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1.  Predictors of viable germ cell tumor in postchemotherapeutic residual retroperitoneal masses 
Urology Annals  2014;6(1):27-30.
Objective:
The aim of this study was to identify predictors of viable germ cell tumor (GCT) in postchemotherapeutic residual retroperitoneal masses.
Materials and Methods:
The pertinent clinical and pathologic data of 16 male patients who underwent postchemotherapeutic retroperitoneal lymph node dissection (PC-RPLND) at King Faisal Specialist Hospital and Research Centre between 1994 and 2005 were reviewed retrospectively. It was found that all patients received cisplatin-based chemotherapy for advanced testicular GCT.
Results:
Out of the 16 male patients, 2 (13%), 8 (50%), and 6 (37%) had viable GCT, fibrosis, and teratoma, respectively. Ten (10) of the patients with prechemotherapeutic S1 tumor markers did not have viable GCT, and two of the six patients who had prechemotherapeutic S2 tumor markers have viable GCT. All tumor marker levels normalized after chemotherapy even in patients with viable GCT. Four patients had vascular invasion without viable GCT. Furthermore, four patients had more than 60% embryonal elements in the original pathology, but only 1 had viable GCT at PC-RPLND. Four of the five patients with immature teratoma had teratoma at PC-RPLND but no viable GCT; however, out of the four patients with mature teratoma, one had viable GCT and two had teratoma at PC-RPLND. Of the two patients with viable GCT, one had 100% embryonal cancer in the original pathology, prechemotherapeutic S2 tumor markers, history of orchiopexy, and no vascular invasion; the other patient had yolk sac tumor with 25% embryonal elements and 40% teratoma in the original pathology, and prechemotherapeutic S2 tumor markers.
Conclusion:
None of the clinical or pathological parameters showed a strong correlation with the presence of viable GCT in PC-RPLND. However, patients with ≥S2 may be at higher risk to have viable GCT. Further studies are needed to clarify this.
doi:10.4103/0974-7796.127017
PMCID: PMC3963339  PMID: 24669118
Chemotherapy; germ cell tumor; predictor; retroperitoneal lymph node dissection
2.  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
3.  Tallness is associated with risk of testicular cancer: evidence for the nutrition hypothesis 
British Journal of Cancer  2008;99(9):1517-1521.
The pathogenesis of testicular germ cell tumours (GCTs) is potentially influenced by high-energy nutrition during infancy. As adult height is a proxy for childhood nutrition, we investigated the role of nutrition in GCT pathogenesis by comparing stature of patients with healthy men. In a matched case–control study, 6415 patients with GCT were compared with healthy army conscripts (1:6 matching modus) with regard to height (cm) and body mass index (BMI; kg/m2). Statistical analysis involved tabulation of descriptive height measures and BMI. Conditional logistic regression models were used to quantify the association of GCT with height, with odds ratios (OR) adjusted for BMI. The literature was searched for studies on stature in GCT patients. Body size is significantly associated with risk of GCT, very tall men (>195 cm) having a GCT risk of OR=3.35 (95% confidence intervals (CI): 2.88–3.90; adjusted). Short stature is protective (OR=0.798; 95% CI: 0.68–0.93). Both histologic subgroups are associated with tallness. Of 16 previous reports, 7 were confirmative, 5 had null and 4 equivocal results. The association of stature with GCT risk accords with the nutrition hypothesis of GCT. This study expands the current view of GCT tumorigenesis by suggesting that high-calorie intake in childhood promotes GCT precursors originating in utero.
doi:10.1038/sj.bjc.6604695
PMCID: PMC2579680  PMID: 18827809
testicular cancer; body size; childhood nutrition; seminoma; non-seminoma; BMI
4.  An Abnormal Screening Glucose Challenge Test in Pregnancy Predicts Postpartum Metabolic Dysfunction, Even When the Antepartum Oral Glucose Tolerance Test is Normal 
Clinical endocrinology  2008;71(2):208-214.
Objective
In pregnancy, a normal result on the oral glucose tolerance test (OGTT) that follows an abnormal screening glucose challenge test (GCT) is considered a reassuring finding, requiring no further intervention. The obstetrical and metabolic implications of this presentation, however, have not been well-studied. Thus, we sought to characterize the obstetrical and postpartum metabolic significance of an abnormal GCT in women with normal glucose tolerance (NGT) on antepartum OGTT.
Design/Patients/Measurements
259 women with NGT on antepartum OGTT (166 with an abnormal GCT and 93 with normal GCT) underwent (i) metabolic evaluation in pregnancy, (ii) assessment of obstetrical outcome at delivery and (iii) repeat metabolic characterization by OGTT at 3-months postpartum.
Results
Neither infant birthweight nor Caesarian-section rate differed between the abnormal GCT and normal GCT groups. At 3-months postpartum, however, compared to the normal GCT group, the abnormal GCT group exhibited greater glycemia (mean area-under-the-glucose-curve (AUCgluc) 19.6 vs 18.3, p=0.0021), lower insulin sensitivity (median ISOGTT 9.5 vs 11.3, p=0.0243) and poorer beta-cell function (median insulinogenic index/HOMA-IR 9.8 vs 14.1, p=0.0013). On multiple linear regression analyses, an abnormal GCT emerged as (i) the strongest independent predictor of postpartum AUCgluc (t=2.77, p=0.006) and (ii) the strongest independent negative predictor of log insulinogenic index/HOMA-IR (t=−2.36, p=0.0191). Furthermore, the GCT was the antepartum parameter that best predicted postpartum pre-diabetes (area-under-receiver-operating-characteristic-curve=0.754).
Conclusions
An abnormal antepartum GCT, even when followed by a normal OGTT, is associated with postpartum glycemia and beta-cell dysfunction, factors that may portend an increased future risk of diabetes in this patient population.
doi:10.1111/j.1365-2265.2008.03460.x
PMCID: PMC2878325  PMID: 19178531 CAMSID: cams818
glucose challenge test; pregnancy; glucose intolerance; postpartum
5.  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
6.  Testicular Germ Cell Tumors with Sarcomatous Components: An Analysis of 33 Cases 
The American journal of surgical pathology  2009;33(8):10.1097/PAS.0b013e3181adb9d7.
The development of sarcomatous component (SC) in testicular germ cell tumor (GCT) is an uncommon phenomenon. We searched our surgical pathology files from 1985 to 2007 and identified 33 cases of testicular GCTs with SC. The average age of patients was 31 years. All patients underwent radical orchiectomy, which demonstrated a GCT in all patients except for 3 patients who had received neoadjuvant chemotherapy. All testicular GCTs contained a teratomatous component. The GCTs were pure teratomas in 3 cases, and were mixed GCTs in the other cases. The SC was observed in primary testicular tumor (n = 19), in metastasis (n = 11), or in both primary testicular tumor and metastasis (n=3). The average percentage of the SC in the primary testicular GCT was 32% (range, 5% to 99%). The most common histologic type of SC was rhabdomyosarcoma (n = 24), followed by high-grade unclassified sarcoma (n = 5), rhabdomyosarcoma admixed with high-grade unclassified sarcoma (n = 2), angiosarcoma (n = 1), and low-grade myxoid sarcoma (n = 1). Clinical follow-up information was available for 27 patients. Of the 13 patients whose SC was limited to the testicular GCT, 2 died of GCT not otherwise specified (NOS) at 37 and 68 months, respectively; and 11 patients were free of disease at a mean of 46 months. Of the 14 patients with a SC in the metastasis, 7 patients died of GCT NOS at a mean of 95 months, and 7 patients were free of disease at a mean of 104 months. These results suggest that patients with a SC confined to the primary testicular GCT may not have a higher risk of mortality than those at a comparable stage without a SC. However, patients with a SC in the metastasis have an increased risk of mortality.
doi:10.1097/PAS.0b013e3181adb9d7
PMCID: PMC3812063  PMID: 19561445
testicular germ cell tumor; sarcomatous component; rhabdomyosarcoma
7.  Risk of Thromboembolic Events after Perioperative Chemotherapy Versus Surgery Alone for Esophageal Adenocarcinoma 
Annals of Surgical Oncology  2011;19(2):684-692.
Background
Major oncologic surgery is associated with a high incidence of thromboembolic events (TEE). Addition of perioperative chemotherapy in esophageal cancer surgery may increase the risk of TEE.
Methods
The thromboembolic toxicity profile was analyzed in patients with esophageal adenocarcinoma (EAC). Two groups were identified: patients who underwent esophagectomy and received perioperative chemotherapy with epirubicin, cisplatin, and capecitabine (ECC; n = 52), and patients who were treated with surgery alone (n = 35).
Results
A total of 22 TEEs was observed in 17 patients (32.7%) in the chemotherapy group and 3 patients (7.5%) in the surgery-alone group (P < .01). The relative risk of developing a TEE for patients receiving perioperative chemotherapy during the whole treatment period was 3.8 (95% confidence interval 1.2–12.0). A preoperatively occurring TEE did not increase the risk of postoperative TEE, nor did it increase postoperative hospital stay (P = .325). Median postoperative hospital stay was 23 days (range 14–78) for patients with a postoperative TEE and 15 days (range 10–105) for patients without TEE (P = .126). Perioperative chemotherapy with the epirubicin, cisplatin, and capecitabine regimen was independently associated with the development of TEE in the combined preoperative and postoperative period (P = .034).
Conclusions
Perioperative chemotherapy improves survival for operable esophageal cancer but comes at the price of toxicity. Perioperative chemotherapy for EAC increases the risk of TEE. However, chemotherapy-related preoperative TEE did not increase the risk of postoperative TEE, nor did it increase postoperative hospital stay, justifying its use in clinical practice.
doi:10.1245/s10434-011-2005-8
PMCID: PMC3264865  PMID: 21837523
8.  Responses and adverse effects of carboplatin-based chemotherapy for pediatric intracranial germ cell tumors 
Korean Journal of Pediatrics  2011;54(3):128-132.
Purpose
Cisplatin-based chemotherapy has been commonly used for the treatment of intracranial germ cell tumors (IC-GCTs). However, this treatment exhibits some adverse effects such as renal problems and hearing difficulty. Carboplatin-based chemotherapy was administered to pediatric patients with IC-GCTs from August 2004 at the Samsung Medical Center. In this study, we assessed the responses and adverse effects of carboplatin-based chemotherapy in pediatric IC-GCTs patients according to the risk group, and compared the results with those of the previous cisplatin-based chemotherapy.
Methods
We examined 35 patients (27 men and 8 women) diagnosed with IC-GCTs between August 2004 and April 2008 and received risk-adapted carboplatin-based chemotherapy at the Samsung Medical Center. Patients were divided into either low-risk (LR) or high-risk (HR) groups and a retrospective analysis was performed using information from the medical records.
Results
Although hematological complications were common, hearing difficulties or grade 3 or 4 creatinine level elevation were not observed in patients who underwent carboplatin-based chemotherapy. The frequency of febrile neutropenia did not differ between the risk groups. The overall survival was 100% and event-free survival (EFS) was 95.7%. The EFS rate was 100% in the LR group and 90% in the HR group, respectively.
Conclusion
Despite their common occurrence in high-risk patients, no lethal hematological complications were associated with carboplatin-based treatment. The current carboplatin-based chemotherapy protocol is safe and effective for the treatment of pediatric patients with IC-GCTs.
doi:10.3345/kjp.2011.54.3.128
PMCID: PMC3120999  PMID: 21738543
Intracranial germ cell tumor; Carboplatin; Adverse effects
9.  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
10.  Recent Advances in Granulosa Cell Tumor Ovary: A Review 
Granulosa cell tumors constitute less than 5 % of all ovarian tumors. Unlike epithelial ovarian tumors, they occur in a younger age group, are usually detected in an early stage and often have features of hyperestrogenism. The presenting symptoms are usually nonspecific with abdominal pain or distension. They follow an indolent course and are characterized by a long natural history. Mutation of FOXL2 (402C->G) seen in 97 % of adult GCT may be pathognomonic for adult GCT. Only stage of the disease has been consistently shown in various studies to affect survival of patients with GCT. The initial management of patients, for whom fertility is not an issue, is total abdominal hysterectomy, bilateral salpingo-oophorectomy and removal of all gross disease. Nodal dissection is not a significant factor for survival and is not recommended in surgical staging of GCT. Fertility preserving surgery with unilateral salpingo-oophorectomy is feasible in young patients with stage Ia GCT. Patients with early stage disease (stage I and II) have a very good prognosis with 5 year DFS and OS of 89 % and 99 % respectively and these groups of patients usually don’t require any postoperative treatment. Patients with stage Ic disease associated with poor prognostic factors like large tumor size or high mitotic index and stage II, have a higher chance of relapse, and may benefit with postoperative treatment but role of chemotherapy is still debatable. In advanced stage disease (stage III and IV) the 5 year DFS and OS disease was 72 % and 80 % respectively hence the option of postoperative treatment with 6 cycles of BEP should be considered in this group. Recently paclitaxel is being investigated as an effective tool in GCT. The efficacy of radiation in GCT is not well defined but in optimally debulked cases postoperative radiation is a viable option. Due to high chance of recurrence even years after apparent clinical cure of the primary tumor, lifelong follow up with clinical examination and tumor markers like inhibin B is recommended. About 25 % GCT develop recurrence and the median time to recur is usually 4–5 years. Most recurrences are intraperitoneal and usually a complete debulking of the disease is feasible even in the recurrent setting. Postoperative chemotherapy (platinum based) is usually given after surgery more so in cases with widespread disease or after suboptimal cytoreduction. Recurrent chemoresistant, progressive non-responding GCT or patients with high surgical risk are ideal candidates for targeted therapy.
doi:10.1007/s13193-012-0201-z
PMCID: PMC3578540  PMID: 24426698
Granulosa cell tumor; Inhibin B
11.  Salvage high-dose chemotherapy for children with extragonadal germ-cell tumours 
British Journal of Cancer  2005;93(4):412-417.
We reviewed the European Group for Blood and Marrow Transplantation (EBMT) experience with salvage high-dose chemotherapy (HDC) in paediatric patients with extragonadal germ-cell tumour (GCT). A total of 23 children with extragonadal GCT, median age 12 years (range 1–20), were treated with salvage HDC with haematopoietic progenitor cell support. The GCT primary location was intracranial site in nine cases, sacrococcyx in eight, retroperitoneum in four, and mediastinum in two. In all, 22 patients had a nongerminomatous GCT and one germinoma. Nine patients received HDC in first- and 14 in second- or third-relapse situation. No toxic deaths occurred. Overall, 16 of 23 patients (70%) achieved a complete remission. With a median follow-up of 66 months (range 31–173 months), 10 (43%) are continuously disease-free. Of six patients who had a disease recurrence after HDC, one achieved a disease-free status with surgical resection followed by chemotherapy and radiotherapy. In total, 11 patients (48%) are currently disease-free. Eight of 14 patients (57%) with extracranial primary and three of nine patients (33%) with intracranial primary GCT are currently disease-free. HDC induced impressive long-term remissions as salvage treatment in children with extragonadal extracranial GCTs. Salvage HDC should be investigated in prospective trials in these patients.
doi:10.1038/sj.bjc.6602724
PMCID: PMC2361583  PMID: 16106248
extragonadal germ cell tumour; high-dose chemotherapy; salvage therapy; children
12.  P32 - A Case of Multicentric Giant Cell Tumours with 25-Year Follow Up 
Giant cell tumour of bone (GCT) is a relatively rare benign bone tumour more frequent in young people (20–40 years). Histologically, two cell types are represented, stromal cells of osteoblastic origin and a distinctive osteoclast-like population probably of monocytic origin. GCTs can be aggressive and they recur locally in up to 50% of cases; up to 5% of GCTs metastasise to the lungs and spontaneous transformation to a high-grade malignancy occurs in 1–3% of patients. The aetiology of GCT is not known, and no risk factors have been recognised, although familial clustering of both Paget’s disease and GCT has been reported.
GCTs account for approximately 3–5% of primary bone tumours. GCT is rarely multicentric and usually occurs at the epiphyses of long bones, but may also affect other bones.
There are few randomised, prospective clinical trials available to guide clinical management of GCT. Recent developments have led to evaluation of newer therapeutic agents, including biphosphonates and denosumab, with encouraging results. We report the case of a 66-year-old woman affected by GCT. In 1985 the patient, then 41 years old, presented a cystic lesion on her left tibia, which was removed surgically. This lesion relapsed two years later. Therefore the patient was hospitalised and received a diagnosis of “multicentric giant cell bone lesions” (limb-girdle, sternum, mandible, ribs), confirmed by histological examination. These lesions showed hyperactivity on bone scintigraphy. Plain radiographs demonstrated destructive lytic lesions. Blood and urinary examinations showed markedly elevated levels of bone alkaline phosphatase and urine pyridinoline and there was persistent bone pain. In 1993 normocalcaemic primary hyperparathyroidism was diagnosed and an adenoma was removed, with no relapse of the disease. Subsequently the patient started clodronate therapy, i.v., followed by alendronate-neridronate per os and clodronate i.m. for about nine years. Biphosphonate therapy caused a modest and transient decrease in bone indexes. Initial bone lesions were unchanged on computed tomography 25 years after diagnosis, but new bone lesions had appeared. MEN1 gene and CasR analyses were negative.
This is a rare case of a patient affected by multicentric giant cell tumours with a 25-year follow up. A slow progression of the lesion is documented, as well as the absence of significant effect of biphosphonate therapy.
PMCID: PMC3213768
13.  Circadian Variation in the Response to the Glucose Challenge Test in Pregnancy 
Diabetes Care  2012;35(7):1578-1584.
OBJECTIVE
A common approach to screening for gestational diabetes mellitus (GDM) is the universal testing of all pregnant women with a 1-h, 50-g glucose challenge test (GCT), followed by a diagnostic oral glucose tolerance test (OGTT) in those in whom the GCT is positive (≥7.8 mmol/L). More important, the GCT is performed at any time of day, but there has been limited study of the effect of time of day on test performance. Thus, using their subsequent OGTT (performed in the morning), we sought to characterize the metabolic function of women with positive GCTs in relation to the timing of their test.
RESEARCH DESIGN AND METHODS
A total of 927 women with positive GCTs underwent a 3-h 100-g OGTT. They were stratified into four groups by time of day (hours) of their GCT: <0900 (n = 171), 0900–1059 (n = 288), 1100–1259 (n = 189), and ≥1300 (n = 279).
RESULTS
On the OGTT, the prevalence of GDM progressively decreased across the GCT groups from <0900 h (26.9%) to 0900–1059 h (25.0%) to 1100–1259 h (21.7%) to ≥1300 h (21.5%; P = 0.0022). After adjustment for GDM risk factors, mean adjusted glucose area under the curve (AUCgluc) similarly decreased across the groups, while insulin sensitivity (Matsuda index) and β-cell function (Insulin Secretion-Sensitivity Index-2) progressively increased (all P < 0.0001). In particular, compared with the <0900- and 0900–1059-h groups, women whose positive GCT occurred after 1300 h had superior metabolic function, as evidenced by lower AUCgluc, higher insulin sensitivity, and better β-cell function (all P ≤ 0.0097).
CONCLUSIONS
Among women with a positive GCT, those tested in the afternoon have better metabolic function and a lower risk of GDM on subsequent OGTT.
doi:10.2337/dc11-2217
PMCID: PMC3379574  PMID: 22723584
14.  Risk factors and incidence of thromboembolic events (TEEs) in older men and women with breast cancer 
Annals of Oncology  2011;22(11):2394-2402.
Background: The purpose of this study is to evaluate the risk factors and the prevalence of thromboembolic events (TEEs) in breast cancer patients.
Patients and methods: This is a retrospective cohort study using the Surveillance, Epidemiology, and End Results-Medicare database. Breast cancer patients diagnosed from 1992 to 2005 ≥66 years old were identified. International Classification of Diseases, Ninth Revision, and Healthcare Common Procedure Coding System codes were used to identify TEEs within 1 year of the breast cancer diagnosis. Analyses were conducted using descriptive statistics and logistic regression.
Results: A total of 89 841 patients were included, of them 2658 (2.96%) developed a TEE. In the multivariable analysis, males had higher risk of a TEE than women [odd ratio (OR) = 1.57; confidence interval (CI) 1.10–2.25] and blacks had higher risk than whites (OR = 1.20; CI 1.04–1.40). Compared with stage I patients, patients with stage II, III and IV had 22%, 39% and 98% increase, respectively, in risk. Placement of central catheters (OR = 2.71; CI 2.43–3.02), chemotherapy treatment (OR = 1.66; CI 1.48–1.86) or treatment with erythropoiesis-stimulating agents (ESAs) (OR = 1.33; CI 1.33–1.52) increase the risk. Other significant predictors included comorbidities, age, receptor status, marital status and year of diagnosis. Similar estimates were seen for pulmonary embolism, deep vein thromboembolism and other TEEs.
Conclusions: In total, 2.96% of patients in this cohort developed a TEE within 1 year from breast cancer diagnosis. Stage, gender, race, use of chemotherapy and ESAs, comorbidities, receptor status and catheter placement were associated with the development of TEEs.
doi:10.1093/annonc/mdq777
PMCID: PMC3200221  PMID: 21393379
breast cancer; cancer-associated thrombosis; deep venous thrombosis; population-based study; thromboembolic events; thrombosis
15.  Pediatric germ cell tumors and parental infertility and infertility treatment: a Children’s Oncology Group Report 
Cancer epidemiology  2011;35(5):e25-e31.
Background
Few risk factors have been established for childhood germ cell tumors (GCT). Parental infertility and infertility treatment may be associated with GCT development but these risk factors have not been fully investigated.
Methods
A case-control study of childhood GCT was conducted through the Children’s Oncology Group (COG). Cases, under the age of 15 years at diagnosis, were recruited through COG institutions from January 1993 to December 2002. Controls were obtained through random digit dialing. Information about infertility and infertility treatment along with demographic factors was collection through maternal interviews. Subgroups created by gender, age at diagnosis, and tumor location were examined separately. Statistical analysis was performed using multivariate logistic regression models.
Results
Overall, no association between GCT and infertility or its treatment was found. In subgroup analysis, females whose mothers had two or more fetal losses were found to be at increased risk for non-gonadal tumors (Odds ratio (OR) = 3.32, 95% Confidence interval (CI) = 1.12–9.88). Younger maternal age was associated with a lower risk of gonadal GCT in females (OR = 0.52, 95% CI = 0.28–0.96). There was an increased risk of all GCT and gonadal GCT in males born to older mothers (OR = 2.88, 95% CI = 1.13–7.37 and OR = 3.70, 95% CI = 1.12–12.24).
Conclusion
While no association between parental infertility or its treatment and childhood GCT was found overall, possible associations with maternal age and history of recurrent fetal loss were found in subgroups defined by gender.
doi:10.1016/j.canep.2011.01.009
PMCID: PMC3142313  PMID: 21474408
Germ cell tumor; infertility; pediatrics; epidemiology
16.  Giant cell tumour of bone: a new evaluating system is necessary 
International Orthopaedics  2012;36(12):2521-2527.
Giant cell tumour (GCT) of bone is still one of the most obscure and intensively studied tumours of bone. The histogenesis of GCT remains unclear. The recommended therapy of GCT evolved during the 20th century. The best treatment should ensure local control and maintain function. Curettage has been the preferred treatment for most GCTs. Good results have also been published on the use of high-speed burr and local adjuvants. Local tumour control can be satisfactorily achieved by wide excision. However, treatment options for GCT have remained fairly static over the past 30 years and there is no widely held consensus regarding the standard treatment selection for all patients. This challenge may result from the fact that there are no single clinical, radiographic, histological or morphological aspects that allow surgeons to accurately predict the trend of a single lesion to recur. In this research, a comprehensive review of the previously described radiographic staging systems by Enneking and Campanacci et al. and the shortfalls associated with them are provided, and then the possible risk factors of predicting local recurrence or evaluating functional outcome of GCT are also discussed. A new preoperative evaluating system of GCT may be necessary and feasible, so that surgeons may accurately assess the aggressiveness or severity of GCT in order to reliably guide treatment decisions and predict outcomes.
doi:10.1007/s00264-012-1664-9
PMCID: PMC3508056  PMID: 23052276
17.  Role of chemotherapy prior to orchiectomy in metastatic testicular cancer—is testis really a sanctuary site? 
ecancermedicalscience  2014;8:407.
A germ-cell tumour (GCT) of the testis is a chemosensitive tumour with high cure rates even in advanced disease. Radical inguinal orchiectomy is the initial procedure used to diagnose it which helps to risk-stratify these patients. However, in patients with life-threatening metastases, primary chemotherapy was attempted in a few studies, followed by delayed orchiectomy. The aim of this review is to study the histopathological findings of delayed orchiectomy and the retroperitoneal lymph node dissection (RPLND) specimens, to assess difference and concordance in response rates in histological types of GCTs in pathological specimens. Overall, 352 patients received initial chemotherapy followed by orchiectomy, and 235 of them had undergone RPLND. Delayed orchiectomy specimens had viable tumour in 74 (21%) patients, scarring/necrosis in 171 patients (48.5%), and teratoma in 107 (30.3%) patients. RPLND specimens had residual disease in 36 (15.3%) patients, scarring/necrosis in 100 patients (42.5%), and teratoma in 99 patients (42.3%). Patients with seminoma who underwent delayed orchiectomy had complete disappearance of tumour in 81.3% of cases, and in non-seminomatous GCT, it was 43.4%. These results raise the question of the existence of a blood–testis barrier in patients with advanced GCT and argue against the testis as a sanctuary site.
doi:10.3332/ecancer.2014.407
PMCID: PMC3936913  PMID: 24624227
primary chemotherapy; delayed orchiectomy; advanced germ-cell tumours; germ-cell tumours
18.  Resistance to Platinum-Containing Chemotherapy in Testicular Germ Cell Tumors Is Associated with Downregulation of the Protein Kinase SRPK11 
Neoplasia (New York, N.Y.)  2004;6(4):297-301.
Abstract
Male germ cell tumors (GCTs) are extremely sensitive to platinum-containing chemotherapy, with only 10% of patients showing therapy resistance. However, the biological basis of the high curability of disseminated GCTs by chemotherapy is still unknown. Recently, we demonstrated that the mammalian serine/arginine-rich protein-specific kinase 1 (SRPK1) is a cisplatin-sensitive gene, inactivation of which leads to cisplatin resistance. Because, in mammalians, the expression of SRPK1 is preferentially high in testicular tissues, cisplatin responsiveness of male GCTs might be associated with SRPK1 levels. In the present study, we monitored SRPK1 protein expression in a unique series of nonseminomatous GCTs by immunohistochemistry. Randomly selected GCTs (n = 70) and tumors from patients responding to standard chemotherapy (n = 20) generally showed strong SRPK1 staining. In contrast, expression in refractory GCTs (n = 20) as well as in GCTs from poor-prognosis patients responding to high-dose chemotherapy only (n = 11) was significantly lower (two-sided Wilcoxon rank sum test: P < .001). In conclusion, our data suggest that SRPK1 expression might be an important prognostic indicator for the chemoresponsiveness of nonseminomatous GCTs.
PMCID: PMC1502111  PMID: 15256051
Chemotherapy resistance; germ cell tumors; chemotherapy sensitivity; protein kinase SRPK1; immunohistochemistry
19.  Diagnostic Utility and Correlation of Tumor Markers in the Serum and Cerebrospinal Fluid of Children with Intracranial Germ Cell Tumors 
Purpose
In order to predict whether tumor markers assist in the histopathologic diagnosis of germ cell tumors (GCTs), we analyzed the correlation of beta human chorionic gonadotropin (bHCG) and alpha-fetoprotein (AFP) in serum and cerebrospinal fluid (CSF) samples at baseline and subsequent follow-up examinations.
Method
A retrospective study of patients diagnosed with intracranial GCTs between July 1985 and February 2011 at our institution was conducted to review clinical, surgical, radiological, laboratory and histopathologic data.
Results
Of 67 patients eligible for the study, 42 had germinomas and 25 non germinomatous GCTs. At baseline, serum and CSF AFP agreed in 97.9% of patients (Cohen’s Kappa 0.93). Baseline bHCG samples agreed in only 72.5% of patients (Cohen’s Kappa 0.46). In most cases, values were higher in serum for AFP and in CSF for bHCG. ROC curves estimated from logistic regression model indicated that CSF and serum samples had almost equal diagnostic utility, and the DeLong test showed that the difference in area under curves was not statistically significant. During follow-up (185 paired CSF and serum values from 43 patients), 90.3% of AFP values correlated between CSF and serum (Cohen’s Kappa 0.22, showing fair agreement). For bHCG, 96.2% of values agreed in serum and CSF (Cohen’s Kappa 0.61).
Conclusions
In some patients, intracranial GCTs can be diagnosed based solely upon positive serum AFP values. In addition, marker values from serum only may be sufficient to predict tumor relapse at interval follow-up examinations.
doi:10.1007/s00381-012-1762-4
PMCID: PMC3526807  PMID: 22547227
germ cell tumors; tumor markers; beta human chorionic gonadotropin; alpha-fetoprotein; correlation of markers; diagnostic utility
20.  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
21.  Effectivity of pazopanib treatment in orthotopic models of human testicular germ cell tumors 
BMC Cancer  2013;13:382.
Background
Cisplatin (CDDP) resistance in testicular germ cell tumors (GCTs) is still a clinical challenge, and one associated with poor prognosis. The purpose of this work was to test pazopanib, an anti-tumoral and anti-angiogenic multikinase inhibitor, and its combination with lapatinib (an anti-ErbB inhibitor) in mouse orthotopic models of human testicular GCTs.
Methods
We used two different models of human testicular GCTs orthotopically grown in nude mice; a CDDP-sensitive choriocarcinoma (TGT38) and a new orthotopic model generated from a metastatic GCT refractory to first-line CDDP chemotherapy (TGT44). Nude mice implanted with these orthotopic tumors were treated with the inhibitors and the effect on tumoral growth and angiogenesis was evaluated.
Results
TGT44 refractory tumor had an immunohistochemical profile similar to the original metastasis, with characteristics of yolk sac tumor. TGT44 did not respond when treated with cisplatin. In contrast, pazopanib had an anti-angiogenic effect and anti-tumor efficacy in this model. Pazopanib in combination with lapatinib in TGT38, an orthotopic model of choriocarcinoma had an additive effect blocking tumor growth.
Conclusions
We present pazopanib as a possible agent for the alternative treatment of CDDP-sensitive and CDDP-refractory GCT patients, alone or in combination with anti-ErbB therapies.
doi:10.1186/1471-2407-13-382
PMCID: PMC3751347  PMID: 23937707
Pazopanib; Lapatinib; Testicular cancer; Germ-cell tumors; Cisplatin; Refractory
22.  Transesophageal Echocardiography Screening in Subjects with a First Cerebrovascular Ischemic Event 
Our goal was to develop decision guides to predict the presence of a high risk source of embolus and to predict a change in management following transesophageal echocardiography (TEE) in subjects who present with a first cerebral ischemic event. We conducted a retrospective review of subjects ≥18 years who underwent TEE after a first ischemic event and were admitted to our stroke service from 2004-2007 (n=287). A high risk source of embolus and a change in clinical management (including medication changes or subsequent testing) were analyzed as separate endpoints using multivariate techniques and receiver-operator characteristic curves. 14.3% of subjects had a high risk source while an additional 61.3% had a potential (or low risk) source of embolus. Increasing age and no history of diabetes mellitus were independently associated with a high risk source of embolus. TEE would be recommended for non-diabetic individuals who are ≥66 years (sensitivity: 68%, specificity: 76%). The area under the curve (AUC) for detecting a high risk source was 0.773. TEE results changed medications or clinical management in 30.3% of patients. Current smokers were less likely to undergo a change in management. The AUC was uninformative (0.56) for predicting changes in management. Subjects presenting with a first ischemic event who are ≥66 years may benefit from TEE. While changes in management occurred in at least 30% of our cohort, no factors could be identified that predicted a change in management better than chance alone.
doi:10.1016/j.jstrokecerebrovasdis.2010.03.001
PMCID: PMC2997382  PMID: 20813548
Transesophageal echocardiography; cardioembolic sources; patient care management
23.  Pediatric primary central nervous system germ cell tumors of different prognosis groups show characteristic miRNome traits and chromosome copy number variations 
BMC Genomics  2010;11:132.
Background
Intracranial pediatric germ cell tumors (GCTs) are rare and heterogeneous neoplasms and vary in histological differentiation, prognosis and clinical behavior. Germinoma and mature teratoma are GCTs that have a good prognosis, while other types of GCTs, termed nongerminomatous malignant germ cell tumors (NGMGCTs), are tumors with an intermediate or poor prognosis. The second group of tumors requires more extensive drug and irradiation treatment regimens. The mechanisms underlying the differences in incidence and prognosis of the various GCT subgroups are unclear.
Results
We identified a distinct mRNA profile correlating with GCT histological differentiation and prognosis, and also present in this study the first miRNA profile of pediatric primary intracranial GCTs. Most of the differentially expressed miRNAs were downregulated in germinomas, but miR-142-5p and miR-146a were upregulated. Genes responsible for self-renewal (such as POU5F1 (OCT4), NANOG and KLF4) and the immune response were abundant in germinomas, while genes associated with neuron differentiation, Wnt/β-catenin pathway, invasiveness and epithelial-mesenchymal transition (including SNAI2 (SLUG) and TWIST2) were abundant in NGMGCTs. Clear transcriptome segregation based on patient survival was observed, with malignant NGMGCTs being closest to embryonic stem cells. Chromosome copy number variations (CNVs) at cytobands 4q13.3-4q28.3 and 9p11.2-9q13 correlated with GCT malignancy and clinical risk. Six genes (BANK1, CXCL9, CXCL11, DDIT4L, ELOVL6 and HERC5) within 4q13.3-4q28.3 were more abundant in germinomas.
Conclusions
Our results integrate molecular profiles with clinical observations and provide insights into the underlying mechanisms causing GCT malignancy. The genes, pathways and microRNAs identified have the potential to be novel therapeutic targets.
doi:10.1186/1471-2164-11-132
PMCID: PMC2837036  PMID: 20178649
24.  Highlights from the Third International Central Nervous System Germ Cell Tumour symposium: laying the foundations for future consensus 
ecancermedicalscience  2013;7:333.
The Third International Central Nervous System (CNS) Germ Cell Tumour (GCT) Symposium brought together over 100 delegates from all over the world to learn about the latest developments in these tumours and discuss future strategies for their management. Some areas of consensus were agreed upon, and controversies were discussed. Among these, the classification of GCTs and the surgical approach to their management were among the greatest areas of difference between different parts of the world. The need for radiotherapy (RT) as a part of standard first-line management for all malignant CNS GCTs was agreed, as well as the need for additional chemotherapy to maximise the cure in nongerminomatous malignant GCTs; the benefit of the addition of chemotherapy in localised germinoma to reduce the RT burden was also accepted as a good practice. The potential of biological parameters to assist the future diagnosis, treatment stratification, and disease monitoring for CNS GCTs was discussed. Such biological parameters may also represent targets for the development of novel therapies. The need for further collaboration between groups engaged in biological studies was agreed. The merits of proton beam RT were debated, and the importance of mitigating the long-term side effects of the treatment was underlined by a session on late effects.
doi:10.3332/ecancer.2013.333
PMCID: PMC3709531  PMID: 23861728
Third International CNS GCT Symposium; central nervous system; germ cell tumour; germinoma; nongerminoma
25.  GIANT CELL TUMOR OF THE SACRUM AND SPINE: SERIES OF 23 CASES AND A REVIEW OF THE LITERATURE 
Although there have been a few large case series of giant cell tumor (GCT) in the spine and sacrum, the treatment of these lesions remains controversial. We are reporting 23 additional cases of giant cell tumor in the spine and sacrum gathered from our institution and the personal consultation files of the senior author. Ten lesions occurred in the sacrum with an average age of 31 years (range of 13-49) and 13 occurred in the mobile spine with an average age of 39.1 years (range of 13-64). Most patients presented with pain or neurologic deficit at the site of tumor involvement, and symptoms were usually present for many months prior to diagnosis. Six of the sacral GCT patients were treated with pre-operative arterial embolization and intralesional surgical resection, and two developed a recurrence. Two of the sacral GCT patients had an en bloc resection and neither developed a recurrence. One sacral GCT patient was treated only with serial arterial embolization with good disease control. One sacral GCT patient did not receive any treatment. Eleven spinal GCT patients were treated with en bloc surgical resection and two developed a recurrence, the other two spinal GCT patients were treated with intralesional surgical resection and both developed a recurrence. Giant cell tumors of the spine and sacrum should be managed with en bloc resections whenever possible as this provides the greatest chance for cure. When the risk of post-operative neurologic deficit after en bloc excision is high, as in most of our sacral lesions, conservative therapy involving arterial embolization and intralesional resection offers the best results.
PMCID: PMC2958273  PMID: 21045974

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