Operative Results and Perioperative Morbidity After Intensified Neoadjuvant Chemotherapy with FLOT for Gastroesophageal Adenocarcinoma Impact of Intensified Neoadjuvant Treatment.

BACKGROUND: Perioperative treatment is the standard of care in Western Europe for locally advanced gastric cancer (GC) and adenocarcinoma of the gastroesophageal junction (GEJ). Intensified neoadjuvant treatment within the NeoFLOT trial proved to be safe and effective. Yet, the influence of such intensification with 6 cycles of FLOT in the neoadjuvant setting has not been analyzed regarding its possible impact on perioperative results. MATERIALS AND METHODS: A total of 537 patients were enrolled in this study; of whom, 132 had followed a standard neoadjuvant protocol (CTx), 356 had not received any neoadjuvant treatment (NoCTx), and 49 patients had undergone an intensified chemotherapy within the NeoFLOT trial (IntCTx) with 6 cycles of FLOT (5-FU, leucovorin, oxaliplatin, docetaxel) every 2 weeks. RESULTS: Our results reveal no significant difference in perioperative morbidity or mortality with regard to the neoadjuvant treatment. Postoperative bleeding and hematoma occurred less frequently in the IntCTx group compared to the NoCTx and the CTx groups (2.0% vs. 5.33% vs. 5.1%). Postoperative lymph fistulas were slightly more frequent in the IntCTx group (4.1% vs. 0.3% vs. 1.6%). Patients treated within the NeoFLOT trial had a higher risk for blood transfusions (OR 5.5; 95%-KI, 2.49-12.19), whereas patients without neoadjuvant therapy had the longest ICU stay (mean 8.3 vs. CTx 4.5 vs. IntCTx 6.7 days). CONCLUSION: The results of the current study indicate that also an intensification of neoadjuvant chemotherapy with 6 preoperative cycles of FLOT does not significantly increase perioperative complications. Thus, prolonged neoadjuvant chemotherapy with FLOT is safe for patients with locally advanced GC or GEJ tumors.

Propofol and Sevoflurane Differentially Impact MicroRNAs in Circulating Extracellular Vesicles during Colorectal Cancer Resection: A Pilot Study.

BACKGROUND: Extracellular vesicles and their microRNA cargo are crucial facilitators of malignant cell communication and could mediate effects of anesthetics on tumor biology during cancer resection. The authors performed a proof-of-concept study to demonstrate that propofol and sevoflurane have differential effects on vesicle-associated microRNAs that influence signaling pathways involved in tumor progression and metastasis. METHODS: Circulating vesicles were investigated in a prospective, matched-case pilot study in two cohorts of colorectal cancer patients receiving either propofol (n = 8) or sevoflurane (n = 9), matched for tumor stage and location. Serum was sampled before anesthesia and after tumor resection. Vesicular microRNA profiles were analyzed by next generation sequencing and confirmed by real-time polymerase chain reaction. Next, we assessed perioperative changes in microRNA expression induced by either anesthetic and compared their biologic effects on tumor-relevant pathways. Additionally, vesicles from pre- and postoperative sera were biologic characterized. RESULTS: Postoperative microRNA profiles were shifted in both groups with overlap in the perioperative response. A total of 64 (48 up, range of log2 fold change 1.07 to 3.76; 16 down, -1.00 to -1.55) and 33 (32 up, 1.02 to 2.98; 1 down, -1.36) microRNAs were significantly regulated (adjusted P value less than 0.05) by propofol and sevoflurane, respectively. Thirty-six (propofol) and five (sevoflurane) microRNAs were specifically responsive to either anesthetic agent. In silico target analyses of microRNA expression patterns indicated an inhibitory effect of propofol on crucial carcinoma-related pathways such as proliferation (z-score, -1.73) and migration (z-score, -1.97), as well as enhanced apoptosis (z-score, 1.19). While size distribution and protein markers of circulating vesicles were not affected by anesthesia, their concentration was reduced after surgery using both anesthetic procedures. CONCLUSIONS: This proof-of-concept study provides preliminary evidence that anesthetic agents have specific effects on microRNA profiles in circulating vesicles. These findings could form the basis for larger and mechanistically oriented outcome studies in cancer patients.

[Design and Evaluation of a Clinical Investigator Training for Student-lead Prospective Multicentre Clinical Trials: a CHIR-Net SIGMA Research-based Learning Project]. / Design und Evaluation eines Prüf-Studierenden-Kurses für studentische prospektive Multicenterstudien ­ ein CHIR-Net-SIGMA-Projekt zum forschenden Lernen.

BACKGROUND: Scientific skills are not sufficiently taught during medical training, neither in medical school nor during postgraduate education. This results in a lack of clinician scientists. In order to counter this problem, the surgical study network (CHIR-Net) founded SIGMA (Student-initiated German Medical Audit). This paper describes the development, performance and evaluation of a Clinical Investigator Training (CIT) aiming to qualify students to autonomously conduct clinical trials. MATERIAL AND METHODS: Based on the Kern cycle, a curriculum was developed, composed of three parts: online tutorials, a workshop and a follow-up period. The educational objectives were defined according to Bloom's taxonomy of knowledge. The learning objectives were based on the requirements of the "Network of Coordinating Centers for Clinical Trials" and the German Medical Association as well as content relevant to clinical studies. A wide range of educational instruments and assessments were used. By including all relevant professional groups involved in clinical trials, an interconnected working environment for students was generated. The increase in knowledge was assessed by a multiple-choice pre/post exam. The satisfaction of participants was analysed by a 5-point Likert scale, on which 5 indicated full approval. RESULTS: The first SIGMA CIT was realised in 2018; the workshop took place in Heidelberg in February. Thirty-two medical students from thirteen different centres participated. On average, 53.8 ± 8.3% of questions were answered correctly in the pre-test, compared with 71.2 ± 7.2% in the post-test (p < 0.0001). The maximal individual improvement was 30%; the lowest difference compared to the pre-test was 5%. Subjective evaluation results were positive with an average result of 4.63 ± 0.34 on a 5-point Likert scale. CONCLUSION: It is feasible to teach medical students the fundamentals of clinical trials. A compact Clinical Investigator Training using modern principles of teaching is able to prepare students for an autonomous performance of clinical trials.

Functional outcome after pouch-anal reconstruction with primary and secondary mucosectomy for patients with familial adenomatous polyposis (FAP).

INTRODUCTION: Restorative proctocolectomy and ileal pouch-anal reconstruction is the surgical standard for the majority of patients with familial adenomatous polyposis (FAP). The pouch-anal anastomosis may be performed handsewn after primary mucosectomy or by double stapling. Better functional results favour the latter; however, higher rates of remaining rectal mucosa with adenomas often necessitate secondary mucosectomy. Data on functional outcome after secondary mucosectomy is scarce. The aim of the study was to analyse whether patients who undergo secondary mucosectomy maintain their functional benefits compared to patients with primary mucosectomy. PATIENTS AND METHODS: Twenty patients after secondary mucosectomy and 31 patients after primary mucosectomy were compared with respect to their functional outcome, using the MSKCC score, the Wexner score and ano-rectal physiology testing. RESULTS: The MSKCC global score and the Wexner score showed a non-significant trend towards slightly better results after secondary mucosectomy (63.1 vs. 56.6, p = 0.0188 and 9.5 vs. 11, p = 0.3780). Patients after secondary mucosectomy also showed a tendency towards less bowel movements per 24 h (7 (range 4-11) vs. 8.5 (range 3-20), p = 0.1518). Resting pressures were slightly higher after secondary (44 vs. 39.6 mmHg, p = 0.4545) and squeeze pressures slightly higher after primary mucosectomy (87.6 vs. 81.2 mmHg, p = 0.6126). However, the results did not reach statistical significance. CONCLUSION: The results of this study cannot ultimately resolve the controversy concerning handsewn versus stapled ileal pouch-anal anastomosis. Our results suggest a trend towards better functional results after stapled anastomosis with secondary mucosectomy.

Risk Factors Associated With Pouch Adenomas in Patients With Familial Adenomatous Polyposis.

BACKGROUND: Restorative proctocolectomy with ileal pouch-anal reconstruction is the standard prophylactic surgical procedure for patients with familial adenomatous polyposis. However, several groups have reported the development of adenomas and even carcinomas within the ileal pouch. The predisposing factor was the time interval after pouch surgery in some studies, but it was the severity of the initial colonic disease and duodenal adenomatosis in others. OBJECTIVE: The aim of this study was to further clarify the prevalence of pouch adenomas, clinical risk factors, and a possible phenotype-genotype relation in a large population of patients with familial adenomatous polyposis, as well as to analyze pouch adenoma-free survival. DESIGN: This study was designed as a cohort study. SETTINGS: This study was conducted in a specialized outpatient clinic at the University of Heidelberg. PATIENTS: A total of 192 patients with familial adenomatous polyposis were included, and all of the available endoscopy reports after pouch surgery were screened for pouch adenomas. Additional clinical information was retrieved from the Heidelberg Polyposis Register. MAIN OUTCOME MEASURES: This present study revealed 3 main independent risk factors for the development of pouch adenomas: age <18 years at the time of IPAA, male sex, and the presence of gastric adenomas. Secondary outcome measures were adenoma progression and overall pouch adenoma-free survival. RESULTS: Pouch adenomas were detected in 46.9% of patients. Median follow-up was 12.8 years (interquartile range, 9.0-17.0 y) for patients with pouch adenomas and 7.3 years (interquartile range, 2.5-12.2 y) for those without them. Patients underwent pouch surgery at a median age of 27.5 years (range, 10.2-58.5 y), and pouch adenomas occurred a median of 8.5 years (range, 0.9-25.1 y) after surgery. Also detected were gastric adenomas in 37.2%, duodenal adenomas in 80.3%, and desmoid tumors in 24.5% of patients. Estimation of pouch adenoma-free survival revealed that, after 20 years, only ≈22% of patients would be free of pouch adenomas. Male sex, age ≦18 years at the time of pouch surgery, and gastric adenomas were found to be independent risk factors for the development of pouch adenomas in a multivariate Cox regression analysis (p = 0.0002, p = 0.0059, and p = 0.0020). No predisposing germline mutation for pouch adenoma development was detected. LIMITATIONS: Detailed information on the initial preoperative findings was not fully available, and the study was only carried out as a single-center study. CONCLUSIONS: A severe upper intestinal phenotype, male sex, and age <18 years at the time of IPAA all increase the risk for development of pouch adenomas. See Video Abstract at http://links.lww.com/DCR/A675.

Extra-capsular growth of lymph node metastasis correlates with poor prognosis and high SOX9 expression in gastric cancer.

BACKGROUND: Extra-capsular growth (ECG) describes the extension of neoplastic cells beyond the lymph node capsule. Aim of this study was to investigate the prognostic value of ECG and its association with a stem cell like phenotype indicated by expression of the transcription factor SOX9 in gastric cancer. METHODS: By histological evaluation, 199 patients with nodal positive gastric cancer or adeoncarcinoma of the esophageal-gastric junction (AEG) were divided into two groups according to the presence (ECG) or absence (ICG) of extracapsular growth in at least one nodal metastasis. Of these, 194 patients were stained for SOX9 and SOX2 using immunohistochemistry. Seventeen nodal negative patients (pT3/4, pN0, pM0) served as controls. RESULTS: Seventy-three patients (36.7%) showed ECG. ECG was associated with lower overall survival (p < 0.0001), advanced pT- (p = 0.03) and pN- category (p < 0.0001) and lymphovascular invasion (p = 0.014). In multivariate analysis, ECG was found to be an independent prognostic factor (HR = 2.1; 95% CI 1.7-3.4; p = 0.001). SOX9 expression correlated significantly with ECG (96% SOX9 high in ECG patients vs. 79% SOX9 high in patients with ICG; p = 0.002). Controls showed significantly reduced SOX9 expression compared to nodal positive carcinomas (59% vs. 85% high SOX9 expression; p = 0.006). No significant correlation of ECG and SOX2 (59% SOX2 negative in ECG patients vs. 64% in patients with ICG, p = 0.48) could be obtained. CONCLUSIONS: Patients with ECG exhibit poorer prognosis and ECG was found to be an independent prognostic factor. Thus, ECG turns out to be a morphological biomarker for a more aggressive phenotype in gastric cancer. This is supported by the fact that ECG correlates with the expression of SOX9, which has been described in the context of pro-oncogenic properties of tumours. However, the fact that SOX2 failed to show significant results indicate that ECG is not associated with a distinct cancer stem cell phenotype in gastric cancer.

Postoperative outcome and quality of life after surgery for FAP-associated duodenal adenomatosis.

INTRODUCTION: Prophylactic colon surgery has increased life expectancy of familial adenomatous polyposis patients. Extracolonic manifestations are life limiting, above all duodenal adenomas. Severe duodenal adenomatosis or cancer may necessitate pancreas-preserving total duodenectomy or partial pancreatico-duodenectomy, mostly after previous proctocolectomy and often after limited local resections of duodenal adenomas. Scarce information on long-term postoperative outcome and quality of life after surgery for duodenal adenomatosis is available. Aim of the present study was to analyze perioperative and long-term outcome after PD and PPTD for FAP-associated duodenal adenomatosis, including QoL and recurrence of adenomas in the neoduodenum after PPTD. MATERIAL, METHODS AND PATIENTS: Thirty-eight patients, 27 after pancreas-preserving duodenectomy and 11 after partial pancreaticoduodenectomy, were included. RESULTS: Pancreas-preserving total duodenectomy was associated with shorter operation time and less blood loss than partial pancreatico-duodenectomy. Clinically relevant pancreatic fistula occurred in 31.5%. In-hospital mortality was 5.3%. Long-term follow-up revealed recurrent pancreatitis after pancreas-preserving total duodenectomy in 22% of patients, two (7.4%) required re-operation. Recurrent adenomatosis was detected in 26% of patients. Quality of life was comparable to the German normal population after both surgical procedures. Patients with postoperative complications showed worse results than those without complications. Disease-specific 10-year survival rate with respect to duodenal adenomatosis was 100%. CONCLUSION: Surgery for FAP-associated duodenal adenomatosis and cancer can be carried out with reasonable morbidity rates despite previous proctocolectomy. Long-term outcome, quality of life, and survival rates are favorable.

Double germline mutations in APC and BRCA2 in an individual with a pancreatic tumor.

We report on three brothers affected by pancreatic tumors, all due to different causes, including mutations associated with two different cancer predisposition syndromes in the same individual. In the index patient a germline mutation both in the APC and BRCA2 gene was identified while one affected brother showed the BRCA2 mutation only and another brother is supposed to have developed pancreatic cancer due to multiple non-genetic risk factors. We outline the impact of a double germline mutation in two tumor predisposition genes in one individual and proven heterogeneity of multiple cases of pancreatic tumors in one family. With the growing implementation of next generation sequence based panel testing for multiple genes involved in tumor predisposition syndromes, relevant variants in two (or more) genes will be found more frequently. This family illustrates the importance of family studies, especially when using gene panel tests.

Residual rectal mucosa after stapled vs. handsewn ileal J-pouch-anal anastomosis in patients with familial adenomatous polyposis coli (FAP)--a critical issue.

INTRODUCTION: Restorative proctocolectomy has become the standard surgical procedure for familial adenomatous polyposis (FAP) patients. The use of stapler devices has initiated a controversial discussion concerning the ileal pouch-anal reconstruction. Some authors advocate a handsewn anastomosis after transanal mucosectomy. A double-stapled anastomosis leads to better functional results but seems to bear a higher risk of residual rectal mucosa with dysplasia and adenomas. The present study systematically analyses the rate of residual rectal mucosa after restorative proctocolectomy and handsewn vs. stapled anastomosis. PATIENTS AND METHODS: One hundred FAP patients after restorative proctocolectomy undergoing regular follow-up at our outpatient clinic were included in the study. Proctoscopy with standardised biopsy sampling was performed. RESULTS: Of the 100 patients, 50 had undergone a stapled and 50 a handsewn anastomosis. Median follow-up was 146.1 months (handsewn) vs. 44.8 months (stapled) (P < 0.0001). Eighty-seven patients received a proctoscopy with standardised biopsy sampling. Thirteen patients had been diagnosed with residual rectal mucosa before. Sixty-three patients (63 %) showed remaining rectal mucosa (42 (66.6 %) stapler, 21 (33.3 %) handsewn, P < 0.0001). Patients after stapled anastomosis had higher rates of circular rectal mucosa seams, while small mucosa islets predominated in the handsewn group. The rate of rectal adenomas was significantly higher in the stapler group (21 vs. 10, P = 0.02). CONCLUSION: Rectal mucosa, especially wide mucosa seams, as well as rectal adenomas are found significantly more often after a stapled than after a handsewn anastomosis. As the follow-up interval in the stapler group was significantly shorter, the impact of these findings may still be underestimated.

Quality of life ten and more years after restorative proctocolectomy for patients with familial adenomatous polyposis coli.

PURPOSE: Few studies on long-term quality of life after restorative proctocolectomy and ileal pouch-anal anastomosis have been published. Most of them survey a mixed patient population of familial adenomatous polyposis and ulcerative colitis. The present study analyzes long-term results more than 10 years after ileal pouch-anal anastomosis for patients with familial adenomatous polyposis, exclusively. METHODS: One hundred thirty-five patients who underwent ileal pouch-anal anastomosis more than 10 years ago were identified from the prospective familial adenomatous polyposis registry at Heidelberg University hospital. They received the German version of the health-specific Short Form 36 Health Survey and the disease-specific Gastrointestinal Quality of Life Index by mail. To assess the impact of disease-specific factors, 10 questions asking for ability to work, current medication, pouchitis, and extracolonic manifestations of familial adenomatous polyposis were added to the Gastrointestinal Quality of Life Index questionnaire. RESULTS: Among 84 patients who answered the questionnaires the median follow-up was 13.4 years (range, 10.3-23.8 y).The results of the Short Form 36 Health Survey were comparable to a German normative population in all dimensions, whereas the overall score for the Gastrointestinal Quality of Life Index was significantly reduced compared with healthy individuals (111.8 vs 120.8, P = .0014). Carcinoma at the time of ileal pouch-anal anastomosis, desmoid tumors, or duodenal adenomas had no significant influence on quality of life. More than 7 bowel movements during the daytime were found to reduce quality of life significantly (103.5 vs 115, P = .0127). More than 2 defecations per night diminished the score further (101 vs 125, P < .0001). Patients younger than 40 years at the time of ileal pouch-anal anastomosis had significantly better results than older patients (120 vs 109.5, P = .0076). CONCLUSION: Ileal pouch-anal anastomosis is a safe surgical procedure with a high quality of life comparable to that of a normative population after long-term follow-up of patients with familial adenomatous polyposis.