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BackgroundDespite the widespread use of glucocorticoids in inflammatory and autoimmune disorders, there is uncertainty about the safe cessation of long-term systemic treatment, as data from prospective trials are largely missing. Due to potential disease relapse or glucocorticoid-induced hypocortisolism, the drug is often tapered to sub-physiological doses rather than stopped when the underlying disease is clinically stable, increasing the cumulative drug exposure. Conversely, the duration of exposure to glucocorticoids should be minimized to lower the risk of side effects.MethodsWe designed a multicenter, randomized, triple-blinded, placebo-controlled trial to test the clinical noninferiority of abrupt glucocorticoid stop compared to tapering after ≥28 treatment days with ≥420 mg cumulative and ≥7.5 mg mean daily prednisone-equivalent dose. 573 adult patients treated systemically for various disorders will be included after their underlying disease has been stabilized. Prednisone in tapering doses or matching placebo is administered over 4 weeks. A 250 mg ACTH-test, the result of which will be revealed a posteriori, is performed at study inclusion; all patients are instructed on glucocorticoid stress cover dosing. Follow-up is for 6 months. The composite primary outcome measure is time to hospitalization, death, initiation of unplanned systemic glucocorticoid therapy, or adrenal crisis. Secondary outcomes include the individual components of the primary outcome, cumulative glucocorticoid doses, signs and symptoms of hypocortisolism, and the performance of the ACTH test in predicting the clinical outcome. Cox proportional hazard, linear, and logistic regression models will be used for statistical analysis.ConclusionThis trial aims to demonstrate the clinical noninferiority and safety of abrupt treatment cessation after ≥28 days of systemic glucocorticoid therapy in patients with stabilized underlying disease.Trial registrationClinicalTrials.gov Identifier: NCT03153527; EUDRA-CT: 2020-005601-48 https://clinicaltrials.gov/ct2/show/NCT03153527?term=NCT03153527&draw=2&rank=1.

Sessile serrated adenomas/polyps (SSA/Ps) are the putative precursors of the ~20% of colon cancers with the CpG island methylator phenotype (CIMP). To investigate the epigenetic phenotype of these precancers, we prospectively collected fresh-tissue samples of 17 SSA/Ps and 15 conventional adenomas (cADNs), each with a matched sample of normal mucosa. Their DNA was subjected to bisulfite next-generation sequencing to assess methylation levels at ~2.7 million CpGs located predominantly in gene regulatory regions and spanning 80.5Mb; RNA was sequenced to define the samples’ transcriptomes. Compared with normal mucosa, SSA/Ps and cADNs exhibited markedly remodeled methylomes. In cADNs, hypomethylated regions were far more numerous (18,417 vs 4288 in SSA/Ps) and rarely affected CpG islands/shores. SSA/Ps seemed to have escaped this wave of demethylation. Cytosine hypermethylation in SSA/Ps was more pervasive (hypermethylated regions: 22,147 vs 15,965 in cADNs; hypermethylated genes: 4938 vs 3443 in cADNs) and more extensive (region for region), and it occurred mainly within CpG islands and shores. Given its resemblance to the CIMP typical of SSA/Ps' putative descendant colon cancers, we refer to the SSA/P methylation phenotype as proto-CIMP. Verification studies of six hypermethylated regions in an independent series of precancers demonstrated DNA methylation markers’ high potential for predicting the diagnosis of SSA/Ps and cADNs. Surprisingly, proto-CIMP in SSA/Ps was associated with upregulated gene expression; downregulation was more common in cADNs. In conclusion, the epigenetic landscape of SSA/Ps differs markedly from that of cADNs. These differences are a potentially rich source of novel tissue-based and noninvasive biomarkers.

Abstract Background Electrosurgery is fundamental to the precise, fast and bloodless preparation of internal thoracic artery grafts in cardiac surgery. The PEAK PlasmaBlade is a monopolar electrosurgical device that uses pulsed radiofrequency energy to generate a plasma-mediated discharge along an insulated electrode, creating a cutting edge while the blade stays near body temperature. The aim of this study is to compare the histological samples, cardiac computed-tomography of graft patency, and clinical outcomes of patients after off-pump coronary artery bypass grafting with preparation of the internal thoracic arteries by a conventional electrosurgical device and the PlasmaBlade. Methods In twenty subjects one internal thoracic artery was prepared with PlasmaBlade and the other artery with a conventional electrosurgical device. Histological samples were evaluated for three factors for potential graft failure: endothelial damage, integrity of the vessel wall and adventitial hemorrhage. Five samples per artery were evaluated by a novel scoring method based on the exposed circumference of the histological sample (“0”: 0%, “1”: 1–25%, “2”: 26–50%, “3”: 51–75%, “4”: ≥76% of the circumference). The Wilcoxon signed ranks test for mean scores within subjects was performed. Six-month-follow up by cardiac computed tomography for evaluation of graft patency was completed in 16 patients. Results Histological results demonstrated significantly less endothelial damage after PlasmaBlade (83% vs 60%, absolute: 75/90 vs. 53/89 samples with score “0–1”, p = 0.04). PlasmaBlade samples demonstrated a tendency to better wall integrity (72% vs. 54%, absolute: 64/89 vs. 47/87 samples with score “0–1”, p = 0.32). There were no differences in endothelial bleeding (PlasmaBlade 46% vs. electrosurgery 53%, absolute: 41/88 vs. 48/90 samples with score “0–1”, p = 0.63). Computed tomography confirmed non-inferiority of the PlasmaBlade to conventional electrosurgery with a patency rate of 94%. Conclusion Histologically, internal thoracic arteries harvested with PlasmaBlade demonstrate a more intact endothelial layer and a tendency to better wall integrity. Computed tomography of graft patency speaks for non-inferiority to conventional electrosurgery. PlasmaBlade may be preferable to conventional electrosurgery, if further follow-up confirms patency of internal thoracic arteries. Trial registration NCT03510026, registered 4th April 2018 (retrospectively registered).

Abstract Background Although the majority of solitary fibrous tumors of the pleura (SFTP) follow a benign course, 10–25% of patients suffer from recurrence or metastatic disease. Several scoring models have been proposed to predict the outcome. However, none of these included immunohistochemical (IHC) markers as possible prognosticators. Methods In this multicenter study, we collected clinical data and formalin-fixed and paraffin-embedded (FFPE) tissue blocks of patients with histologically proven SFTP which had been surgically resected between 2000 und 2015. After systematic and extensive IHC staining on tissue microarrays, the results were analyzed and compared to histomorphological and clinical data for their possible prognostic value. Results In total, 78 patients (mean age 61 ± 11 years) were included. Of these, 9 patients (11%) had an adverse outcome including SFTP recurrence (n = 6) or SFTP-related death (n = 3). Mean overall survival was 172 ± 13 months. 1 and 10-year event-free survival rates were 99% and 93%. In the multivariable analysis only MIB-1 proliferation index (Ki-67) ≥10% (HR 12.3, CI 1.1–139.5, p = 0.043), ≥4 mitoses per 10 high power fields (HR 36.5, CI 1.2–1103.7, p = 0.039) and tumor size larger than 10 cm (HR 81.8, CI 1.7–4016.8, p = 0.027) were independently associated with adverse outcome. Conclusion A high proliferation rate by MIB-1 IHC was associated with impaired outcome. Upon this, we established a new score using mitosis, necrosis, size of the tumor and MIB-1, which performed better than the traditional scores in our data set. This prognostic score could help to better evaluate outcome of SFTP, but requires external validation.

Objective: To report first-hand narrative experience of autoimmune encephalitis and to briefly review currently available evidence of autoimmune encephalitis in cancer patients treated with immune checkpoint inhibitors. Setting: A case study is presented on the management of a patient who developed autoimmune encephalitis during nivolumab monotherapy occurring after 28 weeks on anti-PD-1 monotherapy (nivolumab 3 mg/kg every 2 weeks) for non-small cell lung cancer. Results: No substantial improvement was observed by antiepileptic treatment. After administration of 80 mg methylprednisolone, neurologic symptoms disappeared within 24 h and the patient fully recovered. Conclusions: Immune checkpoint inhibitor treatment can lead to autoimmune encephalitis. Clinical trial data indicate a frequency of autoimmune encephalitis of ≥0.1 to

Anal canal cancer is a rare tumor without clear treatment evidence in the metastatic setting. In terms of the bad prognosis of patients with metastatic anal cancer, further therapeutic options are urgently needed. In this paper we present the case of a 64-year-old man suffering from undifferentiated squamous cell carcinoma with liver metastases. After progression on cisplatin and fluorouracil, tumor tissue was analyzed with respect to anti-EGFR therapy with cetuximab. There was no KRAS mutation and the EGFR expression level in the tumor tissue was 2+; ideal conditions for the immunotherapy. Encouraged by these results we started a therapy using FOLFIRI in combination with cetuximab. Fortunately the patient showed a partial response after 6 cycles. On patient’s preference we did a therapy break of 6 weeks. Within this time period the disease was progressive indicating its aggressiveness. However, the same immunotherapy was able to stabilize the disease for a further 3 months. The patient died 21 months after diagnosis because of liver failure. Nevertheless, from our perspective the combination of FOLFIRI and cetuximab is quite a promising therapeutic option for patients with metastatic anal cancer. Potential predictive factors of the immunochemotherapy are discussed in this paper.

Inflammatory myopathies such as dermatomyositis and polymyositis are well-recognized paraneoplastic syndromes. Little is known, however, about necrotizing myopathies in association with cancer. We here describe a case of paraneoplastic necrotizing myopathy with a mild inflammatory infiltrate in a patient with adenocarcinoma. After the rapid development of a severe, disabling muscle weakness, the patient experienced near complete recovery within 4 months under oral prednisone treatment. In the context of the presented case, we will review current knowledge about paraneoplastic necrotizing myopathies.