Riviste scientifiche

[Editorial] Purdah and the gagging of science

The Lancet - Sa, 27/05/2017 - 00:00
The UK's National Institute for Health Research (NIHR) has issued guidance discouraging publication of—and commentary on—NIHR-funded research for the remainder of the country's General Election purdah. Purdah is a controlled period restricting public-facing activity, intended to prevent influence on election outcomes (currently enforced from April 22 to June 8). Using purdah to control science communication is an abuse of its intended purpose, and is not part of the original code. The guidance prevents dissemination and commentary on all NIHR-funded research covering public health, social care, health-system finance and workforce, and “any other areas where there is a risk of political interpretation”.

[Editorial] National progress on antimicrobial resistance

The Lancet - Sa, 27/05/2017 - 00:00
On May 22, in the shadow of WHO Director-General elections, WHO, the Food and Agriculture Organization of the UN, and the World Organisation for Animal Health presented progress on the first open survey of countries' national action plan preparedness on Antimicrobial Resistance (AMR) at the 70th World Health Assembly.

[Comment] Financing preparedness at a national level

The Lancet - Sa, 27/05/2017 - 00:00
For far too long, the approach to pandemics has been one of panic and neglect: throwing money and resources at the problem when a serious outbreak occurs; then neglecting to sustain funding of preparedness when the news headlines move on. The result has been far too many lives lost and too much damage to human livelihoods. As news of new cases of Ebola virus disease in the DR Congo1 shows, the threat of deadly pathogens is ever present. New outbreaks will occur, but by investing in preparedness—in prevention, detection, containment, and control—their frequency and impact can be reduced.

[Comment] A new chapter for the NCD Alliance: stronger together

The Lancet - Sa, 27/05/2017 - 00:00
The 70th World Health Assembly (WHA) coincides with a milestone in the history and development of the NCD Alliance (NCDA), and a new chapter for non-communicable disease (NCD) advocacy.

[Comment] Respiratory medicine and critical care: a call for papers for ERS

The Lancet - Sa, 27/05/2017 - 00:00
The Lancet and The Lancet Respiratory Medicine would like to hear from authors of research papers in the fields of respiratory medicine and critical care, as the two journals are planning special issues to coincide with the 2017 European Respiratory Society (ERS) International Congress that will take place in Milan, Italy, on Sept 9–13, 2017.

[Comment] Offline: B-day—time to get real

The Lancet - Sa, 27/05/2017 - 00:00
It wasn't 9/11. But it felt like it. The shock of waking up on June 24, 2016, was palpable. Bewilderment and bereavement. Those of us who believed in the UK as an outward-looking European nation couldn't accept the fact that by the slimmest of majorities (51·9% vs 48·1%), Britain had voted to leave the European Union (EU). Even today, that sense of incomprehension, even trauma, is still felt by many. The Liberal Democrats have promised a final public vote on a Brexit settlement, together with an option to vote to stay in the EU.

[World Report] Scott Gottlieb sworn in to head the FDA

The Lancet - Sa, 27/05/2017 - 00:00
Scott Gottlieb becomes commissioner of the FDA, as the agency's role is threatened by an administration adverse to regulation. Susan Jaffe, The Lancet's Washington correspondent, reports.

[World Report] Data reveal state of Venezuelan health system

The Lancet - Sa, 27/05/2017 - 00:00
Epidemiological data released by the Government of Venezuela after 2 years of silence betrays how the political and economic crisis has taken a toll on the health system. Barbara Fraser reports.

[Perspectives] When Big Men ruled global health: a cautionary tale

The Lancet - Sa, 27/05/2017 - 00:00
There was a time in world health efforts when Big Men (yes, all men, European and North American) had Big Ideas, backed by money and power. They had offices in places like the World Bank, UNICEF, and the Rockefeller Foundation. And they made scientific and programmatic decisions, financing and executing schemes that affected the survival and lives of hundreds of millions of people. When their decisions were sagacious and well executed the results could be breathtaking. Millions of children might in a single year be spared death from measles, for example, thanks to a targeted immunisation campaign.

[Perspectives] Parkinson's disease: what's in the name

The Lancet - Sa, 27/05/2017 - 00:00
It is 200 years since James Parkinson (1755–1824) published his observations on slowly and differentially developing involuntary movements, which he contended constituted “the same species” of disease. In An Essay on the Shaking Palsy, first published in May, 1817, Parkinson argued that specific forms of shaking, weakness, and altered posture and gait, together amounted to a previously uncharacterised “highly afflictive” malady. He called it “the Shaking Palsy” and rendered it in the Essay once only—and pointedly in brackets—as “(Paralysis Agitans)”.

[Obituary] Helen Carty

The Lancet - Sa, 27/05/2017 - 00:00
Leading paediatric radiologist. Born in Dungarvan, Ireland, on May 12, 1944, she died in Liverpool, UK, on April 23, 2017, aged 72 years.

[Correspondence] New era for health in The Gambia?

The Lancet - Sa, 27/05/2017 - 00:00
We appreciate Andrew Green's timely World Report (Feb 18, p 684)1 on The Gambia. At this crucial moment, The Gambia and west Africa face serious public health challenges. During the recent leadership change, the Economic Community of West African States (ECOWAS) gave vital diplomatic and military support to The Gambia. Continued ECOWAS-wide collaboration could improve overall public health, particularly in response to regional issues such as climate change. Gambian leaders must repair infrastructure corroded by decades of misgovernance that has left a depleted treasury and staggering debt load.

[Correspondence] STREAM characterisation correction

The Lancet - Sa, 27/05/2017 - 00:00
In their discussion of modern management of acute myocardial infarction, Reed and colleagues (Jan 14, p 197)1 incorrectly assign our Strategic Reperfusion Early after Myocardial Infarction (STREAM) study to their section on rescue and facilitated percutaneous coronary intervention (PCI) and assert it “is not recommended”.2 STREAM was designed to address the needs of the large proportion of patients worldwide who present within 3 h of symptom onset and cannot undergo timely PCI within 1 h of first medical contact.

[Correspondence] STREAM characterisation correction – Authors' reply

The Lancet - Sa, 27/05/2017 - 00:00
We greatly appreciate the thoughtful response to our Seminar by Paul Armstrong and Frans Van de Werf. In our Seminar (Jan 14, p 197),1 we cite the Strategic Reperfusion Early after Myocardial Infarction (STREAM) study to support the statement that immediate or very early percutaneous coronary intervention (PCI) after fibrinolytic therapy has no ischaemic benefit and might cause harm by increasing bleeding.2 We feel that this is a justified application of this reference, because in STREAM, a greater proportion of patients who had intracranial haemorrhage in the fibrinolysis group was recorded compared with the proportion in the primary PCI only group (1·0% vs 0·2%; p=0·04), particularly in patients older than 75 years of age.

[Correspondence] The MERIDIAN trial: caution is needed

The Lancet - Sa, 27/05/2017 - 00:00
We congratulate Paul Griffiths and colleagues (Feb 4, p 538)1 for their Article showing that in-utero MRI changed prognostic information in at least 20% of cases of fetal brain abnormalities, and led to changes in clinical management in over a third of cases compared with ultrasound. However, we have several concerns about this Article.

[Correspondence] Artificial trachea transplantation is not ready for patients

The Lancet - Sa, 27/05/2017 - 00:00
Although one assignment of a university hospital is to develop health care, the safety of each and every patient treated can never be challenged. Therefore, I, as the Chief Executive Officer of Karolinska University Hospital, feel the urge to share the lessons learned from the world's first artificial trachea transplantations in patients.

[Correspondence] Acromegaly in Lorenzo the Magnificent, father of the Renaissance

The Lancet - Sa, 27/05/2017 - 00:00
Lorenzo de' Medici (1449–92), also known as the Magnificent, was a statesman, patron of arts, and a key supporter of the Renaissance, a cultural movement in Italy that spread throughout Europe, marking the beginning of the Early Modern Age (from the 14th to the 17th century).

[Series] Management of patients at risk of acute kidney injury

The Lancet - Sa, 27/05/2017 - 00:00
Acute kidney injury (AKI) is a multifaceted syndrome that occurs in different settings. The course of AKI can be variable, from single hit and complete recovery, to multiple hits resulting in end-stage renal disease. No interventions to improve outcomes of established AKI have yet been developed, so prevention and early diagnosis are key. Awareness campaigns and education for health-care professionals on diagnosis and management of AKI—with attention to avoidance of volume depletion, hypotension, and nephrotoxic interventions—coupled with electronic early warning systems where available can improve outcomes.

[Series] Strategies for long-term preservation of kidney graft function

The Lancet - Sa, 27/05/2017 - 00:00
Kidney transplantation has become a routine procedure in the treatment of patients with kidney failure, and requires collaboration of experts from different disciplines, such as nephrology, surgery, immunology, pathology, infectious disease medicine, cardiology, and oncology. Grafts can be obtained from deceased or living donors, with different logistical requirements and implications for long-term graft patency. 1-year graft survival rates are greater than 95% in many centres but improvement of long-term function remains a challenge.

Contribution of systemic and somatic factors to clinical response and resistance to PD-L1 blockade in urothelial cancer: An exploratory multi-omic analysis

PLoS Medicine - Ve, 26/05/2017 - 23:00

by Alexandra Snyder, Tavi Nathanson, Samuel A. Funt, Arun Ahuja, Jacqueline Buros Novik, Matthew D. Hellmann, Eliza Chang, Bulent Arman Aksoy, Hikmat Al-Ahmadie, Erik Yusko, Marissa Vignali, Sharon Benzeno, Mariel Boyd, Meredith Moran, Gopa Iyer, Harlan S. Robins, Elaine R. Mardis, Taha Merghoub, Jeff Hammerbacher, Jonathan E. Rosenberg, Dean F. Bajorin

Background

Inhibition of programmed death-ligand 1 (PD-L1) with atezolizumab can induce durable clinical benefit (DCB) in patients with metastatic urothelial cancers, including complete remissions in patients with chemotherapy refractory disease. Although mutation load and PD-L1 immune cell (IC) staining have been associated with response, they lack sufficient sensitivity and specificity for clinical use. Thus, there is a need to evaluate the peripheral blood immune environment and to conduct detailed analyses of mutation load, predicted neoantigens, and immune cellular infiltration in tumors to enhance our understanding of the biologic underpinnings of response and resistance.

Methods and findings

The goals of this study were to (1) evaluate the association of mutation load and predicted neoantigen load with therapeutic benefit and (2) determine whether intratumoral and peripheral blood T cell receptor (TCR) clonality inform clinical outcomes in urothelial carcinoma treated with atezolizumab. We hypothesized that an elevated mutation load in combination with T cell clonal dominance among intratumoral lymphocytes prior to treatment or among peripheral T cells after treatment would be associated with effective tumor control upon treatment with anti-PD-L1 therapy. We performed whole exome sequencing (WES), RNA sequencing (RNA-seq), and T cell receptor sequencing (TCR-seq) of pretreatment tumor samples as well as TCR-seq of matched, serially collected peripheral blood, collected before and after treatment with atezolizumab. These parameters were assessed for correlation with DCB (defined as progression-free survival [PFS] >6 months), PFS, and overall survival (OS), both alone and in the context of clinical and intratumoral parameters known to be predictive of survival in this disease state.Patients with DCB displayed a higher proportion of tumor-infiltrating T lymphocytes (TIL) (n = 24, Mann-Whitney p = 0.047). Pretreatment peripheral blood TCR clonality below the median was associated with improved PFS (n = 29, log-rank p = 0.048) and OS (n = 29, log-rank p = 0.011). Patients with DCB also demonstrated more substantial expansion of tumor-associated TCR clones in the peripheral blood 3 weeks after starting treatment (n = 22, Mann-Whitney p = 0.022). The combination of high pretreatment peripheral blood TCR clonality with elevated PD-L1 IC staining in tumor tissue was strongly associated with poor clinical outcomes (n = 10, hazard ratio (HR) (mean) = 89.88, HR (median) = 23.41, 95% CI [2.43, 506.94], p(HR > 1) = 0.0014). Marked variations in mutation loads were seen with different somatic variant calling methodologies, which, in turn, impacted associations with clinical outcomes. Missense mutation load, predicted neoantigen load, and expressed neoantigen load did not demonstrate significant association with DCB (n = 25, Mann-Whitney p = 0.22, n = 25, Mann-Whitney p = 0.55, and n = 25, Mann-Whitney p = 0.29, respectively). Instead, we found evidence of time-varying effects of somatic mutation load on PFS in this cohort (n = 25, p = 0.044). A limitation of our study is its small sample size (n = 29), a subset of the patients treated on IMvigor 210 (NCT02108652). Given the number of exploratory analyses performed, we intend for these results to be hypothesis-generating.

Conclusions

These results demonstrate the complex nature of immune response to checkpoint blockade and the compelling need for greater interrogation and data integration of both host and tumor factors. Incorporating these variables in prospective studies will facilitate identification and treatment of resistant patients.

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