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* Context.--Mutant KRAS is the main oncogenic driver in pancreatic ductal adenocarcinomas (PDACs). However, the clinical and phenotypic implications of harboring different mutant KRAS alleles remain poorly understood. Objective.--To characterize the potential morphologic and clinical outcome differences in PDACs harboring distinct mutant KRAS alleles. Design.--Cohort 1 consisted of 127 primary conventional PDACs with no neoadjuvant therapy, excluding colloid/ mucinous, adenosquamous, undifferentiated, and intraductal papillary mucinous neoplasm-associated carcinomas, for which an in-house 42-gene mutational panel had been performed. A morphologic classification system was devised wherein each tumor was assigned as conventional, papillary/ large duct (P+LD, defined as neoplastic glands with papillary structure and/or with length [greater than or equal to]0.5 mm), or poorly differentiated (when the aforementioned component was 60% or more of the tumor). Cohort 2 was a cohort of 88 PDACs in The Cancer Genome Atlas, which were similarly analyzed. Results.--In both cohorts, there was significant enrichment of P+LD morphology in PDACs with KRAS G12V and G12R compared with G12D. In the entire combined cohort, Kaplan-Meier analyses showed longer overall survival (OS) with KRAS G12R as compared with G12D (median OS of 1255 versus 682 days, P = .03) and in patients whose PDACs displayed P+LD morphology as compared with conventional morphology (median OS of 1175 versus 684 days, P = .04). In the adjuvant-only subset, KRAS G12R had the longest OS compared with G12D, G12V, and other alleles (median OS unreached/undefined versus 1009,1129, and 1222 days, respectively). Conclusions.--PDACs with different mutant KRAS alleles are associated with distinct morphologies and clinical outcomes, with KRAS G12R allele associated with P+LD morphology and longer OS when compared with G12D using Kaplan-Meier studies. (Arch Pathol Lab Med. 2024;148:1299-1309; doi: 10.5858/arpa.2023-0005-OA), Pancreatic cancer, the majority of which consists of pancreatic ductal adenocarcinomas (PDACs), is projected to become the second leading cause of cancer-related deaths by 2030. (1) Surgical resectability is the [...]

Abstract Background Dementia is a progressive disease, and as the disease progresses, many families seek help through activities and therapies. In contrast to some other therapies, horticultural therapy (HT) is widely accepted by most people with dementia (PWD) because it invites them to the natural world. Objectives To explore whether HT emotional and communication measures (i.e. appropriate expression of emotions, ability to communicate with others) are higher than in other activities offered to PWD in adult day care centers (ADCC) and continuing care retirement community (CCRC), and whether there is a difference between the impact of HT on the number of “positive actions” (communication actions and actions that fit the guided activity) vs. the other activities. Research design and methods Fifty-one PWD attending ADCCs and living in one CCRC were recruited to a structured HT activity and other activities that took place in the ADCCs and CCRC. The activity took place over 10 weeks. The effects were assessed using Dementia Care Mapping (DCM) and questionnaires. Results Paired t-tests found that higher levels of mood and behavior were observed during HT activities compared to the other activities. Also, communication and function actions were higher in the HT activities as compared to the other activities. Discussion and implications This study adds to the growing evidence of the benefits of HT for PWD regardless of past experience in gardening/agriculture. HT seems to provide high therapeutic benefits and should be more prevalent in centers caring for PWD.

Abstract Background Self-directed violence (SDV) comprises both suicide and self-injury and represents a pressing problem among incarcerated persons. Negative impacts of SDV in correctional settings also extend to behavioral health clinicians (BHCs) (e.g., job turnover). Correctional SDV risk assessment and management standards include staff training as part of the comprehensive approach. The Core Competency Model for Corrections (CCM-C) is a novel, evidence-informed training program for BHCs covering both clinician self-management and clinical care skills. Methods This pilot trial is a type 3 hybrid implementation–effectiveness approach. It will employ a wait-list control sequential cross-over design. Participants (N = 50–100) will be BHCs employed by the North Carolina Department of Adult Corrections. Following stratification for years of clinical experience, BHCs will be randomly assigned to (1) a training group that receives CCM-C immediately and (2) a wait-list control receiving CCM-C approximately 6 weeks later. Electronically administrated survey evaluation will occur across baseline and two follow-up (i.e., 2 weeks after each training session) time points. Discussion The primary outcome is feasibility assessed through collaboration with a Corrections Advisory Panel and feedback from BHCs. Secondary effectiveness outcomes that will be evaluated over time include SDV-related knowledge, attitudes, stigma, and intent to use training content. We will examine a tertiary outcome, namely compassion fatigue. Clinical trial limitations and impacts are discussed. Trial registration Clinicaltrials.gov, NCT06359574. This study was registered on 04/05/2024.

Abstract Background Smartphone-based digital mental health interventions (DMHI) have been described as a purported solution to meet growing healthcare demands and lack of providers, but studies often don’t account for whether patients are concurrently in another treatment modality. Methods This preregistered quasi-experimental intent-to-treat study with 354 patients enrolled in a therapist-supported DMHI examined the treatment effectiveness of the Meru Health Program (MHP) as a stand-alone treatment as compared to the MHP in combination with any other form of treatment, including (1) in-person therapy, (2) psychotropic medication use, and (3) in-person therapy and psychotropic medication use. Results Patients with higher baseline depressive and anxiety symptoms were more likely to self-select into multiple forms of treatment, an effect driven by patients in the MHP as adjunctive treatment to in-person therapy and psychotropic medication. Patients in combined treatments had significantly higher depressive and anxiety symptoms across treatment, but all treatment groups had similar decreasing depressive and anxiety symptom trajectories. Exploratory analyses revealed differential treatment outcomes across treatment combinations. Patients in the MHP in combination with another treatment had higher rates of major depressive episodes, psychiatric hospitalization, and attempted death by suicide at baseline. Conclusions Patients with higher depressive and anxiety symptoms tend to self-select into using DMHI in addition to more traditional types of treatment, rather than as a stand-alone intervention, and have more severe clinical characteristics. The use the MHP alone was associated with improvement at a similar rate to those with higher baseline symptoms who are in traditional treatments and use MHP adjunctively.

Healthcare providers play a key role in early identification of eating disorders (EDs), especially in underserved states where ED treatment resources are lacking. Currently, there is little known about ED screening and treatment practices in underserved states. The current study assessed current ED screening and treatment practices among healthcare providers in an underserved state using data collected by a government-formed state ED council. Healthcare providers (N = 242; n = 209 behavioral health providers; n = 33 medical providers) practicing in Kentucky completed a brief, anonymous survey on ED screening and treatment practices, comfort with screening for EDs, and interest in continued education. Over half of healthcare providers indicated screening for EDs, with the majority using a clinical interview. After identification of ED symptoms, providers reported a combination of treating in-house, referring out, or seeking consultation. In bivariate analyses, medical providers were significantly more likely than behavioral health providers to use a screening tool specifically designed for EDs. The majority of medical providers indicated that they received education about EDs and feel knowledgeable about ED screening tools, though most reported infrequent use of these screening tools in their practice. Nearly all behavioral health and medical providers expressed interest in continuing education on ED screening and treatment. These findings indicate a need for, and interest in, education on evidence-based ED screening and treatment resources in underserved states and demonstrate the utility of a state ED council to collect these data to inform future education and treatment strategies.

Abstract Patients with ESCC (squamous cell carcinoma of the esophagus) are most commonly diagnosed with locally advanced tumor stages. Early metastatic disease and late diagnosis are common reasons responsible for this tumor's poor clinical outcome. The prognosis of esophageal cancer is very poor because patients usually do not have symptoms in early disease stages. Squamous cell carcinoma of the esophagus frequently complicates patients with multiple co-morbidities and these patients often require interdisciplinary diagnosis and treatment procedures. At present time, neoadjuvant radiation therapy and chemotherapy followed by surgery are regarded as the international standard of care. Meta-analyses have confirmed that this approach provides the patient with better local tumor control and an increased overall survival rate. It is recommended that patients with positive tumor response to neoadjuvant therapy and who are poor surgical candidates should consider definitive radiochemotherapy without surgery as a treatment option. In future, EGFR antibodies may also be administered to patients during therapy to improve the current treatment effectiveness. Positron-emission tomography proves to be an early response-imaging tool used to evaluate the effect of the neoadjuvant therapy and could be used as a predictive factor for the survival rate in ESCC. The percentage proportions of residual tumor cells in the histopathological analyses represent a gold standard for evaluating the response rate to radiochemotherapy. In the future, early response evaluation and molecular biological tests could be important diagnostic tools in influencing the treatment decisions of ESCC patients.

Abstract Objective Insulin-like growth factor (IGF)-1, -2 and Insulin like growth factor binding proteins (IGFBP) are involved in the proliferation and differentiation of cells. It has never been evaluated, if the IGF-system can serve as a tumor marker in neoplasms. Methods In our prospective study 163 patients with colorectal cancer (22), prostate cancer (21), head and neck tumors (17), lymphomas (20), lung cancer (34) and other entities (49) were analysed for their IGF and IGFBP serum levels at the beginning and the end of radiotherapy and compared to 13 healthy people. Subgroups of patients with local tumor disease versus metastatic disease, primary and recurrent therapy and curative versus palliative therapy were compared. Results The serum levels of IGF-2 were significantly elevated in patients with prostate and colorectal cancer. However, sensitivity and specificity were only 70%. IGFBP-2 serum levels were elevated in patients with head and neck tumors. Again sensitivity and specificity were only 73%. A difference between local disease and metastatic disease could not be found. A difference between IGF serum levels before and after radiotherapy could not be detected. Conclusion The IGF-system cannot serve as a new tumor marker. The detected differences are very small, sensitivity and specificity are too low. IGF measurement is not useful for the evaluation of the success of radiotherapy in malignancies.

Abstract Both locally advanced adenocarcinoma of the stomach and gastro-esophageal junction are associated with poor prognosis due to the lack of effective treatment. Recently multimodal treatment consisting of neoadjuvant chemotherapy in combination with radiotherapy is reported to improve survival when compared to surgery alone. Neoadjuvant therapy in these locally advanced tumors allows for early tumor responses and the extent of tumor regression that can be achieved is considered a significant prognostic factor. This, in turn, increases the resectability of these tumors. Also due to the high frequency of lymph node metastasis, patients with locally advanced adenocarcinoma should undergo a D2 lymphadenectomy. Postoperative chemoradiation and perioperative chemotherapy have been studied in gastric adenocarcinomas and showed a survival benefit. However, the surgical techniques used in these trials are no longer considered to be standard by today's surgical practice. In addition, there are no standard recommendations for adjuvant chemotherapy or chemoradiation after R0 resection and adequate lymph node dissection.

Abstract Objective Treatment options for patients with diffuse type gastric cancer (linitis plastica) are discussed controversial. It is sometimes discussed that these patients should be treated primarily in palliative intention conservative without resection. Methods In a single-center analysis, we investigated 120 patients with diffuse type gastric cancer. All patients underwent a total gastrectomy, 45 patients even a multivisceral resection because of infiltrating growth, or metastases. Serum tumor marker CEA, CA 72-4, and CA 19-9 were recorded in all patients before surgery. An immunocytochemical detection of free peritoneal tumor cells (FPTC) using Ber-EP4 antibody was correlated with tumor stage and survival. Median follow-up time was 38 months. Results Complete resection rate was 31% (n = 37). 61% (n = 73) of all patients had already distant metastases at the time of surgery, 80% of them peritoneal carcinomatosis. Median survival for the whole group was 8 months, after complete resection 17 months. Lavage cytology, distant metastases, resection rate, and CA19-9 levels had significant influence on survival. Conclusion A significant survival advantage for patients with diffuse type gastric cancer can only be achived after complete resection. We could define a subset of patients with an extremely poor prognosis even after surgical resection. Meticulous preoperative staging, including a diagnostic laparoscopy to exclude peritoneal carcinomatosis and free peritoneal tumor cells before resection should be mandatory in these patients.

Abstract Background Classic wound drainage is still common in hip replacement but its benefit is doubtful. The role of systemic administration of proteinase inhibitors like aprotinin to avoid perioperative blood loss is still unclear. Patients and Methods In a prospective randomized trial, the perioperative blood loss in alloplastic hip replacement under the influence of proteinase inhibitor (aprotinin, Trasylol®) using wound drainage as well as compression treatment alone were compared. 80 patients were prospectively randomized in 4 arms. Patients received either aprotinin or placebo during surgery as well as drainage or targeted external wound compression. Results Observing the "drug therapy" aprotinin had no effect on the intraor postoperative blood loss (p > 0.05), a trend to lower postoperative hemoglobin decline was found, but without significance. thrombosis occurred in neither the aprotinin nor in the placebo group. Two patients had a severe allergic drug reaction and were excluded from the study. Under "non drug therapy" with compression therapy and wound drainage a significant difference in blood loss was found (p < 0.001). The blood loss was higher under the wound drainage. There was no influence on the infection rate. Yet we could observe increased bruising under the sole external compression treatment. Conclusion The administration of aprotinin did not achieve the desired reduction of perioperative blood loss. Hence, costs and two severe allergic drug reactions in our study represent arguments against its use in regular treatment. Furthermore, it seems that wound drainage is neglectable in hip replacement and can be substituted by a sole compression treatment.

Abstract Background The constantly growing amount of different kinds of colloid fluids necessitates comparative investigations with regards to the safety and effectivity in clinical use of these preparations. Hence we compared three colloid fluids in an observational study. The objective was the exploration of the influence of these three colloids on blood coagulation, hemodynamics and renal function of the cardiac surgical patient. Methods We included 90 patients undergoing an elective open-heart surgery with the use of the heart-lung machine and observed them consecutively. Group 1 [gelatin 4% (n = 30)], Group 2 [HES 200/0,5 (n = 30)] and Group 3 [HES 130/0,42 (n = 30)]. We measured the perioperative volume replacement, the administration of blood- and coagulation-products, the application of catecholamines, the renal function, blood gas and the platelet aggregation using multiplate electrode analyzer (Multiplate®, Dynabyte medical, Munich, Germany). Results The gelatin-group needed significantly more norepinephrine than the HES 130/0.42 group. The responsible surgeon considered the blood coagulation in the HES 200/0.5 group most frequently as impaired. Furthermore we saw a significant decrease in platelet function in the HES 200/0.5 group when performing the multiplate®-analysis (ADP-and COL-test). HES 130/0.4 as well as gelatin 4% showed no significant change in platelet function. The gelatin-group and the HES 200/0.5 needed significantly more aprotinine than the HES 130/0.4 group. We saw no significant difference with regards to administration of blood and coagulation products between the three groups. The urinary excretion during the intervention was significantly higher in the HES 200/0.5 group and in the gelatin group than in the HES 130/0.4 group. Conclusions Our results confirm the lower stabilizing effect of gelatin on circulation during fluid resuscitation. The blood coagulation was mostly impaired due to HES 200/0.5 confirmed by the multiplate®-analysis as well as by different clinical findings.

Abstract Introduction The deadly threat of systemic infections with coagulase negative Staphylococcus lugdunensis despite an appropriate antibiotic therapy has only recently been recognized. The predominant infectious focus observed so far is left-sided native heart valve endocarditis, but bone and soft tissue infections, septicaemia and vascular catheter-related bloodstream infections have also been reported. We present a patient with a fatal Staphylococcus lugdunensis septicaemia following zoster bacterial superinfection of the pelvic region. Case presentation A 71-year old male diagnosed with IgG kappa plasmocytoma presented with a conspicuous weight loss, a hypercalcaemic crisis and acute renal failure. After initiation of haemodialysis treatment his condition improved rapidly. However, he developed a varicella-zoster virus infection of the twelfth thoracic dermatome requiring intravenous acyclovir treatment. Four days later the patient presented with a fulminant septicaemia. Despite an early intravenous antibiotic therapy with ciprofloxacin, piperacillin/combactam and vancomycin the patient died within 48 hours, shortly before the infective isolate was identified as Staphylococcus lugdunensis by polymerase chain reaction. Conclusion Despite S. lugdunensis belonging to the family of coagulase-negative staphylococci with an usually low virulence, infections with S. lugdunensis may be associated with an aggressive course and high mortality. This is the first report on a Staphylococcus lugdunensis septicaemia following a zoster bacterial superinfection of the pelvic region.

Abstract Diffuse large B-cell lymphoma usually starts as a rapidly growing mass in an internal lymph node and can grow in other areas such as the bone or intestines. About 1/3 of these lymphomas are confined to one part of the body when they are localized. In the case of a 78-year-old man, an extensive tumour was located on the right thigh. Biopsies of the tumour revealed diffuse proliferation of large lymphoid cells which have totally affected the normal architecture of striated muscle. The patient received multimodality treatment including chemotherapy of the CHOP regimen and adjuvant radiotherapy. Despite this being a fast growing lymphoma, about 3 out of 4 people will have no signs of disease after initial treatment, and about half of all people with this lymphoma are cured with therapy.

Abstract Background Tumor-related methylated DNA and circulating tumor cells (CTC) in the peripheral blood might be of prognostic importance in breast cancer. Thus, the aim of our study was to examine free methylated DNA and CTC in the blood from breast cancer patients and to correlate it with clinicopathological features known to influence prognosis. Materials and methods We prospectively obtained serum samples from 85 patients with breast cancer and 22 healthy volunteers. Sera were analysed by methylation specific PCR (MethyLight PCR) for five genes: adenomatous polyposis coli (APC), ras association domain family protein 1A (RASSF1A), estrogen receptor 1 (ESR1), CDKN2A (p16) and glutathione s-transferase pi 1 (GSTP1). Beta actin (ACTB) served as control. In parallel matched peripheral blood of 63 patients was used to assay for circulating tumor cells in the peripheral blood by a modified immunomagnetic AdnaTest BreastCancerSelect with PCR detection for EPCAM, MUC1, MGB1 and SPDEF. Results We found a hypermethylation in the APC gene in 29% (25/85), in RASSF1A in 26% (22/85), in GSTP1 in 18% (14/76) and in ESR1 in 38% (32/85) of all breast cancer patients. No hypermethylation of CDKN2A was found (0/25). Blood samples of patients were defined CTC positive by detecting the EPCAM 13% (8/63), MUC1 16% (10/63), MGB 9% (5/55), SPDEF 12% (7/58) and in 27% detecting one or more genes (15/55). A significant difference was seen in methylated APC DNA between cancer patients and healthy volunteers. Moreover, methylated APC, RASSF1 and CTC were significantly different in metastatic versus non-metastatic disease. In addition, the presence of methylated APC, RASSF1A and CTC correlated significantly with AJCC-staging (p = 0.001, p = 0.031 and 0.002, respectively). High incidences of methylations were found for the genes RASSF1 and ESR1 in healthy individuals (both 23% 5/22). Methylated GSTP1 was predominantly found in the serum of patients with large primaries (p = 0.023) and was highly significantly correlated with positive Her2/neu status (p = 0.003). Elevated serum CA15.3 was strongly correlated with methylated APC and CTC detection (both p = 0.000). Methylated ESR1 failed to exhibit significant correlations with any of the above mentioned parameters. The presence of CTC in peripheral blood was significantly associated with methylated APC (p = 0.012) and methylated GSTP1 (p = 0.001). Conclusion The detection of methylated APC and GSTP1 DNA in serum correlated with the presence of CTC in the blood of breast cancer patients. Both methylated DNA and CTC correlated with a more aggressive tumor biology and advanced disease.

Abstract Background Antiseptics are frequently used for the prophylaxis and treatment of local infections of chronic wounds. Whereas local antiseptics in general have a positive effect on wound healing an uncritical use may impair wound healing due to toxic side effects. Objective We sought to assess the vascular irritation potential of different antiseptic solutions and ointments commonly used for short and long term application as a measure of tissue toxicity. Method The vascular irritation was evaluated by the hen's egg test (HET) on the chorioallantoic membrane (CAM). The effects on the vessels of a mucous membrane were directly assessed by stereomicroscopic observation in vivo. Results Severe CAM irritation was observed after short-term applications of 1% octenidin-2HCl (Octeni sept™), 72% isopropanol (Cutasept™), 0.35% chloroxylenol (Dettol™) and 10% PVP-I ointment (Betaisodona™). Medium irritations were observed for 10% PVP-I solution (Betaisodona™), 3% lysosomal PVP-I ointment (Repithel™), 1.8% cadexomer-iodine ointment (Iodosorb™) and 1% cadexomer-iodine pellets (Iodosorb™). Finally, slight irritations were observed for 1% PVP-I solution (Betaisodona™), 0.1% polyhexanid plus betain (Prontosan™) and 1% silver-sulfadiazine ointment (Flammazine™), whereas 0.04% polyhexanid solution (Lavanid™), washings from sterile maggots of Lucilia sericata and filtrated enzymes from Clostridium histolyticum (Iruxol-N™) showed no effects of irritation. In the long-term approaches, no vascular irritations were found for polyhexanid, washings from Lucilia sericata and enzyme filtrations from Clostridium histolyticum. Conclusion The vascular injuries caused by the studied antiseptics are an indirect indicator of their tissue toxicity. Strikingly, even therapeutic substances, which have been regarded as safe in their application for the treatment of chronic wounds in clinical studies, showed severe irritations on the CAM. We suggest that agents with no or low irritation potential on the CAM should be preferred in the clinical practice in order to obtain optimal results.

Abstract The sequences of many genomes are available; therefore, relevant methods are needed for rapid and efficient identification of functional genes. The ability of tumour cells to resist apoptosis induced by anticancer agents may decide the success of failure of tumour elimination. Although the CD95-signalling pathway is functional in tumour cells, the increased resistance of tumour cells to CD95-mediated apoptosis has been widely reported. In order to identify genes that might determine the response of tumour cells to CD95-mediated apoptosis, we modified the conventional technical knock out (TKO) strategy for isolation of genes that function in CD95-mediated apoptosis. Due to the fact that multiple different plasmids are usually introduced into the same cells, the effectiveness of the conventional TKO strategies is low. To overcome this obstacle, we replaced the conventional TKO strategy (based on stably expressed randomly fragmented cDNA libraries) with a multi-cycle selection procedure (based on transiently expressed randomly fragmented cDNA libraries with multi-cycle selection). Using this approach we could rapidly and significantly identify small numbers of antisense mRNA molecules, whose re-introduction into different tumour types confirmed their ability to block the pro-apoptotic function of their cognate genes. Thus, our modified TKO strategy provides a generally applicable procedure for the identification of functional genes with pro-apoptotic properties that may be clinically relevant to tumor therapy.

Abstract Today, the biomechanical fundamentals of skin expansion are based on viscoelastic models of the skin. Although many studies have been conducted in vitro, analyses performed in vivo are rare. Here, we present in vivo measurements of the expansion at the skin surface as well as measurement of the corresponding intracutaneous oxygen partial pressure. In our study the average skin stretching was 24%, with a standard deviation of 11%, excluding age or gender dependency. The measurement of intracutaneous oxygen partial pressure produced strong inter-individual fluctuations, including initial values at the beginning of the measurement, as well as varying individual patient reactions to expansion of the skin. Taken together, we propose that even large defect wounds can be closed successfully using the mass displacement caused by expansion especially in areas where soft, voluminous tissue layers are present.

Abstract Background The aim of the present study was to determine whether regular exercise training (ET) is effective at promoting the mobilization of CPCs and improving their functional activity in patients with recently acquired myocardial infarction(STEMI). Regular physical training has been shown to improve myocardial perfusion and cardiovascular function. This mayberelatedin part to a mobilization of bonemarrow-derived circulating progenitor cells (CPCs) as well as an enhanced vascularisation. Methods 37 patients with STEMI were randomly assigned to an ET group or a non-ET group(controls). Two weeks after STEMI, three weeks after regular ET and three months after ET, BNP levels, exercise echocardiography and exercise spiroergometry were evaluated. The number of CD34+/CD45+ and CD133+/CD45+CPCs was measured by flow cytometry analysis. The migration capacity of the CPCs was determined with a boyden chamber and the clonogenic capacity by CFU-assay. Results In the ET-group the number and migration capacity of CPCs increased significantly after regular exercise training. The BNP level decreased significantly from 121 ± 94 to 75 ± 47 pg/ml (p < 0.001) after the ET period, the left ventricular rejection fraction raised in parallel at peak exercise, and the cardiorespiratory condition improved as demonstrated by an increase of VO2max (from 1641 ± 522 to 1842 ± 724 ml/min, p < 0.02). These three effects persist till three months after the ET period. Conclusions Regular physical activity appears to predispose the mobilization and enhanced functional activity of CPCs, a phenomenon which might lead to an improved cardiac function in patients with recently acquired acute myocardial infarction.

Abstract Introduction Intramural dissection of the esophagus is a rare disorder characterized by a lesion between the submucosa and mucosa dividing the esophagus into a false and true lumen. The etiology of esophageal dissection remains uncertain but it affects predominantly women in their seventies and eighties. Symptoms may include uncharacteristic ones such as retrosternal pain, odynophagia or dysphagia. Conservative management is thought to be adequate and surgery should only be performed if complications such as abscess formation or perforation appear. Here we report the case and surgical management of a combined esophageal perforation and dissection. Case presentation We report the case of a combined esophageal perforation and dissection in a 45-year-old Caucasian woman with a history of relapsing periods of dysphagia since her childhood. The clinical course in this patient was complicated by progression to a second perforation, which made a definitive surgical management by esophagectomy necessary. Conclusion To the best of our knowledge, this is the first reported case of a combined esophageal perforation and dissection complicated by progression to a second perforation. This emphasizes that cautious and intensive observation is necessary in patients with esophageal dissection.

Abstract Background Breast cancer (BC) represents one of the leading causes of cancer related deaths worldwide. New tools for diagnostic staging and therapeutic monitoring are needed to improve individualized therapies and improve clinical outcome. The analyses of circulating tumour cells may provide important prognostic information in the clinical setting. Materials and methods Circulating tumour cells (CTC) of 63 BC patients were isolated from peripheral blood (PB) through immunomagnetic separation. Subsequently, RT-PCR or mPCR for the genes ga733.2, muc-1, c-erbB2, mgb-1, spdef and c-erbB2 were performed. Subsequently, expression data were correlated with the tumour stages. Fourteen healthy individuals served as controls. Results Significant correlations with tumour stages were found in single gene analyses of ga733.2, muc-1 and in multi-gene analyses of ga733.2/muc-1/mgb1/spdef. Furthermore, a significant correlation of Ca 15-3 and all studied genes was also observed. Conclusion Herein, we demonstrated a positive correlation of a gene signature consisting of ga733.2, muc-1, mgb1 and spdef and advanced stages of BC. Moreover, all studied genes and gene patterns revealed a significant correlation with Ca 15-3 positive cases.

Abstract Background The diagnostic tools to predict the prognosis in patients suffering from breast cancer (BC) need further improvements. New technological achievements like the gene profiling of circulating tumour cells (CTC) could help identify new prognostic markers in the clinical setting. Furthermore, gene expression patterns of CTC might provide important informations on the mechanisms of tumour cell metastasation. Materials and methods We performed realtime-PCR and multiplex-PCR analyses following immunomagnetic separation of CTC. Peripheral blood (PB) samples of 63 patients with breast cancer of various stages were analyzed and compared to a control group of 14 healthy individuals. After reverse-transcription, we performed multiplex PCR using primers for the genes ga733.3, muc-1 and c-erbB2. Mammaglobin1, spdef and c-erbB2 were analyzed applying realtime-PCR. Results ga733.2 overexpression was found in 12.7% of breast cancer cases, muc-1 in 15.9%, mgb1 in 9.1% and spdef in 12.1%. In this study, c-erbB2 did not show any significant correlation to BC, possibly due to a highly ambient expression. Besides single gene analyses, gene profiles were additionally evaluated. Highly significant correlations to BC were found in single gene analyses of ga733.2 and muc-1 and in gene profile analyses of ga733.3*muc-1 and GA7 ga733.3*muc-1*mgb1*spdef. Conclusion Our study reveals that the single genes ga733.3, muc-1 and the gene profiles ga733.3*muc-1 and ga733.3*3muc-1*mgb1*spdef can serve as markers for the detection of CTC in BC. The multigene analyses found highly positive levels in BC patients. Our study indicates that not single gene analyses but subtle patterns of multiple genes lead to rising accuracy and low loss of specificity in detection of breast cancer cases.

Abstract Introduction Seborrheic keratoses are very common findings in elderly patients. However, a sudden onset and dramatic increase in the number and size of these benign lesions deserves special attention, since this may represent the Leser Trélat sign, a rare paraneoplastic cutaneous syndrome. Case presentation A 92-year-old female presented to our clinic with multiple eruptive seborrheic keratoses, which had dramatically increased in size and number over the past two years. A diagnostic work-up revealed an ovarian carcinoma. Hence, cutaneous findings in our patient were consistent with the diagnosis of the Leser-Trélat sign. Conclusion The Leser-Trélat sign may coincide with the diagnosis of occult cancer or follow or precede it by months or years. Practitioners should take cases of eruptive seborrheic keratoses seriously and perform thorough patient examinations.

Abstract Desmoid tumors are fibroblastic/myofibroblastic neoplasms, which originate from musculo-aponeurotic structures and are classified as deep fibromatoses. Despite their benign histologic appearance and lack of metastatic potential, desmoid tumors may cause aggressive local infiltrations and compression of surrounding structures. They are often associated with female gender, familial adenomatous polyposis (FAP) and sporadically may occur at sites of previous trauma, scars or irradiation. Molecular studies have demonstrated that these patients are associated with a bi-allelic APC mutation in the affected tissue. Radical tumor resection with free margins remains the first therapy of choice. In cases with anatomical or technical limitations for a wide excision, radiation therapy represents a proven and effective alternative or supplementary treatment.

Abstract Stereotactic radiosurgery is related to the history of "radiotherapy" and "stereotactic neurosurgery". The concepts for neurosurgeons and radiooncologists have been changed during the last decade and have also transformed neurosurgery. The gamma knife and the stereotactically modified linear accelerator (LINAC) are radiosurgical equipments to treat predetermined intracranial targets through the intact skull without damaging the surrounding normal brain tissue. These technical developments allow a more precise intracranial lesion control and offer even more conformal dose plans for irregularly shaped lesions. Histological determination by stereotactic biopsy remains the basis for any otherwise undefined intracranial lesion. As a minimal approach, it allows functional preservation, low risk and high sensitivity. Long-term results have been published for various indications. The impact of radiosurgery is presented for the management of gliomas, metastases, brain stem lesions, benign tumours and vascular malformations and selected functional disorders such as trigeminal neuralgia. In AVM's it can be performed as part of a multimodality strategy including resection or endovascular embolisation. Finally, the technological advances in radiation oncology as well as stereotactic neurosurgery have led to significant improvements in radiosurgical treatment opportunities. Novel indications are currently under investigation. The combination of both, the neurosurgical and the radiooncological expertise, will help to minimize the risk for the patient while achieving a greater treatment success.

Abstract Neurofibromatosis (NF) is one of the most common genetic disorders. Inherited in an autosomal dominant fashion, this phacomatosis is classified into two genetically distinct subtypes characterized by multiple cutaneous lesions and tumors of the peripheral and central nervous system. Neurofibromatosis type 1 (NF1), also referred to as Recklinghausen's disease, affects about 1 in 3500 individuals and presents with a variety of characteristic abnormalities of the skin and the peripheral nervous system. Neurofibromatosis type 2 (NF2), previously termed central neurofibromatosis, is much more rare occurring in less than 1 in 25 000 individuals. Often first clinical signs of NF2 become apparent in the late teens with a sudden loss of hearing due to the development of bi-or unilateral vestibular schwannomas. In addition NF2 patients may suffer from further nervous tissue tumors such as meningiomas or gliomas. This review summarizes the characteristic features of the two forms of NF and outlines commonalities and distinctions between NF1 and NF2.

Abstract Background To evaluate the expression and test the clinical significance of the epithelial cellular adhesion molecule (Ep-CAM) in esophageal squamous cell carcinoma (SCC) to check the suitability of esophageal SCC patients for Ep-CAM directed targeted therapies. Methods The Ep-CAM expression was immunohistochemically investigated in 70 primary esophageal SCCs using the monoclonal antibody Ber-EP4. For the interpretation of the staining results, we used a standardized scoring system ranging from 0 to 3+. The survival analysis was calculated from 53 patients without distant metastasis, with R0 resection and at least 2 months of clinical follow-up. Results Ep-CAM neo-expression was observed in 79% of the tumors with three expression levels, 1+ (26%), 2+ (11%) and 3+ (41%). Heterogeneous expression was observed at all expression levels. Interestingly, tumors with 3+ Ep-CAM expression conferred a significantly decreased median relapse-free survival period (log rank, p = 0.0001) and median overall survival (log rank, p = 0.0003). Multivariate survival analysis disclosed Ep-CAM 3+ expression as independent prognostic factor. Conclusion Our results suggest Ep-CAM as an attractive molecule for targeted therapy in esophageal SCC. Considering the discontenting results of the current adjuvant concepts for esophageal SCC patients, Ep-CAM might provide a promising target for an adjuvant immunotherapeutic intervention.

Cerebral cavernous malformation (CCM) is a genetic, cerebrovascular disease. Familial CCM is caused by genetic mutations in KRIT1, CCM2, or PDCD10 Disease onset is earlier and more severe in individuals with PDCD10 mutations. Recent studies have shown that lesions arise from excess mitogen-activated protein kinase kinase kinase 3 (MEKK3) signaling downstream of Toll-like receptor 4 (TLR4) stimulation by lipopolysaccharide derived from the gut microbiome. These findings suggest a gut-brain CCM disease axis but fail to define it or explain the poor prognosis of patients with PDCD10 mutations. Here, we demonstrate that the gut barrier is a primary determinant of CCM disease course, independent of microbiome configuration, that explains the increased severity of CCM disease associated with PDCD10 deficiency. Chemical disruption of the gut barrier with dextran sulfate sodium augments CCM formation in a mouse model, as does genetic loss of Pdcd10, but not Krit1, in gut epithelial cells. Loss of gut epithelial Pdcd10 results in disruption of the colonic mucosal barrier. Accordingly, loss of Mucin-2 or exposure to dietary emulsifiers that reduce the mucus barrier increases CCM burden analogous to loss of Pdcd10 in the gut epithelium. Last, we show that treatment with dexamethasone potently inhibits CCM formation in mice because of the combined effect of action at both brain endothelial cells and gut epithelial cells. These studies define a gut-brain disease axis in an experimental model of CCM in which a single gene is required for two critical components: gut epithelial function and brain endothelial signaling.

Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease.