Real-world outcomes with durvalumab after chemoradiotherapy in patients with unresectable stage III NSCLC: interim analysis of overall survival from PACIFIC-R.

BACKGROUND: Based on the findings of the PACIFIC trial, consolidation durvalumab following platinum-based chemoradiotherapy (CRT) is a global standard of care for patients with unresectable, stage III non-small-cell lung cancer (NSCLC). An earlier analysis from the ongoing PACIFIC-R study (NCT03798535) demonstrated the effectiveness of this regimen in terms of progression-free survival (PFS). Here, we report the first planned overall survival (OS) analysis. PATIENTS AND METHODS: PACIFIC-R is an observational/non-interventional, retrospective study of patients with unresectable, stage III NSCLC who started durvalumab (10 mg/kg intravenously every 2 weeks) within an AstraZeneca-initiated early access program between September 2017 and December 2018. Primary endpoints are OS and investigator-assessed PFS, estimated using the Kaplan-Meier method. RESULTS: By 30 November 2021, the full analysis set included 1154 participants from 10 countries (median follow-up in censored patients: 38.7 months). Median OS was not reached, and the 3-year OS rate was 63.2% (95% confidence interval 60.3% to 65.9%). Three-year OS rates were numerically higher among patients with programmed death-ligand 1 (PD-L1) expression on ≥1% versus <1% of tumor cells (TCs; 67.0% versus 54.4%) and patients who received concurrent CRT (cCRT) versus sequential CRT (sCRT) (64.8% versus 57.9%). CONCLUSIONS: PACIFIC-R data continue to provide evidence for the effectiveness of consolidation durvalumab after CRT in a large, diverse, real-world population. Better outcomes were observed among patients with PD-L1 TCs ≥1% and patients who received cCRT. Nevertheless, encouraging outcomes were still observed among patients with TCs <1% and patients who received sCRT, supporting use of consolidation durvalumab in a broad population of patients with unresectable, stage III NSCLC.

Zinc-depletion associates with tissue eosinophilia and collagen depletion in chronic rhinosinusitis.

BACKGROUND: Zinc plays an important role in many biological processes. Reduced zinc levels have been found in chronic rhinosinusitis (CRS) patients, however, its role in the pathophysiology of this disease remains unknown. This study examined zinc levels in the serum, mucus and tissue from CRS patients in relation to collagen content and eosinophil infiltration. The effect of zinc depletion on inflammatory cytokine production and collagen synthesis was assessed in vitro. METHODOLOGY: Zinc levels were determined in serum, mucus and tissue from controls, CRS with (CRSwNP) and without nasal polyps (CRSsNP) patients. Tissue zinc levels, collagen and inflammatory cell infiltration was examined using zinquin assays, immunofluorescence and histology on Tissue Micro Arrays. Cytokine expression and collagen synthesis was evaluated in zinc depleted primary human nasal epithelial cells (HNECs) and primary fibroblasts. RESULTS: CRSwNP patients showed reduced tissue zinc levels in correlation with a reduction in collagen content, and increased eosinophil numbers. Zinc depletion of HNECs and fibroblasts induced the production of pro-inflammatory cytokines and MUC5AC and reduced collagen secretion. CONCLUSIONS: These results suggest mucosal zinc depletion associates with tissue eosinophilia and collagen depletion in CRSwNP and induces pro-inflammatory cytokine expression and reduction of collagen synthesis in vitro.

Scoping review of chronic rhinosinusitis proteomics.

BACKGROUND: Progressive advances in proteomic technology has improved our understanding of the chronic rhinosinusitis (CRS) pathogenesis and endotypes. This scoping review aims to present a comprehensive and descriptive analysis of nasal mucosa and mucus proteome of CRS patients. METHODOLOGY: Studies investigating the proteome of nasal mucosa and mucus from healthy and CRS patients via mass spectrometry were included. Critical appraisal of methodological quality was conducted with extraction of protein lists. Gene set enrichment analysis (GSEA) was performed on studies including CRS patients. RESULTS: 2962 proteins were identified in the 21 studies included in this review. Eleven studies investigated the nasal mucus proteome and ten studies investigated the nasal mucosa proteome. Studies demonstrated heterogeneity in patients, sampling and mass spectrometry methodology. Samples from CRS patients suggested a trend in enrichment of immune system and programmed cell death pathways. Increased expression of proteins involved in cellular components including the cytoskeleton and adherens junctions was also present in CRS. CONCLUSIONS: Alterations in the healthy sinonasal proteome may lead to the increased immunological, metabolic and tissue remodeling processes observed in CRS. However, it is difficult to draw significant conclusions from the GSEA due to the heterogeneity present in the limited literature available. These findings allow us to direct further research to better understand CRS pathogenesis and its endotypes.

Recombinant HIV-1 vaccine candidates based on replication-defective flavivirus vector.

Multiple approaches utilizing viral and DNA vectors have shown promise in the development of an effective vaccine against HIV. In this study, an alternative replication-defective flavivirus vector, RepliVax (RV), was evaluated for the delivery of HIV-1 immunogens. Recombinant RV-HIV viruses were engineered to stably express clade C virus Gag and Env (gp120TM) proteins and propagated in Vero helper cells. RV-based vectors enabled efficient expression and correct maturation of Gag and gp120TM proteins, were apathogenic in a sensitive suckling mouse neurovirulence test, and were similar in immunogenicity to recombinant poxvirus NYVAC-HIV vectors in homologous or heterologous prime-boost combinations in mice. In a pilot NHP study, immunogenicity of RV-HIV viruses used as a prime or boost for DNA or NYVAC candidates was compared to a DNA prime/NYVAC boost benchmark scheme when administered together with adjuvanted gp120 protein. Similar neutralizing antibody titers, binding IgG titers measured against a broad panel of Env and Gag antigens, and ADCC responses were observed in the groups throughout the course of the study, and T cell responses were elicited. The entire data demonstrate that RV vectors have the potential as novel HIV-1 vaccine components for use in combination with other promising candidates to develop new effective vaccination strategies.

Reviewing indications for panendoscopy in the investigation of head and neck squamous cell carcinoma.

BACKGROUND: The role of panendoscopy in the modern investigation of head and neck cancer is changing with the development of improved radiological techniques, in-office biopsy capabilities and the low rate of synchronous primary tumours. This study aimed to review the indications for panendoscopy in the investigation of newly diagnosed head and neck cancer. METHOD: A retrospective review was conducted of 186 patients with newly diagnosed head and neck cancer, between January 2014 and December 2015, at two tertiary centres. RESULTS: Obtaining a tissue diagnosis was the most common indication for panendoscopy (65 per cent), followed by surgical planning including transoral robotic surgery suitability assessment (22.6 per cent), and the investigation of carcinoma of an unknown primary (11.3 per cent). Two synchronous primary tumours were identified, generating a yield of 1.1 per cent. CONCLUSION: Panendoscopy remains integral in the assessment of transoral robotic surgery suitability. Refining indications for modern panendoscopy could reduce the need for this procedure in this cohort of patients.

Balloon Pulmonary Angioplasty for Chronic Thromboembolic Pulmonary Hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a potentially lethal outcome of pulmonary embolism. Balloon pulmonary angioplasty (BPA) is aimed at improving pulmonary perfusion and pulmonary hemodynamics and has gained a lot of interest recently in patients either unsuitable for or refractory to surgical pulmonary endarterectomy. This article outlines the clinical features and diagnostic criteria, imaging evaluation, current medical and surgical treatment options for CTEPH. BPA is discussed in detail, focusing on the rationale, patient selection, technical details, post-procedural care and outcomes.

An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma.

This corrects the article DOI: 10.1038/bjc.2017.85.

A comparison of oncological outcomes between transoral surgical and non-surgical treatment protocols in the management of oropharyngeal squamous cell carcinoma.

BACKGROUND: The incidence of oropharyngeal squamous cell carcinoma in the Western world is increasing, with the human papillomavirus epidemic implicated in this observed trend. The optimal treatment modality is yet undetermined regarding oncological outcomes. METHODS: This study comprised 98 patients with oropharyngeal squamous cell carcinoma, treated with either primary transoral surgery with adjuvant therapy or primary chemoradiotherapy with curative intent, between 2008 and 2012. Clinicopathological characteristics including tumour-node-metastasis stage, human papillomavirus status, treatment modality, recurrence and overall survival were collated. RESULTS: Five per cent of primary surgical patients had locoregional recurrences compared with 25 per cent of primary chemoradiotherapy patients. A lower rate of locoregional recurrence was observed in the human papillomavirus positive group. CONCLUSION: This paper reports higher rates of overall survival and local control for oropharyngeal squamous cell carcinoma treated with primary surgery compared with primary chemoradiotherapy. This reflects overall lower tumour stage and higher human papillomavirus status in this group.

A systematic review of validated sinus surgery simulators.

BACKGROUND: Simulation provides a safe and effective opportunity to develop surgical skills. A variety of endoscopic sinus surgery (ESS) simulators has been described in the literature. Validation of these simulators allows for effective utilisation in training. OBJECTIVE OF REVIEW: To conduct a systematic review of the published literature to analyse the evidence for validated ESS simulation. SEARCH STRATEGY: Pubmed, Embase, Cochrane and Cinahl were searched from inception of the databases to 11 January 2017. EVALUATION METHOD: Twelve thousand five hundred and sixteen articles were retrieved of which 10 112 were screened following the removal of duplicates. Thirty-eight full-text articles were reviewed after meeting search criteria. Evidence of face, content, construct, discriminant and predictive validity was extracted. RESULTS: Twenty articles were included in the analysis describing 12 ESS simulators. Eleven of these simulators had undergone validation: 3 virtual reality, 7 physical bench models and 1 cadaveric simulator. Seven of the simulators were shown to have face validity, 7 had construct validity and 1 had predictive validity. None of the simulators demonstrated discriminate validity. CONCLUSION: This systematic review demonstrates that a number of ESS simulators have been comprehensively validated. Many of the validation processes, however, lack standardisation in outcome reporting, thus limiting a meta-analysis comparison between simulators.

Survival outcomes following salvage surgery for oropharyngeal squamous cell carcinoma: systematic review.

BACKGROUND: Recurrent oropharyngeal squamous cell carcinoma causes great morbidity and mortality. This systematic review analyses survival outcomes following salvage surgery for recurrent oropharyngeal squamous cell carcinoma. METHODS: A comprehensive search of various electronic databases was conducted. Studies included patients with recurrent or residual oropharyngeal squamous cell carcinoma treated with salvage surgery. Primary outcomes were survival rates following salvage surgery. Secondary outcomes included time to recurrence, staging at time of recurrence, post-operative complications, and factors associated with mortality and recurrence. Methodological appraisal and data extraction were conducted as per Joanna Briggs Institute methodology. RESULTS: Eighteen articles were included. The two- and five-year survival rates of the patients were 52 per cent and 30 per cent respectively. CONCLUSION: Improvements in treatment modalities for recurrent oropharyngeal squamous cell carcinoma were associated with improvements in two-year overall survival rates, with minimal change to five-year overall survival rates. Various factors were identified as being associated with long-term overall survival, thus assisting clinicians in patient counselling and selection for salvage surgery.

Validity of the American College of Surgeons' National Surgical Quality Improvement Program risk calculator in South Australian glossectomy patients.

BACKGROUND: Appropriate selection of tongue cancer patients considering surgery is critical in ensuring optimal outcomes. The American College of Surgeons' National Surgical Quality Improvement Program ('ACS-NSQIP') risk calculator was developed to assess patients' 30-day post-operative risk, providing surgeons with information to guide decision making. METHOD: A retrospective review of 30-day actual mortality and morbidity of tongue cancer patients was undertaken to investigate the validity of this tool for South Australian patients treated from 2005 to 2015. RESULTS: One hundred and twenty patients had undergone glossectomy. Predicted length of stay using the risk calculator was significantly different from actual length of stay. Predicted mortality and other complications were found to be similar to actual outcomes. CONCLUSION: The American College of Surgeons' National Surgical Quality Improvement Program risk calculator was found to be effective in predicting post-operative complication rates in South Australian tongue cancer patients. However, significant discrepancies in predicted and actual length of stay may limit its use in this population.

GSK3ß controls epithelial-mesenchymal transition and tumor metastasis by CHIP-mediated degradation of Slug.

This corrects the article DOI: 10.1038/onc.2013.279.

Outcomes of patients with non-melanoma solid tumours receiving self-funded pembrolizumab at Chris O'Brien Lifehouse.

BACKGROUND: Immunotherapy agents show anti-cancer activity in several solid cancers. Efficacy in non-melanoma solid tumours for non-approved indications is unknown. AIM: To evaluate patient and disease characteristics, rate and duration of response, and toxicity of self-funded pembrolizumab in patients with non-melanoma solid cancers. METHOD: Retrospective review describing outcomes and toxicity of self-funded pembrolizumab in patients with non-melanoma solid cancers treated at Chris O'Brien Lifehouse. RESULTS: From April 2015 to December 2015, 21 patients received or were planned to receive self-funded pembrolizumab. The median age was 50 years (16-76), 28 and 10% had an Eastern Cooperative Oncology Group performance status of 2, and 3-4 respectively. Sixty-two percent received at least two to four lines of prior drug treatment. Median follow-up was 3.0 months (range, 0.4-9.6). Fourteen (67%) patients requested pembrolizumab. Pembrolizumab was clinician offered for 7 (33%) patients. Patients who requested pembrolizumab had worse outcomes. Three patients died before receiving pembrolizumab. Of the 18 patients that received at least one dose, a partial response was observed in 3 (17%). Progressive disease occurred in 83%. Four patients received only one cycle of pembrolizumab and died after a median of 27 days (range 13-43). Immune-related adverse events of any grade occurred in 33%. No grade 3-4 events were observed. CONCLUSION: Pembrolizumab was well tolerated. Meaningful responses were observed in 17% of treated patients. Response continues after 5-6.5 months follow-up in 11% and >8 months of follow-up for the other responding patient. Financial impact to the patient can be substantial. Outcomes for 33% were poor with three patients dying prior to receiving therapy and four dying within weeks of receiving one dose. This highlights issues regarding the careful selection of patients, futility of anti-cancer therapy at the end-of-life and patients' perceived benefit of receiving this therapy.

Rhabdomyolysis caused by the moderate CYP3A4 inhibitor fluconazole in a patient on stable atorvastatin therapy: a case report and literature review.

WHAT IS KNOWN AND OBJECTIVE: Rhabdomyolysis is a severe potential adverse drug reaction of statin therapy. We report a case of rhabdomyolysis due to drug-drug interaction (DDI) between atorvastatin and fluconazole and review the literature. CASE SUMMARY: A 70-year-old woman received atorvastatin for hyperlipidaemia without any problem for 4 years. When intravenous fluconazole was added for treating a fungal infection, rhabdomyolysis developed 2 weeks later. Removal of atorvastatin led to the resolution of her rhabdomyolysis. WHAT IS NEW AND CONCLUSION: Our case demonstrates that in some subjects even a moderate CYP3A4 inhibitor such as fluconazole may lead to rhabdomyolysis in subjects receiving a statin.

Altered nociception and morphine tolerance in neuropeptide FF receptor type 2 over-expressing mice.

BACKGROUND: The neuropeptide FF system is thought to act as an anti-opioid modulator and plays a role in nociception, morphine antinociception and dependence. Two receptor subtypes, NPFFR1 and NPFFR2, have been identified, but their respective roles in these processes remain uncertain. METHODS: In the present study, the role of NPFFR2 was investigated using transgenic mice over-expressing NPFFR2 in addition to a NPFFR2 agonist AC-263093. RESULTS: NPFFR2 Tg mice exhibited increased sensitivity to both mechanical and thermal noxious stimuli compared to the WT mice, while the antinociceptive effects of morphine at three different doses (6.25, 12.5 and 25 mg/kg, s.c.) were similar in both strains. The development of tolerance to morphine antinociception after chronic morphine treatment (12.5 mg/kg, s.c.; twice daily × 5 days) was attenuated in NPFFR2 Tg mice when compared to WT mice. Similarly, WT mice receiving AC-263093 pretreatment (2.5 mg/kg, i.p.) showed attenuated morphine tolerance compared to vehicle controls. Most naloxone-precipitated morphine withdrawal symptoms were not attenuated in NPFFR2 Tg mice, with the exception of wet dog shake that was significantly reduced. Both NPFFR2 Tg and WT mice displayed similar degree of morphine rewarding. CONCLUSIONS: Our results suggest that neuropeptide FF R2 is mainly involved in the modulation of nociception and tolerance to morphine antinociception.

Benign prostatic enlargement is not associated with diabetes: a population-based study.

The association between diabetes and benign prostatic hyperplasia remains inconclusive. In this case-control study, we examined the association of diabetes with benign prostatic enlargement (BPE) using the Longitudinal Health Insurance Database 2000 in Taiwan. In total, 20 152 patients with BPE as cases and 20 152 age-matched patients without BPE were included as controls. Conditional logistic regression analyses were performed to calculate the odds ratio (OR) and corresponding 95% CI for having been previously diagnosed with diabetes between cases and controls. We found that of the 40 304 sampled patients, 9492 (23.6%) had a history of diabetes before the index date. This mean age for the sampled patients was 65.9 with a standard deviation of 12.0 years. A Chi-squared test revealed that there was a significant difference in the prevalence of prior diabetes between cases and controls (25.3% vs. 21.8%, p < 0.001). The conditional logistic regression found that the OR of prior diabetes for cases was 1.21 (95% CI = 1.15-1.27) compared with controls. However, after adjusting for geographic region, monthly income, urbanization level, hypertension, coronary heart disease (CHD), hyperlipidemia, tobacco use disorder, and obesity, the association between prior diabetes and BPE did not reach a statistically significant level (OR = 1.03, 95% CI = 0.98-1.08). In addition, it was noteworthy that hypertension (OR = 1.25, 95% CI = 1.20-1.31), CHD (OR = 1.40, 95% CI = 1.32-1.48), and hyperlipidemia (OR = 1.30, 95% CI = 1.24-1.36) were all significantly associated with BPE. We found that men with a diagnosis of diabetes were not significantly associated with BPE after adjusting for patient's sociodemographic characteristics and comorbidities.

Hospital Authority audit of the outcome of endoscopic resection of superficial upper gastro-intestinal lesions in Hong Kong.

OBJECTIVES: To review the short-term outcome of endoscopic resection of superficial upper gastro-intestinal lesions in Hong Kong. DESIGN: Historical cohort study. SETTING: All Hospital Authority hospitals in Hong Kong. PATIENTS: This was a multicentre retrospective study of all patients who underwent endoscopic resection of superficial upper gastro-intestinal lesions between January 2010 and June 2013 in all government-funded hospitals in Hong Kong. MAIN OUTCOME MEASURES: Indication of the procedures, peri-procedural and procedural parameters, oncological outcomes, morbidity, and mortality. RESULTS: During the study period, 187 lesions in 168 patients were resected. Endoscopic mucosal resection was performed in 34 (18.2%) lesions and endoscopic submucosal dissection in 153 (81.8%) lesions. The mean size of the lesions was 2.6 (standard deviation, 1.8) cm. The 30-day morbidity rate was 14.4%, and perforations and severe bleeding occurred in 4.3% and 3.2% of the patients, respectively. Among patients who had dysplasia or carcinoma, R0 resection was achieved in 78% and the piecemeal resection rate was 11.8%. Lateral margin involvement was 14% and vertical margin involvement was 8%. Local recurrence occurred in 9% of patients and 15% had residual disease. The 2-year overall survival rate and disease-specific survival rate was 90.6% and 100%, respectively. CONCLUSION: Endoscopic mucosal resection and endoscopic submucosal dissection were introduced in low-to-moderate-volume hospitals with acceptable morbidity rates. The short-term survival was excellent. However, other oncological outcomes were higher than those observed in high-volume centres and more secondary procedures were required.

Variability in inpatient serum creatinine: its impact upon short- and long-term mortality.

BACKGROUND: Long-staying medical inpatients carry a significant burden of acute and chronic illness. Prediction of their in-hospital and longer-term mortality risk is important. AIM: The aim of this study was to determine to what extent creatinine variability predicts in-hospital and 1-year mortality in inpatients. DESIGN: Retrospective cohort analysis. METHODS: Patients were included if aged 18 years or older and if admitted for 7 days or longer. The main outcome variables were mortality in hospital and after discharge. RESULTS: Increasing age, the presence of heart failure and a reduced estimated glomerular filtration rate (eGFR) on admission (<60 ml/min/1.73 m(2)) all associated with death risk (both in hospital and within a year of discharge). The creatinine change was related to mortality risk for the patient whilst in hospital and within 1 year after discharge independently of these other factors. The threshold of creatinine change, above which the in-hospital mortality rose significantly was 25 µmol/l (P < 0.001). A creatinine change of >10 µmol/l predicted significantly higher mortality within a year of discharge (P < 0.001). Every 5 µmol/l change in creatinine was associated with an in-hospital mortality increase of 3% (P < 0.001) and a 1-year mortality increase of 1% (P < 0.007). CONCLUSIONS: Patients with a creatinine rise or fall of >10 µmol/l during admission are at higher risk of death after discharge than those with more stable creatinine. These patients therefore merit further attention that might include more focused nutritional assessment, cardiovascular risk factor management or advance care planning.