Treatment Of Germ Cell Tumors Research Articles

Abstract 1144: Micro RNA profiling of intracranial germ cell tumors

Abstract Purpose: Intracranial germ cell tumors (GCTs) are rare brain tumors affecting primarily adolescents and young adults. They usually arise at the pineal or suprasellar region, where surgical intervention is very challenging. There are two major subtypes, germinoma and nongerminomatous GCT (NGGCT). The treatment of intracranial GCT (iGCT) is based on histologic classification and therefore correct classification is vital to the improvement of the outcome. However, due to frequent mixed histology and relatively low sensitivity and specificity of tumor markers, it is a challenging task to accurately subclassify iGCT based on limited biopsy. Recently, aberrant expression of microRNA (miRNA) in various cancers has been reported and thus miRNA holds great promise as a biomarker for cancer diagnosis and classification as well as for understanding tumor biology. We did genome-wide miRNA expression profiling of 45 cases of iGCT and studied the utility of miRNA as diagnostic markers and classifier in iGCT. Methods: Tumor samples were collected from Texas Children's Cancer Center and three other collaborating institutions. Expression of 367 miRNA was measured by real time qPCR TaqMan assay. Differentially expressed miRNAs were used to train various supervised multivariate classification algorithms. Leave-one-out cross validation was used to estimate the overall accuracy, sensitivity and specificity of the classifier. We used a reiterative process to reduce the number of miRNAs in the classifier without sacrificing its discriminating power. Result: Using 33 fresh frozen and 23 formalin-fixed paraffin-embedded (FFPE) samples (11 cases with matched samples), each set of samples showed distinct clusters of germinomas and NGGCTs by unsupervised clustering. We confirmed that good quantification of miRNA expression was possible by using FFPE samples, which are generally more challenging to use for mRNA expression profiling. The classifier based on 7 miRNAs profiled in FFPE samples showed high sensitivity (87.5%) and specificity (100%) in distinguishing germinomas from NGGCTs. The same 7-miRNA classifier identified in FFPE series was able to distinguish the subtypes in fresh frozen samples with 93.3% sensitivity and 87.5% specificity. Similarly, the classifier based on 5 miRNAs profiled in fresh frozen samples was able to classify the subtypes in FFPE samples accurately. Many highly expressed miRNAs in iGCT are identical to those found in embryonal stem cells (ESCs). It is interesting to note that the miRNAs that are differentially expressed between two subtypes of iGCTs are similar to those that show significant changes in expression when undifferentiated ESCs undergo induced differentiation in vitro. Conclusion: We demonstrated that miRNA expression in FFPE specimens could be used in clinical diagnosis and classification of iGCT. Our results also suggest that iGCT and ESCs show similar miRNA profiles and could have implications on the cell of origin of iGCTs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1144. doi:10.1158/1538-7445.AM2011-1144

Antitumor effects of AR-42, a novel histone deacetylase inhibitor, in embryonal carcinoma.

232 Background: Histone deacetylase inhibitors (HDACIs) modulate gene expression and induce cellular differentiation, growth inhibition and apoptotic cell death by chromatin hyperacetylation. Developmental arrest of germ cell differentiation earlier in the life is responsible for the pathogenesis of germ cell tumors (GCT). With current treatment nearly 95% of patients with GCT can be cured. Yet, effective agents with less toxicity are desired. In addition, those with relapsed/refractory disease have a dismal prognosis, indicating a clear need for new, more effective agents. Here we assess the antitumor effects of AR-42, a novel HDACI in in vitro and in vivo models of embryonal carcinoma. Methods: In vitro effects of AR-42 and suberoylanilide hydroxamic acid (SAHA) were evaluated in NTERA-2, an embryonal carcinoma (EC) cell line derived from a human testicular cancer. Cell viability (MTS assay), apoptosis (caspase 3/7 activity and PARP cleavage), cell cycle analysis (flow cytometry) and HDAC inhibition (immunoblotting) were assessed. The in vivo efficacy of AR-42 was assessed in a NTERA-2 xenograft tumor model in male athymic nude mice. Mice were fed control diet and diet containing AR-42 at an average dose of 25 mg/kg/day. Tumor volumes and weights were used as in vivo endpoints. Results: Treatment of NTERA-2 cells with both agents at 0.1-10 μM concentrations showed a time- and dose-dependent reduction in cell viability. Both agents significantly induced apoptosis, cell cycle inhibition and hyperacetylation of histones H-3 and H-4 in a dose-dependent manner. In vitro studies showed that AR-42 was more potent than SAHA. In our rodent model, AR-42-containing diet resulted in a significant reduction in tumor volumes and weights (50% and 56%, respectively). The results for intratumoral changes of proliferation and apoptosis are pending. There were no significant toxicities associated with AR-42, except for testicular atrophy, known to be reversible. Conclusions: AR-42 appears to be a potent inhibitor of EC through different mechanisms, orally bioavailable and well tolerated in our rodent model. Our data indicates that AR- 42 may have clinical value in the treatment of GCT and requires further investigation in clinical trials. No significant financial relationships to disclose.

Growing Teratoma Syndrome and Peritoneal Gliomatosis

The growing teratoma syndrome (GTS) is defined as a detection of an enlarged mass during or after chemotherapy treatment for germ cell tumor. We report a case of an 18-year-old girl treated for growing teratoma syndrome after chemotherapy for malignant germ cell tumor of the ovary associated with peritoneal gliomatosis. Chemotherapy induced normalisation of alpha-fetoprotein rate whereas there was an enlargement of the mass. Subsequent complete resection was performed, and the patient remained in good control for 60 months. This clinical picture suggested the diagnosis of “GTS”. This syndrome can lead to confusion with progression or relapse of a germ cell tumour because of increase in tumour volume during chemotherapy, so it is important to recognize it.

Pineal region tumors in children

Pineal tumors are rare in children, with pineoblastoma and germ cell tumors (GCTs) being the most common. Here we discuss recent advances in treatment and controversies in the management of these tumors. There is significant heterogeneity in the clinical behavior of pineoblastoma in children. We will discuss differences in outcome of children with pineoblastoma who are less than and greater than 3 years of age, and between pineoblastoma and nonpineal supratentorial primitive neuro-ectodermal tumors when treated with multiple different strategies. Significant controversies exist in the treatment of GCTs as well, including the levels of tumor markers in the blood and cerebrospinal fluid that are required to establish without biopsy the diagnosis of a GCT, the role of surgery in GCTs and the optimal treatment for germinomas as well as mixed malignant GCTs. Although pineoblastoma in infants and very young children still remains a therapeutic challenge, significant progress has been made in the treatment of pineal GCTs with treatment strategies using a combination of chemotherapy and reduced dose and volume irradiation, resulting in increased survival rates and reduced long-term morbidity.

Update on current standard treatments in central nervous system germ cell tumors

Various approaches have been used for the management of patients with germ cell tumors (GCTs) in the central nervous system (CNS); however, the optimal treatment of both germinoma and nongerminomatous GCTs remains unknown. This review discusses current management strategies and late effects of therapy for CNS GCTs. To reduce the late complications of radiation therapy for patients with germinoma, many investigators have introduced dose reduction of radiation therapy in association with platinum-based chemotherapy. In addition, the radiation field has been restricted to the whole ventricular area for localized germinoma. This type of combination therapy has shown promising results and preserves cognitive function and quality of life. Despite various approaches including high-dose chemotherapy against highly malignant or relapsed GCTs, the prognoses of these patients remain dismal except for a few successful reports. The 10-year survival rate of CNS germinoma is approximately 90%. Most patients with CNS GCTs are children and young adults. Therefore, with the improving life prognosis of young patients, secondary neoplasms, secondary cerebral vasculopathy, neurocognitive deficits, and many other adverse effects induced by the initial treatments are problems to be solved in the next decade.

Treatment and survival patterns for germ cell tumors among 13- to 24-year olds in Yorkshire, UK

Teenage and young adult (TYA) patient care can fall into gaps between adult and children's services. Increasingly UK TYA multi-disciplinary teams manage germ cell tumors (GCT) in locally agreed collaborations and age ranges. Patterns of care are changing rapidly. However, between disciplines protocols define different assessment and management in GCT. We aimed to document changes in incidence, treatment, and survival since 1990, to record the baseline to which future trends can be compared. Details were extracted from the UK population-based Yorkshire Specialist Cancer Register on 237 TYA aged 13-24 years diagnosed with a GCT between 1990 and 2004, followed-up until 2009. Incidence and survival patterns were assessed using Poisson and Cox regression. Testicular (n = 190; 80%) and ovarian (n = 22; 9%) GCT were the most common malignancies, and 90% of GCT occurred aged 17-24 years. The overall incidence rate was 26.9 per million person years. Rates increased significantly by 4.0% (95% CI: 1.0-7.1%) per year on average. The most common treatment modality was surgery combined with chemotherapy (49%). Initial treatment changed significantly over time (P = 0.003) and by age (P = 0.005). There were significant differences in the management of stage 1 testicular tumors by age. Among 13- to 16-year olds, 56% were treated exclusively in adult departments. Five-year survival rates were 93-95% for gonadal GCT, and 70-75% for other sites. Survival did not differ by age (P = 0.65) or period (P = 0.41). The age-related differences observed in the approach to GCT treatment suggest a collaborative approach to the models of care among TYA is required.

The usefulness of chemotherapy for control of ventricular arrhythmias secondary to cardiac metastasis of germ cell tumor

A 14-year-old boy was referred to our hospital because of treatment of germ cell tumor in the anterior mediastinum. Computerized tomographic (CT) scan of the chest and abdomen revealed a large tumor in the anterior mediastinum and multiple metastatic tumors in the lung, liver, kidney, pancreas, and heart. There was a mass in the interventricular septum. A 24-h Holter monitor showed sinus rhythm with 358 premature ventricular complexes (VPC) and 30 ventricular runs including 9 non-sustained ventricular tachycardias per day. The patient was treated with 4 cycles of chemotherapy with good response. Approximately 12 weeks after the start of the chemotherapy, serial CT scan showed regression of the tumors in the anterior mediastinum, lung, and kidney, and disappearance of the tumors in the liver, pancreas, and heart. Repeat Holter monitor showed that VPC and ventricular runs disappeared completely. The chemotherapy for the germ cell tumor was very useful for ventricular arrhythmias secondary to cardiac metastasis of the tumor.

Long-Term Cardiovascular Risk Following Platinum-Based Chemotherapy for Germ Cell Tumors

Background Germ cell tumors (GCTs) are one of the most curable of the solid neoplasms. They are highly sensitive to platinum-based chemotherapy, which contributes to 5 - year survival rates exceeding 90%. Any late effects of treatment are a key consideration when treating a highly curable disease in a young population. There is good evidence that platinum-based chemotherapy increases the risk of cardiovascular morbidity and mortality late in life; the exact nature of the risk is not well understood, nor is there any consensus on a mechanism for this effect. This article examines the current literature to assess the nature and size of the risk posed, and considers possible mechanisms for the effect. We consider the implications of treatment for GCT with platinum-based chemotherapy, as well as the implications for long-term follow-up and optimal clinical care of patients requiring systemic therapy. Discussion

Polyadenosine diphosphate-ribose polymerase (PARP) inhibition as a means of protecting the inner ear from cisplatin (CDDP)-mediated ototoxicity without affecting antitumor efficacy in vitro.

e13501 Background: Hearing loss can be the dose limiting toxicity of CDDP. In the treatment of germ cell tumors (GCT) or adjuvant therapy of non-small cell lung cancer (NSCLC), CDDP cannot be replaced without loss of efficacy. Inhibition of PARP, an enzyme of the base excision repair pathway, is a novel anti-neoplastic principle. PARP-activation has been identified to induce cell death following inner ear trauma. We evaluated PARP-inhibition by pirenzepin as a means to protect the ear from CDDP. Methods: In an in vitro culture model, inner ears were treated continuously with 1.4 μM CDDP. Ears were obtained from heterozygous and homozygous PARP-knock out mice and wild-type controls at postnatal day 7. The number of preserved hair cell stereocilia bundles was counted by fluorescence microscopy after labeling with phalloidin. Cytotoxicity of CDDP and the effect of pirenzepin were assessed by MTS-assays and flow cytometry using the cell lines 2102EP, NT2 (both GCT) and NCI-H460 (NSCLC). Results: In wild-type mice, only 45% of the inner and 30% of the outer hair cells were preserved following CDDP-exposure compared to untreated controls. In heterozygous PARP-knock out mice, 90% and 80% of the hair cells survived CDDP exposure. The fractions of surviving hair cells in the homozygous knock out mice were 70% and 50%, respectively, the difference was significant (p<0.05). Protection of 60-80% hair cells could be achieved by pirenzepin in wild-type mice with the maximum protective effect at intermediate dose levels. Pirenzepin alone did not affect growth in any cell line. Cytotoxicity of CDDP as measured by IC50 determination in MTS assay or by flow-cytometric assessment of vital cells was not affected by pirenzepin. Conclusions: PARP-activation seems to play a relevant role in CDDP-induced ototoxicity. Thus, PARP-inhibition appears to be a promising means to protect hearing under CDDP therapy, especially since PARP-inhibition did not diminish sensitivity of GCT and NSCLC cell lines to CDDP, even though no synergistic effect could be observed. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ProteoSys AG ProteoSys AG

Primary chemotherapy for intracranial germ cell tumors: Results of the third international CNS germ cell tumor study

The treatment of central nervous system (CNS) germ cell tumors (GCT) remains controversial. The purpose of this study was to demonstrate efficacy of a chemotherapy only strategy, with less morbidity, when compared to regimens with irradiation. Between January 2001 and December 2004 newly diagnosed patients with CNS GCT were treated with one of two risk-tailored chemotherapy regimens. Twenty-five patients aged 4 months to 24.5 years were stratified: Regimen A consisted of 4-6 cycles of carboplatin/etoposide alternating with cyclophosphamide/etoposide for low risk (LR) localized germinoma with normal cerebrospinal fluid (CSF) and serum tumor markers. Regimen B consisted of 4-6 cycles of carboplatin/cyclophosphamide/etoposide for intermediate-risk (IR) germinoma with positive human chorionic gonadotrophin-beta (HCGbeta) and/or CSF HCGbeta <50 mIU/ml and high-risk (HR) biopsy-proven non-germinomatous malignant elements (MMGCT) or elevated serum/CSF alpha-fetoprotein and/or HCGbeta serum/CSF >50 mIU/ml. Eleven patients were classified as LR, 2 IR, and 12 HR. Seventeen (68%) patients achieved complete radiographic and marker responses after two courses and 19 (76%) after four courses of chemotherapy. Eleven patients relapsed at a mean of 30.8 months; eight of them subsequently received irradiation. The 6-year event free and overall survival for the 25 patients was 45.6% and 75.3%, respectively. These intensive chemotherapy regimens proved less effective than irradiation containing regimens. Our results indicate that, at the present time, standard treatment for CNS GCT continues to include irradiation either alone or combined with chemotherapy for pure germinomas and with chemotherapy for those with MMGCT.

Tatsuya Kobayashi, Dade Lunsford (Eds), Progress in Neurosurgery Series-Vol. 23 Pineal Region Tumors, Diagnosis and Treatment Options

The introduction is a presentation of the statistical analysis of pineal tumors based on the data of the brain tumor registry of Japan. The frequency of pineal tumors in Japan is five times as high as in western countries. The first section deals with Tumors of Pineal Cell Origin. The first chapter deals with the pathology of pineal parenchymal tumors including immunohistology and electron microscopy. It ends with a brief account of genetic alterations. The second chapter of this section describes the occipital transtentorial approach and combined treatments of pineal parenchymal tumors. It also includes a brief description of histopathological findings. The third chapter addresses the role of streotactic radiosurgery in the management of pineal parenchymal tumors. The second section deals with Tumors of Germ Cell Origin. The first chapter of this section describes the pathology of these tumors including their histogenesis and classification as well as a brief account of genetic alterations; then, follows a chapter on the general management of these tumors and another one on the strategy of combined treatment of germ cell tumors with a classification according to prognosis. The next chapter is on radiation therapy and includes a review of prospective studies with chemotherapy and radiation, followed by a chapter on stereotactic radiosurgery for pineal and related tumors (germ cell as well as pineal parenchymal tumors). The next chapter is a proposal for a modern strategy with radiation and chemotherapy. The last chapter deals with the quality of life of extremely long-time germinoma survivors mainly treated with radiotherapy. This book provides a good picture of the state of the art in the management of pineal tumors. From the purely technical neurosurgical point of view, I missed the description of the infratentorial supracerebellar approach. The volume has the drawback of a multi-author book with some repetitions from one chapter to another. It can be of interest for neurosurgeons, radiotherapists, and medical oncologists.

7183 Outcomes in metastatic (met) germ cell tumours (GCT): 5-year experience from a single institution

Germ cell tumours (GCTs) of the testis are the most common cancer in young men; they are also one of the most curable cancers. Standard treatment of metastatic GCTs has evolved on the basis of randomised trials and prognostic factors.This review summarises the evolving role of chemotherapy in the treatment of previously treated and untreated patients with metastatic GCTs and outlines the current standard treatment.Randomised and nonrandomised trials of first-line, salvage, and palliative therapy were reviewed.Three cycles of standard bleomycin, etoposide, and platinum (BEP) can be considered the gold-standard treatment in good-risk patients, and four cycles of the same combination can result in cure in approximately 80% of intermediate-risk and 50% of poor-risk patients. The routine use of high-dose chemotherapy in patients with intermediate- or poor-prognosis GCT has not improved treatment outcome, but the role of tumour marker decline during the first cycles may provide useful prognostic information. Prognostic variables in patients who experience treatment failure after cisplatin-based chemotherapy can be used to guide salvage strategies, and many new drugs or combinations have shown activity in this setting. Patients and physicians should be aware of the risk of short- and long-term toxicity of treatments, and guidelines for screening and prevention of this risk should be established.A risk-based strategy offers the best chance of cure, even in patients with refractory GCT.

F-18 FDG PET/CT Imaging in a Case of Primary Choriocarcinoma in the Retroperitoneum

Nonseminomatous germ cell tumors (GCTs) represent 60% of all GCTs, the most common malignancy in young men. Extragonadal primary GCTs are a rare entity and their origin remains unclear. F-18 fluorodeoxyglucose positron emission tomography (PET) is a promising imaging tool for GCT staging and treatment evaluation. We report the case of a 23-year-old man presenting with retroperitoneal primary choriocarcinoma associated with pulmonary and hepatic metastases. In addition to conventional imaging techniques, the F-18 fluorodeoxyglucose PET evaluation at staging and after chemotherapy improved the management of this patient. Particularly, PET findings before surgery were correlated with histologic results.

Intracranial growing teratoma syndrome mimicking tumor relapse: a diagnostic dilemma

It is important to differentiate growing teratoma syndrome (GTS) from tumor recurrence in the setting of an enlarging residual mass present after treatment of intracranial germ cell tumors (GCTs). The aim of this study was to determine the incidence of intracranial GTS and present its clinical manifestations in detail. The authors performed a retrospective cohort study of 52 consecutive patients with newly diagnosed intracranial GCTs who presented between January 2000 and December 2006. The records were screened to identify a study cohort in which all patients had regrowing tumor mass despite normalization of tumor markers during or after treatment of GCTs. In 6 (11.5%) of 52 patients the pathological diagnosis was GTS. The median patient age at diagnosis was 14.5 years (range 2 months-17 years), and the primary tumors included 4 mixed GCTs and 2 immature teratomas. After second-look surgery, histological testing revealed the lesions to be mature teratoma in all patients. Three of 6 patients subsequently underwent radiation therapy and 1 patient received additional chemotherapy for spinal seeding. In enlarging residual masses after treatment of intracranial GCTs, GTS should be kept in mind in the differential diagnosis of tumor recurrence especially if there is a radiographic mismatch with serum marker test results. If technically feasible, second-look surgery may be necessary for an accurate diagnosis.

Gemcitabine Plus Vinorelbine as an Effective Salvage Chemotherapeutic Regimen in Cisplatin-Refractory Germ Cell Tumor

Germ cell tumors (GCT) are the most common malignancies among male adolescents. Approximately 5% of GCTs are of extragonadal origin. Cisplatin-based chemotherapy is the standard first-line treatment for GCT. Patients who fail to respond to first-line treatment usually have poor outcomes. High-dose chemotherapy with stem cell support, paclitaxel, gemcitabine, and oxaliplatin are reported as effective salvage treatment. We report two patients with cisplatin-refractory, metastatic, nonseminomatous, and extragonadal GCT treated successfully with gemcitabine plus vinorelbine (GV). One patient achieved good partial remission and had a five-month progression-free period. Another patient is still alive with stable disease after 4 cycles of treatment. In heavily treated, cisplatin-refractory GCT patients, GV could be considered an effective chemotherapeutic regimen.

Microsatellite Instability, Mismatch Repair Deficiency, and BRAF Mutation in Treatment-Resistant Germ Cell Tumors

Mismatch repair (MMR) deficiency and microsatellite instability (MSI) are associated with cisplatin resistance in human germ cell tumors (GCTs). BRAF mutation (V600E) is found in MSI colorectal cancers. The role of RAS/RAF pathway mutations in GCT treatment response is unknown. Two patient cohorts were investigated: 100 control GCTs (50 seminomas and 50 nonseminomas) and 35 cisplatin-based chemotherapy-resistant GCTs. MMR proteins were analyzed by immunohistochemistry, and eight microsatellite loci were examined for MSI. Tumors were assessed for specific BRAF and KRAS mutations. Resistant tumors showed a higher incidence of MSI than controls: 26% versus 0% in two or more loci (P < .0001). All resistant tumors were wild-type KRAS, and two controls (2%) contained a KRAS mutation. There was a significantly higher incidence of BRAF V600E mutation in resistant tumors compared with controls: 26% versus 1% (P < .0001). BRAF mutations were highly correlated with MSI (P = .006), and MSI and mutated BRAF were correlated with weak or absent staining for hMLH1 (P = .017 and P = .008). Low or absent staining of hMLH1 was correlated with promoter hypermethylation (P < .001). Tumors lacking expression of hMLH1 or MSH6 were significantly more frequent in resistant GCTs than in controls (P = .001 and 0.0036, respectively). Within the subgroup of resistant tumors, patients with MSI showed a trend to longer progression-free survival (P = .068). We report for the first time a correlation between a gene mutation--BRAF V600E--and cisplatin resistance in nonseminomatous GCTs. Furthermore, a correlation between MMR deficiency, MSI, and treatment failure is confirmed.

Clinical Relevance of “Late” in the Management of Late Relapse After Treatment for a Germ Cell Tumor

Dramatic improvements in treatment for germ cell tumors occurred in the late 1970s with the introduction of cisplatin-based combination chemotherapy. For the first time, cure was achievable for the majority of patients treated for metastatic disease. 1 As a medical oncology trainee in the mid-1980s, I was taught the prevailing dogma that relapses virtually never occurred more than 2 years after completion of this chemotherapy. However, as early as 1983, reports began to emerge of “late” relapses after cisplatin-based combination chemotherapy. 2 By the mid-1990s, investigators at Indiana University reported 81 cases of late relapse, including 34 patients experiencing relapse 2 to 5 years after treatment and 47 patients experiencing relapse more than 5 years after treatment. 3 The authors concluded that late relapse was associated with relative resistance to chemotherapy, and surgery was recommended as the preferred mode of therapy. There have been multiple subsequent publications reporting experience with late relapse, mostly single-institution series from large referral centers. Interpretation of these reports is difficult because of variability of the cases considered with respect to prior therapy, histologic group, stage at initial diagnosis, primary site, and inclusion of cases with prior relapse. A recent comprehensive review of published literature concluded that the risk of late relapse was 3.2% in nonseminoma and 1.2% in seminoma. 4 The accepted definition of late relapse was relapse beyond 2 years after completing therapy or after achieving complete response, in the absence of a new primary tumor. The most common site of relapse was the retroperitoneum in both seminoma and nonseminoma. In this issue ofJournalofClinicalOncology, Sharp et al 5 report the single-institution experience of late relapse at Memorial SloanKettering Cancer Center (New York, NY), analyzing prognostic factors for cancer-specific survival (CSS). As with many prior series, they have included chemotherapy-naive patients experiencing relapse after orchiectomy followed by surveillance, retroperitoneal lymph node dissection, or radiation therapy. They report 75 cases of late relapse, comprising 70 patients with nonseminoma and five patients with pure seminoma. The time to relapse was 2 to 5 years in 28 patients (38%), 5 to 10 years in 19 patients (26%), and more than 10 years in 27 patients (36%). Eighteen patients (24%) had not received any chemotherapy at the time of relapse. The 5-year CSS was 93% in chemotherapy-naive patients but only 49% in those who had received prior chemotherapy. Complete resection of disease at relapse was associated with improved CSS. In multivariate analyses, considering only those who had received prior chemotherapy, the presence of symptoms and multifocal disease at relapse were each associated with an inferior CSS. The authors state “complete surgical resection is central to the management of late relapse” but qualify this elsewhere with the statement “we believe that the definition of late relapse should be limited to patients

Is histological diagnosis necessary to start treatment for germ cell tumours in the pineal region?

The significance of histological diagnosis was retrospectively investigated in the treatment of 79 consecutive patients with pineal region tumours. Histological diagnoses were consistent with clinical diagnoses in 38 out of 39 patients with germ cell tumours and in all eight patients with non-germ cell tumours. The single exception was pineoblastoma. Forty-one patients were treated under a clinical diagnosis of pineal germ cell tumour using neoadjuvant chemotherapy and radiation therapy without histological verification. Of the 41 patients, 32 achieved an excellent response, whereas nine required the delayed resection of a residual tumour. Of these nine tumours, seven were mature or immature teratomas or scars. These patients had elevated levels of tumour markers. Most cases of pineal germ cell tumour could be identified on the basis of clinical findings only, and could be treated appropriately using neoadjuvant chemotherapy and radiation therapy without histological diagnosis. However, second-look surgery should be considered in cases with residual teratomatous components or unusual responses.

IGG* Practice Guidelines on Germ Cell Tumor in Adult Male Patients

Germ cell tumors are rare neoplasms that affect young males. Nearly 99% of patients with localized stage I disease and nearly 80% of patients with metastatic disease can be cured. Even patients who relapse following chemotherapy can achieve a long-term survival in approximately 30-40% of cases. The main objective in early stages and in good prognosis patients has changed in recent years, and it has become of major importance to reduce treatment-related morbidity without compromising the excellent long-term survival rate. In poor prognosis patients, there is a correlation between the experience of the treating institution and the long-term clinical outcome of the patients, particularly when the most sophisticated therapies are needed. So far, of utmost importance is the information from updated practice guidelines for the diagnosis and treatment of germ cell tumors. The Italian Germ cell cancer Group (IGG) has developed the following clinical recommendations, which identify the current standards in diagnosis and treatment of germ cell tumors in adult males.

New Drugs in the Treatment of Germ Cell Tumours

New Drugs in the Treatment of Germ Cell Tumours