Biomedical subjects
Publications and source records attributed to Daniel J Culkin.
Sclerosing mesenteritis is part of a spectrum of benign, inflammatory diseases of the abdominal mesentery. It has been called retractile mesenteritis, and other forms include mesenteric panniculitis and mesenteric lipodystrophy. The disease rarely involves the retroperitoneum. We present a case of sclerosing mesenteritis that progressed to ureteral involvement.
BACKGROUND: Tumor metastasis and changes in host immunosurveillance are important components in cancer development. Tumor cell invasion into the bloodstream is an essential step for systemic metastasis. Currently, the detection of tumor cells in the circulation is mainly dependent upon the utilization of known epithelial cell markers. However, expression of these molecules is not limited to cancer patients; healthy people also have a small number of epithelial cells in their circulation. Utilizing these markers to detect circulating tumor cells (CTCs) cannot adequately explain the mechanisms of tumor cell survival or their development of metastatic potential in peripheral blood. The immune system can also evolve along with the cancer, actually promoting or selecting the outgrowth of tumor variants. Unfortunately, both metastasis and immunosurveillance remain mysterious and are debatable because we have yet to define the molecules that participate in these processes. We are interested in identifying the existence of expressed genes, or mRNA species, that are specifically associated with circulating cells of cancer-bearing patients using prostate cancer (PCa) as a model. RESULTS: We established two comprehensive subtracted cDNA libraries using a molecular technique called suppression subtractive hybridization. This technique selectively amplifies transcripts that are specifically expressed in circulating cells of either PCa patients or healthy men. Following sequencing reaction, we showed that 17 out of 23 (73.9%) sequenced clones did not match any mRNAs in the GenBank database. This result suggests that genes associated with alterations in circulating cells of cancer-bearing patients are largely unknown. Semi-quantitative RT-PCR confirmed that two genes are up-regulated in circulating cells of PCa patients, whereas another two genes are down-regulated in the same patients. CONCLUSION: The comprehensive gene expression analysis is capable of identifying differentially expressed genes in circulating cells of healthy men and PCa patients. We did not attempt to enrich specific cell types in this study because phenotypes of CTCs and subsets of leukocytes participating in immunosurveillance remain largely unknown. Continuous studies of these differentially expressed genes will eventually lead us to understand the mechanisms involved in tumor metastasis and immune modulation during cancer development.
PURPOSE: We compared intravesical bacillus Calmette-Guerin (BCG) to placebo instillations in patients with treatment refractory interstitial cystitis (IC). MATERIALS AND METHODS: Subjects who met the National Institutes of Health-National Institute for Diabetes and Digestive and Kidney Diseases criteria for IC, and reported at least moderate pain and frequency for a minimum of 6 months before study entry, were randomized to 6 weekly double-blinded intravesical instillations of either BCG or placebo, and then followed for a total of 34 weeks. The primary outcome was a patient reported global response assessment at week 34, supplemented with medications for IC during weeks 31 to 34. Secondary outcomes included a 24-hour voiding diary, pain, urgency, validated IC symptom indexes and adverse events. The target sample size was 260 participants, designed to detect a difference in response rates between placebo and BCG of 30% and 50%, respectively. RESULTS: A total of 265 participants were randomized and 17 (6%) patients withdrew from study. The response rates for the primary outcome were 12% for placebo and 21% for BCG (p = 0.062). Small improvements were observed for all secondary outcomes, some more so with BCG, but these differences were of borderline statistical significance. Although a large number of adverse events were reported in the BCG arm, there was no statistically significant difference between the treatment arms in overall adverse event rates. CONCLUSIONS: Although the BCG safety profile was acceptable, the response rate for the primary outcome was low. Effective medical treatment for patients with moderate to severe interstitial cystitis remains elusive.
Prostate cancer and its various forms of treatment remain a source of significant controversy and morbidity despite recent advances. In response, there is an increasing trend toward the development of treatments aimed at cancer prevention and at maximizing the preservation of function without sacrificing cancer control. This article reviews the current prostate cancer literature and reports on improvements in existing surgical treatments and developing technologies aimed toward achieving these goals. Specific therapies addressed include improvements in surgical techniques, laparoscopy, robotics, cryosurgical and thermal ablation, and high-intensity focused ultrasound.
PURPOSE: Despite a lack of consensus concerning the etiology of interstitial cystitis (IC) the loss of impermeability and other abnormalities of the urothelium are features of the disease. In this study the distribution of proteins involved with epithelial adhesion, cellular differentiation and bladder impermeability in urothelial biopsies were explored by the immunohistochemical assessment of E-cadherin, ZO-1, uroplakin and chondroitin sulfate. MATERIALS AND METHODS: Biopsies obtained from 27 patients with IC and 7 controls were immediately fixed in formalin, immunohistochemically labeled for the described proteins and scored for protein expression, morphology and differentiation. RESULTS: Only 3 IC samples appeared completely normal, while 24 of the 27 showed an abnormality in at least 1 marker and in 6 all 4 markers were abnormal. In patients vs controls findings were abnormal for uroplakin in 13 of 27 vs 1 of 7 (p = 0.085), for E-cadherin (over expressed) in 18 of 27 vs 0 of 7 (p = 0.0021), for ZO-1 in 11 of 27 vs 0 of 7 (p = 0.046) and for chondroitin sulfate in 15 of 27 vs 0 of 7 (p = 0.0054). The morphology/polarity score significantly correlated with ZO-1 (Pearson r = 0.3935, p = 0.0423) and chondroitin sulfate (Pearson r = 0.7079, p <0.0001) expression. Chondroitin sulfate and ZO-1 showed a high correlation with each other (Pearson r = 0.5587, p = 0.0025). Uroplakin and E-cadherin expression were independent of all other markers. CONCLUSIONS: The findings reported strongly suggest abnormal differentiation in the IC bladder. The disruption of ZO-1 is similar to that reported in feline IC. Elevated E-cadherin may represent an adaptation to increased bladder permeability.
PURPOSE: We report preliminary experience with the transsphincteric, transanal surgical approach to correct acquired urethrorectal fistula. MATERIALS AND METHODS: Five men with an acquired urethrorectal fistula underwent surgical correction. Mean patient age was 56.6 years (range 37 to 72). The etiology was surgical (radical prostatectomy) in 3 cases, traumatic in 1 and idiopathic in 1. All 5 patients had urinary tract infection and pneumaturia, and 3 (60%) had watery stool. Conservative treatments had failed in all cases. The time from the diagnosis of urethrorectal fistula to surgery was 4 weeks to 4 years. RESULTSFive men underwent excision and closure of a urethrorectal fistula with diverting colostomy. In 4 men (80%) urinary continence subsequently returned with adequate sphincter tone, while in 1 (20%) with perineal trauma and active proctitis the fistula recurred 6 weeks after surgery. CONCLUSIONS: Urethrorectal fistulas are rare and surgically challenging. The transsphincteric, transanal surgical approach provides many advantages, including easy access and identification of the fistula tract, good surgical exposure, adequate resection to well vascularized tissue and access to several vascularized flaps for interposition between the repaired urinary and gastrointestinal tracts.
PURPOSE: In the United States penile carcinoma is an uncommon malignancy that represents only 0.4% of all male malignancies and 2% to 4% of genitourinary malignancies. Of penile cancer cases 30% are diagnosed with advanced disease. Improved understanding of the natural history, appropriate and accurate staging, and tailored, less morbid lymphadenectomy have led to improved survival and decreased the adverse effects of therapy. However, the management of advanced penile carcinoma remains a challenge to urological, medical and radiation oncologists. The rarity and paucity of well designed clinical studies of medical and/or surgical therapy for advanced penile cancer have hampered progress in the treatment of this disease. However, there is clear evidence that identifies active chemotherapy and radiation treatments. This review aims to provide the treating physician with an overview of available data for surgical, chemotherapeutic and radiation treatments, and provide guidelines for appropriate patient selection for these therapies. MATERIALS AND METHODS: We performed a detailed review of the available literature regarding advanced penile carcinoma to include its etiology, epidemiology, natural history, staging classification and treatment. RESULTS: Penile carcinoma typically spreads along an echelon of nodal pathways that permits fairly accurate staging. Prognosis correlates well with clinical nodal status and grade, and the TNM classification developed by the UICC should be uniformly used by clinicians. Treatment recommendations are tightly associated with disease stage. Although tailored lymphadenectomy as currently recommended has greatly decreased morbidity, improved staging accuracy and improved treatment results, controversies still exist regarding the need for lymphadenectomy in patients with impalpable lymph node (cN0) disease, and the role and timing of pelvic lymphadenectomy. There is evidence of modest activity for chemotherapy in advanced penile carcinoma. Active agents include cisplatin, bleomycin and methotrexate. Combination chemotherapy regimens with promising activity and toxicity profiles include cisplatin and 5-fluorouracil, and vincristine, bleomycin and methotrexate. Radiation in combination with surgery and/or chemotherapy in advanced disease have also demonstrated activity. CONCLUSIONS: The natural history of penile carcinoma and its proclivity to spread via regional lymphatics has been well defined. This understanding has led to the development of effective locoregional treatment strategies. Penile carcinoma is sensitive to radiation and certain chemotherapeutic agents. A threshold volume of nodal metastases is associated with significant mortality. The optimal application of these strategies remains to be determined. Improvements in survival and quality of life likely require the incorporation of multiple modalities into the treatment of advanced penile carcinoma. A multi-institutional, international effort is essential to perform appropriately powered clinical trials to advance the standard of care in this rare disease.
Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in men, following lung cancer. Although radical prostatectomy continues to be a curative treatment for most patients diagnosed with prostate cancer, nearly 25% of patients undergoing radical prostatectomy will have biochemical recurrence as defined by an increase in serum prostate-specific antigen (PSA) level to >0.4 ng/mL after prostatectomy or a rapid doubling of the PSA over a 10-year follow-up period. The clinical challenges, an overview of available data, and a framework for the integration of this information for clinical management of biochemical recurrence postprostatectomy for prostate carcinoma are presented in this article. Therapeutic options, in addition to conservative management and watchful waiting, include radiation therapy and androgen deprivation. These options are discussed herein along with expected outcomes.
Elucidating the mechanisms by which the phenotype of cancer cells is modulated by the extracellular matrix (ECM) potentially identifies mechanisms that could be exploited for cancer control. Three readily available bladder cancer cell lines of different aggressiveness were grown on a bioscaffold material (Small Intestine Submucosa: SIS) under a variety of media and nutrient schedules to determine the influence of epigenetic factors on phenotype. The aggressive TCCSUP and J82 lines displayed an invasive phenotype when fed twice weekly with medium containing 10% fetal calf serum (FCS), but grew as a layered, noninvasive structure when fed daily with the same nutrient. The papillary RT4 cells grew as a nearly normal appearing layered phenotype when fed with medium containing 10% FCS, regardless of the feeding schedule. The papillary phenotype appeared only when the fetal calf serum concentration was reduced to 1% and the cells were fed twice weekly. Immunohistochemical staining showed E-cadherin was detected in the nucleus of the TCCSUP line rather than on the cell periphery, thus, demonstrating that normalization of the TCCSUP line into a layered phenotype did not alter the fundamental dysregulation of the cadherin-B-catenin-cytoskeleton complex. In contrast, in the RT4 cells the biomarker was distributed discretely around the cell periphery in 10% fetal calf serum but in the nucleus in 1% fetal calf serum and twice weekly feeding. Modulating the phenotype of cancer cells from invasive to noninvasive through manipulation of matrix and nutrient components presents a model system for identifying the key factors involved in invasiveness and may identify new therapeutic targets and markers.