Prognosis and tumor biology of pancreatic cancer patients with isolated lung metastases: translational results from the German multicenter AIO-YMO-PAK-0515 study.

BACKGROUND: Pulmonary metastasis (M1-PUL) as first site of dissemination in pancreatic ductal adenocarcinoma (PDAC) is a rare event and may define a distinct biological subgroup. PATIENTS AND METHODS: Arbeitsgemeinschaft Internistische Onkologie-Young Medical Oncologists-Pankreas-0515 study (AIO-YMO-PAK-0515) was a retrospective German multicenter study investigating clinical and molecular characteristics of M1-PUL PDAC patients; 115 M1-PUL PDAC patients from 7 participating centers were included. Clinical characteristics and potential prognostic factors were defined within the M1-PUL cohort. Archival tumor samples were analyzed for Her2/neu, HNF1A and KRT81 expression. Additionally, messenger RNA (mRNA) expression analysis (using a 770-gene immune profiling panel) was carried out in the M1-PUL and in a control cohort (M1-ANY). RESULTS: Median overall survival in the entire M1-PUL cohort was 20 months; the most favorable prognosis (median survival: 28 months) was observed in the subgroup of 66 PDAC patients with metachronous lung metastases after previous curative-intent surgery. The number of metastatic lesions, uni- or bilateral lung involvement as well as metastasectomy were identified as potential prognostic factors. Her2/neu expression and PDAC subtyping (by HNF1A and KRT81) did not differ between the M1-PUL and the M1-ANY cohort. mRNA expression analysis revealed significant differentially expressed genes between both cohorts: CD63 and LAMP1 were among the top 20 differentially expressed genes and were identified as potential mediators of organotropism and favorable survival outcome of M1-PUL patients. CONCLUSION: M1-PUL represents a clinically favorable cohort in PDAC patients. Site of relapse might already be predetermined at the time of surgery and could potentially be predicted by gene expression profiling.

Real-World Efficacy of Nintedanib Plus Docetaxel After Progression on Immune Checkpoint Inhibitors: Results From the Ongoing, Non-interventional VARGADO Study.

AIMS: To evaluate the efficacy and safety of nintedanib plus docetaxel in patients with advanced adenocarcinoma non-small cell lung cancer (NSCLC) who progressed after chemotherapy and immune checkpoint inhibitor (ICI) therapy. MATERIALS AND METHODS: VARGADO (NCT02392455) is an ongoing, prospective, non-interventional, real-world study of nintedanib plus docetaxel after first-line chemotherapy in the routine clinical treatment of patients with locally advanced, metastatic or locally recurrent adenocarcinoma NSCLC. Data were collected during routine visits. We report the results from cohort B (n = 80), who received third-line nintedanib plus docetaxel after first-line chemotherapy and second-line ICI therapy. RESULTS: The median duration of follow-up was 12.4 months. Median progression-free survival from initiation of third-line nintedanib plus docetaxel was 6.4 months (95% confidence interval 4.8, 7.3); median overall survival was 12.1 months (95% confidence interval 9.4, 13.5). The 1-year overall survival rate after initiation of third-line nintedanib plus docetaxel treatment (primary end point) was 52% (95% confidence interval 38.0%, 64.4%). Among 64 patients with a documented response, the objective response rate was 50% (n = 32; one complete response and 31 partial responses) and the disease control rate was 86% (n = 55). There were no new safety signals or unexpected toxicities. Among all treated patients, 74% (n = 59) experienced drug-related adverse events, most commonly (nintedanib-related/docetaxel-related) diarrhoea (34%/24%), a decreased white blood cell count (11%/19%) and nausea (13%/16%). CONCLUSIONS: Nintedanib plus docetaxel demonstrated a high response rate and disease stabilisation in the third-line setting after failure of prior chemotherapy and ICI treatment, with a manageable safety profile. These results suggest that nintedanib plus docetaxel represents an efficient treatment option after failure of prior ICIs. The ongoing VARGADO study provides valuable real-world data to inform clinical decision-making regarding treatment sequencing after chemotherapy and ICI failure in patients with adenocarcinoma NSCLC.

Alterations in regulatory T cells and immune checkpoint molecules in pancreatic cancer patients receiving FOLFIRINOX or gemcitabine plus nab-paclitaxel

Purpose This pilot study aimed on generating insight on alterations in circulating immune cells during the use of FOLFIRINOX and gemcitabine/nab-paclitaxel in pancreatic ductal adenocarcinoma (PDAC). Patients and methods Peripheral blood mononuclear cells were isolated before and 30 days after initiation of chemotherapy from 20 patients with advanced PDAC. Regulatory T cells (FoxP3+) and immune checkpoints (PD-1 and TIM-3) were analyzed by flow cytometry and immunological changes were correlated with clinical outcome. Results Heterogeneous changes during chemotherapy were observed in circulating T-cell subpopulations with a pronounced effect on PD-1+ CD4+/CD8+ T cells. An increase in FoxP3+ or PD-1+ T cells had no significant effect on survival. An increase in TIM3+/CD8+ (but not TIM3+/CD4+) T cells was associated with a significant inferior outcome: median progression-free survival in the subgroup with an increase of TIM-3+/CD8+ T cells was 6.0 compared to 14.0 months in patients with a decrease/no change (p = 0.026); corresponding median overall survival was 13.0 and 20.0 months (p = 0.011), respectively. Conclusions Chemotherapy with FOLFIRNOX or gemcitabine/nab-paclitaxel induces variable changes in circulating T-cell populations that may provide prognostic information in PDAC (AU)

[Management of Adult Community-Acquired Pneumonia and Prevention - Update 2021 - Guideline of the German Respiratory Society (DGP), the Paul-Ehrlich-Society for Chemotherapy (PEG), the German Society for Infectious Diseases (DGI), the German Society of Medical Intensive Care and Emergency Medicine (DGIIN), the German Viological Society (DGV), the Competence Network CAPNETZ, the German College of General Practitioneers and Family Physicians (DEGAM), the German Society for Geriatric Medicine (DGG), the German Palliative Society (DGP), the Austrian Society of Pneumology Society (ÖGP), the Austrian Society for Infectious and Tropical Diseases (ÖGIT), the Swiss Respiratory Society (SGP) and the Swiss Society for Infectious Diseases Society (SSI)]. / Behandlung von erwachsenen Patienten mit ambulant erworbener Pneumonie ­ Update 2021.

The present guideline provides a new and updated concept of the management of adult patients with community-acquired pneumonia. It replaces the previous guideline dating from 2016.The guideline was worked out and agreed on following the standards of methodology of a S3-guideline. This includes a systematic literature search and grading, a structured discussion of recommendations supported by the literature as well as the declaration and assessment of potential conflicts of interests.The guideline has a focus on specific clinical circumstances, an update on severity assessment, and includes recommendations for an individualized selection of antimicrobial treatment.The recommendations aim at the same time at a structured assessment of risk for adverse outcome as well as an early determination of treatment goals in order to reduce mortality in patients with curative treatment goal and to provide palliation for patients with treatment restrictions.

Behandlung von erwachsenen Patienten mit ambulant erworbener Pneumonie: update 2021

Die vorliegende Leitlinie umfasst ein aktualisiertes Konzept der Behandlung und Prävention von erwachsenen Patienten mit ambulant erworbener Pneumonie und löst die bisherige Leitlinie aus dem Jahre 2016 ab. Sie wurde entsprechend den Maßgaben zur Methodologie einer S3-Leitlinie erarbeitet und verabschiedet. Hierzu gehören eine systematische Literaturrecherche und -bewertung, die strukturierte Diskussion der aus der Literatur begründbaren Empfehlungen sowie eine Offenlegung und Bewertung möglicher Interessenskonflikte. Die Leitlinie zeichnet sich aus durch eine Zentrierung auf definierte klinische Situationen, eine aktualisierte Maßgabe der Schweregradbestimmung sowie Empfehlungen zu einer individualisierten Auswahl der initialen antimikrobiellen Therapie. Die Empfehlungen zielen gleichzeitig auf eine strukturierte Risikoevaluation als auch auf eine frühzeitige Bestimmung des Therapieziels, um einerseits bei kurativem Therapieziel die Letalität der Erkrankung zu reduzieren, andererseits bei palliativem Therapieziel eine palliative Therapie zu eröffnen.

The present guideline provides a new and updated concept of the management of adult patients with community-acquired pneumonia. It replaces the previous guideline dating from 2016.The guideline was worked out and agreed on following the standards of methodology of a S3-guideline. This includes a systematic literature search and grading, a structured discussion of recommendations supported by the literature as well as the declaration and assessment of potential conflicts of interests.The guideline has a focus on specific clinical circumstances, an update on severity assessment, and includes recommendations for an individualized selection of antimicrobial treatment.The recommendations aim at the same time at a structured assessment of risk for adverse outcome as well as an early determination of treatment goals in order to reduce mortality in patients with curative treatment goal and to provide palliation for patients with treatment restrictions.

Alterations in regulatory T cells and immune checkpoint molecules in pancreatic cancer patients receiving FOLFIRINOX or gemcitabine plus nab-paclitaxel.

PURPOSE: This pilot study aimed on generating insight on alterations in circulating immune cells during the use of FOLFIRINOX and gemcitabine/nab-paclitaxel in pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Peripheral blood mononuclear cells were isolated before and 30 days after initiation of chemotherapy from 20 patients with advanced PDAC. Regulatory T cells (FoxP3+) and immune checkpoints (PD-1 and TIM-3) were analyzed by flow cytometry and immunological changes were correlated with clinical outcome. RESULTS: Heterogeneous changes during chemotherapy were observed in circulating T-cell subpopulations with a pronounced effect on PD-1+ CD4+/CD8+ T cells. An increase in FoxP3+ or PD-1+ T cells had no significant effect on survival. An increase in TIM3+/CD8+ (but not TIM3+/CD4+) T cells was associated with a significant inferior outcome: median progression-free survival in the subgroup with an increase of TIM-3+/CD8+ T cells was 6.0 compared to 14.0 months in patients with a decrease/no change (p = 0.026); corresponding median overall survival was 13.0 and 20.0 months (p = 0.011), respectively. CONCLUSIONS: Chemotherapy with FOLFIRNOX or gemcitabine/nab-paclitaxel induces variable changes in circulating T-cell populations that may provide prognostic information in PDAC.

Afatinib plus gemcitabine versus gemcitabine alone as first-line treatment of metastatic pancreatic cancer: The randomised, open-label phase II ACCEPT study of the Arbeitsgemeinschaft Internistische Onkologie with an integrated analysis of the 'burden of therapy' method.

BACKGROUND: Targeting the epidermal growth factor receptor pathway remains controversial in pancreatic cancer. Afatinib is an oral irreversible ErbB family blocker approved in non-small-cell lung cancer. This open-label, multicenter, randomised phase II trial evaluated gemcitabine plus afatinib (Gem/afatinib) versus gemcitabine (Gem) alone as first-line treatment for metastatic pancreatic cancer. PATIENTS AND METHODS: Patients were randomised in a 2:1 ratio to either Gem (1000 mg/m2 weekly for three weeks followed by one week of rest, repeated every four weeks) and afatinib (40 mg orally once daily) or Gem alone. Overall survival (OS) was the primary study end-point. The novel BOTh©™ methodology was implemented to derive a quantitative estimate for the 'Burden of Therapy/Toxicity' (BOTh) for each patient on every day during the clinical study. RESULTS: One hundred nineteen patients from 25 centres were randomised, 79 patients for Gem/afatinib and 40 for Gem. Median OS was 7.3 months in the Gem/afatinib arm versus 7.4 months in the Gem-alone arm (hazard ratio [HR]: 1.06, p = 0.80). Median progression-free survival was identical in both arms (3.9 months versus 3.9 months, HR: 0.85, p = 0.43). Adverse events were more frequent in the Gem/afatinib arm, especially diarrhoea (71% vs. 13%) and skin rash (65% vs. 5%). The BOTh©™ analysis revealed a significantly higher burden of toxicity in the combination arm (p = 0.0005). CONCLUSION: The addition of afatinib to Gem did not improve treatment efficacy and was more toxic. The BOTh©™ methodology allowed a detailed insight into the course of treatment-related adverse events over the study period. The trial was registered at clinicaltrials.gov (NCT01728818) and Eudra-CT (2011-004063-77).

[Lymphangiomatosis: Rare Cause of Pleural Effusion]. / Lymphangiomatose − seltene Ursache eines Pleuraergusses.

A 33-year-old man presented to us with slowly progressive dyspnea. At the physical examination we found pleural effusion on the right side, lymph edema of the left lower limb and foot and blotchy map-like skin changes. The pleural puncture revealed a chylous effusion. In whole body MRI we saw the pleural effusion on the right, an increase in lymph vessels in the pelvis and paraaortic, and prominent chylous vessels. There was no bone involvement. The abdominal thoracic duct was enlarged by up to 3 mm. We diagnosed a general lymphatic anomaly (GLA) - lymphangiomatosis. GLA is a rare disease of unknown origin with dysplasia of the lymphatic system. The thoracic manifestation is often the development of chylous pleural effusions. However, many other organs can also be involved. Therapy includes in most cases symptomatic relief and the attempt to slow the progression of the disease.

[Lung Cancer with Prominent Mediastinal Lymphadenopathy - Who Thinks of NUT Carcinoma?] / Lungenkarzinom mit ausgeprägter mediastinaler Lymphadenopathie ­ wer denkt an ein NUT-Karzinom?

A 39-year-old woman presented with back pain at an orthopaedic clinic. Magnet resonance tomography revealed a spinal tumour. Further imaging also showed a pulmonary tumour, massive mediastinal lymphadenopathy as well as unilateral pleural effusion. Histology from biopsies from the spinal tumour and from a mediastinal lymph node revealed NUT carcinoma. The NUT carcinoma that earlier has been named NUT midline carcinoma is a very rare, aggressive tumour with a poor prognosis. Initially, the NUT carcinoma was thought to develop from organs in the midline such as upper airways or mediastinal cavity. However, the NUT carcinoma is not limited to structures in the midline. NUT carcinoma often affects young patients. Due to its low incidence, a standardized therapy could not be established until now.

Neurotrophic tropomyosin receptor kinase (NTRK) and nerve growth factor (NGF) are not expressed in Caucasian patients with biliary tract cancers: pooled data from three independent cohorts.

BACKGROUND: Neuronal signaling has been implicated in the pathophysiology of multiple malignancies. In biliary tract cancers (BTCs), tumor cell expression of nerve growth factor (NGF) and its receptor neurotrophic tropomyosin receptor kinase (NTRK) has been reported in Asian patients and linked to inferior clinical outcome. Furthermore, NTRK fusions have emerged as a promising target in various cancers. Expression patterns of these markers in Caucasian patients remain unknown. METHODS: In this study, 106 patients with BTCs were included. Immunohistochemistry for pan-NTRK and NGF-beta was performed on > 90 samples of this cohort. Additionally, samples from two independent cohorts, incorporating 254 cases, were used to confirm the findings of the original cohort. RESULTS: While expression of pan-NTRK and NGF-beta was readily detectable in peri-tumoral nerves, these markers were not detectable in malignant epithelial cells in our cohort. CONCLUSIONS: In a large cohort of Caucasian patients with BTC, NTRK and NGF-beta were not detectable, underscoring potential differences between Caucasian and Asian patient populations.

Numerical simulation of the electric field distribution in an electrical stimulation device for scaffolds settled with cartilaginous cells.

Electrical stimulation is a promising approach to enhance cell viability and differentiation. We aim to develop a stimulation device for the investigation and realization of cartilaginous cell engineering. The stimulation setup is capable of applying well-defined electric fields to several scaffolds at the same time. The setup consists of a flat plate with multiple test tubes for the scaffolds. A flexible printed circuit board containing a separate pair of electrodes for each tube is fixed at the bottom of the plate. In this context, numerical simulation using Finite Element Method (FEM) is a valuable tool to gain a better understanding of the electric field distribution in such devices. The thin insulating layer of the flexible printed circuit board allows sufficient field strength to be achieved at moderate input voltages but presents challenges for modelling. In simulations, thin layers would usually require a fine discretization with many degrees of freedom (DOF). This leads to large models, which are expensive regarding memory and computation time. Based on the 'contact impedance' boundary condition available in COMSOL Multiphysics® 5.4, an alternative approach is proposed that can model thin layers in capacitively coupled setups. The resulting electric field distribution in the new stimulation setup is presented and discussed.

Repeated mutKRAS ctDNA measurements represent a novel and promising tool for early response prediction and therapy monitoring in advanced pancreatic cancer.

Background: The presence of mutated KRAS (mutKRAS ctDNA) in plasma samples has been consistently shown to be a negative prognostic indicator in pancreatic cancer (PC). Only small pilot studies have evaluated the value of serial mutKRAS ctDNA-measurements in PC. Patients and methods: The aim of the present study was to explore the potential of repeated mutKRAS ctDNA measurements for response prediction and therapy monitoring in advanced PC patients. We used the BEAMing technology to determine levels of mutKRAS ctDNA, CA 19-9, CEA and CYFRA 21-1 in 284 plasma samples of 54 patients with advanced PC receiving gemcitabine-based chemotherapy. Absolute levels and kinetics of mutKRAS ctDNA, CA 19-9, CEA and CYFRA 21-1 were correlated to radiological response, progression-free and overall survival. Results: mutKRAS ctDNA was present in a majority of advanced PC patients (n = 36/54, 67%) and indicated tissue KRAS mutation status with a high sensitivity (75%) and specificity (100%). The presence of mutKRAS ctDNA, as well as higher levels of CA 19-9, CEA and CYFRA 21-1 before initiation of the first-line chemotherapy, was significantly correlated to an adverse overall survival. During therapy, changes in mutKRAS ctDNA levels were more rapid and pronounced than changes in protein-based tumor markers. A decrease in mutKRAS ctDNA levels during therapy was an early indicator of response to therapy, while there was no significant correlation between kinetics of CA 19-9, CEA or CYFRA 21-1 and response to chemotherapy during the first four weeks of treatment. Repeated mutKRAS ctDNA measurements during follow-up appeared to be superior to protein-based tumor markers in detecting progressive disease (sensitivity: 83%, specificity: 100%). Conclusion: mutKRAS ctDNA kinetics appear to be a powerful and highly specific tool in early response prediction and therapy monitoring of advanced PC patients receiving chemotherapy.

Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer.

Background: We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC). Patients and methods: ALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders. Results: Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4-5.6) versus 10.3 months (95% CI: 8.6-12.0), P < 0.001; OS 15.0 months (95% CI: 5.0-24.9) versus 50.0 months (95% CI: 22.9-77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3-4.1) versus 6.2 months (95% CI: 1.8-10.5), P = 0.021; OS 2.0 months (95% CI: 0.0-4.6) versus 9.0 months (95% CI: 6.1-11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9-7.2) versus 14.0 months (95% CI: 8.0-20.1), P < 0.001; OS 17.0 months (95% CI: 6.7-27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1-10.7) versus 9.9 months (95% CI: 6.4-13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001). Conclusions: In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.

[Granular Cell Tumor of the Lung - a Visual Diagnosis on Bronchoscopy?] / Granularzelltumor der Lunge ­ eine bronchoskopische Blickdiagnose?

A 38 years old patient presented with a progressive reduction of his general condition and weight loss. Chest imaging revealed consolidations and cavities suggesting a mycobacterial infection. For further diagnosis, a bronchoscopy was performed. In fact, a nontuberculous mycobacterial infection was found. As an incidental finding, we saw a white polypoid tumor in the middle lobe bronchus. The histology of this tumor revealed a granular cell tumor (GCT). The GCT is a rare tumor entity which occurs at different anatomical locations. In the lungs, the GCT may become symptomatic as it can cause bronchial obstruction. In chest imaging, it can manifest as infiltration, atelectasis or nodule. Likewise, GCT can be found as an incidental finding in bronchoscopy. First choice treatment is surgical resection of the tumor.

Pain and structural alterations in knee joints in patients with haemophilia.

INTRODUCTION: Patients with haemophilia (PwH) suffer from haemophilic arthropathy which leads to an enhanced pain sensitivity. The aim of this study was to determine whether the individual pain condition in terms of pressure pain thresholds (PPT) at the knee joints is linked to changes of underlying anatomical structures in PwH. MATERIAL AND METHODS: Eleven landmarks at both knee joints of 36 PwH and 36 controls were examined in terms of PPT and ultrasound sonography (US). PPT were used to generate four groups: pain sensitive and insensitive knees of PwH and controls. RESULTS: PPT of the knee joints were significantly decreased at all landmarks in PwH when compared to controls (P ≤ .004). US findings revealed that especially osteophytes are more pronounced in pain-sensitive knees of PwH in comparison with pain-insensitive knees of PwH or pain-(in)sensitive knees of controls. The synovia tissue was also thickened in PwH when PPT was altered. In contrast to findings in osteoarthritis-related pain, no differences between the groups were found regarding effusion, whether assessed, for example on the distal edge of m. vastus lateralis (P = .893) or on the lateral joint space (P = .417). CONCLUSION: Particular degenerative changes in terms of osteophytes and thickness of synovial tissue are associated with an enhanced pain sensitivity in PwH. Altered PPT which were not associated with structural findings may be an indicator for a complex peripheral and/or central sensitization of the affected joints in PwH. The role of this mechanism should be clarified in further studies.

A novel heterozygous variant in ERLIN2 causes autosomal dominant pure hereditary spastic paraplegia.

BACKGROUND AND PURPOSE: Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous monogenic disorders. To date, nearly 70 genes are known to be causative. The aim of this project was to identify the genetic cause of autosomal dominantly inherited pure HSP in two large, unrelated non-consanguineous families. METHODS: The two families were characterized clinically and selected members underwent whole exome sequencing. Potentially disease-causing variants were confirmed by Sanger sequencing and their functional consequences on protein function were predicted by bioinformatic prediction tools. RESULTS: The patients presented with pure spastic paraplegia with age of onset between 9 and 46 years. In both families, a novel heterozygous missense variant in ERLIN2, c.386G>C; p.Ser129Thr, was the only potentially pathogenic variant identified that segregated with the disease. CONCLUSIONS: Biallelic variants in ERLIN2 are known to cause recessive HSP type SPG18. Here, the first two families with an autosomal dominant, pure form of HSP caused by a novel ERLIN2 heterozygous missense variant are described. These findings expand the mutational and inheritance spectrum of SPG18. ERLIN2 variants should also be considered in the diagnostic evaluation of patients with autosomal dominant HSP.