Blockade of CCR5 in melanoma: An alternative immune checkpoint modulator

Melanoma is a deadly tumor, which in recent years has been successfully treated with immune checkpoint inhibitors as PD-1/PD-L1 and CTLA-4 inhibitors and targeted therapy as BRAF and MEK inhibitors. However, immunotherapy poses deleterious side effects and pursuit of new therapeutic targets is warranted. As knowledge of tumor immunology advances, such targets are being recognized. C-motif chemokine receptor-5 (CCR5) is a receptor found on immune cells whose effects impact the immune response both to induce inflammation and to activate suppressor cells causing an anti-inflammatory effect. CCR5 is well known as a target for HIV therapy where its blockade is efficient and safe, it is also known that its mutation CCR5delta32 is for the most part non-pathological to its carriers. In oncology, activation of the CCR5 receptor has been observed in high-stage disease and CCR5 blockade has been associated with an increased immune response. In this letter, we build up the rationale to utilize CCR5 as a therapeutic target for metastatic melanoma.     

Postoperative radiotherapy of the prostate for patients undergoing radical prostatectomy with positive margins, seminal vesicle involvement and/or penetration through the capsule

A group of 159 patients previously reported as having margins positive for disease after radical prostatectomy with or without adjunctive postoperative radiation was reanalyzed to determine whether the reported benefit did indeed exist. Upon re-examination of the 159 patients 15 were identified who did not receive radical prostatectomy but who were analyzed as if they had received this therapy. An updated review of the total pool of 159 patients with analysis as to failure, death of any cause or death of prostatic cancer demonstrated no benefit of postoperative radiation therapy for margin positive disease. Exclusion of patients who did not receive radical prostatectomy and analysis as described also failed to identify any benefit of postoperative adjunctive radiation therapy.     

Increased Radiosensitivity as an Indicator of Genes Conferring Breast Cancer Susceptibility

PURPOSE: This paper briefly summarizes the research on increased radiosensitivity in breast cancer patients measured by the micronucleus test (MNT) and its association to genetic variants in DNA repair genes. More preliminary data are presented on the distribution of chromosomes and chromosome fragments in micronuclei (MN) in order to gain more information on clastogenic and aneugenic effects and better understand the phenotype of increased radiosensitivity. MATERIAL AND METHODS: Reports of relevant studies obtained from a search of PubMed and studies referenced in those reports were reviewed. In four patients with high MN frequency (three cancer patients, one control) and four probands with low MN frequency, the presence of chromosome fragments or whole chromosomes in MN was determined by fluorescence in situ hybridization analysis for chromosomes 1, 7, and 17. RESULTS: An increased MN frequency in breast cancer patients compared to controls has consistently been reported with high significance. Higher MN frequencies were observed in 20-50% of breast cancer patients. Chromosomal fragments of chromosome 17, but not of chromosomes 1 and 7 were more frequent in the probands with high MN frequency than in those with low frequency (p = 0.045). CONCLUSION: The MNT detects a cellular phenotype common to a portion of sporadic breast cancer patients. This phenotype is very likely to be genetically determined. For the genetic dissection of breast cancer susceptibility this phenotype may turn out to be more efficient than breast cancer itself. Additional parameters which can be measured simultaneously with the MN frequency may be able to further enhance its usefulness.     

Fusion of bone marrow-derived stem cells with cardiomyocytes in a heterologous in vitro model.

OBJECTIVE: Recent studies have demonstrated that transplanted bone marrow-derived stem cells (BMCs) possess a broad differentiation potential and are able to form new cardiomyocytes. However, the identity of BMCs as true cardiomyocytes is still ambiguous. Therefore, we investigated the fate of transplanted fluorescence labeled BMCs and cardiomyocytes in co-culture. METHODS: For cell tracking we used two different fluorescent probes, Vybrant/DiO and Vybrant/DiI. BMCs were taken from human sternal marrow, purified using a Ficoll-gradient-centrifugation, treated with 5-azacytidine and stained with Vybrant/DiO. Furthermore, isolated spontaneous beating cardiomyocytes of neonatal rats (CM) were labeled with Vybrant/DiI. Thereafter, the BMCs were transplanted into CM-cultures and investigated on day 1, 4, 7, 14 and 28 using two-color fluorescence phenotyping by laser-scanning-cytometry (LSC). Two-color positive cells were harvested by patch-clamp technique and beta-MHC mRNA expression was analyzed by single-cell PCR. RESULTS: Two different morphological phenotypes were observed by LSC. First, isolated DiO labeled BMCs without contact or with direct cell contact to DiI labeled CMs. Second, some BMCs and CMs were double positive for DiO/DiI spontaneously forming hybrids. This population increased by 18% from day 1 to 4 and decreased only slightly until day 28. Additionally, few two-color positive cell formations expressed both human and rat specific beta-MHC mRNA as well as only human beta-MHC mRNA indicating that cell-fusion and transdifferentiation has occurred. CONCLUSION: These observations provide in vitro evidence for spontaneous cell fusion and transdifferentiation of BMCs in co-culture, raising the possibility that the observed phenomenons may contribute to development or maintenance of these cell types.     

Epididymal cystadenomas in von Hippel-Lindau disease

Objectives. Epididymal cystadenomas (ECs) are frequently found in association with von Hippel-Lindau disease (VHL), but little has been reported about their sonographic appearance. We review the sonographic appearance of ECs, the relationship of ECs to other manifestations of VHL, and the specific genetic mutations associated with ECs.Methods. Fifty-six male patients with VHL were examined with scrotal sonography and physical examination as part of a larger screening program for VHL. The head of the epididymis was measured in two planes on sonography and compared with age-matched normal controls. All VHL patients with palpable epididymal abnormalities or enlargement (more than two standard deviations) of the head of the epididymis on ultrasound were considered positive for EC.Results. Thirty of 56 (54%) male patients with VHL demonstrated a unilateral (n = 10; 33%) or bilateral (n = 20; 67%) solid abnormality in the head of the epididymis suggestive of EC. Sonographic appearances ranged from a solid mass with multiple tiny cysts to an almost completely solid mass. The most common appearance was a 15- to 20-mm solid mass with small cystic components. Dilated efferent ductules were seen within the testicle in 7 men, evidently a result of chronic obstruction. There was no association between the clinical subtype of VHL and the presence of ECs (P >0.10, chi square). Mutations resulting in a truncated gene product were associated with the development of ECs but the association did not reach statistical significance (P = 0.06).Conclusions. ECs are a common manifestation of VHL in men and exhibit a range of appearances on ultrasound. Sonography can be used to identify ECs and determine the extent of cystic dilation of the rete testes. The benign course of ECs and the usual absence of clinical symptoms favor a conservative approach to their management.     

Simple renal cysts, atypical renal cysts, and renal cell carcinoma in von Hippel-Lindau disease: a lectin and immunohistochemical study in six patients

We compare the expression of four markers of renal tubular differentiation in six renal cell carcinomas, five atypical renal cysts, and five simple renal cysts from six patients with von Hippel-Lindau disease. Proximal tubular markers were expressed by five of six renal cell carcinomas, three of five atypical renal cysts, and zero of five simple renal cysts. Distal tubular markers were expressed by one of six renal cell carcinomas, five of five atypical renal cysts, and four of five simple renal cysts. One of the three atypical cysts which expressed distal tubular markers was associated with a renal cell carcinoma which also expressed distal tubular markers. Our findings suggest that simple renal cysts in von Hippel-Lindau disease arise more commonly from distal rather than proximal tubules, while atypical renal cysts show tubular origin similar to renal cell carcinomas.     

Intraoperative management of penile erection with intracorporeal phenylephrine during endoscopic surgery

Intraoperative penile tumescence during endoscopic surgery is a troublesome complication that often is refractory to recommended methods of management. We report a new approach of pharmacological management with intracorporeal penile injections of phenylephrine (total dose of 0.1 mg.), which was successful in 3 successive patients. This approach is prompt, safe and reproducible, and it provides sustained resolution of erection without systemic side effects. It is concluded that local intracorporeal penile administration of this sympathomimetic agent appears to be a potent new tool in the armamentarium of the endoscopic surgeon dealing with this frustrating clinical situation, which merits further clinical trial.     

Suramin inhibits bone resorption and reduces osteoblast number in a neonatal mouse calvarial bone resorption assay.

The antineoplastic properties of suramin, a polyanionic agent with demonstrated antigrowth factor activity, are under evaluation in vitro, in vivo, and in clinical trials. Suramin has been shown to have antitumor activity in patients with advanced, hormone refractory prostate cancer. During these trials, significant resolution of osseous pain was observed in nearly three quarters of the patients treated with suramin. To evaluate the effect of suramin on bone cells, we studied the effect of suramin on bone resorption in a neonatal mouse calvarial assay. Suramin inhibited bone-resorbing activity in a dose-related fashion and had an additive effect with calcitonin. Calvaria pretreated with suramin had less bone-resorbing activity, fewer attached osteoblasts, and less medium alkaline phosphatase activity than control calvaria. Suramin also inhibited osteoclastic release of tritiated proline from labeled bone in a dose-dependent fashion. The effect of metastatic prostate carcinoma on bone is incompletely understood, but may be moderated by tumor-produced factors and/or cytokines. The effects of several such agents, therefore, were examined in combination with suramin. Bone resorption induced by PTH, epidermal growth factor, tumor necrosis factor, and a tumor-produced factor, PTH related-protein, was blocked by suramin. The ability of suramin to inhibit the bone-resorbing effects of several cytokines suggests that its mechanism may involve direct action on bone metabolism. Autoradiography performed on calvaria treated with labeled suramin demonstrated heavy deposition of suramin on the outer surface of the matrix, adjacent to osteoblasts and osteoclasts lining the outer table, suggesting that bone cells may be subject to high local concentrations of the drug, in keeping with this hypothesis.