Complications of bone metastases from malignant melanoma

Introduction: Metastatic bone disease (MBD) carries significant morbidity for patients with cancer. MBD from malignant melanoma (MM) is understudied. We examined the characteristics, morbidity, management and outcome of MBD in patients with MM. Methods: Patients with metastatic MM managed at two referral cancer centres in England were identified. Those with bone metastases (BMs) were selected. Patient and disease characteristics including skeletal related events (SREs) were extracted from medical records. The Kaplan Meier method was used to calculate median survival. Results: Five hundred and eighteen patients with metastatic MM were managed between years 2000 and 2008. Eighty nine (17.2%) patients had BMs and are the subject of this study. Median age at diagnosis was 53 years and 55% were males. BMs were identified at the time of diagnosis of metastatic disease in 68.5% patients. Sixty-six (74.2%) had multiple bone lesions and 80.9% had axial skeleton involvement. One hundred and twenty nine skeletal related events occurred in 59 (66.3%) patients (50 radiotherapy, 28 hypercalcaemia, 20 bone fractures, 18 spinal cord compression and 13 orthopaedic surgery). The annual skeletal morbidity rate was 2.5. Median survival from diagnosis of BMs was 17.3 weeks and was 5.6 weeks from the first episode of hypercalcaemia. Conclusion: MBD affects a clinically important proportion (17.2%) of patients with metastatic MM. It carries a substantial morbidity and mortality exceeding that caused by BMs from breast and prostate cancer. These patients should receive the currently licensed bone modifying agents and should be included in clinical trials addressing MBD

Surgery of primary melanomas

Surgery remains the mainstay of melanoma therapy, regardless of the tumor site. Only the early diagnosis combined with proper surgical therapy currently gives patients affected by this malignancy the chance for a full cure. The main goal of surgical therapy is to provide the local control of the disease and to secure long-term survival of the patient without reasonable functional and esthetic impairment. The recommended method of biopsy-excisional biopsy, as an initial diagnostic and, to some extent, therapeutic procedure-is performed under local anesthesia as an elliptical incision with visual clear margins of 1-3 mm and with some mm of subcutaneous tissue. The extent of radical excision of the primary tumor (or scar after excisional biopsy) is based on the histopathologic characteristics of the primary tumor and usually consists of 1-2 cm margins with primary closure. The philosophy behind conducted randomized clinical trials has been to find the most conservative surgical approach that is able to guarantee the same results as more demolitive treatment. This has been the background of the trials designed to define the correct margins of excision around a primary cutaneous melanoma. Much less definition can be dedicated to the surgical management of patients with non-cutaneous melanomas

Personalizing, not patronizing: the case for patient autonomy by unbiased presentation of management options in stage I testicular cancer

Testicular cancer (TC) is the most common neoplasm in males aged 15 to 40 years and approximately 65%-75% have clinical stage I (CSI) disease. Both surveillance and adjuvant chemotherapy may be applied with indistinguishable long-term survival rates. Therefore, the patient should decide based on risk factors and potential benefits and harms rather than adopting a uniform recommendation for al

The present and future of serum diagnostic tests for testicular germ cell tumours.

Testicular germ cell tumours (GCTs) are the most common malignancy occurring in young adult men and the incidence of these tumours is increasing. Current research priorities in this field include improving overall survival for patients classified as being 'poor-risk' and reducing late effects of treatment for patients classified as 'good-risk'. Testicular GCTs are broadly classified into seminomas and nonseminomatous GCTs (NSGCTs). The conventional serum protein tumour markers α-fetoprotein (AFP), human chorionic gonadotrophin (hCG) and lactate dehydrogenase (LDH) show some utility in the management of testicular malignant GCT. However, AFP and hCG display limited sensitivity and specificity, being indicative of yolk sac tumour (AFP) and choriocarcinoma or syncytiotrophoblast (hCG) subtypes. Furthermore, LDH is a very nonspecific biomarker. Consequently, seminomas and NSGCTs comprising a pure embryonal carcinoma subtype are generally negative for these conventional markers. As a result, novel universal biomarkers for testicular malignant GCTs are required. MicroRNAs are short, non-protein-coding RNAs that show much general promise as biomarkers. MicroRNAs from two 'clusters', miR-371-373 and miR-302-367, are overexpressed in all malignant GCTs, regardless of age (adult or paediatric), site (gonadal or extragonadal) and subtype (seminomas, yolk sac tumours or embryonal carcinomas). A panel of four circulating microRNAs from these two clusters (miR-371a-3p, miR-372-3p, miR-373-3p and miR-367-3p) is highly sensitive and specific for the diagnosis of malignant GCT, including seminoma and embryonal carcinoma. In the future, circulating microRNAs might be useful in diagnosis, disease monitoring and prognostication of malignant testicular GCTs, which might also reduce reliance on serial CT scanning. For translation into clinical practice, important practical considerations now need addressing.The authors would like to acknowledge grant funding from CwCUK/GOSHCC (M.J.M. N.C. grant W1058), SPARKS (M.J.M. N.C. grant 11CAM01), CRUK (N.C. grant A13080) MRC (M.J.M. grant MC_EX_G0800464) and National Health Service funding to the Royal Marsden/Institute of Cancer Research National Institute for Health Research Biomedical Research Centre for Cancer (R.A.H.). The authors also thank the Max Williamson Fund, the Josh Carrick Foundation and The Perse Preparatory School, Cambridge for support.This is the author accepted manuscript. The final version is available fromNature Publishing Group via https://doi.org/10.1038/nrurol.2016.17

miR-371a-3p Predicting Viable Tumor in Patients Undergoing Retroperitoneal Lymph Node Dissection for Metastatic Testicular Cancer: The SWENOTECA-MIR Study

Purpose: The SWENOTECA-MIR prospective multicenter study aims to assess the clinical value of miR-371a-3p as a novel marker in metastatic germ cell tumor patients undergoing retroperitoneal lymph node dissection (RPLND), to predict the presence of viable residual tumor. Materials and Methods: A total of 114 patients (86 nonseminomas, 28 seminomas) who underwent surgery for presumed metastatic disease pre chemotherapy (primary RPLND) and post chemotherapy RPLND were included. The expression of miR-371a-3p was evaluated using reverse transcription–digital droplet polymerase chain reaction before and after RPLND. Pre- and postoperative miR-371a-3p levels were statistically compared, and optimism-corrected performance calculations compared with conventional serum tumor markers. Associations were evaluated by logistic regression. Patients who underwent primary RPLND were categorized into seminoma and nonseminoma groups. Results: - Among the seminoma patients (n = 24) undergoing primary RPLND, all had normal conventional markers. Six patients received adjuvant treatment before surgery. miR-371a-3p exhibited a sensitivity of 74%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 21% for viable tumor. The levels of miR-371a-3p significantly decreased after surgery. In the nonseminoma group (n = 18) treated with primary RPLND, 22% had elevated conventional markers and 3 had received prior adjuvant treatment. miR-371a-3p showed a sensitivity of 34%, specificity of 88%, positive predictive value of 67%, and negative predictive value of 62% for the primary nonseminoma patients. No association was observed between stage or prior adjuvant treatment and the outcome of the miR test. In the postchemotherapy group (n = 72), the miR-371a-3p sensitivity was 9%, reducing to 0 when excluding patients with seminoma (n = 4). Teratomas and benign histology were essentially negative. Conclusions: Our study highlights miR-371a-3p as a fairly sensitive and highly specific marker for prechemotherapy seminomas, outperforming conventional markers. However, in prechemotherapy nonseminomas as well as in postchemotherapy patients, we observed low sensitivity and no significant differences in miR-371a-3p levels before and after surgery, suggesting limited utility for miR-371a-3p in this context. Testicular germ cell tumor (TGCT) is the most common cancer in young males, with rising incidence.1 Although treatment for metastatic TGCT is highly effective, the chemotherapy regimens used are associated with significant long-term side effects, including cardiovascular disease and secondary malignancies.2 Survivors may also experience excess mortality due to prior therapy.3 Staging and monitoring of TGCTs involve repeated CT and MRI, and measuring serum protein biomarkers beta human chorionic gonadotropin (β-hCG), alpha fetoprotein (AFP), and lactate dehydrogenase. However, the markers lack sensitivity and specificity, with 40% of all TGCTs being marker negative, especially seminomas and teratomas.4 Chemotherapy typically includes bleomycin, etoposide, and cisplatin (BEP) courses varying by clinical stage (CS) and risk group. Adjuvant treatment by one course of carboplatin or BEP is offered to selected CS I patients, according to the SWENOTECA protocol. BEP was administered as adjuvant treatment to seminoma patients within the randomized ABC-study.5 Surgery is indicated for nonseminoma patients with a visible residual tumor ≥ 10 mm in the retroperitoneum after first-line chemotherapy,5 while for seminoma patients with small retroperitoneal metastases, surgery is being evaluated as a primary treatment in prospective clinical trials.6-8 Retroperitoneal lymph node dissection (RPLND) is a complex surgical procedure, associated with perioperative morbidity and risk of long-term sequelae, including loss of antegrade ejaculation. In previous studies, 44% to 72% of RPLND patients harbored only necrosis or fibrosis in residual masses.9-11 Reliable diagnostic tools are needed to distinguish patients requiring RPLND from those who can be spared. In 2011, the microRNA clusters miR-302/367 and miR-371 to 373 were identified as potential novel markers for TGCTs.12 Subsequent research revealed miR-371a-3p as the most promising micro-RNA marker, as it has been found to be present in nearly all cases of TGCTs other than teratoma.13-16 Dieckmann et al demonstrated that miR-371a-3p expressed sensitivity and specificity over 90% in TGCTs at various CSs.14 Further studies reported similar results for miR-371a-3p in postchemotherapy patients with retroperitoneal residual masses or relapse.17,18 Teratomas have consistently shown negative results in miR-371a-3p measurements across various studies.19 To determine the clinical value of the lead candidate miR-371a-3p as a tumor marker, large prospective clinical trials are required. The first part of the SWENOTECA-MIR study on miR-371a-3p in 180 orchiectomy patients showed better performance than conventional markers, with an overall sensitivity of 89%.20 This study aims to assess miR-371a-3p expression before and after RPLND in TGCT patients, to evaluate its accuracy and potential as a predictor of viable disease, and to see whether cytoreductive surgery affects its values

A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation

Background Testicular dysgenesis syndrome (TDS) is a common disease that links testicular germ cell cancer, cryptorchidism and some cases of hypospadias and male infertility with impaired development of the testis. The incidence of these disorders has increased over the last few decades, and testicular cancer now affects 1% of the Danish and Norwegian male population. Methods To identify genetic variants that span the four TDS phenotypes, the authors performed a genome-wide association study (GWAS) using Affymetrix Human SNP Array 6.0 to screen 488 patients with symptoms of TDS and 439 selected controls with excellent reproductive health. Furthermore, they developed a novel integrative method that combines GWAS data with other TDS-relevant data types and identified additional TDS markers. The most significant findings were replicated in an independent cohort of 671 Nordic men. Results Markers located in the region of TGFBR3 and BMP7 showed association with all TDS phenotypes in both the discovery and replication cohorts. An immunohistochemistry investigation confirmed the presence of transforming growth factor beta receptor type III (TGFBR3) in peritubular and Leydig cells, in both fetal and adult testis. Single-nucleotide polymorphisms in the KITLG gene showed significant associations, but only with testicular cancer. Conclusions The association of single-nucleotide polymorphisms in the TGFBR3 and BMP7 genes, which belong to the transforming growth factor b signalling pathway, suggests a role for this pathway in the pathogenesis of TDS. Integrating data from multiple layers can highlight findings in GWAS that are biologically relevant despite having border significance at currently accepted statistical levels

The clinicopathological significance of monocarboxylate transporters in testicular germ cell tumors

Metabolic reprogramming is one of the hallmarks of cancer. The hyperglycolytic phenotype is often associated with the overexpression of metabolism-associated proteins, such as monocarboxylate transporters (MCTs). MCTs are little explored in germ cell tumors (GCTs), thus, the opportunity to understand the relevance of these metabolic markers and their chaperone CD147 in this type of tumor arises. The main aim of this study was to evaluate the expression of MCT1, MCT2, MCT4 and CD147 in testicular GCT samples and the clinicopathological significance of these metabolism related proteins.CNPq, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brasil (480119/2013-9 and 306195/2016-0)info:eu-repo/semantics/publishedVersio

Association of polymorphisms in genes encoding hormone receptors ESR1, ESR2 and LHCGR with the risk and clinical features of testicular germ cell cancer.

Testicular germ cell cancer (TGCC) is the most common malignancy in young men. Genetic variants known to be associated with risk of TGCC only partially account for the observed familial risks. We aimed to identify additional polymorphisms associated with risk as well as histological and clinical features of TGCC in 367 patients and 214 controls. Polymorphisms in ESR2 (rs1256063; OR=0.53, 95% CI: 0.35-0.79) and LHCGR (rs4597581; OR=0.68, 95% CI: 0.51-0.89, and rs4953617; OR=1.88, 95% CI: 1.21-2.94) associated with risk of TGCC. Polymorphisms in ESR1 (rs9397080; OR=1.85, 95% CI: 1.18-2.91) and LHCGR (rs7371084; OR=2.37, 95% CI: 1.26-4.49) associated with risk of seminoma and metastasis, respectively. SNPs in ESR1 (rs9397080) and LHCGR (rs7371084) were predictors of higher LH levels and higher androgen sensitivity index in healthy subjects. The results suggest that polymorphisms in ESR1, ESR2 and LHCGR contribute to the risk of developing TGCC, histological subtype, and risk to metastasis