MicroRNA-371a-3p (miR371) has been suggested as a sensitive biomarker in testicular germ cell cancer (TGCC). We aimed to compare miR371 with the classical biomarkers α-fetoprotein (AFP) and β-human chorionic gonadotropin (hCGβ). Overall, 180 patients were prospectively enrolled in the study, with serum samples collected before and after orchiectomy. We compared the use of digital droplet PCR (RT-ddPCR) with the quantitative PCR used by others for detection of miR371. The novel RT-ddPCR protocol showed high performance in detection of miR371 in serum samples. In the study cohort, miR371 was measured using RT-ddPCR. MiR371 detected CS1 of the seminoma and the non-seminoma sub-types with a sensitivity of 87% and 89%, respectively. The total sensitivity was 89%. After orchiectomy, miR371 levels declined in 154 of 159 TGCC cases. The ratio of miR371 pre- and post-orchiectomy was 20.5 in CS1 compared to 6.5 in systemic disease. AFP and hCGβ had sensitivities of 52% and 51% in the non-seminomas. MiR371 is a sensitive marker that performs better than the classical markers in all sub-types and clinical stages. Especially for the seminomas CS1, the high sensitivity of miR371 in detecting TGCC cells may have clinical implications.
Background: The distribution of retroperitoneal lymph node metastases for patients with nonseminoma and a residual tumour of 10-49 mm in a population-based setting is unknown. This information is needed to justify selection of patients for a unilateral template resection. Objective: To describe the location of retroperitoneal metastases and recurrences in patients with nonseminoma germ cell tumour (NSGCT) with a residual tumour of 10-49 mm. Design, setting, and participants: RETROP is a population-based prospective observational mapping study of 213 patients in Sweden and Norway with a retroperitoneal residual tumour of 10-49 mm who underwent postchemotherapy retroperitoneal lymph node dissection for metastatic NSGCT during 2007-2014 with median follow-up of 100 mo. Patients were classified according to the testis primary tumour and the distribution of unilateral or bilateral lymph node metastases
Our aim was to investigate whether guinea pig urothelium-derived bioactivities compatible with the existence of urothelium-derived inhibitory factor could be demonstrated by in vitro serial bioassay and whether purinergic P1 receptor agonists, nitric oxide, nitrite or prostaglandins might explain observed activities. In a cascade superfusion system, urothelium-denuded guinea pig ureters were used as bioassay tissues, recording their spontaneous rhythmic contractions in presence of scopolamine. Urothelium-intact or -denuded guinea pig urinary bladders were used as donor tissues, stimulated by intermittent application of carbachol before or during the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), the adenosine/P1 nucleoside receptor antagonist 8-(p-sulfophenyl)theophylline (8-PST) or the cyclo-oxygenase inhibitor diclofenac infused to bath donor and bioassay tissues. The spontaneous contractions of bioassay ureters were unaltered by application of carbachol 1–5 µM in the presence of scopolamine 5–30 µM. When carbachol was applied over the urothelium-denuded bladder, the assay ureter contraction rate was unaltered. Introducing carbachol over the everted urothelium-intact bladder significantly inhibited the contraction frequency of the assay ureter, suggesting the transfer of an inhibitory activity from the bladder to the assay ureter. The transmissible inhibitory activity was not markedly antagonized by L-NAME, 8-PST or diclofenac, while L-NAME nearly abolished nitrite release from the urothelium-intact bladder preparations. We suggest that urothelium-derived inhibitory factor is a transmissible entity over a significant distance as demonstrated in this novel cascade superfusion assay and seems less likely to be nitric oxide, nitrite, an adenosine receptor agonist or subject to inhibition by administration of a cyclo-oxygenase inhibitor.
Background: Testicular germ cell tumours (TGCTs) are the most frequent tumour type among young, adult men. TGCTs can be efficiently treated, but metastases of the teratoma subtype, for which there are no circulating biomarkers, represent a challenge. Materials and Methods: Global microRNA expression in teratoma tissue and embryoid bodies was assessed using next-generation sequencing. Levels of microRNAs identified as potential biomarkers were obtained from serum of patients with teratoma and matched healthy men. Results: We identified miR- 222-5p, miR-200a-5p, miR-196b-3p and miR-454-5p as biomarker candidates from the tumour tissue and embryoid body screening but the expression of these microRNAs was very low in serum and not statistically different between patients and controls. miR-375-3p was highly expressed, being highest in patients with teratoma (p=0.012) but the levels of expression in serum from these patients and healthy controls overlapped. miR-371a-3p was not expressed in serum from patients with pure teratoma, only in patients with mixed tumours. Conclusion: The microRNA profiles of the teratoma subtype of TGCT and embryoid bodies were obtained and assessed for candidate circulating biomarkers, but none with high sensitivity and specificity for teratoma were identified in our study. We conclude that neither the proposed teratoma marker miR-375-3p nor miR-371a-3p are suitable as circulating teratoma markers.Testicular germ cell tumours (TGCT) are rare and account for less than 1% of all male cancer but represent the most common malignancy among young men between 15-40 years (1). The incidence of TGCT has been rising and is highest in men of northern European ancestry (2). Known main risk factors for TGCT are cryptorchism, prior diagnosis, increased adult height and a familial history of TGCT (3, 4). Gain of chromosome 12p and aneuploidy are found in nearly all cases (5) and more than 40 susceptibility loci with moderate risk have been identified (6, 7). These include KIT and KRAS, but with no major high-risk genes (8-10). Although genetic risk factors are observed, the rapid increase in TGCT incidence seen in Western countries since the 1950s cannot be explained by genetic factors alone. A gene-environmental model has been proposed where genetic factors work in concert with environmental and lifestyle factors (11). The associations of TGCT with environmental/lifestyle factors are debated and are generally considered weak, but include, among others, dietary intake, physical exercise, birth weight, exposure to hormones in utero, maternal smoking, parity and reduced gestational age (12).The majority of TGCTs are thought to arise from intratubular, incompletely differentiated embryonal cells where a failure in control of their latent developmental potential and reprogramming gives raise to germ cell neoplasia in situ (13,14). According to the World Health Organization's 2016 classification of testicular germ cell tumours, germ cell neoplasia in situ-derived tumours are further classified into seminom...
Background Both testicular germ cell tumours (TGCT) and neurodevelopmental disorders are associated with urogenital malformations. Few studies have investigated the association between psychiatric disorders and TGCT. We investigated whether history of any psychiatric or neurodevelopmental disorder is associated with increased risk or mortality of TGCT. Method This is a nested case–control study including 6166 TGCT patients diagnosed during 1992–2014, individually matched for age and calendar period to 61,660 controls. We calculated odds ratios (ORs) for the association between type of psychiatric diagnoses and TGCT risk. Among the cases, we used a cohort design and calculated hazard ratios (HRs) of the association between psychiatric diagnose and all-cause and TGCT-specific death. Results History of a neurodevelopmental disorder (attention deficit hyperactivity disorder, autism spectrum disorder and intellectual disabilities) was associated with an increased risk of seminoma (OR: 1.54; 1.09–2.19). Seminoma patients with neurodevelopmental disorders were younger (34 versus 38 years, p = 0.004) and had more stage IV disease (5.4% versus 1.2%) than those without. Psychiatric history overall was not associated with TGCT. Patient history of any psychiatric disorder was associated with an increased all-cause and TGCT-specific death. Conclusions We report an association between neurodevelopmental disorders and testicular seminoma, and an increased TGCT-specific mortality for TGCT patients with psychiatric disorders.
ObjectiveTo validate Vergouwe's prediction model using the Swedish and Norwegian Testicular Cancer Group (SWENOTECA) RETROP database and to define its clinical utility.Materials and methodsVergouwe's prediction model for benign histopathology in post‐chemotherapy retroperitoneal lymph node dissection (PC‐RPLND) uses the following variables: presence of teratoma in orchiectomy specimen; pre‐chemotherapy level of alpha‐fetoprotein; β‐Human chorionic gonadotropin and lactate dehydrogenase; and lymph node size pre‐ and post‐chemotherapy. Our validation cohort consisted of patients included in RETROP, a prospective population‐based database of patients in Sweden and Norway with metastatic nonseminoma, who underwent PC‐RPLND in the period 2007–2014. Discrimination and calibration analyses were used to validate Vergouwe's prediction model results. Calibration plots were created and a Hosmer–Lemeshow test was calculated. Clinical utility, expressed as opt‐out net benefit (NBopt‐out), was analysed using decision curve analysis.ResultsOverall, 284 patients were included in the analysis, of whom 130 (46%) had benign histology after PC‐RPLND. Discrimination analysis showed good reproducibility, with an area under the receiver‐operating characteristic curve (AUC) of 0.82 (95% confidence interval 0.77–0.87) compared to Vergouwe's prediction model (AUC between 0.77 and 0.84). Calibration was acceptable with no recalibration. Using a prediction threshold of 70% for benign histopathology, NBopt‐out was 0.098. Using the model and this threshold, 61 patients would have been spared surgery. However, only 51 of 61 were correctly classified as benign.ConclusionsThe model was externally validated with good reproducibility. In a clinical setting, the model may identify patients with a high chance of benign histopathology, thereby sparing patients of surgery. However, meticulous follow‐up is required.
Background: Chemotherapy or radiotherapy have been standard treatment for stage II seminomas with excellent survival but are associated with significant long-term treatment-related toxicities. Several prospective trials have shown primary retroperitoneal lymph node dissection (RPLND) to be an effective and safe alternative. The current SWENOTECA treatment program recommends primary RPLND in seminoma stage IIA to IIB ≤ 3 cm with 1-2 metastatic nodes as the standard treatment modality. We present preliminary results combined with data from Cologne. Methods: Within SWENOTECA, RPLND is centralized to 5 hospitals and Cologne is a tertiary centre for patients recruited from different parts of Germany. Both patients with recurrence after initial stage I disease and patients with primary stage IIA and IIB at diagnosis were included. We collected information on operation time, bleeding, peri- and postoperative complications. We also analyzed histologic outcome and whether adjuvant chemotherapy was given. We followed the patients for any recurrence of disease. Results: We have included 94 patients operated from May 2018 to November 2022. The number of operations per site varied from 4 to 28. The mean age of patients at time of RPLND was 41.8 years (range 21-79). Overall, 54 patients had recurrence after initial stage I disease and 40 patients had primary stage IIA/IIB disease at diagnosis (one missing data). At time of RPLND 62 patients had IIA-disease and 31 stage IIB-disease (one missing data). The histology from RPLND showed seminoma in 83 patients, benign/necrosis in eight patients, vital non-seminomatous GCT in one patient, teratoma only in one patient and lymphoma in one patient. Mean number of resected nodes was 19, and mean number of positive nodes were 1.5. Twenty-six patients (28%) were operated with robotic laparoscopic technique. Ten patients (10.6%) had a Clavien-Dindo postoperative complication > 2. Twenty-three of the patients were given adjuvant oncological treatment after RPLND, most of them one course of BEP. The patients have been followed for in median 18 months (range 2-59). Nine patients (9.6 %) have had recurrences, all but one in the first year after RPLND. Conclusions: Our early results of primary RPLND of seminomas IIA-IIB ≤ 3 cm are promising. Longer follow-up is required to ensure this as a safe treatment option.
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