion: This study provides evidence that CBCT influences endodontic therapeutic decision-making regarding immature traumatised teeth with suspected pulp necrosis, chiefly when expectant management (i.e., watchful and waiting) was selected before access to CBCT.

Purpose: Genomic signatures, such as EndoPredict®, may help clinicians to decide which adjuvant treatment is the most appropriate. Methods: We propose the EndoPredict® assay for unclear cases of adjuvant treatment in patients treated in our comprehensive cancer center. We prospectively and retrospectively report the decision of adjuvant treatment before and after the EndoPredict® assay, respectively, compared to the PREDICT’s tool scores. Results: From November 2016 to March 2019, 159 breast cancer tumors were analyzed and presented before and after the EndoPredict® assay. Before the EndoPredict® results, clinicians recommended chemotherapy for 57 patients (57/159, 36%). A total of 108 patients (108/159, 68%) were classified as EPclin high-risk score. There was only a slight agreement between clinicians’ decisions and EPclin risk score. The EPclin score led to 37% changes in treatment (59/159); chemotherapy was favored in 80% of cases (47/59). The PREDICT tool recommended chemotherapy for 16 high-risk patients (16/159, 10%). Conclusion: Although genomic tests were developed in order to de-escalate adjuvant treatment, in our comprehensive cancer center the use of the EndoPredict® assay led to an increase in prescribed chemotherapy.

Objective. The ability of pharmacy students to self-regulate and reflect on knowledge and skills is important as proficient self-assessment skills guide learning strategies and prompt students to bridge their knowledge gaps. The objectives for this study were to determine how well third-year pharmacy students self-assess, explore the rationales behind their self-assessments and determine whether there is a correlation between self-assessment accuracy and academic performance. Methods. A quasi-experimental one-group pre-/post-test design was conducted with third-year pharmacy students. Examiner grades, student self-assessment grades, comparative reports, and end-of-semester grades were collected. Students were categorized into tertiles based on academic performance for data analysis. Paired t tests, Pearson r and percentage agreements were conducted to investigate self-assessment accuracy. Correlational statistical tests were implemented to examine the relationships between self-assessment accuracy and academic performance. Results. One hundred sixty-two third-year pharmacy students were included. On average, students demonstrated poor self-evaluation skills and underestimated themselves by 4.9%. Lower performing students were generally overconfident in evaluating their performance. There was no significant correlation between students’ self-assessment accuracy and academic performance on the subsequent end-of-semester examination questions. Conclusion. Overall, students tended to underestimate their academic performance. Further research on self-assessment is needed to better understand how students think about their performance, which may help to improve education methods, such as inclusion of reflective practices after case-based activities.

Background and Purpose— Therapeutic decision making for small unruptured intracranial aneurysms ( Methods— We analyzed 338 small unruptured aneurysms; 35 ruptured during the observation period, and 303 remained stable. Clinical, morphological, and hemodynamic parameters were considered. Computational fluid dynamics was used to calculate hemodynamic parameters based on computed tomography images of all aneurysms in their unruptured state. Differences between the ruptured and unruptured groups were tested by the Mann-Whitney U or Fisher exact tests. Multivariate logistic regression was applied to obtain a rupture risk model. Its predictive ability was investigated by receiver operating characteristic analysis. Results— The risk model revealed that rupture may be more likely to in younger patients (odds ratio [OR], 0.92 for each age increase of 1 year [95% CI, 0.88−0.96] P P =0.03), located at a bifurcation (OR, 5.45 [95% CI, 1.87−15.85] P =0.002), with a bleb (OR, 4.09 [95% CI, 1.42−11.79] P =0.009), larger length (OR, 1.91 for each increase of 1 mm [95% CI, 1.42−2.57] P P =0.01). The sensitivity, specificity, and area under the curve were 0.800, 0.752, and 0.826 (95% CI, 0.739−0.914) respectively. Conclusions— Younger age, presence of multiple aneurysms, location at a bifurcation, presence of a bleb, larger length, and lower pressure loss coefficient were identified as risk factors for rupture of small intracranial aneurysms. The risk model should be validated in further studies.

Drs. Tan and Nunes carefully interpret the results of this study [(1)][1] toward potential impact on subsequent therapeutic decision making. As pointed out correctly, the contemporary pathophysiologic concept of secondary mitral regurgitation (sMR) identifies 2 key mechanisms, each of which might

Active surveillance trials for low-risk ductal carcinoma in situ (DCIS) are in progress in the United States and Europe. In some of these trials, the presence of comedo necrosis in the DCIS has been an exclusion criterion for trial entry. However, the minimum amount of necrosis required by pathologists for a diagnosis of comedo necrosis is not well-defined. We surveyed 35 experienced breast pathologists to assess their diagnostic threshold for comedo necrosis. Pink circles representing necrosis ranging in extent from 10 to 80% of the duct diameter were superimposed on eight replicate histologic images of a single duct involved by low nuclear grade, solid pattern DCIS. These images were circulated by e-mail to the participating pathologists who were asked to select the image that represents the minimum amount of necrosis that they require for a diagnosis of comedo necrosis. Among the 35 participants, the minimum extent of the duct diameter required for a diagnosis of comedo necrosis was 10% for 4 pathologists, 20% for 5, 30% for 11, 40% for 7, 50% for 6, 60% for 1 and 70% for 1. There was no single threshold about which more than one-third of the pathologists agreed met the minimal criteria for comedo necrosis. We conclude that even among experienced breast pathologists, the threshold for comedo necrosis is highly variable. Our findings highlight the need for a standardized definition of comedo necrosis as a trial criterion, and more generally where it may be used as a marker of increased risk of recurrence for therapeutic decision making.

Acute heart failure (HF) is a major public health concern, responsible for >26 million hospitalizations per year worldwide. Many trials have investigated new therapeutic options for acute HF, with most revealing equivocal results. Successful innovations in therapy for acute HF have remained limited, and standard of care has remained largely unchanged over the past decade, suggesting the need for a new approach for therapeutic decision making and clinical trial design in acute HF. This manuscript focuses on one approach that could prove useful in the development and application of novel therapies: classification of patients based on clinical profiles. While previous attempts at developing clinical profiles were successful in stratifying patients based on clinical and laboratory variables, they have not been utilized for personalized treatment strategies that improve patient outcomes. We suggest a new approach to the creation of clinical profiles that could stratify patients based on their underlying aetiology and their response to novel interventions. We also investigate novel analytic approaches to the creation of new clinical profiles that both investigators and clinicians alike could utilize to inform clinical trial design and the application of new therapies. Despite a large number of clinical trials for new therapeutic options, the treatment of acute HF has seen few advances over the past decades. Innovative approaches to patient selection through the use of clinical profiles could help to identify patients most likely to benefit from novel interventions and lead to the discovery of new therapeutic options.

The lytic recombinant tissue plasminogen activator (rt-PA) is the only drug approved by the Food and Drug Administration for treating ischemic stroke. Less than 40% of patients with large vessel occlusions who are treated with rt-PA have improved blood flow. However, up to 6% of all patients receiving rt-PA develop intracerebral hemorrhage. Predicting the efficacy of rt-PA treatment a priori could help guide therapeutic decision-making, such that rt-PA is administered only to those individuals who would benefit from this treatment. Clot composition and structure affect the lytic efficacy of rt-PA and have an impact on elasticity. However, the relationship between clot elasticity and rt-PA lytic susceptibility has not been adequately investigated. The goal of this study was to quantify the relationship between clot elasticity and rt-PA susceptibility in vitro. Human and porcine highly retracted and mildly retracted clots were fabricated in glass pipettes. The rt-PA lytic susceptibility was evaluated in vitro using the percent clot mass loss. The Young’s moduli of the clots were estimated using ultrasound-based single-track-location shear wave elasticity imaging. The percent mass loss in mildly retracted porcine and human clots (28.9 ± 6.1% and 45.2 ± 7.1%, respectively) were significantly higher (p < 0.05) than those in highly retracted porcine and human clots (10.9 ± 2.1% and 25.5 ± 10.0%, respectively). Furthermore, the Young’s moduli of highly retracted porcine and human clots (5.33 ± 0.92 kPa and 3.21 ± 1.97 kPa, respectively) were significantly higher (p < 0.05) than those of mildly retracted porcine and human clots (2.66 ± 0.55 kPa and 0.79 ± 0.21 kPa, respectively). The results revealed an inverse relationship between the percent clot mass loss and Young’s modulus. These findings motivate continued investigation of ultrasound-based methods to assess clot stiffness in order to predict rt-PA thrombolytic efficacy.

We present the case of a 59-year-old woman who undergoes surgery 12 years after the Bentall-de Bono operation (replacement of the aortic valve and ascending aorta with valvular duct and direct reimplantation of the coronaryan ostia in the duct). For the acute aortic dissection of type I De Bakey (Stanford type A), diagnosed with subacute infectious endocarditis at the level of the aortic valvular duct with abscess in the aortic root.

Radiomics, via the extraction of quantitative information from conventional radiologic images, can identify imperceptible imaging biomarkers that can advance the characterization of coronary plaques and the surrounding adipose tissue. Such an approach can unravel the underlying pathophysiology of atherosclerosis which has the potential to aid diagnostic, prognostic and, therapeutic decision making. Several studies have demonstrated that radiomic analysis can characterize coronary atherosclerotic plaques with a level of accuracy comparable, if not superior, to current conventional qualitative and quantitative image analysis. While there are many milestones still to be reached before radiomics can be integrated into current clinical practice, such techniques hold great promise for improving the imaging phenotyping of coronary artery disease.

International audience; Background. - According to the guidelines, surgical aortic valve replacement (SAVR) is recommended in patients at low surgical risk (EuroSCORE II < 4%), whereas for other patients, the decision between transcatheter aortic valve implantation (TAVI) and surgery should be made by the Heart Team, with TAVI being favoured in elderly patients. Aim. - The RAC prospective multicentre survey assessed the respective contributions of age and surgical risk scores in therapeutic decision making in elderly patients with severe symptomatic aortic stenosis. Methods. - In September and October 2016, 1049 consecutive patients aged >= 75 years were included in 32 centres with on-site TAVI and surgical facilities. The primary endpoint was the decision between medical management, TAVI or SAVR. Results. - Mean age was 84 +/- 5 years and 53% of patients were female. The surgical risk was classified as high (EuroSCORE II > 8%) in 18% of patients, intermediate (EuroSCORE II 4-8%) in 34% and low (EuroSCORE II = 80 years were referred for TAVI, despite a low estimated surgical risk. Conclusions. - The impact of risk scores depends strongly on age, and decreases considerably after 80 years, most patients being referred for TAVI, independent of their estimated surgical risk. Despite medical advancements, 10% of patients were still denied any intervention. (C) 2021 Elsevier Masson SAS. All rights reserved.

Intraoperative pathologic consultation plays an essential role in therapeutic decision making, possibly avoiding under or overtreatment of the patient. Common indications for intraoperative consultation include obtaining a diagnosis in an unknown pathology, ruling out malignancy, confirming a provisional diagnosis, and assessing margin status. Fifty patients undergoing surgery for soft tissue tumors or tumor-like lesions were included in the present prospective study to evaluate the role of intraoperative pathologic consultation by imprint and scrape cytology. Careful and quick gross examination of the specimen was performed, followed by processing for imprint and scrape smears. The prepared smears were evaluated by three pathologists and the cytological diagnosis compared subsequently with final histopathological diagnosis. Intraoperative consultation was primarily requested to make or confirm preoperative diagnosis. In 44.0% cases, no previous tissue/cytological diagnosis was available. In 56.0% cases, previous pathological diagnosis was available, but the reports were inconclusive or were reported from outside our institute. The diagnostic yield of imprint smears was 24% (5 malignant, 6 benign, and 1 inconclusive), and scrape smears was 100% (10 malignant, 38 benign, and 2 inconclusive). Paraffin-embedded sections yielded diagnosis in 100% cases (11 malignant, 38 benign, and 1 nonneoplastic). Imprint smears alone were not of much help in intraoperative diagnosis. Scrape smears were found to be superior to imprint smears in terms of diagnostic yield and accuracy. Combined imprint and scrape smear cytology did not provide any advantage in intraoperative provisional tissue diagnosis in soft tissue tumors.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by cardiac arrest during sudden exertion. However, standard exercise stress testing (EST) lacks sensitivity, leading to misdiagnosis and undertreatment. After a nondiagnostic standard gradual EST, we report 6 patients who underwent a novel burst exercise test characterized by sudden high workload at the outset of testing. In 5 of 6 patients, the burst EST induced new and more complex arrhythmias versus standard EST, which compelled medication initiation in 3 patients. We postulate that this simple EST modification better mimics a typical CPVT triggering event and could improve diagnostic sensitivity and therapeutic decision making.

Endovascular aneurysm repair is currently the most frequently treatment modality for infrarenal aortic aneurysms. Endoleaks are the most common cause of reintervention after endovascular aneurysm repair. It is often unclear which type of endoleak is the correct diagnose, making the treatment decision difficult. We report the case of a 72-year-old man with an endoleak two years after endovascular aneurysm repair. Images suggested a type III endoleak, but this was not confirmed by contrast aortography. We proceeded with the investigation using aortography with carbon dioxide and observed a type IA endoleak. This was successfully treated by implantation of a proximal cuff. A review of the literature shows that the role of carbon dioxide in endoleak management is still unclear. We present a case in which carbon dioxide was essential to both diagnosis and therapeutic decision-making in a type IA endoleak.

Membranous glomerulonephritis is one of the common causes of nephrotic syndrome in the adult population. It is idiopathic in the majority of patients, but the secondary forms can be seen in the setting of autoimmune disease, cancer, infection, and following exposure to certain medications. However, subclinical syphilis-related membranous nephropathy remains a particularly rare clinicopathologic entity in modern times. In this article, we chronicle an interesting case of latent syphilis masquerading as membranous glomerulonephritis, which resolved with benzathine penicillin without requiring immunosuppressive treatment. We further supplement this paper with a concise review of the relevant literature that delineates the utility of appropriate antibiotic therapy in the management of luetic membranous nephropathy. Clinicians should remain cognizant of secondary syphilis while evaluating patients for possible glomerulonephritis or those presenting with proteinuria. Additionally, patients with hepatitis B, hepatitis C, and human immunodeficiency virus infections are not infrequently coinfected with Treponema pallidum. Therefore, a high index of suspicion for systemic manifestations of syphilis such as nephrotic syndrome is warranted in the setting of a coinfection. Prompt diagnosis and treatment of syphilis may result in resolution of proteinuria, without the need for standard immunosuppressive therapy commonly used in clinical practice.

Opportunistic infections caused by fungi and unusual bacteria are predominantly encountered in the setting of immunosuppressed host. Co-infections with multiple such organisms can pose multiple challenges even to the astute clinician from establishing the diagnosis to drug interactions during treatment of such infections. We hereby present one such case of a triple opportunistic infection in an immunocompetent host and the difficulties faced in the therapeutic decision making.

Accurate definition of the extent and severity of left-ventricular assist device (LVAD) infection may facilitate therapeutic decision making and targeted surgical intervention. Here, we explore the value of (18)F-FDG PET/CT for guidance of patient management. Methods: Fifty-seven LVAD-carrying patients received 85 whole-body (18)F-FDG PET/CT scans for the work-up of device infection. Clinical follow-up was obtained for up to 2 y. Results: PET/CT showed various patterns of infectious involvement of the 4 LVAD components: driveline entry point (77% of patients), subcutaneous driveline path (87%), pump pocket (49%), and outflow tract (58%). Driveline smears revealed Staphylococcus or Pseudomonas strains as the underlying pathogen in most cases (48 and 34%, respectively). At receiver-operating-characteristic analysis, an (18)F-FDG SUV of more than 2.5 was most accurate to identify smear-positive driveline infection. Infection of 3 or all 4 LVAD components showed a trend toward lower survival than did infection of 2 or fewer components (P = 0.089), whereas involvement of thoracic lymph nodes was significantly associated with an adverse outcome (P = 0.001 for nodal SUV above vs. below median). Finally, patients who underwent early surgical revision within 3 mo after PET/CT (n = 21) required significantly less inpatient hospital care during follow-up than did those receiving delayed surgical revision (n = 11; P < 0.05). Conclusion: Whole-body (18)F-FDG PET/CT identifies the extent of LVAD infection and predicts adverse outcome. Initial experience suggests that early image-guided surgical intervention may facilitate a less complicated subsequent course.

The assessment of fracture healing is still marked by a subjective and diffuse outcome due to the lack of clinically available quantitative measures. Without reliable information on the progression of healing and uniform criteria for union and non-union, therapeutic decision making, e.g. regarding the allowed weight bearing, hinges on the experience and the subjective evaluation of physicians. Already decades ago, fracture stiffness has been identified as a valid outcome measure for the maturity of the repair tissue. Despite early promising results, so far no method has made its way into practice beyond clinical studies. However, with current technological advancements and a general trend towards digital health care, measuring fracture healing seems to regain momentum. New generations of instrumented implants with sensoring capabilities, often termed as "smart implants", are under development. They target X-ray free and timely provision of reliable feedback upon the mechanical competence of the repair tissue and the healing environment to support therapeutic decision making and individualized after-care. With the gained experience from these devices, the next generations of smart implants may become increasingly sophisticated by internally analyzing the measured data and suggesting adequate therapeutic actions on their own.

(1) Background: The processes and skills required to make decisions about drug therapy have been termed &ldquo, therapeutic decision-making&rdquo, in pharmacy practice. The aim of this study was to evaluate a tool constructed to measure the development of therapeutic-decision-making skills by practicing pharmacists undertaking a university-based continuing professional development program. (2) Methods: A pre- and post-intervention crossover study design was used to investigate the qualitative and quantitative features of practicing pharmacists&rsquo, responses to two clinical vignettes designed to measure the development of therapeutic-decision-making skills. The vignettes were assigned a score using a five-point scale and compared pre- and post-intervention. (3) Results: There was a median increase in score of 2 units on the five-point scale in the post-intervention scores compared to pre-intervention (p &lt, 0.0001). (4) Conclusions: The results were interpreted to suggest that the participants&rsquo, responses to the vignettes are a reasonable measure of student learning. Therefore, we infer that the teaching and learning intervention successfully enabled the development of therapeutic-decision-making skills by practicing pharmacists.

Elite athletes face extreme challenges to perform at peak levels. Acute and chronic musculoskeletal injuries are an occupational hazard while pressures to return to play post-injury are commonplace. Therapeutic options available to elite athletes range from novel 'cutting edge' biomedical therapies, established biomedical and surgical techniques, and physiotherapy, to a variety of non-orthodox therapies. Little is known about how different treatment options are selected, evaluated, nor how their uses are negotiated in practice. We draw on data from interviews with 27 leading sports medicine physicians working in professional football and cycling in the UK, collected 2014-16. Using idea of the 'therapeutic landscape' as a conceptual frame, we discuss how non-orthodox tools, technologies and/or techniques enter the therapeutic landscape of elite sports medicine, and how the boundaries between orthodox and non-orthodox therapy are conceptualised and navigated by sports medicine practitioners. The data provide a detailed and nuanced examination of heterogenous therapeutic decision -making, reasoning and practice. Our data show that although the biomedical paradigm remains dominant, a wide range of non-orthodox therapies are frequently used, or authorised for use, by sports medicine practitioners, and this is achieved in complex and contested ways. Moreover, we situate debates around nonorthodox medicine practices in elite sports in ways that critically inform current theories on Complementary and Alternative Medicine (CAM)/biomedicine. We argue that existing theoretical concepts of medical pluralism, integration, diversity and hybridisation, which are used to explain CAMs through their relationships with biomedicine, do not adequately account for the multiplicity, complexity and contestation that characterise contemporary forms of CAM use in elite sport. ispartof: SOCIAL SCIENCE & MEDICINE vol:251 ispartof: location:England status: published

Metastatic cancer is a medical challenge that has been historically resistant to treatments. One area of leverage in cancer care is the development of molecularly-driven combination therapies, offering the possibility to overcome resistance. The selection of optimized treatments based on the complex molecular features of a patient&rsquo, s tumor may be rendered easier by using a computer-assisted program. We used the PreciGENE&reg, platform that uses multi-pathway molecular analysis to identify personalized therapeutic options. These options are ranked using a predictive score reflecting the degree to which a therapy or combination of therapies matches the patient's biomarker profile. We searched PubMed from February 2010 to June 2017 for all patients described as exceptional responders who also had molecular data available. Altogether, 70 patients with cancer who had received 202 different treatment lines and who had responded (stable disease &ge, 12 months/partial or complete remission) to &ge, 1 regimen were curated. We demonstrate that an algorithm reflecting the degree to which patients were matched to the drugs administered correctly ranked the response to the regimens with a sensitivity of 84% and a specificity of 77%. The difference in matching score between successful and unsuccessful treatment lines was significant (median, 65% versus 0%, p-value &lt, 0.0001).