Oxathiazinane derivatives display both antineoplastic and antibacterial activity: a structure activity study.

PURPOSE: The Oxathiazinane substance class is characterized by a high diversity of chemical structures yet to be fully investigated. Our research group recently proved that the 1.4.5-oxathiazine-4.4-dioxide, known as substance GP-2250, possesses antineoplastic properties as shown on pancreatic carcinoma. This current study aims to gain insights into the structure and activity relationship of a series of different Oxathiazinanes regarding their antineoplastic activity and the potential correlation with antibacterial activity. We investigated the newly synthesized Oxathiazinane derivatives: 2255, 2256, 2287, 2289, 2293 and 2296 in comparison to GP-2250. METHODS: The antineoplastic effect was evaluated in different cancer entities (breast, skin, pancreas and colon cancer cell lines) by viability, proliferation, and cell migration assays in vitro. Disc diffusion tests were performed on various bacteria strains to examine the antibacterial potential. Additionally, reactive oxygen species (ROS) assays were conducted to investigate mechanistic aspects. RESULTS: The substances GP-2250, 2293, 2289 and 2296 not only showed antineoplastic activity in four different cancer entities but also antibacterial effects, as tested on multiple bacteria strains including MRSA (Methicillin-resistant Staphylococcus aureus). Furthermore, these substances also induced high ROS levels up to 110% in the treated cancer cell lines compared to untreated control cells. These results indicate a correlation between an antineoplastic capacity and antibacterial properties of these derivatives. Both activities appear to be ROS driven. The Oxathiazinane derivatives 2255, 2256 and 2287 lacked both, antineoplastic and antibacterial activity. CONCLUSION: Thus, a comparable structure activity relationship became apparent for both the antineoplastic and antibacterial activity.

[Results of the Limberg flap procedure in acute and chronic pilonidal abscesses]. / Ergebnisse des Limberg-Plastik-Verfahrens bei akuten und chronischen Pilonidalabszessen.

BACKGROUND: A number of different treatment algorithms are recommended for the treatment of an acute pilonidal abscess and a chronic pilonidal sinus. While a 1-stage surgical procedure using excision or plastic reconstruction according to Limberg or Karydakis is suggested for chronic pilonidal sinus, a 2­stage procedure is recommended for an acute pilonidal abscess. The aim of this study was to compare the results of the 1­stage surgery with plastic reconstruction according to Limberg for acute pilonidal abscess and chronic pilonidal sinus in terms of recurrence, disorders of wound healing, inpatient length of stay and patient satisfaction. METHODS: From 2009 to 2014 a total of 39 patients were included in this prospective observational study: 21 patients with acute pilonidal abscess and 18 patients with chronic pilonidal sinus. All patients were surgically treated with a 1­stage procedure using the Limberg flap method. The groups were compared in terms of postoperative complication rates and frequency of recurrence. RESULTS: Both groups were basically comparable with respect to demographic characteristics and risk factor profiles. Analysis of the postoperative results showed a comparable rate of postoperative wound healing disorders (10% vs. 17%, p = 0.647). In the group with acute pilonidal abscesses there was no recurrence during the observational period, while in the chronic pilonidal sinus group there were 2 (11%) recurrences (p = 0.206). CONCLUSION: The results of the Limberg flap procedure regarding acute pilonidal abscesses were comparable to those of chronic pilonidal sinus. The results of this study show a trend to a lower risk of recurrence. The use of the Limberg flaps therefore also seems to be an adequate treatment option in an acute infection situation.

Lipomatous pancreas facilitates late onset of renal cell carcinoma metastases.

BACKGROUND: Late metastasizing into pancreatic tissue is a special hallmark of renal cell carcinomas (RCC). A very low prevalence leads to scarce data about therapy, prognosis and spreading pathways. The aim of the study was to analyze whether a high fat content in the pancreas facilitates RCC metastases formation. A model for density measurement of pancreatic tissue has been developed and evaluated. Pancreatic fat content was measured comparing Hounsfield units (HU) of CT scans. METHODS: In a consecutive single centre retrospective database of 3600 patients with pancreatic resections, only 12 patients (0.3%) cases of RCC metastases in the pancreas were found. HU were measured in 3 pancreatic regions: head, body and tail in patients' CT scans. HU values were compared to a control population and results aligned with recent literature. RESULTS: We revealed a prevalence of pancreatic metastases of RCC in 0.3% of cases. The formation of RCC in the pancreas occurred within 14 ± 5.6 years after initial diagnosis of RCC. 83.3% of the patients were alive after a follow-up period of up to 48 months. Clinical data analysis revealed an affinity for metastatic formation to lipomatous pancreas. This could be objectivized by HU analysis in CT scans. CONCLUSION: Pancreatic metastases occur late after the first diagnosis of renal carcinoma and show an affinity for lipomatous pancreatic tissues. Due to its rarity in occurrence, multicentric studies are highly recommended to further analyze this correlation between fatty pancreas and RCC.

[Treatment of abdominal tuberculosis : Background, diagnostics and treatment of a global problem]. / Therapie der abdominellen Tuberkulose : Hintergrund, Diagnostik und Therapie einer globalen Problematik.

BACKGROUND: Tuberculosis (TB) is among the 10 leading causes of global deaths and is a special threat to immunocompromised patients with human immunodeficiency virus (HIV). Due to migration from endemic areas cases in central Europe can also increase. OBJECTIVE: This article gives an overview of background information, detection methods, treatment and the role of surgery in abdominal manifestation of a systemic infection. MATERIAL AND METHODS: A PubMed search was carried out using the following keywords: abdominal TB, incidence, symptoms, diagnostics, treatment and surgery. RESULTS: The detection of TB in cases of abdominal manifestation can be carried out via percutaneous biopsy; however, laparoscopy is recommended due to the better detection rate, low complication rate and its ability to differentiate other diseases, such as peritoneal carcinomatosis and lymphomas. Antituberculous drugs are the primary treatment. An acute abdomen can occur in up to approximately 30% of cases. Complications such as strictures and perforations require surgical treatment. CONCLUSION: Although the prevalence of TB is decreasing, the infection causes more than 1 million deaths per year. The correct diagnosis can be impeded by a misleading clinical presentation. A multidisciplinary approach enables rapid and efficient diagnostics and treatment.

Diagnostic double strike in the emergency room - two cases of complete pancreatic ruptures due to bicycle handlebar injuries on two consecutive days.

BACKGROUND: Pancreatic injuries are rare in cases of blunt abdominal trauma and therefore easily misdiagnosed at time of hospital admission. They are associated with a significantly elevated morbidity and lethality. Bicycle handlebar injuries are the most common cause of pancreatic trauma in children and adolescents. CASE PRESENTATION: We report two cases of a 23-year-old Caucasian woman and a 15-year-old Caucasian boy who presented to our clinic with a similar history of a bicycle accident on 2 consecutive days. Both suffered from a fall from a bicycle with bicycle handlebar injury 4 and 6 days prior to admission in our clinic. Emergency distal pancreatectomies were performed in both cases. CONCLUSIONS: Pancreatic injuries must be highly suspected in bicycle handlebar injuries, even if amylase/lipase levels or ultrasound findings seem unremarkable. The best initial strategies are early computed tomography and a quick referral to a level 1 trauma center. Distal pancreatectomy is the treatment of choice in cases of complete rupture of the pancreatic body.

Innovative substance 2250 as a highly promising anti-neoplastic agent in malignant pancreatic carcinoma - in vitro and in vivo.

BACKGROUND: Former studies already revealed the anti-neoplastic properties of the anti-infective agent Taurolidine (TRD) against many tumor species in vitro and in vivo. Its anti-proliferative and cell death inducing capacity is largely due to its main derivative Taurultam (TRLT). In this study it could be demonstrated, that substance 2250 - a newly defined innovative structural analogue of TRLT - exhibits an anti-neoplastic effect on malignant pancreatic carcinoma in vitro and in vivo. METHODS: The anti-neoplastic potential of substance 2250 as well as its mode of action was demonstrated in extensive in vitro analysis, followed by successful and effective in vivo testings, using xenograft models derived from established pancreatic cancer cell lines as well as patient derived tissue. RESULTS: Our functional analysis regarding the role of oxidative stress (ROS) and caspase activated apoptosis showed, that ROS driven programmed cell death (PCD) is the major mechanisms induced by substance 2250 in pancreatic carcinoma. What is strongly relevant towards clinical practice is especially the observed inhibition of patient derived pancreatic cancer tumor growth in mice treated with this new substance in combination with its sharply higher metabolic stability. CONCLUSION: These encouraging results provide new therapeutical opportunities in pancreatic cancer treatment and build the basis for further functional analysis as well as first clinical studies for this promising agent.

Circumportal Pancreas-a Must Know Pancreatic Anomaly for the Pancreatic Surgeon.

PURPOSE: Circumportal pancreas is a rare congenital pancreatic anomaly with encasement of the portal vein and/or the superior mesenteric vein by pancreatic tissue. It is often overlooked on cross-sectional imaging studies and can be encountered during pancreatic surgery. Pancreatic head resection with circumportal pancreas is technically difficult and bears an increased risk of postoperative pancreatic fistula. MATERIALS AND METHODS: A retrospective chart review of our data base for all patients who had undergone pancreatic head resection between 2004 and 2015 was performed. RESULTS: We identified six patients out of 1102 patients who had undergone pancreatic head surgery in the study period. CT-scan and MRI were never able to identify circumportal pancreas prior to surgery. The right hepatic an artery derived from the superior mesenteric artery in four cases (67%). Additional resection of the pancreatic body was always performed. Postoperative course was uneventful in all cases without occurrence of pancreatic fistula. CONCLUSIONS: Circumportal pancreas is a rare entity every pancreatic surgeon should be aware of. It is difficult to identify on cross-sectional imaging studies. A right hepatic artery arising from the superior mesenteric artery should raise suspicion of circumportal pancreas. Additional pancreatic tissue resection should be performed during pancreatic head resections to avoid pancreatic fistula.

[Distal Pancreatectomy with Autologous Fibrin Sealant - Implementation of an Established Concept of Tissue Sealing in Pancreatic Surgery]. / Die Pankreaslinksresektion mit autologem Fibrinkleber ­ Anwendung eines etablierten Versiegelungskonzepts in der Pankreaschirurgie.

Background: Postoperative pancreatic fistulas (POPF) remain a major concern after distal pancreatectomy. Irrespective of the technique to close the pancreatic remnant, pancreatic fistulas will occur in approximately 30 % of patients undergoing distal pancreatectomy. For the first time ever, autologous fibrin sealant (Vivostat®) was used to additionally seal the pancreatic remnant after a distal pancreatectomy. The aim was to analyse whether this changes the postoperative outcome. Patients/Material and Methods: In 2015, a technical case series was performed in 15 patients who underwent distal pancreatectomy. The pancreatic remnant was additionally sealed with autologous fibrin sealant (Vivostat®). Results: A postoperative pancreatic fistula (POPF) occurred in 5/15 patients (33 %). One patient had a POPF grade A (1/15, 6.7 %), whereas a POPF grade B occurred in 4/15 patients (26.7 %). 75 % (3/4) of the patients with a POPF grade B were sufficiently treated with antibiotics, whereas a CT-guided percutaneous drainage had to be placed only in one case. Conclusion: Autologous fibrin sealant is simple to apply and seems to be well tolerated. However, it does not seem to avoid the development of postoperative pancreatic fistulas after distal pancreatectomy.

Effects of animal positioning on catecholamine and vasopressin levels in pigs undergoing laparoscopy.

BACKGROUND: The aim of this study was to determine the influence of different therapeutic interventions and positions on catecholamine and vasopressin levels in the pneumoperitoneum (PN) in a porcine model. METHODS: In 43 pigs, a 14-mm-Hg PN was established and plasma concentrations of epinephrine, norepinephrine and vasopressin were measured in head-up, supine and head-down positions. Additionally, the effects of the following changes were studied: (1) increase in intrathoracic blood volume (ITBV) by means of hydroxyethyl starch infusion; (2) vasodilatation induced by sodium nitroprusside, or (3) selective sympathicolysis induced by esmolol. Again, catecholamines (ELISA) and vasopressin (RIA) were determined. RESULTS: After PN, epinephrine levels did not significantly increase in the head-up position (p = 0.075) and remained also unchanged in the supine or head-down position. Plasma norepinephrine statistically significantly decreased in the head-up position (p = 0.046). Vasopressin concentrations remained unaltered. After increased ITBV, neither catecholamine nor vasopressin concentrations changed in any body position. Application of sodium nitroprusside or esmolol caused no changes. CONCLUSION: Changes in endogenous catecholamine levels safely prevent cardiocirculatory instability in small pigs. Volume substitution might reduce endocrine responses to PN in the head-up position.

[Distal trachea and bronchial large lesions and suture reinforcement with Polyglicol Acid (PGA) patch. First clinical experience]. / Lesioni estese della trachea e dei bronchi principali. Prime esperienze con l'impiego di Polyglycol Acid (PGA) patch riassorbibile.

BACKGROUND: Iatrogenic lacerations of the trachea and the bronchies are mostly complications of emergent intubations or percutaneous tracheotomies. The outcome is mainly influenced by thorough diagnostics, severity of the lesions, and urgent treatment. New materials are used to reduce the tension at the sutured points during ventilation. PATIENTS AND METHODS: Four patients were operatively treated with primary suturing of trachea and bronchies with Polydioxanon. The large wounds were then covered using resorbable Soft PGA Mesh (resorbable Polyglykol Acid patch). The first two patients were found hypoxic and was orotracheally intubated in an emergency. An air leckage was detected in the hospital due to a large lesion of the pars membranacea. The third patient was operated in an emergency due to ileus caused by progressive colonic carcinoma. The weaning period on Intensive Care Unite (ICU) was unsuccessful. In a difficult procedure she underwent a percutaneous tracheotomy (dystopia of the trachea due to an arteria lusoria) mainly resulting in esophagotracheal fistulae. The fourth patient was treated by esophagectomy due to a local progressive carcinoma. A long lesion between the carina and left main bronchus resulted. All lacerations were treated by single knot suture technique with Polydioxanone and finally covered (patched) with PGA Mesh. The outcome of the surgical treatment was analyzed. RESULTS: In bronchoscopies and CT-scans no air leackages during respiratory ventilation periods were observed. The first patient could be transferred into a normal ward from ICU at day 38. The second patient was found to be tetraplegic and was discharged into another hospital at day 48. One patient died at the 15th postoperative day due to urosepsis. The fourth patient left the ICU on day 10 and was discharged home at day 23. CONCLUSIONS: Large iatrogenic airway lacerations of the distal trachea should be managed by early surgical repair due to their life-threatening outcome. Although only a small number of patients were analyzed so far, a PGA Mesh might be useful to increase the suture safety reducing the tension at the suture points due to the cuff pressure during long ventilation periods.

Strangulated appendix within a trocar site incisional hernia following laparoscopic low anterior rectal resection. A case report.

Appendix strangulation caused by an incisional trocar site hernia following laparoscopy is an extremely rare entity. A 63-year-old man was admitted to our department with continuous abdominal pain and irreducible minimal swelling in the right abdomen. His surgical history was significant for rectal cancer one year previously. The patient had undergone a laparoscopic low anterior rectal resection with construction of a protective temporary end ileostomy (pT1, pN0, G2, M0). The ileostomy was reversed 3 months after initial surgery. An incarcerated herniation was diagnosed. Subsequent surgery surprisingly revealed that the right lower trocar point incisional hernia contained a strangulated appendix. Routine appendectomy was performed and the hernias were repaired using a typical sublay technique.

Stress takotsubo cardiomyopathy after pylorus preserving pancreaticoduodenectomy for cancer. A case report.

A pylorus-preserving cephalic pancreaticoduodenectomy was performed for tumor removal in a male elderly patient. In the following course no surgical complications occurred but ST-elevations and increase of Troponin T were observed. A coronary angiography revealed no relevant stenosis although a severe hypokinesis of the apex region was determined by echocardiography--a Takotsubo syndrome was assumed. This led to a significant prolonged clinical course. No residual problems remained but the cause of Takotsubo could not be identified. Analyzing the current knowledge, a feasible preoperative screening for this severe condition seems to be quite impossible.

Wound healing is not impaired in rats undergoing perioperative treatment with the antineoplastic agent taurolidine.

BACKGROUND/AIM: The aim of this study was to determine whether an intravenous or an intraperitoneal application of the antineoplastic agent taurolidine (TRD) impairs wound healing in the absence of tumor load in rats. METHODS: Eighty rats were randomized into eight groups (n = 10). Median laparotomy was performed in all animals. Three groups were treated by intravenous injection and three groups by local administration using a central port catheter system. For each group, 1 ml was applied: isotone sodium chloride solution (control groups), 1% TRD, 2% TRD, and 3% TRD. Fascia and skin were closed using a standardized running suture technique with 4-0 Vicryl. Wounds were evaluated once a day. Animals were treated every 8 h for 7 days (ports were then removed) and wounds were evaluated at day 28. Macroscopic and histopathologic examinations of scar tissue biopsies (hemalaun-eosin stain) were performed at the end of the experiment. RESULTS: No animal died. No relevant impairment of wound healing was observed independent of the different treatment strategies. CONCLUSION: Our results suggest that wound healing does not seem to be impaired by TRD in rats.

Leukopoiesis is not affected after intravenous treatment with the novel antineoplastic agent taurolidine. Results of an experimental study in rats.

BACKGROUND/AIM: Chemotherapy can induce serious leukopenia. The aim of our study was to investigate the effects on leukopoiesis when the antineoplastic agent taurolidine (TRD) is administered by a bolus injection or during repetitive treatment (21 cycles) over 7 days in rats. METHODS: Rats were intravenously treated with a single injection (A) or by a 7-day treatment (B) with increasing doses of TRD versus control (isotone sodium) in a standardized animal model. Hematological adverse effects on leukopoiesis were analyzed in peripheral blood. RESULTS: (A) Neither the highest TRD concentration (3%) nor 1 or 2% caused a significant difference between the control and TRD groups (p > 0.085) in the perioperative course after bolus administration. (B) The administration of TRD 3% led to a slight change of granulocyte and monocyte counts compared to the control group particularly on postoperative day 7, but this difference was not significant. In both protocols a slight postoperative increase in leukocytes was observed. CONCLUSION: We report that TRD administered intravenously in an antitumor dose does not affect leukopoiesis in rats. Thus, the agent offers a promising and safe means in cancer treatment. The effects are currently investigated in incurable cancer patients.

[Minimally invasive thymus surgery]. / Minimal-invasive Chirurgie des Thymus.

There are absolute and relative indications for complete removal of the thymus gland. In the complex therapy of autoimmune-related myasthenia gravis, thymectomy plays a central role and is performed with relative indication. In case of thymoma with or without myasthenia, thymectomy is absolutely indicated. Thymus resection is further necessary for cases of hyperparathyroidism with ectopic intrathymic parathyroids or with certain forms of multiple endocrine neoplasia. The transcervical operation technique traditionally reflected the well-founded desire for minimal invasiveness for thymectomy. Due to the requirement of radicality however, most of these operations were performed using sternotomy. With the evolution of therapeutic thoracoscopy in thoracic surgery, several pure or extended minimally invasive operation techniques for thymectomy have been developed. At present uni- or bilateral, subxiphoid, and modified transcervical single or combination thoracoscopic techniques are in use. Recently a very precise new level of thoracoscopic operation technique was developed using robotic-assisted surgery. There are special advantages of this technique for thymectomy. An overview of the development and experiences with minimally invasive thymectomy is presented, including data from the largest series published so far.

Instillation of taurolidine/heparin after laparotomy reduces intraperitoneal tumour growth in a colon cancer rat model.

OBJECTIVE: To investigate whether irrigation of the abdominal cavity after laparotomy for caecum resection with taurolidine/heparin or adhesion prophylactic substances reduces intraperitoneal tumour growth or the local recurrence rate in a colon carcinoma rat model. METHODS: 60 BDIX rats underwent caecum resection after intraperitoneal inoculation of 1 x 10(4) colon carcinoma cells (DHD/K12/TRb). Intergel, Interceed, taurolidine/heparin or NaCl 0.9% were intraperitoneally applied after randomisation. Finally, the total number and total weight of intraperitoneal metastases were determined as well as the adhesion score according to Moreno. Metastatic tissue was examined histologically and immunohistochemically (E-cadherin, CD44, beta(1)-integrin). RESULTS: Taurolidine/heparin significantly reduced not only the total number (3 vs. 11 in the control group) but also the total weight (65 vs. 330 mg) of intraperitoneal metastases in comparison to the control group (p = 0.003 and p = 0.005). E-Cadherin expression in the metastatic tissue of animals treated with taurolidine/heparin was significantly decreased (p = 0.016). CONCLUSION: Taurolidine/heparin effectively reduces intraperitoneal tumour growth when used as an intraoperative lavage. These results represent a good rationale for intraoperative adjuvant irrigation with taurolidine/heparin during resection of colon cancer.

[Impact of pneumoperitoneum on expression of E-cadherin, CD44v6 and CD54 (ICAM-1) on HT-29 colon-carcinoma cells]. / Einfluss des Pneumoperitoneums auf die Expression von E-Cadherin, CD44v6 und CD54 (ICAM-1) auf HT-29-Kolonkarzinomzellen.

INTRODUCTION: The mechanism of potential tumor cell spread and growth during laparoscopy is poorly understood. Nevertheless, different experimental studies reported a stimulation of tumor cell growth and an increased metastatic potential of carcinoma cells using carbon dioxide as an insufflation medium. Adhesion molecules do play an important and regulatory function in the process of metastatic spread and invasion of cancer cells. Therefore we investigated the influence of CO2 and Helium insufflation on the in-vitro expression of E-Cadherin, CD44v6 and CD54 (ICAM-1) on HT-29 colon carcinoma cells. METHODS: HT-29 carcinoma cells were exposed to either CO2 or helium insufflation. Expression of E-Cadherin, CD44v6 and CD54 (ICAM-1) on HT-29 colon carcinoma cells were measured 1, 12, 24, 48 and 96 h after CO2 and helium insufflation using flowcytometry (FACScan). Data were analyzed by Friedman-test. RESULTS: HT-29 cell line showed a short decrease in E-Cadherin expression after CO2 exposure while helium insufflation had no influence. In contrasts to these findings the expression of CD44v6 and CD54 on HT-29 cells were not influenced significantly by either CO2 or helium. CONCLUSION: CO2 seems only to have a minor influence on the expression of E-Cadherin while expression of other adhesion molecules did not change after CO2 incubation. The alternative gas helium did not cause any significant changes of the expression of either E-Cadherin, CD44v6 and CD54. Further investigations are needed to elucidate the changes of the metastatic potential of tumor cells after laparoscopic and open procedures.

Pneumatosis intestinalis--a pitfall for surgeons?

Pneumatosis intestinalis (PI) is characterized by multiple gas cysts in the wall of the gastrointestinal tract. Primary PI is extremely rare. In most of the cases PI is due to an underlying disease (traumatic and mechanical, inflammatory and autoimmune diseases, infectious and pulmonary diseases, drug induced, immunosuppression, transplantation, or neoplasm). A 69-year-old woman was treated with mixed connective tissue disease and PI twice operatively and once conservatively in our department. Review of the English literature showed 13 more cases of PI with underlying mixed connective tissue disease. Most published cases of pneumatosis intestinalis with radiological finding of pneumoperitoneum were treated conservatively and should have not been considered as a reason for surgery. Therefore, the treatment of PI can present as a major dilemma for the surgeon.