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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.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  Testicular cancer: seminoma 
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
15.  Gonadal germ cell tumors in children and adolescents 
Pediatric germ cell tumors (GCT) are rare tumors: 80% are benign, 20% malignant (2-3% of all malignant pediatric tumors). The gonadal sites (ovary and testis) account for 40% of cases.
Ovarian GCTs:
Represent 30% of GCTs and 70% of neoplastic ovarian masses, being the most common ovarian neoplasms in children and teenagers. Benign and immature forms (teratomas) constitute about 80% of all ovarian GCTs, malignant forms represent 20% increasing during adolescence. The most common malignant entity in children is the yolk sac tumors (YST); dysgerminoma is frequent during adolescence and being bilateral in 10% of cases. Presentation is similar in malignant and benign lesions; abdominal pain (70-80%) and lower abdominal mass are common symptoms. Evaluation of alpha-fetoprotein (αFP) or beta subunit of human chorionic gonadotropin (βHCG) is essential to address the nature of the tumors: Their elevation means presence of malignancy. Surgery includes intraoperative staging procedures and requires ovariectomy or ovarosalpingectomy for malignant lesions, but may be conservative in selected benign tumors. Since malignant GCTs are very chemosensitive, primary chemotherapy is recommended in metastatic or locally advanced tumors.
Testicular GCT:
Represent 10% of pediatric GCT, and about 30% of malignant GCT with two age peaks: Children <3 years may experience mature teratoma and malignant GCTs, represented almost exclusively by YST, while adolescents may also show seminomas or other mixed tumors. The main clinical feature is a painless scrotal mass. Surgery represents the cornerstone of the management of testicular GCTs, with an inguinal approach and a primary high orchidectomy for malignant tumors, while a testis-sparing surgery can be considered for benign lesions. A retroperitoneal lymph node (LN) biopsy may be necessary to define the staging when the involvement of retroperitoneal LN is uncertain at imaging investigations.
Conclusion:
Patients with gonadal malignant GCTs fare better than those with extragonadal mediastinal germ cell tumors (MGCTs) and survival rate exceeds 90% in localized forms. Chemotherapy has significantly improved the outcome of malignant forms since the introduction of platinum based regimens. The surgical procedure has to be performed in agreement with the ongoing protocols.
doi:10.4103/0971-9261.141995
PMCID: PMC4204242  PMID: 25336799
Children; germ cell tumors; gonadal
16.  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
17.  Retroperitoneal lymphadenectomy and resection for testicular cancer: an update on best practice 
Therapeutic Advances in Urology  2012;4(4):187-205.
Clinical stage I testicular nonseminomatous germ cell tumours (NSGCTs) are highly curable. Following orchidectomy a risk-adapted approach using active surveillance (AS), nerve-sparing retroperitoneal lymph node dissection (nsRPLND) and primary chemotherapy is recommended by the current guidelines. Clinical stage I is defined as negative or declining tumour markers to their half-life following orchidectomy and negative imaging studies of the chest, abdomen and retroperitoneum. Active surveillance can be performed in low-risk and in high-risk NSGCTs with an anticipated relapse rate of about 15% and 50%. The majority of patients will relapse with good and intermediate prognosis tumours which have to be treated with three to four cycles chemotherapy. About 25–30% of these patients will have to undergo postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for residual masses. Primary chemotherapy with one or two cycles of cisplatin (Platinol), etoposide and bleomycin (PEB) is a therapeutic option for high-risk clinical stage I NSGCT associated with a recurrence rate of only 2–3% and a minimal acute and long-term toxicity rate. nsRPLND, if performed properly, will cure about 85% of all high-risk patients with clinical stage I NSGCT without the need for chemotherapy. PC-RPLND forms an integral part of the multimodality treatment in patients with advanced testicular germ cell tumours (TGCTs). According to current guidelines and recommendations, PC-RPLND in advanced seminomas with residual tumours is only indicated if a positron emission tomography (PET) scan performed 6–8 weeks after chemotherapy is positive. In nonseminomatous TGCT, PC-RPLND is indicated for all residual radiographic lesions with negative or plateauing markers. Loss of antegrade ejaculation represents the most common long-term complication which can be prevented by a nerve-sparing or modified template resection. The relapse rate after PC-RPLND is around 12%, however it increases significantly to about 45% in cases with redo RPLND and late relapses. Patients with increasing markers should undergo salvage chemotherapy. Only select patients with elevated markers who are thought to be chemorefractory might undergo desperation PC-RPLND if all radiographically visible lesions are completely resectable. PC-RPLND requires a complex surgical approach and should be performed in experienced, tertiary referral centres only.
doi:10.1177/1756287212443170
PMCID: PMC3398597  PMID: 22852029
testicular cancer; germ cell tumour; retroperitoneal lymph node dissection; retroperitoneal lymphadenectomy; postchemotherapy RPLND
18.  Clinical profile and problems of management of 108 cases of germ cell tumours of testis at Institute Rotary Cancer Hospital, All India Institute of Medical Sciences New Delhi 1985-1990. 
British Journal of Cancer  1993;67(3):573-577.
A retrospective analysis of 108 cases of primary germ cell tumours of testis seen over a 6 year period at Institute Rotary Cancer Hospital of All India Institute of Medical Sciences, New Delhi is presented. There were 45 (42%) cases of seminoma and 63 (48%) of non-seminomatous germ cell tumours (NSGCT). The median age at presentation was 35 and 30 years respectively. Almost half (56) patients presented in advanced stage (stages IIc-IV). Tumours in undescended testis formed an important subgroup (14%). The standard approach of treatment was radiotherapy in stages I & II seminomas and chemotherapy in bulky seminomas and metastatic NSGCT. Chemotherapy protocols used were VAB-6 and PVB. Although a policy of surveillance has been practised for stage I NSGCT, it is debatable whether it is universally suitable for our patients. The results of treatment in low volume disease are comparable to that in the west but the management of bulky disease requires a more aggressive approach. Unfortunately only 74 out of 108 (68.5%) patients were able to complete the treatment prescribed. Most of the defaulters were from the chemotherapy group because of inability to afford the drugs. The probability of survival of those who completed treatment was 0.77 at 4 years. Since testicular tumours are largely curable, a more vigorous policy of detection, follow up and treatment needs to be pursued. Better screening of children with undescended testis will reduce cancer in this group. Failure to provide chemotherapy to all patients is particularly unfortunate for a curable disease like testis cancer.
PMCID: PMC1968273  PMID: 8439506
19.  Germ cell tumours in uncorrected cryptorchid testis at Institute Rotary Cancer Hospital, New Delhi. 
British Journal of Cancer  1995;71(2):380-382.
Twenty-four out of 164 (14%) adult patients with primary germ cell tumours of testis seen over the last 6 years at the Institute Rotary Cancer Hospital (IRCH) of the All India Institute of Medical Sciences (AIIMS), New Delhi, were found to have cryptorchidism. Only one patient had undergone correction. As a result the testes were intra-abdominal in the vast majority, and patients presented late. Twenty-two patients presented with stage IIb or more advanced disease. Twelve patients had seminoma and the others had mixed or non-seminomatous germ cell tumour (NSGCT), i.e. 50% each. The earlier patients were managed by initial resection followed by radiation and/or chemotherapy. As experience grew the seven patients who presented late were given initial chemotherapy followed by resection in those with residual tumours. The probability of overall survival was 0.65 at 36 months and, was not significantly different from survival in 114 patients with tumours of normally descended testis. Early orchipexy facilitates the detection, but whether it reduces the incidence of tumours is controversial. Uncorrected cryptorchidism is now rarely seen in the West, but in India and many other developing countries tumours of uncorrected cryptorchid testes continue to be seen.
PMCID: PMC2033575  PMID: 7841056
20.  Unequal access to interventional cardiac care in Nova Scotia in patients with acute myocardial infarction complicated by cardiogenic shock 
BACKGROUND
The optimal treatment of cardiogenic shock (CS) complicating acute myocardial infarction (AMI) remains controversial and continues to be associated with a high mortality rate. The present study evaluated the outcomes of all patients having AMI complicated by CS in a single Canadian province.
METHODS
All consecutive patients diagnosed with AMI and CS from October 1997 to December 2002 in Nova Scotia were included in the present study. The Improving Cardiac Outcomes in Nova Scotia (ICONS) registry was used as the principal source of data. The outcome of interest was in-hospital mortality.
RESULTS
During the study period, a total of 11,300 patients with AMI were identified, with 707 complicated by CS, for an incidence of AMI+CS of 6.3%. The overall mortality rate for patients with AMI+CS was 60.1%. Multivariate regression analysis identified age older than 65 years (OR 2.0; 95% CI 1.4 to 2.9) and renal insufficiency (OR 2.1; 95% CI 1.4 to 3.2) as independent predictors of mortality, while access to invasive cardiac care (defined as admission or transfer to the only cardiac catheterization-capable centre in Halifax, Nova Scotia) was found to be an independent predictor of survival (OR 0.4; 95% CI 0.3 to 0.5). Access to invasive cardiac care was limited to 414 (59%) patients, 250 (35%) of whom actually underwent cardiac catheterization.
CONCLUSIONS
Admissions to a tertiary care centre that can provide invasive care was independently associated with improved survival, and older age and renal insufficiency were associated with death among patients with AMI and CS.
PMCID: PMC2560526  PMID: 16568158
Catheterization; Health outcomes; Myocardial infarction; Shock
21.  Physicians’ attitudes towards office-based delivery of methadone maintenance therapy: results from a cross-sectional survey of Nova Scotia primary-care physicians 
Background
Approximately 90,000 Canadians use opioids each year, many of whom experience health and social problems that affect the individual user, families, communities and the health care system. For those who wish to reduce or stop their opioid use, methadone maintenance therapy (MMT) is effective and supporting evidence is well-documented. However, access and availability to MMT is often inconsistent, with greater inequity outside of urban settings. Involving community based primary-care physicians in the delivery of MMT could serve to expand capacity and accessibility of MMT programs. Little is known, however, about the extent to which MMT, particularly office-based delivery, is acceptable to physicians. The aim of this study is to survey physicians about their attitudes towards MMT, particularly office-based delivery, and the perceived barriers and facilitators to MMT delivery.
Methods
In May 2008, facilitated by the College of Physicians and Surgeons of Nova Scotia, a cross-sectional, e-mail survey of 950 primary-care physicians practicing in Nova Scotia, Canada was administered via the OPINIO on-line survey software, to assess the acceptability of office-based MMT. Logistic regressions, adjusted for physician sociodemographic characteristics, were used to examine the association between physicians’ willingness to participate in office-based MMT, and a series of measures capturing physician attitudes and knowledge about treatment approaches, opioid use, and methadone, as well as perceived barriers to MMT.
Results
Overall, 19.8% of primary-care physicians responded to the survey, with 56% who indicated that they would be willing to be involved in MMT under current or similar circumstances; however, willingness was associated with numerous attitudinal and systemic factors. The barriers to involvement in MMT that were frequently cited included a lack of training or experience in MMT, lack of support services, and potential challenges of working with an MMT patient population.
Conclusions
Study findings provide valuable information to help facilitate greater involvement of primary-care physicians in MMT, while highlighting concerns around administration, support, and training. Even limited uptake by primary-care physicians would greatly enhance MMT access in Nova Scotia, particularly for methadone clients located in rural communities. These findings are applicable broadly, to any jurisdictions where office-based MMT is not currently available.
doi:10.1186/1477-7517-9-20
PMCID: PMC3444893  PMID: 22694814
Methadone Maintenance Therapy (MMT); Primary care physicians; Office-based delivery; Access; Barriers
22.  Prognostic factors in patients progressing after cisplatin-based chemotherapy for malignant non-seminomatous germ cell tumours 
British Journal of Cancer  1999;80(9):1392-1399.
The aim of this study was to define prognostic parameters for survival in patients with malignant germ cell tumours progressing after platinum-based induction chemotherapy with or without surgery. A total of 164 progressing patients (testicular: 83%, extragonadal: 17%) were identified out of 795 patients treated with platinum-based induction chemotherapy for metastatic germ cell malignancy with or without surgery. ‘Progressive disease’ included patients who had progressed after a previous partial or complete remission as well as patients who failed primary therapy. Salvage chemotherapy consisted of ‘conventional’ platinum-based chemotherapy. Prognostic factors for survival were assessed by uni- and multivariate analyses. The resulting prognostic model was validated in an independent data set of 66 similar patients. For all 164 patients the median time from start of induction chemotherapy to progression was 10 months (range: 0–99). Thirty-eight (23%) patients relapsed after 2 years. The 5-year survival rate for all progressing patients was 30% (95% confidence interval 23–38%). In the univariate analysis the following factors most importantly predicted a poor prognosis: progression-free interval < 2 years: initial poor prognosis category (MRC criteria), < CR to induction chemotherapy, initial treatment early in the 1980s and treatment given at a ‘small’ centre. Three prognostic factors remained in the multivariate analysis: progression-free interval, response to induction treatment and the level of serum human chronic gonadotrophin (hCG) and alpha fetoprotein (AFP) at relapse. One hundred and twenty-four patients could be classified on the basis of these characteristics, Those patients with progression-free interval < 2 years, < CR to induction chemotherapy and high markers at relapse (AFP >100 kU l−1 or hCG >100 IU l−1) formed a poor prognosis group of 30 patients, none of whom survived after 3 years. Patients with at most two of these three risk factors formed a good prognosis group of 94 patients (76%) with a 47% (37–56%) 5-year survival. Thirty-eight patients from the good prognosis group with a progression-free interval of >2 years had a 2-year survival of 74% (60–88%) and 5-year survival of 61%. These prognostic groups were validated in the independent data set, in which 5-year survival rates in the good and poor risk groups were 51% and 0% respectively. One-third of patients progressing during or after platinum-based induction chemotherapy for metastatic germ cell malignancy may be cured by repeated ‘conventional’ platinum-based chemotherapy. Good prognosis parameters are: progression-free interval of > 2 years, CR to induction treatment and normal or low serum markers at relapse (hCG < 100 IU l−1 and AFP < 100 kU l−1). The results of high-dose salvage chemotherapy should be interpreted on the background of these prognostic factors. © 1999 Cancer Research Campaign
doi:10.1038/sj.bjc.6690534
PMCID: PMC2363071  PMID: 10424741
germ cell malignancy; relapse; cisplatin-based chemotherapy; survival
23.  An analysis of surveillance for stage I combined teratoma--seminoma of the testis. 
British Journal of Cancer  1996;74(1):59-62.
We analysed 973 patients with stage I testicular tumours presenting between 1983 and 1994. The median ages at presentation for non-seminomatous germ cell tumour (teratoma) were 27 years, seminoma 36 years and combined tumour 33 years. These differences were statistically significant (Mann-Whitney P < 0.05), suggesting that combined tumours may have a separate natural history. We, therefore, analysed all stage I patients managed with surveillance (530 in total) post orchidectomy. The actuarial 5 year relapse-free survival and anatomical patterns of relapse were identical for non-seminomatous germ cell tumour (NSGCT) and combined tumour and both were statistically distinct from seminoma (P = 0.01, log-rank test, chi-square test P = 0.001). The association of seminoma within a histologically confirmed NSGCT has no influence on the clinical outcome.
Images
PMCID: PMC2074607  PMID: 8679458
24.  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
25.  Consolidative high-dose chemotherapy after conventional-dose chemotherapy as first salvage treatment for male patients with metastatic germ cell tumours 
Introduction:
Some men with metastatic germ cell tumours that have progressed after response to initial cisplatin-based combination chemotherapy are cured with conventional dose first salvage chemotherapy (CDCT) – however, many are not. High-dose chemotherapy with autologous stem cell rescue (HDCT) may be of value in these patients. Prognosis has recently been better defined by International Prognostic Factor Study Group (IPFSG) prognostic factors. HDCT after response to CDCT has been offered at our institution over the past two decades. We retrospectively assessed the validity of the IPFSG prognostic factors in our patients and evaluated the value of HDCT.
Methods:
We identified eligible men with metastatic germ cell tumour progressed after at least 3 cycles of cisplatin-based chemotherapy and treated with cisplatin-based CDCT alone or with carboplatin-based HDCT. We also collected their clinical data. Patients were classified into risk groups using IPFSG factors, and progression-free and overall survival factors were analyzed and compared in patients treated with CDCT alone and with HDCT.
Results:
We identified 38 eligible first salvage patients who had received a median of 4 cycles (range, 1 to 7 cycles) of CDCT. Twenty patients received CDCT alone and 18 patients received CDCT plus HDCT. The overall median progression- free survival was 24.6 months (95%CI, 7.3 to 28.7 months) and overall median overall survival was 34.6 months (95%CI, 17.2 to 51.3 months). Distribution by IPFSG category and 2-year progression- free survival and 3-year overall survival rates within each risk category were very similar to the IPFSG results. There were two toxic deaths with CDCT and none with HDCT. Overall, patients treated with CDCT plus HDCT had improved progression- free survival and overall survival.
Conclusions:
The IPFSG prognostic risk factors appeared valid in our patient population. The safety of HDCT with etoposide and carboplatin was confirmed. HDCT was associated with improved progression- free survival and overall survival outcomes, consistent with observations of the IPFSG group. Ideally, the value of optimal HDCT should be determined in comparison to optimal CDCT as first salvage therapy in men with metastatic germ cell tumour with a randomized trial.
doi:10.5489/cuaj.11233
PMCID: PMC3328550  PMID: 22511417

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