Expression of immunosuppresive B7-H3 ligand by hormone-treated prostate cancer tumors and metastases.

PURPOSE: Prostate cancer cells uniformly express the immune cell inhibitory B7-H3 ligand. Enhanced B7-H3 expression correlates with increased disease progression and cancer-specific death after radical prostatectomy (RP). EXPERIMENTAL DESIGN: To further assess whether B7-H3 expression is hormone regulated and persists as a viable target during (or after) androgen-ablative therapy, we examined B7-H3 ligand expression within primary and metastatic cancer lesions in response to neoadjuvant hormone therapy (NHT) or palliative hormone deprivation. Tumor B7-H3 in RP specimens from men treated with >/=3 months of NHT was compared with B7-H3 in tumors from matched patients who received no therapy before RP. Hormone-treated and untreated metastatic lesions involving bone were also compared for levels of B7-H3 expression. RESULTS: Of 165 consecutive RP specimens in each cohort studied, sufficient tissues were available for 148 patients (89.7%) treated with NHT versus 127 patients (77.0%) treated with surgery alone. B7-H3 was expressed in 142 (95.9%) tumors from NHT patients compared with 122 (96.0%) tumors from patients treated with surgery alone (P = 0.91). B7-H3 expression intensity in RP specimens was not affected by NHT (P = 0.12). Bone metastases from 11 (32.4%) untreated and 23 (67.6%) androgen-ablated patients revealed that B7-H3 expression increased in response to hormone therapy (P = 0.04) relative to untreated lesions. CONCLUSIONS: Taken together, B7-H3 expression seems to remain stable (or may even increase) in response to hormone therapy. As such, B7-H3 may represent an attractive target to improve treatment of men with high-risk hormone-treated or refractory prostate cancer.

Sacral neuromodulation in children with dysfunctional elimination syndrome: description of incisionless first stage and second stage without fluoroscopy.

OBJECTIVES: To detail a percutaneous technique of sacral nerve neuromodulation (SN) that eliminates the first-stage incisions and the need for second-stage fluoroscopy. Our group has previously described the results of SN in children with medically refractory dysfunctional elimination syndrome. The drawbacks to SN include the use of fluoroscopy and the need to reopen recent skin incisions during the second stage. This results in increased radiation exposure, poor cosmesis, and possible wound infection. METHODS: The incisionless first stage consisted of percutaneously tunneling the temporary external appliance to the contralateral axillary line at the buttock after localization of the S3 nerve root and placement of a quadripolar tined lead under fluoroscopic guidance. A subcutaneous bolus of methylene blue marked the lead connector site, obviating the need for later fluoroscopic localization to place the implantable pulse generator at the second stage. RESULTS: A total of 27 children with refractory dysfunctional elimination syndrome underwent SN using the InterStim device. Of the 27 patients, 19 underwent our modified technique. The operative time for our modified tunneling and placement technique was < or = 2 minutes. The mean hospital stay was 0.6 day, with no patient requiring postoperative intravenous narcotics. At a mean follow-up of 35.9 months, no wound infections had occurred in the incisionless cohort compared with 1 postoperative wound infection requiring device explantation in the conventional lead placement group. CONCLUSIONS: The incisionless technique of SN device implantation is technically simple, quick to perform, and results in decreased radiation exposure, excellent pain control, and improved cosmesis without compromising the outcomes.

Tumor cell and tumor vasculature expression of B7-H3 predict survival in clear cell renal cell carcinoma.

PURPOSE: Although the prognostic value of B7-H1 and B7-H4 expression by tumor cells in clear cell renal cell carcinoma (ccRCC) has been established, the role of B7-H3 is unknown. As such, we evaluated the association of B7-H3 expression with clinicopathologic outcomes in patients treated for ccRCC. EXPERIMENTAL DESIGN: Nephrectomy specimens from 743 consecutive patients treated for ccRCC at our institution from 1990 to 1999 were evaluated for B7-H3 expression by immunohistochemical staining. Associations of B7-H3 expression with clinical and pathologic features were evaluated using chi2 and Fisher's exact tests. Associations of B7-H3 expression with death from RCC were evaluated using Cox proportional hazards regression models. RESULTS: B7-H3 expression by tumor cells or tumor vasculature was noted in 17% and 95% of specimens, respectively. The presence of either tumor cell or diffuse tumor vasculature expression of B7-H3 was present in 46% of specimens and was associated with multiple adverse clinical and pathologic features. After multivariable adjustment, the presence of either tumor cell or diffuse tumor vasculature B7-H3 expression was significantly associated with an increased risk of death from RCC (risk ratio, 1.38; 95% confidence interval, 1.03-1.84; P = 0.029). CONCLUSIONS: Both tumor cell and tumor vasculature B7-H3 expression convey important information to predict ccRCC outcomes. Collectively, our past and present studies pertaining to B7-H ligand expression indicate that ccRCC may use redundant mechanisms to compromise host antitumoral immunity. Future studies will focus on the effect of combined B7-H ligand expression in RCC.

Sacral neuromodulation for the dysfunctional elimination syndrome: a single center experience with 20 children.

PURPOSE: Recent advances in neuromodulation have demonstrated promise in treating children with the dysfunctional elimination syndrome refractory to medical management. Sacral nerve stimulation with the InterStim implantable device has been used in adults for management of chronic urinary complaints. However, there are few data regarding the usefulness of sacral nerve stimulation in children. We report our experience with sacral nerve stimulation for severe dysfunctional elimination syndrome. MATERIALS AND METHODS: A total of 20 patients 8 to 17 years old with the dysfunctional elimination syndrome refractory to maximum medical treatment underwent sacral nerve stimulation at our institution. Patients were followed prospectively for a median of 27 months after the procedure. RESULTS: Urinary incontinence, urgency and frequency, nocturnal enuresis and constipation were improved or resolved in 88% (14 of 16), 69% (9 of 13), 89% (8 of 9), 69% (11 of 16) and 71% (12 of 17) of the patients, respectively. Urinary retention requiring intermittent catheterization persisted in 75% of the patients (3 of 4) despite sacral nerve stimulation. Complications requiring operative treatment occurred in 20% of the patients (4 of 20). Following marked symptomatic improvement 2 devices were explanted at 20 and 19 months following placement, and both patients have remained symptom-free. CONCLUSIONS: Sacral nerve stimulation is effective in the majority of our patients, and should be considered in children with severe dysfunctional elimination syndrome refractory to maximum medical treatment.

B7-H3 ligand expression by prostate cancer: a novel marker of prognosis and potential target for therapy.

B7 coregulatory ligands can be aberrantly expressed in human disease. In the context of cancer, these ligands may act as antigen-specific inhibitors of T-cell-mediated antitumoral immunity. We recently reported that B7-H1 expression by carcinomas of the kidney and bladder portends aggressive disease and diminished survival. The expression of these proteins in prostate cancer, however, has not been investigated. We evaluated B7-H3 and B7-H1 protein expression in the pathologic specimens of 338 men treated for clinically localized prostate cancer between 1995 and 1998 with radical retropubic prostatectomy. Expression levels of B7-H3 in prostate cancer were correlated with pathologic indicators of aggressive cancer as well as clinical outcome. We report that B7-H3 is uniformly and aberrantly expressed by adenocarcinomas of the prostate, high-grade prostatic intraepithelial neoplasia, and four prostate cancer cell lines, whereas B7-H1 is rarely expressed. B7-H3 is expressed by benign prostatic epithelia, although at a more reduced level relative to neoplastic tissue. Increasing levels of B7-H3 intensity correlate with worsening clinicopathologic features of prostate cancer. Marked B7-H3 intensity, present in 67 (19.8%) specimens, confers a >4-fold increased risk of cancer progression after surgery (risk ratio, 4.42; P < 0.001). A survey of normal tissues revealed that B7-H3 is expressed within the liver, urothelium, and fetal kidney. In summary, B7-H3 is aberrantly expressed in all prostate cancers and represents an independent predictor of cancer progression following surgery. Moreover, B7-H3 encompasses a novel diagnostic and potential therapeutic target for the clinical management of prostate cancer and, perhaps, other malignancies as well.

Human-yeast chimeric repair protein protects mammalian cells against alkylating agents: enhancement of MGMT protection.

Chemotherapeutic DNA alkylating agents are common weapons employed to fight both pediatric and adult cancers. In addition to cancerous cells, nontarget tissues are subjected to the cytotoxicity of these agents, and dose-limiting toxicity in the form of myelosuppression is a frequent result of treatment. One approach to prevent myelosuppression that results from the use of chemotherapeutic agents is to increase the levels of DNA repair proteins in bone marrow cells. Here we report our second successful attempt to create a fusion protein that possesses both direct reversal and base excision repair pathway DNA repair activities. The chimeric protein is composed of the human O(6)-Methylguanine-DNA Methyltransferase (MGMT) and the yeast Apn1 proteins and retains both MGMT and AP endonuclease activities as determined by biochemical analysis. We have also demonstrated that the chimeric protein is able to protect mammalian cells from the DNA alkylating agents 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) and methyl methanesulfonate (MMS). The protection by the chimeric protein against BCNU is even greater than MGMT alone, which has potential translational significance given that MGMT is currently in clinical trials. Additionally, we show that the chimeric MGMT-Apn1 protein can protect mammalian cells from dual treatments of BCNU and MMS and that this effect is greater than that provided by MGMT alone. The data support our previous finding that a protein with multiple DNA repair activities can be constructed and that this and other constructs may play an important clinical role in guarding against dose-limiting effects of chemotherapy, particularly in situations of multiple drug use.

Urethral adenocarcinoma associated with urethral diverticulum in a patient with progressive voiding dysfunction.

Urethral adenocarcinoma associated with urethral diverticulum is a rare condition that requires a high index of suspicion to ensure early diagnosis and appropriate therapy. The development of urethral stenosis in a patient with a urethral diverticulum warrants early biopsy to rule out a malignant lesion.