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1.  Application of the Adult International Germ Cell Classification System to Pediatric Malignant Non-Seminomatous Germ Cell Tumors: A Report From the Children’s Oncology Group 
Pediatric blood & cancer  2008;50(4):10.1002/pbc.21304.
Background
The purpose of this analysis is to explore whether the International Germ Cell Classification Consensus (IGCCC) tumor marker criteria, developed for adult males with metastatic malignant germ cell tumors (MGCT), are prognostic among pediatric patients and whether tumor marker data may be relevant in pediatric risk stratification.
Procedure
The IGCCC was applied to 436 pediatric germ cell patients treated on Pediatric Intergroup Studies from 1990 to 1996. Multivariable Cox proportional hazards model identified prognostic variables; survival rates among IGCCC risk groups were compared using the log-rank test. Concordance and relative performance of IGCCC versus COG risk stratification was evaluated.
Results
Applying the IGCCC, 21% of pediatric patients were good risk (GR), 35% intermediate risk (IR), and 44% poor risk (PR). Only modest concordance between IGCCC and COG stratification systems was noted (49%). Nonetheless, the IGCCC identified a group of PR patients who had significantly worse event-free survival (EFS) versus GR/IR patients (6-year EFS 80% vs. 91%), which was similar to the difference observed using the COG system (6-year EFS 77% vs. 90%). The IGCCC performed well within subgroups for which the IGCCC is not intended (prepubertal, female, and non-metastatic patients).
Conclusions
Applying the IGCCC system to pediatric patients produces a different stratification than does the application of the COG system, although both are prognostic. Development of a de novo pediatric prognostic classification is warranted.
doi:10.1002/pbc.21304
PMCID: PMC3836436  PMID: 18085675
germ cell tumors; International Germ Cell Classification; pediatric germ cell tumors; risk stratification; tumor markers
2.  Low RBM3 Protein Expression Correlates with Clinical Stage, Prognostic Classification and Increased Risk of Treatment Failure in Testicular Non-Seminomatous Germ Cell Cancer 
PLoS ONE  2015;10(3):e0121300.
Background
Expression of the RNA-binding motif protein 3 (RBM3) has been shown to correlate with favourable clinicopathological parameters and prognosis in several cancer diseases. The aim of this study was to examine the expression and prognostic ability of RBM3 in patients with testicular non-seminomatous germ cell tumours (NSGCT).
Patients and Methods
Immunohistochemical RBM3 expression was analysed in tissue microarrays with tumours from 206 patients. Chi-square test was applied to analyze associations between RBM3 expression and clinicopathological parameters. Kaplan-Meier analysis was used to assess the impact of RBM3 expression on cancer-specific survival (CSS) and failure-free survival (FFS). Cox regression proportional hazards models were used to estimate the relative risk for failure.
Results
In the entire cohort, there was a significant association between clinical stage (p=0.044) and RBM3 expression. Weak RBM3 expression correlated with a significantly reduced FFS [79.3% versus 90.4% (p=0.019)] and CSS [87.5% versus 97.3% (p=0.047)]. For patients with metastatic disease (n = 88), significant associations were found between RBM3 expression and IGCCC group (p=0.007). The FFS was significantly inferior for patients with low tumour-specific RBM3 expression [59.3% versus 79.0% (p=0.013)], and this association remained significant in a multivariable model for patients with metastatic disease (HR=3.67; 95% CI 1.14, 11.89).
Conclusion
Low RBM3 expression is an independent predictor of treatment failure in metastatic NSGCT, in relation to the prognostic factors included in the International Germ Cell Consensus Classification (IGCCC). These findings suggest that RBM3 may be a potential biomarker for treatment stratification in patients with metastatic non-seminomatous germ cell tumours, and therefore merit further validation.
doi:10.1371/journal.pone.0121300
PMCID: PMC4374873  PMID: 25811459
3.  Late Relapse and Follow-up Protocols in Testicular Germ Cell Tumours: The Edinburgh Cancer Centre Experience and Review of the Literature 
Aims
To identify clinicopathological features and outcomes in patients with late relapse (LR) of testicular germ cell tumours (GCTs) in order to guide follow-up policy.
Materials and Methods
The Edinburgh Cancer Centre (ECC) database identified all patients diagnosed with testicular GCT between 1988 and 2002. Of 703 patients, six relapsed more than 24 months after their initial treatment. A retrospective casenote review was performed to extract clinical, pathological, treatment and outcome data.
Results
Six patients (0.85%) underwent late relapse. All patients presented initially with stage I disease and five were classified as good risk (International Germ Cell Consensus Classification, IGCCC). Median time to LR was 31 months. Two patients had previously relapsed less than 24 months from initial diagnosis. Markers at the time of relapse were normal in all patients. In all cases of late relapse disease was confined to axial lymphadenopathy. Three patients were treated with chemotherapy alone, two patients underwent surgical resection and one patient received combined treatment. All patients obtained a complete response and all remain disease free with a median follow-up of 52 months.
Conclusions
The incidence of late relapse in this series is low. Chemo-naive patients with LR were successfully salvaged with chemotherapy alone and patients previously exposed to cisplatin-based chemotherapy were salvaged with complete surgical excision. The optimal length of follow-up in patients with testicular germ cell tumours is not known and practice varies widely. In this cohort of 703 patients, only one patient who relapsed was picked up by additional clinic follow-up between 5 and 10 years. Thus, on the basis of this small series, the authors suggest that follow-up after five years may not be justified.
PMCID: PMC3161629  PMID: 21892262
follow-up; germ cell tumors; late relapse
4.  Identification and Validation of a Gene Expression Signature That Predicts Outcome in Adult Men With Germ Cell Tumors 
Journal of Clinical Oncology  2009;27(31):5240-5247.
Purpose
Germ cell tumor (GCT) is the most common malignancy in young adult men. Currently, patients are risk-stratified on the basis of clinical presentation and serum tumor markers. The introduction of molecular markers could improve outcome prediction.
Patients and Methods
Expression profiling was performed on 74 nonseminomatous GCTs (NSGCTs) from cisplatin-treated patients (ie, training set) and on 34 similarly treated patients with NSGCTs (ie, validation set). A gene classifier was developed by using prediction analysis for microarrays (PAM) for the binary end point of 5-year overall survival (OS). A predictive score was developed for OS by using the univariate Cox model.
Results
In the training set, PAM identified 140 genes that predicted 5-year OS (cross-validated classification rate, 60%). The PAM model correctly classified 90% of patients in the validation set. Patients predicted to have good outcome had significantly longer survival than those with poor predicted outcome (P < .001). For the OS end point, a 10-gene model had a predictive accuracy (ie, concordance index) of 0.66 in the training set and a concordance index of 0.83 in the validation set. Dichotomization of the samples on the basis of the median score resulted in significant differences in survival (P = .002). For both end points, the gene-based predictor was an independent prognostic factor in a multivariate model that included clinical risk stratification (P < .01 for both).
Conclusion
We have identified gene expression signatures that accurately predict outcome in patients with GCTs. These predictive genes should be useful for the prediction of patient outcome and could provide novel targets for therapeutic intervention.
doi:10.1200/JCO.2008.20.0386
PMCID: PMC3651602  PMID: 19770384
5.  Development and Validation of a Gene-Based Model for Outcome Prediction in Germ Cell Tumors Using a Combined Genomic and Expression Profiling Approach 
PLoS ONE  2015;10(12):e0142846.
Germ Cell Tumors (GCT) have a high cure rate, but we currently lack the ability to accurately identify the small subset of patients who will die from their disease. We used a combined genomic and expression profiling approach to identify genomic regions and underlying genes that are predictive of outcome in GCT patients. We performed array-based comparative genomic hybridization (CGH) on 53 non-seminomatous GCTs (NSGCTs) treated with cisplatin based chemotherapy and defined altered genomic regions using Circular Binary Segmentation. We identified 14 regions associated with two year disease-free survival (2yDFS) and 16 regions associated with five year disease-specific survival (5yDSS). From corresponding expression data, we identified 101 probe sets that showed significant changes in expression. We built several models based on these differentially expressed genes, then tested them in an independent validation set of 54 NSGCTs. These predictive models correctly classified outcome in 64–79.6% of patients in the validation set, depending on the endpoint utilized. Survival analysis demonstrated a significant separation of patients with good versus poor predicted outcome when using a combined gene set model. Multivariate analysis using clinical risk classification with the combined gene model indicated that they were independent prognostic markers. This novel set of predictive genes from altered genomic regions is almost entirely independent of our previously identified set of predictive genes for patients with NSGCTs. These genes may aid in the identification of the small subset of patients who are at high risk of poor outcome.
doi:10.1371/journal.pone.0142846
PMCID: PMC4666461  PMID: 26624623
6.  Oncological Outcomes in Japanese Men Undergoing Orchiectomy for Stage I Testicular Germ Cell Tumor 
Current Urology  2015;8(2):84-90.
Background
The objective of this study was to retrospectively review oncological outcomes in patients with stage I testicular germ cell tumor (GCT).
Patients and Methods
This study included 265 consecutive Japanese men undergoing orchiectomy for stage I testicular GCT, and a retrospective review of their records was performed.
Results
Of these 265 patients, 192 and 73 were pathologically classified with seminoma and nonseminoma, respectively. Prophylactic radiation and chemotherapy were performed in 62 patients with seminoma and 6 with nonseminoma, respectively. Disease recurrence occurred in 12 seminoma patients, of whom 11 had not received prophylactic radiation therapy; however, all 12 achieved a complete response to bleomycin, etoposide and cisplatin therapy. Of the nonseminoma patients, 19 experienced disease recurrence and were then treated with bleomycin, etoposide and cisplatin followed additionally by the surgical resection of residual tumors and salvage chemotherapy in 7 and 4, respectively. There was no cancer-specific death in the 265 patients, and 5-year recurrence-free survival rates in patients with seminoma and nonseminoma were 92.6 and 72.8%, respectively. Furthermore, following factors appeared to be significantly associated with recurrence-free survival in these patients: age, T classification, microvascular invasion and adjuvant therapy for those with seminoma, and microvascular invasion for those with nonseminoma.
Conclusions
Despite a generally favorable prognosis in Japanese men with stage I testicular GCT, intensive follow-up or prophylactic therapy should be considered for men with possible risk factors of disease recurrence.
doi:10.1159/000365695
PMCID: PMC4748785  PMID: 26889123
Stage I testicular germ cell tumor; Seminoma; Nonseminoma
7.  WHOLE EXOME SEQUENCING IDENTIFIED THAT THE MAPK AND PI3K PATHWAYS ARE THE MAIN TARGETS FOR MUTATIONS IN INTRACRANIAL GERM CELL TUMORS 
Neuro-Oncology  2014;16(Suppl 3):iii23.
BACKGROUND: Intracranial germ cell tumors (iGCTs) are rare in the Western countries, however they are the second most common brain tumors in patients under 14 in Japan. Unlike other common pediatric brain tumors, the biology of iGCTs is largely unknown. METHODS: We performed a whole exome sequencing in a large series of iGCTs to elucidate their molecular pathogenesis. A total of 198 germ cell tumors (GCTs) including 133 iGCTs (69 pure germinomas, 56 NGGCTs and 8 metastatic tumors) as well as 65 testicular germ cell tumors (tGCTs) (39 seminomas and 26 non-seminoma GCTs) were collected from 13 centers participating in the Intracranial Germ Cell Tumor Consortium in Japan. Somatic mutations in all coding exons were investigated by whole exome sequencing (WES) in 41 tumors and the matched normal DNAs. Based on the WES data, 41 candidate genes were selected according to the frequency and/or significance of the mutations found. All coding exons of these 41 genes spanning over 160kb were PCR-amplified in a further 157 GCTs and sequenced using the IonTorrent system. The results were integrated with the patients' clinical information that was available for 124 iGCT patients. RESULTS: On average, 15.4 non-synonymous somatic mutations were observed in each tumor, ranging from 1 to 140 by WES in 41 iGCTs. The combined WES and IonTorrent screenings showed that KIT was the most frequently mutated gene in both iGCTs (27%) and tGCTs (18%). MTOR was the second most frequently mutated also in both iGCTs (7%) and tGCTs (6%). RAS mutations (KRAS, HRAS, NRAS) were altogether found in 13% of iGCTs and 12% of tGCTs. These mutations were mutually exclusive to each other and also to KIT mutations. Collectively, the genes involved in the MAPK pathway (e.g., KIT, RAS, NF1) and the PI3K/MTOR pathway (e.g., MTOR, PTEN) were mutated in 44% and 13% of all GCTs. Among the iGCTs, these alterations were significantly more common among pure germinomas than NGGCTs. The mutated MTOR protein was shown to have increased kinase activity, which was suppressed by specific MTOR inhibitors. CONCLUSIONS: Our comprehensive mutational genomic analysis of GCTs revealed that alterations of the MAPK and/or PI3K/MTOR pathways play a critical role in the pathogenesis of both iGCTs and tGCTs, although the extent of their involvement depends on the histopathological subtypes. Our findings will hopefully lead to the development of a targeted therapy for treatment-resistant iGCTs. SECONDARY CATEGORY: Tumor Biology.
doi:10.1093/neuonc/nou208.2
PMCID: PMC4144564
8.  Survival outcomes for men with mediastinal germ-cell tumors: The University of Texas M. D. Anderson Cancer Center experience✩ 
Urologic oncology  2010;30(6):879-885.
Objective
Primary mediastinal germ-cell tumors are rare, and the effect of newer drugs and treatment strategies in this disease on overall survival is not known. We retrospectively assessed treatment outcomes at a single institution.
Materials and methods
We identified men seen at our institution from 1998 through 2005 for mediastinal germ-cell tumors. Medical records were reviewed for patient characteristics, histology, tumor markers, treatment, and survival outcome.
Results
Thirty-four patients met study criteria, of whom 27 had nonseminomatous germ-cell tumor (NSGCT) and 7 had pure seminoma. Eleven patients (41%) with NSGCT were alive at last contact with a median overall survival time of 33.5 months. Among 13 patients with NSGCT referred to us at initial diagnosis, 7 (54%) were alive and recurrence-free at a median follow-up of 56.5 months. Progression-free survival was associated with absence of risk factors (any histology other than endodermal sinus tumor, β-hCG > 1000 mIU/mL, or disease outside the mediastinum). For the patients whose disease progressed (n = 5) or who had been referred to us for salvage treatment (n = 14), the 3-year overall survival from the date of first progression was 23%. Conversely, patients with seminoma did uniformly well with platinum-based chemotherapy; most did not undergo radiation or surgery.
Conclusion
Chemotherapy given to maximum effect followed by surgical consolidation resulted in long-term progression-free survival for 54% of patients with mediastinal NSGCT. The number of risk factors present at diagnosis may be associated with survival outcome and should be studied in a larger test group.
doi:10.1016/j.urolonc.2010.08.005
PMCID: PMC3956468  PMID: 20933444
Mediastinal neoplasms; Germ-cell neoplasms; Seminoma; Tumor markers; Resection; Outcome
9.  The epidemiology of cutaneous malignant melanoma in Nova Scotia 
BACKGROUND:
Since 1993, the annual increase in cutaneous malignant melanoma (MM) incidence has been one of the highest for all cancers registered in Canada, with the leading rate in Nova Scotia (NS). The purpose of the present study was to document the pathological and epidemiological data on MM cases found in NS.
PATIENTS AND METHODS:
All MM cases identified by the Nova Scotia Cancer Registry from January 1998 to December 2002 were evaluated. The five-year survival outlook, by major prognostic factors, was also determined. In addition, the annual incidence and mortality rates from 1972 to 2002 were computed.
RESULTS:
Between 1998 and 2002, 925 MM cases were recorded. The age-standardized incidence rate for males and females in this period was 19.2 and 16.1 per 100,000 respectively. Men 65 years of age or older had the highest age-specific rate. The most common MM had a Breslow’s depth of less than 1.0 mm (61.9%) and was Clark’s level II (34.9%). There was no significant seasonal variation noted in the time of diagnosis. Survival analyses indicated that sex, age, tumour location and thickness were significant independent predictors. Despite the increase in incidence, there have only been modest changes in the annual mortality rate.
CONCLUSION:
The incidence of MM in NS increases with age, and is nearly double for men 65 years of age or older, compared with women in the same age group. Thin melanomas on the extremities of young females have the best prognosis in NS, which is similar to other parts of the world. Incidence appears to be unrelated to season. Public health interventions are necessary to reduce the burden of this disease.
PMCID: PMC2686053  PMID: 19554137
Canada; Cancer registry; Epidemiology; Melanoma; Nova Scotia
10.  Sequential bilateral testicular tumours presenting with intervals of 20 years and more 
BMC Urology  2013;13:71.
Background
About 3 – 5% of all patients with testicular germ cell tumour (GCT) develop a contralateral cancer, the majority of which arise within 10–15 years. Little is known about the risk of second GCTs after more than two decades. Here we present 3 cases with very late presenting contralateral GCT and provide a summary of similar cases reported previously.
Case presentations
(1) This white Caucasian man underwent right-sided orchiectomy for a nonseminomatous GCT at the age of 22 years. Additional treatment consisted of retroperitoneal lymph node dissection (RPLND) and chemotherapy with 4 cycles of vinblastin / bleomycin. 36 years later, contralateral seminoma clinical stage 1 developed. Cure was achieved by orchiectomy. Histologically, testicular intraepithelial neoplasia (TIN; intratubular germ cell neoplasia) was detected in the tumour-surrounding tissue.
(2) This white Caucasian male had right-sided orchiectomy for nonseminomatous GCT at the age of 29 years. Pathological stage 1 was confirmed by RPLND. 25 years later, he received left sided orchiectomy for seminoma stage 1. Histologically, TIN was found in the tissue adjacent to seminoma. Two brothers had testicular GCT, too, one with bilateral GCT. (3) This 21 year old white Caucasian man underwent left-sided orchiectomy for nonseminomatous GCT. Pathological stage 1 was confirmed by RPLND. 21 years later, he received organ-preserving excision of a right-sided seminoma, followed by BEP chemotherapy for stage 3 disease. Histologically, TIN was found in the surrounding testicular tissue.
22 cases of bilateral GCT with intervals of 20 or more years have previously been reported, thereof three with intervals of more than 30 years, the longest interval being 40 years.
Conclusion
Apart from increased risks of cardiovascular diseases and non-testicular malignancies, patients with GCT face the specific probability of a second GCT in the long run. This risk persists life-long and is not eliminated by chemotherapy. Contralateral testicular biopsy can identify patients at risk by revealing precursor cells of GCT though false-negative biopsies may occur sporadically. However, in view of the multi-facetted late hazards of GCT patients, this minor surgical procedure might somewhat simplify the long-time care of these patients.
doi:10.1186/1471-2490-13-71
PMCID: PMC4028980  PMID: 24321309
Testicular germ cell neoplasms; Bilateral tumours; Testicular biopsy; Seminoma; Familial germ cell tumours
11.  Management consideration in nonpulmonary visceral metastatic seminoma of testis. 
Journal of Korean Medical Science  1999;14(4):431-437.
To develop a more appropriate therapeutic strategy for treatment of nonpulmonary visceral metastatic testicular seminoma based on the International Germ Cell Consensus Classification, we reviewed the medical records of patients with nonpulmonary visceral metastatic testicular seminoma who were treated over a 20-year period. Only 15 (2.2%) of the 686 cases of testicular seminoma were nonpulmonary visceral metastatic seminoma. The median age of patients was 38 years (range, 22-53 years). Ten (67%) of the patients had an initial diagnosis of supradiaphragmatic or visceral metastatic disease. In addition to nonpulmonary visceral metastasis, all patients had lymph node metastasis as well, the majority of which involved the retroperitoneal lymph nodes. The median and mean progression-free survival durations after chemotherapy for advanced disease were 19 months and 63.7 months, respectively. Six patients (40%) survived, five relapsed after radiation therapy and four died of chemorefractory disease not dependent on the specific regimen. Although the number of cases reviewed in this study was small, we conclude that the choice of chemotherapeutic regimen among the current treatments for nonpulmonary visceral metastatic seminoma of testis primary does not present a different outcome. Therefore, multimodality therapies using new strategies or new agents are well indicated.
PMCID: PMC3054405  PMID: 10485624
12.  Retroperitoneal Histology of Patients with Elevated Serum Alpha-Fetoprotein and Pure Seminoma at Orchiectomy 
Urology  2011;78(4):844-847.
Objectives
A histologic diagnosis of seminoma at orchiectomy with an elevation in serum alpha-fetoprotein (AFP) indicates the likelihood of unrecognized NSGCT elements. We report the retroperitoneal histology of a contemporary series of patients with pure seminoma at orchiectomy with an elevation in serum AFP that were managed as NSGCT.
Methods
We identified 22 patients between 1989 and 2009 with pure seminoma diagnosed at orchiectomy with an elevated serum AFP (> 15 ng/ml) either pre- or post-orchiectomy. Retroperitoneal histology and relapse data are reported.
Results
Median pre-orchiectomy and pre-chemotherapy serum AFP levels were 248 ng/ml (IQR 48, 4693) and 279 ng/ml (IQR 66, 5311), respectively. Percentage of patients with clinical stage I, II, and III was 5%, 50%, and 45%, respectively. Percentage of patients with IGCCCG good, intermediate, and poor risk status was 32%, 32%, and 36%, respectively. Twenty-one patients had induction chemotherapy followed by PC-RPLND. Overall, 67% of patients had NSGCT elements in the retroperitoneum. Histologic findings were pure teratoma in 38%, malignant transformation in 14%, and viable NSGCT in 14%. Fifty-nine percent had some component of teratoma in the RP. One patient (5%) had any seminoma in the RP, but this patient also had RP teratoma. Seven patients relapsed and received salvage chemotherapy. Actuarial relapse free survival at 5 and 10 years was 76% and 61% reflecting a high percentage of patients with stage II/III disease.
Conclusions
Pure seminoma at orchiectomy with an elevated serum AFP portends a high likelihood of harboring NSGCT elements in the RP.
doi:10.1016/j.urology.2011.02.002
PMCID: PMC4237276  PMID: 21782217
testicular cancer; seminoma; AFP; RPLND
13.  Prevalence of smoking among pregnant women in Nova Scotia from 1988 to 1992. 
OBJECTIVE: To determine the prevalence of smoking during pregnancy in Nova Scotia and to identify women at high risk of smoking during pregnancy. DESIGN: Population-based descriptive study. SETTING: All hospitals providing obstetric services in Nova Scotia. PATIENTS: All 60 754 women residing in Nova Scotia who had a baby in hospital between 1988 and 1992; smoking data were available for 57,750 (95.1%) of them. OUTCOME MEASURES: Proportion of women who smoked during pregnancy and the maternal smoking rates by age, marital status, parity, attendance at prenatal classes and residence. RESULTS: Overall, 32.4% of the women smoked at some point during their pregnancy. The rate was highest among the women less than 20 years of age (47.0%) and decreased with each increasing 5-year age interval. Overall, the unmarried women were 2.1 times as likely to smoke as the married women. The smoking rates were highest among the women who were para 3 or greater regardless of age (women less than 20 were excluded here, since very few had such a parity). Of the nulliparous women, those who attended prenatal classes were less likely to smoke during pregnancy than those who did not attend. There was no relation between urban or rural residence and smoking rates. The smoking rates decreased little between 1988 and 1992 and in fact increased among the women 35 and over and among those who were para 3 or greater. CONCLUSIONS: The smoking rates among pregnant women in Nova Scotia changed little between 1988 and 1992. Therefore, it seems that current strategies for smoking cessation have not been successful. Since prenatal classes are more likely to attract nonsmokers than smokers, other avenues for education and cessation are necessary.
PMCID: PMC1337573  PMID: 7820800
14.  Current Management of Testicular Cancer 
Korean Journal of Urology  2013;54(1):2-10.
Germ cell tumors (GCTs) of the testis are rare, but are the most common cancer in young men. GCTs may consist of one predominant histologic pattern or may represent a mixture of multiple histologic types. For treatment purposes, two broad categories are recognized: 1) pure seminoma and 2) others, which together are termed nonseminomatous GCTs (NSGCTs). In general, seminoma tends to be less aggressive, to be diagnosed at an earlier stage, and to spread predictably along lymphatic channels to the retroperitoneum before spreading hematogenously to the lung or other organs. Compared with NSGCTs, seminoma is exquisitely sensitive to radiation therapy and platinum-based chemotherapy. NSGCTs are usually mixed tumors and teratoma often exists at the sites of metastasis with other GCT elements; cure often requires chemotherapy to kill the chemosensitive-components and surgery to remove the teratomatous components. The main factors contributing to excellent cure rates of GCTs are careful staging at diagnosis; adequate early treatment using chemotherapeutic combinations, with or without radiotherapy and surgery; and very strict follow-up and salvage therapy. We review several clinical studies and summarize the current trends in the management of GCTs.
doi:10.4111/kju.2013.54.1.2
PMCID: PMC3556548  PMID: 23362440
Neoplasms; Testis; Therapeutics
15.  TI-CE High-Dose Chemotherapy for Patients With Previously Treated Germ Cell Tumors: Results and Prognostic Factor Analysis 
Journal of Clinical Oncology  2010;28(10):1706-1713.
Purpose
We previously reported a dose-finding and phase II trial of the TI-CE regimen (paclitaxel [T] plus ifosfamide [I] followed by high-dose carboplatin [C] plus etoposide [E] with stem-cell support) in germ cell tumor (GCT) patients predicted to have a poor prognosis with conventional-dose salvage therapy. We now report the efficacy of TI-CE with prognostic factors for disease-free survival (DFS) and overall survival (OS) in our full data set of 107 patients.
Patients and Methods
Eligible patients had advanced GCTs with progressive disease following chemotherapy and unfavorable prognostic features (extragonadal primary site, incomplete response [IR] to first-line therapy, or relapse/IR to ifosfamide-cisplatin–based conventional-dose salvage). Univariate and multivariate analyses (MVAs) of prognostic factors were performed. The predictive ability of the Einhorn and Beyer prognostic models was assessed.
Results
Most patients were platinum refractory and had an IR to first-line chemotherapy. There were 54 (5%) complete and eight (8%) partial responses with negative markers; 5-year DFS was 47% and OS was 52% (median follow-up, 61 months). No relapses occurred after 2 years. Five (24%) of 21 primary mediastinal nonseminomatous GCTs are continuously disease free. On MVA, primary mediastinal site (P < .001), two or more lines of prior therapy (P < .001), baseline human chorionic gonadotropin ≥ 1,000 U/L (P = .01), and lung metastases (P = .02) significantly predicted adverse DFS. Poor-risk patients did worse than good- or intermediate-risk patients according to both Beyer (P < .002) and Einhorn (P < .05) models.
Conclusion
TI-CE is effective salvage therapy for GCT patients with poor prognostic features. Mediastinal primary site and two or more lines of prior therapy were most predictive of adverse DFS. Beyer and Einhorn models can assist in predicting outcome.
doi:10.1200/JCO.2009.25.1561
PMCID: PMC3651604  PMID: 20194867
16.  Time trends in accuracy of classification of testicular tumours, with clinical and epidemiological implications. 
British Journal of Cancer  1992;66(2):396-401.
Initial classifications of 1009 testicular tumours were reviewed as part of a population based survey of all testicular neoplasms in Victoria, Australia, between 1950 and 1978. All reviews were made by one of two pathologists at the Peter MacCallum Cancer Institute, using the system of the British Testicular Tumour Panel. Accuracy of diagnosis varied markedly over the time period and with pathological category. Seven cases were initially designated malignancies but were determined to be non-malignant conditions upon review. In each decade, review reduced the proportion of seminomas and increased the proportion of non-seminoma germ cell tumours (NSGCT) and non germ cell tumours. Reclassification resulted in changed age specific incidences of seminoma and NSGCT, most noticeably in 1950-59. Trends in age standardised incidence of seminoma and NSGCT were not affected by reclassification although the values were. The trend in age standardised incidence of non germ cell tumours was affected by reclassification. The implications of the changes in classification for epidemiological studies and clinical management are discussed.
PMCID: PMC1977811  PMID: 1503914
17.  INTRACRANIAL GERM CELL TUMORS WITH MTOR MUTATION ARE COMMON IN BASAL GANGLIA 
Neuro-Oncology  2014;16(Suppl 3):iii28.
BACKGROUND: Intracranial germ cell tumors (iGCTs) are the second most common CNS tumors in patients under 14 years old in Japan. But, their molecular genetic profile is largely unknown. METHODS: We have analyzed a total of 198 germ cell tumors (GCTs) including 133 iGCTs (69 pure germinomas, 56 non-germinomatous GCTs and 8 metastatic tumors) as well as 65 testicular germ cell tumors (tGCTs) (39 seminomas and 26 non-seminoma GCTs) were collected from 13 centers participating in the Intracranial Germ Cell Tumor Consortium in Japan. Somatic mutations in all coding exons were investigated by whole exome sequencing (WES) using SureSelectXT Human All Exon v4 and a GAIIx or HiSeq 2000 system in 41 tumors and the matched normal DNAs. Targeted sequencing with a set of custom made PCR primers was performed using either an IonTorrent PGM or Proton System. The results were integrated with the patients' clinical information that was available for 124 iGCT patients. RESULTS: On average, 15.4 non-synonymous somatic mutations were observed in each tumor, ranging from 1 to 140 by WES in 41 iGCTs. MTOR was the second most frequently mutated in both iGCTs (9 cases, 7%) and tGCTs (6%). Collectively, the genes involved in the PI3K/MTOR pathway (e.g., MTOR, PTEN) were mutated in 13% of all GCTs. Clinical parameters of the 9 iGCTs with MTOR mutation were: median age of onset = 15 years old; 7 males and 2 females; 5 germinomas, 3 teratomas and one yolk sac tumor; 5 basal ganglia tumors, 2 pineal tumors, one neurohypophyseal tumor and a medulla oblongata tumor. Age, sex, histology and clinical behavior are within the scope of iGCT except for extraordinary high frequency of basal ganglia GCTs. CONCLUSIONS: iGCTs with MTOR mutation are frequent in iGCTs in basal ganglia. SECONDARY CATEGORY: Pediatrics.
doi:10.1093/neuonc/nou208.19
PMCID: PMC4144563
18.  Testicular cancer: seminoma 
BMJ Clinical Evidence  2011;2011:1807.
Introduction
More than half of painless solid swellings of the body of the testis are malignant, with a peak incidence in men aged 25 to 35 years. Most testicular cancers are germ cell tumours and half of these are seminomas, which tend to affect older men and have a good prognosis.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments in men with stage 1 seminoma (confined to testis) who have undergone orchidectomy? What are the effects of treatments in men with good-prognosis non-stage 1 seminoma who have undergone orchidectomy? What are the effects of maintenance chemotherapy in men who are in remission after orchidectomy and chemotherapy for good-prognosis non-stage 1 seminoma? What are the effects of treatments in men with intermediate-prognosis seminoma who have undergone orchidectomy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 29 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: chemotherapy (maintenance, adjuvant, single-agent carboplatin, 3 or 4 cycles, different number of cycles of adjuvant, using bleomycin added to vinblastine plus cisplatin, using etoposide plus cisplatin with or without bleomycin, adding higher doses to a 2-drug chemotherapy regimen using cisplatin or vinblastine); radiotherapy (different adjuvant regimens [20 Gy in 10 fractions to para-aortic area, 30 Gy in 15 fractions to para-aortic area and iliac nodes], different drug combinations, 30–36 Gy in 15–18 fractions); and surveillance.
Key Points
More than half of painless solid swellings of the body of the testis are malignant, with a peak incidence in men aged 25 to 35 years. Most testicular cancers are germ cell tumours and about half of these are seminomas, which tend to affect older men and have a good prognosis.
In men with seminoma confined to the testis (stage 1), standard treatment is orchidectomy followed by radiotherapy, chemotherapy, or surveillance. All 3 management options are associated with cure rates approaching 100% because of successful salvage therapy. Adjuvant chemotherapy reduces the risk of relapse after orchidectomy compared with surveillance, but is associated with short-term adverse effects (nausea, diarrhoea, and indigestion) and possible long-term risks of reduced fertility and development of second malignancies.We don't know which is the most effective chemotherapy regimen, or the optimum number of cycles to use. The high cure rate with standard therapy makes it difficult to show which alternative therapy is superior.Toxicity is lower, but efficacy the same, with adjuvant irradiation of 20 Gy in 10 fractions compared with 30 Gy in 15 fractions, or with irradiation to para-aortic nodes compared with ipsilateral iliac nodes.
In men with good-prognosis non-stage 1 seminoma who have had orchidectomy, radiotherapy may improve survival and be less toxic than chemotherapy, except in men with large-volume disease, in whom chemotherapy may be more effective. Combined chemotherapy may be more effective than single agents, but 3 cycles seem to be as effective as 4 and with less toxicity.A standard radiotherapy treatment comprises 30 to 36 Gy in 15 to 18 fractions (2 Gy per fraction), although we don't know whether this is more effective than other regimens.
In men who are in remission after orchidectomy plus chemotherapy for good-prognosis, non-stage 1 seminoma, further chemotherapy is unlikely to reduce relapse rates or increase survival. Chemotherapy increases survival in men with intermediate-prognosis seminomas who have had orchidectomy; although evidence for this is derived mostly from treatment of intermediate-prognosis non-seminoma, it is likely to be generalisable to intermediate-prognosis seminoma.
PMCID: PMC3217763  PMID: 21477387
19.  Childhood exposure to ionizing radiation from computed tomography imaging in Nova Scotia 
Paediatrics & Child Health  2015;20(7):381-385.
BACKGROUND:
Examining radiation dose in the paediatric population is particularly important due to the vulnerability of paediatric patients (increased radiosensitive tissues and postexposure life-years) and risk for future radiogenic malignancy.
OBJECTIVES:
To evaluate trends in paediatric computed tomography (CT) use and ionizing radiation exposure using population-based data from Nova Scotia.
METHODS:
A retrospective, population-based cohort study of CT use in patients <20 years of age, from January 1, 2004 to December 31, 2011, was performed in Nova Scotia. CT examination data were retrieved from a provincial imaging repository. Trends in CT use were described, and both annual and cumulative effective dose exposures were calculated.
RESULTS:
In total, 29,452 CT events, involving up to 22,867 individuals were retrieved. Overall annual paediatric CT examination rates remained static (range 17.4 to 18.8 per 1000 per year). However, use in children <10 years of age decreased by >50% (P<0.001); this was counterbalanced by a steady increase among 15- to 19-year-olds (P<0.0001). Overall, 15.4% of scanned patients underwent ≥2 examinations, of which 58 patients (1.6%) exceeded 50 mSv of exposure.
CONCLUSIONS:
Despite a static rate in CT imaging among the entire cohort, children <15 years of age and, particularly, those <10 years of age displayed marked reductions in CT use. This may reflect increased awareness of campaigns emphasizing judicious CT use, revised clinical practice guidelines and increased availability of alternative modalities. A small subgroup demonstrated high-dose exposure (>50 mSv), and rates in individuals >15 years of age steadily increased, suggesting further exposure reduction efforts are necessary.
PMCID: PMC4614092  PMID: 26526506
Cancer; Computed tomography; Ionizing radiation; Paediatrics; Risk
20.  Prognostic factors in children with extracranial germ cell tumors treated with cisplatin-based chemotherapy 
Korean Journal of Pediatrics  2015;58(10):386-391.
Purpose
To evaluate the outcomes and prognostic factors in children with extracranial germ cell tumors (GCTs) treated at a single institution.
Methods
Sixty-six children diagnosed with extracranial GCTs between 1996 and 2012 were included in the study. Primary treatment was surgical excision, followed by six cycles of cisplatin-based chemotherapy. The survival rates were compared according to the International Germ Cell Cancer Cooperative Group classification used for GCTs in adults to validate the classification guidelines for GCTs in children.
Results
The median patient age was 4.4 years. In 34 patients (51.5%), the primary tumor site was the gonad. Extragonadal GCTs were detected in 32 patients. The 5-year overall survival and event-free survival (EFS) were 92.0%±3.5% and 90.4%±3.7%, respectively. In univariate analysis, tumor histology, metastasis, and elevated alpha-fetoprotein were not prognostic factors in children with extracranial GCTs. However, EFS was poorer in patients with mediastinal disease (n=12, 66.7%±13.6 %) than in those with nonmediastinal disease (n=54, 96.0%±2.8%) (P=0.001). The 5-year EFS was lower in patients older than 10 years, (n=21, 80.0%±8.9%) compared with those younger than 10 years (n=45, 95.2%±3.3%) (P=0.04). Multivariate analysis identified the mediastinal tumor site as the only independent prognostic factor.
Conclusion
The prognosis of children with extracranial GCTs was favorable. However, nongerminomatous mediastinal tumors were associated with poor survival in children. Further research is needed to improve the prognosis of children with malignant mediastinal GCTs.
doi:10.3345/kjp.2015.58.10.386
PMCID: PMC4644767  PMID: 26576183
Germ cell and embryonal neoplasms; Child; Prognosis; Mediastinum; Survival
21.  The relationship between type of drug therapy and blood glucose self-monitoring test strips claimed by beneficiaries of the Seniors' Pharmacare Program in Nova Scotia, Canada 
Background
The healthcare expenditure on self-monitoring of blood glucose (SMBG) test strips under the Nova Scotia Seniors' Pharmacare Program (NSSPP) has increased significantly in recent years. The objective of this study was to identify the frequency and cost of claims for blood glucose monitoring test strips by NSSPP beneficiaries in the fiscal year 2005/06 and to explore the variation in the use of test strips by type of treatment, age and sex.
Methods
Retrospective analysis was conducted using pharmacy administrative claims data for NSSPP beneficiaries. Study subjects were aged ≥ 65 years on October 1, 2004, received SMBG test strips in the 110 days prior to April 1, 2005, and were alive throughout the twelve month study period. Subjects were categorized into four groups: insulin only, oral antihyperglycemic agents (OAA) only, both OAA and insulin; and no reimbursed diabetes medications. Statistical analysis was performed to identify differences in expenditure by medication group and in frequency of SMBG test strips claimed by medication group, age, and sex.
Results
Of 13,564 included beneficiaries, 13.2% were categorized as insulin only, 53.5% OAA only, 7.2% both OAA and insulin, and 26.0% no reimbursed diabetes medications. Over half (58.7%) were femle. The insulin only category had the highest mean (± SD) number of SMBG test strips claimed per day (2.0 ± 1.5) with a mean annual total cost of $615 ± $441/beneficiary. Beneficiaries aged 80 years and above claimed fewer test strips than beneficiaries below 80 years.
Conclusion
This population based study shows that in Nova Scotia the SMBG test strips claimed by the majority of seniors were within Canadian guidelines. However, a small proportion of beneficiaries claimed for SMBG test strips infrequently or too frequently, which suggests areas for improvement. The provincial drug plan covers the majority of the costs of test strip utilization, suggesting that the majority of test strips claimed did not exceed the maximum allowable cost (MAC) established in the program's MAC policy. Drug insurance programs need to work with healthcare providers to determine if patients are using test strips optimally; and to determine their impact on patient outcomes. In addition, they need to determine the cost-effectiveness of their SMBG test strip reimbursement policies.
doi:10.1186/1472-6963-8-111
PMCID: PMC2426696  PMID: 18501012
22.  Treatment of a Population Based Sample of Men Diagnosed with Testicular Cancer in the United States 
Urologic oncology  2008;27(6):604-610.
Objectives
Testicular cancer is the most common cancer in men age 25 to 35 years. We examined therapy, compliance with guidelines, and survival in a population based sample of men newly diagnosed with testicular cancer.
Materials and Methods
We analyzed the National Cancer Institute's (NCI) patterns of care data on 702 men diagnosed with testicular cancer in 1999. These studies supplement routine data collection by verifying therapy with the patients' treating physician. Follow-up for vital status was available through December 31, 2004.
Results
The majority of the men with localized seminoma were diagnosed while their cancer was localized and more than 80% of received orchiectomy with radiation. For men with seminoma and nonseminoma (NSGCT) tumors the percent receiving chemotherapy increased markedly as stage increased. More than 90% of men with regional and distant NSGCT received chemotherapy. Less than 25% of men with localized NSGCT received orchiectomy and retroperitoneal lymph node dissection (RPLND), about 40% had surveillance following an orchiectomy alone and the other third received orchiectomy and chemotherapy.
Conclusions
The majority of these patients received therapy consistent with guidelines. While there was no significant difference in the use of RPLND in men with localized NSGCT by geographic region, chemotherapy use varied widely. Over 90% of men with localized or regional disease diagnosed in 1999 were alive at the end of 2004. The excellent survival rates point to the need to monitor for late effects of therapy.
doi:10.1016/j.urolonc.2008.06.004
PMCID: PMC2782764  PMID: 18799329
Testicular cancer; treatment; surgery; radiotherapy; guideline adherence
23.  Management of the primary malignant mediastinal germ cell tumors: experience with 54 patients 
Diagnostic Pathology  2014;9:33.
Background
Primary malignant mediastinal germ cell tumor (PMMGCT) is rare and sometimes the prognosis of the patients with PMMGCT is not very satisfactory.
Methods
A total of 54 patients with PMMGCT in a follow-up from 1990 to 2009. We evaluated the role of the surgical treatment and the effect of multimodality treatment strategy for patients with PMMGCT.
Results
Fifty-two patients underwent surgical resections, while the other two patients just received chemoradiotherapy. Among the 52 patients, 28 cases received preoperative adjuvant therapy and 24 cases underwent surgery as initial treatment; 30 cases with complete resections, 18 cases with partial resections and 4 cases with only biopsies. There was no perioperative mortality. Histopathologic results revealed 18 cases of seminomas and 36 cases of nonseminomatous germ cell tumors (NSGCT). The last follow-up showed that 17 patients were alive, including 11 patients with seminoma and 6 patients with NSGCT. The 5-year overall survival rate of patients with seminomas was 87.7%. The 3-year and 5-year overall survival rates of patients with NSGCT were 47.4% and 23.0%, respectively.
Conclusions
It could be concluded that a complete surgical resection of PMMGCT after chemoradiotherapy showed favorable long-term survival. Patients with pure seminomas have a better prognosis compared with that with NSGCT.
Virtual slides
The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1676987232116837.
doi:10.1186/1746-1596-9-33
PMCID: PMC3996080  PMID: 24552239
Mediastinum; Nonseminomatous germ cell tumor; Seminoma
24.  Effect of Utilization Policies for Fluoroquinolones: A Pilot Study in Nova Scotia Hospitals 
Background:
Antimicrobial resistance results in increased morbidity, mortality, and costs to the health care system. Evidence suggests an association between the use of antimicrobials in hospitals and the development of antimicrobial resistance. Fluoroquinolones constitute one group of antimicrobials that are effective against a variety of bacterial infections, yet they may be subject to misuse. Many hospitals in Nova Scotia have implemented policies to improve antimicrobial prescribing, but the impact of these policies on utilization is unknown.
Objectives:
To evaluate the use of fluoroquinolones in Nova Scotia hospitals using the World Health Organization’s Anatomical Therapeutic Chemical classification system with defined daily doses (ATC/DDD) and to examine the influence of hospital policies for utilization of fluoroquinolones in community-acquired pneumonia.
Methods:
During the study period (April 1, 1997, to March 31, 2003), fluoroquinolones were administered at 31 of the 37 hospitals in Nova Scotia’s 9 district health authorities. Hospital administrative data, hospital characteristics, and pharmaceutical purchasing data related to use of these drugs were aggregated using the ATC/DDD methodology for the fiscal years 1997/1998 to 2002/2003. District pharmacy directors were surveyed to obtain information about district and individual hospital antibiotic policies. Descriptive statistics were calculated, and univariable regression and multilevel analyses were performed.
Results:
Mean overall fluoroquinolone use increased over the study period, from 47.2 DDD/1000 bed-days per year in fiscal year 1997/1998 to 163.8 DDD/1000 bed-days per year in fiscal year 2002/2003 (p < 0.001). Multilevel analysis showed that utilization policies aimed at appropriate prescribing did not affect the use of fluoroquinolones.
Conclusion:
This study revealed that drug purchasing, hospital administrative, and diagnostic data could be combined to compare the utilization of fluoroquinolones among different hospitals and district health authorities. Utilization policies had little effect on the amount, type, or route of fluoroquinolone use.
PMCID: PMC2826907  PMID: 22478860
drug utilization; antimicrobials; fluoroquinolones; policies; utilisation des médicaments; antimicrobiens; fluoroquinolones; politiques
25.  Survival after a diagnosis of testicular germ cell cancers in Germany and the United States, 2002–2006: A high resolution study by histology and age 
Cancer epidemiology  2013;37(4):492-497.
Introduction
The aim of this study was to provide detailed age-specific (5-year age groups) and histology-specific (histologic subtypes of seminoma and nonseminoma) relative survival estimates of testicular germ cell cancer patients in Germany and the United States (U.S.) for the years 2002–2006 and to compare these estimates between countries.
Methods
We pooled data from 11 cancer registries of Germany and used data from the U.S. (SEER-13 database) including 11 508 and 10 774 newly diagnosed cases (1997–2006) in Germany and the U.S. respectively. We estimated 5-year relative survival (5-year-RS) by histology and age based on period analysis.
Results
5-year-RS for testicular germ cell tumors was 96.7% and 96.3% in Germany and the U.S. respectively. 5-year-RS for spermatocytic seminoma was close to 100% in both countries. 5-year-RS for nonseminoma was lower than for classical seminoma in Germany (93.3% versus 97.6%) and the U.S. (91.0% versus 98.2%). Among nonseminomas, choriocarcinomas provided the lowest 5-year-RS in both countries (Germany 80.1%, U.S. 79.6%). Age-specific 5-year-RS for seminoma showed only little variation by age. 5-year-RS for nonseminomas tended to be lower at higher ages, especially for malignant teratoma.
Discussion
This is the first study that provides up-to-date survival estimates for testicular cancer by histology and age in Germany and the U.S. Survival after a diagnosis of testicular cancer is very comparable between Germany and the U.S. 5-year-RS for spematocytic seminoma was close to 100% and the lowest 5-year-RS occurred among choriocarcinoma. Higher age at diagnosis is associated with a poorer prognosis among nonseminoma patients.
doi:10.1016/j.canep.2013.03.017
PMCID: PMC4024392  PMID: 23623488
Testicular neoplasms; germinoma; seminoma; nonseminomatous germ cell tumor; survival; Germany; United States

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