DYRK1B blockade promotes tumoricidal macrophage activity in pancreatic cancer.

OBJECTIVE: Highly malignant pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant immunosuppressive and fibrotic tumour microenvironment (TME). Future therapeutic attempts will therefore demand the targeting of tumours and stromal compartments in order to be effective. Here we investigate whether dual specificity and tyrosine phosphorylation-regulated kinase 1B (DYRK1B) fulfil these criteria and represent a promising anticancer target in PDAC. DESIGN: We used transplantation and autochthonous mouse models of PDAC with either genetic Dyrk1b loss or pharmacological DYRK1B inhibition, respectively. Mechanistic interactions between tumour cells and macrophages were studied in direct or indirect co-culture experiments. Histological analyses used tissue microarrays from patients with PDAC. Additional methodological approaches included bulk mRNA sequencing (transcriptomics) and proteomics (secretomics). RESULTS: We found that DYRK1B is mainly expressed by pancreatic epithelial cancer cells and modulates the influx and activity of TME-associated macrophages through effects on the cancer cells themselves as well as through the tumour secretome. Mechanistically, genetic ablation or pharmacological inhibition of DYRK1B strongly attracts tumoricidal macrophages and, in addition, downregulates the phagocytosis checkpoint and 'don't eat me' signal CD24 on cancer cells, resulting in enhanced tumour cell phagocytosis. Consequently, tumour cells lacking DYRK1B hardly expand in transplantation experiments, despite their rapid growth in culture. Furthermore, combining a small-molecule DYRK1B-directed therapy with mammalian target of rapamycin inhibition and conventional chemotherapy stalls the growth of established tumours and results in a significant extension of life span in a highly aggressive autochthonous model of PDAC. CONCLUSION: In light of DYRK inhibitors currently entering clinical phase testing, our data thus provide a novel and clinically translatable approach targeting both the cancer cell compartment and its microenvironment.

Multiple Endocrine Neoplasia Type 1: The Current Status of Disease Management.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a rare genetic disease of autosomal dominant inheritance, with an estimated prevalence of 3-20/100 000. Its main feature is neuroendocrine neoplasia in the parathyroid glands, the endocrine pancreas, the duodenum, and the pituitary gland. In this article, we review the diagnostic and therapeutic options for MEN1-associated tumors. METHODS: We present an analysis and evaluation of retrospective case studies retrieved from PubMed, guidelines from Germany and abroad, and our own experience. RESULTS: The disease is caused by mutations in the MEN1 gene. Mutation carriers should participate in a regular, specialized screening program from their twenties onward. The early diagnosis and individualized treatment of MEN1-associated tumors can prevent the development of life-threatening hormonal syndromes and prolong the expected life span of MEN1 patients from 55 to 70 years, as well as improving their quality of life. Surgical treatment is based on the location, size, growth dynamics, and functional activity of the tumors. The evidence for treatment strategies is derived from retrospective studies only (level III evidence) and the optimal treatment is often a matter of debate. This is a further reason for treatment in specialized centers. CONCLUSION: MEN1 is a rare disease, and, consequently, the evidence base for its treatment is limited. Carriers of disease-causing mutations in the MEN1 gene should be cared for in specialized interdisciplinary centers, so that any appreciable tumor growth or hormonal activity can be detected early and organ-sparing treatment can be provided.

[Local resection of small intestine neuroendocrine neoplasms (SI-NEN) : Current principles]. / Lokale Resektion von neuroendokrinen Tumoren des Dünndarms (SI-NEN) : Aktuelle Prinzipien.

BACKGROUND: Neuroendocrine tumors of the small bowel (small intestine neuroendocrine neoplasms, SI-NEN) are the most frequent tumors of the small intestine and approximately 30-40% are still surgically treatable with curative intent at the time of diagnosis. Certain surgical principles must be followed for optimal oncological outcomes and good postoperative quality of life. METHODS: Based on international guidelines and own experiences, the locoregional surgical treatment of SI-NENs is presented. RESULTS: Locoregional SI-NENs should always be resected if technically feasible, as only this approach can achieve a long-term cure and even small primary tumors (< 10 mm) often already show lymphatic metastasis. The resectability of SI-NENs and their difficulty depend on the extent of lymphatic metastasis, which should be assessed based on preoperative imaging of the extent around the superior mesenteric artery. Currently, the surgical gold standard for SI-NENs is open surgery with bidigital palpation of the entire small intestine followed by primary tumor resection via small bowel segment resection, right hemicolectomy or ileocecal resection and vessel-sparing, and therefore organ-preserving lymphadenectomy (≥ 8 lymph nodes). The guidelines consider that laparoscopic or robotic approaches are justified only for early stages of SI-NENs. CONCLUSION: Guideline-compliant surgical treatment of locoregional SI-NEN enables recurrence-free long-term survival with good quality of life.

Surgical aspects related to hereditary pancreatic cancer.

The goal of surveillance programs for individuals at risk (IAR) from familial pancreatic cancer (FPC) families or families with other inherited tumor syndromes predisposing to the development of pancreatic adenocarcinoma (PDAC), such as hereditary pancreatitis or Peutz-Jeghers syndrome, is the dectection and consecutive curative resection of early PDAC or even better its high-grade precursor lesions. Although the indication for surgery is quite established, the extent of surgery is not well defined due to the lack of evidence-based data. In addition, multiple factors have to be taken into account to determine an optimal personalized surgical strategy. This holds especially true since pancreatic surgery is associated with a relatively high morbidity and might impair the quality of life significantly. In this article the surgical aspects in the setting of hereditary PDAC are discussed.

The Value of Textbook Outcome in Benchmarking Pancreatoduodenectomy for Nonfunctioning Pancreatic Neuroendocrine Tumors.

BACKGROUND: Textbook outcome (TO) is a composite variable that can define the quality of pancreatic surgery. The aim of this study is to evaluate TO after pancreatoduodenectomy (PD) for nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs). PATIENTS AND METHODS: All patients who underwent PD for NF-PanNETs (2007-2016) in different centers were included in this retrospective study. TO was defined as the absence of severe postoperative complications and mortality, length of hospital stay ≤ 19 days, R0 resection, and at least 12 lymph nodes harvested. RESULTS: Overall, 477 patients were included. The TO rate was 32%. Tumor size [odds ratio (OR) 1.696; p = 0.013], a minimally invasive approach (OR 12.896; p = 0.001), and surgical volume (OR 2.062; p = 0.023) were independent predictors of TO. The annual frequency of PDs increased over time as well as the overall rate of TO. At a median follow-up of 44 months, patients who achieved TO had similar disease-free (p = 0.487) and overall survival (p = 0.433) rates compared with patients who did not achieve TO. TO rate in patients with NF-PanNET > 2 cm was 35% versus 27% in patients with NF-PanNET ≤ 2 cm (p = 0.044). Considering only NF-PanNETs > 2 cm, patients with TO and those without TO had comparable 5-year overall survival rates (p = 0.766) CONCLUSIONS: TO is achieved in one-third of patients after PD for NF-PanNETs and is not associated with a benefit in terms of long-term survival.

Acinar content at pancreatic resection margin is significantly associated with clinically relevant pancreatic fistula after partial pancreatoduodenectomy.

BACKGROUND: This study aimed to evaluate the clinical significance of acinar content at the pancreatic resection margin after partial pancreatoduodenectomy (PD). METHODS: A total of 228 consecutive patients undergoing PD were included for analysis. Resection margins were assessed for acinar, fibrosis, and fat contents by 2 pathologists blinded to the patients' clinical data. Univariate and multivariable analyses of possible predictors for clinically relevant postoperative pancreatic fistula (cr-POPF) were performed. RESULTS: The median acinar, fibrosis, and fat contents were 70% (IQR, 25%-82%), 13% (IQR, 5%-40%), and 15% (IQR, 9.25%-25%), respectively. The rates of cr-POPF were significantly higher in patients with an acinar content of >70% than in patients with an acinar content of ≤70% (26.4% vs 5.5%, respectively; P < .001). In addition, the rates of postoperative hyperamylasemia (POH) were significantly higher in patients with an acinar content of ≥70% than in patients with an acinar content of ≤70% (55.2% vs 13.8%, respectively; P < .001). The median fat content did not differ between patients with and without cr-POPF (13.0% [IQR, 7.5%-20.0%] vs 15.0% [IQR, 10.0%-30.0%], respectively; P = .06). An acinar content of >70% at the pancreatic resection margin (odds ratio [OR], 4.85; 95% CI, 1.61-14.58; P = .005) and a soft pancreatic texture (OR, 2.82; 95% CI, 1.02-7.76; P = .046) were independent predictive factors of cr-POPF in the multivariable analysis. CONCLUSION: An acinar content of ≥70% at the pancreatic resection margin was a significant predictive factor for cr-POPF after PD and was also significantly associated with POH, a precursor of cr-POPF after PD in many cases. Fatty infiltration of the pancreatic resection margin was not associated with cr-POPF.

PITX2 as a Sensitive and Specific Marker of Midgut Neuroendocrine Tumors: Results from a Cohort of 1157 Primary Neuroendocrine Neoplasms.

As neuroendocrine tumors (NETs) often present as metastatic lesions, immunohistochemical assignment to a site of origin is one of the most important tasks in their pathologic assessment. Because a fraction of NETs eludes the typical expression profiles of their primary localization, additional sensitive and specific markers are required to improve diagnostic certainty. We investigated the expression of the transcription factor Pituitary Homeobox 2 (PITX2) in a large-scale cohort of 909 NET and 248 neuroendocrine carcinomas (NEC) according to the immunoreactive score (IRS) and correlated PITX2 expression groups with general tumor groups and primary localization. PITX2 expression (all expression groups) was highly sensitive (98.1%) for midgut-derived NET, but not perfectly specific, as non-midgut NET (especially pulmonary/duodenal) were quite frequently weak or moderately positive. The specificity rose to 99.5% for a midgut origin of NET if only a strong PITX2 expression was considered, which was found in only 0.5% (one pancreatic/one pulmonary) of non-midgut NET. In metastases of midgut-derived NET, PITX2 was expressed in all cases (87.5% strong, 12.5% moderate), whereas CDX2 was negative or only weakly expressed in 31.3% of the metastases. In NEC, a fraction of cases (14%) showed a weak or moderate PITX2 expression, which was not associated with a specific tumor localization. Our study independently validates PITX2 as a very sensitive and specific immunohistochemical marker of midgut-derived NET in a very large collective of neuroendocrine neoplasms. Therefore, our data argue toward implementation into diagnostic panels applied for NET as a firstline midgut marker.

Mesenteric fibrosis in patients with small intestinal neuroendocrine tumors is associated with enrichment of alpha-smooth muscle actin-positive fibrosis and COMP-expressing stromal cells.

Neuroendocrine tumors of the small intestine (SI-NETs) often develop lymph node metastasis (LNM)-induced mesenteric fibrosis (MF). MF can cause intestinal obstruction as well as ischemia and render surgical resection technically challenging. The underlying pathomechanisms of MF are still not well understood. We examined mesenteric LNM and the surrounding stroma compartment from 24 SI-NET patients, including 11 with in situ presentation of strong MF (MF+) and 13 without MF (MF-). Differential gene expression was assessed with the HTG EdgeSeq Oncology Biomarker Panel comparing MF+ with MF- within LNM and paired stromal samples, respectively. Most interesting differentially expressed genes were validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in combination with validation of associated protein levels utilizing immunohistochemistry (IHC) staining of MF+ and MF- formalin-fixed, paraffin-embedded (FFPE) patient samples. Overall, 14 genes measured with a 2549-gene expression panel were differentially expressed in MF+ patients compared to MF-. Of those, nine were differentially expressed genes in LNM and five genes in the stromal tissue (>2-fold change, p < .05). The top hits included increased COMP and COL11A1 expression in the stroma of MF+ patients compared to MF-, as well as decreased HMGA2, COL6A6, and SLC22A3 expression in LNM of MF+ patients compared to LNM of MF- patients. RT-qPCR confirmed high levels of COMP and COL11A1 in stroma samples of MF+ compared to MF- patients. IHC staining confirmed the enrichment of α-smooth muscle actin-positive fibrosis in MF+ compared to MF- patients with corresponding increase of COMP-expressing stromal cells in MF+. Since COMP is associated with the known driver for fibrosis development transforming growth factor beta and with a cancer-associated fibroblasts enriched environment, it seems to be a promising new target for MF research.

Joint Linkage and Association Analysis Using GENEHUNTER-MODSCORE with an Application to Familial Pancreatic Cancer.

INTRODUCTION: Joint linkage and association (JLA) analysis combines two disease gene mapping strategies: linkage information contained in families and association information contained in populations. Such a JLA analysis can increase mapping power, especially when the evidence for both linkage and association is low to moderate. Similarly, an association analysis based on haplotypes instead of single markers can increase mapping power when the association pattern is complex. METHODS: In this paper, we present an extension to the GENEHUNTER-MODSCORE software package that enables a JLA analysis based on haplotypes and uses information from arbitrary pedigree types and unrelated individuals. Our new JLA method is an extension of the MOD score approach for linkage analysis, which allows the estimation of trait-model and linkage disequilibrium (LD) parameters, i.e., penetrance, disease-allele frequency, and haplotype frequencies. LD is modeled between alleles at a single diallelic disease locus and up to three diallelic test markers. Linkage information is contributed by additional multi-allelic flanking markers. We investigated the statistical properties of our JLA implementation using extensive simulations, and we compared our approach to another commonly used single-marker JLA test. To demonstrate the applicability of our new method in practice, we analyzed pedigree data from the German National Case Collection for Familial Pancreatic Cancer (FaPaCa). RESULTS: Based on the simulated data, we demonstrated the validity of our JLA-MOD score analysis implementation and identified scenarios in which haplotype-based tests outperformed the single-marker test. The estimated trait-model and LD parameters were in good accordance with the simulated values. Our method outperformed another commonly used JLA single-marker test when the LD pattern was complex. The exploratory analysis of the FaPaCa families led to the identification of a promising genetic region on chromosome 22q13.33, which can serve as a starting point for future mutation analysis and molecular research in pancreatic cancer. CONCLUSION: Our newly proposed JLA-MOD score method proves to be a valuable gene mapping and characterization tool, especially when either linkage or association information alone provide insufficient power to identify the disease-causing genetic variants.

[Individualized approach for MEN1-associated duodenopancreatic neuroendocrine neoplasms]. / Individualisiertes Vorgehen bei MEN1-assoziierten duodenopankreatischen neuroendokrinen Neoplasien.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1)-associated duodenopancreatic neuroendocrine neoplasms (dpNEN) represent the most frequent syndrome-associated cause of death, but the adequate treatment is sometimes considered controversial. OBJECTIVE: Presentation of possible diagnostic and therapeutic options for MEN1-associated dpNENs. MATERIAL AND METHODS: In this review article retrospective case studies, expert recommendations, national and international guidelines as well as personal experiences were analyzed and evaluated. RESULTS: Due to early detection programs and the use of the most modern imaging techniques, dpNEN are nowadays diagnosed much earlier. Nonfunctional pNENs currently represent the most frequent dpNENs with about 70%, followed by gastrinomas and insulinomas. Regardless of their functional activity, dpNENs with a size of > 2 cm are generally an indication for surgery. The choice of the optimal treatment strategy, however, in most cases remains the subject of controversial discussions, although nowadays surgery should always be performed in an organ-preserving and minimally invasive way when feasible. Recurrences or new dpNENs are expected in more than 60% of cases, necessitating a reoperation in up to 40% of these cases. Duodenopancreatic resections and reoperations can be carried out safely by experienced practitioners and with an acceptable level of risk. CONCLUSION: The planning of treatment requires careful consideration of the suitable timing, the extent of the operation, the risk of recurrence and potential morbidities. Furthermore, preserving pancreatic function and the quality of life is of utmost importance. In view of the complexity of the disease, MEN1 patients should be treated in specialized centers.

[Personalized approach to anaplastic thyroid carcinoma]. / Personalisiertes Vorgehen beim anaplastischen Schilddrüsenkarzinom.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) represents the rarest but most aggressive tumor entity of the thyroid gland. In this respect, the treatment of advanced ATC has rapidly evolved in recent years. Recently, new personalized forms of treatment that address the somatic mutational status of the tumor have been increasingly used. The aim of this article is to provide an overview of current molecular-based and personalized treatment options for ATC. METHODS: A current literature search was performed with a focus on personalized molecular-based treatment options for ATC. RESULTS: The majority of patients suffering from ATC have an advanced tumor disease at the time of initial diagnosis. Despite multimodal treatment approaches consisting of surgery, external beam radiation therapy (EBRT) and chemotherapy (CTX), the prognosis of ATC is still poor. Accordingly, the focus of innovative treatment approaches is on molecular-based, individualized tumor therapy, including in particular BRAFV600E and multikinase inhibitors. The potential of the latter seems to lie particularly in combination therapy with immune checkpoint inhibitors. These treatment options can be used in both adjuvant and neoadjuvant settings. Neoadjuvant treatment of advanced ATC can achieve a potentially resectable treatment setting and improve the poor prognosis of affected patients; however, larger prospective and randomized studies on these combination therapies are currently pending. CONCLUSION: The focus of future treatment approaches for ATC will be on individualized, molecular-based tumor therapy. In particular, the neoadjuvant use of these therapies may change the paradigm of ATC surgery as locally advanced as well as metastatic carcinomas can be converted to a potentially resectable status and made amenable to surgery.

Reduction of volume loss after left atrial injury by balloon occlusion-an experimental study.

Background: Advanced-stage lung cancers sometimes require an extensive surgical approach. There is a risk of severe bleeding due to injury to the cardiac atria. Due to the fact that in most cases the surgical planning does not involve the expertise of a heart surgeon or the availability of a heart lung machine, only rapid effective action can avert this life-threatening complication. Methods: In an experimental study of porcine heart-lung packs, three different methods were used to investigate the most effective way of controlling mass hemorrhage due to left atrial injury. In order to obtain a realistic model, the heart-lung packet was connected to a heart-lung machine after appropriate preparation and perfused with volume support. The damage control to the left atrial injury was either performed by manual compression, surgical clamping or balloon catheter occlusion. Results: In addition to manual compression and clamping, the use of a balloon catheter inserted into the atrial lesion was found to be the most effective method. The blood loss of 41.88±7.53 mL (vs. 105.00±31.74 and 106.00±50.67 mL) proved to be the lowest value. Conclusions: For extensive resections of lung carcinoma, balloon catheters of different sizes should be kept ready to rapidly control massive blood loss due to injury of the cardiac atria.

Options for regulating new genomic techniques for plants in the European Union.

Which option for regulating plants derived from new genomic techniques in European Union law is feasible and justifiable scientifically? The European Commission has proposed a new regulation on plants obtained by specific new genomic techniques, which is now subject to discussion in the legislative process. From the perspective of the European Commission's envisaged legal reforms of European Union law towards the integration of greater sustainability, we conclude that the option focusing on plant traits delivering sustainability benefits should be chosen, which is most fitting to facilitate a contribution to climate action, the transition towards climate neutrality, and promptly integrate sustainability into all food-related policies. To assist the decision-making in the legislative process, we outline six regulatory options resulting from regulatory research involving interdisciplinary teams.