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1.  Predictors of viable germ cell tumor in postchemotherapeutic residual retroperitoneal masses 
Urology Annals  2014;6(1):27-30.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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).
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).
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.
PMCID: PMC3264865  PMID: 21837523
8.  The Impact of Maternal Age, Pre-Pregnancy Body Mass Index, Weight Gain and Parity on Glucose Challenge Test (GCT) 
Gestational diabetes mellitus (GDM) complicates 3-7% of all pregnancies and fetomaternal outcomes are strongly related to early diagnosis of GDM. The aim of this study was to determine the impact of risk factors in the prediction of an abnormal glucose challenge test (GCT).
Materials and Methods
This was a prospective study conducted during 2009-2010 in two prenatal clinics in Rey, Iran. A total of 711 pregnant women who were in their first trimester of pregnancy and met the inclusion criteria were selected. The women were observed once every other week until 24- 28 weeks of gestation. All patients at 24-28 weeks of gestation were screened with 50 g oral glucose GCT. The effects of pre-pregnancy body mass index (BMI), maternal age, and weight gain until the time of GCT, and parity on abnormal GCT were evaluated. All confident intervals were calculated at the 95% level. Data was analyzed using student’s t test and the logistic regression test.
Maternal age (p<0.001), pre-pregnancy BMI (p<0.00), parity (p=0.05) and weight gain during pregnancy (p=0.05), were significantly higher in women with abnormal GCT compared to women who had normal GCT. Logistic regression analyses confirmed that pre-pregnancy BMI (OR=1.09), maternal age (OR=1.14), and weight gain during pregnancy (OR=1.13) were associated with abnormal GCT.
Weight gain had a profound impact on the prevalence of abnormal GCT in our population. Therefore, we propose that pregnant women should only gain the recommended amount of weight during pregnancy.
PMCID: PMC4152182  PMID: 25210604
BMI; GCT; Maternal Age; Parity; Weight Gain
9.  Responses and adverse effects of carboplatin-based chemotherapy for pediatric intracranial germ cell tumors 
Korean Journal of Pediatrics  2011;54(3):128-132.
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.
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.
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.
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.
PMCID: PMC3120999  PMID: 21738543
Intracranial germ cell tumor; Carboplatin; Adverse effects
10.  Clinicopathological and immunohistochemical features of primary central nervous system germ cell tumors: a 24-years experience 
Primary central nervous system (CNS) germ cell tumors (GCTs) are a rare heterogeneous group of lesions, which the clinicopathological features have a marked degree of heterogeneity comparing with that of gonadal GCTs. Accurately diagnosing CNS GCTs might be extremely difficult and requires immunohistochemical verification. This study was to investigate the biological feature of CNS GCTs and diagnostic value of immunohistochemical markers OCT3/4, C-kit, PLAP, and CD30 in CNS GCTs. A retrospective study was performed on 34 patients with CNS germ cell tumors between 1990 and 2014. 34 CNS GCTs account for 9.2% of all primary CNS neoplasms. The sellar region (35.3%) and pineal gland (17.6%) were the most common sites of intracranial GCTs. Hydrocephalus (82.4%) and diplopia (46.9%) were the two most common clinical presentations. The most common histological subtypes were germinoma (67.6%). PLAP, c-kit, OCT3/4 were highly expressed in gernimomas. CD30 and CK AE1/3 stainings were positive in embryonal carcinoma. Yolk sac tumor component showed positive staining for AFP and CK AE1/3. β-HCG staining was positive in choriocarcinoma and STGC. Patients with mature teratomas and germinomas had a better prognosis (a 5-year survival rate) than those with embryonal carcinoma and choriocarcinoma (a 5-year survival rates were 0). Our finding suggest that the incidences of primary CNS GCTs are higher in South China than in the West, but mixed GCTs are uncommon in our study. The judicious use of a panel of selected markers is helpful in diagnosing and predicting the prognosis for CNS GCTs.
PMCID: PMC4230147  PMID: 25400782
Central nervous system; germ cell tumors; C-kit; PLAP; OCT3/4; CD30
11.  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.
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.
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).
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.
PMCID: PMC3651602  PMID: 19770384
12.  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.
PMCID: PMC3578540  PMID: 24426698
Granulosa cell tumor; Inhibin B
13.  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.
PMCID: PMC2361583  PMID: 16106248
extragonadal germ cell tumour; high-dose chemotherapy; salvage therapy; children
14.  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
15.  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.
PMCID: PMC3200221  PMID: 21393379
breast cancer; cancer-associated thrombosis; deep venous thrombosis; population-based study; thromboembolic events; thrombosis
16.  Circadian Variation in the Response to the Glucose Challenge Test in Pregnancy 
Diabetes Care  2012;35(7):1578-1584.
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.
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).
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).
Among women with a positive GCT, those tested in the afternoon have better metabolic function and a lower risk of GDM on subsequent OGTT.
PMCID: PMC3379574  PMID: 22723584
17.  Pediatric germ cell tumors and parental infertility and infertility treatment: a Children’s Oncology Group Report 
Cancer epidemiology  2011;35(5):e25-e31.
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.
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.
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).
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.
PMCID: PMC3142313  PMID: 21474408
Germ cell tumor; infertility; pediatrics; epidemiology
18.  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.
PMCID: PMC3508056  PMID: 23052276
19.  Association of immunohistochemical markers with premalignancy in Gonadal Dysgenesis 
Gonadal dysgenesis (GD) is associated with increased risk of gonadal malignancy. Determining a patient’s risk and appropriate timing of gonadectomy is challenging, but immunohistochemical markers (IHM) may help establish the diagnosis of malignant germ cell tumors (GCT). Our objective was to identify the prevalence of specific IHM expression in patients with GD and determine if the patterns of expression can help identify malignancy versus pre-malignancy state. We evaluated the published literature using the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) system to provide recommendations on the predictive role of IHM in the detection of germ cell malignancy.
The data for this retrospective study included karyotype, gonadal location, external masculinization score, age at time of gonadectomy or biopsy, microscopic description and diagnosis of gonadal tissue, and immunohistochemical staining, including octamer binding transcription factor (OCT) 3/4, placental-like alkaline phosphatase (PLAP), β-catenin, alpha-fetoprotein (AFP), and stem cell factor receptor CD117 (c-KIT). Patients with complete or partial GD who had undergone gonadectomy or gonadal tissue biopsy were included.
The study included 26 patients with GD, 3 of whom had evidence of GCT (11.5 %, gonadoblastoma, dysgerminoma): 2 had Swyer syndrome, 1 had 46,XY partial GD. One patient with XY partial GD had gonadoblastoma-like tissue. All 4 patients (15 %) had strong expressions of 4 tumor markers (OCT 3/4, PLAP, β-catenin, CD117), as did 5 other patients (19 %, ages 2–14 months) without GCT: 4 had XY GD, 1 had 46,XX GD. β-catenin was expressed in 96 % of patients in a cytoplasmic pattern, CD117 in 78 %, OCT 3/4 in 55 %, PLAP in 37 %, and AFP in 1 patient (4 %). Tumor marker expression was not specific for ruling out malignancy in patients <1 year.
In patients older than 1 year, expression of all three markers (OCT 3/4, PLAP, CD117) may be instrumental in the decision-making process for gonadectomy, even in the absence of overt germ cell malignancy. Our literature review suggests that OCT 3/4 expression is most helpful in predicting risk of malignancy. Additional criteria are needed to stratify risk in patients younger than 1 year of age, as these markers are not reliable in that age group.
PMCID: PMC4472165  PMID: 26089923
Gonadal dysgenesis; Germ cell tumor; Gonadectomy; Immunohistochemical markers
20.  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.
PMCID: PMC3936913  PMID: 24624227
primary chemotherapy; delayed orchiectomy; advanced germ-cell tumours; germ-cell tumours
21.  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.
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
22.  Paclitaxel, ifosfamide, and cisplatin (TIP) as salvage and consolidation chemotherapy for advanced germ cell tumor 
The purpose of the study was to assess the efficacy of TIP as salvage chemotherapy for germ cell tumor (GCT) patients with relapsed disease or cisplatin (CDDP)-refractory disease and consolidation chemotherapy for patients who responded unfavorably to first-line chemotherapy.
Forty-three patients with advanced GCT were treated with TIP. Eleven with relapsed disease and five with CDDP-refractory disease received TIP as salvage chemotherapy. The remaining 27 received TIP as consolidation chemotherapy following initial induction chemotherapy. All patients received prophylactic granulocyte colony-stimulating factor.
In total, 116 cycles of TIP were administered with a median of three cycles (range 1–4 cycles) per patient. Before TIP, 33 patients showed elevated tumor marker and 23 patients (70 %) achieved marker normalization with the chemotherapy. One of six (17 %) patients with refractory disease and 5 of 10 (50 %) patients with relapsed disease achieved durable complete response (CR) after TIP with or without surgery. Eighteen of 27 (67 %) patients receiving TIP as consolidation chemotherapy achieved durable CR. Five additional patients were given further chemotherapy and achieved durable CR. Grade 4 leukocytopenia and thrombocytopenia were observed in 91 and 42 % of patients, respectively; all were managed with routine supportive care. Grade 2 and grade 3 sensory neuropathy was observed in 37 and 2 % of patients, respectively.
The TIP was effective for relapsed patients with favorable risk features and selected CDDP-refractory GCT patients. Results of TIP as consolidation for patients with unfavorable response to the initial chemotherapy were also encouraging. The toxicities were mainly myelosuppression and sensory neuropathy.
PMCID: PMC4282876  PMID: 25062721
TIP; Salvage; Chemotherapy; Germ cell tumor
23.  The clinical characteristics and treatment outcome of 57 children and adolescents with primary central nervous system germ cell tumors 
Chinese Journal of Cancer  2014;33(8):395-401.
Primary central nervous system germ cell tumors (CNS-GCTs) in children and adolescents have unique clinical features and methods of treatment compared with those in adults. There is little information about Chinese children and adolescents with CNS-GCTs. Therefore, in this study we retrospectively analyzed the clinical features and treatment outcome of Chinese children and adolescents with primary CNS-GCTs. Between January 2002 and December 2012, 57 untreated patients from a single institution were enrolled. They were diagnosed with CNS-GCTs after pathologic or clinical assessment. Of the 57 patients, 41 were males and 16 were females, with a median age of 12.8 years (range, 2.7 to 18.0 years) at diagnosis; 43 (75.4%) had non-germinomatous germ cell tumors (NGGCTs) and 14 (24.6%) had germinomas; 44 (77.2%) had localized disease and 13 (22.8%) had extensive lesions. Fifty-three patients completed the prescribed treatment, of which 18 underwent monotherapy of surgery, radiotherapy, or chemotherapy, and 35 underwent multimodality therapies that included radiotherapy combined with chemotherapy or surgery combined with chemotherapy and/or radiotherapy. PEB (cisplatin, etoposide, and bleomycin) protocol was the major chemotherapy regimen. The median follow-up time was 32.3 months (range, 1.2 to 139 months). Fourteen patients died of relapse or disease progression. The 3-year event-free survival (EFS) and overall survival rates for all patients were 72.2% and 73.8%, respectively. The 3-year EFS was 92.9% for germinomas and 64.8% for NGGCTs (P = 0.064). The 3-year EFS rates for patients with NGGCTs who underwent monotherapy and multimodality therapies were 50.6% and 73.5%, respectively (P = 0.042). Our results indicate that multimodality therapies including chemotherapy plus radiotherapy were better treatment option for children and adolescents with CNS-GCTs.
PMCID: PMC4135369  PMID: 25011460
Primary central nervous system germ cell tumors; chemotherapy; radiotherapy; survival rate; children
24.  Biology of childhood germ cell tumours, focussing on the significance of microRNAs 
Andrology  2014;3(1):129-139.
Genomic and protein-coding transcriptomic data have suggested that germ cell tumours (GCTs) of childhood are biologically distinct from those of adulthood. Global messenger RNA profiles segregate malignant GCTs primarily by histology, but then also by age, with numerous transcripts showing age-related differential expression. Such differences are likely to account for the heterogeneous clinico-pathological behaviour of paediatric and adult malignant GCTs. In contrast, as global microRNA signatures of human tumours reflect their developmental lineage, we hypothesized that microRNA profiles would identify common biological abnormalities in all malignant GCTs owing to their presumed shared origin from primordial germ cells. MicroRNAs are short, non-protein-coding RNAs that regulate gene expression via translational repression and/or mRNA degradation. We showed that all malignant GCTs over-express the miR-371–373 and miR-302/367 clusters, regardless of patient age, histological subtype or anatomical tumour site. Furthermore, bioinformatic approaches and subsequent Gene Ontology analysis revealed that these two over-expressed microRNAs clusters co-ordinately down-regulated genes involved in biologically significant pathways in malignant GCTs. The translational potential of this finding has been demonstrated with the detection of elevated serum levels of miR-371–373 and miR-302/367 microRNAs at the time of malignant GCT diagnosis, with levels falling after treatment. The tumour-suppressor let-7 microRNA family has also been shown to be universally down-regulated in malignant GCTs, because of abundant expression of the regulatory gene LIN28. Low let-7 levels resulted in up-regulation of oncogenes including MYCN, AURKB and LIN28 itself, the latter through a direct feedback mechanism. Targeting LIN28, or restoring let-7 levels, both led to effective inhibition of this pathway. In summary, paediatric malignant GCTs show biological differences from their adult counterparts at a genomic and protein-coding transcriptome level, whereas they both display very similar microRNA expression profiles. These similarities and differences may be exploited for diagnostic and/or therapeutic purposes.
PMCID: PMC4409859  PMID: 25303610
biomarker; germ cell tumour; let-7; LIN28; microRNA; miR-302/367; miR-371–373; serum
25.  Diagnostic Utility and Correlation of Tumor Markers in the Serum and Cerebrospinal Fluid of Children with Intracranial Germ Cell Tumors 
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.
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.
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).
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.
PMCID: PMC3526807  PMID: 22547227
germ cell tumors; tumor markers; beta human chorionic gonadotropin; alpha-fetoprotein; correlation of markers; diagnostic utility

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