Chester B. Algood

Tumor-Associated Macrophages Mediate Immunosuppression in the Renal Cancer Microenvironment by Activating the 15-Lipoxygenase-2 Pathway

Renal cell carcinoma (RCC), the most common human kidney cancer, is frequently infiltrated with tumor-associated macrophages (TAM) that can promote malignant progression. Here, we show that TAMs isolated from human RCC produce substantial amounts of the proinflammatory chemokine CCL2 and immunosuppressive cytokine IL-10, in addition to enhanced eicosanoid production via an activated 15-lipoxygenase-2 (15-LOX2) pathway. TAMs isolated from RCC tumors had a high 15-LOX2 expression and secreted substantial amounts of 15(S)-hydroxyeicosatetraenoic acid, its major bioactive lipid product. Inhibition of lipoxygenase activity significantly reduced production of CCL2 and IL-10 by RCC TAMs. In addition, TAMs isolated from RCC were capable of inducing in T lymphocytes, the pivotal T regulatory cell transcription factor forkhead box P3 (FOXP3), and the inhibitory cytotoxic T-lymphocyte antigen 4 (CTLA-4) coreceptor. However, this TAM-mediated induction of FOXP3 and CTLA-4 in T cells was independent of lipoxygenase and could not be reversed by inhibiting lipoxygenase activity. Collectively, our results show that TAMs, often present in RCCs, display enhanced 15-LOX2 activity that contributes to RCC-related inflammation, immunosuppression, and malignant progression. Furthermore, we show that TAMs mediate the development of immune tolerance through both 15-LOX2-dependent and 15-LOX2-independent pathways. We propose that manipulating LOX-dependent arachidonic acid metabolism in the tumor microenvironment could offer new strategies to block cancer-related inflammation and immune escape in patients with RCC.

Circulating and tumor-infiltrating myeloid cell subsets in patients with bladder cancer

Both cancer‐related inflammation and tumor‐induced immune suppression are associated with expansion of myeloid cell subsets including myeloid‐derived suppressor cells. However, little known regarding characteristics of myeloid cells in patients with bladder cancer. In this study, we analyzed myeloid cells from peripheral blood (PBMC) and tumor tissue that were collected from patients with superficial noninvasive and invasive urothelial carcinomas. Our results demonstrate that PBMC from bladder cancer patients contain two major CD11b myeloid cell subsets: granulocyte‐type CD15high CD33low cells and monocyte‐type CD15low CD33high cells. The number of circulating granulocytic but not monocytic myeloid cells in cancer patients was markedly increased when compared to healthy individuals. Both myeloid cell subsets from cancer patients were highly activated and produced substantial amounts of proinflammatory chemokines/cytokines including CCL2, CCL3, CCL4, G‐CSF, IL‐8 and IL‐6. Granulocytic myeloid cells were able to inhibit in vitro T cell proliferation through induction of CD4+Foxp3+ T regulatory cells. Analysis of bladder cancer tissues revealed that tumors were infiltrated with monocyte–macrophage CD11b+HLA‐DR+ and granulocytic CD11b+CD15+HLA‐DR‐ myeloid cells. Collectively, this study identifies myeloid cell subsets in patients with bladder cancer. We demonstrate that these highly activated inflammatory myeloid cells represent a source of multiple chemokines/cytokines and may contribute to inflammation and immune dysfunction in bladder cancer.

Physical and emotional predictors of depression after radical prostatectomy.

Radical prostatectomy commonly results in urinary, sexual, and bowel dysfunction that bothers men and may lead to depressive symptomatology (hereafter depression) that occurs at a rate 4 times greater for men with prostate cancer than healthy counterparts. The purpose of this study was to assess depressive symptoms in men shortly after radical prostatectomy and to identify associated risk factors. Seventy-two men were interviewed 6 weeks after surgery. Measured were depression (Geriatric Depression Scale), self-efficacy (Stanford Inventory of Cancer Patient Adjustment), social support (Modified Inventory of Socially Supportive Behaviors), physical and emotional factors (UCLA Prostate Cancer Index), and social function (SF-36 subscale). Results indicate that men with high self-efficacy and less sexual bother were 45% and 55% less likely to have depressive symptoms, respectively. Findings from this study add to the limited amount of information on the complex relationship between prostate cancer treatment and depression in men.

Smoothelin immunohistochemistry is a useful adjunct for assessing muscularis propria invasion in bladder carcinoma

Bovio I M, Al‐Quran S Z, Rosser C J, Algood C B, Drew P A & Allan R W
(2010) Histopathology 56, 951–956 
Smoothelin immunohistochemistry is a useful adjunct for assessing muscularis propria invasion in bladder carcinoma

Combination therapy for renal cell cancer: what are possible options?

Antiangiogenic therapy has shown promise in the treatment of patients with renal cell carcinoma (RCC). Two classes of antiangiogenic drugs, the anti-vascular endothelial growth factor antibody bevacizumab and the tyrosine kinase inhibitors sorafenib, sunitinib and pazopanib, have shown efficacy in patients with RCC and are approved by the US Food and Drug Administration for treatment of this cancer. In practice, the clinical benefit of antiangiogenic drugs in RCC has been heterogeneous, and in patients who do respond, benefits are modest and/or short-lived. To improve efficacy, combination targeted therapy has been attempted, but with either very limited additional efficacy or nontolerable toxicities. Recent advances in the molecular understanding of tumor angiogenesis and mechanism of resistance, along with the rapid development of targeted drug discovery, have made it possible to further explore novel combination therapy for RCC.

Metastatic epithelioid trophoblastic tumor in a male patient with mixed germ-cell tumor of the testis.

This report describes a rare case of a concurrent epithelioid trophoblastic tumor (ETT) and a teratoma in a para-aortic lymph node from a 39-year-old male patient with the initial diagnosis of testicular malignant mixed germ-cell tumor. The metastatic lesion was excised 2 years after orchiectomy and chemotherapy. Microscopically, the metastatic lesion contained a teratoma component and dispersed small nests of cohesive chorionic-type intermediate trophoblastic cells, closely resembling gestational ETT in female patients. The diagnosis of ETT in this case was confirmed by stepwise immunohistochemistry. Demonstration of ETT as one of the histologic manifestations of recurrent testicular germ-cell tumors should encourage pathologists to recognize this unique feature in assessing posttreatment mixed germ-cell neoplasm. Furthermore, this case represents a unique opportunity to understand the pathobiology of trophoblastic neoplasms arising from germ-cell tumors.

Radiotherapy for spermatic cord sarcoma.

Objectives: Spermatic cord sarcomas are rare paratesticular tumors affecting older men. Current management is based on small series, case reports, and literature reviews, with surgery still the mainstay of treatment. Local-regional recurrence is common after definitive surgery (∼50%), but patients treated with adjuvant radiotherapy may have improved outcomes. Methods: We reviewed the outcomes of 15 patients with intermediate-grade to high-grade spermatic cord sarcomas treated with radiation at our institution from 1974 to 2009. Patients were treated to 40 to 60 Gy using conformal opposed anterior-posterior/posterior-anterior ports to the scrotum, inguinal canal, and lower pelvic wall with various beam energies. Some patients were managed with surgical exploration and resection, followed by radiotherapy and/or definitive surgery. More recently treated patients had an initial biopsy, followed by preoperative radiation or planned resection with postoperative radiation therapy. Results: No patient experienced a local recurrence. Two patients had regional nodal recurrences and 1 had distant metastases. All recurrences were in patients who had initial “exploration” with unexpected findings of sarcoma during surgery versus planned, definitive resection with planned adjuvant radiotherapy. At 5 years, overall survival was 53%, but cause-specific survival was 80%. Complications were minimal, with only 4 grade 2 or 3 toxicities and no grade 4 toxicities. Conclusions: Although most patients die from causes other than disease progression, this sarcoma carries grave morbidity. Optimizing the primary management is of utmost importance. Unplanned treatments complicate definitive therapy and increase the risk of local-regional contamination and recurrence. Proactive management is therefore consistent with sarcomas of other primary sites, ideally with preoperative radiotherapy and definitive resection.