Gene-expression memory-based prediction of cell lineages from scRNA-seq datasets.

Assigning single cell transcriptomes to cellular lineage trees by lineage tracing has transformed our understanding of differentiation during development, regeneration, and disease. However, lineage tracing is technically demanding, often restricted in time-resolution, and most scRNA-seq datasets are devoid of lineage information. Here we introduce Gene Expression Memory-based Lineage Inference (GEMLI), a computational tool allowing to robustly identify small to medium-sized cell lineages solely from scRNA-seq datasets. GEMLI allows to study heritable gene expression, to discriminate symmetric and asymmetric cell fate decisions and to reconstruct individual multicellular structures from pooled scRNA-seq datasets. In human breast cancer biopsies, GEMLI reveals previously unknown gene expression changes at the onset of cancer invasiveness. The universal applicability of GEMLI allows studying the role of small cell lineages in a wide range of physiological and pathological contexts, notably in vivo. GEMLI is available as an R package on GitHub ( https://github.com/UPSUTER/GEMLI ).

Clinical implantation of 92 VACStents in the upper gastrointestinal tract of 50 patients-applicability and safety analysis of an innovative endoscopic concept.

Introduction: Endoscopic vacuum therapy (EVT) has emerged as a promising treatment option for upper gastrointestinal wall defects, offering benefits such as evacuation of secretions and removal of wound debris by suction, and reduction and healing of wound cavities to improve clinical outcomes. In contrast, covered stents have a high rate of migration and lack functional drainage, while endoluminal EVT devices obstruct the GI tract. The VACStent is a novel device that combines the benefits of EVT and stent placement. Its design features a fully covered Nitinol-stent within a polyurethane sponge cylinder, enabling EVT while maintaining stent patency. Methods: This study analyzes the pooled data from three different prospective study cohorts to assess the safe practicality of VACStent placement, complete leak coverage, and effective suction-treatment of esophageal leaks. By pooling the data, the study aims to provide a broader base for analysis. Results: In total, trans-nasal derivation of the catheter, suction and drainage of secretion via vacuum pump were performed without any adversity. In the pooled study cohort of 92 VACStent applications, the mean stent indwelling time was 5.2 days (range 2-8 days) without any dislocation of the device. Removal of the VACStent was done without complication, in one case the sponge was lost but subsequently fully preserved. Minor local erosions and bleeding and one subsequent hemostasis were recorded unfrequently during withdrawal of the device (5.4%, 5/92) but no perforation or pressure ulcer. Despite a high heterogeneity regarding primary disease and pretreatments a cure rate of 76% (38/50 patients) could be achieved. Discussion: In summary, insertion and release procedure was regarded as easy and simple with a low potential of dislocation. The VACStent was well tolerated by the patient while keeping the drainage function of the sponge achieving directly a wound closure by continuous suction and improving the healing process. The implantation of the VACStent provides a promising new procedure for improved clinical treatment in various indications of the upper gastrointestinal wall, which should be validated in larger clinical studies.Clinical Trial Registration: Identifier [DRKS00016048 and NCT04884334].

The VACStent trial: combined treatment of esophageal leaks by covered stent and endoscopic vacuum therapy.

BACKGROUND: Endoscopic treatment of esophageal leaks, mostly by covered stents or endoscopic vacuum therapy (EVT), has largely improved the clinical outcome in the last decade. However, both techniques suffer from significant limitations. Covered stents are hampered by a high rate of migration and missing functional drainage, whereas endoluminal EVT devices are limited by obstruction of the GI tract. The new design of the VACStent makes it a fully covered stent within a polyurethane sponge cylinder, allowing EVT while stent passage is still open. Initial clinical applications have demonstrated the fundamental concept of the VACStent. METHOD: A prospective multicenter open-label study was performed with the primary endpoint safe practicality, complete leak coverage, and effective suction-treatment of esophageal leaks. Secondary endpoints were prevention of septic conditions, successful leak healing, and complications, in particular stent-migration, local erosions and bleeding. RESULTS: Fifteen patients with different, mostly postoperative anastomotic leaks were enrolled in three centers. A total of 41 VACStents were implanted. The mean number of VACStents per patient was 2.7, with a mean duration of VACStent treatment of 15 days. The primary endpoint was met in all VACStent applications (41/41 implants), resulting in a leak healing rate of 80% (12/15 patients). Septic episodes were prevented in 93% (14/15 patients) and there was no mortality. There were no severe device-related adverse events (SADE) nor significant local bleeding or erosion. Minor stent-dislocation and migration, respectively, was observed in 7%. Oral intake of liquids or food was documented in 87% (13/15 patients). One anastomotic stenosis was seen during follow-up. CONCLUSIONS: VACStent treatment is a safe and effective treatment in esophageal leaks which can be covered by the sponge cylinder. Its application was described as easy and resembling that of conventional GI stents, with an impressive clinical success rate comparable to EVT outcomes. The VACStent offers a new option for clinical treatment of critical situations in esophageal perforations and anastomotic sutureline failures.

Improvement of functional outcome for patients with newly diagnosed grade 2 or 3 gliomas with co-deletion of 1p/19q - IMPROVE CODEL: the NOA-18 trial.

BACKGROUND: Given the young age of patients with CNS WHO grade 2 and 3 oligodendrogliomas and the relevant risk of neurocognitive, functional, and quality-of-life impairment with the current aggressive standard of care treatment, chemoradiation with PCV, of the tumour located in the brain optimizing care is the major challenge. METHODS: NOA-18 aims at improving qualified overall survival (qOS) for adult patients with CNS WHO grade 2 and 3 oligodendrogliomas by randomizing between standard chemoradiation with up to six six-weekly cycles with PCV and six six-weekly cycles with lomustine and temozolomide (CETEG) (n = 182 patients per group accrued over 4 years) thereby delaying radiotherapy and adding the chemoradiotherapy concept at progression after initial radiation-free chemotherapy, allowing for effective salvage treatment and delaying potentially deleterious side effects. QOS represents a new concept and is defined as OS without functional and/or cognitive and/or quality of life deterioration regardless of whether tumour progression or toxicity is the main cause. The primary objective is to show superiority of an initial CETEG treatment followed by partial brain radiotherapy (RT) plus PCV (RT-PCV) at progression over partial brain radiotherapy (RT) followed by procarbazine, lomustine, and vincristine (PCV) chemotherapy (RT-PCV) and best investigators choice (BIC) at progression for sustained qOS. An event concerning a sustained qOS is then defined as a functional and/or cognitive and/or quality of life deterioration after completion of primary therapy on two consecutive study visits with an interval of 3 months, tolerating a deviation of at most 1 month. Assessments are done with a 3-monthly MRI, assessment of the NANO scale, HRQoL, and KPS, and annual cognitive testing. Secondary objectives are evaluation and comparison of the two groups regarding secondary endpoints (short-term qOS, PFS, OS, complete and partial response rate). The trial is planned to be conducted at a minimum of 18 NOA study sites in Germany. DISCUSSION: qOS represents a new concept. The present NOA trial aims at showing the superiority of CETEG plus RT-PCV over RT-PCV plus BIC as determined at the level of OS without sustained functional deterioration for all patients with oligodendroglioma diagnosed according to the most recent WHO classification. TRIAL REGISTRATION: Clinicaltrials.gov NCT05331521 . EudraCT 2018-005027-16.

The influence of the SARS-CoV-2 lockdown on patients with inflammatory rheumatic diseases on their adherence to immunomodulatory medication: a cross sectional study over 3 months in Germany.

OBJECTIVES: To evaluate the influence of the SARS-CoV-2 pandemic on the adherence of patients with inflammatory rheumatic diseases (IRD) to their immunomodulatory medication during the three-month lockdown in Germany. METHODS: From 16th March until 15th June 2020, IRD patients from private practices and rheumatology departments were asked to answer a questionnaire addressing their behaviour with respect to their immunomodulating therapy. Eight private practices and nine rheumatology departments that included rheumatology primary care centres and university hospitals participated. A total of 4252 questionnaires were collected and evaluated. RESULTS: The majority of patients (54%) were diagnosed with RA, followed by psoriatic arthritis (14%), ankylosing spondylitis (10%), connective tissue diseases (12%) and vasculitides (6%). Most of the patients (84%) reported to continue their immunomodulatory therapy. Termination of therapy was reported by only 3% of the patients. The results were independent from the type of IRD, the respective immunomodulatory therapy and by whom the patients were treated (private practices vs rheumatology departments). Younger patients (<60 years) reported just as often as older patients to discontinue their therapy. CONCLUSION: The data show that most of the patients continued their therapy in spite of the pandemic. A significant change in behaviour with regard to their immunomodulatory therapy was not observed during the three months of observation. The results support the idea that the immediate release of recommendations of the German Society of Rheumatology were well received, supporting the well-established physician-patient relationship in times of a crisis.

[A cross sectional study on patients with inflammatory rheumatic diseases in terms of their compliance to their immunsuppressive medication during COVID-19 pandemic]. / Einstellung von Patienten mit entzündlich-rheumatischen Erkrankungen zur immunsuppressiven Therapie im Rahmen der COVID-19 Pandemie ­ eine Situationsanalyse.

The current COVID-19 pandemic inherits an unprecedented challenge for the treating rheumatologists. On the one hand, antirheumatic drugs can increase the risk of infection and potentially deteriorate the course of an infection. On the other hand, an active inflammatory rheumatic disease can also increase the risk for an infection. In the recommendations of the German Society for Rheumatology (www.dgrh.de), it is recommended that our patients continue the antirheumatic therapy to maintain remission or low state of activity despite the pandemic. In this study, patients with inflammatory rheumatic disease were asked in the first weeks of the pandemic on their opinion of their immunomodulating therapy. The result shows that over 90% of the patients followed the recommendation of the rheumatologist to continue the antirheumatic therapy, and only a small percentage of the patients terminated the therapy on their own. This result was independent of the individual anti-rheumatic therapy. Taken together, the results of this study illustrate not only the trustful patient-physician partnership in a threatening situation but also the high impact of state-of-the art recommendations by the respective scientific society.

[Radiofrequency ablation effectively treats chronic radiation proctitis]. / Therapie der chronischen Strahlenproktitis - Effektive Lokaltherapie durch RFA.

Chronic radiation proctitis can develop after radiation therapy of pelvic malignancies. Symptoms include haematochezia, diarrhoea, tenesmus, urgency, faecal incontinence, and rectal pain. Various therapies have been attempted with argon plasma coagulation (APC) currently being the treatment of choice, but complications such as ulceration and stricture are commonly encountered. There are limited data suggesting that radiofrequency ablation (RFA) may be an effective alternative to APC, in particular in transfusion-dependent patients. Here we report two cases of chronic radiation proctitis, one of whom was transfusion-dependent, who were safely and successfully treated with focal RFA. Haematochezia decreased significantly the day subsequent to treatment, and transfusion independence was achieved after a single session. Three to four sessions were required to eradicate the neovascular lesions. Post-therapeutic rectal re-epithelialisation occurred, and no bleeding was encountered during up to nine months of follow-up.

[Management of the buried bumper syndrome: a new minimally invasive technique--the push method]. / Management bei Buried-Bumper-Syndrom: neue endokopische minimalinvasive Push-Methode.

The so-called buried bumper syndrome is characterised by a pathological alteration of the percutaneous endoscopic gastrostomy (PEG) in the form of a tissue overgrowth of the internal bumper of the tube. A lack of mobilisation of the tube and/or continuous traction on the PEG causes the bumper to be impacted by stomach mucosa. The consequence is a local chronic inflammatory process that may result in the occlusion of the feeding tube. As of now, different therapeutic methods exist: the surgical technique based on common laparotomy, the local invasive removal by cutting along the tube and inner flange from the outside and pulling it out (pull method) and the endoscopic recovery from inside the stomach. The authors have developed and evaluated a new endoscopic, minimally invasive technique (push method). In eight of nine patients the inner bumper could be freed by cutting with a papillotome which is brought into the stomach through the shortened PEG from the outside while maintaining endoscopic control. Afterwards the bumper is pushed to the inside with a dilatator and the patients are provided with a balloon system using the persisting stoma. The subsequent healing process proved to yield no further complications.

[Gastropexy supported single-step button gastrostomy - clinical results of a new technique for percutanous feeding tube implantation]. / Einzeitige Button-Gastrostomie mittels Gastropexie - klinische Ergebnisse einer neuen Technik zur perkutanen Sondenanlage.

BACKGROUND: Skin-level gastrostomy devices have been established to maintain enteral nutrition in clinical practice. Unfortunately there is still a need for a second intervention to place the secondary system. The combination of a new introducer technique with endoscopic controlled gastropexy for PEG and the primary placement of a button system leads to a safe stomal fixation of the balloon device. The aim of this study was to evaluate for the first time the safety of this combined approach. METHODS: Between 2000 and 2005 five patients were treated with this new technique and received a single-step button gastrostomy. All patients were followed with a standardised protocol. RESULTS: No major complications were seen during follow-up. The system could be removed within 6 - 18 weeks without any problems. CONCLUSIONS: On the basis of our first experience we conclude that by combination of the three techniques, introducer PEG with gastropexy, Seldinger wire, and balloon-type button, a single-step button gastrostomy can be safely performed.

[A 76-year-old male patient with iron deficiency anaemia - first experience with single-balloon enteroscopy]. / 76-jähriger Patient mit chronischer Eisenmangelanämie - erste Erfahrungen mit dem Single-Ballon-Enteroskopiesystem.

Diagnosis of and therapy for small bowl disease is a new challenge for modern endoscopy. Following the development of capsule endoscopy it is possible to inspect the whole small intestine. Therefore one needs adequate endoscopes in order to take tissue samples and perform the corresponding therapeutic measures. Today, the technical procedure of double-ballon enteroscopy is established and is available for routine clinical use. Double-ballon enteroscopy is usable both perorally and peranally, and can be used to inspect the entire small intestine. However, there are a few difficulties with the handling, which are time-consuming. Recently, the new single-ballon enteroscopy system SIF-Q180 was introduced which consists of a dedicated endoscope without an attached balloon, an overtube with a balloon, and an air controller to inflate or deflate the balloon of the overtube. We report the case of a patient admitted to our hospital in order to to detect the reason for an iron deficiency anaemia.

[Duodenal ileus due to an intramural duodenal haematoma. Conservative therapy using a multiple lumen intestinal probe]. / Duodenalileus bei Darmwandhämatom. Konservative Therapie mit einer mehrlumigen Intestinalsonde.

HISTORY AND ADMISSION FINDINGS: A 68-year-old woman was admitted with upper abdominal symptoms, epigastric fullness and nausea, eight days after initiation of heparin anticoagulation for deep-vein thrombosis. There were no other clinical abnormalities. INVESTIGATIONS: Abdominal ultrasound and computed tomography showed an intramural duodenal haematoma. Endoscopy revealed a stenosing lesion in the duodenum. TREATMENT AND COURSE: Instead of conventional parenteral nutrition, a triple-lumen feeding tube was placed, one lumen in the jejunum for feeding, the other for gastric decompression. Six months later the symptoms had completely disappeared and ultrasound, endoscopy and computed tomography no longer detected any lesion. CONCLUSION: Intrajejunal feeding and gastric decompression via a multi-lumen tube provided effective conservative treatment of duodenal ileus together with gastric decompression.

[Multiple focal liver lesions of a 33 year-old female. Presentation of an unexpected differential diagnosis]. / Multiple Rundherde der Leber bei einer 33-jährigen Patientin. Falldarstellung einer ungewöhnlichen Differenzialdiagnose.

We report the case of a 33 year-old female with a history of 16 years of oral contraception who had been admitted to hospital for further diagnosis of multiple focal liver lesions; laboratory findings showed elevated levels of gamma-GT und AP. Diagnostic procedures showed no primary malignancy as possible reason for metastasis. All further imaging procedures compared with doppler-enhanced ultrasound did not help in diagnosis and lead to inconsistent results. Transcutaneous liver-biopsy showed normal liver histology. In laparoscopic biopsy the result was multifocal adenoma. Because of the rupture risk and potential malignant transformation and no change of sonomorphologic appearance within 12 months a liver-segment resection has been undertaken. Pathology revealed the diagnosis of a multifocal hyperplastic-adenomateous focal-nodular hyperplasia. This case shows that there is no need to use different methods of medical imaging redundantly. We favor a fine-needle double-puncture (lesion and extra-lesion) and tissue examination through an experienced pathologist. A total resection of the lesion is necessary in case of resting uncertainty to characterize its tissue characteristics.

[Skin-level gastrostomy -- long-term results from a prospective trial in gastric and jejunal application]. / Button-Gastrostomie -- Langzeitergebnisse einer prospektiven Untersuchung bei gastraler und jejunaler Anwendung.

OBJECTIVE: The usefulness of skin-level gastrostomy tubes (button systems) for maintaining nutrition support after primary insertion of percutaneous endoscopic gastrostomy (PEG) is widely accepted. After first promising experiences with newly developed skin-level gastrostomy system (Freka-Button Gastrostomy) the safety and long-term stability of this new tube was not defined. MATERIAL AND METHODS: In a cohort study we prospectively evaluated from 2.1998 until 12.2001 for ease of use, complications, time to failure and long-term follow-up of 61 Freka button gastrostomies inserted in 50 patients (mean age 57.6 years, range 6 - 78 years, 44 men, 6 women). Mean time after primary PEG placement was 6.3 months (range 1 - 30 months). RESULTS: Correct application of all buttons (48 gastric, 2 jejunal) was easy and fast (median time 11 minutes) to perform. In 56 % we used a new Seldinger guide wire technique to improve stomal passage. Within the first ten days and during long-term follow-up (median 248, range 2 - 593 days) no major complication was seen. 11 systems had to be replaced mainly due to balloon failure (median 352, range 186 - 593 days). The total observation time were 15,128 days with a system failure rate of 0.26 per year. CONCLUSION: The Freka-button systems provides an easy-to-use, safe, and feasible alternative for long-term use of skin-level gastrostomy. First jejunal application of this new device was promising but needs further evaluation.

[Gastrointestinal stromal tumours (GIST) of the jejunum in a patient with neurofibromatosis type 1 (von Recklingshausen's disease)]. / Gastrointestinale Stromatumoren (GIST) des Jejunums bei einer Patientin mit Neurofibromatose Typ 1 (Morbus von Recklinghausen).

CASE REPORT: A 72-year-old female patient with known neurofibromatosis type 1 was admitted to the hospital with symptomatic anaemia and a history of melaena. Upper and lower endoscopy did not show any signs of bleeding. Ultrasound and computed tomography revealed an abdominal mass. The histological analysis of a US-guided puncture showed a mesenchymal tumour with spindle-shaped appearance. Laparotomy revealed two jejunal tumours which could be classified as gastrointestinal stromal tumours (GIST) by immunohistochemistry. CONCLUSION: Patients with neurofibromatosis type 1 have an increased risk of developing gastrointestinal tumours including rare types such as GIST. Because the localisation in the small intestine by conventional endoscopy can be difficult, further diagnostic means such as ultrasound, computed tomography or possibly capsule endoscopy should be considered.

[Biliary ascariasis after cholecystectomy and papillotomy in a non-endemic area]. / Biliäre Askariasis nach Cholezystektomie und Papillotomie in einem Nicht-Endemiegebiet.

HISTORY AND ADMISSION FINDINGS: A 61-year-old woman was admitted to hospital with nausea and vomiting. Four years earlier she had undergone cholecystectomy and papillotomy. INVESTIGATIONS: Laboratory examination showed a slight increase of aspartate and alanine aminotransferase, glutamyl transpeptidase, and moderate eosinophilia. Ultrasound revealed an elongated echogenic structure within the common bile duct. At endoscopic cholangiopancreaticography (ERCP) a 23 cm-long Ascaris lumbricoides was found. TREATMENT AND COURSE: The worm was removed endoscopically with forceps. Antihelmintic therapy with mebendazole was given. After that the patient was well and laboratory findings were normal. CONCLUSION: Biliary ascariasis should also be considered in a non-endemic area. Previous cholecystectomy and papillotomy are predisposing factors. In our case ERCP was the diagnostic and therapeutic method of choice.

Self-expanding metal stents for gastroduodenal malignancies: systematic review of their clinical effectiveness.

BACKGROUND AND STUDY AIMS: The current standard approach to the management of malignant gastric outlet obstruction mainly involves bypass surgery, which is associated with significant rates of mortality and morbidity. Recently, metal stents have emerged as a new therapeutic option. The aim of the present study was to review the currently published evidence on the effectiveness and safety of this form of endoscopic treatment. MATERIALS AND METHODS: A systematic review of the published data was carried out by searching medline, embase, and abstracts from the major gastroenterological conferences from January 1992 to September 2003. A total of 136 relevant publications were identified (case series, single case reports, letters and editorials, or reviews). The systematic review included 32 case series from a total of 46 publications identified as reporting primary clinical data. Abstracts and single case reports were not taken into account. Analysis of these 32 case series included data on technical success (successful stent placement and deployment), clinical success (relief of symptoms such as nausea and vomiting, and/or improvement of food intake), and complications. Pooled results were calculated from the 32 studies (10 of which were prospective). RESULTS: Stent insertion was attempted in 606 patients with malignant symptomatic gastroduodenal obstruction; 94 % of the patients were unable to take food orally or were mainly ingesting liquids. Stent placement and deployment were successful in 589 of the patients (97 %). Clinical success was achieved in 526 patients in the group in which technical success was reported (89 %; 87 % of the entire group undergoing stenting). Disease-related factors accounted for the majority of clinical failures. Oral intake became possible in all of the patients in whom a successful procedure was carried out, with 87 % taking soft solids or a full diet, with final resolution of symptoms occurring after a mean of 4 days. There was no procedure-related mortality. Severe complications (bleeding and perforation) were observed in seven patients (1.2 %). Stent migration was reported in 31 patients (5 %). Stent obstruction occurred in 104 cases (18 %), mainly due to tumor infiltration. The mean survival period was 12.1 weeks. CONCLUSIONS: Published evidence from case series suggests that gastroduodenal stenting offers good palliation and is a safe and effective treatment option in patients with a short remaining lifespan. However, patient selection for this intervention continues to be an issue requiring thorough consideration, and studies comparing the method with surgery are needed.