Correction to: Prognostic Assessment of Non-functioning Neuroendocrine Pancreatic Neoplasms as a Basis for Risk-Adapted Resection Strategies.

This article contains parts of the doctoral thesis of F. Meyer.

Cisplatin and 5-fluorouracil with or without epidermal growth factor receptor inhibition panitumumab for patients with non-resectable, advanced or metastatic oesophageal squamous cell cancer: a prospective, open-label, randomised phase III AIO/EORTC trial (POWER).

BACKGROUND: Palliative chemotherapy of advanced oesophageal squamous cell cancer (ESCC) consists of cisplatin/5-fluorouracil (CF) to target epidermal growth factor receptor (EGFR) with panitumumab (P); chemotherapy enhanced overall survival (OS) in advanced colorectal or squamous cell head and neck cancers. With prospective serum and tumour biomarkers, we tested if P added to CF (CFP) improved OS in advanced ESCC. PATIENTS AND METHODS: Eligible patients with confirmed ESCC that was not curatively resectable or did not qualify for definitive radiochemotherapy, were randomised 1 : 1 to receive CF [cisplatin (C) 100 mg/m2 i.v., day 1; 5-fluorouracil (F) 1000 mg/m2 i.v., days 1-4] or CF plus P (9 mg/kg, i.v., day 1, each q3-week cycle) until progressive disease or unacceptable toxicity. Safety was reviewed by the Data Safety Monitoring Board after 40, 70 and 100 patients who completed at least one cycle. After 53 enrolled patients, cisplatin was reduced from 100 mg/m2 to 80 mg/m2. RESULTS: The trial was stopped early based on interim efficacy results triggered by the third safety analysis: median OS (mOS) favoured CF over CFP, regardless of cisplatin dose [hazard ratio (HR) 1.77, 95% confidence interval (CI) 1.06-2.98; P = 0.028]. In the final analysis, mOS was 10.2 versus 9.4 months for CF versus CFP, respectively (HR 1.17, 95% CI 0.79-1.75; P = 0.43). One hundred (70.4%) of 142 patients in the safety population died, 51 (51.0%) with CFP. Most deaths were related to disease progression [44/49 (90%) deaths in CF versus 34/51 (67%) deaths in CFP]; objective responses [27/73 (37.0%)] were identical. The most common serious adverse events were kidney injury [3 (4.3%) versus 7 (9.7%)], general health deterioration [5 (7.1%) versus 5 (6.9%)] and dysphagia [4 (5.7%) versus 4 (5.6%)] in CF versus CFP, respectively. There were three (4.3%) and 17 (23.6%) common terminology criteria for adverse events (CTCAE) grade 5 events in CF versus CFP, respectively. Low soluble (s)EGFR levels were associated with better progression-free survival; sEGFR was induced under CFP. CONCLUSION: EGFR inhibition added to CF did not improve survival in unselected advanced ESCC patients. The results support further liquid biopsy studies. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01627379) and EudraCT (2010-020606-15).

Prognostic Assessment of Non-functioning Neuroendocrine Pancreatic Neoplasms as a Basis for Risk-Adapted Resection Strategies.

BACKGROUND: In contrast to exocrine pancreatic carcinomas, prognosis and treatment of pancreatic neuroendocrine neoplasms (PNEN) are significantly different. The variable growth pattern and associated clinical situation of functioning and non-functioning PNEN demand an individualized surgical approach. However, due to the scarce evidence associated with the rare disease, guidelines lack detailed recommendations for indication and for the required extent of surgical resection. METHODS: In a retrospective single-center study from 1990 to 2018, 239 patients with PNEN were identified. Clinical data were collected in the MaDoc database of the University Medical Center Mainz. A total of 155 non-functional PNEN were selected for further analysis. RESULTS: According to the classification of NET by the WHO in 2017, 28.8% (n = 40) of the tumors were G1, 61.9% (n = 86) G2, and 9.4% (n = 13) G3. In 73 patients, hepatic metastases were present. Sixty patients had lymph node metastasis. An R0 resection was achieved in 98 cases, an R1 situation in 10 cases. Five times, a tumor debulking was carried out (R2) and 5 times the operation was aborted without any resection because of the advanced tumor stage. A relapse occurred in 29 patients. Different prognostic factors (grade, tumor size, age) were analyzed. Grade-dependent 10-year overall survival rates were 79.5% (grade 1) and 60.1% (grade 2), respectively. The survival rate of grade 3 patients was limited to 66.7% after 13 months. CONCLUSION: In our study, patients with non-functioning PNEN had a longer overall survival after successful R0 resection. The risk analysis confirmed a Ki-67 cutoff value of 5%, which divided a high- and low-risk group. Patients with a PNEC G3 (Ki-67 index > 50%) had a very poor prognosis.

[Liver injury induced by immune checkpoint inhibitor-therapy : Example of an immune-mediated drug side effect]. / Leberschaden durch Therapie mit Immun-Checkpoint-Inhibitoren : Beispiel einer immunvermittelten Medikamentennebenwirkung.

BACKGROUND: Drug-induced liver injury is increasing, especially in elderly patients with polymedication and multimorbidity. OBJECTIVES: Clinicopathologic correlation of immune-mediated liver injury, specifically liver injury following therapy with immune checkpoint inhibitors against PD-1, PDL-1, and CTLA4. METHODS: Histologic assessment of liver biopsies of nine patients after therapy with immune checkpoint inhibitors and correlation with clinical parameters. RESULTS: In all nine patients, liver injury was apparent after variable administration of immune checkpoint inhibitors. Transaminase levels were increased up to a maximum of 3818 U/l. Liver histology showed liver injury resembling autoimmune hepatitis respective cholangitis. In two patients, veno-occlusive disease was seen. Corticosteroid therapy was initiated in eight patients, subsequently four patients showed decreasing transaminases and five patients died of tumor progress. In three patients, it remains unclear whether liver injury by immune checkpoint inhibitors may have ultimately contributed to the fatal course, especially in one patient with liver cirrhosis and hepatocellular carcinoma. CONCLUSIONS: Therapy with immune checkpoint inhibitors may lead to potentially fatal immune phenomena in susceptible patients, which may affect liver and/or other organs independently. Other causes of hepatopathy need to be ruled out clinically and/or histologically.

[Unusual dysphagia in IgG4-related disease]. / Ungewöhnliche Schluckbeschwerden bei IgG4­assoziierter Erkrankung.

This article presents the case of an IgG4-related disease in a patient with clinical signs of a malignant tumor of the oral cavity. After excluding the suspicion of a malignant lesion, vasculitis and various infectious diseases were ruled out. Finally, due to further immunohistochemical studies, IgG4-related disease was diagnosed.

Surgical Treatment of NEN of Small Bowel: A Retrospective Analysis.

BACKGROUND: Neuroendocrine Neoplasms of the small intestine have been noticed more frequently over the past 35 years. They constitute about 25% of all NENs and 29% of all tumors of the small intestine. Due to the predominantly indolent nature and overall good prognosis, the benefit of surgical treatment is still debated. METHODS: In a retrospective study, data of 83 surgically treated patients with neuroendocrine neoplasms of the small intestine, 48 males and 35 females with a median age of 62 years (range 25-86 years) were analyzed. Patient data were documented in the MaDoc database for neuroendocrine tumors of the University Medical Center of Mainz. IBM SPSS Statistics 20 was used for statistical analysis. Kaplan-Meier survival curves and Log-Rank tests, censoring patients at the time of last follow-up, were used to compare the overall survival depending on potential prognostic factors (stage, grade, surgical treatment). RESULTS: At the time of diagnoses, the most common clinical symptoms were abdominal pain (n = 31, 37.3%), bowel obstruction (n = 11, 13.3%), bowel perforation and peritonitis (n = 3, 3.6%), gastrointestinal bleeding (n = 9, 10.8%), weight loss (n = 11, 13.3%), and carcinoid syndrome (n = 27, 32.5%). 65 patients (78.3%) had lymph node metastasis and in 58 patients (69.9%) distant metastasis were present. Segmental bowel resection (44) was the most common surgical procedure, followed by right hemi-colectomy (32) and explorative laparotomy (7). In most patients (78.9%), lymphadenectomy (systematic/selective) was performed. The 5-year survival of patients who underwent a systematic or a selective lymphadenectomy differed significantly (82.2 vs. 40.0%). The overall 3-, 5-, and 10-year survival rates were 88.2, 80.3, and 71.0%, respectively. CONCLUSION: Mesenteric lymph node metastases are almost invariably present and have significant impact on patients' prognosis. Systematic lymphadenectomy prevents complications and improves the survival. Early surgical treatment should be the goal in order to prevent complications.

Pulmonary effects of expiratory-assisted small-lumen ventilation during upper airway obstruction in pigs.

Novel devices for small-lumen ventilation may enable effective inspiration and expiratory ventilation assistance despite airway obstruction. In this study, we investigated a porcine model of complete upper airway obstruction. After ethical approval, we randomly assigned 13 anaesthetised pigs either to small-lumen ventilation following airway obstruction (n = 8) for 30 min, or to volume-controlled ventilation (sham setting, n = 5). Small-lumen ventilation enabled adequate gas exchange over 30 min. One animal died as a result of a tension pneumothorax in this setting. Redistribution of ventilation from dorsal to central compartments and significant impairment of the distribution of ventilation/perfusion occurred. Histopathology demonstrated considerable lung injury, predominantly through differences in the dorsal dependent lung regions. Small-lumen ventilation maintained adequate gas exchange in a porcine airway obstruction model. The use of this technique for 30 min by inexperienced clinicians was associated with considerable end-expiratory collapse leading to lung injury, and may also carry the risk of severe injury.