Ronald L. Yap

Metronomic Low-Dose Chemotherapy Boosts CD95-Dependent Antiangiogenic Effect of the Thrombospondin Peptide ABT-510: A Complementation Antiangiogenic Strategy

Blocking angiogenesis is a promising approach in cancer therapy. Natural inhibitors of angiogenesis and derivatives induce receptor-mediated signals, which often result in the endothelial cell death. Low-dose chemotherapy, given at short regular intervals with no prolonged breaks (metronomic chemotherapy), also targets angiogenesis by obliterating proliferating endothelial cells and circulating endothelial cell precursors. ABT-510, a peptide derivative of thrombospondin, kills endothelial cell by increasing CD95L, a ligand for the CD95 death receptor. However, CD95 expression itself is unaffected by ABT-510 and limits its efficacy. We found that multiple chemotherapy agents, cyclophosphamide (cytoxan), cisplatin, and docetaxel, induced endothelial CD95 in vitro and in vivo at low doses that failed to kill endothelial cells (cytoxan > cisplatin > docetaxel). Thus, we concluded that some of these agents might complement each other and together block angiogenesis with maximal efficacy. As a proof of principle, we designed an antiangiogenic cocktail combining ABT-510 with cytoxan or cisplatin. Cyclophosphamide and cisplatin synergistically increased in vivo endothelial cell apoptosis and angiosuppression by ABT-510. This synergy required CD95, as it was reversible with the CD95 decoy receptor. In a mouse model, ABT-510 and cytoxan, applied together at low doses, acted in synergy to delay tumor take, to stabilize the growth of established tumors, and to cause a long-term progression delay of PC-3 prostate carcinoma. These antitumor effects were accompanied by major decreases in microvascular density and concomitant increases of the vascular CD95, CD95L, and apoptosis. Thus, our study shows a “complementation” design of an optimal cancer treatment with the antiangiogenic peptide and a metronomic chemotherapy.

Pathological characteristics of prostate cancer detected through prostate specific antigen based screening.

PURPOSE Since the introduction of PSA testing for CaP, there has been an increase in CaP detection. However, it is uncertain to what extent clinically insignificant tumors are being diagnosed and treated. In a large, community based population we determined the pathological characteristics of screening detected cancers. MATERIALS AND METHODS From 1989 to 2001, 35,661 men were enrolled in a longitudinal prostate cancer screening study. Data were available on 3,492 of the 3,568 men (98%) diagnosed with CaP during this study period. Radical prostatectomy was performed in 2,254 men (63%). Clinical stage, Gleason score and pathological analysis were recorded and analyzed in the context of preoperative PSA, digital rectal examination findings, PSA velocity and the year of cancer detection. RESULTS CaP was detected in 10% of men. Virtually all cases were clinically localized (99.8%) and approximately 70% treated with radical prostatectomy were pathologically organ confined disease. Fewer than 10% of tumors would be considered clinically insignificant based on 2 previously published pathological criteria. CONCLUSIONS Compared to the high prevalence of CaP found in autopsy studies there is a lower detection rate using current screening protocols. Although the outcomes are unknown if these tumors had been left untreated, the majority met pathological criteria for significant cancer.

In vivo upregulation of CD95 and CD95L causes synergistic inhibition of angiogenesis by TSP1 peptide and metronomic doxorubicin treatment.

Antiangiogenic thrombospondin-1 (TSP1) induces endothelial cell death via a CD95-mediated cascade. We used this signaling pathway, where CD95/Fas is a rate-limiting intermediate, as a target to optimize the efficacy of TSP1 active peptide, DI-TSP. Like TSP1, DI-TSP upregulated endothelial CD95L in vivo. To modulate CD95 levels, we chose chemotherapy agent doxorubicin (DXR). DXR caused sustained upregulation of CD95 in the activated endothelium at 1/100 of the maximal tolerated dose. DI-TSP and DXR synergistically induced endothelial apoptosis in vitro, and in vivo, in developing murine vessels. Fas decoy, TSP1 receptor antibody and Pifithrin, a p53 inhibitor, severely decreased apoptosis and restored angiogenesis by DXR–DI-TSP combination, evidencing critical roles of CD95 and TSP1. Combined therapy synergistically blocked neovascularization and progression of the bladder and prostate carcinoma. Such informed design of a complex antiangiogenic therapy based on the rate-limiting molecular targets is a novel concept, which may yield new approaches to cancer treatment.

Inflammatory pseudotumor of the testis: A novel presentation of acute retroviral syndrome

Abstract  Inflammatory pseudotumors are a rare entity, the etiology of which is not well understood. It has been postulated that these non‐neoplastic lesions are the result of a reaction to trauma, surgery, infection or local irritation, though in many cases an underlying cause is never found. In this case, a 30‐year‐old man with previously undiagnosed human immunodeficiency virus presented with a 2‐week history of painless right testicular mass measuring 1 × 1 cm. The patient underwent right radical orchiectomy with histopathological analysis revealing an inflammatory pseudotumor of the testis. Further work up pointed to acute retroviral syndrome as the likely cause.

Rapid ambulatory pathway laser prostatectomy is safe: results within the global period.

Study Type – Therapy (case series)

How Readable Is BPH Treatment Information on the Internet? Assessing Barriers to Literacy in Prostate Health:

Information about benign prostatic hyperplasia (BPH) has become increasingly accessible on the Internet. Though the ability to find such material is encouraging, its readability and impact on informing patient decision making are not known. To evaluate the readability of Internet-based information about BPH in the context of website ownership and Health on the Net certification, three search engines were queried daily for 1 month with BPH-related keywords. Website ownership data and Health on the Net certification status were verified. Three readability analyses were performed: SMOG test, Dale–Chall readability formula, and Fry readability graph. An adjusted SMOG calculation was performed to reduce overestimation from medical jargon. After a total of 270 searches, 52 websites met inclusion criteria. Mean SMOG grade was 10.6 (SD = 1.4) and 10.2 after adjustment. Mean Dale–Chall score was 9.1 (SD = 0.6), or Grades 13 to 15. Mean Fry graph coordinates (173 syllables, 5.1 sentences) corresponded to Grade 15. Seven sites (13%) were at or below the average adult reading level based on SMOG; none of the sites qualified based on the other tests. Readability was significantly poorer for academic versus commercial sites and for Health on the Net-certified versus noncertified sites. In conclusion, online information about BPH treatment markedly exceeds the reading comprehension of most U.S. adults. Websites maintained by academic institutions and certified by the Health on the Net standard have more difficult readability. Efforts to improve literacy with respect to urological health should target content readability independent of reliability.

Mannitol extravasation during partial nephrectomy leading to forearm compartment syndrome

We present the first known complication of forearm compartment syndrome after mannitol infusion during partial nephrectomy. We stress the importance of excellent intravenous catheter access and constant visual monitoring of the intravenous catheter site during and after mannitol infusion as ways to prevent this complication. Prompt recognition of compartment syndrome with appropriate intervention can prevent long-term sequelae.

Adenocarcinoma Arising From A Defunctionalized Bladder

A 45-year-old white man with a history of neurogenic bladder and imperforate anus presented to our clinic complaining of a dark red discharge from the penis. He had undergone ileal loop urinary diversion at age 6 with the bladder left in situ. The fecal stream was diverted with an end colostomy in 1981. Cystoscopy revealed a 5 cm. sessile tumor on the left anterior lateral wall of the bladder. Examination with the patient under anesthesia showed no bladder fixation. Biopsy of the tumor revealed muscle invasive bladder adenocarcinoma. Metastatic workup was negative. We then performed a radical cystoprostatectomy (fig. 1). Microscopic evaluation of the specimen revealed grade III mucinous adenocarcinoma with extensive intestinal metaplasia of the bladder mucosa (fig. 2). The prostate, seminal vesicles, urethra and ureters were free of tumor. The patient experienced a satisfactory recovery. He declined adjuvant radiation therapy and chemotherapy. Followup imaging at 6 months showed no evidence of local recurrence or metastatic disease.

Primary plasmacytoma of the testicle: a case report.

IntroductionExtramedullary plasmacytoma is a rare plasma cell neoplasm. Plasmacytomas are most commonly found in the head and neck region, but can occur in many other locations. They rarely occur in the testis, and are commonly associated with concurrent multiple myeloma at the time of diagnosis. Isolated plasmacytoma of the testis is exceedingly rare, with few cases reported in the literature.Case presentationA 72-year-old Caucasian man presented with a painless testicular mass treated by orchiectomy. The mass was determined to be plasmacytoma on pathological examination. At the time of diagnosis, our patient did not have multiple myeloma, and is currently undergoing chemotherapy for treatment of his disease.ConclusionIsolated plasmacytoma of the testicle is a rare cause of testicular mass, and is seldom reported in the literature. Patients with this disease require careful monitoring because of their high risk of progression to multiple myeloma. The diagnosis of testicular plasmacytoma can be challenging for primary care doctors and urologic specialists. This condition should be in the differential diagnosis in elderly men.

Trends in Urological Direct-to-Consumer Advertising during Prime-Time Television News Programs

Introduction: The purpose of this study is to characterize contemporary trends in direct‐to‐consumer advertising of urological pharmaceutical products on American prime‐time television programs. Television is the highest expenditure segment of the consumer drug marketing industry. The extent of advertising in urology and its potential impact on patients are not well understood. Methods: We retrospectively analyzed an indexed database of prime‐time news broadcasts on 5 national networks in the United States. The database was queried with the names of 77 urological pharmaceutical products to identify all commercials that aired during a 36‐month period between 2010 and 2013. Noncommercial segments were excluded. Descriptive and linear regression analysis was performed. Results: We analyzed 4,574 broadcasts, representing 3,067.5 hours of prime‐time television. A total of 2,068 commercials for 8 products and 4 urological indications were aired, including sildenafil and tadalafil for erectile dysfunction; 2 testosterone products for hypogonadism; fesoterodine, oxybutynin and solifenacin for overactive bladder; and sipuleucel‐T for metastatic castration resistant prostate cancer. Commercials for male oriented indications accounted for 90% of the sample. At least 1 urological advertisement was contained in 1,744 broadcasts (38%). The introduction of television marketing for newly approved testosterone supplementation products in 2012 corresponded to strongly linear growth in overall urological advertising, reaching peak levels in 2013. Conclusions: Urological pharmaceutical products have been consistently advertised on television. Commercials have extensively targeted male oriented indications. Viewers of national news programs were exposed to urological advertising during about 40% of broadcasts with steadily increasing exposure since 2012. Providers should be aware of these trends to contextualize demand and monitor prescribing patterns.