Pharmacological Strategy for Selective Targeting of Glioblastoma by Redox-active Combination Drug - Comparison With the Chemotherapeutic Standard-of-care Temozolomide.

BACKGROUND/AIM: We describe a pharmacological strategy for selectively targeting glioblastoma using a redox-active combination drug menadione/ascorbate (M/A), compared to the chemotherapeutic standard-of-care temozolomide (TMZ). MATERIALS AND METHODS: Experiments were conducted on glioblastoma mice (GS9L cell transplants - intracranial model), treated with M/A or TMZ. Tumor growth was monitored by magnetic resonance imaging. Effects of M/A and TMZ on cell viability and overproduction of mitochondrial superoxide were also evaluated on isolated glioblastoma cells (GS9L) and normal microglial cells (EOC2). RESULTS: M/A treatment suppressed tumor growth and increased survival without adverse drug-related side effects that were characteristic of TMZ. Survival was comparable with that of TMZ at the doses we have tested so far, although the effect of M/A on tumor growth was less pronounced than that of TMZ. M/A induced highly specific cytotoxicity accompanied by dose-dependent overproduction of mitochondrial superoxide in glioblastoma cells, but not in normal microglial cells. CONCLUSION: M/A differentiates glioblastoma cells from normal microglial cells, causing redox alterations and oxidative stress only in the tumor. This easier-to-tolerate treatment has a potential to support the surgery and conventional therapy of glioblastoma.

Accuracy of the Sequential Organ Failure Assessment Score for In-Hospital Mortality by Race and Relevance to Crisis Standards of Care.

Importance: Crisis Standards of Care (CSC) are guidelines for rationing health care resources during public health emergencies. The CSC adopted by US states ration intensive care unit (ICU) admission using the Sequential Organ Failure Assessment (SOFA) score, which is used to compare expected in-hospital mortality among eligible patients. However, it is unknown if Black and White patients with equivalent SOFA scores have equivalent in-hospital mortality. Objective: To investigate whether reliance on SOFA is associated with bias against Black patients in CSC. Design, Setting, and Participants: This cohort study was conducted using data from the eICU Collaborative Research Database of patients admitted to 233 US ICUs in 2014 to 2015. Included individuals were Black and White adult patients in the ICU, who were followed up to hospital discharge. Data were analyzed from May 2020 through April 2021. Exposure: SOFA scores at ICU admission. Main Outcomes and Measures: Hierarchical logistic regression with hospital fixed effects was used to measure the interaction between race and SOFA as a factor associated with in-hospital mortality, as well as the odds of death among Black and White patients with equivalent priority for resource allocation according to the SOFA-based ranking rules of 3 statewide CSC (denoted A, B, and C) under shortage conditions that were severe (ie, only patients with the highest priority would be eligible for allocation), intermediate (ie, patients in the highest 2 tiers would be eligible for allocation), or low (ie, only patients with the lowest priority would be at risk of exclusion). Results: Among 111 885 ICU encounters representing 95 549 patients, there were 16 688 encounters with Black patients (14.9%) and 51 464 (46.0%) encounters with women and the mean (SD) age was 63.3 (16.9) years. The median (interquartile range) SOFA score was not statistically significantly different between Black and White patients (4 [2-6] for both groups; P = .19), but mortality was lower among Black individuals compared with White individuals with equivalent SOFA scores (odds ratio [OR], 0.98; 95% CI, 0.97-0.99; P < .001). This was associated with lower mortality among Black patients compared with White patients prioritized for resource allocation in 3 CSC under shortage conditions that were severe (system A: OR, 0.65; 95% CI, 0.58-0.74; P < .001; system B: OR, 0.70; 95% CI, 0.64-0.78; P < .001; system C: OR, 0.73; 95% CI, 0.67-0.80; P < .001), intermediate (system A: OR, 0.73; 95% CI, 0.67-0.80; P < .001; system B: OR, 0.83; 95% CI, 0.77-0.89; P < .001; system C: OR, 0.82; 95% CI, 0.77-0.89; P < .001), and low (system A: OR, 0.83; 95% CI, 0.77-0.89; P < .001; system C: OR, 0.86; 95% CI, 0.81-0.92; P < .001; not applicable for system B, which had fewer tiers). When SOFA-based ranking rules were adjusted for Black patients to simulate equitable allocation based on observed mortality, the proportion upgraded to higher priority ranged from 379 Black patient encounters (2.3%) in low shortage conditions to 2601 Black patient encounters (15.6%) in severe shortage conditions. Conclusions and Relevance: This study found that SOFA scores were associated with overestimated mortality among Black patients compared with White patients, and this was associated with a structural disadvantage for Black patients in CSC allocation systems. These findings suggest that guidelines should be revised to correct this inequity and alternative methods should be developed for more equitable triage.

Do standards of care and early outcomes of periprosthetic fractures change during the COVID-19 pandemic? A multicentre study.

BACKGROUND: Periprosthetic fractures (PPFs) are a growing matter for orthopaedic surgeons, and patients with PPFs may represent a frail target in the case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The purpose of this study is to investigate whether hospital reorganisations during the most severe phase of the SARS-CoV-2 pandemic affected standards of care and early outcomes of patients treated for PPFs in Northern Italy. MATERIALS AND METHODS: Data were retrieved from a multicentre retrospective orthopaedics and traumatology database, including 14 hospitals. The following parameters were studied: demographics, results of nasopharyngeal swabs, prevalence of coronavirus disease 2019 (COVID-19), comorbidities, general health status (EQ-5D-5L Score), frailty (Clinical Frailty Scale, CFS), pain (visual analogue scale, VAS), anaesthesiologic risk (American Society of Anaesthesiology Score, ASA Score), classification (unified classification system, UCS), type of operation and anaesthesia, in-hospital and early complications (Clavien-Dindo Classification, CDC), and length of stay (LOS). Data were analysed by means of descriptive statistics. Out of 1390 patients treated for any reason, 38 PPFs were included. RESULTS: Median age was 81 years (range 70-96 years). Twenty-three patients (60.5%) were swabbed on admission, and two of them (5.3%) tested positive; in three patients (7.9%), the diagnosis of COVID-19 was established on a clinical and radiological basis. Two more patients tested positive post-operatively, and one of them died due to COVID-19. Thirty-three patients (86.8%) presented a proximal femoral PPF. Median ASA Score was 3 (range, 1-4), median VAS score on admission was 3 (range, 0-6), median CFS was 4 (range, 1-8), median EQ-5D-5L Score was 3 in each one of the categories (range, 1-5). Twenty-three patients (60.5%) developed post-operative complications, and median CDC grade was 3 (range, 1-5). The median LOS was 12.8 days (range 2-36 days), and 21 patients (55.3%) were discharged home. CONCLUSIONS: The incidence of PPFs did not seem to change during the lockdown. Patients were mainly elderly with comorbidities, and complications were frequently recorded post-operatively. Despite the difficult period for the healthcare system, hospitals were able to provide effective conventional surgical treatments for PPFs, which were not negatively influenced by the reorganisation. Continued efforts are required to optimise the treatment of these frail patients in the period of the pandemic, minimising the risk of contamination, and to limit the incidence of PPFs in the future. LEVEL OF EVIDENCE: IV.

Validation of a Crisis Standards of Care Model for Prioritization of Limited Resources During the Coronavirus Disease 2019 Crisis in an Urban, Safety-Net, Academic Medical Center.

OBJECTIVES: The coronavirus disease 2019 pandemic has overwhelmed healthcare resources even in wealthy nations, necessitating rationing of limited resources without previously established crisis standards of care protocols. In Massachusetts, triage guidelines were designed based on acute illness and chronic life-limiting conditions. In this study, we sought to retrospectively validate this protocol to cohorts of critically ill patients from our hospital. DESIGN: We applied our hospital-adopted guidelines, which defined severe and major chronic conditions as those associated with a greater than 50% likelihood of 1- and 5-year mortality, respectively, to a critically ill patient population. We investigated mortality for the same intervals. SETTING: An urban safety-net hospital ICU. PATIENTS: All adults hospitalized during April of 2015 and April 2019 identified through a clinical database search. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 365 admitted patients, 15.89% had one or more defined chronic life-limiting conditions. These patients had higher 1-year (46.55% vs 13.68%; p < 0.01) and 5-year (50.00% vs 17.22%; p < 0.01) mortality rates than those without underlying conditions. Irrespective of classification of disease severity, patients with metastatic cancer, congestive heart failure, end-stage renal disease, and neurodegenerative disease had greater than 50% 1-year mortality, whereas patients with chronic lung disease and cirrhosis had less than 50% 1-year mortality. Observed 1- and 5-year mortality for cirrhosis, heart failure, and metastatic cancer were more variable when subdivided into severe and major categories. CONCLUSIONS: Patients with major and severe chronic medical conditions overall had 46.55% and 50.00% mortality at 1 and 5 years, respectively. However, mortality varied between conditions. Our findings appear to support a crisis standards protocol which focuses on acute illness severity and only considers underlying conditions carrying a greater than 50% predicted likelihood of 1-year mortality. Modifications to the chronic lung disease, congestive heart failure, and cirrhosis criteria should be refined if they are to be included in future models.

Towards standardized reporting of service organization in rehabilitation for clinical trials.

Meta-analysis of clinical trials in rehabilitation is often inconclusive, even when similar interventions are investigated. A possible reason for this is the influence of the settings in which rehabilitation services are delivered. Examples show that factors related to service organization in rehabilitation can influence study outcomes. This, in particular, is relevant, as contextual factors in rehabilitation are known to influence the participation and functioning of persons with disability. The Consolidated Statement of Reporting Trials (CONSORT) group and other initiatives published standards for reporting relevant factors for clinical trials. However, description of the rehabilitation setting of factors related to rehabilitation service provision is under-represented. Systematic reviews show that, on the one hand, these factors are scarcely reported, and only a few studies systematically evaluated the influence of factors related to service organization on rehabilitation outcomes. The International Classification of Service Organization in Rehabilitation (ICSO-R) provides a framework to systematically describe rehabilitation services. It contains 40 categories and sub-categories for the domains "provider" and "service delivery". Therefore, it is important and relevant to develop a minimum reporting set for factors relevant to service organization for rehabilitation trials. This paper sets out a methodological approach for this purpose, including literature reviews, Delphi survey focus group discussion, and consensus conference.

Adoptive T Cell Therapy for Solid Tumors: Pathway to Personalized Standard of Care.

Adoptive cell therapy (ACT) with tumor-infiltrating T cells (TILs) has emerged as a promising therapy for the treatment of unresectable or metastatic solid tumors. One challenge to finding a universal anticancer treatment is the heterogeneity present between different tumors as a result of genetic instability associated with tumorigenesis. As the epitome of personalized medicine, TIL-ACT bypasses the issue of intertumoral heterogeneity by utilizing the patient's existing antitumor immune response. Despite being one of the few therapies capable of inducing durable, complete tumor regression, many patients fail to respond. Recent research has focused on increasing therapeutic efficacy by refining various aspects of the TIL protocol, which includes the isolation, ex vivo expansion, and subsequent infusion of tumor specific lymphocytes. This review will explore how the therapy has evolved with time by highlighting various resistance mechanisms to TIL therapy and the novel strategies to overcome them.

Early discontinuation of PD-1 blockade upon achieving a complete or partial response in patients with advanced melanoma: the multicentre prospective Safe Stop trial.

BACKGROUND: The introduction of programmed cell death protein 1 (PD-1) blockers (i.e. nivolumab and pembrolizumab) has significantly improved the prognosis of patients with advanced melanoma. However, the long treatment duration (i.e. two years or longer) has a high impact on patients and healthcare systems in terms of (severe) toxicity, health-related quality of life (HRQoL), resource use, and healthcare costs. While durable tumour responses have been observed and PD-1 blockade is discontinued on an individual basis, no consensus has been reached on the optimal treatment duration. The objective of the Safe Stop trial is to evaluate whether early discontinuation of first-line PD-1 blockade is safe in patients with advanced and metastatic melanoma who achieve a radiological response. METHODS: The Safe Stop trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 200 patients with advanced and metastatic cutaneous melanoma and a confirmed complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumours (RECIST) v1.1 will be included to early discontinue first-line monotherapy with nivolumab or pembrolizumab. The primary objective is the rate of ongoing responses at 24 months after discontinuation of PD-1 blockade. Secondary objectives include best overall and duration of response, need and outcome of rechallenge with PD-1 blockade, and changes in (serious) adverse events and HRQoL. The impact of treatment discontinuation on healthcare resource use, productivity losses, and hours of informal care will also be assessed. Results will be compared to those from patients with CR or PR who completed 24 months of treatment with PD-1 blockade and had an ongoing response at treatment discontinuation. It is hypothesised that it is safe to early stop first-line nivolumab or pembrolizumab at confirmed tumour response while improving HRQoL and reducing costs. DISCUSSION: From a patient, healthcare, and economic perspective, shorter treatment duration is preferred and overtreatment should be prevented. If early discontinuation of first-line PD-1 blockade appears to be safe, early discontinuation of PD-1 blockade may be implemented as the standard of care in a selected group of patients. TRIAL REGISTRATION: The Safe Stop trial has been registered in the Netherlands Trial Register (NTR), Trial NL7293 (old NTR ID: 7502), https://www.trialregister.nl/trial/7293 . Date of registration September 30, 2018.

Minimum standards for practices offering assisted reproductive technologies: a committee opinion.

This document is designed to provide a framework for assisted reproductive technology (ART) programs that meet or exceed the requirements suggested by the Centers for Disease Control and Prevention for certification of ART laboratories. This document replaces the document "Revised Minimum Standards for Practices Offering Assisted Reproductive Technologies: A Committee Opinion" published in 2019.

Targeting of the diabetes prevention program leads to substantial benefits when capacity is constrained.

OBJECTIVE: Approximately 84 million people in the USA have pre-diabetes, but only a fraction of them receive proven effective therapies to prevent type 2 diabetes. We estimated the value of prioritizing individuals at highest risk of progression to diabetes for treatment, compared to non-targeted treatment of individuals meeting inclusion criteria for the Diabetes Prevention Program (DPP). METHODS: Using microsimulation to project outcomes in the DPP trial population, we compared two interventions to usual care: (1) lifestyle modification and (2) metformin administration. For each intervention, we compared targeted and non-targeted strategies, assuming either limited or unlimited program capacity. We modeled the individualized risk of developing diabetes and projected diabetic outcomes to yield lifetime costs and quality-adjusted life expectancy, from which we estimated net monetary benefits (NMB) for both lifestyle and metformin versus usual care. RESULTS: Compared to usual care, lifestyle modification conferred positive benefits and reduced lifetime costs for all eligible individuals. Metformin's NMB was negative for the lowest population risk quintile. By avoiding use when costs outweighed benefits, targeted administration of metformin conferred a benefit of $500 per person. If only 20% of the population could receive treatment, when prioritizing individuals based on diabetes risk, rather than treating a 20% random sample, the difference in NMB ranged from $14,000 to $20,000 per person. CONCLUSIONS: Targeting active diabetes prevention to patients at highest risk could improve health outcomes and reduce costs compared to providing the same intervention to a similar number of patients with pre-diabetes without targeted selection.

Heads-up Surgery: Endoscopes and Exoscopes for Otology and Neurotology in the Era of the COVID-19 Pandemic.

A new era of surgical visualization and magnification is poised to disrupt the field of otology and neurotology. The once revolutionary benefits of the binocular microscope now are shared with rigid endoscopes and exoscopes. These 2 modalities are complementary. The endoscope improves visualization of the hidden recesses through the external auditory canal or canal-up mastoidectomy. The exoscope provides an immersive visual experience and superior ergonomics compared with binocular microscopy. Endoscopes and exoscopes are poised to disrupt the standard of care for surgical visualization and magnification in otology and neurotology.

Patient-Reported Outcome Measures Used in Routine Care Predict for Survival at Disease Progression in Patients With Advanced Lung Cancer.

BACKGROUND: Patient-reported outcome (PRO) measures have been increasingly implemented in routine care to aid in clinical decision-making. However, the prognostic value of PRO measures as a tool for decision making is not easily interpreted by clinicians. Our aims were to explore the prognostic value of PRO measures at disease progression and the changes in PRO measures between treatment start (baseline) and disease progression. PATIENTS AND METHODS: Since 2014, patients with lung cancer have completed an electronic version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires C30 and LC-13 before every outpatient visit at the Department of Oncology, Hospital Unit West, Jutland, Denmark. The patients' responses were used in routine care. Patients receiving palliative antineoplastic treatment were eligible for analysis if the questionnaire had been completed at the initiation of first-line treatment and at disease progression. The prognostic value of the scores was evaluated using a Cox proportional hazard model. A P value < .01 was considered statistically significant. RESULTS: A total of 94 screened patients were included. At disease progression, survival could be predicted from the absolute score of the global health scale, 3 functional scales (physical, role, emotional), and 7 symptom scales (fatigue, pain, dyspnea, hemoptysis, lung cancer dyspnea, chest pain). In addition, changes in hemoptysis, dysphagia, dyspnea, and chest pain predicted for survival at progression. CONCLUSION: PRO measures used in routine care can provide clinicians with relevant prognostic information about patients with lung cancer at disease progression. These results show the potential value of PRO measures when used in clinical decision-making.

Activities related to inflammatory bowel disease management during and after the coronavirus disease 2019 lockdown in Italy: How to maintain standards of care.

BACKGROUND AND AIMS: Restructuring activities have been necessary during the lockdown phase of the coronavirus disease 2019 (COVID-19) pandemic. Few data are available on the post-lockdown phase in terms of health-care procedures in inflammatory bowel disease (IBD) care, and no data are available specifically from IBD units. We aimed to investigate how IBD management was restructured during the lockdown phase, the impact of the restructuring on standards of care and how Italian IBD units have managed post-lockdown activities. METHODS: A web-based online survey was conducted in two phases (April and June 2020) among the Italian Group for IBD affiliated units within the entire country. We investigated preventive measures, the possibility of continuing scheduled visits/procedures/therapies because of COVID-19 and how units resumed activities in the post-lockdown phase. RESULTS: Forty-two referral centres participated from all over Italy. During the COVID-19 lockdown, 36% of first visits and 7% of follow-up visits were regularly done, while >70% of follow-up scheduled visits and 5% of first visits were done virtually. About 25% of scheduled endoscopies and bowel ultrasound scans were done. More than 80% of biological therapies were done as scheduled. Compared to the pre-lockdown situation, 95% of centres modified management of outpatient activity, 93% of endoscopies, 59% of gastrointestinal ultrasounds and 33% of biological therapies. Resumption of activities after the lockdown phase may take three to six months to normalize. Virtual clinics, implementation of IBD pathways and facilities seem to be the main factors to improve care in the future. CONCLUSION: Italian IBD unit restructuring allowed quality standards of care during the COVID-19 pandemic to be maintained. A return to normal appears to be feasible and achievable relatively quickly. Some approaches, such as virtual clinics and identified IBD pathways, represent a valid starting point to improve IBD care in the post-COVID-19 era.

Targeted Microsurgical Denervation of the Spermatic Cord for Chronic Orchialgia: the Current Standard of Care.

PURPOSE OF REVIEW: This paper reviews the pathophysiology, current literature, techniques for full microsurgical denervation (MDSC) and targeted microsurgical denervation (TMDSC) of the spermatic cord, and outcomes for these treatment options for patients with chronic scrotal content pain (CSCP) or orchialgia. RECENT FINDINGS: Significant reduction in pain (77-100%) is reported across various studies for CSCP patients with minimal patient morbidity. The testicular atrophy/loss risk is less than 1%. Testosterone levels do not appear to be affected by TMDSC/MDSC. The outcomes between TMDSC and MDSC are comparable (not statistically significantly different). However, TMDSC is significantly more efficient and a lot less tedious to perform. TMSCD had a shorter microsurgical operative time (21 min vs 53 min, P = 0.0001) than MDSC. Targeted or full microsurgical denervation of the spermatic cord is a safe and effective treatment option that is well published across several studies. The targeted MDSC approach is a more efficient and potentially less risky approach with similar outcomes to full MDSC.

The crisis standard of care: Considerations for risk management.

Many writers and organizations have postulated that health care facilities and providers may need to implement a "crisis standard of care" to deal with the exigent circumstances associated with the massive influx of patients infected with the novel coronavirus and suffering from COVID-19. There is a relative scarcity of critical resources, such as intensive care unit beds, emergency department beds, ventilators, personal protective equipment, and medications. Facilities can become overwhelmed. A crisis standard of care can act as a guidepost for rationing supplies and care, should that become necessary. However, that is not without danger. Health care facilities and providers should plan carefully and then act with due deliberation in implementing a crisis standard of care to mitigate or prevent future liability.

Patient Reported Outcomes Show Newer Drug Combinations Maintain Quality of Life Longer Than Current Standard of Care Treatments.

Multiple studies showed improved patient outcomes and increased quality of life among various treatments that previously demonstrated clinical benefits. these patient-centric findings, along with a promising new combination therapy for patients with advanced hepatocellular carcinoma highlight some of the latest research to come out of the 2020 Gastrointestinal Cancers Symposium.