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Systemic sclerosis-related interstitial lung disease (SSc-ILD) is the leading cause of death in SSc. In this study, we aimed to describe the baseline severity and evolution of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) in patients with SSc-ILD and to assess the baseline clinical, biological and high-resolution CT scan (HRCT) predictors of this evolution. Baseline and serial FVC and DLCO were collected in 75 SSc-ILD patients followed during 6.4±4.2 years (n = 557 individual data). FVC and DLCO evolution was modelled using a linear mixed model with random effect. During follow-up, FVC was stable while DLCO significantly decreased (-1.5±0.3%/year (p<0.0001). Baseline NYHA functional class III/IV, extensive SSc-ILD on HRCT and DLCO<80% were associated with a lower baseline FVC. Absence of digital ulcers extensive SSc-ILD, and FVC<80% and were associated with a lower baseline DLCO. Presence or history of digital ulcers and presence of pulmonary hypertension at baseline or during follow-up were associated with a faster decline of DLCO overtime. Neither age, gender, subtype of SSc nor specificity of autoantibodies were associated with baseline severity or outcome of lung function tests. In this SSc-ILD population, FVC was therefore stable while DLCO significantly declined over time. ILD extension was associated with baseline FVC and DLCO but not with their evolution. Presence or history of digital ulcers and pulmonary hypertension were predictors of a faster decline of DLCO over time.

The revised 2017 European LeukemiaNet (ELN) recommendations for genetic risk stratification of acute myeloid leukemia have been widely adopted, but have not yet been validated in large cohorts of AML patients. We studied 1116 newly diagnosed AML patients (age range, 18–86 years) who had received induction chemotherapy. Among 771 patients not selected by genetics, the ELN-2017 classification re-assigned 26.5% of patients into a more favorable or, more commonly, a more adverse-risk group compared with the ELN-2010 recommendations. Forty percent of the cohort, and 51% of patients ≥60 years, were classified as adverse-risk by ELN-2017. In 599 patients <60 years, estimated 5-year overall survival (OS) was 64% for ELN-2017 favorable, 42% for intermediate-risk and 20% for adverse-risk patients. Among 517 patients aged ≥60 years, corresponding 5-year OS rates were 37, 16, and 6%. Patients with biallelic CEBPA mutations or inv(16) had particularly favorable outcomes, while patients with mutated TP53 and a complex karyotype had especially poor prognosis. DNMT3A mutations associated with inferior OS within each ELN-2017 risk group. Our results validate the prognostic significance of the revised ELN-2017 risk classification in AML patients receiving induction chemotherapy across a broad age range. Further refinement of the ELN-2017 risk classification is possible.

Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. We used conditional probability and logistic regression to model the sequential distribution of tau pathologies across different brain regions. Tau pathology uniformly predominates in the neurons of the pallido-nigro-luysian axis in different clinical subtypes. However, clinical subtypes are distinguished not only by total tau load but rather cell-type (neuronal versus glial) specific vulnerability patterns of brain regions suggesting distinct dynamics or circuit-specific segregation of propagation of tau pathologies. For Richardson syndrome ( n  = 81) we recognize six sequential steps of involvement of brain regions by the combination of cellular tau pathologies. This is translated to six stages for the practical neuropathological diagnosis by the evaluation of the subthalamic nucleus, globus pallidus, striatum, cerebellum with dentate nucleus, and frontal and occipital cortices. This system can be applied to further clinical subtypes by emphasizing whether they show caudal (cerebellum/dentate nucleus) or rostral (cortical) predominant, or both types of pattern. Defining cell-specific stages of tau pathology helps to identify preclinical or early-stage cases for the better understanding of early pathogenic events, has implications for understanding the clinical subtype-specific dynamics of disease-propagation, and informs tau-neuroimaging on distribution patterns.

Background Since the onset of the COVID-19 pandemic in December 2019, many countries around the world have imposed lockdown measures in order to reduce virus spread. Social isolation is known to have a significant psychological impact, potentially triggering alcohol misuse in adults. In our study, we aimed to investigate the effect of COVID-19 lockdown measures on alcohol consumption in adults in Bavaria. Methods In this cross-sectional study, we enrolled 2067 participants, with 1961 young adults (mean age 23.3 ± 4.1) and 106 mature adults (mean age 66.7 ± 9.7). Participants were asked to complete a standardized questionnaire, semi-quantitatively evaluating the alcohol drinking behaviour before and during the pandemic lockdown. Results After implementation of lockdown, the alteration of alcohol consumption was significantly different between young and mature adults ( p  <  0.001). Among young adults, 42% reported unchanged drinking behaviour compared to 76% in the mature adult group; 44% of young adults reported to drink less compared to only 7% of mature adults. An increase in alcohol consumption was only reported by 14% of young adults and 17% of mature adults. Interestingly, in the entire cohort, the change of alcohol intake was most pronounced among moderate drinkers (> 0 to < 5 drinks/week) in both age groups ( p  <  0.001). Ordinal logistic regression revealed female sex, low BMI and younger age to be associated with a decrease in number of self-reported drinks/week. Conclusion The COVID-19 pandemic lockdown significantly affected alcohol drinking behaviour. Further studies exploring long-term effects on potential alcohol misuse and the relevance on public health are warranted. Trial registration The study was retrospectively registered at ClinicalTrials.gov ( NCT04361877 ) on April 24, 2020.

Background After radical resection, patients with adrenocortical carcinoma (ACC) frequently experience recurrence and, therefore, effective adjuvant treatment is urgently needed. The aim of the study was to investigate the role of adjuvant platinum-based therapy. Methods In this retrospective multicentre cohort study, we identified patients treated with adjuvant platinum-based chemotherapy after radical resection and compared them with patients without adjuvant chemotherapy. Recurrence-free and overall survival (RFS/OS) were investigated in a matched group analysis and by applying a propensity score matching using the full control cohort ( n  = 268). For both approaches, we accounted for immortal time bias. Results Of the 31 patients in the platinum cohort (R0 n  = 25, RX n  = 4, R1 n  = 2; ENSAT Stage II n  = 11, III n  = 16, IV n  = 4, median Ki67 30%, mitotane n  = 28), 14 experienced recurrence compared to 29 of 31 matched controls (median RFS after the landmark at 3 months 17.3 vs. 7.3 months; adjusted HR 0.19 (95% CI 0.09–0.42; P  < 0.001). Using propensity score matching, the HR for RFS was 0.45 (0.29–0.89, P  = 0.021) and for OS 0.25 (0.09–0.69; P  = 0.007). Conclusions Our study provides the first evidence that adjuvant platinum-based chemotherapy may be associated with prolonged recurrence-free and overall survival in patients with ACC and a very high risk for recurrence.

SummaryThe aim of this prospective study is to evaluate the clinical use and real-world efficacy of durvalumab maintenance treatment after chemoradiotherapy (CRT) in unresectable stage, locally advanced non-small cell lung cancer (NSCLC). All consecutive patients with unresectable, locally advanced NSCLC and PD-L1 expression (≥1%) treated after October 2018 were included. Regular follow up, including physical examination, PET/CT and/or contrast-enhanced CT-Thorax/Abdomen were performed every three months after CRT. Descriptive treatment pattern analyses, including reasons of discontinuation and salvage treatment, were undertaken. Statistics were calculated from the last day of thoracic irradiation (TRT). Twenty-six patients were included. Median follow up achieved 20.6 months (range: 1.9–30.6). Durvalumab was initiated after a median of 25 (range: 13–103) days after completion of CRT. In median 14 (range: 2–24) cycles of durvalumab were applied within 6.4 (range 1–12.7) months. Six patients (23%) are still in treatment and seven (27%) have completed treatment with 24 cycles. Maintenance treatment was discontinued in 13 (50%) patients: 4 (15%) patients developed grade 3 pneumonitis according to CTCAE v5 after a median of 3.9 (range: 0.5–11.6) months and 7 (range: 2–17) cycles of durvalumab. Four (15%) patients developed grade 2 skin toxicity. One (4%) patient has discontinued treatment due to incompliance. Six and 12- month progression-free survival (PFS) rates were 82% and 62%, median PFS was not reached. No case of hyperprogression was documented. Eight (31%) patients have relapsed during maintenance treatment after a median of 4.8 (range: 2.2–11.3) months and 11 (range: 6–17) durvalumab cycles. Two patients (9%) developed a local-regional recurrence after 14 and 17 cycles of durvalumab. Extracranial distant metastases and brain metastases as first site of failure were detected in 4 (15%) and 2 (8%) patients, respectively. Three (13%) patients presented with symptomatic relapse. Our prospective study confirmed a favourable safety profile of durvalumab maintenance treatment after completion of CRT in unresectable stage, locally advanced NSCLC in a real-world setting. In a median follow-up time of 20.6 months, durvalumab was discontinued in 27% of all patients due to progressive disease. All patients with progressive disease were eligible for second-line treatment.

ObjectivesTo assess the diagnostic accuracy (ACC) of post-mortem computed tomography (PMCT) for fractures of the isolated larynx-hyoid complex (LHC) in comparison to post-mortem fine preparation (PMFP).MethodsThis monocentric prospective study enclosed 54 LHCs that were extracted during autopsy, fixed in formalin, and underwent a PMCT scan (64-row multidetector CT, helical pitch). Two radiologists independently analyzed the LHC scans for image quality (IQ) and fractures (4-point Likert scales). A specialized forensic preparator dissected the specimens under the stereomicroscope. The PMFP results were standardized documented, and used as the standard of reference for the comparison to PMCT.ResultsThe PMCT-IQ of 95% of the LHC images was rated as good or excellent. IQ was decreased by decay, incisions during autopsy, and separation of the hyoid from the cartilaginous components in 7, 3, and 12 specimens, respectively. PMFP detected 119 fractures in 34 LHCs (63.0%). PMCT identified 91 fractures in 32 specimens (59.3%). PMFP and PMCT significantly agreed concerning the location (Cohen’s κ = 0.762; p < 0.001) and the degree of dislocation (κ = 0.689; p < 0.001) of the fractures. Comparing PMCT to PMFP resulted in a sensitivity of 88.2%, a specificity of 90.0%, and an ACC of 88.9% for the LHC. The ACCs for the hyoid, thyroid, and cricoid were 94.4%, 87.0%, and 81.5%, respectively. PMCT procedure was significantly faster than PMFP (28.9 ± 4.1 min vs. 208.2 ± 32.5 min; p < 0,001).ConclusionsPMCT can detect distinct injuries of the isolated LHC and may promptly confirm violence against the neck as cause of death. PMFP outmatches PMCT in the detection of decent injuries like tears of the cricoid cartilage.Key Points• Post-mortem computed tomography is able to assess fractures of the larynx-hyoid complex.• Prospective monocentric in vitro study showed that post-mortem computed tomography of the larynx-hyoid complex is faster than post-mortem fine preparation.• Post-mortem computed tomography can confirm violence against the neck as cause of death.

Background Sarcoid lesions may mimic metastatic disease or recurrence in thyroid cancer (TC) patients as both diseases may affect the lungs and lymph nodes. We present the first study to systematically evaluate the clinical course of patients with (TC) after adjuvant radioactive iodine therapy (RIT) and concomitant sarcoidosis of the lung or the lymph nodes. Methods We screened 3285 patients and retrospectively identified 16 patients with TC (11 papillary thyroid cancer (PTC), 3 follicular thyroid cancer (FTC), 1 oncocytic PTC, 1 oncocytic FTC) and coexisting sarcoidosis of the lung and/or the lymph nodes treated at our institute. All patients had undergone thyroidectomy and initial adjuvant RIT. Challenges in diagnosing and the management of these patients were evaluated during long term follow-up (median 4.9 years (0.8–15.0 years)). Results Median age at first diagnosis of TC was 50.1 years (33.0–71.5 years) and of sarcoidosis 39.4 years (18.0–63.9 years). During follow-up, physicians were able to differentiate between SA and persistent or recurrent TC in 10 of 16 patients (63%). Diagnosis was complicated by initial negative thyroglobulin (Tg), positive Tg antibodies and non-specific imaging findings. Histopathology can reliably distinguish between SA and TC in patients with one suspicious lesion. Conclusion Physicians should be aware of the rare coexistence of sarcoidosis and TC. Lymphadenopathy and pulmonary lesions could be metastases, sarcoidosis or even a mix of both. Therefore, this rare patient group should receive a thorough work up including histopathological clarification and, if necessary, separately for each lesion.

Purpose Autologous chondrocyte implantation is an established method for the treatment of joint cartilage damage. However, to date it has not been established that autologous chondrocyte implantation is an appropriate procedure for cartilage defects therapy in athletic persons. The aim of this study is to analyze if third-generation autologous chondrocyte implantation is an appropriate treatment for athletic persons with full cartilage defect of the knee joints. Methods A total of 84 patients were treated with third-generation autologous chondrocyte implantation (NOVOCART ® 3D). The mean follow-up time was 8 years (5–14). Sports activity was measured via UCLA Activity Score and Tegner Activity Scale before the onset of knee pain and postoperatively in an annual clinical evaluation. 41 athletic persons and 43 non-athletic persons (UCLA-Cut-off: 7; Tegner Activity Scale-Cut-off: 4) were analyzed. Patient reported outcomes were captured using IKDC subjective, KOOS, Lysholm score and VAS score on movement. Results Patient reported outcomes (IKDC, VAS at rest, VAS on movement) showed significant improvement ( p  < 0.001) postoperatively. Athletic persons demonstrated significantly better results than non-athletic persons in the analyzed outcome scores (IKDC: p  < 0.01, KOOS: p  < 0.01, Lysholm score: p  < 0.01). 96.4% of the patients were able to return to sport and over 50% returned or surpassed their preinjury sports level. The remaining patients were downgraded by a median of two points on the UCLA- and 2.5 on the Tegner Activity Scale. A shift from high-impact sports to active events and moderate or mild activities was found. Furthermore, it was shown that preoperative UCLA score and Tegner Activity Scale correlated significantly with the patient reported outcome postoperatively. Conclusion Autologous chondrocyte implantation is a suitable treatment option for athletic persons with full-thickness cartilage defects in the knee. The return to sports activity is possible, but includes a shift from high-impact sports to less strenuous activities.

Background The Apolipoprotein E ε4 allele (i.e. ApoE4) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). TREM2 (i.e. Triggering receptor expressed on myeloid cells 2) is a microglial transmembrane protein brain that plays a central role in microglia activation in response to AD brain pathologies. Whether higher TREM2-related microglia activity modulates the risk to develop clinical AD is an open question. Thus, the aim of the current study was to assess whether higher sTREM2 attenuates the effects of ApoE4-effects on future cognitive decline and neurodegeneration. Methods We included 708 subjects ranging from cognitively normal (CN, n  = 221) to mild cognitive impairment (MCI, n  = 414) and AD dementia ( n  = 73) from the Alzheimer’s disease Neuroimaging Initiative. We used linear regression to test the interaction between ApoE4-carriage by CSF-assessed sTREM2 levels as a predictor of longitudinally assessed cognitive decline and MRI-assessed changes in hippocampal volume changes (mean follow-up of 4 years, range of 1.7-7 years). Results Across the entire sample, we found that higher CSF sTREM2 at baseline was associated with attenuated effects of ApoE4-carriage (i.e. sTREM2 x ApoE4 interaction) on longitudinal global cognitive ( p  = 0.001, Cohen’s f 2  = 0.137) and memory decline ( p  = 0.006, Cohen’s f 2  = 0.104) as well as longitudinally assessed hippocampal atrophy ( p  = 0.046, Cohen’s f 2  = 0.089), independent of CSF markers of primary AD pathology (i.e. Aβ 1–42 , p-tau 181 ). While overall effects of sTREM2 were small, exploratory subanalyses stratified by diagnostic groups showed that beneficial effects of sTREM2 were pronounced in the MCI group. Conclusion Our results suggest that a higher CSF sTREM2 levels are associated with attenuated ApoE4-related risk for future cognitive decline and AD-typical neurodegeneration. These findings provide further evidence that TREM2 may be protective against the development of AD.