Histopronostic factors in superficial colorectal adenocarcinomas treated by endoscopy: reproducibility and impact of immunohistochemistry and digital pathology.

Endoscopic dissection is the first-choice treatment for superficial pT1 colorectal adenocarcinoma (sCRC). Complementary surgery decision is influenced by histopronostic factors. Prognostic significance and reproducibility of each factor are not well established. The role of immunohistochemistry (IHC) and digital pathology in this context is unknown. Our aims were (1) to evaluate each histopronostic factor reproducibility comparing HES and IHC ± digital pathology and (2) to evaluate how the different techniques would affect indications for additional surgery. We performed a single-centre retrospective study of 98 patients treated between 2010 and 2019 in Hospices Civils de Lyon, France. We analyzed physical or digital slides of HES and keratin/desmin immunostaining of 98 sCRC dissection specimens. Three pathologists evaluate the histopronostic factors including submucosal invasion depth (SMI) measured using different recommended methods. Assessment of SMI with Ueno or JSCCR methods showed good to excellent interobserver reproducibility (IOR) (ICCs of 0.858 to 0.925) using HES staining and IHC. Assessment of budding on HES sections was poorly reproducible compared to IHC which exhibit moderate IOR (κ = 0.714). IHC increased high-grade budding detection. For lymphovascular invasion and poor differentiation, the IOR was poor (κ = 0.141, 0.196 and 0.313 respectively). IHC gave a better reproducibility for further treatment indication according to JSCCR criteria (κ = 0.763) or forthcoming European guidelines (κ = 0.659). Digital pathology was equivalent to the microscope for all analyses. Histopronostic factor reproducibility in sCRC is moderate. Immunohistochemistry may facilitate the evaluation of certain criteria and improve the reproducibility of treatment decisions.

Challenges for quality and utilization of real-world data for diffuse large B-cell lymphoma in REALYSA, a LYSA cohort.

ABSTRACT: Real-world data (RWD) are essential to complement clinical trial (CT) data, but major challenges remain, such as data quality. REal world dAta in LYmphoma and Survival in Adults (REALYSA) is a prospective noninterventional multicentric cohort started in 2018 that included patients newly diagnosed with lymphoma in France. Herein is a proof-of-concept analysis on patients with first-line diffuse large B-cell lymphoma (DLBCL) to (1) evaluate the capacity of the cohort to provide robust data through a multistep validation process; (2) assess the consistency of the results; and (3) conduct an exploratory transportability assessment of 2 recent phase 3 CTs (POLARIX and SENIOR). The analysis population comprised 645 patients with DLBCL included before 31 March 2021 who received immunochemotherapy and for whom 3589 queries were generated, resulting in high data completeness (<4% missing data). Median age was 66 years, with mostly advanced-stage disease and high international prognostic index (IPI) score. Treatments were mostly rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP 75%) and reduced dose R-CHOP (13%). Estimated 1-year event-free survival (EFS) and overall survival rates were 77.9% and 90.0%, respectively (median follow-up, 9.9 months). Regarding transportability, when applying the CT's main inclusion criteria (age, performance status, and IPI), outcomes seemed comparable between patients in REALYSA and standard arms of POLARIX (1-year progression-free survival 79.8% vs 79.8%) and SENIOR (1-year EFS, 64.5% vs 60.0%). With its rigorous data validation process, REALYSA provides high-quality RWD, thus constituting a platform for numerous scientific purposes. The REALYSA study was registered at www.clinicaltrials.gov as #NCT03869619.

Is 25OH Vitamin D Excess before 36 Weeks Corrected Age an Independent Risk Factor for Bronchopulmonary Dysplasia or Death?

Low 25-Hydroxyvitamin D (25(OH)D) in preterm infants is a risk factor for bronchopulmonary dysplasia (BPD), but increased supplementation failed to demonstrate a beneficial effect on BPD. In neonatal animal models, deficiency and excessive vitamin D exposure have been associated with increased mortality and histological alterations in the lung evocative of BPD. Our hypothesis is that 25(OH)D levels ≥ 120 nmol/L are also a risk factor for BPD or death. This retrospective single-center cohort study included only infants born at <31 weeks gestational age without major malformations with at least a determination of 25(OH)D at <36 weeks corrected age and no determination <50 nmol/L. Routine 25(OH)D determination was performed at 1 month and monthly thereafter. A total of 175 infants were included. Infants with BPD or who died had a significantly lower term and weight, but a similar frequency of 25(OH)D ≥120 nmol/L (50.5% vs. 43.9%, p = 0.53). The logistic regression identified weight (OR 0.997, 95% CI [0.995-0.998]) and term (OR 0.737, 95% CI [0.551-0.975]) as significantly associated with BPD or death; the occurrence of excessive 25(OH)D was not significantly associated (OR 1.029, 95% CI [0.503-2.093]). The present study did not demonstrate any significant association between excessive 25(OH)D after one month of age and BPD or death.

Approximating missing epidemiological data for cervical cancer through Footprinting: A case study in India.

Local cervical cancer epidemiological data essential to project the context-specific impact of cervical cancer preventive measures are often missing. We developed a framework, hereafter named Footprinting, to approximate missing data on sexual behaviour, human papillomavirus (HPV) prevalence, or cervical cancer incidence, and applied it to an Indian case study. With our framework, we (1) identified clusters of Indian states with similar cervical cancer incidence patterns, (2) classified states without incidence data to the identified clusters based on similarity in sexual behaviour, (3) approximated missing cervical cancer incidence and HPV prevalence data based on available data within each cluster. Two main patterns of cervical cancer incidence, characterized by high and low incidence, were identified. Based on the patterns in the sexual behaviour data, all Indian states with missing data on cervical cancer incidence were classified to the low-incidence cluster. Finally, missing data on cervical cancer incidence and HPV prevalence were approximated based on the mean of the available data within each cluster. With the Footprinting framework, we approximated missing cervical cancer epidemiological data and made context-specific impact projections for cervical cancer preventive measures, to assist public health decisions on cervical cancer prevention in India and other countries.

Lymphomas associated with Epstein-Barr virus infection in 2020: Results from a large, unselected case series in France.

Background: Despite mounting evidence for a causal role in an increasing number of lymphoma subtypes, very few studies have systematically tested the entire spectrum of Hodgkin and non-Hodgkin lymphomas for the presence of Epstein-Barr virus (EBV). Here, we describe the prevalence of EBV in a large, unselected series of patients diagnosed with any type of lymphoma during 2020, in the pathology department of a single University Hospital in France. Methods: A total of 756 lymphoma cases (89% new diagnoses and 11% relapses), were registered in the department between Jan 1 and Sept 30, 2020 and 616 were successfully tested for EBV presence in tumour cells by EBV-encoding RNA in-situ hybridisation, using double-blinded assessment and a scoring system designed in accordance with the current state of knowledge in the literature. Findings: A strong association with EBV was described in 27/87 (31%) classic Hodgkin lymphomas, 12/223 (5%) diffuse large B-cell lymphomas, and 18/71 (25%) NK and T-cell lymphomas: 4 extranodal NK/T-cell lymphomas, nasal type, 14 angioimmunoblastic T-cell lymphomas (48%). In Hodgkin and NK and T-cell lymphomas, there was a statistically significant association between EBER positivity and relapse (p < 0·01). Among other subtypes, a potential association with EBV (≥10% stained cells) was found in 2/97 (2%) follicular lymphomas, both of grades 1-2, 1/19 (5%) chronic lymphocytic leukaemia (CLL), 1/9 lymphoplasmacytic lymphomas (11%), and 2/47 (4%) marginal zone lymphomas. Interpretation: When applied to the distribution of lymphomas in France as described in the Lymphopath database, our data suggested that at least 8% of all combined Hodgkin and non-Hodgkin lymphomas are associated with EBV. Funding: International Agency for Research on Cancer (IARC/WHO).

Evaluation of the Correlation between Regional Retinal Ganglion Cell Damage and Visual Field Sensitivity in Patients with Advanced Glaucoma.

(1) Background: to investigate the correlation between structural (retinal ganglion cells and retinal nerve fibers) and functional alterations analyzed point-by-point in the central 10 degrees of the visual field of patients with advanced glaucoma using Humphrey 10-2 visual field tests. (2) Methods: Single-center prospective cohort study carried on from October 2018 to February 2019 at the Croix-Rousse hospital, Lyon, France. The primary outcome measure was the point-by-point correlation between retinal sensitivity (Humphrey 10-2) and retinal ganglion cell complex (GCC) thickness. (3) Results: 29 eyes of 27 patients were examined. Of these, 15 eyes had a mean deviation (MD) less than −20 dB. There were statistically significant linear relationships between GCC thickness and 10-2 visual field sensitivity for several points in the lower part of the visual field, with lower retinal sensitivity being associated with thicker GCC layers. There were no strong linear relationships or statistically significant correlations in the other regions of the visual field. For the patients with MD < −20 dB, there were statistically significant linear relationships between GCC thickness and 10-2 visual field sensitivity for several points in the superior nasal region. Retinal sensitivity was not correlated with retinal nerve fibre layer thickness. (4) Conclusions: In this study of patients with advanced glaucoma, GCC thickness was linearly associated with 10-2 visual field sensitivity in certain regions, negatively for patients with less-severe glaucoma. The initial thickening raises questions about the apoptosis mechanism, while the thinning observed in the most severe cases is consistent with the ganglion cell death identified on visual field tests.

The anticholinergic burden is not associated with cognitive impairments in patients treated by electroconvulsive therapy for treatment-resistant depression.

BACKGROUND: Electroconvulsive therapy (ECT) is the most effective non-pharmacological treatment for treatment-resistant depression (TRD) but can expose to transient cognitive impairments. Understanding factors underlying these cognitive side effects is important. This study investigated the impact of anticholinergic treatments on cognitive performances after ECT courses for TRD in naturalistic condition. METHODS: Impact of anticholinergic burden (Anticholinergic Impregnation Scale, AIS) on cognitive changes (Montreal Cognitive Assessment, MoCA) adjusted on depression level (Montgomery and Asberg Depression Scale, MADRS) was investigated in 42 patients who received an ECT course between 2017 and 2020 for unipolar or bipolar TRD. Collection of daily treatments given during ECT was carried out via the computerized traceability of treatments validated by nurses. RESULTS: Among the 31 treatments identified with an anticholinergic score, which represent only 38% of total treatments, the three most frequently given treatments were Lorazepam (47%), Venlafaxine (36%) and Cyamemazine (26%). Delayed recall was the most frequently impaired cognitive function after ECT courses. Using logistic regression, we found no association between the anticholinergic burden and the decrease in cognitive scores after ECT courses, adjusted on MADRS score evolution (p > 0.1). Conversely, improvement in MADRS scores were correlated with improvement in attention MoCA subscores. LIMITATIONS: This is a retrospective monocentric study with a moderate sample size using anticholinergic scales to calculate the anticholinergic burden without plasma dosage. CONCLUSION: Anticholinergic treatments did not seem to explain ECT-related cognitive impairments. This warrants further large prospective investigations including different measures of anticholinergic burden.

Long-Term Outcome of Lobectomy for Thyroid Cancer.

INTRODUCTION: Recent guidelines of the American Thyroid Association (ATA) suggest that a lobectomy may be sufficient to treat low- to intermediate-risk patients with thyroid tumors ≤40 mm, without extrathyroidal extension or lymph node metastases. The present study aimed to evaluate long-term recurrence after lobectomy for differentiated thyroid cancer and to analyze factors associated with recurrence. METHODS: In this retrospective cohort study, patients who underwent a lobectomy for thyroid cancer in a tertiary center between 1970 and 2010 were included. The outcome was the proportion of pathology-confirmed thyroid cancer recurrence, assessed in the whole cohort or in subgroups according to tumor size (≤ or >40 mm). RESULTS: A total of 295 patients were included, and these were followed-up for a mean (standard deviation, SD) 19.1 (7.8) years (5,649 patient-years); 61 (20.7%) were male and the mean (SD) age at diagnosis was 39.7 (12) years. Histological subtype was papillary in 263 (89.2%) patients and mean cancer size was 22.9 (16.9) mm. According to the 2015 ATA guidelines, 271 (91.9%) cancers had a low risk of recurrence and 24 (8.1%) an intermediate risk. A reoperation was performed in 54 patients (18.3%) and recurrence was confirmed in 40 (13.6%), diagnosed for 55% of cases more than 10 years after their initial surgery. Among recurrent patients, 14 (4.8% of the cohort) were operated for a contralateral papillary thyroid microcarcinoma and 26 (8.8% of the cohort) for a locoregional or metastatic recurrence. Non-suspicious nodular recurrences were monitored without reoperation in 53 (18.0%) patients. At the end of follow-up, 282 (95.6%) patients were in remission. Tumors with locoregional or metastatic recurrence were more frequent among tumors with aggressive histology (19.2 vs. 4.1%, p = 0.015) and of intermediate risk category (28.6 vs. 7.1%, p = 0.018). Tumors >40 mm, which would have been treated by thyroidectomy according to the 2015 ATA guidelines criteria, were found in 34 (11.5%) patients and were associated with a higher frequency of recurrence (20.6 vs. 7.3%, p = 0.024) and less remission (85.3 vs. 96.9%, p = 0.001). CONCLUSION: The outcome of thyroid cancer treated by lobectomy is very good, particularly for cancer ≤40 mm. A prolonged follow-up is required due to the risk of late recurrence.

Self-consciousness impairments in schizophrenia with and without first rank symptoms using the moving rubber hand illusion.

INTRODUCTION: The moving rubber hand illusion allows the evaluation both the sense of body ownership and agency using visuo-motor stimulations. METHODS: We used the moving rubber hand illusion in anatomic congruence with explicit measures to compare active asynchronous and passive synchronous movements in patients diagnosed with schizophrenia with first rank symptoms (FRS) (n = 31) versus without FRS (n = 25). RESULTS: Patients with FRS are characterized by a lack of agency in active asynchronous condition. The two groups had no sense of ownership in synchronous passive condition. Using a multivariate regression model, we found an association between agency and body ownership measures in the active asynchronous condition in two groups (OR: 1.825, p < 0.001). In the passive condition, this association was only present in the group with first rank symptoms (OR: 2.04, p < 0.001). CONCLUSION: Temporal proximity and sensorimotor information are essential in the understanding of self-consciousness disorders in schizophrenia.

Global estimates of expected and preventable cervical cancers among girls born between 2005 and 2014: a birth cohort analysis.

BACKGROUND: WHO has launched an initiative aiming to eliminate cervical cancer as a public health problem. Elimination is a long-term target that needs long-lasting commitment. To support local authorities in implementing human papillomavirus (HPV) vaccination, we provide regional and country-specific estimates of cervical cancer burden and the projected impact of HPV vaccination among today's young girls who could develop cervical cancer if not vaccinated. METHODS: The expected number of cervical cancer cases in the absence of vaccination among girls born between 2005 and 2014 was quantified by combining age-specific incidence rates from GLOBOCAN 2018 and cohort-specific mortality rates by age from UN demographic projections. Preventable cancers were estimated on the basis of HPV prevalence reduction attributable to vaccination and the relative contribution of each HPV type to cervical cancer incidence. We assessed the number of cervical cancer cases preventable through vaccines targeting HPV types 16 and 18, with and without cross-protection, and through vaccines targeting HPV types 16, 18, 31, 33, 45, 52, and 58. FINDINGS: Globally, without vaccination, the burden of cervical cancer in these birth cohorts is expected to reach 11·6 million (95% uncertainty interval 11·4-12·0) cases by 2094. Approximately 75% of the burden will be concentrated in 25 countries mostly located in Africa and Asia, where the future number of cases is expected to increase manyfold, reaching 5·6 million (5·4-6·0) cases in Africa and 4·5 million (4·4-4·6) cases in Asia. Worldwide immunisation with an HPV vaccine targeted to HPV types 16 and 18, with cross-protection against HPV types 31, 33, and 45, could prevent about 8·7 million (8·5-9·0) cases. INTERPRETATION: Detailed estimates of the increasing burden of cervical cancer and projected impact of HPV vaccination is of immediate relevance to public health decision makers. Shifting the focus of projections towards recently born girls who could develop cervical cancer if not vaccinated is fundamental to overcome stakeholders' hesitancy towards HPV vaccination. FUNDING: Bill & Melinda Gates Foundation, Canadian Institutes of Health Research.

The role and utility of population-based cancer registries in cervical cancer surveillance and control.

Population-based cancer registries (PBCR) are vital to the assessment of the cancer burden and in monitoring and evaluating national progress in cervical cancer surveillance and control. Yet the level of their development in countries exhibiting the highest cervical cancer incidence rates is suboptimal, and requires considerable investment if they are to document the impact of WHO global initiative to eliminate cervical cancer as a public health problem. As a starting point we propose a comprehensive cancer surveillance framework, positioning PBCR in relation to other health information systems that are required across the cancer control continuum. The key concepts of PBCR are revisited and their role in providing a situation analysis of the scale and profile of the cancer-specific incidence and survival, and their evolution over time is illustrated with specific examples. Linking cervical cancer data to screening and immunization information systems enables the development of a comprehensive set of measures capable of assessing the short- and long-term achievements and impact of the initiative. Such data form the basis of national and global estimates of the cancer burden and permit comparisons across countries, facilitating decision-making or triggering cancer control action. The initiation and sustainable development of PBCR must be an early step in the scale-up of cervical cancer control activities as a means to ensure progress is successfully monitored and appraised.

Age- and Sex-Specific TSH Upper-Limit Reference Intervals in the General French Population: There Is a Need to Adjust Our Actual Practices.

It is well known that thyroid dysfunction increases with age. This study is aimed to determine reference intervals, in males and females, suitable for thyroid disease exploration during adult life using routinely collected serum thyrotropin (TSH) data in a tertiary center from 2007 to 2018. Over 11 years, 295,775 TSH levels were measured in a single lab. Among the 156,025 TSH results available for analysis, 90,538 values were from female subjects, 82,019 were from patients aged >60 years and 26,825 were from patients aged >80 years. By using an indirect approach, we determined reference values of TSH adapted to age and sex, and we then evaluated the proportion of patients who would have been reclassified with these reference values. The median TSH ranged from 1.2-1.4 mUI/L during the study period. The upper limit of reference range of TSH increased with age; in females the median to 97.5th percentile values increased continuously from the age of 30 years to the oldest age group. Using new calculated reference values in patients with TSH above the conventional upper-limit reference value (4 mUI/L), the proportion of results reclassified as within the reference interval among patients aged >60 years ranged, according to age group, from 50.5% to 65.1% of females and from 33.0% to 37.7% of males. The use of TSH age-specific and sex-specific upper-limit reference values led to the reclassification of a great number of samples, notably among women. This suggests that age-specific TSH upper-limit reference intervals in daily practice should be used in order to avoid misclassification.

MRI monitoring of small and medium-sized vestibular schwannomas: predictors of growth.

Background: Vestibular schwannomas are among the most common intracranial tumours. Their growth is difficult to predict.Objectives: To study the evolution of small and medium-sized vestibular schwannomas (VSs) and identify factors predictive of growth.Material and methods: This was a retrospective longitudinal study at a tertiary referral centre from January 2011 to January 2018. The inclusion criteria were radiological diagnosis of sporadic unilateral VS of stage I or II. Radiological and clinical data were analysed descriptively and by multivariate logistic regression to identify factors predictive of growth.Results: A total of 1105 cases were discussed in multidisciplinary meetings and 336 patients were included with a mean age of 57.8 years and a mean follow-up time of 24 months. Around two thirds of these patients (62.8%) had non-progressive tumours. Factors identified as predictive of VS growth were the size at diagnosis (OR = 2.622, 95% CI, 1.50-4.66; p = .001) and internal auditory canal filling (OR = 7.672; 95% CI, 4.52-13.43; p < .001).Conclusions and significance: Monitoring is the primary treatment modality for small or medium-sized VSs. As reported here for the first time, internal auditory canal filling is significantly associated with VS growth.