In-vitro model to mimic T cell subset change in human PDAC organoid co-culture.

PURPOSE: Immunotherapies have largely failed as treatment options for pancreatic ductal adenocarcinoma (PDAC). In this field, clinical translational studies into personalized treatment are of fundamental importance. In our study, we model tumor-cell immune-cell interactions in a co-culture of primary human PDAC organoids and matched peripheral blood mononuclear cells (PBMCs). METHODS: Using flow cytometry, we evaluated changes in T cell subtypes upon co-culture of patient-derived PDAC organoids and matched PBMCs. RESULTS: After co-culturing PDAC organoids with PBMCs, we observed changes in CD4+, CD8+ and Treg cell populations. We observed favorable clinical outcome in patients whose PBMCs reacted to the co-culture with organoids. CONCLUSION: This experimental model allows to investigate interactions between patient derived PDAC organoids and their PBMCs. This co-culture system could serve as a preclinical platform to guide personalized therapeutic strategies in the future.

Age and metastasis - How age influences metastatic spread in cancer. Colorectal cancer as a model.

Metastasis is the major cause of death in cancer patients. Whereas colorectal cancer (CRC) incidence increases with age, metastatic spread seems to decline. Furthermore, the epidemiology of CRC is changing. There is an increase in CRC incidence in the young, presenting at an advanced stage with higher likelihood of synchronous or metachronous metastases, and a decline in CRC incidence and metastatic spread in the oldest-old. Emerging data suggest that age-related changes with regard to tumor biology (e.g. genomic instability), the tumor microenvironment (e.g. inflammaging) and the immune system (e.g. immunosenescence), complemented by interaction between the genome and exposome might contribute to the observed metastatic patterns. As aging is a key prognostic factor, this highlights the need for further studies investigating age-related patterns and underlying mechanisms of tumor growth and dissemination. Eventually, this might allow for better risk stratification, refinement of screening strategies and follow-up care as well as therapies tailored to reflect patient age and that might possibly target responsible biomarkers in a precision medicine approach. This review aims to discuss the influence of aging on metastatic spread in colorectal cancer and elucidate underlying mechanisms responsible for the observed metastatic patterns.

Postoperative chyle leak after pancreatic surgery - Is treatment effective?

PURPOSE: With increasing soft tissue clearance in pancreatic cancer surgery, postoperative chyle leak (CL) has become a more commonly observed complication. Recently, a new consensus definition was established by the International study group of pancreatic surgery (ISGPS). The aim of the present analysis was to evaluate risk factors and treatment options of patients with CL after pancreatic surgery. METHODS: Two hundred and twenty-eight patients with serous or chylous drainage after pancreatic surgery were included in this analysis of a prospectively collected database between 01/2014 and 12/2016. Risk factors for CL and treatment options were compared. A subgroup analysis on those patients, who had drain removal despite of persistent CL with respect to the need of subsequent percutaneous drainage or reoperation within three months postoperatively, was performed. RESULTS: Sixty patients with CL were identified. Of those, 41 patients were treated with medium-chain triglyceride-diet, with a median duration of therapy of 12 days. In patients with CL, the type of treatment had no effect on time to drain removal (P=0.29) and morbidity (P=0.15). Furthermore, morbidity was not increased in patients who had their drains removed despite persistent CL (P=0.84). None of the latter patients had percutaneous drainage or reoperation for CL after removal of the surgical drains. CONCLUSIONS: Dietary treatment may not be very effective in treating CL. Further research is warranted to explore the effect and necessity of CL treatment.

LIN28 promotes tumorigenesis in colorectal cancer but is not associated with metastatic spread.

BACKGROUND: Tumor stem cells play a role in metastatic spread in colorectal cancer (CRC). The oncogene LIN28A/B, a prognostic marker in CRC, is involved in tumorigenesis and maintains stem cell function. Therefore, it was the aim of the present study to clarify whether LIN28A/B is involved in metastatic spread in CRC. METHODS: Expression of LIN28A/B was analyzed in patients with colon adenocarcinoma in a matched case-control study comparing patients with corresponding liver metastases (n = 42) and patients without hepatic spread within five years (n = 42) by applying immunohistochemistry. Further, LIN28A/B expression was correlated with stem cell associated markers (SOX2, CD133). RESULTS: LIN28A and B expression significantly correlated with SOX2 expression (p = .02, and p = .04 respectively) but not with CD133 expression. This correlation between LIN28 A/B and SOX2 was not reflected in differences in hepatic spread. In this respect, there was no significant association between LIN28A/B expression and liver metastases. CONCLUSION: LIN28A/B might be involved in tumor initiation and progression in CRC but is not associated with hepatic spread.

Effect of platelet inhibition with perioperative aspirin on survival in patients undergoing curative resection for pancreatic cancer: a propensity score matched analysis.

BACKGROUND: The importance of platelets in the pathogenesis of metastasis formation is increasingly recognized. Although evidence from epidemiologic studies suggests positive effects of aspirin on metastasis formation, there is little clinical data on the perioperative use of this drug in pancreatic cancer patients. METHODS: From all patients who received curative intent surgery for pancreatic cancer between 2014 and 2016 at our institution, we identified 18 patients that took aspirin at time of admission and continued to throughout the inpatient period. Using propensity score matching, we selected a control group of 64 patients without aspirin intake from our database and assessed the effect of aspirin medication on overall, disease-free, and hematogenous metastasis-free survival intervals as endpoints. RESULTS: Aspirin intake proved to be independently associated with improved mean overall survival (OS) (46.5 vs. 24.6 months, *p = 0.006), median disease-free survival (DFS) (26 vs. 10.5 months, *p = 0.001) and mean hematogenous metastasis-free survival (HMFS) (41.9 vs. 16.3 months, *p = 0.005). Three-year survival rates were 61.1% in patients with aspirin intake vs. 26.3% in patients without aspirin intake. Multivariate cox regression showed significant independent association of aspirin with all three survival endpoints with hazard ratios of 0.36 (95% CI 0.15-0.86) for OS (*p = 0.021), 0.32 (95% CI 0.16-0.63) for DFS (**p = 0.001), and 0.36 (95% CI 0.16-0.77) for HMFS (*p = 0.009). CONCLUSIONS: Patients in our retrospective, propensity-score matched study showed significantly better overall survival when taking aspirin while undergoing curative surgery for pancreatic cancer. This was mainly due to a prolonged metastasis-free interval following surgery.

[Oligometastases of neuroendocrine tumors-extent of surgery]. / Oligometastasierung bei neuroendokrinen Tumoren ­ Ausmaß der Chirurgie.

Neuroendocrine tumors (NETs) are rare neoplasms, which represent complex challenges in diagnosis and treatment. Even in the metastatic stage there are important differences in the type of tumor in comparison to gastrointestinal and pancreatic adenocarcinomas. Therefore, the disease courses are substantially different depending on the grade of differentiation. Even in the metastatic stage the 5­year survival rates of G1 tumors is up to 83%. Approximately 20% of small intestine NETs additionally show hormone activity, which can compromise survival and the quality of life. For individual treatment decisions the special tumor biology of these tumors must be taken into consideration more so than for other tumor entities. Surgery always becomes important for these tumors when a R0 resection appears possible. Oligometastasis of the liver and the lymph drainage system can be meaningfully approached by surgical treatment. In selected patients with an isolated liver involvement, a liver transplantation can be considered; however, even tumor debulking can lead to improvement in the quality of life and survival, especially for hormone active tumors with a carcinoid syndrome which cannot be conservatively controlled. The aim of this review is to present the value of surgical treatment options in the case of (oligo)metastasized NETs.

Moon phases and moon signs do not influence morbidity, mortality and long-term survival, after living donor kidney transplantation.

BACKGROUND: Approximately 11% of the German population are convinced that certain moon phases and moon signs may impact their health and the onset and clinical course of diseases. Before elective surgery, a considerable number of patients look to optimize the timing of the procedure based on the lunar cycle. Especially patients awaiting living donor kidney transplantation (LDKT) commonly look for an adjustment of the date of transplantation according to the moon calendar. This study therefore investigated the perioperative and long-term outcome of LDKT dependent on moon phases and zodiac signs. METHODS: Patient data were prospectively collected in a continuously updated kidney transplant database. Two hundred and seventy-eight consecutive patients who underwent LDKT between 1994 and December 2009 were selected for the study and retrospectively assigned to the four moon phases (new-moon, waxing-moon, full-moon, and waning-moon) and the corresponding zodiac sign (moon sign Libra), based on the date of transplantation. Preexisting comorbidities, perioperative mortality, surgical outcome, and long-term survival data were analyzed. RESULTS: Of all LDKT procedures, 11.9, 39.9, 11.5, and 36.5% were performed during the new, waxing, full, and waning moon, respectively, and 6.2% during the moon sign Libra, which is believed to interfere with renal surgery. Survival rates at 1, 5, and 10 years after transplantation were 98.9, 92, and 88.7% (patient survival) and 97.4, 91.6, and 80.6% (graft survival) without any differences between all groups of lunar phases and moon signs. Overall perioperative complications and early graft loss occurred in 21.2 and 1.4%, without statistical difference (p > 0.05) between groups. CONCLUSION: Moon phases and the moon sign Libra had no impact on early and long-term outcome measures following LDKT in our study. Thus, concerns of patients awaiting LDKT regarding the ideal time of surgery can be allayed, and surgery may be scheduled independently of the lunar phases.

Should ALPPS be Used for Liver Resection in Intermediate-Stage HCC?

BACKGROUND: Extended liver resections in patients with hepatocellular carcinoma (HCC) are problematic due to hepatitis, fibrosis, and cirrhosis. Associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) has been promoted as a novel method to induce hypertrophy for patients with extensive colorectal liver metastases, but outcomes in HCC have not been well investigated. METHODS: All patients registered in the international ALPPS Registry ( www.alpps.org ) from 2010 to 2015 were studied. Hypertrophy of the future liver remnant, perioperative morbidity and mortality, age, overall survival, and other parameters were compared between patients with HCC and patients with colorectal liver metastases (CRLM). RESULTS: The study compared 35 patients with HCC and 225 patients with CRLM. The majority of patients undergoing ALPPS for HCC fall into the intermediate-stage category of the Barcelona clinic algorithm. In this study, hypertrophy was rapid and extensive for the HCC patients, albeit lower than for the CRLM patients (47 vs. 76 %; p < 0.002). Hypertrophy showed a linear negative correlation with the degrees of fibrosis. The 90-day mortality for ALPPS used to treat HCC was almost fivefold higher than for CRLM (31 vs. 7 %; p < 0.001). Multivariate analysis showed that patients older than 61 years had a significantly reduced overall survival (p < 0.004). CONCLUSION: The ALPPS approach induces a considerable hypertrophic response in HCC patients and allows resection of intermediate-stage HCC, albeit at the cost of a 31 % perioperative mortality rate. The use of ALPPS for HCC remains prohibitive for most patients and should be performed only for a highly selected patient population younger than 60 years with low-grade fibrosis.

Spiegelmer Inhibition of MCP-1/CCR2--Potential as an Adjunct Immunosuppressive Therapy in Transplantation.

The rejection process remains the key unsolved issue after transplantation of disparate tissue. The CC chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) has been reported to be involved in the process of alloimmune interaction. Spiegelmers are l-oligonucleotides that can be designed to bind to pharmacologically relevant target molecules. Here, we tested a high-affinity Spiegelmer-based MCP-1 inhibitor (mNOX-E36) in an allogeneic heart transplant model. Fully vascularized allogeneic heterotopic heart transplantations from BALB/c to C57BL/6 mice were performed. Mice were either treated with the anti-MCP-1-Spiegelmer (mNOX-E36) in monotherapy or in combination with subtherapeutic doses of cyclosporine A (CsA) (10 mg/kgBW/day) for 10 days. Controls received equivalent doses of a non-functional Spiegelmer (revmNOX-E36). Graft survival of allogeneic heart transplants was slightly but significantly prolonged under mNOX-E36 monotherapy (median graft survival 10 day ± 0.7) compared to revmNOX-E36 (median graft survival 7 day ± 0.3; P = 0.001). A synergistic beneficial effect could be seen when mNOX-E36 was administered in combination with subtherapeutic doses of CsA (18 day ± 2.8 versus 7 day ± 0.3; P < 0.0001). Levels of inflammatory cytokines and 'alarmins' were significantly reduced, and the number of F4/80(+) cells was lower under combination therapy (1.8% ± 1.3%; versus 14.6% ± 4.4%; P = 0.0002). This novel inhibitor of the MCP-1/CCR2 axis (mNOX-E36), which has already proven efficacy and tolerability in early clinical trials, alleviates acute rejection processes in allogeneic transplantation especially when combined with subtherapeutic doses of CsA. Thus, mNOX-E36 may have potential as an adjunct immunomodulatory agent.

[Requirements for final year medical studies in the era of generation Y - implementation for general and visceral surgery at the Ludwig Maximilians University of Munich]. / Anforderungen an das Praktische Jahr im Zeitalter der Generation Y - Umsetzung für die Allgemein- und Viszeralchirurgie an der Ludwig-Maximilians-Universität München.

The revision of the medical licensing regulations in 2012 has changed the underlying conditions for the practical year (PY), especially in the sense of markedly more flexibility for the medical students. The driving force for these and future changes, however, is not the legislature but rather the students themselves who are explicitly demanding that their training be adapted to their requirements and wishes. Time for the realisation of personal aims, planning of leisure time activities, for the family and social contacts as well as an altogether balanced work-life balance have replaced the wish for professional advancement as premise for the lifestyle of generation Y. Many hospitals, especially the privately-supported, attract students with special offers - university hospitals are called upon to defend their position in the competition for newly qualified students. The present article describes the changes of 2012 as part of a programme for a sustainable increase in the attractivity of the surgical PY at the Ludwig-Maximilian University (LMU) in Munich.

[Operative therapy of abdominal and retroperitoneal sarcoma]. / Operative Therapie der abdominellen und retroperitonealen Sarkome.

Retroperitoneal soft tissue sarcomas are characterized by a high rate of local recurrence. Complete tumor resection is the only potentially curative therapeutic option. The concept of a systematic compartmental resection is to remove the tumor en bloc with a margin of uninvolved tissue and organs. This is frequently only achieved by multivisceral resection which often includes kidney, colon, pancreas and parts of the diaphragm or the psoas muscle. The adoption of such a policy of multivisceral organ resection improves the proportion of curative resections and, ultimately, results in lower local recurrence rates. The present article comprehensively describes the operative procedures, perioperative treatment and the oncological results of surgery for retroperitoneal sarcomas. The role of surgery in oncological treatment plans and the importance of specialized centres are outlined in detail.

Recombinant TIMP-1-GPI inhibits growth of fibrosarcoma and enhances tumor sensitivity to doxorubicin.

Fibrosarcomas show a high incidence of recurrence and general resistance to apoptosis. Limiting tumor regrowth and increasing their sensitivity to chemotherapy and apoptosis represent key issues in developing more effective treatments of these tumors. Tissue inhibitor of metalloproteinase 1 (TIMP-1) broadly blocks matrix metalloproteinase (MMP) activity and can moderate tumor growth and metastasis. We previously described generation of a recombinant fusion protein linking TIMP-1 to glycosylphophatidylinositol (GPI) anchor (TIMP-1-GPI) that efficiently directs the inhibitor to cell surfaces. In the present report, we examined the effect of TIMP-1-GPI treatment on fibrosarcoma biology. Exogenously applied TIMP-1-GPI efficiently incorporated into surface membranes of human HT1080 fibrosarcoma cells. It inhibited their proliferation, migration, suppressed cancer cell clone formation, and enhanced apoptosis. Doxorubicin, the standard chemotherapeutic drug for fibrosarcoma, was tested alone or in combination with TIMP-1-GPI. In parallel, the influence of treatment on HT1080 side population cells (exhibiting tumor stem cell-like characteristics) was investigated using Hoechst 33342 staining. The sequential combination of TIMP-1-GPI and doxorubicin showed more than additive effects on apoptosis, while TIMP-1-GPI treatment alone effectively decreased "stem-cell like" side population cells of HT1080. TIMP-1-GPI treatment was validated using HT1080 fibrosarcoma murine xenografts. Growing tumors treated with repeated local injections of TIMP-1-GPI showed dramatically inhibited fibrosarcoma growth and reduced angiogenesis. Intraoperative peritumoral application of GPI-anchored TIMP-1 as an adjuvant to surgery may help maintain tumor control by targeting microscopic residual fibrosarcoma cells and increasing their sensitivity to chemotherapy.

[Pancreatic cancer in the elderly: guidelines and individualized therapy]. / Pankreaskarzinom im hohen Alter: Leitlinien und individualisierte Therapie.

The considerable increase of the aged population in western civilisation within the next years will result in a rising incidence of pancreatic cancer. Until the year 2020 an increment of 20  % of patients beyond 65 years old can be anticipated. Therefore, the focus will be on management of old and geriatric surgical patients leading to strategical re-evaluation of surgical indications under critical consideration of feasibility and purpose. Even under modern interdisciplinary therapy concepts the prognosis of ductal adenocarcinoma of the pancreas remains poor with an overall 5-year survival rate of less than 5  %. The surgical resection is still considered as the only potential curative treatment option with extended life expectancy; however, it is technically demanding and furthermore associated with significant morbidity. In particular, the quality of surgery of the now interdisciplinary therapy of pancreatic cancer is markedly improved when performed at a high-volume centres. Until now only a few retrospective data analyses evaluating the perioperative and long-term outcome after pancreatic tumor resections in geriatric patients exist. The available results, however, support radical surgical procedures even beyond the age of 75 years.

Targeting the vasculature of visceral tumors: novel insights and treatment perspectives.

BACKGROUND: Angiogenesis, the formation of new blood vessels from the endothelium of the existing vasculature, describes a crucial process in tumor growth, disease progression, and metastasis. Therefore, the upcoming strategy of inhibiting tumor angiogenesis has generated different treatment modalities, which have been transferred into clinical practice in recent years. Currently, this concept is applied to target the vasculature of different visceral tumors and intensive clinical research has just started. MATERIALS AND METHODS: This review summarizes the modifications of systemic treatment of visceral tumors by targeting the vasculature in the past years. Moreover, novel targets and treatment strategies will be discussed to evaluate future directions. RESULTS: Leading antiangiogenic drugs combined with systemic chemotherapy have been applied with increasing success during the last years. Therefore, the concept of combining vascular targeting agents with established chemotherapeutic regimens has been increasingly adopted into the therapies of different visceral tumors. CONCLUSION: Targeting the vasculature of visceral tumors in combination with established standard tumor therapies includes major clinical potential for future therapy concepts.

[Learning from aviation - how to increase patient safety in surgery]. / Kann die Chirurgie wirklich von der Luftfahrt lernen?

During the last years attempts have been made to draw lessons from aviation to increase patient safety in medicine. In particular similar conditions are present in surgery as pilots and surgeons may have to support high physical and mental pressure. The use of a few safety instruments from aviation is feasible in an attempt to increase safety in surgery. First a "root caused" accident research may be established. This is achievable by morbidity and mortality conferences and critical incident reporting systems (CIRS). Second, standard operating procedures may assure a uniform mental model of team members. Furthermore, crew resource management illustrates a strategy and attitude concept, which is applicable in all situations. Safety instruments from aviation, therefore, seem to have a high potential to increase safety in surgery when properly employed.

[Non-curable tumours of the female genital tract: therapeutic options in bowel stenosis and bleeding]. / Inoperable Genitaltumoren der Frau: Therapeutische Optionen bei Darmstenose und -blutung.

BACKGROUND: Tumours of the female genital tract are often diagnosed at an advanced stage or re-lapse after initial curative therapy. Ovarian cancer is in particular associated with peritoneal carcinomatosis or local tumour progression entailing different intestinal complications. MATERIAL AND METHODS: Based on our own results and a systemic PubMed search, different intestinal complications in non-curable tumours of the female genital tract were defined and different surgical and non-surgical therapeutic options were analysed. RESULTS: Stenosis of the small bowel is often caused by direct infiltration of the tumour. Peritoneal carcinomatosis or postoperative abdominal adhesions may lead to an acute or even more often chronic recurrent obstruction. The rectum or sigmoid colon is in particular affected by stenosis caused by tumour masses within the pelvis, occurring fistulas or direct tumour infiltration which may lead to bleeding complications or a large bowel obstruction. Radiation-induced abdominal adhesions or stenosis of the small bowel as well as radiation-induced chronic proctocolitis are further common abdominal complications. Special attention with regard to a well balanced indication towards surgical, oncological or conservative management must be given in the palliative setting of the genital tract. CONCLUSION: In particular the dictum of "primum nihil nocere" has to be followed in consideration of the patient's declared intention, the patient's prognosis, general condition, psychological strain as well as the expected complications.

Genetic polymorphisms of TP53 and FAS promoter modulate the progression of coronary artery disease after coronary artery bypass grafting: a gender-specific view.

INTRODUCTION: Progression of coronary artery disease (CAD) after primary coronary artery bypass grafting (CABG) is frequent and may lead to recurrent symptoms. Various data indicate that apoptosis is the main event occurring during development and progression of atherosclerotic plaque. Plaque vascular smooth muscle cells (VSMCs) are more sensitive than regular VSMCs to TP53-mediated apoptosis. METHODS: We investigated EDTA blood of 192 patients (18% female, age 60.9 ± 7.4 years) who had primary CABG more than 5 years ago. CAD progression was defined as clinical endpoints: re-operation (n = 88; 46%), catheter re-intervention (n = 58; 30%), or angina at follow-up (n = 89; 46%). Apoptotic gene polymorphisms (Toll-like receptor 2 A753G, FAS ligand C-844T, FAS promoter G-670A, TP53 Arg72Pro, and CD14 C-260T) were investigated by PCR-RFLP and compared to healthy controls (n = 200, 24% female, age 63.4 ± 5.4). Gender-specific analysis was carried out. RESULTS: Heterozygous, homozygous and wild-type expression of all five genetic polymorphisms showed almost identical distribution between patients with CAD and healthy controls. Looking at clinical endpoints, with GG expression of Toll-like receptor 2 polymorphism and GG expression of FAS promoter polymorphism, results showed a relative increased risk (p = 0.09) for recurrent symptoms and re-intervention. Patients with FAS promoter polymorphism with AA expression had an increased risk of suffering from recurrent symptoms (n = 28, p = 0.04). We found that patients with homozygous expression of TP53 polymorphisms (n = 3, all male) were prone to needing re-intervention after prior CABG (p = 0.03), but not re-operation. Over a period up to 15 years, the re-intervention rate was significantly different in homozygous genotypes of FAS LG, FAS promoter and TP53. CONCLUSIONS: Patients presenting with polymorphisms of FAS LG, FAS promoter and TP53 have an increased risk of CAD progression, as they have a higher rate of re-interventions.

[Impact of systematic lymph node dissection in the resection of pulmonary metastases of solid extrapulmonary tumours]. / Bedeutung der systematischen Lymphknotendissektion im Rahmen der Resektion pulmonaler Metastasen solider extrapulmonaler Tumoren.

BACKGROUND: The systematic mediastinal and hilar lymph node dissection for the treatment of pulmonary metastases has, until now, not attracted much attention. A possible advantage of systematic lymph node dissection is an improved staging and a better locoregional tumour control due to resection of tumour micrometastases and the disintegration of lymphatic vessels. Aim of the study was to investigate the impact of mediastinal and hilar lymphnode metastases on the prognosis of the patient. METHODS AND RESULTS: Between 1978 and 2006, 249  patients underwent resection of pulmonary metastases from renal cell (91), colorectal (89), breast (45) and head and neck cancer (24), in combination with a systematic mediastinal and hilar lymphnode dissection. Survival was analysed by the Kaplan-Meier method. Multivariate analysis was performed using Cox regression analysis. Lymph node metastases were histologically demonstrated in 25.3 % of all patients. They did not correlate with the tumour grading and lymph node status of the primary tumour or the number of pulmonary metastases. Patients with lymph node metastases had a significantly shorter median survival than patients without (18 vs. 53  months, p < 0.001). Patients who underwent a systematic mediastinal and hilar lymph node dissection showed a trend to a prolonged survival (39.1 vs. 31.9  months, p = 0.089). CONCLUSION: Mediastinal and hilar lymph node metastases are significantly correlated with decreased survival. Systematic mediastinal and hilar lymphadenectomy provides valuable information for the staging and prognosis of patients with pulmonary metastases of kidney, head and neck, breast and colorectal cancers and may help to distinguish those patients who might profit from a more aggressive surgical therapy or an adjuvant therapy.