Microsurgical varicocelectomy resulted in significant increases in sperm concentration, total sperm count and testosterone in all age groups studied, including men in the fifth and sixth decades of life. Microsurgical varicocelectomy should be offered to older men for infertility and/or hypogonadism.
To our knowledge, this represents the largest series of postchemotherapy microdissection TESE-ICSI to date. Sperm were retrieved in 37% of patients despite a prevalence of Sertoli cell-only pattern on preoperative biopsy. Although prechemotherapy sperm cryopreservation is recommended, treatment with microdissection TESE and ICSI are effective treatment options for many azoospermic men after chemotherapy.
Maintenance of adult tissues depends on stem cell self-renewal in local niches. Spermatogonial stem cells (SSC) are germline adult stem cells necessary for spermatogenesis and fertility. We show that testicular endothelial cells (TECs) are part of the SSC niche producing glial cell line-derived neurotrophic factor (GDNF) and other factors to support human and mouse SSCs in long-term culture. We demonstrate that FGF-2 binding to FGFR1 on TECs activates the calcineurin pathway to produce GDNF. Comparison of the TEC secretome to lung and liver endothelial cells identified 5 factors sufficient for long-term maintenance of human and mouse SSC colonies in feeder-free cultures. Male cancer survivors after chemotherapy are often infertile since SSCs are highly susceptible to cytotoxic injury. Transplantation of TECs alone restores spermatogenesis in mice after chemotherapy-induced depletion of SSCs. Identifying TECs as a niche population necessary for SSC self-renewal may facilitate fertility preservation for prepubertal boys diagnosed with cancer.
We originally discovered TERE1 as a potential tumor suppressor protein based upon reduced expression in bladder and prostate cancer specimens and growth inhibition of tumor cell lines/xenografts upon ectopic expression. Analysis of TERE1 (aka UBIAD1) has shown it is a prenyltransferase enzyme in the natural bio-synthetic pathways for both vitamin K-2 and COQ10 production and exhibits multiple subcellular localizations including mitochondria, endoplasmic reticulum, and golgi. Vitamin K-2 is involved in mitochondrial electron transport, SXR nuclear hormone receptor signaling and redox cycling: together these functions may form the basis for tumor suppressor function. To gain further insight into mechanisms of growth suppression and enzymatic regulation of TERE1 we isolated TERE1 associated proteins and identified the WD40 repeat, mitochondrial protein TBL2. We examined whether disease specific mutations in TERE1 affected interactions with TBL2 and the role of each protein in altering mitochondrial function, ROS/RNS production and SXR target gene regulation. Biochemical binding assays demonstrated a direct, high affinity interaction between TERE1 and TBL2 proteins; TERE1 was localized to both mitochondrial and non-mitochondrial membranes whereas TBL2 was predominantly mitochondrial; multiple independent single amino acid substitutions in TERE1 which cause a human hereditary corneal disease reduced binding to TBL2 strongly suggesting the relevance of this interaction. Ectopic TERE1 expression elevated mitochondrial trans-membrane potential, oxidative stress, NO production, and activated SXR targets. A TERE1-TBL2 complex likely functions in oxidative/nitrosative stress, lipid metabolism, and SXR signaling pathways in its role as a tumor suppressor.
BACKGROUND: European Urological Association guidelines recommend potentially curative inguinal lymphadenectomy for certain cases of penile cancer such as grade 3 and pT2-4 lesions, among others. Anecdotally, the authors have noticed that few patients undergo inguinal lymphadenectomy. Therefore, they assessed the frequency of inguinal lymphadenectomy and the impact of dissection extent on survival using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: The authors queried 17 SEER registries from 1988 through 2005 for grade 3 and pT2-4 penile cancer patients without distant metastases. Univariate and multivariate analyses examined predictors of inguinal lymphadenectomy. Kaplan-Meier and Cox regression analyses assessed overall 5-year survival across patientand disease-related characteristics for patients receiving inguinal lymphadenectomy involving <8 or 8 lymph nodes, the latter a surrogate for extent of dissection based on other malignancies. RESULTS: Of 593 patients enrolled, only 26.5% received inguinal lymphadenectomy. In addition to grade 3 (P ¼ .031) and pT2-4 disease (P ¼ .004), age <65 years (P < .001) and marital status (P ¼ .002) were significantly associated with receiving lymph node dissection. Increased overall 5-year survival (hazard ratio, 0.54; 95% confidence interval, 0.36-0.79) was observed in patients of all ages who received lymphadenectomy involving 8 lymph nodes. CONCLUSIONS: A significant number of penile cancer patients at risk for metastases have not received potentially curative inguinal lymphadenectomy. Patients receiving inguinal lymphadenectomy involving 8 lymph nodes experienced improved overall 5-year survival. Guidelines should not only be given more emphasis, but possibly be updated to reflect the benefit of extensive lymph node dissection in high-risk penile cancer patients. Cancer 2010;116:2960-6.
Minimally invasive inguinal lymphadenectomy is feasible for patients with melanoma as demonstrated by nodal yield and visual inspection. This technique may reduce complication rates and wound dehiscence, and the risk of exposed vessels is minimized by eliminating the inguinal incision. This obviates the need for routine sartorius muscle transposition. A prospective, randomized trial comparing the open versus the videoscopic approach is currently in progress.
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