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Eric A Klein

Publications and source records attributed to Eric A Klein.

At least 19 recordsLinked to original sources

The Pseudomonas aeruginosa sphBC genes are important for growth in the presence of sphingosine by promoting sphingosine metabolism.

Sphingoid bases, including sphingosine, are important components of the antimicrobial barrier at epithelial surfaces where they can cause growth inhibition and killing of susceptible bacteria. Pseudomonas aeruginosa is a common opportunistic pathogen that is less susceptible to sphingosine than many Gram-negative bacteria. Here, we determined that the deletion of the sphBCD operon reduced growth in the presence of sphingosine. Using deletion mutants, complementation and growth assays in P. aeruginosa PAO1, we determined that the sphC and sphB genes, encoding a periplasmic oxidase and periplasmic cytochrome c, respectively, were important for growth on sphingosine, while sphD was dispensable under these conditions. Deletion of sphBCD in P. aeruginosa PA14, Pseudomonas protegens Pf-5 and Pseudomonas fluorescens Pf01 also showed reduced growth in the presence of sphingosine. The P. aeruginosa sphBC genes were also important for growth in the presence of two other sphingoid bases, phytosphingosine and sphinganine. In WT P. aeruginosa, sphingosine is metabolized to an unknown non-inhibitory product, as sphingosine concentrations drop in the culture. However, in the absence of sphBC, sphingosine accumulates, pointing to SphC and SphB as having a role in sphingosine metabolism. Finally, the metabolism of sphingosine by WT P. aeruginosa protected susceptible cells from full growth inhibition by sphingosine, pointing to a role for sphingosine metabolism as a public good. This work shows that the metabolism of sphingosine by P. aeruginosa presents a novel pathway by which bacteria can alter host-derived sphingolipids, but it remains an open question whether SphB and SphC act directly on sphingosine.

Sphingosine↗

Limited pelvic lymph node dissection at the time of radical prostatectomy does not affect 5-year failure rates for low, intermediate and high risk prostate cancer: results from CaPSURE.

PURPOSE: Limited bilateral pelvic lymph node dissection performed at radical prostatectomy provides staging information that is used to guide further disease management. Given the effects of widespread prostate specific antigen testing and stage migration, most procedures in the United States are performed for low risk disease, which has a low probability (less than 1%) of lymph node metastasis. We compared 5-year treatment failure rates in patients with low, intermediate and high risk disease who underwent radical prostatectomy with or without pelvic lymph node dissection. MATERIALS AND METHODS: We compared treatment failure rates for radical prostatectomy in 4,693 patients enrolled in the CaPSURE database who underwent radical prostatectomy with or without limited pelvic lymph node dissection. Secondary analysis was performed as a function of pelvic lymph node dissection and risk group based on pretreatment stage, grade and prostate specific antigen. Treatment failure rates were estimated by Kaplan-Meier analysis. RESULTS: The 5-year failure-free survival rate was 70% in the no pelvic lymph node dissection group and 74% in the limited pelvic lymph node dissection group (p = 0.11), while the rates in the low, intermediate and high risk groups were 81% and 82% (p = 0.83), 71% and 63% (p = 0.21), and 42% and 48% (p = 0.45) in the no vs limited pelvic lymph node dissection groups, respectively. Multivariate analysis demonstrated that pelvic lymph node dissection status was not a predictor of treatment failure (p = 0.93). CONCLUSIONS: This study demonstrates in a large cohort of patients that limited pelvic lymph node dissection at radical prostatectomy has no effect on treatment failure rates at 5 years in those at low, intermediate and high risk.

Aged↗

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Clinical Trials as Topic↗

Ejaculatory urine incontinence after radical prostatectomy.

OBJECTIVES: Urinary incontinence and erectile dysfunction remain the long-term complications that affect most patients' lives after radical prostatectomy. Previous reports evaluating incontinence have focused on volumes of urine loss and daily pad use to assess these issues. We have observed that small volumes of urinary incontinence during sexual activity can be just as disconcerting to patients. We attempt to further describe and assess the phenomenon of urinary incontinence with ejaculation in a series of patients. METHODS: We reviewed the experience of one physician who received referrals for the treatment of erectile dysfunction after radical prostatectomy from July 2002 to March 2005 and identified 26 men experiencing urine leak predominantly during ejaculation. Questionnaires assessing urinary incontinence were sent to all these patients. RESULTS: The mean age was 62 years (range 54 to 73). Sixteen patients underwent bilateral nerve-sparing, five unilateral nerve-sparing, and five nonnerve-sparing radical retropubic prostatectomy. At a median follow-up of 42 months (range 15 to 118), all patients had experienced urine leakage (volume 0.5 teaspoon to 1 cup) during ejaculation. The incontinence questionnaire revealed that most patients had mild incontinence; however, they experienced ejaculatory urine incontinence "most, or all of the time" and considered it a "big problem." CONCLUSIONS: Although the prevalence of ejaculatory urine incontinence is unclear, in our experience it occurs often enough to be considered a part of the routine postprostatectomy evaluation. A better understanding of the pathophysiology of postprostatectomy incontinence will lead to targeted therapy and an improved quality of life for the patient.

Aged↗

Use of different definitions of biochemical failure after external beam radiotherapy changes conclusions about relative treatment efficacy for localized prostate cancer.

OBJECTIVES: To report biochemical relapse-free survival (bRFS) after radiotherapy (RT) for localized prostate cancer with two separate failure definitions and compare the results with those after radical prostatectomy (RP). METHODS: The study sample comprised 2516 patients with a median follow-up of 78 months. Biochemical relapse after RT was defined as either the American Society for Therapeutic Radiology Oncology definition (definition A [DefA]) or a prostate-specific antigen elevation of more than 2 ng/mL greater than the nadir prostate-specific antigen level (definition N [DefN]). Failure after RP was defined as a prostate-specific antigen level greater than 0.2 ng/mL. RESULTS: Compared with DefA, DefN resulted in a 13% greater bRFS rate at 5 years and a 12% lower bRFS rate at 10 years. On multivariate analysis, the treatment modality (RP versus RT) was a significant predictor of bRFS using DefA in favor of RP (P <0.001), but was not with DefN (P = 0.87). Higher radiation doses were independently associated with a better outcome with either definition. CONCLUSIONS: Compared with DefA, DefN resulted in better outcomes for up to 7 years after RT, but worse outcomes thereafter. The use of DefA versus DefN resulted in opposite conclusions about the relative efficacies of RT and RP, with DefN suggesting RT is equivalent to RP and DefA that it is worse than RP. Different definitions of biochemical failure after RT can result in differences in the conclusions about treatment efficacy in men with localized prostate cancer, thereby potentially affecting clinical decisions.

Adenocarcinoma↗

Outcomes in patients with urothelial carcinoma of the bladder with limited pelvic lymph node dissection.

OBJECTIVES: To evaluate the rates of local and systemic progression (LP and SP), recurrence-free survival and overall survival for patients with urothelial carcinoma of the bladder with limited pelvic lymph node dissection (PLND) in 1987-2000. PATIENTS AND METHODS: A consecutive series was analysed of 385 patients (median age 61.9 years, range 30.7-83.8) treated by limited bilateral PLND and radical cystectomy (RC) between 1987 and 2000, with negative surgical margins on final pathology. All patients were staged N0M0 before RC, and none received neoadjuvant radiotherapy or chemotherapy. The boundaries of the limited PLND were the pelvic side-wall between the genitofemoral and obturator nerves, and bifurcation of iliac vessels to the circumflex iliac vein. LP was defined as a radiographic soft-tissue density of > or = 2 cm below the bifurcation of the aorta. Pathological characteristics, based on the 1997 Tumour-Nodes-Metastasis system, recurrence patterns, and recurrence-free and overall survival, were determined. RESULTS The median (range) overall follow-up was 45.1 (1.1-165.6) months; the number of lymph nodes (LNs) reported per patient was 12 (2-32). Of the 385 patients, 130 (33.8%) had evidence of LP and 60 (15.6%) of SP. The 5-year recurrence-free and overall survival rates were both 71% for patients with organ-confined, N0 tumours, and 23% and 26% for unconfined, N0 tumours. Positive LNs were found in 45 (12%) patients, who had a recurrence-free and overall survival rate of 9% at 5 years. CONCLUSION: Compared with published reports of similar cohorts of patients managed with RC and extended PLND, the present study suggests that limited PLND is associated with suboptimal staging, greater rates of LP, and lower rates of recurrence-free survival, particularly for patients with unconfined or LN-positive disease.

Adult↗

Aggressiveness of familial prostate cancer.

PURPOSE: To report on the aggressiveness of sporadic versus familial prostate cancer. PATIENTS AND METHODS: The study sample consisted of 4,112 stage T1-3 prostate cancer patients. The outcome of interest was biochemical relapse-free survival (bRFS). The analysis was performed for two distinct time periods, 1986 to 1992 (year < or = 1992) and 1993 to 2002 (year > or = 1993), to encompass both the early and late prostate-specific antigen (PSA) eras. RESULTS: A positive family history (FH positive) was reported in 16%. The 10-year bRFS rates for patients with negative family history (FH negative) versus FH positive were 59% and 63%, respectively (P = .90). However, in the year < or = 1992 period, the 10-year bRFS rates for FH negative versus FH positive were 45% and 34%, respectively (P = .015). In the year > or = 1993 period, the 10-year bRFS rates for FH negative versus FH positive were 61% and 67%, respectively (P = .54). Multivariate analysis failed to reveal family history as an independent predictor of relapse (P = .42). However, in the subset of patients in each era, family history was an independent predictor of relapse only for those treated in the year < or = 1992 period (P = .038). CONCLUSION: Family history was an independent predictor of biochemical failure only early in the PSA era, and men with an FH positive presented with more favorable disease later in the PSA era. This suggests that with stage migration and improved therapy, the impact of family history on prognosis has become minimal. However, underlying genetic factors affecting prostate cancer behavior in individuals with familial prostate cancer may still be important in determining individual prognosis.

Aged↗

Radical prostatectomy as primary treatment modality for locally advanced prostate cancer: a prospective analysis.

OBJECTIVES: Locally advanced prostate cancer is frequently treated with radiotherapy and androgen deprivation because of the greater rate of extracapsular disease and the concern that radical prostatectomy (RP) may not be curative in most cases. A case for surgery for locally advanced disease may be made on the basis of a lower rate of local recurrence compared with radiotherapy in our comparative database, data suggesting a survival advantage with pelvic lymph node dissection in those with positive nodes, and the observation of improved survival in those with metastatic disease treated by RP compared with radiotherapy. We report on the feasibility of RP as a primary treatment modality for locally advanced disease. METHODS: A total of 281 consecutive patients treated by RP between January 1998 and June 2004 were reviewed. Locally advanced disease was defined as clinical Stage T2b or worse, prostate-specific antigen level greater than 15 ng/mL, and/or a Gleason score of 8 or greater. Data on the pathologic characteristics, operative complications, and follow-up were obtained from a prospectively maintained institutional review board-approved database. RESULTS: Pathologic examination demonstrated organ-confined disease in 11.7%, extracapsular extension in 56.9%, seminal vesicle involvement in 23.1%, and positive lymph nodes in 8.9%. The overall complication rate was 9.7% compared with 6.9% for all patients undergoing RP. At a mean follow-up of 34 months (range 1 to 78), 198 (70.4%) of 281 patients had an undetectable prostate-specific antigen level at the last follow-up examination. CONCLUSIONS: RP for locally advanced prostate cancer is feasible, with acute morbidity similar to RP for more localized disease. Furthermore, RP results in short-term biochemical recurrence-free survival similar to that of combined radiotherapy and androgen ablation.

Feasibility Studies↗

Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant.

Ribonuclease L (RNase L) is an important effector of the innate antiviral response. Mutations or variants that impair function of RNase L, particularly R462Q, have been proposed as susceptibility factors for prostate cancer. Given the role of this gene in viral defense, we sought to explore the possibility that a viral infection might contribute to prostate cancer in individuals harboring the R462Q variant. A viral detection DNA microarray composed of oligonucleotides corresponding to the most conserved sequences of all known viruses identified the presence of gammaretroviral sequences in cDNA samples from seven of 11 R462Q-homozygous (QQ) cases, and in one of eight heterozygous (RQ) and homozygous wild-type (RR) cases. An expanded survey of 86 tumors by specific RT-PCR detected the virus in eight of 20 QQ cases (40%), compared with only one sample (1.5%) among 66 RQ and RR cases. The full-length viral genome was cloned and sequenced independently from three positive QQ cases. The virus, named XMRV, is closely related to xenotropic murine leukemia viruses (MuLVs), but its sequence is clearly distinct from all known members of this group. Comparison of gag and pol sequences from different tumor isolates suggested infection with the same virus in all cases, yet sequence variation was consistent with the infections being independently acquired. Analysis of prostate tissues from XMRV-positive cases by in situ hybridization and immunohistochemistry showed that XMRV nucleic acid and protein can be detected in about 1% of stromal cells, predominantly fibroblasts and hematopoietic elements in regions adjacent to the carcinoma. These data provide to our knowledge the first demonstration that xenotropic MuLV-related viruses can produce an authentic human infection, and strongly implicate RNase L activity in the prevention or clearance of infection in vivo. These findings also raise questions about the possible relationship between exogenous infection and cancer development in genetically susceptible individuals.

Adenocarcinoma↗

Perineural invasion on prostate needle biopsy does not predict biochemical failure following brachytherapy for prostate cancer.

PURPOSE: To determine if the presence of perineural invasion (PNI) predicts biochemical recurrence in patients who underwent low-dose-rate brachytherapy for the treatment of localized prostate cancer. METHODS AND MATERIALS: A retrospective case control matching study was performed. The records of 651 patients treated with brachytherapy between 1996 and 2003 were reviewed. Sixty-three of these patients developed biochemical failure. These sixty-three patients were then matched in a one-to-one ratio to patients without biochemical failure, controlling for biopsy Gleason score, clinical stage, initial prostate-specific antigen, age, and the use of androgen deprivation. The pathology of the entire cohort was then reviewed for evidence of perineural invasion on initial prostate biopsy specimens. The biochemical relapse free survival rates for these two groups were compared. RESULTS: Cases and controls were well matched, and there were no significant differences between the two groups in age, Gleason grade, clinical stage, initial prostate-specific antigen, and the use of androgen deprivation. PNI was found in 19 (17%) patients. There was no significant difference in the rates of PNI between cases and controls, 19.6% and 14.3% respectively (p = 0.45). PNI did not correlate with biochemical relapse free survival (p = 0.40). CONCLUSION: Perineural invasion is not a significant predictor of biochemical recurrence in patients undergoing brachytherapy for prostate cancer.

Aged↗

Nonseminomatous germ cell tumor after chemotherapy with residual mass invading the spine.

Bony metastasis is a rare feature of metastatic nonseminomatous germ cell tumor. A 25 year-old man presented with back pain radiating down both legs, and a subsequent work-up demonstrated a right-sided testicular mass with bilateral retroperitoneal lymphadenopathy and tumor involvement of the L2 vertebra. Radical inguinal orchiectomy confirmed nonseminomatous germ cell tumor, and the patient underwent chemotherapy with a residual mass and vertebral involvement by MRI. Combined vertebral resection with spinal reconstruction and retroperitoneal lymph node dissection demonstrated residual fibrosis. While bony metastasis of nonseminomatous germ cell tumors is rare, resection with spinal reconstruction can be accomplished with acceptable morbidity.

Adult↗

Podocalyxin variants and risk of prostate cancer and tumor aggressiveness.

We previously reported linkage of a prostate cancer tumor aggressiveness locus to chromosome 7q32-q33, a region also associated with a high frequency of allelic imbalance in prostate tumors. The smallest region of allelic imbalance contains the podocalyxin-like (PODXL) gene, which we evaluate here as a candidate prostate cancer aggressiveness gene mapping to 7q32-q33. DNA from probands of linked families was examined for germ-line mutations in PODXL. A variable in-frame deletion, four missense variants and two nonsense variants were identified in linked men. Variants that affected amino acid sequence were further evaluated for association with risk of prostate cancer and tumor aggressiveness in a family-based case-control population (439 cases and 479 sibling controls). The presence of any single in-frame deletion was positively associated with prostate cancer [odds ratio (OR)=2.14, 95% confidence interval (95%CI)=1.09-4.20, P=0.03] and the presence of two copies of any deletion further increased risk (OR=2.58, 95%CI=1.23-5.45, P=0.01). This finding was strengthened when stratifying among men with more aggressive disease (high grade or stage): OR=3.04 for one deletion (95%CI=1.01-9.15) and OR=4.42 for two deletions (95%CI=1.32-14.85, P=0.02). A weak positive association was also observed between prostate cancer risk and PODXL variant 340A (in linkage disequilibrium with another variant, 587T) (OR=1.48, 95%CI=1.02-2.14, P=0.04). These results implicate PODXL as a candidate prostate cancer tumor aggressiveness gene mapping to chromosome 7q32-q33.

Black or African American↗

Mucinous adenocarcinoma of the prostate does not confer poor prognosis.

OBJECTIVES: To report a series of patients with mucinous (colloid) adenocarcinoma (MC) at prostatectomy who were treated at a single institution from 1987 to 2005. MC is a rare form of prostate cancer reported in some cases to have a more aggressive clinical course than conventional adenocarcinoma (AC). METHODS: Radical prostatectomy specimens with mucinous features were identified from a database of 3613 consecutive patients. Each case was reviewed again by a single pathologist who confirmed the diagnosis of MC in 14 patients. MC was defined by the presence of pools of extracellular mucin in more than 25% of the tumor. Eighteen additional cases were identified in which the mucinous component occupied only a small portion of the tumor and were referred to as AC with focal mucin (AFM). The biochemical and overall survival of 26 patients with MC or AFM who had completed > or = 6 months of follow-up was analyzed using Kaplan-Meier estimates. RESULTS: No patients with MC or AFM died of disease, and 11 (91.7%) of 12 patients with MC and 9 (64.3%) of 14 patients with AFM were clinically and biochemically free of disease. No significant difference was found in biochemical recurrence or overall survival between those with MC or AFM and a matched group of patients with AC. CONCLUSIONS: We report what we believe to be the largest published series of cases of MC (n = 14) with a median overall follow-up of 6.4 years. MC appears to behave clinically in a similar fashion to AC, with no statistically significant difference in biochemical failure or survival.

Adenocarcinoma, Mucinous↗

Improved biochemical relapse-free survival for patients with large/wide glands treated with prostate seed implantation for localized adenocarcinoma of prostate.

OBJECTIVES: To analyze whether prostate size affects biochemical relapse-free survival (bRFS). METHODS: The bRFS outcomes for 390 patients with a minimum of 2 years of follow-up were determined from a review of a prospectively maintained database. All patients were treated with iodine-125 alone as the radiotherapeutic modality and had a minimum of four posttreatment prostate-specific antigen values. None were treated with androgen deprivation. The factors examined in the univariate and multivariate analyses predicting for bRFS included gland volume, patient age, initial prostate-specific antigen value, biopsy Gleason score, clinical stage, and postimplant dosimetric variables. RESULTS: Most patients had low-risk disease, and the median follow-up was 45 months (range 24 to 102). Using the American Society for Therapeutic Radiology Oncology definition of biochemical failure, the overall 5-year bRFS rate was 89.3%. On separate multivariate analyses, only the pretreatment prostate width and volume significantly influenced bRFS favorably (P = 0.0069 and P = 0.0255, respectively). No association was found between gland size/width and postimplant dosimetry. CONCLUSIONS: The results of our study have shown that implantation of large/wide prostates independently confers better bRFS.

Adenocarcinoma↗

Peritumoral lymphatic invasion is associated with regional lymph node metastases in prostate adenocarcinoma.

Lymphangiogenesis, detected by antibodies specific for lymphatic endothelial cells, has been associated with regional lymph node metastases and poor prognosis in carcinomas of head and neck, breast and uterine cervix, but remains largely uninvestigated in prostate adenocarcinoma. We evaluated the lymphatic vessel density and lymphatic vessel invasion by prostate cancer cells in the intratumoral, peritumoral and normal prostate tissue compartments in cancer-bearing prostate glands and correlated them with lymph node metastases, Gleason score and other pathological parameters. Lymphatic vessels were detected by immunohistochemical stain using an antibody specific for the lymphatic endothelial cells (clone D2-40) on 33 radical prostatectomies. In all, 26 patients had lymph node dissection, and 14 of them had lymph node metastasis. The lymphatic vessel density and lymphatic vessel invasion were then recorded for each of the three compartments microscopically. Lymphatic vessel density in the intratumoral, peritumoral and normal prostate compartments was 0.91+/-0.80, 1.54+/-0.68 and 1.58+/-0.96/mm2, respectively. The intratumoral lymphatic vessel density was significantly lower than that of the peritumoral and normal prostate compartments, and the latter two were not significantly different. The lymphatic vessel density of the three compartments was not significantly different between cases with and without lymph node metastasis. The peritumoral lymphatic vessel density correlated inversely with the Gleason score. Lymphatic vessel invasion was present in significantly higher percentage of cases with lymph node metastasis (9/14, 62.3%), as compared to those without lymph node metastasis (1/12, 8.3%, P<0.01). The peritumoral lymphatic vessel invasion had a better correlation with the presence of lymph node metastases than intratumoral lymphatic vessel invasion. There is no evidence of lymphangiogenesis in prostate adenocarcinoma. Peritumoral lymphatic vessel invasion correlates with regional lymph node metastases, suggesting that the peritumoral lymphatic vessels are functionally important and identification of lymphatic vessel invasion in this compartment implies a high probability of regional lymph node metastases.

Adenocarcinoma↗