Graphite foils as potential skin and epithelium dosimeters at therapeutic photon energies.

This work builds upon a prior study, examining the dosimetric utility of pencil lead and thin graphitic sheets, focusing upon the measurement of skin doses within the mammographic regime. In recognizing the near soft-tissue equivalence of graphite and the earlier-observed favourable thermoluminescence yield of thin sheets of graphite, this has led to present study of 50 µm thick graphite for parameters typical of external beam fractionated radiotherapy and skin dose evaluations. The graphite layers were annealed and then stacked to form an assembly of 0.5 mm nominal thickness. Using a 6 MV photon beam and delivering doses from 2- to 60 Gy, irradiations were conducted, the assembly first forming a superficial layer to a solid water phantom and subsequently underlying a 1.5 cm bolus, seeking to circumvent the build-up to electronic equilibrium for skin treatments. Investigations were made of several dosimetric properties arising from the thermoluminescence yield of the 50 µm thick graphite slabs, in particular proportionality and sensitivity to dose. The results show excellent sensitivity within the dose range of interest, the thermoluminescence response varying with increasing depth through the stacked graphite layers, obtaining a coefficient of determination of 90%. Acknowledging there to be considerable challenge in accurately matching skin thickness with dose, the graphite sheets have nevertheless shown considerable promise as dosimeters of skin, sensitive in determination of dose from the surface of the graphite through to sub-dermal depth thicknesses.

A new variant of gallbladder duplication mimicking a choledochal cyst: stepwise management of an unexpected surgical finding.

We present a case of previously unclassified duplicated gallbladder which posed a surgical challenge intraoperatively by mimicking a choledochal cyst. An intraoperative cholangiogram was performed followed by a simple cholecystectomy. No further dissection was performed to avoid bile duct injury and complication from the unconventional anatomy. Postoperative imaging and histology, followed by the second operation confirmed findings consistent with the duplicated gallbladder. Through this case, we have demonstrated the principles of safe cholecystectomy and the importance of a staged approach in an unanticipated encounter of anatomical uncertainty, as well as the description of a new variant of duplicated gallbladder.

Uveal and conjunctival melanomas: disease course and outcomes in Chinese patients.

INTRODUCTION: Epidemiological studies of ocular melanomas have largely focused on Caucasian populations. This study reviewed the course and outcomes of uveal melanoma (UM) and conjunctival melanoma (CM) in Chinese patients. METHODS: This retrospective study included patients with UM and CM who received treatment in a tertiary eye centre in Hong Kong from January 1994 to December 2019. Data were recorded concerning patient demographics, tumour laterality, tumour characteristics, investigations performed, treatment regimen, and final outcomes. RESULTS: During the 25-year study period, there were 13 patients with UM and 11 patients with CM who did not display nodal or systemic involvement at diagnosis. The mean ± standard deviation ages at diagnosis of UM and CM were 59 ± 15.8 and 57 ± 13.9 years, respectively. There were more men among patients with UM than among those with CM (P=0.042). Most patients with UM underwent primary enucleation (n=12; 92.3%), whereas most patients with CM underwent orbital exenteration (n=9; 81.8%). The prognosis was significantly worse for CM than for UM. The median disease-free survival were 5.2 years (range, 0.7-20.5) and 2.1 years (range, 0.1-24.9) for UM and CM, respectively. Melanoma-related mortality was significantly higher among patients with CM than among those with UM (P=0.006). CONCLUSION: Compared with UM, CM has higher rates of systemic metastasis and tumour-related mortality in Hong Kong Chinese patients, regardless of prior definitive treatment.

Plasma ESR1 mutations and outcome to first-line paclitaxel and bevacizumab in patients with advanced ER-positive/HER2-negative breast cancer.

BACKGROUND: ESR1 mutations have been identified as mechanism for endocrine resistance and are also associated with a decreased overall survival. We assessed ESR1 mutations in circulating tumor DNA (ctDNA) for impact on outcome to taxane-based chemotherapy in advanced breast cancer patients. METHODS: ESR1 mutations were determined in archived plasma samples from patients treated with paclitaxel and bevacizumab (AT arm, N = 91) in the randomized phase II ATX study. Samples collected at baseline (n = 51) and at cycle 2 (n = 13, C2) were analyzed using a breast cancer next-generation sequencing panel. This study was powered to detect a benefit in progression-free survival (PFS) at six months for patients treated with paclitaxel/bevacizumab compared to historical trials with fulvestrant. PFS, overall survival (OS), and ctDNA dynamics were exploratory analyses. RESULTS: PFS at six months was 86% (18/21) in patients with an ESR1 mutation detected and 85% (23/27) in wildtype ESR1 patients. In our exploratory analysis, median progression-free survival (PFS) was 8.2 months [95% CI, 7.6-8.8] for ESR1 mutant patients versus 8.7 months [95% confidence interval (CI), 8.3-9.2] for ESR1 wildtype patients [p = 0.47]. The median overall survival (OS) was 20.7 months [95% CI, 6.6-33.7] for ESR1 mutant patients versus 28.1 months [95% confidence interval (CI), 19.3-36.9] for ESR1 wildtype patients [p = 0.27]. Patients with ≥ two ESR1 mutations had a significantly worse OS, but not PFS, compared to those who did not [p = 0.003]. Change in ctDNA level at C2 was not different between ESR1 and other mutations. CONCLUSIONS: Presence of ESR1 mutations in baseline ctDNA might not be associated with inferior PFS and OS in advanced breast cancer patients treated with paclitaxel/bevacizumab.

Investigation of the Radiographer's adherence and compliance with radiation protection and infection control practices during COVID-19 mobile radiography.

Radiological staff, especially radiographers, work as front liners against the COVID-19 outbreak. This study aims to assess compliance with radiation protection and infection control practices during COVID-19 mobile radiography procedures. This cross-sectional study included 234 radiographers (females, 56%, n = 131; males, 44%, n = 103) who were asked to complete an online questionnaire consisting of demographic data, radiation protection and infection control practices during COVID-19 portable cases, and knowledge and awareness. After informed consent was completed, SPSS statistical software was used for the data analysis. The most common age group of participants ranged from 18 to 25 years old (30.3%, n = 71). Bachelor's degree holders were 74.4% (n = 174). Most radiographers (39.7%, n = 93) had a working experience of 1-5 years, followed by 27.8% (n = 65) with more than 16 years of experience. Most respondents (62.4%, n = 146) handled approximately 1-5 cases daily, the majority of them (56%, n = 131) stated affirmatively they had obtained special training to handle COVID-19, and when inquired if they had received any special allowances for handling COVID-19 suspected/confirmed cases most of them stated negative (73.9%, n = 173). Most participants stated that they always wear a TLD during portable cases (67.1%, n = 157) and a lead apron (51.7%, n = 121). Around 73% (n = 171) knew the latest information on COVID-19 and attended the COVID-19 awareness course. A significant association was found between the work experience of the radiographers and their responses to following the best practices (p = 0.018, α = 0.05). Radiographers who had COVID-19 training (µ = 48.78) tend to adhere more to best practices than those who have not (p = 0.04, α = 0.05). Further, respondents who handled more than 16/more COVID-19 suspected/confirmed cases followed the best practices more (µ = 50.38) than those who handled less (p = 0.04, α = 0.05). This study revealed detailed information on radiation protection and infection control practices during COVID-19 mobile radiography. It has been observed that the participants/radiographers have good knowledge and awareness of radiation protection and infection-control practices. The present results may be used to plan future requirements regarding resources and training to ensure patient safety.

Thermoluminescent characterization and defect studies of graphite-rich media under high dose neutron exposure.

Thermoluminescence (TL) materials have a broad variety of uses in various fields, such as clinical research, individual dosimetry, and environmental dosimetry, amongst others. However, the use of individual neutron dosimetry has been developing more aggressively lately. In this regard, present study establishes a relationship between the neutron dosage and the optical property changes of graphite-rich materials caused by high doses of neutron radiation. This has been done with the intention of developing a novel, graphite-based radiation dosimeter. Herein, the TL yield of commercially graphite-rich materials (i.e. graphite sheet, 2B and HB grade pencils) irradiated by neutron radiation with doses ranging from 250 Gy to 1500 Gy has been investigated. The samples were bombarded with thermal neutrons as well as a negligible amount of gamma rays, from the nuclear reactor TRIGA-II installed at the Bangladesh Atomic Energy Commission. The shape of the glow curves was observed to be independent of the given dosage, with the predominant TL dosimetric peak maintained within the region of 163 °C-168 °C for each sample. By studying the glow curves of the irradiated samples, some of the most well theoretical models and techniques were used to compute the kinetic parameters such as the order of kinetics (b), activation energy (E) or trap depth, frequency factor (s) or escape probability, and trap lifetime (τ). All of the samples were found to have a good linear response over the whole dosage range, with 2B grade of polymer pencil lead graphite (PPLGs) demonstrating a higher level of sensitivity than both HB grade and graphite sheet (GS) samples. Additionally, the level of sensitivity shown by each of them is highest at the lowest dosage that was given, and it decreases as the dose increases. Importantly, the phenomenon of dose-dependent structural modifications and internal annealing of defects has been observed by assessing the area of deconvoluted micro-Raman spectra of graphite-rich materials in high-frequency areas. This trend is consistent with the cyclical pattern reported in the intensity ratio of defect and graphite modes in previously investigated carbon-rich media. Such recurrent occurrences suggest the idea of employing Raman microspectroscopy as a radiation damage study tool for carbonaceous materials. The excellent responses of the key TL properties of the 2B grade pencil demonstrate its usefulness as a passive radiation dosimeter. As a consequence, the findings suggest that graphite-rich materials have the potential to be useful as a low-cost passive radiation dosimeter, with applications in radiotherapy and manufacturing.

Low-cost commercial graphite-rich pencils subjected to electron irradiation for passive radiation dosimetry.

Various thicknesses of 2B grade polymer pencil lead graphite (PPLG) were used in the present study, which focussed on the alteration in crystalline lattice and the structural defect caused by the electron irradiation dosage ranging from 0.5 to 20 Gy delivered by an Elekta HD Linac. The fundamental trap parameters i.e. kinetics order (b), activation energy (E), and frequency factor (s) of the PPLG samples have been estimated using the initial rise and peak shape approaches by fitting the thermoluminescence (TL) glow peaks of the PPLG samples exposed to 20 Gy. The lifetime of the TL glow peak is also presented, which provides information on the stability of the TL signal at maximum temperatures. Raman, Photoluminescence (PL), and X-ray diffraction (XRD) spectra are being used to observe the structural changes that have occurred as a result of the radiation doses. These spectroscopies offer an understanding of the physical parameters that are related to the defects and taking part in the luminescence process. When all of the data are taken into account, it is anticipated that 0.3 mm PPLG is an effective material for dosimetry. The results of these lines of research are intended to educate the innovation of versatile graphite radiation dosimeters as a low-cost efficient system for radiation detection. The studied PPLG offers tissue equivalence as well as high spatial resolution, both are desirable criteria for a material to be used in the monitoring of ionising radiation or a variety of medical applications.

Multimodality imaging of extra-nodal lymphoma in the head and neck.

Malignant lymphomas represent approximately 5% of all malignant neoplasms of the head and neck. The head and neck region is the second most frequent anatomical site of extra-nodal lymphomas (after the gastrointestinal tract). Most are non-Hodgkin's lymphomas of B-cell lineage, and overall diffuse large B-cell lymphoma is the most common type. They can present in highly variable appearances in different anatomical subsites in the head and neck. There is little literature on their imaging appearances on different imaging methods including ultrasound, magnetic resonance imaging (MRI), computed tomography (CT), and integrated positron-emission tomography (PET)/CT. The review aims to illustrate the presentation of histopathological-proven extra-nodal lymphoma in the head and neck using various imaging methods.

Glycated haemoglobin and the risk of postoperative complications in people without diabetes: a prospective population-based study in UK Biobank.

The aim of our study was to clarify the association between glycated haemoglobin (HbA1c ) and postoperative outcomes in people without an existing diagnosis of diabetes. Half a million adults were recruited into the UK Biobank prospective cohort study between March 2006 and October 2010. We divided participants into three groups: no diagnosis of diabetes and HbA1c < 42 mmol.mol-1 ; no diagnosis of diabetes and elevated HbA1c (≥ 42 mmol.mol-1 with no upper limit); and prevalent diabetes (regardless of HbA1c concentration) at recruitment. We followed up participants by linkage with routinely collected hospital data to determine any surgical procedures undertaken after recruitment and the associated postoperative outcomes. Our main outcome measure was a composite primary outcome of 30-day major postoperative complications and 90-day all-cause mortality. We used logistic regression to estimate the odds of the primary outcome by group. We limited analyses to those who underwent surgery within one year of recruitment (n = 26,653). In a combined effects logistic regression model, participants not known to have diabetes with HbA1c ≥ 42 mmol.mol-1 had increased odds of the primary outcome (OR [95% CI] 1.43 [1.02-2.02]; p = 0.04), when compared with those without diabetes and HbA1c < 42 mmol.mol-1 . This effect was attenuated and no longer statistically significant in a direct effects model with adjustment for hyperglycaemia-related comorbidity (OR [95% CI] 1.37 [0.97-1.93]; p = 0.07). Elevated pre-operative HbA1c in people without diabetes may be associated with an increased risk of complications, but the association is likely confounded by end-organ comorbidity. In contrast to previous evidence, our findings suggest that to prevent adverse postoperative outcomes, optimisation of pre-existing morbidity should take precedence over reducing HbA1c in people without diabetes.

How should we secure the cystic duct during laparoscopic cholecystectomy? A UK-wide survey of clinical practice and systematic review of the literature with meta-analysis.

INTRODUCTION: It is currently unknown which method of cystic duct closure is most effective at reducing the risk of bile leak after laparoscopic cholecystectomy. The aims of this work were to determine the most common closure methods used in the UK and review available evidence on which method has the lowest risk of bile leak. METHODS: We conducted an online survey through the Association of Upper Gastrointestinal Surgeons (AUGIS). We also undertook a systematic review using PubMed, EMBASE, MEDLINE and the Cochrane Library for studies that compared different methods for cystic duct occlusion and reported postoperative bile leak. FINDINGS: There was significant variation in practice between consultant surgeons. For routine laparoscopic cholecystectomy metal clips were used most (64%) followed by locking polymer clips (33%) and suture ties (3%). In cases of a dilated cystic duct, preferences were locking polymer clips (60%), suture ties (30%) and metal clips (5%). We included six studies in our review with a total of 8,011 patients. Metal clips were associated with an increased odds of bile leak compared with locking polymer clips (OR 5.66, 95% CI 1.13-28.41, p=0.04) or suture ties (OR 4.17, 95% CI 0.72-24.31, p=0.12). Most studies were retrospective, unlikely to be adequately powered, and vulnerable to selection bias. CONCLUSIONS: Limited available evidence suggests that metal clips have the highest risk of bile leak, but results are not strong enough to recommend a change in current clinical practice. A trial is now required to determine the best method of cystic duct closure.

Upper extremity nerve transfers for acute flaccid myelitis: a systematic literature review.

BACKGROUND: Acute flaccid myelitis (AFM) is a rare disease that commonly affects young children. AFM's pathophysiology involves loss of lower motor neurons following a viral infection and induces acute asymmetric flaccid paralysis most commonly in the upper extremities. Nerve transfers have emerged as a treatment option for these patients with permanent motor deficits. OBJECTIVE: To summarize the literature and report safety and efficacy outcomes following nerve transfers for recovery of shoulder abduction and external rotation, and elbow flexion and extension in pediatric patients with AFM. Recovery of at least antigravity function was defined as a successful outcome. This systematic review was performed according to the PRISMA guidelines. The PubMed, Embase and Cochrane databases were utilized. RESULTS: Five studies comprising 44 patients (median age 2.95 years; 71% male), and 93 upper extremity nerve transfers were included. Thirty-eight patients received 65 nerve transfer procedures aiming for recovery of shoulder abduction and/or external rotation with a transfer to the axillary and/or suprascapular nerve. The recovery of shoulder abduction and external rotation was achieved in 40.7% (n = 11/27) and 60% (n = 6/10) of patients, respectively. Time from injury to surgery showed an inverse relationship with the odds for successful recovery (OR: 0.81; 95% CI: 0.64-1.02; p = 0.07); however, statistical significance was not reached. Successful recovery of elbow flexion with a transfer to the musculocutaneous was reported at a rate of 92.3% (n = 12/13). Successful re-innervation of the radial nerve with recovery of elbow extension was found in 75% (n = 6/8) of patients. No complications were reported. CONCLUSIONS: Upper extremity nerve transfers appear to be promising and safe for AFM patients. Shoulder abduction is the most challenging upper extremity function to recover. Further studies are warranted to identify whether nerve transfers are associated with superior outcomes when performed earlier.

Resveratrol enhanced chemosensitivity by reversing macrophage polarization in breast cancer.

BACKGROUND: Resveratrol, a naturally occurring polyphenolic compound, has been shown to inhibit cancer growth by targeting several cancer-related signalling pathways. In the tumor microenvironment (TME), tumor-associated macrophages (TAMs) are the most abundant leukocyte population that are associated with poor prognosis in over 80% of breast cancer cases. However, little is known about the effect of resveratrol in the TME. METHODS: In this study, MDA-MB-231(MB231), cisplatin resistance MDA-MB-231 (cisR), and T47D were used to examine the antitumor effect of resveratrol. The effectiveness of resveratrol, together with cisplatin as breast cancer treatment was investigated in vivo. Gene expressions of M1 (iNOS and CXCL10) and M2 (ARG1, CD163 and MRC1) markers in differentiated macrophages derived from THP-1 cells were examined to investigate the effect of resveratrol on TAM polarization in breast cancer progression. RESULTS: Our results demonstrated that resveratrol significantly reduced cell proliferation and enhanced chemosensitivity in breast cancer cells by inhibiting production of IL-6 and STAT3 activation. Treatment of resveratrol increased CXCL10 (M1 marker) expression. Further, resveratrol decreased IL-6 levels in LPS-treated differentiated macrophages. The use of resveratrol with cisplatin inhibited suppressed tumor growth when compared with cisplatin alone. CONCLUSION: This study revealed that resveratrol inhibited breast cancer cell proliferation by promoting M1/M2 macrophage polarization ratio and suppressing IL-6/pSTAT3 pathway.

Cancer blues? A promising judgment bias task indicates pessimism in nude mice with tumors.

In humans, affective states can bias responses to ambiguous information: a phenomenon termed judgment bias (JB). Judgment biases have great potential for assessing affective states in animals, in both animal welfare and biomedical research. New animal JB tasks require construct validation, but for laboratory mice (Mus musculus), the most common research vertebrate, a valid JB task has proved elusive. Here (Experiment 1), we demonstrate construct validity for a novel mouse JB test: an olfactory Go/Go task in which subjects dig for high- or low-value food rewards. In C57BL/6 and Balb/c mice faced with ambiguous cues, latencies to dig were sensitive to high/low welfare housing: environmentally-enriched animals responded with relative 'optimism' through shorter latencies. Illustrating the versatility of this validated JB task across different fields of research, it further allowed us to test hypotheses about the mood-altering effects of cancer in male and female nude mice (Experiment 2). Males, although not females, treated ambiguous cues as intermediate; and males bearing subcutaneous lung adenocarcinomas also responded more pessimistically to these than did healthy controls. To our knowledge, this is the first evidence of a valid mouse JB task, and the first demonstration of pessimism in tumor-bearing animals. This task still needs to be refined to improve its sensitivity. However, it has great potential for investigating mouse welfare, the links between affective state and disease, depression-like states in animals, and hypotheses regarding the neurobiological mechanisms that underlie affect-mediated biases in judgment.

Expanded criteria for pretreatment staging CT in breast cancer.

BACKGROUND: There is wide variation in the approach to staging for distant metastatic disease in breast cancer. This study sought to identify factors predictive of distant metastatic disease at presentation to enable appropriate selection of patients for pretreatment CT. METHODS: Data were collected retrospectively for all patients with newly diagnosed breast cancer (screening and symptomatic) over 3 years (2014-2017). Detailed demographic, pathological, biological, and management data were recorded at presentation, and outcome data were recorded after follow-up. Binomial logistic regression was used to identify variables independently associated with distant metastatic disease at presentation. RESULTS: A total of 1377 patients with newly diagnosed breast cancer were identified, of whom 1025 had complete data; 323 staging CT examinations were performed. Distant metastases were identified at presentation in 47 (4.6 per cent). Some 30 of 47 patients with metastatic disease met established criteria for staging (T4, recurrence, symptoms of possible distant metastases), leaving 17 patients with metastatic disease potentially missed by use of these criteria alone. Multivariable analysis showed that tumour size at least 3 cm combined with sonographically abnormal axillary lymph nodes predicted a high probability of distant metastatic disease at presentation (positive predictive value 18.8 per cent, odds ratio 4.83, P < 0.001). Addition of this criterion increased the positive CT rate to 17.1 per cent. CONCLUSION: Selective pretreatment CT staging can be further optimized with the addition of tumour size at least 3 cm with abnormal axillary nodes to established staging criteria.

Ocular Sebaceous Carcinoma In Situ With Biphenotypic Differentiation: A Reappraisal of the Alternative Origin of the Tumor.

Ocular sebaceous carcinoma is an uncommon, aggressive tumor arising from the Meibomian gland, Zeis gland, or sebaceous glands in the caruncle or eyelashes. We described a rare case of sebaceous carcinoma in situ in a 51-year-old female that was characterized by intraepithelial growth of sebaceous carcinoma cells with no invasive carcinoma in the underlying sebaceous glands. Early stromal invasion was identified that featured 2 distinctive but focally intermixed populations of sebaceous carcinoma cells and squamous carcinoma cells. The 2 populations of cells exhibited their respective distinct immunophenotype but both showed strong overexpression of p53. This case provides evidence to support the hypothesis that some ocular sebaceous carcinoma may arise from intraepithelial pluripotent stem cells.

Comparison of bone structure and microstructure in the metacarpal heads between patients with psoriatic arthritis and healthy controls: an HR-pQCT study.

Human cadaveric study has indicated that the metacarpal head (MCH) is intracapsular in location. We hypothesized that exposure to the intra-articular inflammatory milieu in psoriatic arthritis (PsA) will lead to bone loss in the MCH. INTRODUCTION: To compare the bone structure and microstructure in the MCH between patients with PsA and healthy controls by high-resolution peripheral quantitative CT (HR-pQCT), and to ascertain factors associated with bone loss in PsA patients. METHODS: Sixty-two PsA patients without joint destruction and 62 age-, gender-, and body mass index-matched healthy subjects underwent HR-pQCT imaging of the second and third MCH (MCH 2&3). The number and volume of bone erosion and enthesiophytes, as well as volumetric bone mineral density (vBMD) and microstructure at the MCH 2&3, were recorded. Correlation analysis and multivariable linear regression models were used to determine the association of demographic and disease-specific variables with compromised bone structure and microstructure in PsA. RESULTS: At the MCH 2&3, bone erosion (p = 0.003) and enthesiophyte (p = 0.000) volumes in PsA patients were significantly larger than healthy controls. In PsA patients, older age was associated with a larger erosion and enthesiophyte volume. Concerning the mean vBMD and microstructure at the MCH 2&3, PsA patients had significantly lower mean vBMD (average vBMD - 6.9%, trabecular vBMD - 8.8%, peri-trabecular vBMD - 7.7%, meta-trabecular vBMD - 9.8%), trabecular bone volume fraction (- 8.8%), and trabecular thickness (- 8.1%) compared with control subjects. Multivariable regression analysis revealed that older age and a higher C-reactive protein level were associated with trabecular bone loss. CONCLUSIONS: PsA patients had a higher burden of bone damages (erosions and enthesiophytes) and trabecular bone loss compared with healthy control at the MCH. Inflammation contributed to the deterioration in trabecular microstructure in these patients.

Safety and patient-reported outcomes of atezolizumab, carboplatin, and etoposide in extensive-stage small-cell lung cancer (IMpower133): a randomized phase I/III trial.

BACKGROUND: The addition of atezolizumab to carboplatin and etoposide (CP/ET) significantly improved progression-free and overall survival for patients with extensive-stage small-cell lung cancer (ES-SCLC) in the IMpower133 study (NCT02763579). We have evaluated adverse events (AEs) and patient-reported outcomes in IMpower133 to assess the benefit-risk profile of this regimen. PATIENTS AND METHODS: Patients received four 21-day cycles of CP/ET plus intravenous atezolizumab 1200 mg or placebo (induction phase), followed by atezolizumab or placebo (maintenance phase) until progression or loss of benefit. AEs were assessed and patient-reported outcomes were evaluated every 3 weeks during treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (QLQ-C30) and QLQ-LC13. RESULTS: Overall, 394 patients were assessable for safety in the induction phase and 318 in the maintenance phase. The frequency of AEs, grade 3-4 AEs, and serious AEs was similar between arms in both phases. Immune-related AEs were more frequent in the atezolizumab arm during both induction (28% versus 17%; leading to atezolizumab/placebo interruption 9% versus 5%, leading to withdrawal 4% versus 0%) and maintenance (26% versus 15%; leading to atezolizumab/placebo interruption, 3% versus 2%, leading to withdrawal 1% versus 1%), most commonly rash (induction 11% versus 9%, maintenance 14% versus 4%), and hypothyroidism (induction 4.0% versus 0%, maintenance 10% versus 1%). Changes in patient-reported treatment-related symptoms commonly associated with quality of life impairment were generally similar during induction and most of the maintenance phase. Patient-reported function and health-related quality of life (HRQoL) improved in both arms after initiating treatment, with more pronounced and persistent HRQoL improvements in the atezolizumab arm. CONCLUSIONS: In patients with ES-SCLC, atezolizumab plus CP/ET has a comparable safety profile to placebo plus CP/ET, and the addition of atezolizumab did not adversely impact patient-reported HRQoL. These data demonstrate the positive benefit-risk profile of first-line atezolizumab plus CP/ET in ES-SCLC and further support this regimen as a new standard of care in this setting. CLINICAL TRIALS NUMBER: NCT02763579.

Composition of the mucosa-associated microbiota along the entire gastrointestinal tract of human individuals.

Background: Homeostasis of the gastrointestinal tract depends on a healthy bacterial microbiota, with alterations in microbiota composition suggested to contribute to diseases. To unravel bacterial contribution to disease pathology, a thorough understanding of the microbiota of the complete gastrointestinal tract is essential. To date, most microbial analyses have either focused on faecal samples, or on the microbial constitution of one gastrointestinal location instead of different locations within one individual. Objective: We aimed to analyse the mucosal microbiome along the entire gastrointestinal tract within the same individuals. Methods: Mucosal biopsies were taken from nine different sites in 14 individuals undergoing antegrade and subsequent retrograde double-balloon enteroscopy. The bacterial composition was characterised using 16 S rRNA sequencing with Illumina Miseq. Results: At double-balloon enteroscopy, one individual had a caecal adenocarcinoma and one individual had Peutz-Jeghers polyps. The composition of the microbiota distinctively changed along the gastrointestinal tract with larger bacterial load, diversity and abundance of Firmicutes and Bacteroidetes in the lower gastrointestinal tract than the upper gastrointestinal tract, which was predominated by Proteobacteria and Firmicutes. Conclusions: We show that gastrointestinal location is a larger determinant of mucosal microbial diversity than inter-person differences. These data provide a baseline for further studies investigating gastrointestinal microbiota-related disease.