Multimodal tumor therapy in a 31-year-old pregnant woman with Wilms tumor.

Wilms tumor, or nephroblastoma, is the most common malignant tumor of the urinary tract in children, but is rarely found in adults. Here, we report the first case of a female patient with a Wilms tumor, diagnosed during pregnancy, who underwent radical nephrectomy and adjuvant chemotherapy before and after delivering a healthy child. Generally, treatment should follow the guidelines established for the pediatric setting.

[Value of cystoprostatectomy in locally advanced prostate carcinoma]. / Stellenwert der Zystoprostatektomie beim lokal fortgeschrittenen Prostatakarzinom.

Patients suffering from locally advanced prostate carcinoma are often stressed by debilitating local symptoms limiting their quality of life. At the same time life expectancy often exceeds several years, whereas urologists and oncologists tend to underestimate their patients' life expectancy. Cystoprostatectomy for locally advanced prostate carcinoma is a reasonable therapeutic option concerning frequency and kind of imminent complications and possibly alleviates or completely eliminates local symptoms in 80% or more. According to the literature cancer-specific 10-year survival rates are 38% or median cancer-specific survival lies between 24 and 31 months. The role of neoadjuvant or adjuvant hormonal therapy, chemotherapy, or radiotherapy has not yet been defined. Mostly after cystoprostatectomy due to locally advanced prostate carcinoma an ileal conduit is formed for urinary diversion, but also orthotopic neobladders or continent pouches are used. Incontinence rates for orthotopic neobladders may reach 50% and more. In synopsis cystoprostatectomy may be a viable therapeutic option for patients suffering from locally advanced prostate carcinoma. It surely is important that the indication for surgery is based on an individual decision.

Frequent loss of expression of the pro-apoptotic protein Bim in renal cell carcinoma: evidence for contribution to apoptosis resistance.

Renal cell carcinoma (RCC) is resistant to chemotherapy, and this resistance is mirrored by a high apoptosis resistance of many RCC lines in vitro. Here, we report the loss of the pro-apoptotic BH3-only protein Bim in a large part of clinical RCC cases and provide evidence for a functional relevance of this loss. Immunohistochemistry of clear cell renal cell carcinoma cases and corresponding normal kidney showed strong Bim reactivity in renal tubules of all cases but loss of Bim in 35 of 45 RCC samples. Out of nine RCC cell lines investigated, six showed strongly diminished or undetectable levels of Bim protein by western blotting. Four RCC lines of varying apoptosis sensitivity were analysed further. Bcl-2, Bcl-x(L), Mcl-1, Bax and Bak expression did not correlate with apoptosis sensitivity. All cell lines underwent apoptosis upon forced expression of Bax and Bim, suggesting an upstream difference. In all four lines, adriamycin induced p53 but not its targets Puma or Noxa. However, apoptosis sensitivity correlated with levels of Bim protein. Bim siRNA reduced apoptosis sensitivity in a susceptible cell line. Furthermore, inhibition of histone deacetylation restored Bim expression in cell lines. These data suggest that Bim has a function as a tumor suppressor in RCC.

Functional evaluation of the apoptosome in renal cell carcinoma.

Renal cell carcinoma (RCC) responds very poorly to chemo- or radiotherapy. Renal cell carcinoma cell lines have been described to be resistant to apoptosis-inducing stimuli and to lack caspase expression. Here, we provide a structural and functional assessment of the apoptosome, the central caspase-activating signalling complex and a candidate for apoptosis-inactivating mutations. Cells from RCC cell lines and clinical samples isolated from RCC patients were included. Apoptosome function was measured as quantitative activation of caspases in protein extracts. In all five cell lines and in 19 out of 20 primary clear cell RCC samples, the expression of apoptosome components and caspase activation appeared normal. Of the four nonclear cell RCC that could be included, both oncocytomas gave no response to cytochrome c (in one case, no Apaf-1 was detected), one chromophobe RCC lacked caspase-9 and failed to activate caspase-3 in response to cytochrome c, and one papillary RCC showed good caspase activation despite the lack of caspase-7. Experiments utilising a peptide derived from Smac/DIABLO gave no indication that inhibitor of apoptosis proteins might exert an inhibiting effect in primary clear cell RCC. Thus, the apoptosome signalling complex is intact in human (clear cell) RCC, and an apoptosis defect must be located at other, probably upstream, sites.

[Virtual endoscopy of the urinary tract]. / Die virtuelle Endoskopie des Harntrakts.

This review article depicts the technique of virtual uro-endoscopy and its diagnostic value and highlights future aspects. The raw data are acquired using CT, MR, or ultrasound. Sufficient contrast between the wall of the hollow organ and its interior is reached by administering gas or contrast medium into the bladder or injecting contrast media i.v. After processing of these data, virtual endoscopic procedures can be watched on a screen in the same way as a cine-film of a conventional endoscopic operation. Virtual endoscopy is a reliable method with a high sensitivity for pathologies larger than 0.5 cm. It is not invasive, and there are situations that cause difficulties in conventional endoscopy (e.g. gross hematuria, diverticula, strictures) that cause no technical problems in virtual endoscopy. Problems encountered in virtual endoscopy are due to its poor sensitivity for pathologies smaller than 0.5 cm, for carcinoma in situ, and for ureteral calculi. So far there are no routine-indications for virtual endoscopy in urology. Nevertheless, it can be of additional value in diagnosis providing the indications are carefully controlled. In future, virtual endoscopy will probably become integrated into the spectrum of urologic diagnostics investigations.

Massive chemokine transcription in acute renal failure due to polymicrobial sepsis.

Abdominal sepsis and septic shock are still major causes of mortality in intensive care units (ICU). Acute renal failure (ARF) is one of the hallmarks encountered in septic shock. The pathophysiological alterations leading to ARF are poorly understood. A novel murine model of polymicrobial sepsis (colon ascendens stent peritonitis [CASP]) was used to investigate functional renal parameters, renal chemokine transcription levels, and recruitment of inflammatory leukocytes in septic ARF. CASP was induced by inserting a 14-gauge stent into the colon ascendens of C57BL/6 mice, generating a septic focus resulting in polymicrobial sepsis. Mice were monitored for urine output and serum azotemia. Kidneys were harvested for analysis of leukocyte infiltration by immunohistochemistry and chemokine gene expression by RNase protection assay (3, 6, 12, and 18 h). CASP, but not sham-CASP, resulted in anuria immediately after surgery and in elevated serum creatinine and BUN detected 18 h after CASP surgery, confirming acute renal failure. Progressive induction of chemokine gene expression was observed for IP-10, MIP-2, MIP-1alpha, MIP-1beta, MCP-1, and RANTES peaking at 12 h with subsequent decrease. Immunohistochemistry revealed an accumulation of neutrophils and monocytes which had adhered to the renal vascular endothelium. Thus, acute renal failure in sepsis is accompanied by a marked upregulation of chemokines of the CC and CXC group within the kidney.

Ischemic spinal cord syndrome after transthoracic esophagectomy: two cases of a rare neurologic complication.

Anterior spinal artery syndrome (ASAS) is a rare complication after surgery of the thoracic or abdominal aorta. The sulco commissuralis syndrome represents a partial or incomplete ASAS. We report two cases of ischemic spinal cord syndromes after transthoracic esophagectomy. This represents a prevalence of this syndrome of 0.2% in more than 1000 consecutive esophagectomies performed at our institution. Patient 1 developed an ASAS on the first day after esophagectomy. Patient 2 showed the pathognomonic clinical signs associated with sulco commissuralis syndrome after an asymptomatic window. In both patients, the extent of the neurologic symptoms initially improved but then remained unchanged for the rest of the follow-up of 9 and 12 months. Although the prognosis of neurologic syndromes resulting from spinal cord infarction is poor, preoperative tests to identify patients at risk appear not to be justified because of the very low incidence of these syndromes after esophagectomy and the poor sensitivity and specificity of currently available diagnostic modalities. However, the possibility of ischemic spinal cord syndrome should be kept in mind when patients present with neurologic symptoms after esophagectomy.

Selective defects of T lymphocyte function in patients with lethal intraabdominal infection.

BACKGROUND: In recent models, compensatory antiinflammatory immune reactions triggered in response to systemic inflammation were considered important for the outcome of sepsis. The present study investigated T-cell functions in patients with postoperative sepsis due to intra-abdominal infection. METHODS: Peripheral T cells were purified from 32 sepsis patients and 41 healthy controls. Proliferation and production of interferon (IFN)-gamma, interleukin (IL)-2, IL-4, tumor necrosis factor (TNF), and IL-10 were stimulated by cross-linking of CD3 and CD28. RESULTS: T-cell proliferation and production of IL-2 and TNF were severely suppressed in patients with lethal intraabdominal infection as compared with survivors and healthy controls. Sepsis survivors showed normal T-cell proliferation and IL-2 release, whereas secretion of TNF was reduced. However, TNF suppression in survivors was less severe than in nonsurviving patients. Defective T-cell functions were observed at the onset of sepsis and persisted throughout the entire observation period. T-cell production of IL-4 and IL-10 was not affected by postoperative intraabdominal infection. CONCLUSIONS: Defective T-cell proliferation and secretion of IL-2 and TNF correlate with sepsis mortality, thus indicating an important role of T 'cells for the immune defense against postoperative infection. Immune defects were evident at the onset of sepsis, suggesting that immunosuppression may develop as a primary response to sepsis without preceding immune hyperactivity.

Impact of experimental peritonitis on bone marrow cell function.

BACKGROUND: The effects of abdominal sepsis on the regulation of cell turnover in bone marrow and on the function of hematopoietic stem cells were investigated. METHODS: In a new mouse model of abdominal sepsis (colon ascendens stent peritonitis [CASP]) the proliferation, apoptosis, and colony-forming capacity of bone marrow cells were determined. RESULTS: Both experimental peritonitis and sham surgery increased proliferation of bone marrow cells significantly (P < .01). Incubation with granulocyte-macrophage colony-stimulating factor but not granulocyte colony-stimulating factor further augmented proliferation of bone marrow cells from septic mice. In contrast to cell proliferation, bone marrow cell apoptosis was significantly (P < .001) increased in response to CASP but not to sham surgery. CASP surgery and treatment of normal bone marrow cells with lipopolysaccharide, tumor necrosis factor-alpha, interleukin 1 beta, and interferon gamma increased the number of apoptotic cells to a similar extent. Stem cell assays revealed that during the late phase of peritonitis the colony formation by granulocytic-monocytic precursors was increased, whereas mature erythroid colony-forming cells were suppressed. Incubation of normal bone marrow cells with lipopolysaccharide and cytokines showed similar effects. CONCLUSIONS: These results reveal differential effects of experimental peritonitis on various hematopoietic lineages and suggest a potential role of inflammatory mediators for the dysregulation of bone marrow cell function during abdominal sepsis.

Mechanisms of acute inflammatory lung injury induced by abdominal sepsis.

Sequestration of neutrophils and release of histotoxic mediators are considered important for the development of pathologic alterations of the lung defined as adult respiratory distress syndrome. Mechanisms of inflammatory lung injury caused by abdominal sepsis were investigated using the colon ascendens stent peritonitis (CASP) model that closely mimics the human disease. In the CASP model, a continuous leakage of intraluminal bacteria into the peritoneal cavity is induced by implantation of a stent in the ascending colon, generating a septic focus. In contrast to the cecal ligation and puncture model of peritonitis, survival of mice following CASP surgery is dependent on IFN-gamma, but independent of tumor necrosis factor (TNF). Here we show that the systemic inflammation induced by CASP surgery results in a rapid and profound increase of lung vascular permeability that was associated with the activation and recruitment of neutrophils to the lung. Activation of circulating granulocytes was characterized by increased production of serine proteinases and reactive oxygen metabolites, as well as elevated expression of cell surface Mac-1. Expression of MIP-2, KC, MIP-1alpha and E-selectin mRNA in lung was strongly increased within 3 h following CASP surgery, whereas up-regulation of IP-10, MCP-1 and P-selectin was delayed. In contrast, induction of RANTES, LIX, ICAM-1 and VCAM-1 mRNA was weak or not detectable after CASP surgery. Importantly, recruitment of leukocytes to the lung was normal in lipopolysaccharide-resistant mice, and was not affected by antibody neutralization of TNF or the chemokines MIP-2 and KC.

Importance of T cells to accelerated rejection and acceptance of renal allografts in sensitized rat recipients.

BACKGROUND: Sensitized recipients often experience fulminant allograft loss by yet ill-defined cellular and/or humoral immune mechanisms. In this study, we analyzed the contribution of cellular elements, in particular T cells, to the accelerated rejection of renal allografts in sensitized rats. METHODS AND RESULTS: LEW rats sensitized with BN skin grafts died of uremia in 3.3+/-0.9 days after transplantation of a BN kidney, similarly to bilaterally nephrectomized animals. Adoptive transfer of 10(6) graft-infiltrating mononuclear cells as well as their CD25+ subset into otherwise normal LEW recipients accelerated rejection of BN test cardiac allografts (5.4+/-0.5 days to 6.6+/-0.4 days vs. 7.8+/-0.8 days in controls, P<0.0007), while the CD25- population was ineffective (8.0+/-0.6 days, NS). Furthermore, alpha/beta-T-cell receptor (TCR)-targeted therapy with R73 monoclonal antibody abrogated accelerated rejection, and produced long-term survival in sensitized animals treated before kidney engraftment (day -7 to day -1). Long-term survival was associated with an up-regulation of intragraft interleukin-4 and interleukin-10 expression in conjunction with depressed Th-1-type cytokines. In addition, alpha/beta-TCR-targeted therapy even in low subtherapeutic dose decreased IgM alloantibody levels, and prevented the switch from IgM to IgG alloantibody response. CONCLUSIONS: This is the first report that documents the striking efficacy of alpha/beta-TCR-targeted therapy in sensitized rat renal transplant recipients. The results provide evidence for a critical role of T cells for both accelerated rejection and long-term graft survival. Up-regulation of Th2-type cytokine profile may, at least in part, contribute to the acquisition of immune unresponsiveness after alpha/beta-TCR-targeted therapy in this well-defined rat renal transplant model.

Increased susceptibility to postoperative sepsis in patients with impaired monocyte IL-12 production.

IL-12 is a potent immunoregulatory cytokine that is essential for the development of protective immunity, as demonstrated by numerous animal models of infection. Here, we provide evidence for a critical role of IL-12 in human sepsis. The results of a prospective study of 184 patients undergoing major elective surgery of the upper and lower gastrointestinal tract revealed that, in contrast to patients showing uneventful recovery, monocyte IL-12 production was severely and selectively impaired in patients developing postoperative sepsis. Moreover, the extent of monocyte IL-12 suppression correlated with the severity of postoperative sepsis. Monocyte IL-12 secretion was suppressed before surgery and remained low until the onset of sepsis. Therefore, the suppression of IL-12 secretion preceded the onset of postoperative sepsis but did not occur as a consequence of major surgery. In contrast, IL-1beta production was only reduced during the late postoperative course in patients developing postoperative sepsis, and TNF-alpha release was even increased at different time intervals before the onset of sepsis. Thus, reduced IL-12 release does not reflect a general defect in monocyte cytokine production. Consequently, these results establish a critical role for IL-12 in early resistance to postoperative infection and may allow for the development of novel therapeutic strategies designed to stimulate host defense mechanisms and to reduce the incidence and severity of septic complications.

Synergism of the malononitrilamides 279 and 715 with cyclosporine A in the induction of long-term cardiac allograft survival.

We tested here the effects of malononitrilamide (MNA) 279 and MNA 715 (derivatives of A771726, the active metabolite of leflunomide) in monotherapy and in combination with cyclosporine A (CSA) on heterotopically transplanted rat cardiac allografts (BN) [Brown Norway Lewis]. Both MNAs (5-20 mg/kg) displayed a dose-dependent increase of efficacy. The combination of CSA (5 mg/kg) with the MNAs (5 and 10 mg/kg) showed a synergistic effect in the prolongation of allograft survival and in the induction of long-term allograft survival. To investigate the immunological mechanism responsible for long-term allograft survival, we transplanted second set (BN) and third party (Dark Agouti) skin allografts on the tail of long-term surviving rats. The cause for long-term allograft survival turned out to be a donor-specific tolerance. We formulate a hypothesis for the mechanism of the synergism of the combination MNA + CSA in the induction of tolerance.

Essential role of gamma interferon in survival of colon ascendens stent peritonitis, a novel murine model of abdominal sepsis.

Despite considerable progress, peritonitis and sepsis remain life-threatening conditions. To improve the understanding of the pathophysiology encountered in sepsis, a new standardized and highly reproducible murine model of abdominal sepsis termed colon ascendens stent peritonitis (CASP) was developed. In CASP, a stent is inserted into the ascending colon, which generates a septic focus. CASP employing a stent of 14-gauge diameter (14G stent) results in a mortality of 100% within 18 to 48 h after surgery. By inserting stents of small diameters, mortality can be exactly controlled. Thus, CASP surgery with insertion of a 22G or 18G stent (22G or 18G CASP surgery) results in 38 or 68% mortality, respectively. 14G CASP surgery leads to a rapid invasion of bacteria into the peritoneum and the blood. As a consequence, endotoxemia occurs, inflammatory cells are recruited, and a systemic inflammatory response syndrome develops. Interestingly, the most pronounced upregulation of inflammatory cytokines (gamma interferon [IFN-gamma], tumor necrosis factor alpha [TNF-alpha] and interleukin-12) is observed in spleen and lungs. CASP surgery followed by stent removal at specific time intervals revealed that all animals survived if intervention was performed after 3 h, whereas removal of the septic focus after 9 h did not prevent death, suggesting induction of autonomous mechanisms of a lethal inflammatory response syndrome. 18G CASP surgery in IFN-gamma receptor-deficient (IFNgammaR-/-) mice revealed an essential role of IFN-gamma in survival of sepsis, whereas TNF receptor p55-deficient (TNFRp55-/-) mice did not show altered survival rates. In summary, this study describes a novel animal model that closely mimics human sepsis and appears to be highly suitable for the study of the pathophysiology of abdominal sepsis. Importantly, this model demonstrates a protective role of IFN-gamma in survival of bacterial sepsis.

[Special therapeutic approaches for interrupting the cascade--from systemic inflammatory response syndrome to multiple organ failure]. / Spezielle Therapieansätze zur Durchbrechung der Kaskade--Von SIRS zu MOF.

SIRS, sepsis and MOF are clinical sequelae related to persistent, uncontrolled inflammation. Therefore, different strategies for treatment were designed to block the cascade from SIRS to MOF (anti-inflammatory therapies). However, clinical trials using these agents have failed to demonstrate any benefit. In sepsis the body also mounts an anti-inflammatory response, which has been largely ignored. If the anti-inflammatory reaction is sufficiently severe, we might increase the susceptibility to infection or even exacerbate immunosuppression by using anti-inflammatory agents. In contrast, agents to stimulate the immune system--like IFN-gamma or G-SCF--may prove beneficial.

alpha/beta-T cell receptor-directed therapy in rat allograft recipients. Long-term survival of cardiac allografts after pretreatment with R73 mAb is associated with upregulation of Th2-type cytokines.

Rejection of vascularized allografts still poses the major problem in organ transplantation. Therefore, transplant rejection of cardiac allografts was investigated in a rat model (BN-to-LEW) under alpha/beta-TCR (R73) mAb-targeted therapy. Two protocols were studied: posttransplant ("immunosuppressive") and pretransplant conditioning therapy. In posttransplant therapy over a wide dose range, R73 mAb only marginally improved cardiac allograft survival (7.8 +/- 0.8 days vs. 12.5 +/- 0.8 days at 0.1 mg/kg for 7 days). In contrast, conditioning treatment with low-dose (0.1 mg/kg) anti-alpha/beta-TCR mAb given 3 to 7 days prior to organ transplantation was highly effective and resulted in 50% permanent acceptance of cardiac allografts. R73 mAb-treated rats were monitored with respect to peripheral lymphocyte populations and intragraft cytokine levels. A temporary, incomplete reduction (CD5+ cells) and partial modulation (alpha/beta-TCR/CD5 double+ cells) in the peripheral blood was observed. In contrast to untreated controls, intragraft production of IL-2 and IFN-gamma at the mRNA and protein level was abolished in both post- and pretreated recipients. Interestingly, pretransplant mAb application was associated with augmented in situ elaboration of the Th2-type cytokines, IL-4 and IL-10, together with up-regulated TGF-beta and PGE. Increased expression of IL-4 and IL-10 continued to be observed in long-term surviving allografts. In conclusion, the mechanism of conditioning therapy with alpha/beta-TCR mAb prior to alloantigen exposure appears to be a switch from Th1 to Th2 response allowing long-term acceptance of allogeneic grafts.

alpha/beta-T cell receptor-directed therapy in rat cardiac allograft recipients. Treatment prior to alloantigen exposure prevents sensitization and abrogates accelerated rejection.

An mAb directed to the alpha/beta-heterodimer of the rat T cell receptor was used to prevent rejection of cardiac allografts in sensitized (accelerated rejection) recipients. Over a wide dose range, alpha/beta-TCR-directed therapy abrogated accelerated rejection at 24-36 hr and extended cardiac allograft survival in a dose-dependent fashion, both when given after heart transplantation as well as during or before the sensitizing skin transplants (8.9 +/- 1.0 days, 12.7 +/- 0.6 days, or 8.7 +/- 1.5 days, respectively). Pretreatment with R73 completely abrogated host sensitization induced by skin grafting. As a result, post-heart transplant cyclosporine course (15 mg/kg for 7 day) has led to long-term graft acceptance (> 90 days vs. 15.2 +/- 1.6 days with postoperative CsA therapy alone). Administration of R73 mAb produced incomplete depletion (CD5+ cells) and partial modulation (alpha/beta-TCR/CD5 double-positive cells) in the peripheral blood. It suppressed in situ protein expression of many cytokines to background levels, in particular that of IL-2 and IFN-gamma, both when given after as well as before cardiac transplantation. However, only pretransplant mAb application was associated with augmented in situ elaboration of IL-4. alpha/beta-TCR-directed therapy induced strong host anti-idiotypic and, to a lesser degree, anti-isotypic antibody responses. Taken together, these results provide the rationale for a novel immunosuppressive strategy involving induction of hyporesponsiveness by alpha/beta-TCR-directed therapy before the alloantigenic exposure.