Jan Scheele

Systematic review and meta-analysis of antibiotic prophylaxis in severe acute pancreatitis

Abstract Objective. The incidence of acute pancreatitis varies from 5 to 80 per 100,000 throughout the world. The most common cause of death in these patients is infection of pancreatic necrosis by enteric bacteria, spurring the discussion of whether or not prophylactic antibiotic administration could be a beneficial approach. In order to provide evidence of the effect of antibiotic prophylaxis in severe acute pancreatitis (SAP) we performed an updated systematic review and meta-analysis on this topic. Methods. The review of randomized controlled trials was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement. We conducted a search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. For assessment of the treatment effects we calculated the risk ratios (RRs) for dichotomous data of included studies. Results. Fourteen trials were included with a total of 841 patients. The use of antibiotic prophylaxis was not associated with a statistically significant reduction in mortality (RR 0.74 [95% CI 0.50–1.07]), in the incidence of infected pancreatic necrosis (RR 0.78 [95% CI 0.60–1.02]), in the incidence of non-pancreatic infections (RR 0.70 [95% CI 0.46–1.06]), and in surgical interventions (RR 0.93 [95% CI 0.72–1.20]). Conclusion. In summary, to date there is no evidence that supports the routine use of antibiotic prophylaxis in patients with SAP.

Dermoid cyst of the pancreas

Dear Editor: Dermoid cysts (cystic teratoma) are congenital developmental abnormalities of germ cell origin derived from any of the three germinal layers, e.g., ectoderm, entoderm, mesoderm. As true cysts, dermoid cysts are usually benign, welldifferentiated lesions. Along the pathway of ectodermal cell migration, they are commonly found in the ovary, testes, and retroperitoneum. The pancreas is extremely rare as a primary site. A 40-year-old Caucasian male presented with a short history of recurrent upper abdominal pain. The patient was in an excellent state of health with a body mass index of 24 kg/m2. Laboratory examination showed normal values except for increased gamma glutamyltransferase by 1.66fold (91 U/l; upper normal limit, 55 U/l) and carbohydrate antigen 19-9 (CA 19-9) by 1.94-fold (62 IU/ml; upper normal limit, 32 IU/ml). Abdominal ultrasound revealed an inhomogenic mass in the area of the pancreas allocated into the pancreas by subsequent endoscopic ultrasound. Magnetic resonance tomography showed a well-defined cystic tumor measuring 64×49×38 mm arising at the border of the pancreatic head to body with a central necrosis. The duodenum and the stomach were displaced ventrally/laterally. The pancreatic main duct was not altered. No signs of irresectability were found. Gastric and duodenal infiltration was excluded by esophagogastroduodenoscopy. There were no signs of metastatic spread. A cytologic (fine-needle aspiration cytology (FNAC)) or histologic assessment before resection was not performed. A symptomatic tumor of more than 2 cm in size is associated with a high risk of malignancy. Therefore, primary surgery was performed. The cystic tumor was found to originate from the border of the pancreatic head and body protruding the major curvature of the stomach and the duodenal bulb and with contact to the portal vein on the backside. Meticulous mobilization finally allowed for pyloric preserving partial duodenopancreatectomy with a resection margin in the pancreas, 3 cm left of the vena mesenterica superior. The postoperative course was uneventful except for a self-limiting low-output pancreatic fistula treated conservatively. Macroscopically, the tumor consisted of an intact lobulated cyst, encapsulating yellow-brown pasty material. Cutting the surface of the tumor revealed a pasty sebaceous filling. On histological examination, the cyst wall was lined by mature stratified squamous epithelium, surrounded by lymphoid tissue containing germinal centers and sebaceous glands. In the lumen of the cyst, masses of keratinous debris were detected. In absence of any atypia, the final diagnosis was a dermoid cyst of the pancreas. In contrast to lympho-epithelial cysts, dermoid cysts are rarely found in the pancreatic tail and with only slightly more frequency in men than in women. There is no predominance of age as they present in all stages of life. This observation underscores the strictly benign nature of this pancreatic tumor without tendency of malign transformation. The majority of patients are symptomatic at the J. Scheele : J. Strasburg :M. Kornmann (*) :D. Henne-Bruns Clinic of General, Visceral, and Transplantion Surgery, University of Ulm, Steinhoevelstrasse 9, 89075 Ulm, Germany e-mail: marko.kornmann@uniklinik-ulm.de

Brain metastasis in pancreatic cancer.

Pancreatic cancer is a fatal disease with a 5-year survival rate below 5%. Most patients are diagnosed at an advanced tumor stage and existence of distant metastases. However, involvement of the central nervous system is rare in pancreatic cancer. We retrospectively analyzed all cases of brain metastases in pancreatic cancer reported to date focusing on patient characteristics, clinical appearance, therapy and survival. Including our own, 12 cases of brain metastases originating from pancreatic cancer were identified. In three patients brain metastases were the first manifestation of pancreatic cancer. All other patients developed brain metastases during their clinical course. In most cases, the disease progressed rapidly and the patients died within weeks or months. However, two patients showed long-term survival. Of note, both patients received resection of the pancreatic cancer as well as curative resection of the metachronous brain metastases. Brain metastases in pancreatic cancer are a rare condition and usually predict a very poor prognosis. However, there is evidence that resection of brain metastases of pancreatic cancer can be immensely beneficial to patient’s survival, even with the chance for cure. Therefore, a surgical approach in metastatic pancreatic cancer should be considered in selective cases.

Quality of Life After Sphincter-Preserving Rectal Cancer Resection

BACKGROUND With an increasing number of cancer survivors quality of life (QoL) becomes more and more important in the treatment of rectal cancer (RC). QoL after sphincter-preserving anterior resection (AR), however, was found nonsuperior to abdominoperineal resection. The aim of our study was to evaluate QoL after AR compared with colon cancer patients after right hemicolectomy (CC) and healthy lay persons without history of cancer (HL) in long-term follow-up. PATIENTS AND METHODS Consecutive alive RC patients (n = 293) who received an AR between 1998 and 2008 were included. CC patients (n = 201) and HL of the same age were used as a surgical and a nonsurgical control group, respectively. QoL was assessed using European Organization of Research and Treatment of Cancer questionnaires QLQ-C 30 and -CR 38. RESULTS Questionnaires from 116 RC patients, 105 CC patients, and 103 HL were evaluable with a median time after surgery of 5 years. The global health status did not differ. Social functioning, future perspectives, and financial difficulties tended to poorer scores in the cancer groups. Physical functioning was better in RC and CC patients compared with HL. Defecation problems and diarrhea were more frequent in RC patients (P < .05). An additional open question revealed a median stool frequency of 3, 2, and 1 per day for RC, CC, and HL, respectively. Defecation problems were more frequent in RC patients who received radiation therapy (P < .05). CONCLUSION Diarrhea and defecation problems impaired QoL after AR for RC, which was worsened after radiation therapy. To improve QoL of RC patients in the future, physicians have to focus on minimization of gastrointestinal side effects while optimizing surgical reconstruction.

Population Pharmacokinetics and Target Attainment of Meropenem in Plasma and Tissue of Morbidly Obese Patients after Laparoscopic Intraperitoneal Surgery.

ABSTRACT Meropenem serves as a clinically important, broad-spectrum antibiotic. While meropenem is commonly used in obese patients, its pharmacokinetics in this patient group is not well known. Our aim was to characterize the population pharmacokinetics and target attainment in plasma, subcutaneous tissue, and peritoneal fluid for meropenem in morbidly obese patients. Four doses of 1g meropenem were given as 15-min infusions every 8 h to five morbidly obese patients (body mass index [BMI], 47.6 to 62.3 kg/m2). After the fourth dose, serial meropenem concentrations were determined in plasma and, via microdialysis, in subcutaneous tissue and peritoneal fluid. All concentrations were analyzed simultaneously via population modeling, and target attainment probabilities predicted via Monte Carlo simulations using the target of unbound meropenem concentrations above the MIC for at least 40% of the dosing interval. For patients with 53 kg fat-free mass, total clearance was 18.7 liters/h and volume of distribution at steady state was 27.6 liters. The concentrations in subcutaneous tissue and peritoneal fluid largely paralleled those in plasma (equilibration half-life, <30 min). The area under the curve (AUC) in subcutaneous tissue divided by the plasma AUC had a mean of 0.721. For peritoneal fluid, this AUC ratio had a mean of 0.943. Target attainment probabilities were >90% after 1 g meropenem every 8 h as a 15-min infusion for MICs of up to 2 mg/liter in plasma and peritoneal fluid and 0.5 mg/liter in subcutaneous tissue. Meropenem pharmacokinetics in plasma and peritoneal fluid of obese patients was predictable, but subcutaneous tissue penetration varied greatly. (This study has been registered at ClinicalTrials.gov under registration no. NCT01407965.)

Pharmacokinetics of Ertapenem in Colorectal Tissue

Background: There are only limited data on tissue kinetics of ertapenem in colorectal tissue more than 3 h after administration of the drug. The purpose of this study was to assess the pharmacokinetics (PK) of ertapenem in colorectal tissue via population PK modeling. Patients and Methods: Patients ≧18 years requiring surgical intervention at the colon and/or rectum were eligible (ClinicalTrials.gov identifier: NCT 00535652). Tissue and blood samples were taken during surgery after a single dose of 1 g ertapenem. Ertapenem concentration was determined by high-performance liquid chromatography/mass spectrometry. Population PK modeling was performed in S-ADAPT. Results: Twenty-three patients were enrolled. The highest tissue concentration was 6.4 ± 2.3 mg/kg, the highest total plasma concentration 51.34 ± 9.4 mg/l, the highest unbound plasma concentration 7.05 ± 1.1 mg/l, and the unbound fraction in plasma was 14–15% for total ertapenem concentrations below approximately 22 mg/l, 19% at 100 mg/l, and 25% at 250 mg/l. The estimated geometric mean terminal half-life was 2.5 h for plasma and tissue. In the Monte Carlo simulation, a single dose of 1,000 mg ertapenem achieved robust (≧90%) probabilities of target attainment up to a minimum inhibitory concentration (MIC) of approximately 2 mg/l for the bacteriostasis target (free time above MIC, fT>MIC = 20%) and up to 0.25–0.5 mg/l for the near-maximal killing target (40% fT>MIC). Conclusion: Our data indicate an adequate penetration of ertapenem into uninfected colorectal tissue up to 8.5 h (35% of the dosing interval) after administration of 1 g intravenously.

Population Pharmacokinetics and Target Attainment of Ertapenem in Plasma and Tissue Assessed via Microdialysis in Morbidly Obese Patients after Laparoscopic Visceral Surgery

ABSTRACT Ertapenem provides broad-spectrum activity against many pathogens, and its use is relevant for the prophylaxis and treatment of infections in morbidly obese patients undergoing surgery. However, its pharmacokinetics and tissue penetration in these patients are not well defined. We assessed the population pharmacokinetics and target attainment for ertapenem in the plasma, subcutaneous tissue, and peritoneal fluid of morbidly obese patients. Six female patients (body mass index, 43.7 to 55.9 kg/m2) received 1,000 mg ertapenem as 15-min infusions at 0 and 26 h. On day 2, the unbound ertapenem concentrations in plasma, subcutaneous tissue, and peritoneal fluid were measured by microdialysis; total plasma concentrations were additionally quantified. The probability of attaining a target of an unbound ertapenem concentration above the MIC for at least 40% of the dosing interval was predicted via Monte Carlo simulations. The population pharmacokinetic model contained two disposition compartments and simultaneously described all concentrations. For unbound ertapenem, total clearance was 12.3 liters/h (coefficient of variation, 21.6% for between-patient variability) and the volume of distribution at steady state was 57.8 liters in patients with a 53-kg fat-free mass. The area under the concentration-time curve (AUC) for ertapenem was 49% lower in subcutaneous tissue and 25% lower in peritoneal fluid than the unbound AUC in plasma. Tissue penetration was rapid (equilibration half-life, <15 min) and was variable in subcutaneous tissue. Short-term ertapenem infusions (1,000 mg every 24 h) achieved robust (>90%) target attainment probabilities for MICs of up to 1 mg/liter in plasma, 0.25 to 0.5 mg/liter in subcutaneous tissue, and 0.5 mg/liter in peritoneal fluid. Ertapenem presents an attractive choice for many pathogens relevant to morbidly obese patients undergoing surgery. (This study has been registered at ClinicalTrials.gov under identifier NCT01407965.)

Brain metastases in gastrointestinal cancers: is there a role for surgery?

About 10% of all cancer patients will develop brain metastases during advanced disease progression. Interestingly, the vast majority of brain metastases occur in only three types of cancer: Melanoma, lung and breast cancer. In this review, we focus on summarizing the prognosis and impact of surgical resection of brain metastases originating from gastrointestinal cancers such as esophageal, gastric, pancreatic and colorectal cancer. The incidence of brain metastases is <1% in pancreatic and gastric cancer and <4% in esophageal and colorectal cancer. Overall, prognosis of these patients is very poor with a median survival in the range of only months. Interestingly, a substantial number of patients who had received surgical resection of brain metastases showed prolonged survival. However, it should be taken into account that all these studies were not randomized and it is likely that patients selected for surgical treatment presented with other important prognostic factors such as solitary brain metastases and exclusion of extra-cranial disease. Nevertheless, other reports have demonstrated long-term survival of patients upon resection of brain metastases originating from gastrointestinal cancers. Thus, it appears to be justified to consider aggressive surgical approaches for these patients.

Chondroid hamartoma of the liver.

A 60-year-old patient presented with a solitary mass within the right hepatic lobe. Diagnostic imaging revealed a solid tumor on the diameter of 3 cm. In absence of any extrahepatic manifestation and based on FNAC findings the lesion was classisfied a primary hepatic chondroid sarcoma. However, after right hemihepatectomy histologic assessment resulted the final diagnosis of a benign chondroid hamartoma. Our findings add another variant to the versatile phenotype of liver hamartoma.

Overstaging: A Challenge in Rectal Cancer Treatment

Background: Preoperative staging, including computed tomography (CT), magnetic resonance imaging (MRI), and endoscopic ultrasound (EUS), is decisive to envisage the therapeutic concept for rectal cancer (RC). Overstaging may subject the patient to neoadjuvant therapy that does not improve survival but may lead to therapy-associated morbidity. Methods: This study retrospectively compares and values EUS, CT, and MRI in Union Internationale Contre le Cancer (UICC) stage I-III RC with a focus on overstaging. RC patients receiving primary operation only at the University Clinic Ulm were analyzed. The therapeutic relevance of preoperative staging was determined by comparison with postoperative pathological workup. Results: 244 examinations in 184 RC patients (EUS: n = 63, CT: n = 143, MRI: n = 38) revealed therapy-relevant overstaging into the T3/4 category in 10 (16%) EUS, 18 (13%) CT, and 10 (26%) MRI cases. Patients were upgraded to the N+ category in 13 (21%) EUS, 29 (20%) CT, and 11 (29%) MRI cases. As a result, UICC stages II and III turned out to be overstaged in 13 (21%) EUS, 18 (13%) CT, and 10 (26%) MRI cases. Conclusion: More than 10% therapy-relevant overstaging by any method represents a major challenge for modern RC therapy. Physicians should scrupulously consider this fact in their treatment considerations to avoid overtreatment.