Summary of pretreatments of our patient cohort: 25 patients received one prior treatment, 33 pati... more Summary of pretreatments of our patient cohort: 25 patients received one prior treatment, 33 patients received two prior treatments, six patients received three prior treatments, two patients four prior treatments and one patient five prior treatments before starting dacarbazine. (DOCX 18Â kb)
The assessment of cancer patient care during the COVID-19 pandemic has been mainly reported from ... more The assessment of cancer patient care during the COVID-19 pandemic has been mainly reported from a physician’s perspective. Patients with rare tumor entities such as neuroendocrine tumors (NET), which require a complex and specialized care infrastructure, were highly affected by the COVID-19 crisis. Using a structured questionnaire consisting of a general section on the disease and a special COVID-19 section to record medical care, vaccination behavior as well as social and psycho-emotional parameters were collected from NET patients. The survey was distributed via direct medical contact and via the patient organization NETZWERK NeT. A total of 684 patients participated in the survey and 79.2% (n = 542) of the participants answered the questionnaire completely (54 questions). Patient characteristics were comparable to those in large NET registries. The majority of participants were patients with pancreatic and small bowel NET on somatostatin analogue (SSA) therapy. Medical care unde...
Background Cytotoxic chemotherapy combinations and targeted agents represent established treatmen... more Background Cytotoxic chemotherapy combinations and targeted agents represent established treatment concepts in advanced pancreatic neuroendocrine tumors (PNETs). However, response rates, side effects and outcome data strongly vary among these therapeutic approaches. Head-to-head comparisons between chemo- and molecular therapies are missing and secondary resistances frequently occur. The RamuNET trial aims to identify the effectiveness of dual treatment with DTIC and ramucirumab in progressive advanced PNET patients. Methods The RamuNET study is an investigator-initiated multicenter prospective single-arm trial to evaluate the efficacy of ramucirumab in combination with dacarbazine (DTIC) over a period of at least 6 months. Patients with progressive well-differentiated and metastatic pancreatic neuroendocrine tumors are eligible. The study aims to include 45 patients over a period of 24 months with a minimum follow-up of 24 months. The primary endpoint is disease control after 6 mon...
Compared to pancreatic adenocarcinoma (PDAC), pancreatic neuroendocrine tumors (PanNET) represent... more Compared to pancreatic adenocarcinoma (PDAC), pancreatic neuroendocrine tumors (PanNET) represent a rare and heterogeneous tumor entity. In addition to surgical resection, several therapeutic approaches, including biotherapy, targeted therapy or chemotherapy are applicable. However, primary or secondary resistance to current therapies is still challenging. Recent genome-wide sequencing efforts in PanNET identified a large number of mutations in pathways involved in epigenetic modulation, including acetylation. Therefore, targeting epigenetic modulators in neuroendocrine cells could represent a new therapeutic avenue. Detailed information on functional effects and affected signaling pathways upon epigenetic targeting in PanNETs, however, is missing. The primary human PanNET cells NT-3 and NT-18 as well as the murine insulinoma cell lines beta-TC-6 (mouse) and RIN-T3 (rat) were treated with the non-selective histone-deacetylase (HDAC) inhibitor panobinostat (PB) and analyzed for funct...
Stroma-infiltrating immune cells, such as tumor-associated macrophages (TAM), play an important r... more Stroma-infiltrating immune cells, such as tumor-associated macrophages (TAM), play an important role in regulating tumor progression and chemoresistance. These effects are mostly conveyed by secreted mediators, among them several cathepsin proteases. In addition, increasing evidence suggests that stroma-infiltrating immune cells are able to induce profound metabolic changes within the tumor microenvironment. In this study, we aimed to characterize the impact of cathepsins in maintaining the TAM phenotype in more detail. For this purpose, we investigated the molecular effects of pharmacological cathepsin inhibition on the viability and polarization of human primary macrophages as well as its metabolic consequences. Pharmacological inhibition of cathepsins B, L, and S using a novel inhibitor, GB111-NH2, led to changes in cellular recycling processes characterized by an increased expression of autophagy- and lysosome-associated marker genes and reduced adenosine triphosphate (ATP) cont...
ABSTRACTObjectiveThe COVID-19 pandemic challenges health care systems worldwide. In this situatio... more ABSTRACTObjectiveThe COVID-19 pandemic challenges health care systems worldwide. In this situation, guidelines for health care professionals in endoscopy units with increased risk of infection from inhalation of airborne droplets, conjunctival contact and faeces are urgently needed. Recently, the European Society of Gastrointestinal Endoscopy (ESGE) and the German Society for Pneumology (DGP) issued recommendations. However, real-world data on the conditions and requirements of endoscopy units to adhere to this guidance are missing.DesignWe conducted an internet-based survey among German endoscopy units from all levels of care from April 1st to 7th, 2020. The survey comprised 33 questions and was distributed electronically by the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS) and the DGP.ResultsIn total, 656 endoscopy units completed the survey. Overall, 253 units (39%) cancelled fewer than 40% of their procedures. Of note, private practices cancelled le...
Pancreatic neuroendocrine tumours (pNETs) represent rare neoplasms of all NETs often presenting w... more Pancreatic neuroendocrine tumours (pNETs) represent rare neoplasms of all NETs often presenting without functional activity. Many sporadic non-functioning pNET patients are already metastatic at the time of diagnosis, and the therapeutic approach to such patients is mostly palliative. In this international, multicentre, retrospective cohort study, we assessed the prognostic value of a set of anthropometric, clinical, biochemical, radiological and pathological parameters at baseline and the impact of the therapeutic strategies on the survival of patients with sporadic grade 1/2, stage IV, non-functioning pNETs. Three hundred and twelve consecutive patients diagnosed between 1993 and 2010 were included. The median overall survival (OS) was 6.6 years and survival at 5 and 10 years was 62 and 34% respectively. On univariate analysis, Eastern Cooperative Oncology Group (ECOG) status ≥2, grade 2, bilobar hepatic metastases, synchronous metastases, and high chromogranin A, alkalinephosphatase and lactic-dehydrogenase were associated with a significant reduction of OS. Palliative/curative surgery and loco-regional hepatic interventions were significant factors improving OS. On multivariate analysis, ECOG status ≥2, synchronous metastases, Ki-67 ≥10%, and high alkalinephosphatase correlated significantly with an increased risk of death. Both palliative/curative surgery and loco-regional hepatic interventions had a positive impact on OS. Although most parameters did not prove to be independent OS predictors at multivariate analysis, they showed a tendency towards that. Future prospective studies including larger patient populations may give greater clarity. We believe the integration of these parameters has the potential to provide a reliable prognostic score for the stratification of patients with sporadic well-differentiated metastatic non-functioning pNETs.
Introduction: The tumor microenvironment plays a role in growth of malignancies. There a many stu... more Introduction: The tumor microenvironment plays a role in growth of malignancies. There a many studies which investigate influence of tumorinfiltrating lymphocytes (TILs). There is great heterogeneity about how to quantify these cells. Aims: Therefore, we present a Quantification of the Tumor Stroma (QTS) Algorithm to quantify cells in the tumor stroma. Materials & methods: Immunohistochemistry of CD3 and CD8 antigens in metastatic colorectal cancer (mCRC), ovarian cancer (OvCa), hepatocellular carcinoma (HCC), and pancreatic cancer (PDAC) was performed (N¼80). Reliability of identification of hot spots was investigated using two blinded observers. Hot spots were defined as regions with highest density of TILs. To examine whether quantification of 1 vs 3 hot spots yields accurate results, CD8 + /CD3 + ratio as well as the absolute cell numbers were compared using intraclass-correlation (ICC). Computed counting software: ZEN 2 (ZC), ImageJ subjective threshold (ISC), and ImageJ colour deconvolution (IAC) were compared to manual counting using linear regression. Results: ICC for detection of hot spots were 0.949 in mCRC, 0.843 in OvCa, 0.805 in HCC, and 0.957 in PDAC. The ICC for CD8 + /CD3 + ratio in 1 hot spot compared to the average from 3 hot spots was consistent. The absolute cell count in 1 vs 3 hot spots reflected poor accuracy. ZC in PDAC yielded inconsistencies. ISC reached excellent results in all groups. IAC reached excellent reliability in mCRC and OvCa. Conclusion: ISC is accurate for sections with high background, whereas IAC for sections with low background staining. With the QTS Algorithm quantification of cells in the tumor stroma is reliable and accurate.
Pancreatic ductal adenocarcinoma is characterized by a poor prognosis and a low median survival, ... more Pancreatic ductal adenocarcinoma is characterized by a poor prognosis and a low median survival, despite improvements observed for many other solid tumours. Intensive research efforts have been undertaken during the last decades to discover new prognostic and treatment predictive biomarkers for pancreatic ductal adenocarcinoma. The mainstay of medical treatment for the disease has been the well-tolerated nucleoside analogue, gemcitabine. The only targeted agent currently used in pancreatic ductal adenocarcinoma patients is the epithelial growth factor receptor inhibitor erlotinib in combination with gemcitabine. Recently, treatment regimens such as a combination of fluorouracilleucovorin-irinotecan-oxaliplatin (FOLFIRINOX) and the combination of nab-paclitaxel with gemcitabine have been introduced for metastatic pancreatic ductal adenocarcinoma. Although these treatment regimens significantly improve survival of patients, there are no good predictive biomarkers available that can be used to identify who would benefit most from them. Therefore, the search for predictive biomarkers that would facilitate personalization of chemotherapy is highly relevant.
Der Barrett-Ösophagus ist eine präkanzeröse Läsion, die mit einem Progressionsrisiko von 0,1-0,3 ... more Der Barrett-Ösophagus ist eine präkanzeröse Läsion, die mit einem Progressionsrisiko von 0,1-0,3 % pro Jahr in ein Adenokarzinom übergehen kann. Die Diagnose eines Barrett-Ösophagus basiert auf der histologischen Verifizierung einer intestinalen Metaplasie, die zirkulär oder zungenformig und größer als 1 cm ist. Kurzstreckige Barrett-Veränderungen unter 1 cm haben ein sehr geringes Risiko für die Entstehung einer hochgradigen Dysplasie und eines Adenokarzinoms. Eine aktuelle prospektive Studie favorisierte daher eine zurückhaltende Indikationsstellung für Verlaufsendoskopien in diesem Patientenklientel. Patienten mit einem Barrett-Ösophagus >1 cm sollte hingegen eine strukturierte endoskopische Kontrolle angeboten werden. Eine amerikanische Kohortenstudie zeigte an fast 30.000 Patienten mit
The systemic treatment of patients with pancreatic neuroendocrine tumors is based on placebo-cont... more The systemic treatment of patients with pancreatic neuroendocrine tumors is based on placebo-controlled trials and long-established chemotherapy approaches. In addition, peptide receptor radionuclide therapy (PRRT) was approved as a parallel approach for pancreatic neuroendocrine tumors (NET), in addition to small bowel NET, after the NETTER-1 trial. The current ESMO and NCCN guidelines attempted to describe treatment algorithms for pancreatic NET based on the current data. In our survey, we recorded therapy decisions for the first- until the third-line of therapy in German-speaking countries (Germany, Austria, and Switzerland) using fictional case reports and discussed these in the context of the current ESMO guidelines. Compared with the recommendations of the guidelines, PRRT was used more frequently and earlier. In patients with NET G1/G2 Ki-67 < 10%, the therapy algorithm consisting of somatostatin analogs (SSA)-PRRT-targeted therapy is a relevant approach. In clinical situa...
The systemic treatment of patients with pancreatic neuroendocrine tumors is based on placebo-cont... more The systemic treatment of patients with pancreatic neuroendocrine tumors is based on placebo-controlled trials and long-established chemotherapy approaches. In addition, peptide receptor radionuclide therapy (PRRT) was approved as a parallel approach for pancreatic neuroendocrine tumors (NET), in addition to small bowel NET, after the NETTER-1 trial. The current ESMO and NCCN guidelines attempted to describe treatment algorithms for pancreatic NET based on the current data. In our survey, we recorded therapy decisions for the first- until the third-line of therapy in German-speaking countries (Germany, Austria, and Switzerland) using fictional case reports and discussed these in the context of the current ESMO guidelines. Compared with the recommendations of the guidelines, PRRT was used more frequently and earlier. In patients with NET G1/G2 Ki-67 < 10%, the therapy algorithm consisting of somatostatin analogs (SSA)-PRRT-targeted therapy is a relevant approach. In clinical situa...
Der Barrett-Ösophagus ist eine präkanzeröse Läsion, die mit einem Progressionsrisiko von 0,1-0,3 ... more Der Barrett-Ösophagus ist eine präkanzeröse Läsion, die mit einem Progressionsrisiko von 0,1-0,3 % pro Jahr in ein Adenokarzinom übergehen kann. Die Diagnose eines Barrett-Ösophagus basiert auf der histologischen Verifizierung einer intestinalen Metaplasie, die zirkulär oder zungenformig und größer als 1 cm ist. Kurzstreckige Barrett-Veränderungen unter 1 cm haben ein sehr geringes Risiko für die Entstehung einer hochgradigen Dysplasie und eines Adenokarzinoms. Eine aktuelle prospektive Studie favorisierte daher eine zurückhaltende Indikationsstellung für Verlaufsendoskopien in diesem Patientenklientel. Patienten mit einem Barrett-Ösophagus >1 cm sollte hingegen eine strukturierte endoskopische Kontrolle angeboten werden. Eine amerikanische Kohortenstudie zeigte an fast 30.000 Patienten mit
BACKGROUND To date, no biomarkers exist to predict response or resistance to immunotherapy in hep... more BACKGROUND To date, no biomarkers exist to predict response or resistance to immunotherapy in hepatocellular carcinoma (HCC). Recent approaches to classify HCC into different immunological states revealed a negative correlation between Wnt/ß-catenin activation and immunogenicity and T-cell infiltration. If these "cold" tumors with primary resistance to checkpoint inhibition (CPI) may benefit from dual treatment of CPI and anti-angiogenic therapy has not been proved. CASE Here, we describe the case of a male patient with metastatic HCC. After failure of standard of care treatment with lenvatinib, sorafenib and ramucirumab fourth-line systemic therapy with atezolizumab and bevacizumab were applied leading to a phenomenal response. Immunohistochemical evaluations were compatible with Wnt/ß-catenin pathway activation and accompanying low T-cell infiltration as well as low PD-L1 score. CONCLUSION Patients with Wnt/ß-catenin activation may benefit from combination therapy with atezolizumab and bevacizumab regardless of potential predictive markers for immune checkpoint inhibition.
Gastroenteropancreatic neuroendocrine neoplasia (GEPNEN) comprises clinically as well as prognost... more Gastroenteropancreatic neuroendocrine neoplasia (GEPNEN) comprises clinically as well as prognostically diverse tumour entities often diagnosed at late stage. Current classification provides a uniform terminology and a Ki67-based grading system, thereby facilitating management. Advances in the study of genomic and epigenetic landscapes have amplified knowledge of tumour biology and enhanced identification of prognostic and potentially predictive treatment subgroups. Translation of this genomic and mechanistic biology into advanced GEPNEN management is limited. ‘Targeted’ treatments such as somatostatin analogues, peptide receptor radiotherapy, tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors are treatment options but predictive tools are lacking. The inability to identify clonal heterogeneity and define critical oncoregulatory pathways prior to therapy, restrict therapeutic efficacy as does the inability to monitor disease status in real time. Chemotherapy in ...
Therapy with gemcitabine and nab-paclitaxel (GNP) is the most commonly used palliative chemothera... more Therapy with gemcitabine and nab-paclitaxel (GNP) is the most commonly used palliative chemotherapy, but its advantage in the neoadjuvant setting remains unclear. Accordingly, our aim is to evaluate the impact of first-line neoadjuvant therapy with GNP in patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC). A systematic search for published studies until August 2020 was performed. The primary endpoint included resection and R0 resection rates in the intention-to-treat population. Secondary endpoints were response rate, survival and toxicity. Among 21 studies, 950 patients who received neoadjuvant GNP were evaluated. Treatment with GNP resulted in surgical resection and R0 resection rates as follows: 49% (95% CI 30–68%) and 36% (95% CI 17–58%) for BRPC and 16% (95% CI 7–26%) and 11% (95% CI 5–19%) for LAPC, respectively. The objective response rates and the median overall survival (mOS) ranged from 0 to 67% and 12 to 30 months, respectively. Neutr...
The treatment and monitoring of patients with neuroendocrine tumors (NET) has been a major challe... more The treatment and monitoring of patients with neuroendocrine tumors (NET) has been a major challenge during the COVID-19 pandemic. In a survey, we investigated the influence of COVID-19 on the care of NET patients in the German speaking countries Germany, Austria and Switzerland. The multidisciplinarity of all treating physicians in the outpatient and inpatient sector was reflected in our survey. Furthermore, we were able to present findings pertaining to the university and non-university medical care. Overall, only a minority of appointments were cancelled, mostly as a result of medical prioritization and less for fear of infection by patients. In the university sector, longer delays for diagnostic measures were observed in comparison to non-university care. During the COVID-19 crisis, NET patients rarely changed their current therapy, but the pandemic impacted the assessment of the different treatment modalities at risk of developing severe COVID-19 disease. This survey provides t...
Summary of pretreatments of our patient cohort: 25 patients received one prior treatment, 33 pati... more Summary of pretreatments of our patient cohort: 25 patients received one prior treatment, 33 patients received two prior treatments, six patients received three prior treatments, two patients four prior treatments and one patient five prior treatments before starting dacarbazine. (DOCX 18Â kb)
The assessment of cancer patient care during the COVID-19 pandemic has been mainly reported from ... more The assessment of cancer patient care during the COVID-19 pandemic has been mainly reported from a physician’s perspective. Patients with rare tumor entities such as neuroendocrine tumors (NET), which require a complex and specialized care infrastructure, were highly affected by the COVID-19 crisis. Using a structured questionnaire consisting of a general section on the disease and a special COVID-19 section to record medical care, vaccination behavior as well as social and psycho-emotional parameters were collected from NET patients. The survey was distributed via direct medical contact and via the patient organization NETZWERK NeT. A total of 684 patients participated in the survey and 79.2% (n = 542) of the participants answered the questionnaire completely (54 questions). Patient characteristics were comparable to those in large NET registries. The majority of participants were patients with pancreatic and small bowel NET on somatostatin analogue (SSA) therapy. Medical care unde...
Background Cytotoxic chemotherapy combinations and targeted agents represent established treatmen... more Background Cytotoxic chemotherapy combinations and targeted agents represent established treatment concepts in advanced pancreatic neuroendocrine tumors (PNETs). However, response rates, side effects and outcome data strongly vary among these therapeutic approaches. Head-to-head comparisons between chemo- and molecular therapies are missing and secondary resistances frequently occur. The RamuNET trial aims to identify the effectiveness of dual treatment with DTIC and ramucirumab in progressive advanced PNET patients. Methods The RamuNET study is an investigator-initiated multicenter prospective single-arm trial to evaluate the efficacy of ramucirumab in combination with dacarbazine (DTIC) over a period of at least 6 months. Patients with progressive well-differentiated and metastatic pancreatic neuroendocrine tumors are eligible. The study aims to include 45 patients over a period of 24 months with a minimum follow-up of 24 months. The primary endpoint is disease control after 6 mon...
Compared to pancreatic adenocarcinoma (PDAC), pancreatic neuroendocrine tumors (PanNET) represent... more Compared to pancreatic adenocarcinoma (PDAC), pancreatic neuroendocrine tumors (PanNET) represent a rare and heterogeneous tumor entity. In addition to surgical resection, several therapeutic approaches, including biotherapy, targeted therapy or chemotherapy are applicable. However, primary or secondary resistance to current therapies is still challenging. Recent genome-wide sequencing efforts in PanNET identified a large number of mutations in pathways involved in epigenetic modulation, including acetylation. Therefore, targeting epigenetic modulators in neuroendocrine cells could represent a new therapeutic avenue. Detailed information on functional effects and affected signaling pathways upon epigenetic targeting in PanNETs, however, is missing. The primary human PanNET cells NT-3 and NT-18 as well as the murine insulinoma cell lines beta-TC-6 (mouse) and RIN-T3 (rat) were treated with the non-selective histone-deacetylase (HDAC) inhibitor panobinostat (PB) and analyzed for funct...
Stroma-infiltrating immune cells, such as tumor-associated macrophages (TAM), play an important r... more Stroma-infiltrating immune cells, such as tumor-associated macrophages (TAM), play an important role in regulating tumor progression and chemoresistance. These effects are mostly conveyed by secreted mediators, among them several cathepsin proteases. In addition, increasing evidence suggests that stroma-infiltrating immune cells are able to induce profound metabolic changes within the tumor microenvironment. In this study, we aimed to characterize the impact of cathepsins in maintaining the TAM phenotype in more detail. For this purpose, we investigated the molecular effects of pharmacological cathepsin inhibition on the viability and polarization of human primary macrophages as well as its metabolic consequences. Pharmacological inhibition of cathepsins B, L, and S using a novel inhibitor, GB111-NH2, led to changes in cellular recycling processes characterized by an increased expression of autophagy- and lysosome-associated marker genes and reduced adenosine triphosphate (ATP) cont...
ABSTRACTObjectiveThe COVID-19 pandemic challenges health care systems worldwide. In this situatio... more ABSTRACTObjectiveThe COVID-19 pandemic challenges health care systems worldwide. In this situation, guidelines for health care professionals in endoscopy units with increased risk of infection from inhalation of airborne droplets, conjunctival contact and faeces are urgently needed. Recently, the European Society of Gastrointestinal Endoscopy (ESGE) and the German Society for Pneumology (DGP) issued recommendations. However, real-world data on the conditions and requirements of endoscopy units to adhere to this guidance are missing.DesignWe conducted an internet-based survey among German endoscopy units from all levels of care from April 1st to 7th, 2020. The survey comprised 33 questions and was distributed electronically by the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS) and the DGP.ResultsIn total, 656 endoscopy units completed the survey. Overall, 253 units (39%) cancelled fewer than 40% of their procedures. Of note, private practices cancelled le...
Pancreatic neuroendocrine tumours (pNETs) represent rare neoplasms of all NETs often presenting w... more Pancreatic neuroendocrine tumours (pNETs) represent rare neoplasms of all NETs often presenting without functional activity. Many sporadic non-functioning pNET patients are already metastatic at the time of diagnosis, and the therapeutic approach to such patients is mostly palliative. In this international, multicentre, retrospective cohort study, we assessed the prognostic value of a set of anthropometric, clinical, biochemical, radiological and pathological parameters at baseline and the impact of the therapeutic strategies on the survival of patients with sporadic grade 1/2, stage IV, non-functioning pNETs. Three hundred and twelve consecutive patients diagnosed between 1993 and 2010 were included. The median overall survival (OS) was 6.6 years and survival at 5 and 10 years was 62 and 34% respectively. On univariate analysis, Eastern Cooperative Oncology Group (ECOG) status ≥2, grade 2, bilobar hepatic metastases, synchronous metastases, and high chromogranin A, alkalinephosphatase and lactic-dehydrogenase were associated with a significant reduction of OS. Palliative/curative surgery and loco-regional hepatic interventions were significant factors improving OS. On multivariate analysis, ECOG status ≥2, synchronous metastases, Ki-67 ≥10%, and high alkalinephosphatase correlated significantly with an increased risk of death. Both palliative/curative surgery and loco-regional hepatic interventions had a positive impact on OS. Although most parameters did not prove to be independent OS predictors at multivariate analysis, they showed a tendency towards that. Future prospective studies including larger patient populations may give greater clarity. We believe the integration of these parameters has the potential to provide a reliable prognostic score for the stratification of patients with sporadic well-differentiated metastatic non-functioning pNETs.
Introduction: The tumor microenvironment plays a role in growth of malignancies. There a many stu... more Introduction: The tumor microenvironment plays a role in growth of malignancies. There a many studies which investigate influence of tumorinfiltrating lymphocytes (TILs). There is great heterogeneity about how to quantify these cells. Aims: Therefore, we present a Quantification of the Tumor Stroma (QTS) Algorithm to quantify cells in the tumor stroma. Materials & methods: Immunohistochemistry of CD3 and CD8 antigens in metastatic colorectal cancer (mCRC), ovarian cancer (OvCa), hepatocellular carcinoma (HCC), and pancreatic cancer (PDAC) was performed (N¼80). Reliability of identification of hot spots was investigated using two blinded observers. Hot spots were defined as regions with highest density of TILs. To examine whether quantification of 1 vs 3 hot spots yields accurate results, CD8 + /CD3 + ratio as well as the absolute cell numbers were compared using intraclass-correlation (ICC). Computed counting software: ZEN 2 (ZC), ImageJ subjective threshold (ISC), and ImageJ colour deconvolution (IAC) were compared to manual counting using linear regression. Results: ICC for detection of hot spots were 0.949 in mCRC, 0.843 in OvCa, 0.805 in HCC, and 0.957 in PDAC. The ICC for CD8 + /CD3 + ratio in 1 hot spot compared to the average from 3 hot spots was consistent. The absolute cell count in 1 vs 3 hot spots reflected poor accuracy. ZC in PDAC yielded inconsistencies. ISC reached excellent results in all groups. IAC reached excellent reliability in mCRC and OvCa. Conclusion: ISC is accurate for sections with high background, whereas IAC for sections with low background staining. With the QTS Algorithm quantification of cells in the tumor stroma is reliable and accurate.
Pancreatic ductal adenocarcinoma is characterized by a poor prognosis and a low median survival, ... more Pancreatic ductal adenocarcinoma is characterized by a poor prognosis and a low median survival, despite improvements observed for many other solid tumours. Intensive research efforts have been undertaken during the last decades to discover new prognostic and treatment predictive biomarkers for pancreatic ductal adenocarcinoma. The mainstay of medical treatment for the disease has been the well-tolerated nucleoside analogue, gemcitabine. The only targeted agent currently used in pancreatic ductal adenocarcinoma patients is the epithelial growth factor receptor inhibitor erlotinib in combination with gemcitabine. Recently, treatment regimens such as a combination of fluorouracilleucovorin-irinotecan-oxaliplatin (FOLFIRINOX) and the combination of nab-paclitaxel with gemcitabine have been introduced for metastatic pancreatic ductal adenocarcinoma. Although these treatment regimens significantly improve survival of patients, there are no good predictive biomarkers available that can be used to identify who would benefit most from them. Therefore, the search for predictive biomarkers that would facilitate personalization of chemotherapy is highly relevant.
Der Barrett-Ösophagus ist eine präkanzeröse Läsion, die mit einem Progressionsrisiko von 0,1-0,3 ... more Der Barrett-Ösophagus ist eine präkanzeröse Läsion, die mit einem Progressionsrisiko von 0,1-0,3 % pro Jahr in ein Adenokarzinom übergehen kann. Die Diagnose eines Barrett-Ösophagus basiert auf der histologischen Verifizierung einer intestinalen Metaplasie, die zirkulär oder zungenformig und größer als 1 cm ist. Kurzstreckige Barrett-Veränderungen unter 1 cm haben ein sehr geringes Risiko für die Entstehung einer hochgradigen Dysplasie und eines Adenokarzinoms. Eine aktuelle prospektive Studie favorisierte daher eine zurückhaltende Indikationsstellung für Verlaufsendoskopien in diesem Patientenklientel. Patienten mit einem Barrett-Ösophagus >1 cm sollte hingegen eine strukturierte endoskopische Kontrolle angeboten werden. Eine amerikanische Kohortenstudie zeigte an fast 30.000 Patienten mit
The systemic treatment of patients with pancreatic neuroendocrine tumors is based on placebo-cont... more The systemic treatment of patients with pancreatic neuroendocrine tumors is based on placebo-controlled trials and long-established chemotherapy approaches. In addition, peptide receptor radionuclide therapy (PRRT) was approved as a parallel approach for pancreatic neuroendocrine tumors (NET), in addition to small bowel NET, after the NETTER-1 trial. The current ESMO and NCCN guidelines attempted to describe treatment algorithms for pancreatic NET based on the current data. In our survey, we recorded therapy decisions for the first- until the third-line of therapy in German-speaking countries (Germany, Austria, and Switzerland) using fictional case reports and discussed these in the context of the current ESMO guidelines. Compared with the recommendations of the guidelines, PRRT was used more frequently and earlier. In patients with NET G1/G2 Ki-67 < 10%, the therapy algorithm consisting of somatostatin analogs (SSA)-PRRT-targeted therapy is a relevant approach. In clinical situa...
The systemic treatment of patients with pancreatic neuroendocrine tumors is based on placebo-cont... more The systemic treatment of patients with pancreatic neuroendocrine tumors is based on placebo-controlled trials and long-established chemotherapy approaches. In addition, peptide receptor radionuclide therapy (PRRT) was approved as a parallel approach for pancreatic neuroendocrine tumors (NET), in addition to small bowel NET, after the NETTER-1 trial. The current ESMO and NCCN guidelines attempted to describe treatment algorithms for pancreatic NET based on the current data. In our survey, we recorded therapy decisions for the first- until the third-line of therapy in German-speaking countries (Germany, Austria, and Switzerland) using fictional case reports and discussed these in the context of the current ESMO guidelines. Compared with the recommendations of the guidelines, PRRT was used more frequently and earlier. In patients with NET G1/G2 Ki-67 < 10%, the therapy algorithm consisting of somatostatin analogs (SSA)-PRRT-targeted therapy is a relevant approach. In clinical situa...
Der Barrett-Ösophagus ist eine präkanzeröse Läsion, die mit einem Progressionsrisiko von 0,1-0,3 ... more Der Barrett-Ösophagus ist eine präkanzeröse Läsion, die mit einem Progressionsrisiko von 0,1-0,3 % pro Jahr in ein Adenokarzinom übergehen kann. Die Diagnose eines Barrett-Ösophagus basiert auf der histologischen Verifizierung einer intestinalen Metaplasie, die zirkulär oder zungenformig und größer als 1 cm ist. Kurzstreckige Barrett-Veränderungen unter 1 cm haben ein sehr geringes Risiko für die Entstehung einer hochgradigen Dysplasie und eines Adenokarzinoms. Eine aktuelle prospektive Studie favorisierte daher eine zurückhaltende Indikationsstellung für Verlaufsendoskopien in diesem Patientenklientel. Patienten mit einem Barrett-Ösophagus >1 cm sollte hingegen eine strukturierte endoskopische Kontrolle angeboten werden. Eine amerikanische Kohortenstudie zeigte an fast 30.000 Patienten mit
BACKGROUND To date, no biomarkers exist to predict response or resistance to immunotherapy in hep... more BACKGROUND To date, no biomarkers exist to predict response or resistance to immunotherapy in hepatocellular carcinoma (HCC). Recent approaches to classify HCC into different immunological states revealed a negative correlation between Wnt/ß-catenin activation and immunogenicity and T-cell infiltration. If these "cold" tumors with primary resistance to checkpoint inhibition (CPI) may benefit from dual treatment of CPI and anti-angiogenic therapy has not been proved. CASE Here, we describe the case of a male patient with metastatic HCC. After failure of standard of care treatment with lenvatinib, sorafenib and ramucirumab fourth-line systemic therapy with atezolizumab and bevacizumab were applied leading to a phenomenal response. Immunohistochemical evaluations were compatible with Wnt/ß-catenin pathway activation and accompanying low T-cell infiltration as well as low PD-L1 score. CONCLUSION Patients with Wnt/ß-catenin activation may benefit from combination therapy with atezolizumab and bevacizumab regardless of potential predictive markers for immune checkpoint inhibition.
Gastroenteropancreatic neuroendocrine neoplasia (GEPNEN) comprises clinically as well as prognost... more Gastroenteropancreatic neuroendocrine neoplasia (GEPNEN) comprises clinically as well as prognostically diverse tumour entities often diagnosed at late stage. Current classification provides a uniform terminology and a Ki67-based grading system, thereby facilitating management. Advances in the study of genomic and epigenetic landscapes have amplified knowledge of tumour biology and enhanced identification of prognostic and potentially predictive treatment subgroups. Translation of this genomic and mechanistic biology into advanced GEPNEN management is limited. ‘Targeted’ treatments such as somatostatin analogues, peptide receptor radiotherapy, tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors are treatment options but predictive tools are lacking. The inability to identify clonal heterogeneity and define critical oncoregulatory pathways prior to therapy, restrict therapeutic efficacy as does the inability to monitor disease status in real time. Chemotherapy in ...
Therapy with gemcitabine and nab-paclitaxel (GNP) is the most commonly used palliative chemothera... more Therapy with gemcitabine and nab-paclitaxel (GNP) is the most commonly used palliative chemotherapy, but its advantage in the neoadjuvant setting remains unclear. Accordingly, our aim is to evaluate the impact of first-line neoadjuvant therapy with GNP in patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC). A systematic search for published studies until August 2020 was performed. The primary endpoint included resection and R0 resection rates in the intention-to-treat population. Secondary endpoints were response rate, survival and toxicity. Among 21 studies, 950 patients who received neoadjuvant GNP were evaluated. Treatment with GNP resulted in surgical resection and R0 resection rates as follows: 49% (95% CI 30–68%) and 36% (95% CI 17–58%) for BRPC and 16% (95% CI 7–26%) and 11% (95% CI 5–19%) for LAPC, respectively. The objective response rates and the median overall survival (mOS) ranged from 0 to 67% and 12 to 30 months, respectively. Neutr...
The treatment and monitoring of patients with neuroendocrine tumors (NET) has been a major challe... more The treatment and monitoring of patients with neuroendocrine tumors (NET) has been a major challenge during the COVID-19 pandemic. In a survey, we investigated the influence of COVID-19 on the care of NET patients in the German speaking countries Germany, Austria and Switzerland. The multidisciplinarity of all treating physicians in the outpatient and inpatient sector was reflected in our survey. Furthermore, we were able to present findings pertaining to the university and non-university medical care. Overall, only a minority of appointments were cancelled, mostly as a result of medical prioritization and less for fear of infection by patients. In the university sector, longer delays for diagnostic measures were observed in comparison to non-university care. During the COVID-19 crisis, NET patients rarely changed their current therapy, but the pandemic impacted the assessment of the different treatment modalities at risk of developing severe COVID-19 disease. This survey provides t...
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