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.

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.

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.

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.

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.

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.

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.

Tools to guide the identification and implementation of care consistent with the psychosocial Standards of care.

Fifteen evidence-based Standards of psychosocial care for children with cancer and their families have been established. Despite the importance of implementing the standards, significant barriers and challenges exist. In order to overcome barriers to implementation and assess the level of current psychosocial care, a model of evaluating psychosocial care (Matrix) and a set of pathways toward achieving optimal care (Guidelines) were developed. This special report describes the process involved in the creation of standard templates and development of content based on rigorous reviews from multidisciplinary psychosocial experts, focus groups, and multiple revisions based on further expert review. The resulting Matrix and Guidelines are included as Supplemental Information.

Standard-of-Care Axicabtagene Ciloleucel for Relapsed or Refractory Large B-Cell Lymphoma: Results From the US Lymphoma CAR T Consortium.

PURPOSE: Axicabtagene ciloleucel (axi-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory large B-cell lymphoma (LBCL) on the basis of the single-arm phase II ZUMA-1 trial, which showed best overall and complete response rates in infused patients of 83% and 58%, respectively. We report clinical outcomes with axi-cel in the standard-of-care (SOC) setting for the approved indication. PATIENTS AND METHODS: Data were collected retrospectively from all patients with relapsed/refractory LBCL who underwent leukapheresis as of September 30, 2018, at 17 US institutions with the intent to receive SOC axi-cel. Toxicities were graded and managed according to each institution's guidelines. Responses were assessed as per Lugano 2014 classification. RESULTS: Of 298 patients who underwent leukapheresis, 275 (92%) received axi-cel therapy. Compared with the registrational ZUMA-1 trial, 129 patients (43%) in this SOC study would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis. Among the axi-cel-treated patients, grade ≥ 3 cytokine release syndrome and neurotoxicity occurred in 7% and 31%, respectively. Nonrelapse mortality was 4.4%. Best overall and complete response rates in infused patients were 82% (95% CI, 77% to 86%) and 64% (95% CI, 58% to 69%), respectively. At a median follow-up of 12.9 months from the time of CAR T-cell infusion, median progression-free survival was 8.3 months (95% CI, 6.0 to15.1 months), and median overall survival was not reached. Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 and elevated lactate dehydrogenase had shorter progression-free and overall survival on univariable and multivariable analysis. CONCLUSION: The safety and efficacy of axi-cel in the SOC setting in patients with relapsed/refractory LBCL was comparable to the registrational ZUMA-1 trial.

NCCN resource-stratified and harmonized guidelines: A paradigm for optimizing global cancer care.

Clinical practice guidelines in oncology lead to improved outcomes in care. However, the most frequently used guidelines are developed for highly resourced systems. Recognizing the significant and increasing burden of cancer in low- and middle-income countries, the National Comprehensive Cancer Network (NCCN) has developed resource-stratified framework and harmonization processes that allow the NCCN Guidelines to be tailored and optimized for specific geographical areas, resource levels, and settings. The critical need for local expertise and involvement in successful development and uptake is emphasized, and the promise of this collaboration for advancement in oncology programs is illustrated.

Geographic disparities in the application of endovascular repair of unruptured abdominal aortic aneurysm - Polish population analysis.

PURPOSE: Differences between the regions of the same country regarding the management of abdominal aortic aneurysm (AAA) have rarely been published. The aim of the study was to analyze the absolute and relative number of unruptured AAA repairs, utilizing endovascular aneurysm repair (EVAR) vs. open aneurysm repairs (OAR) and compare the AAA patients population from all 16 administrative districts in Poland. MATERIAL AND METHODS: We used the Polish National Health Fund data of all patients who underwent elective treatment of AAA between 1st January 2011 and 22nd March 2016 and analyzed the absolute/relative number of all AAA repairs, OAR, EVAR and incidence of concomitant diseases in distinctive regions. Relationships between the utilization of EVAR and the number of procedures, age, gender and concomitant diseases were studied. RESULTS: A total of 7805 patients (mean age 70.9 ± 8.1 yrs) underwent OAR (n = 2336) or EVAR (n = 5469). The age and the incidence of concomitant diseases differed significantly between districts. The highest absolute number of all repairs was performed in the Masovian district (n = 1442), while the highest relative number of all repairs in the Lublin district (36.3/100,000 65+/year). The utilization of EVAR ranged from 34.5% to 93.9% and correlated positively with the number of EVAR, age and chronic obstructive pulmonary disease occurrence and negatively with OAR number. CONCLUSIONS: Striking differences in the relative numbers of unruptured AAA repairs and in the population characteristics in various districts of the country point to the possibility of different health needs in the regions and variations in standards of care.

Biological Background of Resistance to Current Standards of Care in Multiple Myeloma.

A high priority problem in multiple myeloma (MM) management is the development of resistance to administered therapies, with most myeloma patients facing successively shorter periods of response and relapse. Herewith, we review the current knowledge on the mechanisms of resistance to the standard backbones in MM treatment: proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and monoclonal antibodies (mAbs). In some cases, strategies to overcome resistance have been discerned, and an effort should be made to evaluate whether resensitization to these agents is feasible in the clinical setting. Additionally, at a time in which we are moving towards precision medicine in MM, it is equally important to identify reliable and accurate biomarkers of sensitivity/refractoriness to these main therapeutic agents with the goal of having more efficacious treatments and, if possible, prevent the development of relapse.

Academy of Nutrition and Dietetics: Revised 2019 Standards of Professional Performance for Registered Dietitian Nutritionists (Competent, Proficient, and Expert) in Clinical Nutrition Management.

Clinical nutrition management (CNM) encompasses the varied roles of registered dietitian nutritionists (RDNs) with administrative responsibilities for clinical nutrition services within an organization. Although RDNs in CNM are typically employed in acute care, they are also employed in settings where management of nutrition services is required, such as foodservice departments, ambulatory clinics, telehealth services, public health organizations, post-acute and long-term care, rehabilitation, and correctional facilities, or specialty departments, for example, dialysis units or cancer centers. RDNs in CNM aim to create work environments that support high-quality customer-centered care, attract and retain talented staff, and foster an atmosphere of collaboration and innovation. The CNM Dietetic Practice Group, with guidance from the Academy of Nutrition and Dietetics Quality Management Committee, has revised the Standards of Professional Performance (SOPP) for RDNs in CNM for three levels of practice: competent, proficient, and expert. The SOPP describes six domains that focus on professional performance: Quality in Practice, Competence and Accountability, Provision of Services, Application of Research, Communication and Application of Knowledge, and Utilization and Management of Resources. Indicators outlined in the SOPP depict how these standards apply to practice. The standards and indicators for RDNs in CNM are written with the leader in mind-to support an individual in a leadership role or who has leadership aspirations. The SOPP is intended to be used by RDNs for self-evaluation to assure competent practice and for determining potential education and training needs for advancement to a higher practice level in a variety of settings.