These studies were undertaken to determine the effect, if any, of treatment for cancer diagnosed during childhood or adolescence on ovarian function and reproductive outcomes. We reviewed the ...frequency of acute ovarian failure, premature menopause, live birth, stillbirth, spontaneous and therapeutic abortion and birth defects in the participants in the Childhood Cancer Survivor Study (CCSS). Acute ovarian failure (AOF) occurred in 6.3% of eligible survivors. Exposure of the ovaries to high-dose radiation (especially over 10 Gy), alkylating agents and procarbazine, at older ages, were significant risk factors for AOF. Premature nonsurgical menopause (PM) occurred in 8% of participants versus 0.8% of siblings (rate ratio = 13.21; 95% CI, 3.26 to 53.51; P < .001). Risk factors for PM included attained age, exposure to increasing doses of radiation to the ovaries, increasing alkylating agent score, and a diagnosis of Hodgkin's lymphoma. One thousand two hundred twenty-seven male survivors reported they sired 2,323 pregnancies, and 1,915 female survivors reported 4,029 pregnancies. Offspring of women who received uterine radiation doses of more than 5 Gy were more likely to be small for gestational age (birthweight < 10 percentile for gestational age; 18.2% v 7.8%; odds ratio = 4.0; 95% CI, 1.6 to 9.8; P = .003). There were no differences in the proportion of offspring with simple malformations, cytogenetic syndromes, or single-gene defects. These studies demonstrated that women treated with pelvic irradiation and/or increasing alkylating agent doses were at risk for acute ovarian failure, premature menopause, and small-for-gestational-age offspring. There was no evidence for an increased risk of congenital malformations. Survivors should be generally reassured although some women have to consider their potentially shortened fertile life span in making educational and career choices.
Background
Epidermal growth factor receptor (EGFR) mutation positive (M+) non‐small cell lung cancer (NSCLC) is emerging as an important subtype of lung cancer comprising 10% to 15% of non‐squamous ...tumours. This subtype is more common in women than men and is less associated with smoking.
Objectives
To assess the clinical effectiveness of single ‐agent or combination EGFR therapies used in the first‐line treatment of people with locally advanced or metastatic EGFR M+ NSCLC compared with other cytotoxic chemotherapy (CTX) agents used alone or in combination, or best supportive care (BSC). The primary outcome was overall survival. Secondary outcomes included progression‐free survival, response rate, toxicity, and quality of life.
Search methods
We conducted electronic searches of the the Cochrane Register of Controlled Trials (CENTRAL) (2015, Issue 6), MEDLINE (1946 to 1 June 2015), EMBASE (1980 to 1 June 2015), and ISI Web of Science (1899 to 1 June 2015). We also searched the conference s of the American Society for Clinical Oncology and the European Society for Medical Oncology (1 June 2015); Evidence Review Group submissions to the National Institute for Health and Care Excellence; and the reference lists of retrieved articles.
Selection criteria
Parallel randomised controlled trials comparing EGFR‐targeted agents (alone or in combination with cytotoxic agents or BSC) with cytotoxic chemotherapy (single or doublet) or BSC in chemotherapy‐naive patients with locally advanced or metastatic (stage IIIB or IV) EGFR M+ NSCLC unsuitable for treatment with curative intent.
Data collection and analysis
Two review authors independently identified articles, extracted data, and carried out the 'Risk of bias' assessment. We conducted meta‐analyses using a fixed‐effect model unless there was substantial heterogeneity, in which case we also performed a random‐effects analysis as a sensitivity analysis.
Main results
Nineteen trials met the inclusion criteria. Seven of these exclusively recruited people with EGFR M+ NSCLC; the remainder recruited a mixed population and reported results for people with EGFR M+ NSCLC as subgroup analyses. The number of participants with EGFR M+ tumours totalled 2317, of whom 1700 were of Asian origin.
Overall survival (OS) data showed inconsistent results between the included trials that compared EGFR‐targeted treatments against cytotoxic chemotherapy or placebo.
Erlotinib was the intervention treatment used in eight trials, gefitinib in seven trials, afatinib in two trials, and cetuximab in two trials. The findings of one trial (FASTACT 2) did report a statistically significant OS gain for participants treated with erlotinib plus cytotoxic chemotherapy when compared to cytotoxic chemotherapy alone, but this result was based on a small number of participants (n = 97). For progression‐free survival (PFS), a pooled analysis of 3 trials (n = 378) demonstrated a statistically significant benefit for erlotinib compared with cytotoxic chemotherapy (hazard ratio (HR) 0.30; 95% confidence interval (CI) 0.24 to 0.38).
In a pooled analysis with 491 participants administered gefitinib, 2 trials (IPASS and NEJSG) demonstrated a statistically significant PFS benefit of gefitinib compared with cytotoxic chemotherapy (HR 0.39; 95% CI 0.32 to 0.48).
Afatinib (n = 709) showed a statistically significant PFS benefit when compared with chemotherapy in a pooled analysis of 2 trials (HR 0.42; 95% CI 0.34 to 0.53).
Commonly reported grade 3/4 adverse events for afatinib, erlotinib, and gefitinib monotherapy were rash and diarrhoea. Myelosuppression was consistently worse in the chemotherapy arms, fatigue and anorexia were also associated with some chemotherapies.
No statistically significant PFS or OS benefit for cetuximab plus cytotoxic chemotherapy (n = 81) compared to chemotherapy alone was reported in either of the two trials.
Six trials reported on quality of life and symptom improvement using different methodologies. For each of erlotinib, gefitinib, and afatinib, 2 trials showed improvement in one or more indices for the tyrosine‐kinase inhibitor (TKI) compared to chemotherapy.
The quality of evidence was high for the comparisons of erlotinib and gefitinib with cytotoxic chemotherapy and for the comparison of afatinib with cytotoxic chemotherapy.
Authors' conclusions
Erlotinib, gefitinib, and afatinib are all active agents in EGFR M+ NSCLC patients, and demonstrate an increased tumour response rate and prolonged progression‐free survival compared to cytotoxic chemotherapy. We also found a beneficial effect of the TKI compared to cytotoxic chemotherapy. However, we found no increase in overall survival for the TKI when compared with standard chemotherapy. Cytotoxic chemotherapy is less effective in EGFR M+ NSCLC than erlotinib, gefitinib, or afatinib and is associated with greater toxicity. There were no data supporting the use of monoclonal antibody therapy.
Planar perovskite solar cells obtained by low‐temperature solution processing are of great promise, given a high compatibility with flexible substrates and perovskite‐based tandem devices, whilst ...benefitting from relatively simple manufacturing methods. However, ionic defects at surfaces usually cause detrimental carrier recombination, which links to one of dominant losses in device performance, slow transient responses, and notorious hysteresis. Here, it is shown that several different types of ionic defects can be simultaneously passivated by simple inorganic binary alkaline halide salts with their cations and anions. Compared to previous literature reports, this work demonstrates a promising passivation technology for perovskite solar cells. The efficient defect passivation significantly suppresses the recombination at the SnO2/perovskite interface, contributing to an increase in the open‐circuit voltage, the fast response of steady‐state efficiency, and the elimination of hysteresis. By this strong leveraging of multiple‐element passivation, low‐temperature‐processed, planar‐structured perovskite solar cells of 20.5% efficiencies, having negligible hysteresis, are obtained. Moreover, this defect‐passivation enhances the stability of solar cells with efficiency beyond 20%, retaining 90% of their initial performance after 30 d. This approach aims at developing the concept of defect engineering, which can be expanded to multiple‐element passivation from monoelement counterparts using simple and low‐cost inorganic materials.
This paper highlights the potential of simple and cheap inorganic materials for the improvement of efficiency and durability of organic–inorganic hybrid perovskite devices. Upon using a KCl passivation layer between the SnO2 and the perovskite absorber, the efficiencies of low‐temperature‐processed planar‐structural perovskite solar cells significantly rise up to 20.5% with enhanced open‐circuit voltage and the notorious hysteresis fully disappears.
Background
Epidermal growth factor receptor (EGFR) mutation positive (M+) non‐small cell lung cancer (NSCLC) is an important subtype of lung cancer comprising 10% to 15% of non‐squamous tumours. This ...subtype is more common in women than men, is less associated with smoking, but occurs at a younger age than sporadic tumours.
Objectives
To assess the clinical effectiveness of single‐agent or combination EGFR therapies used in the first‐line treatment of people with locally advanced or metastatic EGFR M+ NSCLC compared with other cytotoxic chemotherapy (CTX) agents used alone or in combination, or best supportive care (BSC). The primary outcomes were overall survival and progression‐free survival. Secondary outcomes included response rate, symptom palliation, toxicity, and health‐related quality of life.
Search methods
We conducted electronic searches of the Cochrane Register of Controlled Trials (CENTRAL) (2020, Issue 7), MEDLINE (1946 to 27th July 2020), Embase (1980 to 27th July 2020), and ISI Web of Science (1899 to 27th July 2020). We also searched the conference s of the American Society for Clinical Oncology and the European Society for Medical Oncology (July 2020); Evidence Review Group submissions to the National Institute for Health and Care Excellence; and the reference lists of retrieved articles.
Selection criteria
Parallel‐group randomised controlled trials comparing EGFR‐targeted agents (alone or in combination with cytotoxic agents or BSC) with cytotoxic chemotherapy (single or doublet) or BSC in chemotherapy‐naive patients with locally advanced or metastatic (stage IIIB or IV) EGFR M+ NSCLC unsuitable for treatment with curative intent.
Data collection and analysis
Two review authors independently identified articles, extracted data, and carried out the 'Risk of bias' assessment. We conducted meta‐analyses using a fixed‐effect model unless there was substantial heterogeneity, in which case we also performed a random‐effects analysis as a sensitivity analysis.
Main results
Twenty‐two trials met the inclusion criteria. Ten of these exclusively recruited people with EGFR M+ NSCLC; the remainder recruited a mixed population and reported results for people with EGFR M+ NSCLC as subgroup analyses. The number of participants with EGFR M+ tumours totalled 3023, of whom approximately 2563 were of Asian origin.
Overall survival (OS) data showed inconsistent results between the included trials that compared EGFR‐targeted treatments against cytotoxic chemotherapy or placebo.
Erlotinib was used in eight trials, gefitinib in nine trials, afatinib in two trials, cetuximab in two trials, and icotinib in one trial. The findings of FASTACT 2 suggested a clinical benefit for OS for participants treated with erlotinib plus cytotoxic chemotherapy when compared to cytotoxic chemotherapy alone, as did the Han 2017 trial for gefitinib plus cytotoxic chemotherapy, but both results were based on a small number of participants (n = 97 and 122, respectively).
For progression‐free survival (PFS), a pooled analysis of four trials showed evidence of clinical benefit for erlotinib compared with cytotoxic chemotherapy (hazard ratio (HR) 0.31; 95% confidence interval (CI) 0.25 to 0.39 ; 583 participants ; high‐certainty evidence). A pooled analysis of two trials of gefitinib versus paclitaxel plus carboplatin showed evidence of clinical benefit for PFS for gefitinib (HR 0.39; 95% CI 0.32 to 0.48 ; 491 participants high‐certainty evidence), and a pooled analysis of two trials of gefitinib versus pemetrexed plus carboplatin with pemetrexed maintenance also showed evidence of clinical benefit for PFS for gefitinib (HR 0.59; 95% CI 0.46 to 0.74, 371 participants ; moderate‐certainty evidence). Afatinib showed evidence of clinical benefit for PFS when compared with chemotherapy in a pooled analysis of two trials (HR 0.42; 95% CI 0.34 to 0.53, 709 participants high‐certainty evidence). All but one small trial showed a corresponding improvement in response rate with tyrosine‐kinase inhibitor (TKI) compared to chemotherapy.
Commonly reported grade 3/4 adverse events associated with afatinib, erlotinib, gefitinib and icotinib monotherapy were rash and diarrhoea. Myelosuppression was consistently worse in the chemotherapy arms; fatigue and anorexia were also associated with some chemotherapies.
Seven trials reported on health‐related quality of life and symptom improvement using different methodologies. For each of erlotinib, gefitinib, and afatinib, two trials showed improvement in one or more indices for the TKI compared to chemotherapy.
The quality of evidence was high for the comparisons of erlotinib and gefitinib with cytotoxic chemotherapy and for the comparison of afatinib with cytotoxic chemotherapy.
Authors' conclusions
Erlotinib, gefitinib, afatinib and icotinib are all active agents in EGFR M+ NSCLC patients, and demonstrate an increased tumour response rate and prolonged PFS compared to cytotoxic chemotherapy. We found a beneficial effect of the TKI compared to cytotoxic chemotherapy in adverse effect and health‐related quality of life. We found limited evidence for increased OS for the TKI when compared with standard chemotherapy, but the majority of the included trials allowed participants to switch treatments on disease progression, which will have a confounding effect on any OS analysis. Single agent‐TKI remains the standard of care and the benefit of combining a TKI and chemotherapy remains uncertain as the evidence is based on small patient numbers. Cytotoxic chemotherapy is less effective in EGFR M+ NSCLC than erlotinib, gefitinib, afatinib or icotinib and is associated with greater toxicity. There are no data supporting the use of monoclonal antibody therapy. Icotinib is not available outside China.
The past decade has witnessed growing scientific and commercial interest in the identification of bioactive oral compounds that mimic or potentiate the effects of exercise, so‐called ‘exercise pills’ ...or ‘exercise mimetics.’ These compounds have, to date, typically targeted skeletal muscle in an attempt to stimulate some of the adaptations to exercise induced by endurance training. Accordingly, they fail to impart many of the broad health protecting effects of exercise that are seen in tissues and organs other than skeletal muscle. In the context that multiple integrative regulatory and often redundant pathways have evolved to detect and respond to human movement, here we consider the complex challenges of designing a pill that might mimic the extensive range of exercise benefits. In particular, we consider the limits of the current ‘myocentric’ paradigm given the wide‐ranging array of impacts that exercise exerts on atherosclerosis and the cardiovascular system. We discuss the validity and limitations of the concept that low dose cardiovascular polypills, already in large scale trials, may represent one form of cardiovascular exercise mimetic. Finally, given that some calls for an exercise pill stem from a response to the perceived failure of expert advice, evidence‐based guidelines and current public health approaches, we explore possible strategies that might address the global rise in inactivity. In the event that a broad spectrum exercise mimetic might ever be developed, we discuss some generic issues related to adoption and adherence of therapeutic interventions.
figure legend Voluntary, dynamic exercise provokes widespread perturbations in multiple tissues and organs (left). In an attempt to mimic the effects of exercise training, compounds have focused on selected skeletal muscle signalling pathways (right), ignoring many of the health‐protecting effects of exercise in other organs and tissues, such as the heart.
Summary Background The reproductive implications of mutagenic treatments given to children with cancer are not clear. By studying the risk of untoward pregnancy outcomes, we indirectly assessed the ...risk of transmission of germline damage to the offspring of survivors of childhood cancer who were given radiotherapy and chemotherapy. Methods We did a retrospective cohort analysis, within the Childhood Cancer Survivor Study (CCSS), of the risk of stillbirth and neonatal death among the offspring of men and women who had survived childhood cancer. Patients in CCSS were younger than 21 years at initial diagnosis of an eligible cancer, were treated at 25 US institutions and one Canadian institution, and had survived for at least 5 years after diagnosis. We quantified the chemotherapy given to patients, and the preconception radiation doses to the testes, ovaries, uterus, and pituitary gland, and related these to the risk of stillbirth or neonatal death using Poisson regression analysis. Findings Among 1148 men and 1657 women who had survived childhood cancer, there were 4946 pregnancies. Irradiation of the testes (16 1% of 1270; adjusted relative risk 0·8 95% CI 0·4–1·6; mean dose 0·53 Gy SD 1·40) and pituitary gland (17 3% of 510, 1·1 0·5–2·4 for more than 20·00 Gy; mean dose 10·20 Gy 13·0 for women), and chemotherapy with alkylating drugs (26 2% of 1195 women, 0·9 0·5–1·5; ten 1% of 732 men, 1·2 0·5–2·5) were not associated with an increased risk of stillbirth or neonatal death. Uterine and ovarian irradiation significantly increased risk of stillbirth and neonatal death at doses greater than 10·00 Gy (five 18% of 28, 9·1 3·4–24·6). For girls treated before menarche, irradiation of the uterus and ovaries at doses as low as 1·00–2·49 Gy significantly increased the risk of stillbirth or neonatal death (three 4% of 69, 4·7 1·2–19·0). Interpretation Our findings do not support concern about heritable genetic changes affecting the risk of stillbirth and neonatal death in the offspring of men exposed to gonadal irradiation. However, uterine and ovarian irradiation had serious adverse effects on the offspring that were probably related to uterine damage. Careful management is warranted of pregnancies in women given high doses of pelvic irradiation before puberty. Funding Westlakes Research Institute, National Cancer Institute, and Children's Cancer Research Fund.
Single-center studies have reported an association between early (before day 100) cytomegalovirus (CMV) reactivation and decreased incidence of relapse for acute myeloid leukemia (AML) following ...allogeneic hematopoietic cell transplantation. To substantiate these preliminary findings, the Center for International Blood and Marrow Transplant Research (CIBMTR) Database was interrogated to analyze the impact of CMV reactivation on hematologic disease relapse in the current era. Data from 9469 patients transplanted with bone marrow or peripheral blood between 2003 and 2010 were analyzed according to 4 disease categories: AML (n = 5310); acute lymphoblastic leukemia (ALL, n = 1883); chronic myeloid leukemia (CML, n = 1079); and myelodysplastic syndrome (MDS, n = 1197). Median time to initial CMV reactivation was 41 days (range, 1-362 days). CMV reactivation had no preventive effect on hematologic disease relapse irrespective of diagnosis. Moreover, CMV reactivation was associated with higher nonrelapse mortality relative risk RR among disease categories ranged from 1.61 to 1.95 and P values from .0002 to <.0001; 95% confidence interval CI, 1.14-2.61). As a result, CMV reactivation was associated with lower overall survival for AML (RR = 1.27; 95% CI, 1.17-1.38; P <.0001), ALL (RR = 1.46; 95% CI, 1.25-1.71; P <.0001), CML (RR = 1.49; 95% CI, 1.19-1.88; P = .0005), and MDS (RR = 1.31; 95% CI, 1.09-1.57; P = .003). In conclusion, CMV reactivation continues to remain a risk factor for poor posttransplant outcomes and does not seem to confer protection against hematologic disease relapse.
•Cytomegalovirus after bone marrow transplantation remains associated with lower survival but not prevention of leukemia relapse.
Lung cancer kills more people than any other cancer in the UK (5-year survival < 13%). Early diagnosis can save lives. The USA-based National Lung Cancer Screening Trial reported a 20% relative ...reduction in lung cancer mortality and 6.7% all-cause mortality in low-dose computed tomography (LDCT)-screened subjects.
To (1) analyse LDCT lung cancer screening in a high-risk UK population, determine optimum recruitment, screening, reading and care pathway strategies; and (2) assess the psychological consequences and the health-economic implications of screening.
A pilot randomised controlled trial comparing intervention with usual care. A population-based risk questionnaire identified individuals who were at high risk of developing lung cancer (≥ 5% over 5 years).
Thoracic centres with expertise in lung cancer imaging, respiratory medicine, pathology and surgery: Liverpool Heart & Chest Hospital, Merseyside, and Papworth Hospital, Cambridgeshire.
Individuals aged 50-75 years, at high risk of lung cancer, in the primary care trusts adjacent to the centres.
A thoracic LDCT scan. Follow-up computed tomography (CT) scans as per protocol. Referral to multidisciplinary team clinics was determined by nodule size criteria.
Population-based recruitment based on risk stratification; management of the trial through web-based database; optimal characteristics of CT scan readers (radiologists vs. radiographers); characterisation of CT-detected nodules utilising volumetric analysis; prevalence of lung cancer at baseline; sociodemographic factors affecting participation; psychosocial measures (cancer distress, anxiety, depression, decision satisfaction); and cost-effectiveness modelling.
A total of 247,354 individuals were approached to take part in the trial; 30.7% responded positively to the screening invitation. Recruitment of participants resulted in 2028 in the CT arm and 2027 in the control arm. A total of 1994 participants underwent CT scanning: 42 participants (2.1%) were diagnosed with lung cancer; 36 out of 42 (85.7%) of the screen-detected cancers were identified as stage 1 or 2, and 35 (83.3%) underwent surgical resection as their primary treatment. Lung cancer was more common in the lowest socioeconomic group. Short-term adverse psychosocial consequences were observed in participants who were randomised to the intervention arm and in those who had a major lung abnormality detected, but these differences were modest and temporary. Rollout of screening as a service or design of a full trial would need to address issues of outreach. The health-economic analysis suggests that the intervention could be cost-effective but this needs to be confirmed using data on actual lung cancer mortality.
The UK Lung Cancer Screening (UKLS) pilot was successfully undertaken with 4055 randomised individuals. The data from the UKLS provide evidence that adds to existing data to suggest that lung cancer screening in the UK could potentially be implemented in the 60-75 years age group, selected via the Liverpool Lung Project risk model version 2 and using CT volumetry-based management protocols.
The UKLS data will be pooled with the NELSON (Nederlands Leuvens Longkanker Screenings Onderzoek: Dutch-Belgian Randomised Lung Cancer Screening Trial) and other European Union trials in 2017 which will provide European mortality and cost-effectiveness data. For now, there is a clear need for mortality results from other trials and further research to identify optimal methods of implementation and delivery. Strategies for increasing uptake and providing support for underserved groups will be key to implementation.
Current Controlled Trials ISRCTN78513845.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 40. See the NIHR Journals Library website for further project information.
A kesterite Cu2ZnSnS4 thin film solar cell with efficiency of over 9% is obtained by utilizing Zn1–xCdxS film as a replacement to traditional CdS buffer layer. Zn1–xCdxS film can optimize the ...conduction band offset between Cu2ZnSnS4 absorber and buffer, forming a minor positive conduction band alignment, thereby alleviating the recombination significantly and improving the open circuit voltage and fill factor efficiently.
Sulfurization with various atmosphere and postheat treatments has been reported for earth abundant kesterite Cu2ZnSnS4 (CZTS) preparation as cost‐effective material for next‐generation solar cells. A ...full understanding of the nanoscale microstructure and chemistry of CZTS/CdS interface obtained from these different fabrication routes is currently lacking, yet is critical to developing optimal processing routes for high‐performance kesterite solar cells. Here, the first detailed investigation of the interfacial microstructure and chemistry of CdS/Cu2ZnSnS4 heterojunctions is presented. For CZTS obtained from sulfurization in a sulfur‐only atmosphere where highly defective surfaces are present, air annealing followed by etching in the initial stage of chemical bath deposition (CBD) process can effectively eliminate interfacial defects and allow the epitaxial growth of CBD‐CdS, improving the minority lifetime, open circuit voltage (VOC), and fill factor (FF) of the devices, while blocking Cd diffusion and deteriorating short circuit current (Jsc). For CZTS from sulfurization in a combined sulfur and SnS atmosphere where CBD‐CdS can directly epitaxially grow on CZTS and Cd‐diffusion is clearly observed, associated devices show the longest lifetime and the highest efficiency of 8.76%. Epitaxial growth of CdS and Cd diffusion into CZTS are found to be two crucial features minimizing interfacial recombination and achieving high‐efficiency devices. This will not only enhance the understanding of the device structure and physics of kesterite based solar cells, but also provide an effective way for designing other chalcogenide heterojunction solar cells.
The interfacial microstructure and chemistry of CdS/Cu2ZnSnS4 (CZTS) heterojunction in kesterite Cu2ZnSnS4 solar cells are investigated. The correlations between interfacial properties of CZTS/CdS and film growth processes as well as associated device performance have been revealed. Epitaxial growth of CdS and Cd diffusion into CZTS are found to be two crucial features minimizing interfacial recombination and achieving high‐efficiency device.
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