Intensified therapies improve survival and identification of novel prognostic factors for placental-site and epithelioid trophoblastic tumours.

BACKGROUND: Placental-site trophoblastic (PSTT) and epithelioid trophoblastic tumours (ETT) are the rarest malignant forms of gestational trophoblastic disease (GTD). Our prior work demonstrated that an interval of ≥48 months from the antecedent pregnancy was associated with 100% death rate, independent of the stage. Here, we assess whether modified treatments for these patients have increased survival and identify new prognostic factors. METHODS: The United Kingdom GTD database was screened to identify all PSTT/ETT cases diagnosed between 1973 and 2014. Data and survival outcomes from our prior patient cohort (1976-2006) were compared to our new modern cohort (2007-2014), when intensified treatments were introduced. RESULTS: Of 54,743 GTD patients, 125 (0.23%) were diagnosed with PSTT and/or ETT. Probability of survival at 5 and 10 years following treatment was 80% (95% CI 72.8-87.6%) and 75% (95% CI 66.3-84.3%), respectively. Univariate analysis identified five prognostic factors for reduced overall survival (age, FIGO stage, time since antecedent pregnancy, hCG level, mitotic index) of which stage IV disease (HR 6.18, 95% CI 1.61-23.81, p = 0.008) and interval ≥48 months since antecedent pregnancy (HR 14.57, 95% CI 4.17-50.96, p < 0.001) were most significant on multivariable analysis. No significant differences in prognostic factors were seen between the old and new patient cohort. However, the new cohort received significantly more cisplatin-based and high-dose chemotherapy, and patients with an interval ≥48 months demonstrated an improved median overall survival (8.3 years, 95% CI 1.53-15.1, versus 2.6 years, 95% CI 0.73-4.44, p = 0.·005). CONCLUSION: PSTT/ETT with advanced FIGO stage or an interval ≥48 months from their last known pregnancy have poorer outcomes. Platinum-based and high-dose chemotherapy may help to improve survival in poor-prognosis patients.

The relationship between smoking and quality of life in advanced lung cancer patients: a prospective longitudinal study.

PURPOSE: Smoking is a major cause of lung cancer, and continued smoking may compromise treatment efficacy and quality of life (health-related quality of life (HRQoL)) in patients with advanced lung cancer. Our aims were to determine (i) preference for treatments which promote quality over length of life depending on smoking status, (ii) the relationship between HRQoL and smoking status at diagnosis (T1), after controlling for demographic and clinical variables, and (iii) changes in HRQoL 6 months after diagnosis (T2) depending on smoking status. METHODS: Two hundred ninety-six patients with advanced lung cancer were given questionnaires to assess HRQoL (EORTC QLQ-C30), time-trade-off for life quality versus quantity (QQQ) and smoking history (current, former or never smoker) at diagnosis (T1) and 6 months later (T2). Medical data were extracted from case records. RESULTS: Questionnaires were returned by 202 (68.2 %) patients at T1 and 114 (53.3 %) at T2. Patients favoured treatments that would enhance quality of life over increased longevity. Those who continued smoking after diagnosis reported worse HRQoL than former smokers or those who never smoked. Smoking status was a significant independent predictor of coughing in T1 (worse in smokers) and cognitive functioning in T2 (better in never smokers). CONCLUSIONS: Smoking by patients with advanced lung cancer is associated with worse symptoms on diagnosis and poorer HRQoL for those who continue smoking. The results have implications to help staff explain the consequences of smoking to patients.

Mental health burden for NHS healthcare staff during the COVID-19 pandemic: First results of a longitudinal survey.

Background: The current investigation aimed to assess the mental health burden on healthcare workers during the early stages of the COVID-19 pandemic. Methods: A link to an online survey was sent to an estimate of 18,100 employees of Sheffield Teaching Hospitals NHS Foundation Trust (STH) who had access to email. The survey was completed between 2nd and June 12, 2020.1390 healthcare workers (medical, nursing, administrative and other professions) participated in the first survey. Data from a general population sample (n = 2025) was used for comparison. Severity of somatic symptoms was measured by the PHQ-15. Severity and probable diagnosis of depression, anxiety, and PTSD were measured by the PHQ-9, GAD-7, and ITQ. Linear and logistic regressions were performed to determine if population group predicted the severity of mental health outcomes, and probable diagnosis of depression, anxiety, and PTSD. Additionally, ANCOVAs were performed to compare mental health outcomes between occupational roles in HCWs. Analysis was performed using SPSS. Findings: Healthcare workers are more likely to experience greater severity of somatic symptoms, as well as severity and probable diagnosis of depression and anxiety, compared to the general population, but not increased traumatic stress symptoms. Scientific and technical, nursing and admin staff were more likely to experience worse mental health outcomes, compared to medical staff. Interpretation: The COVID-19 pandemic has led to increased mental health burden in some, but not all healthcare workers during the first acute phase of the pandemic. The findings from the current investigation provide valuable insights into which healthcare workers are particularly vulnerable to developing adverse mental health outcomes during and after a pandemic.

Supportive use of digital technologies during transition to adult healthcare for young people with long-term conditions, focusing on Type 1 diabetes mellitus: A scoping review.

Type 1 diabetes mellitus (T1DM) is the second most common chronic or long-term condition (LTC) affecting young people (YP); when transitioning from paediatric to adult healthcare, young people with LTCs such as T1DM are expected to self-manage medication, diet and clinical appointments. This scoping review aimed to analyse research examining ways digital health technologies were used to support YP with LTCs during transition from paediatric to adult healthcare and to establish YP's needs, experiences and challenges when transitioning. We aimed to identify knowledge gaps and inform development of a novel chatbot with components such as avatars and linked videos to help YP with T1DM gain self-management confidence and competence during transition. Nineteen studies identified through searching five electronic databases were included in this review. A combination of digital health technologies was used to support transition of YP with LTCs to adult healthcare. Barriers to successful transition were reported and YP described the importance of social relationships and transition readiness and expressed the need for individualised interventions that acknowledge social factors such as work and college. No supportive chatbots with components to help YP with T1DM were identified. This contribution will inform future development and evaluation of such a chatbot.

Prevention of anastrozole-induced bone loss with monthly oral ibandronate during adjuvant aromatase inhibitor therapy for breast cancer.

PURPOSE: The aromatase inhibitor anastrozole is a highly effective well-tolerated treatment for postmenopausal endocrine-responsive breast cancer. However, its use is associated with accelerated bone loss and an increase in fracture risk. The ARIBON trial is a double-blind, randomized, placebo-controlled study designed to evaluate the impact of bisphosphonate treatment on bone mineral density (BMD) in women taking anastrozole. EXPERIMENTAL DESIGN: BMD was assessed in 131 postmenopausal, surgically treated women with early breast cancer at two U.K. centers. Of these, 50 patients had osteopenia (T score -1.0 to -2.5) at either the hip or lumbar spine. All patients were treated with anastrozole 1 mg once a day and calcium and vitamin D supplementation. In addition, osteopenic patients were randomized to receive either treatment with ibandronate 150 mg orally every month or placebo. RESULTS: After 2 years, osteopenic patients treated with ibandronate gained +2.98% (range -8.9, +19.9) and +0.60% (range -9.0, +6.9) at the lumbar spine and hip, respectively. Patients treated with placebo, however, lost -3.22% (range -16.0, +4.3) at the lumbar spine and -3.90% (range -12.3, +7.2) at the hip. The differences between the two treatment arms were statistically significant at both sites (P < 0.01). At 12 months, urinary n-telopeptide, serum c-telopeptide, and serum bone-specific alkaline phosphatase levels declined in patients receiving ibandronate (30.9%, 26.3%, and 22.8%, respectively) and increased in those taking placebo (40.3%, 34.9%, and 37.0%, respectively). CONCLUSIONS: Monthly oral ibandronate improves bone density and normalizes bone turnover in patients treated with anastrozole.

An exploratory randomized-controlled trial of the efficacy of the Src-kinase inhibitor saracatinib as a novel analgesic for cancer-induced bone pain.

Pain is a major symptom of bone metastases from advanced cancer and represents a clinical challenge to treat effectively. Basic neurobiology in preclinical animal models implicates enhanced sensory processing in the central nervous system, acting through N-methyl-D-aspartate (NMDA) glutamate receptors, as an important mechanism underpinning persistent pain. The non-receptor tyrosine kinase Src is thought to act as a hub for regulating NMDA receptor activity and the orally available Src inhibitor saracatinib has shown promise as a potential analgesic in recent animal studies. Here we tested the efficacy of saracatinib as a novel analgesic in an exploratory phase II randomized controlled trial on cancer patients with painful bone metastases. Twelve patients completed the study, with 6 receiving saracatinib 125 mg/day for 28 days and 6 receiving placebo. Pharmacokinetic measurements confirmed appropriate plasma levels of drug in the saracatinib-treated group and Src inhibition was achieved clinically by a significant reduction in the bone resorption biomarker serum cross-linked C-terminal telopeptide of type I collagen. Differences between the saracatinib and placebo groups self-reported pain scores, measured using the short form of the Brief Pain Inventory, were not clinically significant after 4 weeks of treatment. There was also no change in consumption of maintenance analgesia in the saracatinib-treated group and no improvement in Quality-of-Life scores. The data were insufficient to demonstrate saracatinib has efficacy as analgesic, although it may have a role as an anti-bone resorptive agent.

Genetic Risk Can Be Decreased: Quitting Smoking Decreases and Delays Lung Cancer for Smokers With High and Low CHRNA5 Risk Genotypes - A Meta-Analysis.

BACKGROUND: Recent meta-analyses show that individuals with high risk variants in CHRNA5 on chromosome 15q25 are likely to develop lung cancer earlier than those with low-risk genotypes. The same high-risk genetic variants also predict nicotine dependence and delayed smoking cessation. It is unclear whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not. METHODS: Meta-analyses examined the association between smoking cessation and lung cancer risk in 15 studies of individuals with European ancestry who possessed varying rs16969968 genotypes (N=12,690 ever smokers, including 6988 cases of lung cancer and 5702 controls) in the International Lung Cancer Consortium. RESULTS: Smoking cessation (former vs. current smokers) was associated with a lower likelihood of lung cancer (OR=0.48, 95%CI=0.30-0.75, p=0.0015). Among lung cancer patients, smoking cessation was associated with a 7-year delay in median age of lung cancer diagnosis (HR=0.68, 95%CI=0.61-0.77, p=4.9∗10-10). The CHRNA5 rs16969968 risk genotype (AA) was associated with increased risk and earlier diagnosis for lung cancer, but the beneficial effects of smoking cessation were very similar in those with and without the risk genotype. CONCLUSION: We demonstrate that quitting smoking is highly beneficial in reducing lung cancer risks for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Smokers with high-risk CHRNA5 genotypes, on average, can largely eliminate their elevated genetic risk for lung cancer by quitting smoking- cutting their risk of lung cancer in half and delaying its onset by 7years for those who develop it. These results: 1) underscore the potential value of smoking cessation for all smokers, 2) suggest that CHRNA5 rs16969968 genotype affects lung cancer diagnosis through its effects on smoking, and 3) have potential value for framing preventive interventions for those who smoke.

Associated Links Among Smoking, Chronic Obstructive Pulmonary Disease, and Small Cell Lung Cancer: A Pooled Analysis in the International Lung Cancer Consortium.

BACKGROUND: The high relapse and mortality rate of small-cell lung cancer (SCLC) fuels the need for epidemiologic study to aid in its prevention. METHODS: We included 24 studies from the ILCCO collaboration. Random-effects panel logistic regression and cubic spline regression were used to estimate the effects of smoking behaviors on SCLC risk and explore their non-linearity. Further, we explored whether the risk of smoking on SCLC was mediated through COPD. FINDINGS: Significant dose-response relationships of SCLC risk were observed for all quantitative smoking variables. Smoking pack-years were associated with a sharper increase of SCLC risk for pack-years ranged 0 to approximately 50. The former smokers with longer cessation showed a 43%quit_for_5-9 years to 89%quit_for_≥ 20 years declined SCLC risk vs. subjects who had quit smoking < 5 years. Compared with non-COPD subjects, smoking behaviors showed a significantly higher effect on SCLC risk among COPD subjects, and further, COPD patients showed a 1.86-fold higher risk of SCLC. Furthermore, smoking behaviors on SCLC risk were significantly mediated through COPD which accounted for 0.70% to 7.55% of total effects. INTERPRETATION: This is the largest pooling study that provides improved understanding of smoking on SCLC, and further demonstrates a causal pathway through COPD that warrants further experimental study.

CHRNA5 risk variant predicts delayed smoking cessation and earlier lung cancer diagnosis--a meta-analysis.

BACKGROUND: Recent meta-analyses show strong evidence of associations among genetic variants in CHRNA5 on chromosome 15q25, smoking quantity, and lung cancer. This meta-analysis tests whether the CHRNA5 variant rs16969968 predicts age of smoking cessation and age of lung cancer diagnosis. METHODS: Meta-analyses examined associations between rs16969968, age of quitting smoking, and age of lung cancer diagnosis in 24 studies of European ancestry (n = 29 072). In each dataset, we used Cox regression models to evaluate the association between rs16969968 and the two primary phenotypes (age of smoking cessation among ever smokers and age of lung cancer diagnosis among lung cancer case patients) and the secondary phenotype of smoking duration. Heterogeneity across studies was assessed with the Cochran Q test. All statistical tests were two-sided. RESULTS: The rs16969968 allele (A) was associated with a lower likelihood of smoking cessation (hazard ratio [HR] = 0.95, 95% confidence interval [CI] = 0.91 to 0.98, P = .0042), and the AA genotype was associated with a four-year delay in median age of quitting compared with the GG genotype. Among smokers with lung cancer diagnoses, the rs16969968 genotype (AA) was associated with a four-year earlier median age of diagnosis compared with the low-risk genotype (GG) (HR = 1.08, 95% CI = 1.04 to 1.12, P = 1.1*10(-5)). CONCLUSION: These data support the clinical significance of the CHRNA5 variant rs16969968. It predicts delayed smoking cessation and an earlier age of lung cancer diagnosis in this meta-analysis. Given the existing evidence that this CHRNA5 variant predicts favorable response to cessation pharmacotherapy, these findings underscore the potential clinical and public health importance of rs16969968 in CHRNA5 in relation to smoking cessation success and lung cancer risk.

The use of a point of care device for monitoring the bone resorption biomarker urinary N-telopeptide in cancer patients with bone metastases.

Type I collagen is the major constituent of bone and its breakdown products are increasingly used as sensitive markers of bone resorption. The N-terminal peptide-bound crosslinks of type I collagen (NTX) can be measured in urine and is useful for the monitoring of patients with metastatic bone disease. Studies have shown that raised NTX levels in metastatic bone disease correlate with an increased risk of complications and pathological fracture. The development of accurate and instantaneous point of care devices (POCD) would facilitate patient treatment and avoid delays in awaiting results from specialist laboratories. This study assesses the clinical performance of a single use POCD (OSTEOMARK NTx Point of Care Rx Home Use) to monitor NTX levels in patients with metastatic bone disease. NTX was measured in duplicate in 136 urine samples from patients attending clinic with metastatic bone disease using the POCDs. In our centre the frequency of bisphosphonate treatment is dependent on the NTX level, which is categorised into three groups (0-50, 50-100 and >100 nmol BCE/mmol creatinine). We used these categories to compare the clinical performance of the POCDs to that of a laboratory immunoassay. From a total of 272 devices, 231 (84.9%) successfully recorded a value in nM BCE/mM creatinine. Statistical analysis of the measure of agreement between POCD and laboratory assay found moderate agreement between the two assays (kappa 0.508). Out of the 72 samples with a laboratory assay value of <50, 53 (73.6%) were found to be within the same group recorded by POCD. From the 20 samples with a laboratory assay value of >100, 19 (95.0%) were found to be within the same category using POCDs. The measurement of urinary NTX by POCD appears to be a viable option for the monitoring of metastatic cancer patients. Whilst POCDs appear to record higher values than laboratory assays, the correlation between devices is good and with further research the NTX categories could be modified to accommodate this variation.

Risk-adjusted prognostic models for Hodgkin's disease (HD) and grade II non-Hodgkin's lymphoma (NHL II): validation on 6728 British National Lymphoma Investigation patients.

Using significant factors from multivariate analyses, based on 20 putative markers from a consecutive series of 1198 Sheffield Lymphoma Group patients, risk-adjusted prognostic models had been previously derived for Hodgkin's disease (HD) (using age, albumin and lymphocyte count) and non-Hodgkin's lymphoma (NHL) grade II (based on albumin, age, erythrocyte sedimentation rate, lactate dehydrogenase and stage). Data from 6728 patients on the British National Lymphoma Investigation database were used for validation: thus the models were applied to 4411 patients with HD and 2317 patients with NHL grade II. Survival curves derived from these validation groups confirmed our risk models.