Fc-Silent Anti-CD154 Domain Antibody Effectively Prevents Nonhuman Primate Renal Allograft Rejection.

The advent of costimulation blockade provides the prospect for targeted therapy with improved graft survival in transplant patients. Perhaps the most effective costimulation blockade in experimental models is the use of reagents to block the CD40/CD154 pathway. Unfortunately, successful clinical translation of anti-CD154 therapy has not been achieved. In an attempt to develop an agent that is as effective as previous CD154 blocking antibodies but lacks the risk of thromboembolism, we evaluated the efficacy and safety of a novel anti-human CD154 domain antibody (dAb, BMS-986004). The anti-CD154 dAb effectively blocked CD40-CD154 interactions but lacked crystallizable fragment (Fc) binding activity and resultant platelet activation. In a nonhuman primate kidney transplant model, anti-CD154 dAb was safe and efficacious, significantly prolonging allograft survival without evidence of thromboembolism (Median survival time 103 days). The combination of anti-CD154 dAb and conventional immunosuppression synergized to effectively control allograft rejection (Median survival time 397 days). Furthermore, anti-CD154 dAb treatment increased the frequency of CD4+ CD25+ Foxp3+ regulatory T cells. This study demonstrates that the use of a novel anti-CD154 dAb that lacks Fc binding activity is safe without evidence of thromboembolism and is equally as potent as previous anti-CD154 agents at prolonging renal allograft survival in a nonhuman primate preclinical model.

[Is vocational reintegration of young cancer patients possible?]. / Lassen sich junge Tumorpatienten beruflich reintegrieren?

BACKGROUND: Besides an improvement in quality of life, one of the major targets of rehabilitation programmes is to preserve the ability to work and to integrate the patient into working life again. Cancer in particular is often associated with a loss of employment and joblessness, frequently caused by incomplete rehabilitation. METHODS: The programme is aimed at young cancer patients aged between 18 and 40 years. In addition to medical rehabilitation, they undergo a specially developed programme which they complete in groups of no more than 5 persons. At baseline and at the end of the 3 weeks rehabilitation, tests on physical and mental capacity are conducted. During rehabilitation, different training programmes concerning mobility at work, fine motor skills and cognitive abilities are held, complemented by an intensive psycho-social training programme. Additionally, patients receive individual social counselling. RESULTS: So far, 34 patients with an average age of 31.8 years have participated in the programme, 65% of them suffering from malignant haematological diseases. The combination of a medical and a vocational rehabilitation programme was judged extremely positively by the participants, which remained the case 6 months after completion of the programme. The rehabilitation programme significantly reduced work incapacity periods: at baseline, only 6% of the participants had not experienced such periods, but after 3 and 6 months, this rate had increased to 61% and 62% respectively. This was accompanied by an increased health-related quality of life and reduced fatigue. CONCLUSION: With our pilot project we were able to show that such a programme is feasible, can be well integrated into clinical routine and is successful.

Tobramycin pharmacokinetics in patients with cystic fibrosis before and after bilateral lung transplantation.

STUDY OBJECTIVES: To compare the pharmacokinetics (PK) of tobramycin in patients with cystic fibrosis (CF) before and after bilateral lung transplantation, in order to evaluate optimal dosing practices post transplant. DESIGN: Retrospective, single-center, chart review study, in which tobramycin concentrations from CF patients were used to calculate PK parameters, including elimination rate constant, half-life, volume of distribution (Vd), area under the curve (AUC), and clearance before and after lung transplantation. SETTING: Medical school-affiliated teaching hospital. PATIENTS: Eight patients with CF, who received a bilateral lung transplant from January 1, 2005 through August 1, 2009 (4 males, 4 females; mean age 26.3 years). INTERVENTIONS: None. MAIN RESULTS: Sixty-nine sets of pre- (n=52) and post transplant (n=17) tobramycin concentrations were available. PK parameters were significantly altered post transplant. Elimination rate constant decreased 38% from 0.26±0.1 to 0.16±0.1 h(-1) (P<0.001), with a related increase of 200% in half-life from 2.8±0.8 to 8.4±8.7 h (P<0.001). Clearance decreased 25% post transplant from 67.3±32.3 to 50.2±15.9 mL/min (P=0.04). No statistically significant change occurred in AUC or Vd after transplant, although a trend was seen toward increased Vd. Dosage requirements after transplantation were significantly lower, 10.7±2.5 and 7.6±1.6 mg/kg/day, pre and post transplant, respectively (P<0.001). Concentrations were also evaluated in 2 time periods: 0-3 weeks and ≥6 weeks post transplant, based on available data. Clearance and Vd ≥6 weeks post transplant did not significantly differ from pre-transplant values (P=0.28 and 0.54, respectively), suggesting that these changes may be temporary. CONCLUSIONS: The results suggest that tobramycin PK are altered in patients with CF after bilateral lung transplantation, although no clear trend was seen owing to inter-patient variability. We propose that PK parameters should be reassessed during each treatment course post transplant.

CpG stimulates protective immunity in Balb/cJ mice infected with larval Taenia crassiceps.

Balb/cJ mice infected in the peritoneal cavity with larval Taenia crassiceps fail to mount a protective immune response. In mice, inflammatory immune responses are believed to control larval reproduction, whereas antibody-mediated responses are believed to be permissive. In the present study, mice were treated with CpG-oligodeoxynucleotides (CpG) to determine whether stimulation of the innate inflammatory response would confer increased resistance to larval growth. Female mice treated with CpG displayed a decrease in mean parasite burden by 54%, while male mice displayed a 73% reduction. Moreover, 5 of 12 CpG-treated male mice completely eliminated all larvae by 9 wk post-infection. In contrast, no female animals were found to be infection free. CpG treatment induced an increase in the transcript levels of tumor necrosis factor-α and inducible nitric oxide synthase (iNOS) from splenocytes and resulted in elevated levels of the proinflammatory molecules monocyte chemotactic protein (MCP)-1, MCP-3, and interleukin-6 at the site of infection. Additionally, CpG administration induced the enhanced recruitment of neutrophils and macrophages to the site of infection. The finding that both neutrophils and macrophages were recruited in significantly higher numbers in the male host as compared to the female host may explain the increased level of protection realized in male animals in response to CpG treatment.

Prostate cancer detection using an extended prostate biopsy schema in combination with additional targeted cores from suspicious images in conventional and functional endorectal magnetic resonance imaging of the prostate.

The purpose of this study is to report our method in detecting prostate cancer (PCa) using an 18-core transrectal ultrasound (TRUS) prostate biopsy (PB) schema, in combination with additional targeted cores from suspicious images in conventional (e-cMRI) and functional (e-fMRI) endorectal magnetic resonance imaging (e-MRI) of the prostate. From 2004 to 2008, 260 consecutive patients with a clinical suspicion of PCa underwent PB and were prospectively studied. e-cMRI and e-fMRI was performed in all patients before PB. The patients were divided into two groups (A and B) according to the results of their radiological findings (group A=suspicious findings, group B=non-suspicious findings). After the images were processed, an 18-core TRUS-guided PB was performed. When a patient exhibited a suspicious site on e-cMRI and e-fMRI images, three additional targeted PBs were obtained from that site. In group A, 17.5% of PCa was detected by the 18-core PB and 56.5% of PCa was detected by the targeted cores. The overall PCa detection rate (18+targeted cores) was 73.9%. The overall specificity was 73.9%. In group B, overall false-positive detection rate reached 19.2%, with the overall sensitivity being 80.8%. The method described above is not only practical but also a promising modality in PCa detection. As seen, PCa was optimally detected when combining the 18-core and targeted-core PB schema together. Non-suspicious images do not rule out the probability of PCa, thus justifying a PB in these patients as well.

[Ascending pancreatitis with mediastinal and parapharyngeal involvement]. / Aszendierende Pankreatitis mit mediastinaler und parapharyngealer Beteiligung.

A male patient who had suffered from alcohol dependence for several years was transferred to the Magdeburg University Hospital with signs of sepsis. The main cause for this was a previously unsuccessfully treated acute episode of chronic pancreatitis. Diagnostic imaging showed a distended ascending abscess extending above the larynx. During interdisciplinary emergency surgery, the neck, mediastinum and abdomen were drained and the pancreatic abscess removed. Under drainage, antibiotic therapy and parenteral nutrition the patient made a full recovery.

A retrospective analysis of emergency double-balloon enteroscopy for small-bowel bleeding.

Although the role of emergency esophagogastroduodenoscopy (EGD) and colonoscopy for upper and lower gastrointestinal bleeding (GIB) is well defined, there are no data on the concept of emergency double-balloon enteroscopy (DBE) for small-bowel bleeding. The aim of this study was to retrospectively evaluate the concept of emergency DBE in overt obscure GIB and assess its impact on patient management. A total of 17 emergency DBEs for overt obscure GIB were carried out in ten patients (six women, four men; mean age 68 years, range 35 - 83). The following diagnoses were made: actively bleeding Dieulafoy lesions of the small bowel, n = 2; bleeding tumors, n = 4 (carcinoids n = 2, adenocarcinoma n = 1, lipoma n = 1); bleeding angiodysplasias and/or large arteriovenous malformation (AVM), n = 2; multiple ulcers, n = 1; and no diagnosis, n = 1. Endoscopic therapies included argon plasma coagulation (n = 6), injection of epinephrine (n = 3), and use of fibrin glue (n = 1). It appears that emergency DBE is technically feasible, facilitates both diagnosis and therapy and enables management of patients with massive overt obscure GIB. This study is a first step in establishing the concept of emergency DBE for patients with suspected small-bowel bleeding.

Small bowel polyps and tumours: endoscopic detection and treatment by double-balloon enteroscopy.

BACKGROUND: Double-balloon enteroscopy has allowed us not only to inspect deeply the small bowel but also to carry out interventions for diseases of the small bowel. AIM: To evaluate the utility of double-balloon enteroscopy for the diagnosis and therapy of these lesions. METHODS: All patients undergoing double-balloon enteroscopy for evaluation of small bowel polyps and tumours during a 3.75-year period at a university referral hospital were studied. The types of polyps and tumours as well as endoscopic technique of removal, surgery and complications were documented. RESULTS: The incidence of small bowel polyps and tumours in-patients undergoing DBE was 9.6%. A total of 40 double-balloon enteroscopy procedures were performed in 29 patients [13 female (44.8%), mean age 51 years, range 22-74]. The following lesions were found most frequently: adenomas in familial adenomatous polyposis syndrome, n = 8; hamartomas, n = 4 (Peutz-Jeghers and Cronkhite Canada syndromes), jejunal adenocarcinoma n = 5, neuroendocrine tumour n = 4 and others n = 6. CONCLUSIONS: The incidence of small bowel tumours in those in-patients who were undergoing double-balloon enteroscopy was 10%. Double-balloon enteroscopy is useful for the diagnosis and treatment of small bowel polyps and tumours.

Influence of hospital volume on the frequency of abdominoperineal resection and long-term oncological outcomes in low rectal cancer.

AIM: Studies analysing the outcome after resection of low rectal cancer that has not infiltrated the anal sphincter reveal poorer long-term outcomes after abdominoperineal resections (APR) in comparison with low anterior resections (LAR). Further, a relationship between the frequency of APR and LAR for low rectal cancer and hospital volume is known. Our aim was to investigate the independent impact of hospital volume and type of resection on oncological outcomes after resection of low rectal cancer. METHOD: In a prospective multi-centre observational study of 1557 patients with low rectal cancer undergoing LAR or APR, the long-term oncological outcomes were analysed for their dependence on hospital volume and type of procedure. RESULTS: Univariate analysis revealed that patients undergoing APR had a higher local recurrence rate (p = 0.022) and shorter disease-free survival (p < 0.001) than patients undergoing LAR, while hospital volume showed merely a tendency to impact the local recurrence rate (p = 0.060). With regard to disease-free survival, no dependence on hospital volume was to be found (p = 0.201). The rate of APR was significantly associated with hospital volume (p < 0.001). Multivariate analysis revealed an independent impact of hospital volume on local recurrence rate, while disease-free survival was influenced by the type of surgical procedure performed. CONCLUSION: In the surgical treatment of low rectal cancer the hospital volume has a major impact on outcome. The type of procedure does not affect the local recurrence rate but the disease free survival.

Balb/Cj male mice do not feminize after infection with larval Taenia crassiceps.

Balb/cJ mice fail to mount an immune response capable of clearing infection with larval Taenia crassiceps. Additionally, male Balb/cJ mice display a lag in larval growth of approximately 3 wk as compared to growth in female mice. It has been reported that male Balb/ cAnN mice generate a protective immune response early in infection, and become permissive to larval growth after they feminize (200-fold increase in serum estradiol and 90% decrease in serum testosterone). To determine if a different strain of Balb/c mice (Balb/cJ) also feminize, serum was collected from infected male mice for 16 wk and levels of 17-beta-estradiol and testosterone were measured via ELISA. In addition, the mounting responses of 12- and 16-wk infected male mice, as well as uninfected control mice, were determined after isolation with a female mouse. The results of these experiments show that male Balb/cJ mice do not feminize during infection with larval T. crassiceps. There was no significant change in serum levels of either 17-beta-estradiol or testosterone during the course of infection (> 16 wk). Moreover, there was no significant decrease in the number of times infected male mice mounted the female mouse as compared to uninfected controls. These results suggest that there may be variances between the substrains of Balb/c mice that lead to the phenotypic differences reported for male Balb/cJ and Balb/cAnN mice.

[Wilms' tumors in adults]. / Wilms-Tumoren im Erwachsenenalter.

Wilms' tumors develop from persistent, primitive metanephrogenic stem cells. Their biology and etiology in adults is still unknown even though remnants of primitive metanephrogenic tissue, which tends to malignancy, is suspected, and there are very few scientific studies on the biology of Wilms' tumors in adults. Such a tumor occurs at a rate of 0.2/million adults in Europe and the USA. In this article, we describe the course of the disease in two adults with histologically confirmed Wilms' tumors. Both patients underwent a radical nephrectomy followed by chemotherapy as indicated by the SIOP nephroblastoma study.

RORA, a large common fragile site gene, is involved in cellular stress response.

Common fragile sites (CFSs) are large genomic regions present in all individuals that are highly unstable and prone to breakage and rearrangement, especially in cancer cells with genomic instability. Eight of the 90 known CFSs have been precisely defined and five of these span genes that extend from 700 kb to over 1.5 Mb of genomic sequence. Although these genes reside within some of the most unstable chromosomal regions in the human genome, they are highly conserved evolutionarily. These genes are targets for large chromosomal deletions and rearrangements in cancer and are frequently inactivated in multiple tumor types. There is also an association between these genes and cellular responses to stress. Based upon the association between large genes and CFSs, we began to systematically test other large genes derived from chromosomal regions that were known to contain a CFS. In this study, we demonstrate that the 730 kb retinoic acid receptor-related orphan receptor alpha (RORA) gene is derived from the middle of the FRA15A (15q22.2) CFS. Although this gene is expressed in normal breast, prostate and ovarian epithelium, it is frequently inactivated in cancers that arise from these organs. RORA was previously shown to be involved in the cellular response to hypoxia and here we demonstrate changes in the amount of RORA message produced in cells exposed to a variety of different cellular stresses. Our results demonstrate that RORA is another very large CFS gene that is inactivated in multiple tumors. In addition, RORA appears to play a critical role in responses to cellular stress, lending further support to the idea that the large CFS genes function as part of a highly conserved stress response network that is uniquely susceptible to genomic instability in cancer cells.

Multicenter phase-I/II study using a combination of gemcitabine and docetaxel in metastasized and unresectable, locally advanced pancreatic carcinoma.

AIMS: To assess the maximum tolerability of a combined therapy regimen of gemcitabine and docetaxel, and to evaluate tumour response rate, survival time and tolerability in patients receiving these agents for advanced pancreatic carcinoma. PATIENTS AND METHODS: Patients (n=68) with pancreatic carcinoma (advanced and/or unresectable tumour growth or histopathologically diagnosed metastases) were enrolled in a multicenter phase-I (n=25) and phase-II study (n=43). Treatment during phase II of the study was continued until either complete tumour remission (CR), tumour progression, indicated clinically or by means of radiological imaging, or until unacceptable toxicity occurred. RESULTS: Phase I: the tolerability maximum of the combined agents was established at gemcitabine 1000 mg/m(2) and docetaxel 35 mg/m(2) with tolerable adverse events. Phase II: a total of 139 chemotherapy cycles were completed (mean, 3.2; range, 1-10). While CR was achieved in three of 43 patients (7%), in five further cases, partial remission (PR) was documented, amounting to an overall response rate (OR) of 18.6%. Eighteen patients showed stable disease (41.9%), whereas in 17 of 43 subjects (39.5%), primary tumour progression was detected. The median survival time was 9.0 months; the 1-year survival rate was 13.9% (six of 43 patients). These results were associated with a side-effect profile of moderate severity and acceptable quality of life (QOL). CONCLUSION: The combination of gemcitabine and docetaxel for chemotherapy in unresectable pancreatic carcinoma was well tolerated. Survival time and 1-year survival rate proved promising and the regimen appears suitable for further evaluation in a prospective phase-III study setting.

Effects of the angiogenesis inhibitor angiostatin on the growth of CC531 colon carcinoma cells in vitro and in a laparoscopic animal model of peritoneal carcinomatosis.

BACKGROUND: As angiogenesis is one of the key steps in tumor growth, invasion, and metastasis, antiangiogenic therapy is supposed to be an attractive approach for antitumor treatment. We investigated the cytotoxic, anti-adhesive, and anti-invasive effects of angiostatin in vitro and on intraperitoneal tumor growth in a laparoscopic rat model of peritoneal carcinomatosis using CC531 colon adenocarcinoma cells. METHODS: The in vitro adhesion and cytotoxicity assays were performed with microtiter plates, and the invasion assay with Transwell dual chambers. Normal saline was used as control. In in vivo experiments, CC531 adenocarcinoma cells were intraperitoneally given to Wistar Albino Glaxo rats after the establishment of a pneumoperitoneum. The animals received angiostatin in different doses intraperitoneally, and in some, angiostatin was additionally administered subcutaneously. Saline was used as control. After 21 days, the animals were euthanized to determine the intra-abdominal tumor weight. RESULTS: In in vitro experiments, there was no effect of angiostatin on the viability of tumor cells in the cytotoxicity assay, but there was a significant inhibition of tumor cell adhesion and invasion (p<0.05 and p<0.01) in all angiostatin concentrations. In in vivo experiments, an intraperitoneal application of 20 microg angiostatin, but not 10 microg, significantly (p<0.005) decreased the intraperitoneal tumor weight compared with controls. This effect was most pronounced after the combined intraperitoneal and subcutaneous applications. CONCLUSION: Angiostatin given intraperitoneally at a dose of 20 microg alone or in combination with subcutaneous application significantly diminishes intraperitoneal tumor growth in rats undergoing laparoscopy. This may offer additional therapeutic options for patients undergoing laparoscopic surgery for colorectal cancer.

Laparoscopic-endoscopic rendezvous resection of upper gastrointestinal tumors.

BACKGROUND: Endoscopic and laparoscopic local resection of gastric tumors has increasingly been performed in recent years. This article describes the technical considerations and early results of laparoscopic-endoscopic rendezvous resection of gastric lesions. PATIENTS AND METHODS: Rendezvous resection was performed in 26 patients with submucosal gastric tumors (n = 22) and early gastric cancer (n = 4). Laparoscopic wedge resection (LWR) was performed in 16 patients with anterior wall tumors and laparoscopic intragastric resection (LIR) in 7 patients with posterior wall tumors. Conversion to open surgery was carried out in 3 cases. RESULTS: Operation times were 53 min (range 35-115) for LWR and 83 min (range 56-130) for LIR, respectively. In submucosal lesions the mean tumor size was 36 mm (range 16-47) and in early gastric cancer 17.3 mm (range 16-20). Rendezvous resection was performed with curative intent and clear resection margins in all patients without lymphatic or vessel permeation. Postoperative complications occurred in 2 patients. After a mean follow-up of 22.8 months (range 2-71), no local recurrence or metastatic disease and no tumor-related death were observed. CONCLUSIONS: When selected properly, the laparoscopic-endoscopic approach is considered to be curative and safe for resection of localized gastric tumors.

Endoscopic treatment of a mid-esophageal diverticulum.

Mid-esophageal diverticulum is a medical rarity. Only patients in whom the condition is symptomatic should receive treatment. Minimally invasive surgery via a thoracoscopic approach is currently the preferred treatment for the condition. This case report describes a 63-year-old woman with a symptomatic mid-esophageal diverticulum, which was successfully treated by endoscopic diverticulotomy using a needle-knife through a flexible endoscope.

[The use of v.a.C.-system in wound management for borderline indications]. / Der Einsatz des V.A.C(R)-Systems im Wundmanagement bei Grenzindikationen.

Vacuum sealing has increasingly become established as a method adapted to treat acute and chronic wounds. Temporary sealing of the open abdomen represents an alternative therapeutic approach. The principle of inverse tissue expansion prevents ventral herniae from developing in the course of delayed abdominal-wall closure. In patients undergoing vascular surgery, the method can be uneventfully adopted in treating chronic ulcer following revascularisation. The accelerated healing process, while reducing the duration of therapy, turns out to be cost-efficient.

Effect of low molecular weight heparin on intra-abdominal metastasis in a laparoscopic experimental study.

BACKGROUND AND AIMS: Metastatization, adhesion, invasion, and growth of tumor cells involve a cascade of complex phenomena which may be affected. We investigated the effect of a low molecular weight heparin, reviparin, on intra-abdominal tumor growth and intra-abdominal metastasis in rats undergoing laparoscopy. METHODS: CC531 adenocarcinoma cells (5x10(6) cells/ml) were administered intraperitoneally to 150 Wistar Albino Glaxo rats, with 15 groups of animals each. During laparoscopy 1 ml saline containing 0.0, 0.5, 2.0,; 4.0, and 10 mg reviparin/kg b.w. was introduced intraperitoneally (i.p.), daily subcutaneously (s.c.), or combined. After 21 days the animals were killed and underwent autopsy, and the tumor weight and the number of metastases on the liver surface were determined. RESULTS: Tumor weight was significantly reduced by 4.0 and 10.0 mg/kg b.w. but not by 0.5 or 2.0 mg/kg b.w. compared to controls. Decreased metastatization was observed in all treated groups. These effects were most pronounced after the s.c. or combined i.p. and s.c. administration, whereas after a sole i.p. administration only the highest dose of 10 mg/kg b.w. induced a significant inhibition of tumor growth. CONCLUSION: Low molecular weight heparin given s.c. or in combination of i.p. lavage and s.c. injections significantly inhibits intra-abdominal tumor growth and intraperitoneal metastasis of CC531 adenocarcinoma cells in rats undergoing laparoscopy. This may offer additional therapeutic options for patients undergoing laparoscopic and also open cancer surgery.

(-)-PHCCC, a positive allosteric modulator of mGluR4: characterization, mechanism of action, and neuroprotection.

Group-III metabotropic glutamate receptors (mGluR4, -6, -7, and -8) modulate neurotoxicity of excitatory amino acids and beta-amyloid-peptide (betaAP), as well as epileptic convulsions, most likely via presynaptic inhibition of glutamatergic neurotransmission. Due to the lack of subtype-selective ligands for group-III receptors, we previously utilized knock-out mice to identify mGluR4 as the primary receptor mediating neuroprotection of unselective group-III agonists such as L-AP(4) or (+)-PPG, whereas mGluR7 is critical for anticonvulsive effects. In a recent effort to find group-III subtype-selective drugs we identified (+/-)-PHCCC as a positive allosteric modulator for mGluR4. This compound increases agonist potency and markedly enhances maximum efficacy and, at higher concentrations, directly activates mGluR4 with low efficacy. All the activity of (+/-)-PHCCC resides in the (-)-enantiomer, which is inactive at mGluR2, -3, -5a, -6, -7b and -8a, but shows partial antagonist activity at mGluR1b (30% maximum antagonist efficacy). Chimeric receptor studies showed that the binding site of (-)-PHCCC is localized in the transmembrane region.Finally, (-)-PHCCC showed neuroprotection against betaAP- and NMDA-toxicity in mixed cultures of mouse cortical neurons. This neuroprotection was additive to that induced by the highly efficacious mGluR1 antagonist CPCCOEt and was blocked by MSOP, a group-III mGluR antagonist. Our data provide evidence for a novel pharmacological site on mGluR4, which may be used as a target-site for therapeutics.