Treatment characteristics and outcomes of pure Acinar cell carcinoma of the pancreas - A multicentric European study on radically resected patients

Background: Acinar cell carcinomas (ACC) belong to the exocrine pancreatic malignancies. Due to their rarity, there is no consensus regarding treatment strategies for resectable ACC. Methods: This is a retrospective multicentric study of radically resected pure pancreatic ACC. Primary endpoints were overall survival (OS) and disease-free survival (DFS). Further endpoints were oncologic outcomes related to tumor stage and therapeutic protocols. Results: 59 patients (44 men) with a median age of 64 years were included. The median tumor size was 45.0 mm. 61.0% were pT3 (n = 36), nodal positivity rate was 37.3% (n = 22), and synchronous distant metastases were present in 10.1% of the patients (n = 6). 5-Years OS was 60.9% and median DFS 30 months. 24 out of 31 recurred systemically (n = 18 only systemic, n = 6 local and systemic). Regarding TNM-staging, only the N2-stage negatively influenced OS and DFS (p = 0.004, p = 0.001). Adjuvant treatment protocols (performed in 62.7%) did neither improve OS (p = 0.542) nor DFS (p = 0.159). In 9 cases, radical resection was achieved following neoadjuvant therapy. Discussion: Radical surgery is currently the mainstay for resectable ACC, even for limited metastatic disease. Novel (neo)adjuvant treatment strategies are needed, since current systemic therapies do not result in a clear survival benefit in the perioperative setting

Secreted factors from mouse embryonic fibroblasts maintain repopulating function of single cultured hematopoietic stem cells

Hematopoietic stem cell self-renewal, proliferation, and differentiation are independently regulated by intrinsic as well as extrinsic mechanisms. We previously demonstrated that murine proliferation of hematopoietic stem cells is supported in serum-free medium supplemented with two growth factors, stem cell factor and interleukin 11. The survival of hematopoietic stem cells is additionally improved by supplementing this medium with two more growth factors, neural growth factor and collagen 1 (four growth factors) or serum-free medium conditioned by the hematopoietic stem cell-supportive stromal UG26-1B6 cells1. Here, we describe a robust and versatile alternative source of conditioned medium from mouse embryonic fibroblasts. We found that this conditioned medium supports survival and phenotypical identity of hematopoietic stem cells, as well as cell cycle entry in single cell cultures of CD34- CD48- CD150+ Lineage- SCA1+ KIT+ cells supplemented with two growth factors. Strikingly, in comparison with cultures in serum-free medium with four growth factors, conditioned medium from mouse embryonic fibroblasts increases the numbers of proliferating clones and the number of Lineage- SCA1+ KIT+ cells, both with two and four growth factors. In addition, conditioned medium from mouse embryonic fibroblasts supports self-renewal in culture of cells with short- and long-term hematopoiesis-repopulating ability in vivo. These findings identify conditioned medium from mouse embryonic fibroblasts as a robust alternative serumfree source of factors to maintain self-renewal of in vivo-repopulating hematopoetic stem cells in culture

Material dependence of 2

Calculations of the material dependence of 2H(d,p)3H cross section and neutron-to-proton branching ratio of d+d reactions have been performed including a concept of the 0+ threshold single particle resonance. The resonance has been assumed to explain the enhanced electron screening effect observed in the d+d reaction for different metallic targets. Here, we have included interference effects between the flat and resonance part of the cross section, which allowed us to enlighten observed suppression of the neutron channel in some metals such as Sr and Li. Since the position of the resonance depends on the screening energy that strongly depends on the local electron density. The resonance width, observed for the d+d reactions in the very hygroscopic metals (Sr and Li) and therefore probably contaminated by oxides, should be much larger than for other metals. Thus, the interference term of the cross section depending on the total resonance width provides the material dependences

A retrospective, multicentric, nationwide analysis of the impact of splenectomy on survival of pancreatic cancer patients

Objective Splenectomy is regularly performed in total and distal pancreatectomy due to technical reasons, lymph node dissection and radicality of the operation. However, the spleen serves as an important organ for competent immune function, and its removal is associated with an increased incidence of cancer and a worse outcome in some cancer entities (Haematologica 99:392–398, 2014 ; Dis Colon Rectum 51:213–217, 2008 ; Dis Esophagus 21:334–339, 2008 ). The impact of splenectomy in pancreatic cancer is not fully resolved (J Am Coll Surg 188:516–521, 1999 ; J Surg Oncol 119:784–793, 2019 ). Methods We therefore compared the outcome of 193 pancreatic cancer patients who underwent total or distal pancreatectomy with (Sp) or without splenectomy (NoSp) between 2015 and 2021 using the StuDoQ|Pancreas registry of the German Society for General and Visceral Surgery. In addition, we integrated our data into the existing literature in a meta-analysis of studies on splenectomy in pancreatic cancer patients. Results There was no difference between the Sp and NoSp groups regarding histopathological parameters, number of examined or affected lymph nodes, residual tumor status, or postoperative morbidity and mortality. We observed a significantly prolonged survival in pancreatic cancer patients who underwent total pancreatectomy, when a spleen-preserving operation was performed (median survival: 9.6 vs. 17.3 months, p  = 0.03). In this group, splenectomy was identified as an independent risk factor for shorter overall survival [HR (95%CI): 2.38 (1.03 – 6.8)]. In a meta-analysis of the existing literature in combination with our data, we confirmed splenectomy as a risk factor for a shorter overall survival in pancreatic cancer patients undergoing total pancreatectomy, distal pancreatectomy, or pancreatic head resection [HR (95%CI): 1.53 (1.11 – 1.95)]. Conclusion Here, we report on a strong correlations between removal of the spleen and the survival of pancreatic cancer patients undergoing total pancreatectomy. This should encourage pancreatic surgeons to critically assess the role of splenectomy in total pancreatectomy and give rise to further investigations.Open Access funding enabled and organized by Projekt DEAL.Technische Universität München (1025

Distribution of some extracellular matrix proteins and ultrastructural findings in sural nerve biopsy in demyelinating disease

The involvement of both the peripheral nervous system (PNS) and central nervous system (CNS) in multiple sclerosis is a seldom encountered combination in neurology clinics. In this report, immunohistochemical and ultrastructural techniques were used to analyse the disease course of a patient exhibiting involvement of both systems. In 1980, a 44-year-old man was admitted to our clinic with progressive weakness and decreased sensation of the right lower extremity, and sensory abnormality exhibiting stocking distribution. In electromyolography (EMG), demyelinating sensory motor polyneuropathy was determined. Ten years later, he was admitted again due to progression of weakness in the four extremities. Pyramidal and cerebellar signs, and loss of deep sensation were included in the clinical picture. An EMG investigation revealed severe segmental demyelination. Hyperintense lesions were determined in the periventricular deep white matter and the corpus callosum using cranial magnetic resonance imaging (MRI). This patient was considered to be exhibiting a course of demyelinating disease in which PNS and CNS were involved. In order to eliminate other reasons for peripheral neuropathy (PN), a sural nerve biopsy was carried out. The expression of several extracellular matrix (ECM) proteins (fibronectin, laminin, collagen type-IV), their respective receptors (integrin α5 and β4 subunits), intermediate filaments (vimentin) and S-100 protein was investigated by means of immunohistochemical methods. In addition, peripheral nerve tissue samples were evaluated ultrastructurally. Immunohistochemical stainings revealed an increase in the expression of ECM molecules, such as fibronectin, laminin and collagen type-IV, and their respective receptors, α5 and β4. This alteration might be a result of a Schwann-axon relationship. Vimentin expression was found to have changed in the Schwann cells and S-100 immunoreactivity decreased in the region near the Schwann-axon interface. Our ultrastructral findings showed myelin fragmentation, axon vacuolisation and degeneration

Activity of Protease-Activated Receptors in Primary Cultured Human Myenteric Neurons

Activity of the four known protease-activated receptors (PARs) has been well studied in rodent enteric nervous system and results in animal models established an important role for neuronal PAR2. We recently demonstrated that, unlike in rodents, PAR1 is the dominant neuronal protease receptor in the human submucous plexus. With this study we investigated whether this also applies to the human myenteric plexus. We used voltage sensitive dye recordings to detect action potential discharge in primary cultures of human myenteric neurons in response to PAR activating peptides (AP). Application of the PAR1-AP (TFLLR) or PAR4-AP (GYPGQV) evoked spike discharge in 79% or 23% of myenteric neurons, respectively. The PAR1-AP response was mimicked by the endogenous PAR1 activator thrombin and blocked by the PAR1 antagonists SCH79797. Human myenteric neurons did not respond to PAR2-AP. This was not due to culture conditions because all three PAR-APs evoked action potentials in cultured guinea pig myenteric neurons. Consecutive application of PAR-APs revealed coexpression (relative to the population responding to PAR-APs) of PAR1/PAR2 in 51%, PAR1/PAR4 in 43% and of PAR2/PAR4 in 29% of guinea pig myenteric neurons. Our study provided further evidence for the prominent role of neuronal PAR1 in the human enteric nervous system

Neural influences on human intestinal epithelium<i>in vitro</i>

We present the first systematic and, up to now, most comprehensive evaluation of the basic features of epithelial functions, such as basal and nerve‐evoked secretion, as well as tissue resistance, in over 2200 surgical specimens of human small and large intestine. We found no evidence for impaired nerve‐evoked epithelial secretion or tissue resistance with age or disease pathologies (stomach, pancreas or colon cancer, polyps, diverticulitis, stoma reversal). This indicates the validity of future studies on epithelial secretion or resistance that are based on data from a variety of surgical specimens. ACh mainly mediated nerve‐evoked and basal secretion in the small intestine, whereas vasoactive intestinal peptide and nitric oxide were the primary pro‐secretory transmitters in the large intestine. The results of the present study revealed novel insights into regional differences in nerve‐mediated secretion in the human intestine and comprise the basis by which to more specifically target impaired epithelial functions in the diseased gut

Associations of body composition parameters with postoperative outcome and perineural tumour invasion after oncological pancreatic resection

&lt;jats:title&gt;Abstract&lt;/jats:title&gt;&lt;jats:sec&gt; &lt;jats:title&gt;Background&lt;/jats:title&gt; &lt;jats:p&gt;Pancreatic cancer is often accompanied by wasting conditions. While surgery is the primary curative approach, it poses a substantial risk of postoperative complications, hindering subsequent treatments. Therefore, identifying patients at high risk for complications and optimizing their perioperative general condition is crucial. Sarcopenia and other body composition abnormalities have shown to adversely affect surgical and oncological outcomes in various cancer patients. As most pancreatic tumours are located close to the neuronal control centre for the digestive tract, it is possible that neural infiltration in this area deranges bowel functions and contributes to malabsorption and malnutrition and ultimately worsen sarcopenia and weight loss.&lt;/jats:p&gt; &lt;/jats:sec&gt;&lt;jats:sec&gt; &lt;jats:title&gt;Methods&lt;/jats:title&gt; &lt;jats:p&gt;A retrospective analysis of CT scans was performed for pancreatic cancer patients who underwent surgical tumour resection at a single high-volume centre from 2007 to 2023. Sarcopenia prevalence was assessed by skeletal muscle index (SMI), and visceral obesity was determined by the visceral adipose tissue area (VAT). Obesity and malnutrition were determined by the GLIM criteria. Sarcopenic obesity was defined as simultaneous sarcopenia and obesity. Postoperative complications, mortality and perineural tumour invasion, were compared among patients with body composition abnormalities.&lt;/jats:p&gt; &lt;/jats:sec&gt;&lt;jats:sec&gt; &lt;jats:title&gt;Results&lt;/jats:title&gt; &lt;jats:p&gt;Of 437 patients studied, 46% were female, the median age was 69 (61;74) years. CT analysis revealed 54.9% of patients with sarcopenia, 23.7% with sarcopenic obesity and 45.9% with visceral obesity. Sarcopenia and sarcopenic obesity were more prevalent in elderly and male patients. Postoperative surgical complications occurred in 67.7% of patients, most of which were mild (41.6%). Severe complications occurred in 22.7% of cases and the mortality rate was 3.4%. Severe postoperative complications were significantly more common in patients with sarcopenia or sarcopenic obesity. Visceral obesity or malnutrition based on BMI alone, did not significantly impact complications. Perineural invasion was found in 80.1% of patients and was unrelated to malnutrition or body composition parameters.&lt;/jats:p&gt; &lt;/jats:sec&gt;&lt;jats:sec&gt; &lt;jats:title&gt;Conclusions&lt;/jats:title&gt; &lt;jats:p&gt;This is the first and largest study evaluating the associations of CT-based body mass analysis with surgical outcome and histopathological perineural tumour invasion in pancreatic cancer patients. The results suggest that elderly and male patients are at high risk for sarcopenia and should be routinely evaluated by CT before undergoing pancreatic surgery, irrespective of their BMI. Confirmation of the results in prospective studies is needed to assess if pancreatic cancer patients with radiographic sarcopenia benefit from preoperative amelioration of muscle mass and function by exercise and nutritional interventions.&lt;/jats:p&gt; &lt;/jats:sec&gt