Felix Berlth

Pathohistological classification systems in gastric cancer: Diagnostic relevance and prognostic value

Several pathohistological classification systems exist for the diagnosis of gastric cancer. Many studies have investigated the correlation between the pathohistological characteristics in gastric cancer and patient characteristics, disease specific criteria and overall outcome. It is still controversial as to which classification system imparts the most reliable information, and therefore, the choice of system may vary in clinical routine. In addition to the most common classification systems, such as the Laurén and the World Health Organization (WHO) classifications, other authors have tried to characterize and classify gastric cancer based on the microscopic morphology and in reference to the clinical outcome of the patients. In more than 50 years of systematic classification of the pathohistological characteristics of gastric cancer, there is no sole classification system that is consistently used worldwide in diagnostics and research. However, several national guidelines for the treatment of gastric cancer refer to the Laurén or the WHO classifications regarding therapeutic decision-making, which underlines the importance of a reliable classification system for gastric cancer. The latest results from gastric cancer studies indicate that it might be useful to integrate DNA- and RNA-based features of gastric cancer into the classification systems to establish prognostic relevance. This article reviews the diagnostic relevance and the prognostic value of different pathohistological classification systems in gastric cancer.

Treatment of early gastric cancer in the Western World

The incidence rate of gastric cancer is much higher in Asia than in the Western industrial nations. According to the different screening programs in Japan and Korea about fifty percent of treated patients had an early tumor stage. In contrast, European and American patients with gastric cancer had an advanced tumor stage. Therefore, the experience for the various therapeutic options for gastric cancer may be different between these regions. In this review we tried to point out the treatment modalities in Western industrial countries for early gastric cancer.

Immune checkpoints programmed death 1 ligand 1 and cytotoxic T lymphocyte associated molecule 4 in gastric adenocarcinoma

ABSTRACT Remarkable efficacy of immune checkpoint inhibition has been reported for several types of solid tumors and early studies in gastric adenocarcinoma are promising. A detailed knowledge about the natural biology of immune checkpoints in gastric adenocarcinoma is essential for clinical and translational evaluation of these drugs. This study is a comprehensive analysis of cytotoxic T lymphocyte associated molecule 4 (CTLA-4) and programmed death 1 ligand 1 (PD-L1) expression in gastric adenocarcinoma. PD-L1 and CTLA-4 were stained on tumor sections of 127 Caucasian patients with gastric adenocarcinoma by immunohistochemistry (IHC) and somatic mutation profiling was performed using targeted next-generation sequencing. Expression of PD-L1 and CTLA-4 on lymphocytes in tumor sections, tumor-draining lymph nodes (TDLN) and peripheral blood were studied by flow-cytometry and immune-fluorescence microscopy in an additional cohort. PD-L1 and CTLA-4 were expressed in 44.9% (57/127) and 86.6% (110/127) of the analyzed gastric adenocarcinoma samples, respectively. Positive tumor cell staining for PD-L1 or CTLA-4 was associated with inferior overall survival. Somatic mutational analysis did not reveal a correlation to expression of PD-L1 or CTLA-4 on tumor cells. Expression of PD-1 (52.2%), PD-L1 (42.2%) and CTLA-4 (1.6%) on tumor infiltrating T cells was significantly elevated compared to peripheral blood. Of note, PD-1 and PD-L1 were expressed far higher by tumor-infiltrating lymphocytes than CTLA-4. In conclusion, specific immune checkpoint-inhibitors should be evaluated in this disease and the combination with molecular targeted therapies might be of benefit. An extensive immune monitoring should accompany these studies to better understand their mode of action in the tumor microenvironment.

Defining Benchmarks for Transthoracic Esophagectomy: A Multicenter Analysis of Total Minimally Invasive Esophagectomy in Low Risk Patients

Objective: To define “best possible” outcomes in total minimally invasive transthoracic esophagectomy (ttMIE). Background: TtMIE, performed by experts in patients with low comorbidity, may serve as a benchmark procedure for esophagectomy. Patients and Methods: From a cohort of 1057 ttMIE, performed over a 5-year period in 13 high-volume centers for esophageal surgery, we selected a study group of 334 patients (31.6%) that fulfilled criteria of low comorbidity (American Society of Anesthesiologists score ⩽2, WHO/ECOG score ⩽1, age ⩽65 years, body mass index 19–29 kg/m2). Endpoints included postoperative morbidity measured by the Clavien-Dindo classification and the comprehensive complication index. Benchmark values were defined as the 75th percentile of the median outcome parameters of the participating centers to represent best achievable results. Results: Benchmark patients were predominantly male (82.9%) with a median age of 58 years (53–62). High intrathoracic (Ivor Lewis) and cervical esophagogastrostomy (McKeown) were performed in 188 (56.3%) and 146 (43.7%) patients, respectively. Median (IQR) ICU and hospital stay was 0 (0–2) and 12 (9–18) days, respectively. 56.0% of patients developed at least 1 complication, and 26.9% experienced major morbidity (≥grade III), mostly related to pulmonary complications (25.7%), anastomotic leakage (15.9%), and cardiac events (13.5%). Benchmark values at 30 days after hospital discharge were ⩽55.7% and ⩽30.8% for overall and major complications, ⩽18.0% for readmission, ⩽3.1% for positive resection margins, and ≥23 for lymph node yield. Benchmarks at 30 and 90 days were ⩽1.0% and ⩽4.6% for mortality, and ⩽40.8 and ⩽42.8 for the comprehensive complication index, respectively. Conclusion: This outcome analysis of patients with low comorbidity undergoing ttMIE may serve as a reference to evaluate surgical performance in major esophageal resection.

Quality of life and visceral surgery

Quality of life (QOL) is becoming more and more relevant in clinical research. An increasing number of publications each year confirmed this. The aim of this review is to summarize current data of QOL after surgical procedures. The results are represented by two examples each of malignant and benign diseases. The evaluation of QOL for patients with cancer is only possible with respect to the prognosis. Prospective randomized trials comparing laparoscopic and open surgery for early gastric cancer are only available from Asia. Data from the USA show that the QOL after gastrectomy was worse regardless of the surgical procedure. During the next 6 months the QOL improved but about one third of the patients had severe impairment during longer follow-up periods. Patients with R1 resection of pancreatic cancer showed only a slightly better prognosis but significantly better QOL compared to patients without resection. The results for the various procedures of cholecystectomy or hernia repair are not always consistent.ZusammenfassungDie Erfassung von Lebensqualität (LQ) rückt immer mehr in den Vordergrund der klinischen Forschung. Dies zeigt sich anhand der jährlich steigenden Anzahl von Publikationen zu diesem Thema. Ziel der Arbeit ist es, aktuelle Daten zur LQ nach viszeralchirurgischen Eingriffen darzustellen und zu bewerten. Beispielhaft werden die Ergebnisse für je zwei maligne bzw. benigne viszeralchirurgische Krankheitsbilder dargestellt. Für Patienten mit Tumorerkrankungen ist die Beurteilung der LQ nur in Abhängigkeit der Prognose möglich. Prospektiv randomisierte Studien beim Frühkarzinom des Magens zum Vergleich der laparoskopischen vs. offenen Verfahren liegen aus dem asiatischen Raum vor. Daten aus den USA zeigen, dass die LQ unabhängig vom Operationsverfahren beim Magenkarzinom in der Zeit nach der Operation deutlich reduziert ist. Die LQ besserte sich bei einem Teil dieser Patienten innerhalb des ersten halben Jahres, bestand aber auch noch bei einem Drittel der Patienten nach längerer Zeit. Die Operation beim Pankreaskarzinom scheint auch bei einer R1-Resektion einen Vorteil hinsichtlich der LQ zu bringen. Für Eingriffe bei benignen Erkrankungen wie Cholezystektomie oder Hernienoperationen sind die Fragestellungen anders und bringen nicht immer einheitliche Ergebnisse.AbstractQuality of life (QOL) is becoming more and more relevant in clinical research. An increasing number of publications each year confirmed this. The aim of this review is to summarize current data of QOL after surgical procedures. The results are represented by two examples each of malignant and benign diseases. The evaluation of QOL for patients with cancer is only possible with respect to the prognosis. Prospective randomized trials comparing laparoscopic and open surgery for early gastric cancer are only available from Asia. Data from the USA show that the QOL after gastrectomy was worse regardless of the surgical procedure. During the next 6 months the QOL improved but about one third of the patients had severe impairment during longer follow-up periods. Patients with R1 resection of pancreatic cancer showed only a slightly better prognosis but significantly better QOL compared to patients without resection. The results for the various procedures of cholecystectomy or hernia repair are not always consistent.

Lebensqualität nach viszeralchirurgischen Operationen

Quality of life (QOL) is becoming more and more relevant in clinical research. An increasing number of publications each year confirmed this. The aim of this review is to summarize current data of QOL after surgical procedures. The results are represented by two examples each of malignant and benign diseases. The evaluation of QOL for patients with cancer is only possible with respect to the prognosis. Prospective randomized trials comparing laparoscopic and open surgery for early gastric cancer are only available from Asia. Data from the USA show that the QOL after gastrectomy was worse regardless of the surgical procedure. During the next 6 months the QOL improved but about one third of the patients had severe impairment during longer follow-up periods. Patients with R1 resection of pancreatic cancer showed only a slightly better prognosis but significantly better QOL compared to patients without resection. The results for the various procedures of cholecystectomy or hernia repair are not always consistent.ZusammenfassungDie Erfassung von Lebensqualität (LQ) rückt immer mehr in den Vordergrund der klinischen Forschung. Dies zeigt sich anhand der jährlich steigenden Anzahl von Publikationen zu diesem Thema. Ziel der Arbeit ist es, aktuelle Daten zur LQ nach viszeralchirurgischen Eingriffen darzustellen und zu bewerten. Beispielhaft werden die Ergebnisse für je zwei maligne bzw. benigne viszeralchirurgische Krankheitsbilder dargestellt. Für Patienten mit Tumorerkrankungen ist die Beurteilung der LQ nur in Abhängigkeit der Prognose möglich. Prospektiv randomisierte Studien beim Frühkarzinom des Magens zum Vergleich der laparoskopischen vs. offenen Verfahren liegen aus dem asiatischen Raum vor. Daten aus den USA zeigen, dass die LQ unabhängig vom Operationsverfahren beim Magenkarzinom in der Zeit nach der Operation deutlich reduziert ist. Die LQ besserte sich bei einem Teil dieser Patienten innerhalb des ersten halben Jahres, bestand aber auch noch bei einem Drittel der Patienten nach längerer Zeit. Die Operation beim Pankreaskarzinom scheint auch bei einer R1-Resektion einen Vorteil hinsichtlich der LQ zu bringen. Für Eingriffe bei benignen Erkrankungen wie Cholezystektomie oder Hernienoperationen sind die Fragestellungen anders und bringen nicht immer einheitliche Ergebnisse.AbstractQuality of life (QOL) is becoming more and more relevant in clinical research. An increasing number of publications each year confirmed this. The aim of this review is to summarize current data of QOL after surgical procedures. The results are represented by two examples each of malignant and benign diseases. The evaluation of QOL for patients with cancer is only possible with respect to the prognosis. Prospective randomized trials comparing laparoscopic and open surgery for early gastric cancer are only available from Asia. Data from the USA show that the QOL after gastrectomy was worse regardless of the surgical procedure. During the next 6 months the QOL improved but about one third of the patients had severe impairment during longer follow-up periods. Patients with R1 resection of pancreatic cancer showed only a slightly better prognosis but significantly better QOL compared to patients without resection. The results for the various procedures of cholecystectomy or hernia repair are not always consistent.

Gastric cancer treatment in the world: Germany

Epidemiologically, around 15,500 persons per year contract gastric cancer with continuously decreasing incidence and a 5-year survival rate of only 30% to 35%. Contrary to the Asian countries, there are no prevention programs for gastric cancer in Germany, which leads to the disease frequently being diagnosed in locally advanced stages and predominantly being treated with multimodal therapy concepts. Complete (R0) resection is the therapy of choice for resectable gastric cancer. Special forms of gastric cancer that are limited to the mucosa can be endoscopically resected with a curative intent. Systematic D2 lymphadenectomy (LAD) plays a decisive role in the management of local advanced tumors because it significantly contributes to the reduction of tumor-related death and both local and regional relapse rates. Perioperative chemotherapy improves prognosis in the advanced stages, whereas palliative chemotherapy is normally indicated for metastatic diseases. Standardized resection procedures and the use of individualized multimodal therapy concepts have led to improvement in the 5-year survival rate.

Upregulation of insulin-like growth factor II mRNA-binding protein 3 (IMP3) has negative prognostic impact on early invasive (pT1) adenocarcinoma of the esophagus

PurposeTherapeutic decisions in esophageal adenocarcinomas (EAC) restricted to mucosa (pT1a) or submucosa (pT1b) depend mainly on classic histomorphology-based criteria like tumor grading or lymphovascular invasion with limited success. There is a strong need for reliable pre-therapeutical biomarker-based evaluation also applicable on endoscopically obtained biopsies.MethodsPatients who underwent esophagectomy due to EAC in a high volume center between 1999 and 2016 were included. Tissue microarrays (TMA) were retrospectively established from the formalin-fixed and paraffin-embedded material of the resected specimens and immunohistochemically stained using a monoclonal primary antibody specific for IMP3. IMP3 staining intensity was scored manually according to a 3-tier-scoring system (negative, weak and strong).Results371 EACs were interpretable for analysis. 109 patients (29%) had early invasive (pT1a/pT1b) and 262 patients (71%) locally advanced EAC (> pT2). 259 EACs (70%) revealed positive immunostaining for IMP3 including 167 strongly and 92 weakly positive. Early EAC had significantly lower IMP3 expression compared to advanced tumor stages (p < 0.0001). IMP3 positive pT1 EAC revealed higher levels of lymph node metastases (LNM) (p = 0.0001) and pT1b tumors showed higher rates of IMP3 positivity compared to pT1a (p = 0.007). Subdividing the submucosa in thirds, there was a significant trend for higher IMP3 expression with deeper tumor infiltration from pT1a to pT1b (sm3) (p = 0.0001). There was an association between IMP3 expression and shortened survival in pT1 EAC (p = 0.038).ConclusionsIMP3 expression correlates with depth of tumor infiltration, rate of LNM and is associated with worse outcome. Thus, IMP3 might be useful for therapeutic decisions in early-invasive EAC.

Web-Based Immersive Patient Simulator as a Curricular Tool for Objective Structured Clinical Examination Preparation in Surgery: Development and Evaluation

Background Objective Structured Clinical Examination is a standard method of testing declarative and process knowledge in clinical core competencies. It is desirable that students undergo Objective Structured Clinical Examination training before participating in the exam. However, establishing Objective Structured Clinical Examination training is resource intensive and therefore there is often limited practice time. Web-based immersive patient simulators such as ALICE (Artificial Learning Interface of Clinical Education) can possibly fill this gap as they allow for the training of complex medical procedures at the user’s individual pace and with an adaptable number of repetitions at home. ALICE has previously been shown to positively influence knowledge gain and motivation. Objective Therefore, the aim of this study was to develop a Web-based curriculum that teaches declarative and process knowledge and prepares students for a real Objective Structured Clinical Examination station. Furthermore, we wanted to test the influence of ALICE on knowledge gain and student motivation. Methods A specific curriculum was developed in order to implement the relevant medical content of 2 surgical Objective Structured Clinical Examination stations into the ALICE simulator framework. A total of 160 medical students were included in the study, where 100 students had access to ALICE and their performance was compared to 60 students in a control group. The simulator performance was validated on different levels and students’ knowledge gain and motivation were tested at different points during the study. Results The curriculum was developed according to the Kern cycle. Four virtual clinical cases were implemented with different teaching methods (structured feedback, keynote speech, group discussion, and debriefing by a real instructor) in order to consolidate declarative and process knowledge. Working with ALICE had significant impact on declarative knowledge gain and Objective Structured Clinical Examination performance. Simulator validation was positive for face, content, construct, and predictive validity. Students showed high levels of motivation and enjoyed working with ALICE. Conclusions ALICE offers Web-based training for Objective Structured Clinical Examination preparation and can be used as a selective didactic intervention as it has positive effect on knowledge gain and student motivation.

Preoperative staging of nodal status in gastric cancer

An accurate preoperative staging of nodal status is crucial in gastric cancer, because it has a great impact on prognosis and therapeutic decision-making. Different staging methods have been evaluated for gastric cancer in order to predict nodal involvement. So far, no technique could meet the necessary requirements, which include a high detection rate of infiltrated lymph nodes and a low frequency of false-positive results. This article summarizes different staging methods used to assess lymph node status in patients with gastric cancer, evaluates the evidence, and proposes to establish new methods.