Citations

Testicular hemangiomas are benign vascular neoplasms usually occurring in children. Pathologists must be aware of this entity when performing intraoperative frozen sections as, after diagnosis, testicle-sparing surgery is adequate. The authors present a typical case with immunohistochemical studies and a review of the literature.

Abstract Purpose: The goals of this study were (a) to investigate whether preconditioning of immunocompetent mice with PC-61-mediated regulatory T-cell (Treg) depletion and interleukin-2 (IL-2) would enhance systemic delivery of reovirus into subcutaneous tumors and (b) to test whether cyclophosphamide (CPA), which is clinically approved, could mimic PC-61 for modification of Treg activity for translation into the next generation of clinical trials for intravenous delivery of reovirus. Experimental Design: C57Bl/6 mice bearing subcutaneous B16 tumors were treated with CPA or PC-61 followed by 10 injections of low-dose IL-2. Mice were then treated with intravenous reovirus. Virus localization to tumor and other organs was measured along with tumor growth and systemic toxicity. Results: Preconditioning with PC-61 and IL-2 enhanced localization of intravenous oncolytic reovirus to tumors with significantly increased antitumor therapy compared with controls (P < 0.01). However, with the maximal achievable dose of reovirus, Treg modification + IL-2 was also associated with systemic toxicity. CPA (100 mg/kg) did not deplete, but did functionally inhibit, Treg. CPA also mimicked PC-61, in combination with IL-2, by inducing “hyperactivated” NK cells. Consistent with this, preconditioning with CPA + IL-2 enhanced therapy of intravenously delivered, intermediate-dose reovirus to a level indistinguishable from that induced by PC-61 + IL-2, without any detectable toxicity. Conclusion: With careful reference to ongoing clinical trials with dose escalation of reovirus alone and in combination with CPA, we propose that future clinical trials of CPA + IL-2 + reovirus will allow for both improved levels of virus delivery and increased antitumor efficacy.

Abstract We previously showed that elevated expression of either protein kinase CβII (PKCβII) or PKCι/λ enhances colon carcinogenesis in mice. Here, we use novel bitransgenic mice to determine the relative importance of PKCβII and PKCι/λ in colon carcinogenesis in two complimentary models of colon cancer in vivo. Bitransgenic mice overexpressing PKCβII and constitutively active PKCι (PKCβII/caPKCι) or kinase-deficient, dominant-negative PKCι (PKCβII/kdPKCι) in the colon exhibit a similar increase in colon tumor incidence, tumor size, and tumor burden in response to azoxymethane (AOM) when compared with nontransgenic littermates. However, PKCβII/kdPKCι mice develop predominantly benign colonic adenomas, whereas PKCβII/caPKCι mice develop malignant carcinomas. In contrast, PKCβ-deficient (PKCβ−/−) mice fail to develop tumors even in the presence of caPKCι. Our previous data indicated that PKCβII drives tumorigenesis and proliferation by activating β-catenin/Apc signaling. Consistent with this conclusion, genetic deletion of PKCβ has no effect on spontaneous tumorigenesis in Apcmin/+ mice. In contrast, tissue-specific knockout of PKCλ significantly suppresses intestinal tumor formation in Apcmin/+ mice. Our data show that PKCβII and PKCι/λ serve distinct, nonoverlapping functions in colon carcinogenesis. PKCβII is required for AOM-induced tumorigenesis but is dispensable for tumor formation in ApcMin/+ mice. PKCι/λ promotes tumor progression in both AOM- and Apcmin/+-induced tumorigenesis. Thus, PKCβII and PKCι, whose expression is elevated in both rodent and human colon tumors, collaborate to drive colon tumor formation and progression, respectively. [Cancer Res 2009;69(2):656–62]

Background: Identification of highly active individuals early after acute anterior cruciate ligament deficiency who are good candidates for nonoperative management is a clinical challenge. The University of Delaware has developed and validated a treatment algorithm and screening examination to distinguish between nonoperative and surgical candidates. Study Design: Review. Evidence Acquisition: A description of the decision-making rules and rehabilitation protocol for highly active individuals with anterior cruciate ligament deficiency is provided. Results from clinical trials, outcome studies, and biomechanical investigations conducted using the treatment algorithm and screening examination are also reviewed. Results: Patients identified as nonoperative rehabilitation candidates using these clinical guidelines have a far greater success rate than what has been reported when patients self-select nonoperative management. Furthermore, nonoperative outcomes are improved when patients participate in a perturbation-enhanced rehabilitation protocol. Divergent lower extremity movement patterns are consistent with the different functional abilities of the dichotomous patient groups identified with the screening examination. Conclusion: Given the differential patient response to anterior cruciate ligament injury, implementation of the decision-making guidelines discussed in this review offers clinicians the opportunity to provide individualized patient care rather than continuing with a blanket surgical treatment strategy.

ABSTRACT Death receptors are members of the tumor necrosis factor receptor superfamily characterized by a cytoplasmic region known as the “death domain” that enables the receptors to initiate cytotoxic signals when engaged by cognate ligands. Binding to the ligand results in receptor aggregation and recruitment of adaptor proteins, which, in turn, initiates a proteolytic cascade by recruiting and activating initiator caspases 8 and 10. Death receptors were once thought to primarily induce cytotoxic signaling cascades. However, recent data indicate that they initiate multiple signaling pathways, unveiling a number of nonapoptosis‐related functions, including regulation of cell proliferation and differentiation, chemokine production, inflammatory responses, and tumor‐promoting activities. These noncytotoxic cascades are not simply a manifestation of inhibiting proapoptotic pathways but are intrinsically regulated by adaptor protein and receptor internalization processes. Insights into these various death receptor signaling pathways provide new therapeutic strategies targeting these receptors in pathophysiological processes.—Guicciardi, M.E., Gores, G.J. Life and death by death receptors. FASEB J. 23, 1625–1637 (2009)

Purpose The US Gastrointestinal Intergroup Radiation Therapy Oncology Group 98-11 anal carcinoma trial showed that cisplatin-based concurrent chemoradiotherapy resulted in a significantly higher rate of colostomy compared with mitomycin-based therapy. Established prognostic variables for patients with anal carcinoma include tumor diameter, clinical nodal status, and sex, but pretreatment variables that would predict the likelihood of colostomy are unknown. Methods A secondary analysis was performed by combining patients in the two treatment arms to evaluate whether new predictive and prognostic variables would emerge. Univariate and multivariate analyses were carried out to correlate overall survival (OS), disease-free survival, and time to colostomy (TTC) with pretreatment and treatment variables. Results Of 682 patients enrolled, 644 patients were assessable and analyzed. In the multivariate analysis, tumor-related prognosticators for poorer OS included node-positive cancer (P ≤ .0001), large (> 5 cm) tumor diameter (P = .01), and male sex (P = .016). In the treatment-related categories, cisplatin-based therapy was statistically significantly associated with a higher rate of colostomy (P = .03) than was mitomycin-based therapy. In the pretreatment variables category, only large tumor diameter independently predicted for TTC (P = .008). Similarly, the cumulative 5-year colostomy rate was statistically significantly higher for large tumor diameter than for small tumor diameter (Gray's test; P = .0074). Clinical nodal status and sex were not predictive of TTC. Conclusion The combined analysis of the two arms of RTOG 98-11, representing the largest prospective database, reveals that tumor diameter (irrespective of the nodal status) is the only independent pretreatment variable that predicts TTC and 5-year colostomy rate in patients with anal carcinoma.