Perioperative or only adjuvant gemcitabine plus nab-paclitaxel for resectable pancreatic cancer (NEONAX)-a randomized phase II trial of the AIO pancreatic cancer group.

BACKGROUND: Data on perioperative chemotherapy in resectable pancreatic ductal adenocarcinoma (rPDAC) are limited. NEONAX examined perioperative or adjuvant chemotherapy with gemcitabine plus nab-paclitaxel in rPDAC (National Comprehensive Cancer Network criteria). PATIENTS AND METHODS: NEONAX is a prospective, randomized phase II trial with two independent experimental arms. One hundred twenty-seven rPDAC patients in 22 German centers were randomized 1 : 1 to perioperative (two pre-operative and four post-operative cycles, arm A) or adjuvant (six cycles, arm B) gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 8 and 15 of a 28-day cycle. RESULTS: The primary endpoint was disease-free survival (DFS) at 18 months in the modified intention-to-treat (ITT) population [R0/R1-resected patients who started neoadjuvant chemotherapy (CTX) (A) or adjuvant CTX (B)]. The pre-defined DFS rate of 55% at 18 months was not reached in both arms [A: 33.3% (95% confidence interval [CI] 18.5% to 48.1%), B: 41.4% (95% CI 20.7% to 62.0%)]. Ninety percent of patients in arm A completed neoadjuvant treatment, and 42% of patients in arm B started adjuvant chemotherapy. R0 resection rate was 88% (arm A) and 67% (arm B), respectively. Median overall survival (mOS) (ITT population) as a secondary endpoint was 25.5 months (95% CI 19.7-29.7 months) in arm A and 16.7 months (95% CI 11.6-22.2 months) in the upfront surgery arm. This difference corresponds to a median DFS (mDFS) (ITT) of 11.5 months (95% CI 8.8-14.5 months) in arm A and 5.9 months (95% CI 3.6-11.5 months) in arm B. Treatment was safe and well tolerable in both arms. CONCLUSIONS: The primary endpoint, DFS rate of 55% at 18 months (mITT population), was not reached in either arm of the trial and numerically favored the upfront surgery arm B. mOS (ITT population), a secondary endpoint, numerically favored the neoadjuvant arm A [25.5 months (95% CI 19.7-29.7months); arm B 16.7 months (95% CI 11.6-22.2 months)]. There was a difference in chemotherapy exposure with 90% of patients in arm A completing pre-operative chemotherapy and 58% of patients starting adjuvant chemotherapy in arm B. Neoadjuvant/perioperative treatment is a novel option for patients with resectable PDAC. However, the optimal treatment regimen has yet to be defined. The trial is registered with ClinicalTrials.gov (NCT02047513) and the European Clinical Trials Database (EudraCT 2013-005559-34).

[Knife injury to the thoracic aorta and spinal cord. Report on an"almost-mistake"]. / Messerstichverletzung von thorakaler Aorta und Myelon. Bericht über einen "Beinahe-Fehler".

We report the surgical treatment of a thoracic knife injury with lesions of the aorta and the myelon. An initially incomplete revision of the wound nearly resulted in a critical situation. Complete revision of a wound is obligatory in a penetrating injury, when a relevant structure is possibly injured.

[Mesh-wrapping of a traumatised liver with active bleeding: a subsequent complication--obstruction of the inferior vena cava]. / Hepatorrhaphie mittels Vicrylnetz bei Leberruptur Grad IV - Eine mögliche Komplikation: Verschluss der V. cava inferior.

In multiply traumatised patients injuries of the -liver are frequently seen. Depending on location and extent of the trauma, different techniques can be applied. In the presented case of a central liver trauma in a 21-year-old man with active bleeding, mesh-wrapping of both liver lobes was applied to achieve control of the bleeding. Postoperatively the patient developed constant hypertension, oliguria and severe anasarka of the lower half of the body caused by a near total obstruction of the inferior vena cava. After removal of the wrappings, all symptoms slowly disappeared. This case and the findings in similar cases in the literature suggest that there is an indication for wrapping a traumatised liver rather with diffuse and peripheral bleeding than with a central liver trauma.

Objective evaluation of minimally invasive surgical skills for transplantation. Surgeons using a virtual reality simulator.

BACKGROUND: The learning curve in laparoscopic surgery may be associated with higher patient risk, which is unacceptable in the setting of kidney donation. Virtual reality simulators may increase the safety and efficiency of training in laparoscopic surgery. The aim of this study was to investigate if the results of a training session reflect the actual skill level of transplantation surgeons and whether the simulator could differentiate laparoscopic experienced transplantation surgeon from advanced trainees. SUBJECTS AND METHODS: 16 subjects were assigned to one of two groups: 5 experienced transplantation surgeon and 11 advanced residents, with only assistant role during transplantation. The level of performance was measured by a relative scoring system that combines single parameters assessed by the computer. RESULTS: The higher the level of transplantation experience of a participant, the higher the laparoscopic performance. Experienced transplantation surgeons showed statistically significant better scores than the advanced group for time and precision parameters. CONCLUSIONS: Our results show that performance of the various tasks on the simulator corresponds to the respective level of experience in transplantation surgery in our research groups. This study confirms construct validity for the LapSim. It thus measures relevant skills and can be integrated in an endoscopic training and assessment curriculum for transplantations surgeons.

[Simulation of endoscopic procedures--an innovation to improve laparoscopic technical skills]. / Simulation d'operations endoscopiques--innovation dans le développement de la dextérité manuelle en chirurgie laparoscopique.

BACKGROUND: Laparoscopic surgery is a technically more demanding procedure compared to open surgery. Safe realistic training and unbiased quantitative assessment of technical skills are required for laparoscopic surgery. Virtual reality (VR) simulators may be useful tools for training and assessing basic and advanced surgical skills and procedures. AIM: to assess the acquisition of laparoscopic skills using virtual reality simulators. METHODS: systematic review of the literature. RESULTS: (1) The simulator can be used to objectively assess the laparoscopic skills of surgeons and distinguish between novices and experienced laparoscopic surgeons. (Evidence level III-B) (2) The target group as well as the benefit of a three-day practical course for laparoscopic surgery can be determined by the simulator. (Evidence level III-C) (3) Novices in laparoscopic surgery seem to benefit mostly from simulation training. (Evidence level III-B) (4) Steepness and plateau of a learning curve may be more dependent on the level of performance required by the particular training session rather than the number of repetitions during a training session. (Evidence level III-B) (5) Clinical background and understanding of the clinical value of a training program lead to faster acquisition and improvement of laparoscopic skills as performed on the laparoscopy simulator. (Evidence level III-B) (6) Non technical skills such as visual-spatial perception and stress coping positively correlates with virtual laparoscopic skills. (Evidence level III-B). CONCLUSION: To date, the best method for teaching laparoscopic surgery has not been defined. However, the use of virtual simulators for laparoscopy training is useful when learning basic techniques allow the surgeon to improve hand dexterity and coordination in laparoscopic surgery.

Clinical background is required for optimum performance with a VR laparoscopy simulator.

OBJECTIVE: To determine the role of clinical background when assessing the learning effect using a virtual-reality (VR) laparoscopy simulator (LapSim). MATERIALS AND METHODS: Test subjects were 12 final-year medical students (Group A) and 12 inexperienced residents (Group B) with no previous experience of VR simulators. First, to establish a baseline, both groups performed the "clip application" task twice. They then completed a training program of increasing difficulty (coordination, cutting and clip application), after which both groups were re-tested using a difficult level of the "cutting" task as an endpoint measurement. Time to complete the tasks, as well as trauma and precision parameters, were scored. RESULTS: Before training, times to complete the baseline task, as well as parameters of trauma and precision, were similar for both groups. After training, Group B (residents) completed the cutting task significantly faster than Group A (students). However, the former group also showed significant improvement in trauma and precision parameter scores in the endpoint measurement. CONCLUSION: These results suggest that clinical background and understanding of the clinical value of a training program lead to faster acquisition and improvement of laparoscopic skills as performed on the laparoscopy simulator. Thus, medical students or other personnel not involved in practical surgery may be unsuitable as candidates for assessing the value of a VR training program.

[Instituting a surgical skills lab at a training hospital]. / Einrichtung eines chirurgischen Trainingslabors an einer Ausbildungsklinik.

The improvement of surgical skills of trainees in Germany often occurs solely in the operating room. In recent years, several countries have established surgical skills labs as an essential part of surgical education, with the goal of improving and refining surgical skills before clinical application. Several years ago, training units were established by the industry wherein the curricula focused on products of the respective company. Selected training courses are still offered in a few clinics. Presently, laboratories which train the surgical skills of novices in an individually adapted form are lacking. A surgical skills lab with a comprehensive curriculum of training courses was introduced at the University Hospital of Marburg in 2005. The present article describes the development and introduction of such facilities. The authors are convinced that surgical skills labs will become increasingly important in German surgical education for improving patient safety in the operating room.

[A virtual reality simulator for objective assessment of surgeons' laparoscopic skill]. / Laparoskopiesimulator Abbildung der manuellen Geschicklichkeit in der laparoskopischen Chirurgie.

BACKGROUND: The aim of this study was to validate computed virtual reality simulation as a tool to assess laparoscopic skills and to establish whether the simulator allows differentiating between surgeons with different laparoscopic experience. METHODS: 27 physicians at the surgical department of the University of Marburg, Germany, with different experience in laparoscopic surgery were divided into three groups: experienced (group I), intermediate (group II), and novices (group III). Following a brief introduction to the virtual reality simulator (LapSim), each participant performed twice a training program consisting of seven tasks (examinations I and II). RESULTS: Comparison of experienced surgeons with less experienced laparoscopic physicians showed a significant (P<0.05) superiority of group I at examinations I and II in most exercises. The groups' difference was more obvious in examination II, since the technique was new for all participants during examination I. Tasks of low complexity in virtual reality such as camera navigation, which are performed by young, not yet responsible surgeons in real surgery, did not show significantly different results between the three groups. CONCLUSION: Differences in laparoscopic experience can be visualised with a virtual reality simulator, and thus a simulator is helpful for assessing surgeons' laparoscopic skills.

[Operation time for suprapubic transumbilical cholecystectomy: Results of a prospective randomized trial]. / Operationszeit bei der suprapubisch-transumbilikalen Cholezystektomie : Ergebnisse einer prospektiv-randomisierten Studie.

BACKGROUND: Over the last decade new innovative minimally invasive techniques (e.g. transvaginal cholecystectomy and single incision laparoscopic cholecystectomy) have been developed to reduce operative trauma, postoperative pain and to achieve better cosmetic results. Nevertheless, most of these techniques are more difficult and time-consuming than conventional laparoscopic cholecystectomy (CLC). A new approach, the Minden technique for combined suprapubic transumbilical cholecystectomy (MI-CHE) has been proven to provide a very good cosmetic outcome with reduced operative trauma. The aim of this study was to survey whether MI-CHE prolongs operation times to a relevant degree compared to CLC. METHODS: A total of 40 patients undergoing laparoscopic cholecystectomy were randomized between both techniques. The duration of the operation and other perioperative data were recorded. Surgery was performed by four resident surgeons who had not yet performed any technique of laparoscopic cholecystectomy, neither MI-CHE nor CLC but were assisted by the same senior staff surgeon in all cases. The two patient groups showed no differences in age, gender and body mass index. The study was registered (DRKS00003271). Non-inferiority was tested using 95% confidence intervals (95% CI). RESULTS: The mean operation time was shorter by - 4.2 min (95% CI, + 6.4 min to - 14.8 min) in the MI-CHE as compared to the CLC group (65.5 min versus 69.7 min). There were no open conversions but in one patient intestinal injury occurred during the umbilical mini-laparotomy. There were no differences in patient satisfaction and perioperative pain between both procedures. CONCLUSION: The MI-CHE, which provides very good cosmetic results, is not more time-consuming than CLC. Additionally, it seems to be safe and not more difficult to learn than CLC.

Higher frequency of DPC4/Smad4 alterations in pancreatic cancer cell lines than in primary pancreatic adenocarcinomas.

The tumor suppressor gene DPC4/Smad4 at 18q21.1 is inactive in about 50% of pancreatic carcinoma xenografts and cell lines. However, the role of DPC4 in the multistep carcinogenesis of primary pancreatic adenocarcinomas remains uncertain. Therefore, we examined 45 primary human pancreatic adenocarcinomas and 12 pancreatic cancer cell lines for DPC4 alterations by single-strand conformational variant (SSCV) analysis and a PCR-based deletion assay. DPC4 was inactivated by either homozygous deletion or point mutation in 6 of 12 cell lines (50%). None of the primary pancreatic carcinomas carried a DPC4 mutation, although 66% revealed LOH of 18q21 sequences. These findings suggest that inactivation of DPC4 occurs more frequently in tumor-derived cell lines than in primary pancreatic adenocarcinomas. In addition, another, yet unidentified, tumor suppressor gene(s) may be linked with the frequent LOH of 18q21 in primary pancreatic adenocarcinomas.

Multiple primaries in pancreatic cancer patients: indicator of a genetic predisposition?

BACKGROUND: The genetic basis of several familial cancers including breast and colon cancers has been identified recently. The occurrence of multiple cancers in one individual is also suggestive of a genetic predisposition. To evaluate inherited predisposition in pancreatic cancer we compared the clinical data of pancreatic cancer patients with and without multiple primaries as well as the frequency of malignancies among their relatives. METHODS: Detailed data on 69 pancreatic cancer patients included survival time and TNM-classification. Index case data were separated into two groups. The first group (group 1) developed only pancreatic cancer during their lifetime, whereas the second group (group 2) developed additional primary tumours. A systematic family history was taken from 59 of these pancreatic cancer patients using a standardized questionnaire. The pancreatic cancers and the multiple primaries of the 59 patients were histologically proven. RESULTS: Of the 69 pancreatic cancer patients, 13 (18.8%) had multiple primaries. Neither the clinical data nor the survival data of the index cases revealed differences between the two groups (all nominal P-values >0.05). In the family history study blood relatives developed a malignancy in 51% (24 of 47) of the families in group 1 compared to 75% (9 of 12) in group 2. The risk of relatives in group 2 of developing a malignant tumour was significantly higher (P = 0.034) than in group 1 after adjustments for family size and age of disease onset of the index case. The cancer spectrum of the 59 families mainly included tumours of the digestive tract and the reproductive organs. CONCLUSIONS: A multiple primary cancer history is a common condition among pancreatic cancer patients. Relatives of these patients seem to have an increased risk for the development of distinct malignant solid tumours, which might be caused by an inherited predisposition. Clinical and genetic investigation of pancreatic cancer patients with multiple primaries and their families might lead to the identification of predisposing gene defects providing a new goal for the understanding of a shared genetic basis of different solid tumours.

p16(INK4a) alterations in chronic pancreatitis-indicator for high-risk lesions for pancreatic cancer.

BACKGROUND: p16(INK4a) alterations are considered to be an early event in pancreatic tumorigenesis and have been described in duct lesions adjacent to pancreatic cancers. This study evaluates whether duct lesions in chronic pancreatitis tissues of patients without pancreatic cancer also harbor genetic alterations in the p16(INK4a) tumor-suppressor gene, and thus represent high-risk precursors for pancreatic cancer. METHODS: Tissues were obtained from 20 pancreatic specimens taken from patients operated on for histologically verified chronic pancreatitis. Pancreatic intraductal neoplasias (PanIN) were identified in hematoxylin-and-eosin-stained slides. p16 protein expression was investigated immunohistochemically in all specimens. DNA from PanIN and non-PanIN tissue was analyzed genetically for p16(INK4a) mutations by single-strand conformation variation analysis and direct sequencing of the encoding region. Additionally, p16(INK4a) promoter methylation was analyzed by a methylation specific polymerase test. RESULTS: PanIN-1a lesions were identified in 10 of the 20 chronic pancreatitis specimens. Four of these 10 PanIN specimens (40%), but none of the 20 non-PanIN tissues, revealed a loss of p16 expression in immunohistochemistry. The mutational analysis of the p16(INK4a) gene showed 1 known polymorphism (c.442G > A; A148T) but no mutations. Two of the 10 specimens with PanIN revealed an inactivating hypermethylation of the p16(INK4a) promoter. CONCLUSIONS: This study shows for the first time that p16(INK4a) alterations can be observed in a considerable number of PanIN1 in chronic pancreatitis tissues not associated with pancreatic cancer. Therefore, p16(INK4a) alterations, especially promoter methylation, might indicate high-risk precursors in chronic pancreatitis that might progress to cancer.

Multiple primary tumors as an indicator for p16INK4a germline mutations in pancreatic cancer patients?

Multiple primary tumors in pancreatic cancer patients might indicate a genetic predisposition to the development of malignancies. In this study we evaluated whether the mutation rate of the TP53 and p16INK4a genes of pancreatic cancers differs in pancreatic cancer patients with and without multiple primaries. Furthermore, we investigated whether pancreatic cancer patients with multiple primaries carry germline mutations in either p16INK4a, TP53, or BRCA2 tumor suppressor genes to detect a genetic alteration that predisposes to the development of different primaries. Fourteen (23%) of 60 pancreatic cancer patients developed histologically verified additional primaries during their lifetimes. Normal constitutional and tumor DNA of the 14 patients with a positive cancer history, but negative family history, were analyzed for p16INK4a, TP53, and BRCA2 mutations by single-strand conformational variant (SSCV) analysis and direct sequencing. Hypermethylation of the p16INK4a promoter region in pancreatic cancers was identified by methylation-specific polymerase chain reaction (PCR; MSP). Four of 14 pancreatic carcinomas carried somatic intragenic p16INK4a mutations, and another four tumors revealed hypermethylation of the p16INK4a promoter region. Somatic intragenic TP53 mutations were identified in six of 14 tumors. None of the pancreatic cancer patients carried TP53 or BRCA2 germline mutations. In contrast, one of 14 pancreatic cancer patients with multiple primaries carried the p16INK4a mutation A68V in his germline. This mutation was localized in the conserved second ankyrin repeat of p16INK4a and did not occur in 100 control patients. The frequency of somatic TP53 and p16INK4a mutations in pancreatic cancer is similar in patients with and without multiple primaries. TP53 and BRCA2 germline mutations seem not to be significantly associated with the occurrence of multiple primaries in pancreatic cancer patients. However, p16INK4a germline mutations might be causative for tumor development in some pancreatic cancer patients with multiple primaries. The genetic investigation of patients with accumulation of different cancers even without a positive family history may be a new approach for the understanding of the relation of different cancers.

Renin producing neuroendocrine pancreatic carcinoma--a case report and review of the literature.

A 44 year old male patient presented with severe hypertension. The diagnostic work-up revealed elevated levels of plasma renin activity (about 10 times the upper limit of normal) in the presence of normal plasma aldosterone levels and serum potassium concentrations. Renovascular disease was excluded by angiography. Selective renal vein sampling did not show any renin gradient. CT-scans of the abdomen demonstrated normal morphology of the kidneys and adrenals but revealed a big mass in the pancreatic corpus and tail with infiltration of the splenic vein and the presence of enlarged local lymph nodes. The endocrine nature of the pancreatic mass was further supported by a positive octreotide scintigraphy scan. Surgical removal of the tumor by left sided pancreatectomy combined with splenectomy resulted in rapid normalization of elevated renin concentrations as well as blood pressure. Histological examination of the tumor tissue revealed the presence of a neuroendocrine pancreatic carcinoma. Highly (x 70) elevated renin levels were detected by radioimmunoassay in the tumor tissue. To our knowledge this is the first renin-producing neuroendocrine pancreatic carcinoma described in the literature. The present paper describes the case in detail and reviews the available literature on clinical symptomatology, diagnosis and treatment of renin-producing tumors.

[Endosonography of the anal canal in functional disorders of the pelvic flow. Initial experiences]. / Endosonographie des Analkanals bei Funktionsstörungen des Beckenbodens. Erste Erfahrungen.

Nine patients were examined by anal endosonography for pelvic floor disorder. Internal anal sphincter thickness was correlated with sphincter function. Six patients with idiopathic incontinence showed a reduction of internal anal sphincter thickness, one patient with outlet obstruction due to chronic anal fissure showed an increase of thickness. Traumatic lesions could be precisely localized because of defects in both internal and external anal sphincter. Anal endosonography can be recommended in the evaluation of pelvic floor disorders.

[Rectal endosonography for detection of free fluid in the abdomen]. / Die rectale Endosonographie zum Nachweis freier Flüssigkeit im Abdomen.

In a study of 60 patients suspicious of free fluid we found a very high sensitivity of 95% and specificity of 100% with endorectal sonography. In 6 patients free fluid could be shown preoperatively by endorectal ultrasound, whereas transabdominal sonography proved to be negative. We conclude that endorectal sonography should be performed in all cases with a clinical suspicion of free fluid when transabdominal sonography is negative. Rectal endosonography is an easy and less stressful examination which clarifies conditions in the pelvis which are not clearly discernible from the transabdominal sonography.

[High-grade intimal sarcoma in an aneurysm of the infrarenal aorta]. / Hochmalignes Intimasarkom in einem Aneurysma der infrarenalen Bauchaorta.

Primary intimal sarcomas of the aorta are extremely rare and aggressive tumors metastasizing into bones and visceral organs including liver, kidneys, adrenal glands, and lung. The first symptoms are often nonspecific and often caused by arterial embolism. We report a case with an incidental finding of primary intimal sarcoma in an aneurysm of a patient with claudication due to tumor embolization.

[The longitudinal muscle of the anal canal]. / Der longitudinale Muskel des Analkanals.

The longitudinal muscle (LM) represents a strong muscular structure of the anal canal situated between the internal (IAS) and the external anal sphincter (EAS). Terminal fibres of this muscle insert at the submucosa of the anal canal, representing the m. canalis ani. Others cross the subcutaneous part of the EAS to become the m. corrugator ani. Thus, the LM connects the visceral and somatic parts of the anal sphincter complex. Histologically ganglionic cells and as Vater-Pacinian corpuscles can be identified inside the LM. Morphology, topography and histology of the LM suggest that this muscle participates in maintaining anorectal continence. It is mandatory that the exact functions of this muscular structure be to elaborated upon, if we are to understand the mechanism of anorectal continence.