Parenchymal sparing surgery in patients with hereditary renal cell carcinoma: 10-year experience.

PURPOSE: von Hippel-Lindau disease, hereditary papillary renal cell carcinoma, the Birt-Hogg-Dubé syndrome and familial renal oncocytoma are familial renal tumor syndromes. These hereditary disorders are noteworthy for the development of multiple bilateral renal tumors and the risk of new tumors throughout life. One management strategy is observation of solid renal tumors until reaching 3 cm, then performing parenchymal sparing surgery. We present a 5-year update on our experience. MATERIALS AND METHODS: From May 1988 to October 1998, 49 patients with hereditary renal cell carcinoma, including von Hippel-Lindau disease in 44, hereditary papillary renal cell carcinoma in 4 and the Birt-Hogg-Dubé syndrome in 1, and 1 with familial renal oncocytoma underwent exploration to attempt renal parenchymal sparing surgery. Patients were followed prospectively with periodic screening for recurrence, metastasis and loss of renal function. Median followup was 79.5 months (range 0.7 to 205). RESULTS: A total of 50 patients underwent 71 operations resulting in unilateral nephrectomy in 6, bilateral nephrectomy in 1 and partial nephrectomy in 65, with 1 to 51 tumors removed from each kidney (mean 14.7). Mean patient age was 39.5 years (range 18 to 70). Of the 65 (40%) partial nephrectomies 26 were performed with cold renal ischemia. Mean blood loss was 2.9 +/- 0.5 l (range 0.15 to 23). Postoperative complications included renal atrophy in 3 patients. Mean preoperative serum creatinine was 1.05 +/- 0.03 mg/dl (range 0.6 to 1.8), and postoperative creatinine was 1.06 +/- 0.04 mg/dl (range 0.6 to 2.0). No patient who underwent renal parenchymal sparing surgery required renal replacement therapy. Metastatic disease developed in 1 patient with a 4.5 cm renal tumor. CONCLUSIONS: Parenchymal sparing surgery with a 3 cm threshold in patients with hereditary renal cancer appears to be an effective therapeutic option to maximize renal function while minimizing the risk of metastatic disease.

Molecular analysis of the von hippel-lindau disease gene.

Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder that predisposes the affected individual to develop characteristic tumors. These include CNS hemangioblastoma, retinal angiomas, endolymphatic sac tumors, pancreatic cysts and tumors, epididymal cystadenomas, pheochromocytomas, renal cysts, and clear-cell renal carcinoma. The VHL gene was localized to 3p25 and then isolated by Latif et al. (1). The gene contains three exons with an open reading frame of 852 nucleotides, which encode a predicted protein of 284 amino acids. The VHL protein is believed to have several functions. It is involved in transcription regulation through its inhibition of elongation by binding to the B and C subunits of elongin. Mutations of VHL allow the B and C subunits to bind with the A subunit. This complex then overcomes "pausing" of RNA polymerase during mRNA transcription (2,3). Several studies suggest that the VHL protein is also involved in regulation of hypoxia-inducible transcripts, particularly vascular endothelial growth factor (VEGF), by altering mRNA stability (4,5). Therefore, VHL gene mutations permit the overexpression of VEGF under normoxic conditions, which leads to the angiogenesis believed to be required for tumor growth. The VHL-elongin BC complex (VBC) also binds two other proteins-CUL2 and Rbx1-in a complex that has structural similarity to other E3 ubiquitin ligase complexes (6). Such complexes mediate the degradation of cell-cycle regulatory proteins.

Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation.

BACKGROUND: Since allogeneic stem-cell transplantation can induce curative graft-versus-leukemia reactions in patients with hematologic cancers, we sought to induce analogous graft-versus-tumor effects in patients with metastatic renal-cell carcinoma by means of nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. METHODS: Nineteen consecutive patients with refractory metastatic renal-cell carcinoma who had suitable donors received a preparative regimen of cyclophosphamide and fludarabine, followed by an infusion of a peripheral-blood stem-cell allograft from an HLA-identical sibling or a sibling with a mismatch of a single HLA antigen. Cyclosporine, used to prevent graft-versus-host disease, was withdrawn early in patients with mixed T-cell chimerism or disease progression. Patients with no response received up to three infusions of donor lymphocytes. RESULTS: At the time of the last follow-up, 9 of the 19 patients were alive 287 to 831 days after transplantation (median follow-up, 402 days). Two had died of transplantation-related causes, and eight from progressive disease. In 10 patients (53 percent) metastatic disease regressed; 3 had a complete response, and 7 had a partial response. The patients who had a complete response remained in remission 27, 25, and 16 months after transplantation. Regression of metastases was delayed, occurring a median of 129 days after transplantation, and often followed the withdrawal of cyclosporine and the establishment of complete donor-T-cell chimerism. These results are consistent with a graft-versus-tumor effect. CONCLUSIONS: Nonmyeloablative allogeneic stem-cell transplantation can induce sustained regression of metastatic renal-cell carcinoma in patients who have had no response to conventional immunotherapy.

Periurethral collagen injection for the treatment of urinary incontinence in children.

PURPOSE: We assessed the efficacy and safety of periurethral collagen injection for urinary incontinence in children with neurogenic bladder dysfunction. MATERIALS AND METHODS: We treated 11 children (mean age 10.6 years) who had incontinence and neurogenic bladder dysfunction with periurethral injections of glutaraldehyde cross-linked collagen. All patients were on anticholinergics and all but 1 were on clean intermittent catheterization preoperatively. Four patients had previously undergone augmentation cystoplasty. All patients were assessed before and after injection with a subjective continence scale and multichannel urodynamics. Followup ranged from 4 to 20 months from the last injection. RESULTS: Mean group Valsalva leak point pressure was 34.5 cm. water. Four of the 11 patients had an identifiable detrusor leak point pressure. Overall success rate was 55% with 4 patients dry and 2 improved. Success correlated with a minimum increase in Valsalva leak point pressure of 20 to 25 cm. water to greater than 60 cm. water. Three patients had no demonstrable Valsalva leak point pressure after injection. All 5 patients in whom treatment failed had no change in Valsalva leak point pressure, including 2 with small capacity, poorly compliant bladders preoperatively. Because they had a component of sphincteric insufficiency, they underwent injection in the hope of increasing capacity with increased continence. In 3 patients Valsalva leak point pressure was greater than 50 cm. water. Detrusor leak point pressure developed in 3 patients postoperatively, including 1 with significantly increased Valsalva leak point pressure. One patient with significantly increased Valsalva leak point pressure had urethral hypermobility postoperatively. Of the 3 patients who subsequently underwent augmentation cystoplasty 1 is now dry, 1 is wet and 1 died of complications unrelated to urological disease. Patients underwent 1 to 4 procedures (mean 2.5). CONCLUSIONS: Periurethral collagen injection may be effective for urinary incontinence in patients who have adequate capacity with good compliance and low Valsalva leak point pressure. When there is no response to repeat injections or a transient response, one should consider the possibility of bladder decompensation.

A randomized, controlled trial of IL-10 in humans. Inhibition of inflammatory cytokine production and immune responses.

In vitro, IL-10 inhibits T cell proliferation and LPS-induced monocyte production of IL-1, TNF-alpha, IL-6, and IL-8. We studied the safety and immunomodulatory effects of IL-10 administration in humans. Seventeen healthy volunteers received a single i.v. bolus injection of either human IL-10 (1, 10, or 25 micrograms/kg) or placebo. Routine safety parameters, lymphocyte phenotypes, T cell proliferative responses, and stimulus-induced cytokine production were assessed before and 3, 6, 24, and 48 h after injection. There were no adverse symptoms or signs after IL-10 administration. A transient neutrophilia and monocytosis that peaked at 6 h (45-160% above base line) was observed. However, lymphocyte counts fell by 25% 3 and 6 h after the injection (p < 0.01). In particular, lymphocytes expressing the T cell surface markers CD2, CD3, CD4, CD7, and CD8 were significantly decreased. Mitogen-induced T cell proliferation was suppressed by up to 50% (p < 0.01) in the two higher dose groups. Significant dose-dependent inhibition (65-95%) of TNF-alpha and IL-1 beta production from whole blood stimulated ex vivo with endotoxin occurred after each dose of IL-10. In contrast, there was no reduction in the production of their respective antagonists, TNF soluble receptor p55 or IL-1 receptor antagonist. We conclude that a single intravenous injection of IL-10 is safe in humans, has inhibitory effects on T cells, and suppresses production of the pro-inflammatory cytokines TNF-alpha and IL-1 beta.

Viral infections in the intensive care unit.

Serious viral infections requiring intensive care generally occur in immunocompromised patients and in those patients with underlying cardiopulmonary disease. However, occasional cases may occur in normal hosts. This article reviews the serious viral diseases that are commonly encountered in the adult ICU, including viral pneumonia, encephalitis, and hepatitis, and focuses on diagnostic techniques and management principles. A separate section is devoted to cytomegalovirus infection, given the prominent role that this virus plays in the immunocompromised host receiving intensive care.

Blood donation and transfusion practices: the 1990 American Association of Blood Banks Institutional Membership Questionnaire.

Responses to the 1990 American Association of Blood Banks (AABB) Institutional Membership Questionnaire were submitted by 2126 regional blood centers, hospital-based blood banks, and transfusion facilities. Data from 2117 of these facilities were considered to be valid. The questionnaire included information on blood donor demographics, number of units collected, and collection procedures; services performed; usage of blood components; and transfusion-transmitted diseases reported during 1989. Institutional members collected 7.4 million whole blood units, of which 90.8 percent were donated for allogeneic use, 6.0 percent were donated for autologous use, and 3.2 percent were donated for directed use. Approximately 630,546 allogeneic and directed-use blood donors were deferred, most often for low hemoglobin or hematocrit values. Approximately 225,205 full allogeneic and directed-donor units were discarded, primarily for elevated alanine aminotransferase levels or the presence of hepatitis B core antibody. The 14.3 million transfused components included 56.7 percent red cell-containing components, 27.4 percent platelets, 11 percent fresh-frozen plasma, and 4.8 percent cryoprecipitate. Institutional members reported 1397 cases of transfusion-associated hepatitis. In this group, 921 patients were tested for hepatitis B surface antigen after the transfusion; 339 (36.8%) were found to be hepatitis B surface antigen positive. The AABB Institutional Questionnaire results provide recent data on blood donor and transfusion-related activities that are vital to the evaluation of current transfusion medicine practices.

Prevalence of antibodies to human immunodeficiency virus type 1 among blood donors prior to screening. The Transfusion Safety Study/NHLBI Donor Repository.

The Transfusion Safety Study (TSS) and the National Heart, Lung, and Blood Institute (NHLBI) established a repository of approximately 200,000 sera from blood donors in late 1984 and early 1985. Collections were made in the four metropolitan areas with the highest prevalence of AIDS. Retrospective testing showed an overall anti-HIV-1 prevalence of 16 cases per 10,000 donations. In this study, the predictive value of a negative initial enzyme-linked immunoassay was estimated from both quality control specimens and the rescreening of 13,461 sera to be greater than 99.99 percent with respect to technical error. Among anti-HIV-1-positive persons, there was a 1.3- to 1.5-fold excess of first-time donors. The anti-HIV-1 prevalence among donors showed that infection was more common among young men than suggested by national reporting of AIDS cases. Anti-HIV-1 prevalence varied among the four metropolitan areas less than did reported AIDS cases, but, by 1987, the differences in the latter had decreased. Anti-HIV-1 prevalence in collection areas outside of the four major cities differed much more widely than that among the cities themselves. The TSS/NHLBI Donor Repository will remain available for the indefinite future for further evaluation of screening procedures for HIV-1 and other viruses for which transfusion is found to be an important route of transmission.

Endobronchial lymphocytic infiltration. Unusual manifestation of chronic lymphocytic leukemia.

This report describes a patient with chronic lymphocytic leukemia followed over a 15-year period. The distinctive feature of her course was the infiltration of the bronchial wall by malignant lymphocytes, which produced endobronchial obstruction, atelectasis, and infection. Symptomatic improvement occurred following local irradiation and steroid therapy. A review of the literature establishes that the development of endobronchial infiltration during the course of chronic lymphocytic leukemia and other lymphoproliferative disorders is distinctly uncommon.

Origin of platelet-derived growth factor in megakaryocytes in guinea pigs.

Growth factor activity, as determined by the stimulation of [3H]thymidine incorporation into the DNA of quiescent 3T3 cells in culture, was found in lysates of guinea pig platelets and megakaryocytes. Quantitative dilution studies demonstrated that, of the cells present in the guinea pig bone marrow, only the megakaryocyte possessed quantitatively significant growth factor activity. The amount of activity present in one megakaryocyte was equivalent to that present in 1,000-5,000 platelets, a value approximately comparable to the number of platelets shed from a single megakaryocyte. It is suggested that guinea pig platelet-derived growth factor has its origin in the megakaryocyte.

Release of platelet-derived growth factor from human platelets by arachidonic acid.

Platelet alpha-granules contain a factor that stimulates the proliferation of arterial smooth muscle cells and may play a role in atherogenesis. We have studied the role of arachidonic acid in mediating the release of the platelet-derived growth factor (PDGF) from human platelets. PDGF was assayed by stimulating of [(3)H]thymidine incorporation into DNA of mouse 3T3 cells. Platelet aggregation and the release of platelet factor 4,beta-thromboglobulin, and serotonin were also studied. A biphasic response pattern was observed when gel-filtered platelets were incubated with arachidonate over the concentration range 0.01-0.4 mM. At low arachidonate levels (approximately 0.025-0.1 mM), specific concentration-dependent aggregation and release of PDGF and of the other components were observed. This effect was not seen with any of five other fatty acids tested and was suppressed by indomethacin (25 muM). At higher arachidonate concentrations (approximately 0.15-0.35 mM), a concentration-dependent turn-off of both aggregation and release occurred. At these concentrations the platelets remained functional, and no release of lactate dehydrogenase was observed. A similar biphasic pattern of arachidonate-induced aggregation and release was observed with platelet-rich plasma, over a similar range of arachidonate to albumin mole ratios. These studies demonstrate that PDGF and other alpha-granule constituents can be released from platelets specifically by arachidonate via an indomethacin-sensitive pathway, most probably involving the platelet cyclooxygenase and conversion of arachidonate to prostaglandin metabolities. The mechanisms responsible for the turn-off of the specific arachidonate-mediated responses at higher arachidonate concentrations remain to be defined.