Oncological Outcomes and Patterns of Recurrence after the Surgical Resection of an Invasive Intraductal Papillary Mucinous Neoplasm versus Primary Pancreatic Ductal Adenocarcinoma: An Analysis from the German Cancer Registry Group of the Society of German Tumor Centers.

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs) are premalignant cystic neoplasms of the pancreas (CNPs), which can progress to invasive IPMN and pancreatic cancer. The available literature has shown controversial results regarding prognosis and clinical outcomes after the resection of invasive IPMN. AIMS: This study aims to characterize the oncologic outcomes and metastatic progression pattern after the resection of non-metastatic invasive IPMN. METHODS: Data were obtained from 24 clinical cancer registries participating in the German Cancer Registry Group of the Society of German Tumor Centers (ADT). Patients with invasive IPMN (n = 217) as well as PDAC (n = 5794) between 2000 and 2021 were included and compared regarding oncological outcomes. RESULTS: Invasive IPMN was significantly smaller in size (p < 0.001) and of a lower tumor grade (p < 0.001), with fewer lymph node metastases (p < 0.001), lymphangiosis (p < 0.001), and consequently a higher R0 resection rate (88 vs. 74%) compared to PDAC. Moreover, invasive IPMN was associated with fewer local (11 vs. 15%) and distant recurrences (29 vs. 46%) and metastasized more frequently in the lungs only (26% vs. 14%). Invasive IPMN was associated with a longer median OS (29 vs. 19 months) and DFS (31 vs. 15 months) compared to PDAC and stayed independently prognostic in multivariable analyses. These survival differences were most pronounced in early tumor stages. Interestingly, postoperative chemotherapy was not associated with improved overall survival in surgically resected invasive IPMN. CONCLUSIONS: Invasive IPMN is a rare pancreatic entity with increasing incidence in Germany. It is associated with favorable histopathological features at the time of resection and longer OS and DFS compared to PDAC, particularly before the locoregional spread has occurred. Invasive IPMNs are associated with lung-only metastasis. The benefit of postoperative chemotherapy after the resection of invasive IPMN remains uncertain.

Cold Atmospheric Plasma Is a Promising Alternative Treatment Option in Case of Split Skin Graft Failure.

Cold atmospheric plasma (CAP) has shown promising potential in promoting wound healing. This case report presents the successful application of CAP in a 42-year-old female patient with extensive wound healing disorders and superinfections following the excision of an abscess in the left thoracic region. After several failed split skin graft attempts, the implementation of CAP led to significant improvements in wound healing. This report highlights the wound healing-promoting effects of CAP and discusses its potential mechanisms of action.

[How I Teach It: Robotic Surgery in the Upper GI Tract]. / How I Teach It: robotische Chirurgie am oberen Gastrointestinaltrakt.

In this manuscript, we present our concept for training in robotic surgery of the upper gastrointestinal tract. The training concept presented here focuses on the two surgical "user groups", assistants (table assists) and specialists (surgeons), and presents the core aspects of training for each group separately.For table assistants, we present opportunities for early involvement in robotics and our approach to learning the first steps in preparing for surgery, assisting during surgery, as well as communication as a key factor in robotic surgery and alternative training.For specialists who are to learn how to perform robotic procedures independently, we discuss virtual training using SimNow Trainer and our preferred early clinical application. We will also present assistance options such as the dual console setup and the telestration system. Finally, we present our training concept for developing robotic surgical skills in the upper gastrointestinal tract through a combination of partial steps and increasing difficulty of the procedures. In our view, it is essential to teach the stepstones of robotic surgery and to master them safely. To this end, training must be structured and regular so that more complex sub-steps and procedures can be taken over step by step.

[Surgical strategy for hiatal hernias]. / Operative Strategie bei Hiatushernien.

The indications for surgical treatment of hiatus hernias differentiate between type I and types II, III and IV hernias. The indications for a type I hernia should include a proven reflux disease but the indications for surgical treatment of types II, III and IV hernias are mandatory due to the symptoms with problems in the passage of food and due to the sometimes very severe possible complications. The primary aims of surgery are the repositioning of the herniated contents and a hiatoplasty, which includes a surgical narrowing of the esophageal hiatus by suture implantation. In addition, depending on the clinical situation other procedures, such as hernia sac removal, mesh implantation, gastropexy and fundoplication can be considered. There are various approaches to the repair, all of which have individual advantages and disadvantages. An adaptation to the specific needs situation of the patient and the expertise of the surgeon is therefore essential.

When Should Lymphadenectomy Be Performed in Non-Metastatic Pancreatic Neuroendocrine Tumors? A Population-Based Analysis of the German Clinical Cancer Registry Group.

BACKGROUND: Patient selection for lymphadenectomy remains a controversial aspect in the treatment of pancreatic neuroendocrine tumors (pNETs), given the growing importance of parenchyma-sparing resections and minimally invasive procedures. METHODS: This population-based analysis was derived from the German Cancer Registry Group during the period from 2000 to 2021. Patients with upfront resected non-functional non-metastatic pNETs were included. RESULTS: Out of 5520 patients with pNET, 1006 patients met the inclusion criteria. Fifty-three percent of the patients were male. The median age was 64 ± 17 years. G1, G2, and G3 pNETs were found in 57%, 37%, and 7% of the patients, respectively. Lymph node metastasis (LNM) was present in 253 (24%) of all patients. LNM was an independent prognostic factor (HR 1.79, CI 95% 1.21-2.64, p = 0.001) for disease-free survival (DFS). The 3-, 5-, and 10-year disease-free survival in nodal negative tumors compared to nodal positive was 82% vs. 53%, 75% vs. 38%, and 48% vs. 16%. LNM was present in 5% of T1 tumors, 25% of T2 tumors, and 49% of T3-T4 tumors. In T1 tumors, G1 was the most predominant tumor grade (80%). However, in T2 tumors, G2 and G3 represented 44% and 5% of all tumors. LNM was associated with tumors located in the pancreatic head (p < 0.001), positive resection margin (p < 0.001), tumors larger than 2 cm (p < 0.001), and higher tumor grade (p < 0.001). The multivariable analysis showed that tumor size, tumor grade, and location were independent prognostic factors associated with LNM that could potentially be used to predict LNM preoperatively. CONCLUSION: LNM is an independent negative prognostic factor for DFS in pNETs. Due to the low incidence of LNM in T1 tumors (5%), parenchyma-sparing surgery seems oncologically adequate in small G1 pNETs, while regional lymphadenectomy should be recommended in T2 or G2/G3 pNETs.

Conception and prospective multicentric validation of a Robotic Surgery Training Curriculum (RoSTraC) for surgical residents: from simulation via laboratory training to integration into the operation room.

There is a lack of training curricula and educational concepts for robotic-assisted surgery (RAS). It remains unclear how surgical residents can be trained in this new technology and how robotics can be integrated into surgical residency training. The conception of a training curriculum for RAS addressing surgical residents resulted in a three-step training curriculum including multimodal learning contents: basics and simulation training of RAS (step 1), laboratory training on the institutional robotic system (step 2) and structured on-patient training in the operating room (step 3). For all three steps, learning content and video tutorials are provided via cloud-based access to allow self-contained training of the trainees. A prospective multicentric validation study was conducted including seven surgical residents. Transferability of acquired skills to a RAS procedure were analyzed using the GEARS score. All participants successfully completed RoSTraC within 1 year. Transferability of acquired RAS skills could be demonstrated using a RAS gastroenterostomy on a synthetic biological organ model. GEARS scores concerning this procedure improved significantly after completion of RoSTraC (17.1 (±5.8) vs. 23.1 (±4.9), p < 0.001). In step 3 of RoSTraC, all participants performed a median of 12 (range 5-21) RAS procedures on the console in the operation room. RoSTraC provides a highly standardized and comprehensive training curriculum for RAS for surgical residents. We could demonstrate that participating surgical residents acquired fundamental and advanced RAS skills. Finally, we could confirm that all surgical residents were successfully and safely embedded into the local RAS team.

The impact of surgical-oncologic textbook outcome in patients with stage I to III pancreatic ductal adenocarcinoma: A cross-validation study of two national registries.

BACKGROUND: Using national registries, we aimed to evaluate oncologic textbook outcomes in pancreatic ductal adenocarcinoma patients. METHODS: Patients with stage I to III pancreatic ductal adenocarcinoma and surgical resection from 2010 to 2020 in the US and Germany were identified using the National Cancer Database and National Cancer Registries data. The surgical-oncologic textbook outcome was defined as complete oncologic resection with no residual tumor and ≥12 harvested lymph nodes. The composite endpoint was defined as surgical-oncologic textbook outcome and receipt of perioperative systemic and/or radiation therapy. RESULTS: In total, 33,498 patients from the National Cancer Database and 14,589 patients from the National Cancer Registries were included. In the National Cancer Database, 28,931 (86%) patients had complete oncologic resection with no residual tumor, and 11,595 (79%) in the National Cancer Registries. 8,723 (26%) patients in the National Cancer Database and 556 (4%) in the National Cancer Registries had <12 lymph nodes harvested. The National Cancer Database shows 26,135 (78%) underwent perioperative therapy and 8,333 (57%) in the National Cancer Registries. Surgical-oncologic textbook outcome was achieved in 21,198 (63%) patients in the National Cancer Database and in 11,234 (77%) patients from the National Cancer Registries. 16,967 (50%) patients in the National Cancer Database and 7,878 (54%) patients in the National Cancer Registries had composite textbook outcome. Median overall survival in patients with composite textbook outcomes was 32 months in the National Cancer Database and 27 months in the National Cancer Registries (P < .001). In contrast, those with non-textbook outcomes had a median overall survival of 23 months in the National Cancer Database and 20 months in the National Cancer Registries (P < .001). CONCLUSION: Surgical-oncologic textbook outcomes were achieved in > 50% of stage I to III pancreatic ductal adenocarcinoma for both the National Cancer Database and the National Cancer Registries. Failure to achieve textbook outcomes was associated with impaired survival across both registries.

Sleep Apnea Detection by Tracheal Motion and Sound, and Oximetry via Application of Deep Neural Networks.

Purpose: Sleep apnea (SA) is highly prevalent, but under diagnosed due to inaccessibility of sleep testing. To address this issue, portable devices for home sleep testing have been developed to provide convenience with reasonable accuracy in diagnosing SA. The objective of this study was to test the validity a novel portable sleep apnea testing device, BresoDX1, in SA diagnosis, via recording of trachea-sternal motion, tracheal sound and oximetry. Patients and Methods: Adults with a suspected sleep disorder were recruited to undergo in-laboratory polysomnography (PSG) and a simultaneous BresoDX1 recording. Data from BresoDX1 were collected and features related to breathing sounds, body motions and oximetry were extracted. A deep neural network (DNN) model was trained with 61-second epochs of the extracted features to detect apneas and hypopneas from which an apnea-hypopnea index (AHI) was calculated. The AHI estimated by BresoDX1 (AHIbreso) was compared to the AHI determined from PSG (AHIPSG) and the sensitivity and specificity of SA diagnosis were assessed at an AHIPSG ≥ 15. Results: Two-hundred thirty-three participants (mean ± SD) 50 ± 16 years of age, with BMI of 29.8 ± 6.6 and AHI of 19.5 ± 22.7, were included. There was a strong relationship between AHIbreso and AHIPSG (r = 0.91, p < 0.001). SA detection for an AHIPSG ≥ 15 was highly sensitive (90.0%) and specific (85.9%). Conclusion: We conclude that the DNN model we developed via recording and analyses of trachea-sternal motion and sound along with oximetry provides an accurate estimate of the AHIPSG with high sensitivity and specificity. Therefore, BresoDX1 is a simple, convenient and accurate portable SA monitoring device that could be employed for home SA testing in the future.

Prognostic factors after resection of locally advanced non-functional pancreatic neuroendocrine neoplasm: an analysis from the German Cancer Registry Group of the Society of German Tumor Centers.

OBJECTIVE: The available literature regarding outcome after pancreatic resection in locally advanced non-functional pNEN (LA-pNEN) is sparse. Therefore, this study evaluates the current survival outcomes and prognostic factors in after resection of LA-pNEN. MATERIALS AND METHODS: This population-based analysis was derived from 17 German cancer registries from 2000 to 2019. Patients with upfront resected non-functional non-metastatic LA-pNEN were included. RESULTS: Out of 2776 patients with pNEN, 277 met the inclusion criteria. 137 (45%) of the patients were female. The median age was 63 ± 18 years. Lymph node metastasis was present in 45%. G1, G2 and G3 pNEN were found in 39%, 47% and 14% of the patients, respectively. Resection of LA-pNEN resulted in favorable 3-, 5- and 10-year overall survival of 79%, 74%, and 47%. Positive resection margin was the only potentially modifiable independent prognostic factor for overall survival (HR 1.93, 95% CI 1.71-3.69, p value = 0.046), whereas tumor grade G3 (HR 5.26, 95% CI 2.09-13.25, p value < 0.001) and lymphangiosis (HR 2.35, 95% CI 1.20-4.59, p value = 0.012) were the only independent prognostic factors for disease-free survival. CONCLUSION: Resection of LA-pNEN is feasible and associated with favorable overall survival. G1 LA-pNEN with negative resection margins and absence of lymph node metastasis and lymphangiosis might be considered as cured, while those not fulfilling these criteria might be considered as a high-risk group for disease progression. Herein, negative resection margins represent the only potentially modifiable prognostic factor in LA-pNEN but seem to be influenced by tumor grade.

Gastrointestinal stromal tumors of the upper GI tract: population-based analysis of epidemiology, treatment and outcome based on data from the German Clinical Cancer Registry Group.

BACKGROUND: Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors. They are most frequently located in the stomach but are also found in the esophagus and the gastroesophageal junction (GEJ). Information regarding the prognostic factors associated with upper gastrointestinal GIST is still scarse. METHODS: In this study, datasets provided by the German Clinical Cancer Registry Group, including a total of 93,069 patients with malignant tumors in the upper GI tract (C15, C16) between 2000 and 2016 were analyzed to investigate clinical outcomes of GIST in the entire upper GI tract. RESULTS: We identified 1361 patients with GIST of the upper GI tract. Tumors were located in the esophagus in 37(2.7%) patients, at the GEJ in 70 (5.1%) patients, and in the stomach in 1254 (91.2%) patients. The incidence of GIST increased over time, reaching 5% of all UGI tumors in 2015. The median age was 69 years. The incidence of GIST was similar between males and females (53% vs 47%, respectively). However, the proportion of GIST in female patients increased continuously with advancing age, ranging from 34.7% (41-50 years) to 71.4% (91-100 years). Male patients were twice as likely to develop tumors in the esophagus and GEJ compared to females (3.4% vs. 1.9% and 6.7% vs. 3.4%, respectively). The median overall survival of upper gastrointestinal GIST was 129 months. The 1-year, 5-year, and 10-year OS was 93%, 79%, and 52% respectively. Nevertheless, tumors located in the esophagus and GEJ were associated with shorter OS compared to gastric GIST (130 vs. 111 months, p = 0.001). The incidence of documented distant metastasis increased with more proximal location of GIST (gastric vs. GEJ vs. esophagus: 13% vs. 16% vs. 27%) at presentation. CONCLUSION: GIST of the esophagus and GEJ are rare soft tissue sarcomas with increasing incidence in Germany. They are characterized by worse survival outcomes and increased risk of metastasis compared to gastric GIST.

[Robot-assisted Minimally Invasive Oesophagectomy - Surgical Variants of Intrathoracic Circular Stapled Oesophagogastric Anastomosis]. / Roboterassistierte minimalinvasive Ösophagektomie ­ Varianten der intrathorakalen Ösophagogastrostomie mittels Zirkularstapler.

INTRODUCTION: Anastomotic insufficiency after oesophagectomy contributes significantly to morbidity and mortality of affected patients. A safe surgical technique can reduce the incidence of such anastomotic insufficiencies. INDICATION: In the treatment of oesophageal cancer, the German guideline recommends minimally invasive or hybrid surgical procedures. In most cases, Ivor-Lewis oesophagectomy and continuity reconstruction using a gastric sleeve are performed. Circular stapler anastomosis seems to be superior. METHOD: The preparation of the anastomosis starts intra-abdominally with mobilisation of the stomach and sparing of the gastroepiploic vessels. After the subsequent intrathoracic mobilisation of the oesophagus, the actual anastomosis construction can take place. Here, the oesophagus is either transected with a stapler closure or openly with scissors. This is followed by a purse-string suture on the open oesophageal stump. Alternatively, partial oesophageal opening with prior purse-string suture may later facilitate insertion of the stapler anvil. The anvil is placed in the oesophageal stump via minithoracotomy or alternatively transorally using a special gastric tube system. Subsequently, the anvil is fixated using the previously performed purse-string suture. Now the gastric sleeve can be pulled into the thorax. The oesophagus and small gastric curvature are placed extrathoracically through the minithoracotomy and a circular stapler is inserted into the gastric tube via an opening of the small curvature. The anastomosis then must be placed remotely from the gastroepiploic arcade. After construction of the anastomosis, the gastric sleeve is separated using a linear stapler. Eventually, the oesophagus and small gastric curvature can be completely recovered. Optionally, an additional suturing over the anastomosis and dissection margin of the gastric sleeve can be performed. CONCLUSION: In robot-assisted oesophagectomy, the reconstruction of continuity with a circular stapler anastomosis is quite possible and seems comparatively easier to learn. Nevertheless, variations are still possible within this procedure. However, there is no scientific evidence on the advantage for any method in a direct comparison.

Specifics of Young Gastric Cancer Patients: A Population-Based Analysis of 46,110 Patients with Gastric Cancer from the German Clinical Cancer Registry Group.

Introduction: 2−8% of all gastric cancer occurs at a younger age, also known as early-onset gastric cancer (EOGC). The aim of the present work was to use clinical registry data to classify and characterize the young cohort of patients with gastric cancer more precisely. Methods: German Cancer Registry Group of the Society of German Tumor Centers­Network for Care, Quality and Research in Oncology (ADT)was queried for patients with gastric cancer from 2000−2016. An approach that stratified relative distributions of histological subtypes of gastric adenocarcinoma according to age percentiles was used to define and characterize EOGC. Demographics, tumor characteristics, treatment and survival were analyzed. Results: A total of 46,110 patients were included. Comparison of different groups of age with incidences of histological subtypes showed that incidence of signet ring cell carcinoma (SRCC) increased with decreasing age and exceeded pooled incidences of diffuse and intestinal type tumors in the youngest 20% of patients. We selected this group with median age of 53 as EOGC. The proportion of female patients was lower in EOGC than that of elderly patients (43% versus 45%; p < 0.001). EOGC presented more advanced and undifferentiated tumors with G3/4 stages in 77% versus 62%, T3/4 stages in 51% versus 48%, nodal positive tumors in 57% versus 53% and metastasis in 35% versus 30% (p < 0.001) and received less curative treatment (42% versus 52%; p < 0.001). Survival of EOGC was significantly better (five-years survival: 44% versus 31% (p < 0.0001), with age as independent predictor of better survival (HR 0.61; p < 0.0001). Conclusion: With this population-based registry study we were able to objectively define a cohort of patients referred to as EOGC. Despite more aggressive/advanced tumors and less curative treatment, survival was significantly better compared to elderly patients, and age was identified as an independent predictor for better survival.

Clinical Outcome and Prognostic Factors of Pancreatic Adenosquamous Carcinoma Compared to Ductal Adenocarcinoma-Results from the German Cancer Registry Group.

Background: Adenosquamous carcinoma of the pancreas (ASCP) is a rare malignancy and its pathophysiology is poorly understood. Sparse clinical data suggest that clinical outcome and overall survival is worse in comparison to common pancreatic ductal adenocarcinoma (PDAC). Methods: We evaluated clinical outcome and prognostic factors for overall survival of patients with ASCP in comparison to patients with PDAC recorded between 2000 and 2019 in 17 population-based clinical cancer registries at certified cancer centers within the Association of German Tumor Centers (ADT). Results: We identified 278 (0.5%) patients with ASCP in the entire cohort of 52,518 patients with pancreatic cancer. Significantly, more patients underwent surgical resection in the cohort of ASCP patients in comparison to patients with PDAC (p < 0.001). In the cohort of 142 surgically resected patients with ASCP, the majority of patients was treated by pancreatoduodenectomy (44.4%). However, compared to the cohort of PDAC patients, significantly more patients underwent distal pancreatectomy (p < 0.001), suggesting that a significantly higher proportion of ASCP tumors was located in the pancreatic body/tail. ASCPs were significantly more often poorly differentiated (G3) (p < 0.001) and blood vessel invasion (V1) was detected more frequently (p = 0.01) in comparison with PDAC. Median overall survival was 6.13 months (95% CI 5.20−7.06) for ASCP and 8.10 months (95% CI 7.93−8.22) for PDAC patients, respectively (p = 0.094). However, when comparing only those patients who underwent surgical resection, overall survival of ASCP patients was significantly shorter (11.80; 95% CI 8.20−15.40 months) compared to PDAC patients (16.17; 95% CI 15.78−16.55 months) (p = 0.007). ASCP was a highly significant prognostic factor for overall survival in univariable regression analysis (p = 0.007) as well as in multivariable Cox regression analysis (HR 1.303; 95% CI 1.013−1.677; p = 0.039). Conclusions: In conclusion, ASCP showed poorer differentiation and higher frequency of blood vessel invasion indicative of a more aggressive tumor biology. ASCP was a significant prognostic factor for overall survival in a multivariable analysis. Overall survival of resected ASCP patients was significantly shorter compared to resected PDAC patients. However, surgical resection still improved survival significantly.

Concepts and Outcomes of Perioperative Therapy in Stage IA-III Pancreatic Cancer-A Cross-Validation of the National Cancer Database (NCDB) and the German Cancer Registry Group of the Society of German Tumor Centers (GCRG/ADT).

(1) Background: The aim of this study is to assess perioperative therapy in stage IA-III pancreatic cancer cross-validating the German Cancer Registry Group of the Society of German Tumor Centers-Network for Care, Quality, and Research in Oncology, Berlin (GCRG/ADT) and the National Cancer Database (NCDB). (2) Methods: Patients with clinical stage IA-III PDAC undergoing surgery alone (OP), neoadjuvant therapy (TX) + surgery (neo + OP), surgery+adjuvantTX (OP + adj) and neoadjuvantTX + surgery + adjuvantTX (neo + OP + adj) were identified. Baseline characteristics, histopathological parameters, and overall survival (OS) were evaluated. (3) Results: 1392 patients from the GCRG/ADT and 29,081 patients from the NCDB were included. Patient selection and strategies of perioperative therapy remained consistent across the registries for stage IA-III pancreatic cancer. Combined neo + OP + adj was associated with prolonged OS as compared to neo + OP alone (17.8 m vs. 21.3 m, p = 0.012) across all stages in the GCRG/ADT registry. Similarly, OS with neo + OP + adj was improved as compared to neo + OP in the NCDB registry (26.4 m vs. 35.4 m, p < 0.001). (4) Conclusion: The cross-validation study demonstrated similar concepts and patient selection criteria of perioperative therapy across clinical stages of PDAC. Neoadjuvant therapy combined with adjuvant therapy is associated with improved overall survival as compared to either therapy alone.

[Complete response after neoadjuvant therapy for esophageal cancer : Implications for surgery]. / Komplettresponse nach neoadjuvanter Therapie beim Ösophaguskarzinom : Implikationen für die Chirurgie.

A relevant number of patients with locally advanced esophageal squamous cell carcinoma and adenocarcinoma show a locoregional complete response of the tumor in the resected material after neoadjuvant therapy with modern chemotherapy and chemoradiation protocols. Due to a high rate of perioperative morbidity and decreased long-term quality of life following esophagectomy, the current treatment algorithm with neoadjuvant therapy and post-neoadjuvant esophagectomy on principle is critically questioned. An individualized treatment algorithm with extended clinical evaluation of post-neoadjuvant remission status and esophagectomy as needed is discussed. Patients with complete remission after neoadjuvant therapy are identified in an extended restaging protocol. Cases of clinical complete remission are treated with an active surveillance concept with esophagectomy as needed, i.e. surgery only when a local tumor recurrence is detected. Retrospective cohort studies have suggested that the active surveillance concept with esophagectomy as needed does not lead to a deterioration of overall survival rates in the patient collective. European prospective randomized, controlled, noninferiority studies with an oncological endpoint are currently evaluating the possibilities of organ-preserving concepts for clinical complete remission of esophageal cancer.

Survival Outcome and Prognostic Factors for Pancreatic Acinar Cell Carcinoma: Retrospective Analysis from the German Cancer Registry Group.

BACKGROUND: Pancreatic acinar cell carcinoma (PACC) is a distinct type of pancreatic cancer with low prevalence. We aimed to analyze prognostic factors and survival outcome for PACC in comparison to pancreatic ductal adenocarcinoma (PDAC), based on data from the German Cancer Registry Group. METHODS: Patients with PACC and PDAC were extracted from pooled data of the German clinical cancer registries (years 2000 to 2019). The distribution of demographic parameters, tumor stage and therapy modes were compared between PACC and PDAC. The Kaplan-Meier method and Cox regression analysis were used to delineate prognostic factors for PACC. Propensity score matching was used to compare survival between PACC and PDAC. RESULTS: There were 233 (0.44%) patients with PACC out of 52,518 patients with pancreatic malignancy. Compared to PDAC, patients with PACC were younger (median age 66 versus 70, respectively, p < 0.001) and the percentage of males was higher (66.1% versus 53.3%, respectively, p < 0.001). More patients were resected with PACC than with PDAC (56.2% versus 38.9%, respectively, p < 0.001). The estimated overall median survival in PACC was 22 months (95% confidence interval 15 to 27), compared to 12 months (95% confidence interval 10 to 13) in the matched PDAC cohort (p < 0.001). Surgical resection was the strongest positive prognostic factor for PACC after adjusting for sex, age, and distant metastases (hazard ratio 0.34, 95% confidence interval 0.22 to 0.51, p < 0.001). There was no survival benefit for adjuvant therapy in PACC. CONCLUSIONS: PACC has overall better prognosis than PDAC. Surgical resection is the best therapeutic strategy for PACC and should be advocated even in advanced tumor stages.

Mutant p53 Mediates Sensitivity to Cancer Treatment Agents in Oesophageal Adenocarcinoma Associated with MicroRNA and SLC7A11 Expression.

TP53 gene mutations occur in 70% of oesophageal adenocarcinomas (OACs). Given the central role of p53 in controlling cellular response to therapy we investigated the role of mutant (mut-) p53 and SLC7A11 in a CRISPR-mediated JH-EsoAd1 TP53 knockout model. Response to 2 Gy irradiation, cisplatin, 5-FU, 4-hydroxytamoxifen, and endoxifen was assessed, followed by a TaqMan OpenArray qPCR screening for differences in miRNA expression. Knockout of mut-p53 resulted in increased chemo- and radioresistance (2 Gy survival fraction: 38% vs. 56%, p < 0.0001) and in altered miRNA expression levels. Target mRNA pathways analyses indicated several potential mechanisms of treatment resistance. SLC7A11 knockdown restored radiosensitivity (2 Gy SF: 46% vs. 73%; p = 0.0239), possibly via enhanced sensitivity to oxidative stress. Pathway analysis of the mRNA targets of differentially expressed miRNAs indicated potential involvement in several pathways associated with apoptosis, ribosomes, and p53 signaling pathways. The data suggest that mut-p53 in JH-EsoAd1, despite being classified as non-functional, has some function related to radio- and chemoresistance. The results also highlight the important role of SLC7A11 in cancer metabolism and redox balance and the influence of p53 on these processes. Inhibition of the SLC7A11-glutathione axis may represent a promising approach to overcome resistance associated with mut-p53.

Effects of therapy modifications during the last decade on the outcome of patients undergoing esophagectomy for esophageal cancer.

BACKGROUND: During the last decade, numerous therapeutic regimes were assessed to improve the outcome of patients with esophageal carcinoma. We analyzed the impact of therapy alterations, including the establishment of a standardized clinical pathway and the introduction of an interdisciplinary tumor conference on the outcome of patients undergoing esophagectomy because of esophageal cancer. METHODS: Three hundred one patients were included (204 adenocarcinoma and 97 squamous cell carcinoma) who underwent an esophagectomy between 2006 and 2015. Patients were divided into 3 groups: interval A (2006-2008), interval B (2009-2011) and interval C (2012-2015) and evaluated separately focusing on therapy management and patients' outcome. RESULTS: Over the time periods, the incidence of tumor entity of adenocarcinoma increased from 61% to 76.2% (P=0.059). Patients with an initial tumor stage uT1 increased significantly from 4% to 15.9% over the intervals (P=0.002), while positive nodal involvement remained comparable (P=0.237). Patients in the later interval suffered from greater physical impairments preoperatively, represented by a significantly increased American Society Anesthesiologists (ASA) score (P=0.023) and a reduced Karnofsky Index (P<0.001). The tumor conference was accompanied by an increasing implementation of neoadjuvant therapy (27.1% vs. 42.2%, P=0.097). After establishing the clinical pathway 30-day mortality decreased (P=0.67). Grad III anastomotic leakage decreased significantly from 6.5% to 2% (P=0.01). However, gastrointestinal (P=0.007), pulmonary complications (P<0.001) including pneumonia (P<0.001) increased. Over the past ten years both overall survival and relapse-free survival prolonged (P=0.056 and P=0.063, respectively). CONCLUSIONS: Patients' collective suffering from esophageal cancer has changed over the last decade. Continuous further developments of the therapy regimes are needed to meet the requirements of reducing perioperative mortality and extending survival time.

MicroRNA Profiling in Oesophageal Adenocarcinoma Cell Lines and Patient Serum Samples Reveals a Role for miR-451a in Radiation Resistance.

Many patients with Oesophageal Adenocarcinoma (OAC) do not benefit from chemoradiotherapy treatment due to therapy resistance. To better understand the mechanisms involved in resistance and to find potential biomarkers, we investigated the association of microRNAs, which regulate gene expression, with the response to individual treatments, focusing on radiation. Intrinsic radiation resistance and chemotherapy drug resistance were assessed in eight OAC cell lines, and miRNA expression profiling was performed via TaqMan OpenArray qPCR. miRNAs discovered were either uniquely associated with resistance to radiation, cisplatin, or 5-FU, or were common to two or all three of the treatments. Target mRNA pathway analyses indicated several potential mechanisms of treatment resistance. miRNAs associated with the in vitro treatment responses were then investigated for association with pathologic response to neoadjuvant chemoradiotherapy (nCRT) in pre-treatment serums of patients with OAC. miR-451a was associated uniquely with resistance to radiation treatment in the cell lines, and with the response to nCRT in patient serums. Inhibition of miR-451a in the radiation resistant OAC cell line OE19 increased radiosensitivity (Survival Fraction 73% vs. 87%, p = 0.0003), and altered RNA expression. Pathway analysis of effected small non-coding RNAs and corresponding mRNA targets suggest potential mechanisms of radiation resistance in OAC.

[Robot-Assisted Upper Gastrointestinal and Hepato-Pancreato-Biliary Surgery: Implementation Using a Stepwise Approach and Analyses of the First 100 Surgical Procedures]. / Robotisch assistierte obere gastrointestinale und hepatopankreatobiliäre Chirurgie: Etablierung durch einen Stepwise Approach und eine Analyse der ersten 100 Operationen.

INTRODUCTION: Robot-assisted surgery is a promising technique for overcoming the limitations of laparoscopic surgery, especially for complex and advanced surgical procedures. We now describe the implementation of our robotic upper GI and HPB surgery program in our centre of excellence for minimally invasive surgery and the results of our first 100 surgical procedures. METHOD: Robot-assisted surgery was performed using the Da Vinci® Xi Surgical System™. Robot-assisted surgical procedures were performed by two surgeons specialising in minimally invasive surgery. Our robotic surgery program for upper GI and HPB surgery was established in three steps. Step 1: firstly, relatively easy surgical procedures were performed robotically, including cholecystectomies, minor gastric resections and fundoplications. Step 2: secondly, pancreatic left sided resections, adrenalectomies and small liver resection were performed, as procedures with moderate degree of difficulty. Step 3: finally, advanced and highly complex procedures were performed, including right hemihepatectomy, complex pancreatic resections, total gastrectomies and oesophagectomies. Data collected from July 2017 till October 2018 were analysed retrospectively with regard to conversion rate, morbidity (Clavien Dindo > 2) and 90-d-mortality. RESULTS: The first step of establishing our robotic surgical program included 26 procedures. Here, conversion rate, morbidity and mortality were 0%. In the second step of implementation, 23 procedures were performed. Conversion rate, morbidity and mortality were 28, 8 and 0% respectively. The last step included 51 advanced and highly complex procedures. These procedures had a morbidity of 41%, a mortality of 4% and a conversion rate of 43%. CONCLUSION: Our stepwise approach enables safe implementation of a robotic surgical program for upper GI and HPB surgery with comparable morbidity and mortality even for highly complex procedures. However, highly complex procedures in the learning curve required a high conversion rate.