The Microbiome and Genitourinary Cancer: A Collaborative Review.

CONTEXT: The recent discovery of the existence of a human genitourinary microbiome has led to the investigation of its role in mediating the pathogenesis of genitourinary malignancies, including bladder, kidney, and prostate cancers. Furthermore, although it is largely recognized that members of the gastrointestinal microbiota are actively involved in drug metabolism, new studies demonstrate additional roles and the potential necessity of the gastrointestinal microbiota in dictating cancer treatment response. OBJECTIVE: To summarize the current evidence of a mechanistic role for the genitourinary and gastrointestinal microbiome in genitourinary cancer initiation and treatment response. EVIDENCE ACQUISITION: We conducted a literature search up to October 2018. Search terms included microbiome, microbiota, urinary microbiome, bladder cancer, urothelial carcinoma, renal cell carcinoma, kidney cancer, testicular cancer, and prostate cancer. EVIDENCE SYNTHESIS: There is preliminary evidence to implicate the members of the genitourinary microbiota as causative factors or cofactors in genitourinary malignancy. Likewise, the current evidence for gastrointestinal microbes in dictating cancer treatment response is mainly correlative; however, we provide examples where therapeutic agents used for the treatment of genitourinary cancers are affected by the human-associated microbiota, or vice versa. Clinical trials, such as fecal microbiota transplant to increase the efficacy of immunotherapy, are currently underway. CONCLUSIONS: The role of the microbiome in genitourinary cancer is an emerging field that merits further studies. Translating microbiome research into clinical action will require incorporation of microbiome surveillance into ongoing and future clinical trials as well as expansion of studies to include metagenomic sequencing and metabolomics. PATIENT SUMMARY: This review covers recent evidence that microbial populations that reside in the genitourinary tract-and were previously not known to exist-may influence the development of genitourinary malignancies including bladder, kidney, and prostate cancers. Furthermore, microbial populations that exist at sites outside of the genitourinary tract, such as those that reside in our gut, may influence cancer development and/or treatment response.

Clinical and metabolic findings in a 6-year-old boy with a Leydig cell tumour.

AIM: To analyse the urinary steroid metabolome in a boy who had true precocious puberty after a Leydig cell tumour. METHOD: Case report and detailed description of clinical and metabolic findings in a 7-year-old-boy with a Leydig cell tumour. RESULTS: Before surgery, the urinary steroid metabolome showed an activation of an alternative route to gonadal androgens independent of dehydroepiandrosterone (DHEA). After surgery, the boy entered true precocious puberty. Under leuprolide acetate treatment, clinical and laboratory findings normalized. CONCLUSION: Central precocious puberty after precocious pseudopuberty may be more common than expected and should be considered in children with persistent or recurrent symptoms after initial treatment of precocious pseudopuberty. Patients with a Leydig cell tumour seem to reactivate the so-called 'back door pathway' of androgen production, which is independent of the classical route via DHEA.

Testicular choriocarcinoma metastatic to skin and multiple organs. Two case reports and review of literature.

Two cases of males with subcutaneous masses as the first clinical sign of testicular choriocarcinoma are reported. The urine and serum human chorionic gonadotropin (hCG) test confirmed high level hCG from male choriocarcinoma. These cases, although very rare, can be a great diagnostic and therapeutic challenge and should be considered in the differential diagnosis of subcutaneous masses occurring in young males.

Monitoring of chemotherapy-induced proteinuria using capillary zone electrophoresis.

Capillary zone electrophoresis (CZE) was investigated for its suitability to monitor proteinuria occurring during nephrotoxic drug therapy. Urine samples of tumor patients receiving chemotherapy consisting of carboplatin, etoposide, and ifosfamide were concentrated and desalted in microconcentrators and analyzed in two different alkaline CZE buffer systems. Reduction of electroosmotic flow (EOF) by the addition of putrescine increased the number of resolved protein peaks. Both CZE methods were linear between 2.5 and 50 microg/ml, exhibited satisfactory precision (relative standard deviation <10%) and were suitable for monitor the time course of proteinuria after chemotherapy administration. In contrast to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), CZE detected interindividual differences in protein patterns. Whereas these differences hampered a direct quantification of proteins in urine, they may contain information on the type or extent of kidney damage.

[Fragments of human chorionic gonadotropin (hCG): diagnosis of pregnancy and tumors]. / Fragmente des humanen Choriongonadotropins (hCG): Schwangerschafts- und Tumordiagnostik.

The pregnancy and tumor marker human chorionic gonadotropin (hCG) belongs to the family of the glycoprotein hormones. Information on epitope forming sequences of hCG and its subunits hCG alpha and hcg beta has significant impact on the examination of intra- and extracellular metabolism and the standardization of diagnostic assay systems. Variants of hCG appear in biological fluids with variable modifications on different parts of the molecule. These changes may influence the binding patterns of monoclonal antibodies (MCA), thereby causing erroneous results in hCG immunoassays. The aim of the present work was to investigate the influence of peptide bond cleavages and the loss of certain segments of the molecule, which were induced by proteases on the expression of the seven hCG alpha-(alpha 1-alpha 7), nine hCG beta- (beta 1-beta 9) and four hCG beta-core-fragment-epitopes (beta 10-beta 13), previously identified by us [1-10]. To this end, we digested hCG alpha and hCG beta with chymotrypsin. Hormone fragments were separated by high performance liquid chromatography (HPLC) and subsequently immunochemically examined by direct binding radioimmunoassay (DB-RIA), competitive RIA and immunoenzymometric assays (IEMA). Fractions containing hCG-like immunoreactivity were sequenced by Edman and carboxypeptidase-Y degradation. It appeared that: (I) Amino acids (AA) alpha 41-47 and the peptide bonds between AA alpha 40/41, alpha 47/48 and alpha 29/30 do not influence the expression of the 7 alpha-epitopes, (II) The absence of the hCG beta N-terminus plays a crucial role for the formation of epitopes beta 10 and beta 13. (III) Neither the presence nor the absence of the C-terminal peptide of hCG beta (hCG beta CTP, AA beta 114-145) has any importance for the expression of epitopes beta 1-beta 7 and beta 10-beta 13 (IV).(ABSTRACT TRUNCATED AT 250 WORDS)

Immunological recognition and clinical significance of nicked human chorionic gonadotropin in testicular cancer.

We studied the physical properties, immunological recognition, and clinical significance of nicked human chorionic gonadotropin (hCGn) in testicular cancer. Upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions, the beta-subunit of hCGn (hCG beta n) dissociated into two peptides, and, by reversed-phase chromatography, hCG beta n was found to be less hydrophobic than hCG beta. Immunologically, hCGn lacked two epitopes specific for holo-hCG (c1, c2), whereas at least five hCG beta epitopes (beta 1-beta 5) were preserved, and, as a result, recognition of hCGn by different hCG assays varied widely. In 309 sera and 88 urine samples from patients with seminomatous or nonseminomatous testicular cancer, hCG-only, hCG+hCGn, and hCG+hCGn+hCG beta+hCG beta n+hCG beta core-fragment assays gave parallel results. hCGn was more abundant in urine than in serum samples. In conclusion, hCGn lacks two conformationally dependent epitopes of hCG, causing a change in hydrophobicity and explaining its failure to react in certain holo-hCG assays. Recognition of hCGn, however, does not seem to be crucial in the routine use of serum hCG as a tumor marker in patients with testicular cancer.

Changes in urinary excretion of endothelin-1-like immunoreactivity in patients with testicular cancer receiving high-dose cisplatin therapy.

To assess the value of endothelin-1 (ET-1) in estimating renal injury in patients receiving high doses of cisplatin, urinary excretion of ET-1-like immunoreactivity (U-ET-1), beta 2-microglobulin (U-beta 2-MG), and N-acetyl-beta-d-glucosaminidase (NAG) were measured before, 1 week after, and 2 weeks after the administration of cisplatin in eight patients with testicular cancer (mean age, 33.3 years). Levels of U-ET-1/creatinine (Cr) during and 1 week after cisplatin treatment were significantly higher than before cisplatin treatment. There were no differences in U-ET-1/Cr levels during, 1 week after, and 2 weeks after cisplatin treatment. The level of U-beta 2-MG/Cr during cisplatin treatment was significantly higher than levels before, 1 week after, and 2 weeks after treatment. However, there were no differences in U-beta 2-MG/Cr levels before, 1 week after, and 2 weeks after cisplatin treatment. The level of U-NAG/Cr during cisplatin treatment was higher than levels before, 1 week after, and 2 weeks after treatment; U-NAG/Cr during cisplatin treatment was higher than levels before, 1 week after, and 2 weeks after treatment; U-NAG/Cr gradually decreased after cisplatin treatment. Among the three parameters, only U-ET-1/Cr maintained a higher level after cisplatin treatment. The U-beta 2-MG/Cr level returned most rapidly to normal after cisplatin treatment. Although U-ET-1/Cr did not show any significant correlation with U-NAG/Cr (r = 0.282, P = NS), it showed a significant correlation with U-beta 2-MG/Cr (r = 0.454, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Urinary endothelin-1-like immunoreactivity in young male patients with testicular cancer treated by cis-platinum: comparison with other urinary parameters.

1. Urinary excretion of endothelin-1-like immunoreactivity and urinary excretion of other parameters (beta 2-microglobulin, N-acetyl-beta-D-glucosaminidase and microalbumin) were measured before, within 1 week after and 2 weeks after the administration of cis-platinum in five young male patients with testicular cancer (mean age 33.0 years) and were compared. 2. Urinary endothelin-1-like immunoreactivity/creatinine during, 1 week after, and 2 weeks after cis-platinum treatment was significantly higher than before cis-platinum. There was no difference in urinary endothelin-1-like immunoreactivity/creatinine during, 1 week after and 2 weeks after cis-platinum. 3. Among the four parameters, urinary endothelin-1-like immunoreactivity/creatinine showed the highest level after cis-platinum treatment. Urinary beta 2-microglobulin/creatinine most rapidly returned to normal levels after cis-platinum. 4. Although urinary endothelin-1-like immunoreactivity/creatinine did not show any significant correlations with urinary N-acetyl-beta-D-glucosaminidase (r = 0.291, not significant) or urinary microalbumin/creatinine (r = 0.076, not significant), it showed a significant correlation with urinary beta 2-microglobulin/creatinine (r = 0.475, P < 0.05). 5. These results suggest that endothelin-1 may be a sensitive urinary parameter in detecting cis-platinum-induced renal tubular injury.

Granulocyte colony-stimulating factor inhibits the endogenous leukotriene production in tumour patients.

Granulocyte colony-stimulating factor (G-CSF) is virtually devoid of inflammatory side-effects when given to patients in therapeutic doses. This is in contrast to other haemopoietic cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) which may promote inflammatory reactions by increasing the number and/or activity of monocytes, eosinophils, mast cells and basophils. Inflammatory reactions to GM-CSF and IL-3 appear to be related to an increased formation of leukotrienes, known as potent mediators of allergy and inflammation. Here we report that, in contrast to GM-CSF or IL-3, G-CSF has the potential to inhibit the leukotriene production in vivo. G-CSF may thus act as an anti-inflammatory agent. The differential effects of G-CSF and other haemopoietins on endogenous leukotrienes may be of major clinical significance.

Melanotic neuroectodermal tumor of infancy. A case report of paratesticular primary with lymph node involvement.

A 17-month-old boy had a melanotic neuroectodermal tumor of infancy in the left paratesticular region affecting the retroperitoneal lymph nodes. Immunohistochemical and ultrastructural study showed phenotypical diversity of the proliferating cells within a spectrum of neuroectodermal differentiation. Urinary catecholamine levels were initially elevated but returned to normal values after complete eradication of the tumor. The patient received chemotherapy and is now well, without evidence of disease 28 months after surgery.

[Clinical study of epidermal growth factor in the urine of the patients with urological malignant tumor].

We measured epidermal growth factor (EGF) in the urine of 54 untreated patients with malignant tumors (7 prostatic cancer, 11 renal tumor, 31 bladder cancer, 3 renal pelvic tumor, 2 ureter tumor) in the Toyama Medical & Pharmaceutical University Hospital. We also measured EGF in the urine of 77 normal subjects (43 males, 34 females). Urinary concentration of EGF in normal subjects decreased with increasing age. It was significantly higher in females than males (p less than 0.05). Urinary concentration of EGF in patients with prostatic cancer or renal tumor was similar to that in normal subjects. The patients with prostatic cancer controlled by estrogen showed a slightly high level of EGF in the urine. In patients with renal tumor, urinary concentration of EGF decreased after nephrectomy. Patients with bladder cancer showed a significant decrease of EGF in the urine compared with normal subjects (p less than 0.05), and urinary concentration of EGF in the patients with bladder cancer of high stage was remarkably low. Low concentration of EGF in the urine was recognized in patients with renal pelvic tumor or ureter tumor. However, the relationship between the decrease of urinary concentration of EGF in these urothelial tumors and the growth of these tumors remains to be elucidated.

A case-control study of cancer among du pont employees with potential for exposure to dimethylformamide.

This case-control study was undertaken to determine whether the risk of developing cancers of the buccal cavity and pharynx (N = 39), liver (N = 6), prostate (N = 43), testis (N = 11), or malignant melanoma of the skin (N = 39) is related to exposure to dimethylformamide (DMF). Case and control subjects were obtained from four Du Pont plants. DMF is produced at one plant and used at the other three. Cancer cases identified from the company Cancer Registry comprise those reported among active male employees at the study plants during 1956 to 1985. For each case, two control subjects were selected, matched on sex, payroll class (wage or salary), birth year, and plant. To determine whether an employee could have been exposed to DMF during his career at the plant, all jobs with potential for exposure to DMF were identified. Each job was assigned an exposure ranking based on DMF industrial hygiene air monitoring, DMF metabolite (measured as N-methylformamide in urine) monitoring, and knowledge of the evolution of manufacturing processes and workplace exposure controls. Each employee's DMF exposure pattern was then characterized as (a) ever v never having been exposed to DMF and (b) highest DMF exposure experienced. Summary analyses for all plants combined showed no statistically significant association between ever having been exposed to DMF and subsequent development of cancers of the buccal cavity and pharynx, liver, malignant melanoma, prostate, and testis. Examined by plant site, prostate cancer at one plant was significantly elevated, based on three case subjects exposed out of four.(ABSTRACT TRUNCATED AT 250 WORDS)

Urine and semen cytomorphology in patients with testicular tumors.

Our original technique of preparing urinary and seminal sediment was modified in order to identify neoplastic cells in cases of testicular malignancies. In a series of 24 patients with testicular tumor-like conditions, 18 tumors were diagnosed, 12 cytologically. In one case, the result of cytological examination was falsely positive since histopathology revealed necrosis of the testicle only. The morphology of neoplastic cells in the seminal sediment is demonstrated.

Single agent activity of methotrexate in advanced non-seminomatous testicular germ cell tumours.

The single agent activity of methotrexate in non-seminomatous germ cell tumours (NSGCT), and thus the rationale for its inclusion in combination regimens, has never been documented clearly. We have therefore reviewed all patients with NSGCT treated in this hospital from 1967 to 1970. Seventeen patients were identified who had a rising HCG excretion and who were treated with methotrexate alone as first line chemotherapy. Nine patients (53%) obtained a partial remission and a further seven patients a reduction in HCG production that was less than one log. Methotrexate is an active agent in testicular germ cell tumours and should be of particular value in treating CNS disease where intrathecal treatment may be required.