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.

Preservation of the round ligament to accommodate transient portal hypertension after major hepatectomy.

PURPOSE: Posthepatectomy liver failure (PHLF) remains a leading cause of death after extensive liver resection. Apart from the size and function of the remaining liver remnant, the development of postresection portal hypertension (pHT) plays a crucial role in the development of PHLF. We hypothesize that the umbilical vein in the preserved round ligament (RL) may recanalize in response to new-onset pHT after extended hepatectomy, thus providing a natural portosystemic shunt. METHODS: In this exploratory study, RL was preserved in 10 consecutive patients undergoing major liver resection. Postoperative imaging was pursued to obtain evidence of reopened umbilical vein in the RL. The postoperative course, including the occurrence of PHLF, as well as the rate of procedure-specific complications were recorded. RESULTS: None of the 10 cases presented with an adverse event due to preservation of the RL. In 6 cases, postoperative imaging demonstrated reopening of the umbilical vein with hepatofugal flow in the RL. The rates of procedure-related surgical complications were lower than would be expected in this population; in particular, the rate of occurrence of PHLF as defined by the International Study Group of Liver Surgery (ISGLS) was low. CONCLUSION: Our results support the theoretical concept of portosystemic pressure relief via a preserved umbilical vein after major liver surgery. As preservation of the RL is easily done, we suggest keeping it intact in extended hepatectomy cases and in patients with preexistent pHT.

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.

Cancer catecholamine conundrum.

Exercise, psychosocial stress, and drugs such as adrenergic agonists and antagonists increase the concentrations of catecholamines and/or alter adrenergic signaling. Intriguingly, exercise studies universally suggest that catecholamines are cancer-inhibiting whereas cancer stress studies typically report the opposite, whereas ß-blocker studies show variable effects. Here, we term variable effects of catecholamines in cancer the cancer catecholamine conundrum. Variable effects of catecholamines can potentially be explained by variable expression of nine adrenergic receptor isoforms and by other factors including catecholamine effects on cancer versus immune or endothelial cells. Future studies on catecholamines and cancer should seek to understand the mechanisms that explain variable effects of catecholamines in cancer to utilize beneficial or block detrimental effects of catecholamines in cancer patients.

Influence of Klebsiella pneumoniae and quinolone treatment on prognosis in patients with pancreatic cancer.

BACKGROUND: An increasing body of evidence suggests that microbiota may promote progression of pancreatic ductal adenocarcinoma (PDAC). It was hypothesized that gammaproteobacteria (such as Klebsiella pneumoniae) influence survival in PDAC, and that quinolone treatment may attenuate this effect. METHODS: This was a retrospective study of patients from the Massachusetts General Hospital (USA) and Ludwig-Maximilians-University (Germany) who underwent preoperative treatment and pancreatoduodenectomy for locally advanced or borderline resectable PDAC between January 2007 and December 2017, and for whom a bile culture was available. Associations between tumour characteristics, survival data, antibiotic use and results of intraoperative bile cultures were investigated. Survival was analysed using Kaplan-Meier curves and Cox regression analysis. RESULTS: Analysis of a total of 211 patients revealed that an increasing number of pathogen species found in intraoperative bile cultures was associated with a decrease in progression-free survival (PFS) (-1·9 (95 per cent c.i. -3·3 to -0·5) months per species; P = 0·009). Adjuvant treatment with gemcitabine improved PFS in patients who were negative for K. pneumoniae (26·2 versus 15·3 months; P = 0·039), but not in those who tested positive (19·5 versus 13·2 months; P = 0·137). Quinolone treatment was associated with improved median overall survival (OS) independent of K. pneumoniae status (48·8 versus 26·2 months; P = 0·006) and among those who tested positive for K. pneumoniae (median not reached versus 18·8 months; P = 0·028). Patients with quinolone-resistant K. pneumoniae had shorter PFS than those with quinolone-sensitive K. pneumoniae (9·1 versus 18·8 months; P = 0·001). CONCLUSION: K. pneumoniae may promote chemoresistance to adjuvant gemcitabine, and quinolone treatment is associated with improved survival.

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.

[Quality of indications in cystic lesions of the pancreas]. / Indikationsqualität bei zystischen Läsionen des Pankreas.

Cystic tumors of the pancreas (PCN) have increasingly gained importance in the clinical routine as they are frequently diagnosed as an incidental finding due to the continuous improvement in cross-sectional imaging. A differentiation is made between non-neoplastic and neoplastic cysts, whereby the latter has a tendency to malignant transformation to a varying extent. Therefore, they can be considered as precursor lesions of pancreatic cancer (PDAC). In addition to a detailed patient history and examination, imaging modalities, such as computed tomography (CT), magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS) with fine needle aspiration (FNA) are used for the differential diagnosis. The indications for surgical resection of these lesions are based on the current European guidelines from 2018; however, the content is not evidence-based but relies on knowledge and recommendations from experts. According to these consensus recommendations asymptomatic serous cystic neoplasms (SCN) are serous lesions with a low tendency for malignant transformation and can be monitored. In contrast resection is warranted for all mucinous cystic neoplasms (MCN) >4 cm and all solid pseudopapillary neoplasms (SPN). Intraductal papillary mucinous neoplasms (IPMN), which are differentiated into main duct (MD-IPMN) and branch duct type (BD-IPMN) IPMN based on the position in the pancreatic duct system, should be resected as MD-IPMN and mixed type (MT)-IPMN. The risk of malignant transformation in BD-IPMN is variable and depends on risk factors, which are defined clinically and by imaging morphology. The treatment management is therefore carried out on an individual basis following risk estimation. In order to quantify the quality of indications in PCN and thereby also contributing to optimized medical care, prospective long-term studies are urgently needed.

[Surgery for isolated local recurrence and metachronous oligometastasis in pancreatic cancer]. / Chirurgie bei isoliertem Lokalrezidiv und metachroner Oligometastasierung beim Pankreaskarzinom.

BACKGROUND: Most patients with pancreatic cancer suffer a relapse, which occurs either locally or systemically in the sense of liver and the lung metastases. Surgery for pancreatic cancer has become more radical due to the increased use of multimodal treatment concepts; however, the role of surgery in cases of recurrence remains controversial. OBJECTIVE: This review summarizes the surgical treatment options for isolated local recurrence and metachronous oligometastatic pancreatic cancer. MATERIAL AND METHODS: A selective literature search was carried out and the current evidence for surgical treatment is summarized. RESULTS: There are currently no randomized studies on surgery for metastatic pancreatic cancer. Currently available data, however, show that after surgery long-term survival of up to 32-47 months after metastasectomy can be achieved, especially in patients with local recurrence or isolated pulmonary metastases with low morbidity and mortality. Individualized treatment concepts including surgical resection after initial systemic therapy seem promising even for liver metastases. The greatest survival benefits are consistently shown for all localizations in patients with a long as possible disease-free interval after the first operation. CONCLUSION: The treatment of isolated local recurrence or metachronous oligometastatic pancreatic cancer is an interdisciplinary challenge that should be performed in specialized pancreatic treatment centers only. Surgical resection embedded in a multimodal treatment concept can be meaningful in selected cases.

Detection and characterisation of disseminated tumour cells in bone marrow of breast cancer patients by immunostaining of Her-2 and MUC-1 in combination with Thomsen-Friedenreich (CD176).

Disseminated tumour cells (DTCs) in the bone marrow derive from many primary tumours, such as breast cancer. Their mere existence hints to present or future metastasis and implicates a worse prognosis for the patient. DTCs may possess different characteristics in comparison to the primary tumour due to events like Epithelial-Mesenchymal-Transition. Therefore, these cells might be able to survive chemotherapy and cause relapses of the disease at a later point. We aimed to detect and further characterise DTCs by an immunostaining approach with three different antigen markers (Her-2, MUC-1 and TF, also known as CD 176). For that reason, bone marrow of 41 breast cancer patients was obtained during surgery; DTCs were enriched by density gradient centrifugation and cytospins were prepared. After fixation, immunofluorescent double-stainings were carried out with antibodies against CD176 in combination with HER-2 or MUC-1. Cells co-expressing two antigens were found in all staining combinations (Her-2 and CD176: 46.14%; MUC-1 and CD176: 18.15% of all cases). Cells that stained for a single antigen only were also found (Her-2: 36.86%; MUC-1: 34.45%; CD176: 29.65% of all cases). Significant correlations between the stainings of all markers could be shown (p<0,001). In conclusion, Thomsen-Friedenreich Antigen (TF, CD176) is a promising marker in combination with the established marker Her-2 and other markers like MUC-1. These results may serve as a basis for future DTC detection routines and help to individualize medical treatment, reducing side effects and increasing the efficiency of the therapy.

Genital tuberculosis as the cause of tuboovarian abscess in an immunosuppressed patient.

BACKGROUND: Although tuberculosis (TB) is a major health problem worldwide, primary extrapulmonary tuberculosis (EPTB), and in particular female genital tract infection, remains a rare event. CASE REPORT: A 35-year-old human immunodeficiency virus (HIV) seropositive woman of African descent with lower abdominal pain and fever of two days duration underwent surgery due to left adnexal mass suggesting pelvic inflammatory disease. The surgical situs showed a four quadrant peritonitis, consistent with the clinical symptoms of the patient, provoked by a tuboovarian abscess (TOA) on the left side. All routine diagnostic procedures failed to determine the causative organism/pathogen of the infection. Histopathological evaluation identified a necrotic granulomatous salpingitis and specific PCR analysis corroborated Mycobacterium tuberculosis (M. Tb). Consequently, antituberculotic therapy was provided. CONCLUSION: In the differential diagnosis of pelvic inflammatory disease, internal genital tuberculosis should be considered. Moreover, physicians should consider tuberculous infections early in the work-up of patients when immunosuppressive conditions are present.