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19/Jul/2022

Stereotactic radiosurgery versus whole brain radiotherapy in patients with intracranial metastatic disease and small-cell lung cancer: a systematic review and meta-analysis

BACKGROUND
Patients with small-cell lung cancer (SCLC) are at high risk for intracranial metastatic disease (IMD). Although stereotactic radiosurgery (SRS) has supplanted whole brain radiotherapy (WBRT) as first-line treatment for IMD in most solid cancers, WBRT remains first-line treatment for IMD in patients with SCLC. We aimed to evaluate the efficacy of SRS in comparison with WBRT and assess treatment outcomes following SRS.

METHODS
In this systematic review and meta-analysis, we searched MEDLINE, Embase, CENTRAL, and grey literature sources for controlled trials and cohort studies published in English reporting on SRS for IMD treatment in patients with SCLC from inception to March 23, 2022. Studies were excluded that did not report on SRS for IMD secondary to SCLC. Summary data were extracted. The primary outcome was overall survival, presented as pooled hazard ratios (HR) through random-effects meta-analysis for studies comparing SRS with WBRT with or without SRS boost, and as medians for single-arm SRS studies. This study is registered with the Open Science Framework, DOI 10.17605/OSF.IO/8M4HC, and PROSPERO, CRD42021258197.

FINDINGS
Of 3823 identified records, 31 were eligible for inclusion; seven were included in the meta-analysis. Overall survival following SRS was longer than following WBRT with or without SRS boost (HR 0·85; 95% CI 0·75–0·97; n=7 studies; n=18 130 patients), or WBRT alone (0·77; 0·72–0·83; n=7 studies; n=16 961 patients), but not WBRT plus SRS boost (1·17, 0·78–1·75; n=4 studies; n=1167 patients). Using single-arm studies, pooled median overall survival from SRS was 8·99 months (95% CI 7·86–10·16; n=14 studies; n=1682 patients). Between-study heterogeneity was considerable when pooled among all comparative studies (I2=71·9%).

INTERPRETATION
These results suggest survival outcomes are equitable following treatment with SRS compared with WBRT in patients with SCLC and IMD. Future prospective studies should focus on tumour burden and differences in local and distant intracranial progression between WBRT-treated and SRS-treated patients with SCLC.

Karolina Gaebe, BMath, Alyssa Y Li, BA, Amy Park, BSc, Ambica Parmar, MD, Benjamin H Lok, MD, Prof Arjun Sahgal, MD, et al

© 2022 Elsevier Ltd. All rights reserved.

Lung cancer


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05/Jul/2022

Mycobacterial infections in adults with haematological malignancies and haematopoietic stem cell transplants: guidelines from the 8th European Conference on Infections in Leukaemia

Mycobacterial infections, both tuberculosis and nontuberculous, are more common in patients with haematological malignancies and haematopoietic stem cell transplant recipients than in the general population—although these infections remain rare. Mycobacterial infections pose both diagnostic and therapeutic challenges. The management of mycobacterial infections is particularly complicated for patients in haematology because of the many drug–drug interactions between antimycobacterial drugs and haematological and immunosuppressive treatments. The management of mycobacterial infections must also consider the effect of delaying haematological management. We surveyed the management practices for latent tuberculosis infection (LTBI) in haematology centres in Europe. We then conducted a meticulous review of the literature on the epidemiology, diagnosis, and management of LTBI, tuberculosis, and nontuberculous mycobacterial infections among patients in haematology, and we formulated clinical guidelines according to standardised European Conference on Infections in Leukaemia (ECIL) methods. In this Review, we summarise the available literature and the recommendations of ECIL 8 for managing mycobacterial infections in patients with haematological malignancies.

Prof Anne Bergeron, MD,Prof Malgorzata Mikulska, MD, Julien De Greef, MD, Louise Bondeelle, MD, Prof Tomas Franquet, MD, Prof Jean-Louis Herrmann, PharmD, et al.

© 2022 Elsevier Ltd. All rights reserved.

 

Leukemia


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30/Jun/2022

Adebrelimab or placebo plus carboplatin and etoposide as first-line treatment for extensive-stage small-cell lung cancer (CAPSTONE-1): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND
21

METHODS
The CAPSTONE-1 study was a randomised, double-blind, placebo-controlled, phase 3 trial, done in 47 tertiary hospitals in China. Key inclusion criteria were patients aged 18–75 years, with previously untreated histologically or cytologically confirmed ES-SCLC and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1. Eligible patients were randomly assigned (1:1) to receive four to six cycles of carboplatin (area under the curve of 5 mg/mL per min, day 1 of each cycle) and etoposide (100 mg/m2 of body-surface area, on days 1–3 of each cycle) with either adebrelimab (20 mg/kg, day 1 of each cycle) or matching placebo, followed by maintenance therapy with adebrelimab or placebo. All treatments were given intravenously in 21-day cycles. Randomisation was done using a centralised interactive web response system with a block size of four, stratified by liver metastases, brain metastases, and lactate dehydrogenase concentration. The primary endpoint was overall survival in patients who received at least one dose of study medication. Safety was analysed in the as-treated population. This study is complete and registered with ClinicalTrials.gov, NCT03711305.

FINDINGS
Between Dec 26, 2018, and Sept 4, 2020, 462 eligible patients were enrolled and randomly assigned: 230 (50%) patients received adebrelimab plus chemotherapy (adebrelimab group) and 232 (50%) patients received placebo plus chemotherapy (placebo group). At data cutoff (Oct 8, 2021), median follow-up was 13·5 months (IQR 8·9–20·1). Median overall survival was significantly improved in the adebrelimab group (median 15·3 months [95% CI 13·2–17·5]) compared with the placebo group (12·8 months [11·3–13·7]; hazard ratio 0·72 [95% CI 0·58–0·90]; one-sided p=0·0017). The most common treatment-related grade 3 or 4 adverse events were decreased neutrophil count (174 [76%] patients in the adebrelimab group and 175 [75%] patients in the placebo group), decreased white blood cell count (106 [46%] and 88 [38%]), decreased platelet count (88 [38%] and 78 [34%]), and anaemia (64 [28%] and 66 [28%]). Treatment-related serious adverse events occurred in 89 (39%) patients in the adebrelimab group and 66 (28%) patients in the placebo group. Four treatment-related deaths were reported: two each in the adebrelimab group (respiratory failure and interstitial lung disease and pneumonia) and placebo group (multiple organ dysfunction and unknown cause of death).

INTERPRETATION
Adding adebrelimab to chemotherapy significantly improved overall survival with an acceptable safety profile in patients with ES-SCLC, supporting this combination as a new first-line treatment option for this population.

FUNDING
Jiangsu Hengrui Pharmaceuticals.

Prof Jie Wang, MD, Prof Caicun Zhou, MD, Prof Wenxiu Yao, PhD, Prof Qiming Wang, MD, Xuhong Min, BS, Prof Gongyan Chen, MD, et al.

© 2022 Elsevier Ltd. All rights reserved.

 

Lung cancer


BiliaryTractCancer.png
14/Jun/2022

Gemcitabine and cisplatin plus durvalumab with or without tremelimumab in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, single-centre, phase 2 study

The recent revelation that the gut microbiome, home to approximately 100 trillion microorganisms, is implicated in the development of both health and disease has spurred an exponential increase in interdisciplinary research involving gut microbiology. In all this hype, there is a need to better understand and contextualize the emerging evidence for the role of the gut microbiota in neurodegenerative and neurodevelopmental diseases, including central nervous system (CNS) malignancies. In this review, we aim to unravel the complex interactions of the microbiota-gut-brain-axis to pave a better understanding of microbiota-mediated pathogenesis, avenues for noninvasive prognosis, and therapeutic possibilities leveraging microbiota-gut-brain-axis modulations. We further provide insights of the ongoing transition from bench to bedside and discuss limitations of current approaches. Ultimately, we urge the continued development of synergistic therapeutic models with considerable consideration of the many gut-resident bacteria that will enable significant progress for the treatment of many neurological diseases.

Do-Youn Oh, MD, Kyung-Hun Lee, MD, Dae-Won Lee, MD, Jeesun Yoon, MD, Tae-Yong Kim, MD, Ju-Hee Bang, MS, et al


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07/Jun/2022

Venetoclax and acute myeloid leukaemia: an expanding new frontier

Venetoclax is an inhibitor of the anti-apoptotic B-cell lymphoma-2 (BCL-2) protein that has revolutionised the management of acute myeloid leukaemia in the past 5 years. Venetoclax in combination with azacitidine has become the new standard of care for the majority of patients with acute myeloid leukaemia who are ineligible for intensive chemotherapy due to age, fitness, or comorbidities. 1 Venetoclax has improved outcomes for this patient population and represents a valuable new treatment option in this setting. There is now interest in studying venetoclax combined with other acute myeloid leukaemia treatment regimens, including intensive chemotherapy.

Kieran D Sahasrabudhe , Alice S Mims.

© 2022 Elsevier Ltd. All rights reserved.

 

Leukemia


Alzheimer.png
31/May/2022

Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer’s disease: a longitudinal observational study

BACKGROUND
Therapeutic modulation of TREM2-dependent microglial function might provide an additional strategy to slow the progression of Alzheimer’s disease. Although studies in animal models suggest that TREM2 is protective against Alzheimer’s pathology, its effect on tau pathology and its potential beneficial role in people with Alzheimer’s disease is still unclear. Our aim was to study associations between the dynamics of soluble TREM2, as a biomarker of TREM2 signalling, and amyloid β (Aβ) deposition, tau-related pathology, neuroimaging markers, and cognitive decline, during the progression of autosomal dominant Alzheimer’s disease.

METHODS
We did a longitudinal analysis of data from the Dominantly Inherited Alzheimer Network (DIAN) observational study, which includes families with a history of autosomal dominant Alzheimer’s disease. Participants aged over 18 years who were enrolled in DIAN between Jan 1, 2009, and July 31, 2019, were categorised as either carriers of pathogenic variants in PSEN1, PSEN2, and APP genes (n=155) or non-carriers (n=93). We measured amounts of cleaved soluble TREM2 using a novel immunoassay in CSF samples obtained every 2 years from participants who were asymptomatic (Clinical Dementia Rating [CDR]=0) and annually for those who were symptomatic (CDR>0). CSF concentrations of Aβ40, Aβ42, total tau (t-tau), and tau phosphorylated on threonine 181 (p-tau) were measured by validated immunoassays. Predefined neuroimaging measurements were total cortical uptake of Pittsburgh compound B PET (PiB-PET), cortical thickness in the precuneus ascertained by MRI, and hippocampal volume determined by MRI. Cognition was measured using a validated cognitive composite (including DIAN word list test, logical memory delayed recall, digit symbol coding test [total score], and minimental status examination). We based our statistical analysis on univariate and bivariate linear mixed effects models.

FINDINGS
In carriers of pathogenic variants, a high amyloid burden at baseline, represented by low CSF Aβ42 (β=–4·28 × 10–2 [SE 0·013], p=0·0012), but not high cortical uptake in PiB-PET (β=–5·51 × 10–3 [0·011], p=0·63), was the only predictor of an augmented annual rate of subsequent increase in soluble TREM2. Augmented annual rates of increase in soluble TREM2 were associated with a diminished rate of decrease in amyloid deposition, as measured by Aβ42 in CSF (r=0·56 [0·22], p=0·011), in presymptomatic carriers of pathogenic variants, and with diminished annual rate of increase in PiB-PET (r=–0·67 [0·25], p=0·0060) in symptomatic carriers of pathogenic variants. Presymptomatic carriers of pathogenic variants with annual rates of increase in soluble TREM2 lower than the median showed a correlation between enhanced annual rates of increase in p-tau in CSF and augmented annual rates of increase in PiB-PET signal (r=0·45 [0·21], p=0·035), that was not observed in those with rates of increase in soluble TREM2 higher than the median. Furthermore, presymptomatic carriers of pathogenic variants with rates of increase in soluble TREM2 above or below the median had opposite associations between Aβ42 in CSF and PiB-PET uptake when assessed longitudinally. Augmented annual rates of increase in soluble TREM2 in presymptomatic carriers of pathogenic variants correlated with decreased cortical shrinkage in the precuneus (r=0·46 [0·22]), p=0·040) and diminished cognitive decline (r=0·67 [0·22], p=0·0020).

INTERPRETATION
Our findings in autosomal dominant Alzheimer’s disease position the TREM2 response within the amyloid cascade immediately after the first pathological changes in Aβ aggregation and further support the role of TREM2 on Aβ plaque deposition and compaction. Furthermore, these findings underpin a beneficial effect of TREM2 on Aβ deposition, Aβ-dependent tau pathology, cortical shrinkage, and cognitive decline. Soluble TREM2 could, therefore, be a key marker for clinical trial design and interpretation. Efforts to develop TREM2-boosting therapies are ongoing.

 

Estrella Morenas-Rodríguez, MD, Yan Li, PhD, Brigitte Nuscher, BSc, Nicolai Franzmeier, PhD, Prof Chengjie Xiong, PhD, Marc Suárez-Calvet, PhD, et al
© 2022 The Authors. Published by Elsevier B.V.

 

Alzheimer’s disease


BiliaryTractCancer-1.png
19/Apr/2022

Microbiota and the gut-brain-axis: Implications for new therapeutic design in the CNS

The recent revelation that the gut microbiome, home to approximately 100 trillion microorganisms, is implicated in the development of both health and disease has spurred an exponential increase in interdisciplinary research involving gut microbiology. In all this hype, there is a need to better understand and contextualize the emerging evidence for the role of the gut microbiota in neurodegenerative and neurodevelopmental diseases, including central nervous system (CNS) malignancies. In this review, we aim to unravel the complex interactions of the microbiota-gut-brain-axis to pave a better understanding of microbiota-mediated pathogenesis, avenues for noninvasive prognosis, and therapeutic possibilities leveraging microbiota-gut-brain-axis modulations. We further provide insights of the ongoing transition from bench to bedside and discuss limitations of current approaches. Ultimately, we urge the continued development of synergistic therapeutic models with considerable consideration of the many gut-resident bacteria that will enable significant progress for the treatment of many neurological diseases.

Longsha Liu, Jun R. Huh, Khalid Shah

© 2022 The Authors. Published by Elsevier B.V.


lung.png
12/Apr/2022

Expanded Lung and Colorectal Cancer Screening — Ensuring Equity and Safety under New Guidelines

In 2021, the U.S. Preventive Services Task Force (USPSTF) recommended major expansions of the populations that should undergo routine screening for lung or colorectal cancer. Both recommendations are evidence-based and, if implemented effectively, will most likely save lives. The changes were made with an eye toward reducing inequities in rates of early cancer detection among women and people who identify as Black, Indigenous, or Latinx. The guidelines, however, were released without adequate attention to how they would be implemented. Efforts to deploy complex, highly personalized screening methods using the patchwork approach that is typical of the U.S. health system could backfire, unless health care organizations, payers, and policymakers invest in preventive care infrastructure.

We believe regulatory and policy solutions are necessary to prevent unintended consequences associated with these important expansions in cancer-screening eligibility. To combat systemic racism and promote safety in ambulatory care, health care systems could collect and report data on disparities in preventive care, and they could design and deploy safety nets to ensure timely follow-up after abnormal screening results. In addition, we need policies that explicitly support equity and safety in preventive care.

When layered atop an already inequitable care delivery system, a substantial increase in the volume of preventive screening could exacerbate inequities in access based on race and other factors and lead to missed or delayed cancer diagnoses because of inadequate follow-up. Twenty million people between 45 and 49 years of age are newly eligible for routine colorectal cancer screening under the guidelines. Another 6.4 million people are newly eligible for lung cancer screening. The recommended age for starting lung cancer screening in current or former smokers dropped from 55 to 50 years, and the recommended number of pack-years of smoking history before screening is initiated dropped from 30 to 20 — which nearly doubles the population of eligible adults.1

Even before these changes, the preventive care system wasn’t functioning well. Under the previous USPSTF screening guidelines, only 5% of eligible people received lung cancer screening, and 69% of adults were up to date for colorectal cancer screening. Eligible populations now include younger people, who have historically had lower preventive-screening rates, are more racially and ethnically diverse, and are more likely to be underinsured than older people. Inequities in screening rates, cancer incidence, and mortality have persisted for decades, in part because health care systems haven’t invested in preventing systemic racism in the delivery of routine preventive care and don’t have functional systems to consistently follow up after test results indicating moderate or high cancer risk.2 Purposeful action will be required to overcome these challenges to meet the goals of the expanded USPSTF guidelines.

We believe the first step is for health care systems to create equity dashboards that report data on disparities in screening rates by race and ethnic group, sexual orientation and gender identity, and language. Because we can’t improve what we don’t measure, equity dashboards tracking key process and outcome measures should become part of the standard performance-management tools deployed throughout the U.S. health system. Our perspective could then shift from caring for only the individual patients who come into our offices to having a more complete understanding of the health of our populations, so that we can begin to systematically address the barriers our patients experience and promote the facilitators our patients need. Such an approach is critical to delivering on the potential of the new guidelines, and it will be required to begin addressing systemic racism and other inequities in our health care systems. Of course, reliable equity dashboards will not be possible unless health systems consistently ask patients to share key demographic data. This will require proactive education and outreach in close partnership with the community, as demonstrated in the “We Ask Because We Care” campaigns deployed by numerous U.S. health systems over the past decade.

Plans to address inequities in preventive care could be mandated by the Joint Commission, the National Committee for Quality Assurance, and other credentialing bodies. Health care systems will then need to focus on solutions for advancing equity, such as employing preventive care navigators, offering after-hours screening and diagnostic services to enhance access, supporting community-based screening sites, and broadly deploying programs offering home-based screening methods, such as fecal immunochemical testing or fecal DNA testing for colorectal cancer. By setting explicit goals regarding equitable access to preventive care and tracking improvement, we can avoid exacerbating health disparities and begin leveraging the USPSTF guidelines to correct long-standing inequities.

As health care systems reap the financial rewards of conducting the various diagnostic evaluations and surveillance tests that frequently follow screening, they could also be mandated to invest in a comprehensive cancer-screening safety-net program. Such a program could include registries and workflows to ensure that follow-up of abnormal test results is completed in a timely and highly reliable manner for all patients. Very few programs for colorectal cancer screening in the United States have a high-reliability system to track all patients who don’t follow up after an abnormal screening result. Although accredited facilities for lung cancer screening that bill Medicare are required to submit data to the Centers for Medicare and Medicaid Services using a registry, there’s no requirement that the registry then be employed to close the loop and ensure that follow-up occurs. An ideal cancer-screening safety-net program would track all patients for various preventive services, regardless of insurance status.

The goal of implementing equitable and safe cancer screening throughout the population will be difficult to achieve without payment and regulatory reform. Several types of reform would be beneficial. First, payers could recognize the role of health navigators as crucial members of the care team. Once navigators are funded, either by means of a fee-schedule adjustment or as part of a primary care subcapitation model, they could engage with the most marginalized patients in their communities to address social barriers to care, facilitate shared decision making, and order and schedule indicated tests. Navigators would also manage cancer-screening safety-net registries and perform patient outreach.

Second, the United States lacks the type of well-organized national screening program that has been adopted in many European countries.3 To address this gap, the federal government and state governments could enter into collaborative agreements with health care organizations to establish interoperable preventive care and safety-net registries that would allow the preventive-screening records of patients who move from one health care system or geographic region to another to be readily accessible to any clinician they see. Third, mandating that employers provide paid leave for preventive care is key to ensuring uptake among the younger populations that are included in the expanded USPSTF guidelines.4

Fourth, Congress could pass legislation that compels both commercial and government payers to immediately cover services that receive grade A or B recommendations from the USPSTF. The current 1-year lag before commercial payers must begin reimbursing providers for recommended services delays screening uptake and could therefore delay the diagnosis of new cancers. Finally, Medicaid expansion under the Affordable Care Act has driven substantial improvement in the provision of preventive care. We believe all efforts should be made to induce the 12 states that haven’t yet expanded Medicaid to do so.5

The expansion of eligibility for lung and colorectal cancer screening outlined by the USPSTF represents an opportunity for the United States to promote health equity, create safety-net registries to ensure adequate follow-up after screening, and implement regulatory and payment reform that facilitates rapid adoption of these and other preventive care guidelines. Given that we are building on a shaky foundation, all policy and regulatory levers should be pulled to generate incentives for the U.S. health system to invest in a more equitable and safer approach to preventive care.

 

Daniel M. Horn, M.D., and Jennifer S. Haas, M.D.

This article was published on January 8, 2022, at NEJM.org.

 

Lung cancer


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05/Apr/2022

Case 1-2022: A 67-Year-Old Man with Motor Neuron Disease and Odd Behaviors during Sleep

A 67-year-old man with progressive motor neuron disease was evaluated in the sleep clinic because of dream enactment, daytime sleepiness, and apnea detected on a sleep study. Four months earlier, he had fallen asleep while washing dishes; this resulted in a fall and unstable C1 spinal fracture. A diagnostic test was performed.
Aleksandar Videnovic, M.D., Suma Babu, M.B., B.S., M.P.H., Brian Zhao, M.D., Haatem M. Reda, M.D., and Jenny J. Linnoila, M.D., Ph.D.

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29/Mar/2022

Nuclear receptors in renal health and disease

As a major social and economic burden for the healthcare system, kidney diseases contribute to the constant increase of worldwide deaths. A deeper understanding of the underlying mechanisms governing the etiology, development and progression of kidney diseases may help to identify potential therapeutic targets. As a superfamily of ligand-dependent transcription factors, nuclear receptors (NRs) are critical for the maintenance of normal renal function and their dysfunction is associated with a variety of kidney diseases. Increasing evidence suggests that ligands for NRs protect patients from renal ischemia/reperfusion (I/R) injury, drug-induced acute kidney injury (AKI), diabetic nephropathy (DN), renal fibrosis and kidney cancers. In the past decade, some breakthroughs have been made for the translation of NR ligands into clinical use. This review summarizes the current understanding of several important NRs in renal physiology and pathophysiology and discusses recent findings and applications of NR ligands in the management of kidney diseases.

 Zhi-Lin Luan, Cong Zhang, Wen-Hua Min, Ying-Zhi Huang, You-Fei Guan, Xiao-Yan Zhang

© 2022 The Authors. Published by Elsevier B.V.



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