Does Failure to Rescue Drive Race/Ethnicity-based Disparities in Survival After Heart Transplantation?

OBJECTIVE: The objective was to assess whether race/ethnicity is an independent predictor of failure to rescue (FTR) after orthotopic heart transplantation (OHT). SUMMARY BACKGROUND DATA: Outcomes following OHT vary by patient level factors; for example, non-White patients have worse outcomes than White patients after OHT. Failure to rescue is an important factor associated with cardiac surgery outcomes, but its relationship to demographic factors is unknown. METHODS: Using the United Network for Organ Sharing database, we included all adult patients who underwent primary isolated OHT between 1/1/2006 snd 6/30/2021. FTR was defined as the inability to prevent mortality after at least one of the UNOS-designated postoperative complications. Donor, recipient, and transplant characteristics, including complications and FTR, were compared across race/ethnicity. Logistic regression models were created to identify factors associated with complications and FTR. Kaplan Meier and adjusted Cox proportional hazards models evaluated the association between race/ethnicity and posttransplant survival. RESULTS: There were 33,244 adult, isolated heart transplant recipients included: the distribution of race/ethnicity was 66% (n=21,937) White, 21.2% (7,062) Black, 8.3% (2,768) Hispanic, and 3.3% (1,096) Asian. The frequency of complications and FTR differed significantly by race/ethnicity. After adjustment, Hispanic recipients were more likely to experience FTR than White recipients (OR 1.327, 95% CI[1.075-1.639], P =0.02). Black recipients had lower 5-year survival compared with other races/ethnicities (HR 1.276, 95% CI[1.207-1.348], P <0.0001). CONCLUSIONS: In the US, Black recipients have an increased risk of mortality after OHT compared with White recipients, without associated differences in FTR. In contrast, Hispanic recipients have an increased likelihood of FTR, but no significant mortality difference compared with White recipients. These findings highlight the need for tailored approaches to addressing race/ethnicity-based health inequities in the practice of heart transplantation.

Rethinking Vision and Action.

Action is an important arbitrator as to whether an individual or a species will survive. Yet, action has not been well integrated into the study of psychology. Action or motor behavior is a field apart. This is traditional science with its need for specialization. The sequence in a typical laboratory experiment of see → decide → act provides the rationale for broad disciplinary categorizations. With renewed interest in action itself, surprising and exciting anomalous findings at odds with this simplified caricature have emerged. They reveal a much more intimate coupling of vision and action, which we describe. In turn, this prompts us to identify and dwell on three pertinent theories deserving of greater notice.

Xenohormesis: sensing the chemical cues of other species.

Many plant molecules interact with and modulate key regulators of mammalian physiology in ways that are beneficial to health, but why? We propose that heterotrophs (animals and fungi) are able to sense chemical cues synthesized by plants and other autotrophs in response to stress. These cues provide advance warning about deteriorating environmental conditions, allowing the heterotrophs to prepare for adversity while conditions are still favorable.

Healthcare providers' perceptions about the unmet needs of their patients with cancer across healthcare systems: results of the International Psycho-Oncology Society survivorship survey.

OBJECTIVE: Systematic understanding of patients' unmet needs is essential for providing effective supportive care. This study sought to compare the unmet needs of patients with cancer identified by health care providers (HCPs) among four major healthcare systems. METHODS: HCPs (n = 247) participated in the International Psycho-Oncology Society (IPOS) Survivorship Online Survey, evaluating their patients' unmet needs. The country of HCPs was grouped into four major healthcare systems: Beveridge model, Bismarck model, National Health Insurance model, and out-of-pocket model. RESULTS: Most HCPs were from countries with the Bismarck model. Substantial levels (> 50%) of unmet needs in all domains are reported across the four healthcare systems. Pediatric patients/survivors living in countries under out-of-pocket healthcare model were evaluated to have less unmet needs for managing decline in physical or cognitive functioning and insomnia/sleep difficulty/fatigue, than those in countries under Beveridge, Bismarck, and National Health Insurance models. Moreover, middle-aged patients/survivors under Beveridge and National Health Insurance models were likely to have greater unmet needs for dealing with cancer-related financial concerns than those under Bismarck model. CONCLUSION: This study provides valuable insights into the unmet needs of patients with cancer in different healthcare systems, highlighting the significance of targeted interventions to address the unique needs of patients across diverse healthcare systems. Further investigation is warranted to identify the system factors associated with patients' unmet needs, enabling the development of effective healthcare policies and interventions to comprehensively address the multifaceted needs of patients with cancer.

Is there a survival processing effect in metacognition?

Memory systems serve an adaptive function for the fitness of organisms. A good example of this is the Survival Processing Effect (SPE) which points to increased retention of information when it is processed in a survival context compared to other contexts. Survival processing may also affect metacognitive processes, by increasing confidence judgments as well as increasing metacognitive sensitivity. No previous study, however, has directly examined whether processing information for survival also has an effect on metacognitive processes. Here we ask whether SPE extends to the metacognitive system in terms of both metacognitive sensitivity and confidence bias. In Experiment 1 participants were asked to rate a list of words in terms of relevance in a survival scenario or a moving scenario. In a surprise old/new recognition test, they were given one word at a time and asked to indicate if they have rated the presented word before and state how confident they are in that choice. Surprisingly, the results did not reveal a SPE, which may have been due to high overall performance in the recognition task. In Experiment 2 we increased the level of difficulty of the memory task, which resulted in a robust SPE, but could not find this effect in metacognitive monitoring. Together, these results suggest that survival processing may not affect metacognitive processes in a reliable fashion.

Survival processing advantage demonstrated with virtual reality-based survival environment: A promising tool for survival processing research.

Many studies have been conducted to demonstrate the survival processing advantage (SPA) as an evolutionary-oriented memory effect. But few studies were conducted to demonstrate this effect in real-life or simulated survival environments. This study tested whether the SPA could be replicated in a survival virtual reality environment (VRE). In Experiment 1, the SPAs were measured in VREs (survival grasslands, survival battlefield, nonsurvival moving) in which Experiment 1A used the standard long instructions and Experiment 1B used the modified short instructions. In Experiment 2, the SPAs were measured again with the scenarios corresponding to the VREs used in Experiment 1A. All experiments demonstrated typical SPAs, suggesting that the survival VRE is a reliable tool in designing and delivering a survival situation. The potential problems of applying survival VRE to survival processing research are discussed at the end.

[An enjoyable 23-year career as a hematologist in metropolitan emergency hospitals, a researcher of post-transplant survivorship, and a community hematologist-oncologist].

I would like to express my sincere gratitude to be given such an honorable opportunity. I am more than happy to share my personal experience as one example of the diversity of women in hematology. After graduating from Tohoku University, I began my residency training at Japanese Red Cross Musashino Hospital and Tokyo Metropolitan Bokutoh Hospital, which are extremely busy designated hospitals in Tokyo. Both had highly active emergency care centers, and I believe that the rigorous training I received there not only honed my basic patient care skills, but also increased my physical and mental strength. Since I referred many patients to National Cancer Center Hospital, I found it amusing that Dr. Fukuda recruited me based on the recommendation of those patients. I was so fortunate to have many opportunities to contribute as a primary investigator in meaningful nationwide clinical studies. At present, I appreciate my country life as a community hematologist-oncologist. I also did not expect that I would have continuing opportunities to collaborate with researchers nationwide thanks to rapid progress in remote communications, and nothing would make me happier than to continue participating in projects on cancer survivorship.

Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a double-blind, randomised, placebo-controlled, phase 2 trial.

BACKGROUND: The Wee1 (WEE1hu) inhibitor adavosertib and gemcitabine have shown preclinical synergy and promising activity in early phase clinical trials. We aimed to determine the efficacy of this combination in patients with ovarian cancer. METHODS: In this double-blind, randomised, placebo-controlled, phase 2 trial, women with measurable recurrent platinum-resistant or platinum-refractory high-grade serous ovarian cancer were recruited from 11 academic centres in the USA and Canada. Women were eligible if they were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, a life expectancy of more than 3 months, and normal organ and marrow function. Women with ovarian cancer of non-high-grade serous histology were eligible for enrolment in a non-randomised exploratory cohort. Eligible participants with high-grade serous ovarian cancer were randomly assigned (2:1), using block randomisation (block size of three and six) and no stratification, to receive intravenous gemcitabine (1000 mg/m2 on days 1, 8, and 15) with either oral adavosertib (175 mg) or identical placebo once daily on days 1, 2, 8, 9, 15, and 16, in 28-day cycles until disease progression or unacceptable toxicity. Patients and the team caring for each patient were masked to treatment assignment. The primary endpoint was progression-free survival. The safety and efficacy analysis population comprised all patients who received at least one dose of treatment. The trial is registered with ClinicalTrials.gov, NCT02151292, and is closed to accrual. FINDINGS: Between Sept 22, 2014, and May 30, 2018, 124 women were enrolled, of whom 99 had high-grade serous ovarian cancer and were randomly assigned to adavosertib plus gemcitabine (65 [66%]) or placebo plus gemcitabine (34 [34%]). 25 women with non-high-grade serous ovarian cancer were enrolled in the exploratory cohort. After randomisation, five patients with high-grade serous ovarian cancer were found to be ineligible (four in the experimental group and one in the control group) and did not receive treatment. Median age for all treated patients (n=119) was 62 years (IQR 54-67). Progression-free survival was longer with adavosertib plus gemcitabine (median 4·6 months [95% CI 3·6-6·4] with adavosertib plus gemcitabine vs 3·0 months [1·8-3·8] with placebo plus gemcitabine; hazard ratio 0·55 [95% CI 0·35-0·90]; log-rank p=0·015). The most frequent grade 3 or worse adverse events were haematological (neutropenia in 38 [62%] of 61 participants in the adavosertib plus gemcitabine group vs ten [30%] of 33 in the placebo plus gemcitabine group; thrombocytopenia in 19 [31%] of 61 in the adavosertib plus gemcitabine group vs two [6%] of 33 in the placebo plus gemcitabine group). There were no treatment-related deaths; two patients (one in each group in the high-grade serous ovarian cancer cohort) died while on study medication (from sepsis in the experimental group and from disease progression in the control group). INTERPRETATION: The observed clinical efficacy of a Wee1 inhibitor combined with gemcitabine supports ongoing assessment of DNA damage response drugs in high-grade serous ovarian cancer, a TP53-mutated tumour type with high replication stress. This therapeutic approach might be applicable to other tumour types with high replication stress; larger confirmatory studies are required. FUNDING: US National Cancer Institute Cancer Therapy Evaluation Program, Ontario Institute for Cancer Research, US Department of Defense, Princess Margaret Cancer Foundation, and AstraZeneca.

Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study.

BACKGROUND: First-line therapy for advanced oesophageal cancer is currently limited to fluoropyrimidine plus platinum-based chemotherapy. We aimed to evaluate the antitumour activity of pembrolizumab plus chemotherapy versus chemotherapy alone as first-line treatment in advanced oesophageal cancer and Siewert type 1 gastro-oesophageal junction cancer. METHODS: We did a randomised, placebo-controlled, double-blind, phase 3 study across 168 medical centres in 26 countries. Patients aged 18 years or older with previously untreated, histologically or cytologically confirmed, locally advanced, unresectable or metastatic oesophageal cancer or Siewert type 1 gastro-oesophageal junction cancer (regardless of PD-L1 status), measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1, and Eastern Cooperative Oncology Group performance status of 0-1, were randomly assigned (1:1) to intravenous pembrolizumab 200 mg or placebo, plus 5-fluorouracil and cisplatin (chemotherapy), once every 3 weeks for up to 35 cycles. Randomisation was stratified by geographical region, histology, and performance status. Patients, investigators, and site staff were masked to group assignment and PD-L1 biomarker status. Primary endpoints were overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 combined positive score (CPS) of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients. This trial is registered with ClinicalTrials.gov, NCT03189719, and is closed to recruitment. FINDINGS: Between July 25, 2017, and June 3, 2019, 1020 patients were screened and 749 were enrolled and randomly assigned to pembrolizumab plus chemotherapy (n=373 [50%]) or placebo plus chemotherapy (n=376 [50%]). At the first interim analysis (median follow-up of 22·6 months), pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more (median 13·9 months vs 8·8 months; hazard ratio 0·57 [95% CI 0·43-0·75]; p<0·0001), oesophageal squamous cell carcinoma (12·6 months vs 9·8 months; 0·72 [0·60-0·88]; p=0·0006), PD-L1 CPS of 10 or more (13·5 months vs 9·4 months; 0·62 [0·49-0·78]; p<0·0001), and in all randomised patients (12·4 months vs 9·8 months; 0·73 [0·62-0·86]; p<0·0001). Pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for progression-free survival in patients with oesophageal squamous cell carcinoma (6·3 months vs 5·8 months; 0·65 [0·54-0·78]; p<0·0001), PD-L1 CPS of 10 or more (7·5 months vs 5·5 months; 0·51 [0·41-0·65]; p<0·0001), and in all randomised patients (6·3 months vs 5·8 months; 0·65 [0·55-0·76]; p<0·0001). Treatment-related adverse events of grade 3 or higher occurred in 266 (72%) patients in the pembrolizumab plus chemotherapy group versus 250 (68%) in the placebo plus chemotherapy group. INTERPRETATION: Compared with placebo plus chemotherapy, pembrolizumab plus chemotherapy improved overall survival in patients with previously untreated, advanced oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients regardless of histology, and had a manageable safety profile in the total as-treated population. FUNDING: Merck Sharp & Dohme.

No major cost of evolved survivorship in Drosophila melanogaster populations coevolving with Pseudomonas entomophila.

Rapid exaggeration of host and pathogen traits via arms race dynamics is one possible outcome of host-pathogen coevolution. However, the exaggerated traits are expected to incur costs in terms of resource investment in other life-history traits. The current study investigated the costs associated with evolved traits in a host-pathogen coevolution system. We used the Drosophila melanogaster (host)-Pseudomonas entomophila (pathogen) system to experimentally derive two selection regimes, one where the host and pathogen both coevolved, and the other, where only the host evolved against a non-evolving pathogen. After 17 generations of selection, we found that hosts from both selected populations had better post-infection survivorship than controls. Even though the coevolving populations tended to have better survivorship post-infection, we found no clear evidence that the two selection regimes were significantly different from each other. There was weak evidence for the coevolving pathogens being more virulent than the ancestral pathogen. We found no major cost of increased post-infection survivorship. The costs were not different between the coevolving hosts and the hosts evolving against a non-evolving pathogen. We found no evolved costs in the coevolving pathogens. Thus, our results suggest that increased host immunity and pathogen virulence may not be costly.

Algorithms for survival: a comparative perspective on emotions.

The nature and neural implementation of emotions is the subject of vigorous debate. Here, we use Bayesian decision theory to address key complexities in this field and conceptualize emotions in terms of their relationship to survival-relevant behavioural choices. Decision theory indicates which behaviours are optimal in a given situation; however, the calculations required are radically intractable. We therefore conjecture that the brain uses a range of pre-programmed algorithms that provide approximate solutions. These solutions seem to produce specific behavioural manifestations of emotions and can also be associated with core affective dimensions. We identify principles according to which these algorithms are implemented in the brain and illustrate our approach by considering decision making in the face of proximal threat.

Evaluation of survivorship care plans in patients attending the Sydney Cancer Survivorship Centre.

PURPOSE: The transitioning of cancer survivors from active treatment to surveillance care has been described as uncoordinated, with lack of communication between healthcare professionals. Survivorship care plans (SCP) are recommended to bridge this transitioning period and help improve coordination of care. SCP contain individualized information about a survivor's cancer diagnosis, treatment, and recommendations for managing treatment-related side effects and improving lifestyle risk factors for cancer recurrence and chronic disease. The aims of the study were to assess the delivery, usefulness, and compliance with SCP of survivors attending a multidisciplinary survivorship clinic and to determine patient suggestions regarding how to improve SCP. METHODS: A total of 110 survivors were interviewed in-person or by phone regarding their SCP following a script with formalized questions. Data were analyzed quantitatively using descriptive statistics. RESULTS: Overall, 65% of participants (72/110) acknowledged having received a SCP and 86% found them useful. Only 11% of survivors (8/72) showed their SCP to other health professionals and about half (33/72) showed it to family/friends. Ninety percent of survivors (65/72) reported following at least one recommendation in their SCP. CONCLUSION: Survivors found SCP helpful but did not share them with other healthcare providers, which questions their usefulness in coordinating care. There were challenges with SCP delivery. Survivors reported they were compliant with SCP lifestyle recommendations. Further research is required to address the utility of SCP to other stakeholders, such as general practitioners, to determine whether they receive the SCP, if they find them helpful, and their expectations regarding SCP.

Effect of Esophageal Pressure-guided Positive End-Expiratory Pressure on Survival from Acute Respiratory Distress Syndrome: A Risk-based and Mechanistic Reanalysis of the EPVent-2 Trial.

Rationale: In acute respiratory distress syndrome (ARDS), the effect of positive end-expiratory pressure (PEEP) may depend on the extent to which multiorgan dysfunction contributes to risk of death, and the precision with which PEEP is titrated to attenuate atelectrauma without exacerbating overdistension. Objectives: To evaluate whether multiorgan dysfunction and lung mechanics modified treatment effect in the EPVent-2 (Esophageal Pressure-guided Ventilation 2) trial, a multicenter trial of esophageal pressure (Pes)-guided PEEP versus empirical high PEEP in moderate to severe ARDS. Methods: This post hoc reanalysis of the EPVent-2 trial evaluated for heterogeneity of treatment effect on mortality by baseline multiorgan dysfunction, determined via Acute Physiology and Chronic Health Evaluation II (APACHE-II). It also evaluated whether PEEP titrated to end-expiratory transpulmonary pressure near 0 cm H2O was associated with survival. Measurements and Main Results: All 200 trial participants were included. Treatment effect on 60-day mortality differed by multiorgan dysfunction severity (P = 0.03 for interaction). Pes-guided PEEP was associated with lower mortality among patients with APACHE-II less than the median value (hazard ratio, 0.43; 95% confidence interval, 0.20-0.92) and may have had the opposite effect in patients with higher APACHE-II (hazard ratio, 1.69; 95% confidence interval, 0.93-3.05). Independent of treatment group or multiorgan dysfunction severity, mortality was lowest when PEEP titration achieved end-expiratory transpulmonary pressure near 0 cm H2O. Conclusions: The effect on survival of Pes-guided PEEP, compared with empirical high PEEP, differed by multiorgan dysfunction severity. Independent of multiorgan dysfunction, PEEP titrated to end-expiratory transpulmonary pressure closer to 0 cm H2O was associated with greater survival than more positive or negative values. These findings warrant prospective testing in a future trial.

Survival and predictors of mortality among chronic kidney disease patients on hemodialysis in Amhara region, Ethiopia, 2021.

BACKGROUND: Despite the high economic and mortality burden of chronic kidney disease, studies on survival and predictors of mortality among patients on hemodialysis in Ethiopia especially in the Amhara region are scarce considering their importance to identify some modifiable risk factors for early mortality to improve the patient's prognosis. So, this study was done to fill the identified gaps. The study aimed to assess survival and predictors of mortality among end-stage renal disease patients on hemodialysis in Amhara regional state, Ethiopia, 2020/2021. METHOD: Institution-based retrospective record review was conducted in Felege Hiwot, Gonder, and Gambi hospitals from March 5 to April 5, 2021. A total of 436 medical records were selected using a simple random sampling technique. A life table was used to estimate probabilities of survival at different time intervals. Multivariable cox regression was used to identify risk factors for mortality. RESULT: Out of the 436 patients 153 (35.1%) had died. The median survival time was 345 days with a mortality rate of 1.89 per 1000 person-days (95%CI (1.62, 2.22)). Patients live in rural residences (AHR = 1.48, 95%CI (1.04, 2.12)), patients whose cause of CKD was hypertension (AHR = 1.49, 95%CI (1.01, 2.23)) and human immune virus (AHR = 2.22, 95%CI (1.41, 3.51)), and patients who use a central venous catheter (AHR = 3.15, 95%CI (2.08, 4.77)) had increased risk of death while staying 4 h on hemodialysis (AHR = 0.43, 95%CI (0.23, 0.80)) decreases the risk of death among chronic kidney disease patients on hemodialysis. CONCLUSIONS: The overall survival rate and median survival time of chronic kidney disease patients on hemodialysis were low in the Amhara region as compared with other developing Sub-Saharan African counties.

Staying alive enhances both women's and men's fitness.

We argue that Benenson et al. need to consider not only sex differences in the effects of care on offspring survival but also in age-specific fertility when predicting how longevity affects fitness. We review evidence that staying alive has important effects on both women's and men's fitness, and encourage consideration of alternative explanations for observed sex differences in threat responses.

Appetitive Memory with Survival Benefit Is Robust Across Aging in Drosophila.

The formation of memory declines with advancing age. However, susceptibility to memory impairments depends on several factors, including the robustness of memory, the responsible neural circuits, and the internal state of aged individuals. How age-dependent changes in internal states and neural circuits affect memory formation remains unclear. Here, we show in Drosophila melanogaster that aged flies of both sexes form robust appetitive memory conditioned with nutritious sugar, which suppresses their high mortality rates during starvation. In contrast, aging impairs the formation of appetitive memory conditioned with non-nutritious sugar that lacks survival benefits for the flies. We found that aging enhanced the preference for nutritious sugar over non-nutritious sugar correlated with an age-dependent increase in the expression of Drosophila neuropeptide F, an ortholog of mammalian neuropeptide Y. Furthermore, a subset of dopaminergic neurons that signal the sweet taste of sugar decreases its function with aging, while a subset of dopaminergic neurons that signal the nutritional value of sugar maintains its function with age. Our results suggest that aging impairs the ability to form memories without survival benefits; however, the ability to form memories with survival benefits is maintained through age-dependent changes in the neural circuits and neuropeptides.SIGNIFICANCE STATEMENT The susceptibility to age-dependent memory impairments depends on the strength of the memory, changes in the responsible neurons, and internal states of aged individuals. How age-dependent changes in such internal states affect neural activity and memory formation remains unclear. We show in Drosophila melanogaster that aged flies of both sexes form robust appetitive memory conditioned with nutritious sugar, which has survival benefits for aged flies. In contrast, aging impairs the formation of appetitive memory conditioned with non-nutritious sugar that lacks survival benefits for the flies. Aging changes the neural circuits including dopamine neurons and neuropeptide F-expressing neurons, leading to the age-dependent impairment in memory with insufficient survival benefits and the preservation of the ability to form memory with survival benefits.

Intrathecal AAVrh10 corrects biochemical and histological hallmarks of mucopolysaccharidosis VII mice and improves behavior and survival.

Mucopolysaccharidosis (MPS) type VII is a lysosomal storage disease caused by ß-glucuronidase deficiency, prompting glycosaminoglycan accumulation in enlarged vesicles, leading to peripheral and neuronal dysfunction. Here, we present a gene therapy strategy using lumbar puncture of AAVrh10 encoding human ß-glucuronidase (AAVrh10-GUSB) to adult MPS VII mice. This minimally invasive technique efficiently delivers the recombinant vector to the cerebrospinal fluid (CSF) with a single intrathecal injection. We show that AAVrh10 delivery to the CSF allows global, stable transduction of CNS structures. In addition, drainage of AAVrh10-GUSB from the CSF to the bloodstream resulted in the transduction of somatic organs such as liver, which provided a systemic ß-glucuronidase source sufficient to achieve serum enzyme activity comparable to wild type mice. ß-glucuronidase levels were enough to correct biochemical and histopathological hallmarks of the disease in the CNS and somatic organs at short and long term. Moreover, the progression of the bone pathology was also reduced. Importantly, the biochemical correction led to a significant improvement in the physical, cognitive and emotional characteristics of MPS VII mice, and doubling their life span. Our strategy may have implications for gene therapy in patients with lysosomal storage diseases.

Disease outcomes and biomarkers of progression in smouldering Waldenström macroglobulinaemia.

Patients with asymptomatic/smouldering Waldenström macroglobulinaemia (SWM) have a variable risk of progression to active WM. Our study evaluated 143 patients with SWM consecutively seen between January 1996 and December 2013. With a median [95% confidence interval (CI)] follow-up of 9·5 [8·1-11·5] years, the cumulative rate of progression was 11% at 1 year, 38% at 3 years and 55% at 5 years. On multivariate analysis, haemoglobin (Hb) ≤123 g/l [risk ratio (RR) 2·08; P = 0·009] and ß2 -microglobulin (ß2 M) ≥2·7 µg/ml (RR 2·0; P = 0·01) were independent predictors of a shorter time-to-progression (TTP) to active WM. Patients with myeloid differentiation factor 88 wild type (MYD88WT ) genotype (n = 11) demonstrated a trend toward shorter TTP [median (95% CI) 1·7 (0·7-8·7) vs. 4·7 (2·4-7·7) years for the MYD88L265P cohort, n = 42; P = 0·11]. The presence of C-X-C chemokine receptor type 4 (CXCR4) mutation (n = 29) did not impact the TTP (median: 3 years for CXCR4WT vs. 5·6 years for CXCR4MUT , P = 0·34). The overall survival (OS) for patients with SWM (median: 18·1 years) was comparable to an age-, sex- and calendar year-matched USA population (median: 20·3 years, P = 0·502). In conclusion, Hb and ß2 M at diagnosis represent independent predictors of progression to active WM. Comparable survival of SWM and a matched USA population argues against pre-emptive intervention in this patient population.

Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation (ARREST): a phase 2, single centre, open-label, randomised controlled trial.

BACKGROUND: Among patients with out-of-hospital cardiac arrest (OHCA) and ventricular fibrillation, more than half present with refractory ventricular fibrillation unresponsive to initial standard advanced cardiac life support (ACLS) treatment. We did the first randomised clinical trial in the USA of extracorporeal membrane oxygenation (ECMO)-facilitated resuscitation versus standard ACLS treatment in patients with OHCA and refractory ventricular fibrillation. METHODS: For this phase 2, single centre, open-label, adaptive, safety and efficacy randomised clinical trial, we included adults aged 18-75 years presenting to the University of Minnesota Medical Center (MN, USA) with OHCA and refractory ventricular fibrillation, no return of spontaneous circulation after three shocks, automated cardiopulmonary resuscitation with a Lund University Cardiac Arrest System, and estimated transfer time shorter than 30 min. Patients were randomly assigned to early ECMO-facilitated resuscitation or standard ACLS treatment on hospital arrival by use of a secure schedule generated with permuted blocks of randomly varying block sizes. Allocation concealment was achieved by use of a randomisation schedule that required scratching off an opaque layer to reveal assignment. The primary outcome was survival to hospital discharge. Secondary outcomes were safety, survival, and functional assessment at hospital discharge and at 3 months and 6 months after discharge. All analyses were done on an intention-to-treat basis. The study qualified for exception from informed consent (21 Code of Federal Regulations 50.24). The ARREST trial is registered with ClinicalTrials.gov, NCT03880565. FINDINGS: Between Aug 8, 2019, and June 14, 2020, 36 patients were assessed for inclusion. After exclusion of six patients, 30 were randomly assigned to standard ACLS treatment (n=15) or to early ECMO-facilitated resuscitation (n=15). One patient in the ECMO-facilitated resuscitation group withdrew from the study before discharge. The mean age was 59 years (range 36-73), and 25 (83%) of 30 patients were men. Survival to hospital discharge was observed in one (7%) of 15 patients (95% credible interval 1·6-30·2) in the standard ACLS treatment group versus six (43%) of 14 patients (21·3-67·7) in the early ECMO-facilitated resuscitation group (risk difference 36·2%, 3·7-59·2; posterior probability of ECMO superiority 0·9861). The study was terminated at the first preplanned interim analysis by the National Heart, Lung, and Blood Institute after unanimous recommendation from the Data Safety Monitoring Board after enrolling 30 patients because the posterior probability of ECMO superiority exceeded the prespecified monitoring boundary. Cumulative 6-month survival was significantly better in the early ECMO group than in the standard ACLS group. No unanticipated serious adverse events were observed. INTERPRETATION: Early ECMO-facilitated resuscitation for patients with OHCA and refractory ventricular fibrillation significantly improved survival to hospital discharge compared with standard ACLS treatment. FUNDING: National Heart, Lung, and Blood Institute.

Association between cytoreductive nephrectomy and survival among patients with metastatic renal cell carcinoma receiving modern therapies: a systematic review and meta-analysis examining effect modification according to systemic therapy approach.

PURPOSE: Cytoreductive nephrectomy (CN) has played a role in treatment of metastatic renal cell carcinoma (mRCC) since trials demonstrated a survival benefit in patients receiving CN with interferon. With the publication of CARMENA, it became clear that the value of CN may depend on the co-therapy administered. We sought to assess the benefit of CN in the era of modern immunotherapy (IO). METHODS: We performed a systematic review to identify studies assessing CN in patients receiving TT or IO. We extracted multivariable-adjusted hazard ratios for the association between CN and overall survival (OS) and performed random effects meta-analysis. We tested for effect modification by systemic therapy approach on the association between CN and OS by pooling the difference in logHR associated with CN for patients treated with TT versus IO. RESULTS: We identified three comparisons assessing CN in patients receiving TT or IO. Pooled analysis indicated improved survival with CN in both the TT (2 cohorts, pooled HR: 0.52, 95% CI 0.46-0.59; I2 = 80%) and IO era (2 cohorts; pooled HR: 0.28, 95% CI 0.16-0.49; I2 = 21%), with a stronger association in the IO era (p = 0.01; I2 = 0%). CONCLUSION: In observational datasets, we observed a larger survival benefit to CN in patients treated with IO-based regimens versus those treated with TT-based regimens. While the role of CN for patients receiving TT has recently been questioned, this suggests that the results of CARMENA do not necessarily preclude a benefit to CN when combined with IO-based regimens.