Metastatic Testicular Germ Cell Tumors Research Articles

Expression of UTF1 in Primary and Metastatic Testicular Germ Cell Tumors

We immunohistochemically evaluated UTF1 in 104 primary and 68 metastatic testicular germ cell tumors and 339 non-germ cell tumors. The percentage of tumor cells stained was semiquantitatively scored (0, no tumor cell staining; 1+, ≤30% of cells; 2+, 31%-60% of cells; 3+, 61%-90% of cells; 4+, >90% of cells). Staining intensity (nuclear) was scored as weak, moderate, or strong. UTF1 staining was seen in all 56 intratubular germ cell neoplasias, unclassified type (2+, 1; 3+, 2; 4+, 53; weak, 4; moderate, 49; strong, 3), all 72 seminomas (1+, 2; 2+, 4; 3+, 8; 4+, 58; weak, 10; moderate, 33; strong, 29), and 59 embryonal carcinomas (3+, 2; 4+, 57; moderate, 1; strong, 58). Weak UTF1 staining was seen in 15 of 37 yolk sac tumors (1+, 10; 2+, 2; 3+, 2; 4+, 1). All 34 teratomas, 9 choriocarcinomas, and 6 spermatocytic seminomas were negative for UTF1 staining. Among the 339 non-germ cell tumors, only 18 showed weak UTF1 staining (1+ to 4+). Normal prepubertal and postpubertal spermatogonia showed weak to strong UTF1 staining. UTF1 was differentially expressed in testicular germ cell tumors. Strong UTF1 staining can be used for diagnosing embryonal carcinoma and seminoma. UTF1 expression in spermatogonia suggests its possible role in spermatogenesis and renewal of spermatogonia.

Cisplatin sensitivity of testis tumour cells is due to deficiency in interstrand-crosslink repair and low ERCC1-XPF expression

BackgroundCisplatin based chemotherapy cures over 80% of metastatic testicular germ cell tumours (TGCT). In contrast, almost all other solid cancers in adults are incurable once they have spread beyond the primary site. Cell lines derived from TGCTs are hypersensitive to cisplatin reflecting the clinical response. Earlier findings suggested that a reduced repair capacity might contribute to the cisplatin hypersensitivity of testis tumour cells (TTC), but the critical DNA damage has not been defined. This study was aimed at investigating the formation and repair of intrastrand and interstrand crosslinks (ICLs) induced by cisplatin in TTC and their contribution to TTC hypersensitivity.ResultsWe observed that repair of intrastrand crosslinks is similar in cisplatin sensitive TTC and resistant bladder cancer cells, whereas repair of ICLs was significantly reduced in TTC. γH2AX formation, which serves as a marker of DNA breaks formed in response to ICLs, persisted in cisplatin-treated TTC and correlated with sustained phosphorylation of Chk2 and enhanced PARP-1 cleavage. Expression of the nucleotide excision repair factor ERCC1-XPF, which is implicated in the processing of ICLs, is reduced in TTC. To analyse the causal role of ERCC1-XPF for ICL repair and cisplatin sensitivity, we over-expressed ERCC1-XPF in TTC by transient transfection. Over-expression increased ICL repair and rendered TTC more resistant to cisplatin, which suggests that ERCC1-XPF is rate-limiting for repair of ICLs resulting in the observed cisplatin hypersensitivity of TTC.ConclusionOur data indicate for the first time that the exceptional sensitivity of TTC and, therefore, very likely the curability of TGCT rests on their limited ICL repair due to low level of expression of ERCC1-XPF.

Histological evidence for the existence of germ cell tumor cells showing embryonal carcinoma morphology but lacking OCT4 expression and cisplatin sensitivity

The biological basis for manifestation of chemotherapy resistance in metastatic testicular germ cell tumors (GCT) remains obscure and is of particular clinical interest. In nonseminomatous GCT (NSGCT) the pluripotent embryonal carcinoma (EC) cells are the precursors of the manifold differentiated structures but also drive the malignant growth. They are known to be hypersensitive towards DNA-damaging agents and to express the embryonal transcription factor OCT4. We recently characterized EC cells that lack OCT4 expression and show cisplatin resistance. In the present, immunohistochemical study we analyzed the composition of NSGCT with the focus on such OCT4-negative EC cells using a NSGCT xenograft model as well as patient-derived NSGCT samples. In the xenograft model, the cisplatin-sensitive cell line H12.1 gives rise to xenografts where EC structures are mainly composed of OCT4-positive cells, whereas xenografts from the resistant cell line 1411HP exclusively comprise OCT4-negative EC areas. We found that post-chemotherapy residual metastatic tumors of patients can be comprised of exclusively OCT4-negative EC, whereas the matched testicular primary tumor harbors OCT4-positive EC. Thorough histological analyses revealed a few examples of such OCT4-negative EC cells also in the testicular primary tumor as well as in xenografts from the cisplatin-sensitive NSGCT-cell line. For these cells we propose an identity as early extraembryonal progenitor cells directly derived from OCT4-expressing EC cells. This challenges the use of the term EC cell. The data also support our hypothesis that malignant growth of resistant NSGCT may be driven by this cell type.

BLMH1 single nucleotide polymorphism correlation with bleomycin chemotherapy in patients with testicular germ cell tumors.

e15100 Background: Bleomycin, the main component of chemotherapy protocol for metastatic testicular germ-cell tumor (TGCT), may be inactivated by bleomycin hydrolase, encoded by BLMH1 gene. SNP A1450G is thought to be involved in controling enzymatic activity and thus the level of bleomycin-induced DNA damage. We suggested hypotesis that this SNP A1450G might influence toxicity in TGCT patients. Methods: Fiftynine patients with metastatic TGCT (6 seminomas, 14 nonseminomas and 39 with mixed germ cell tumors) were treated with three (10 patients) or four cycles (47 patients) of BEP chemotherapy (bleomycin/etoposide/cisplatin), except for 2 patients with bleomycin toxicity who were treated with 1 and 2 cycles of BEP. Blood samples of 59 patients were analysed using the real-time PCR method performed by ABI PRISM 7000 Sequence Detection System (Applied Biosystems) and pre-developed TaqMan SNP genotyping assay (rs1050565) according to the manufactures' instructions Results: We observed a wide range of adverse events casued by toxicity of bleomycin: cough, dyspnea, pneumonitis, pulmonary fibrosis, nail changes, hyperpigmentation, hypersensitivity, pruritus, leukocytopenia, vomiting, nausea and the fever. Two patients revealed severe adverse events (who were treated with 1 and 2 cycles of BEP), one a pulmonary fibrosis (x-ray verified) and the second as a significant dyspnea.The most common adverse effects were dermatological (hyperpigmentation, pruritus, hypersensitivity and nail changes) as well as fever. Patients with AG or GG genotypes developed more adverse events (25) than patients with AA (16) although results didn't reach statistical significance. Conclusions: Our results suggests that application of SNPs in future as a routine method will enable individual approach and recognition of patients who are genetically predisposed for higher toxicological effects of bleomycin. It can be expected that as number of subjects in this cohort will increase statistical significance will be reached. No significant financial relationships to disclose.

Vascular Compromise as a Cause of Sudden Death in a Pediatric Patient With Widely Metastatic Testicular Germ Cell Tumor

During hospitalization for evaluation of a large testicular tumor with extensive metastatic disease, this 14-year-old boy collapsed while showering and could not be resuscitated. At autopsy, there was no evidence of thromboembolic phenomenon, a known cause of sudden death in metastatic testicular tumors and other large abdominal tumors. However, marked compression of the inferior vena cava by a large pelvicoabdominal tumor mass and findings suggestive of systemic-portal shunting were consistent with the death due to the impaired venous return via the inferior vena cava.

Differentiated rhabdomyomatous tumors after chemotherapy for metastatic testicular germ-cell tumors: a clinicopathological study of seven cases mandating separation from rhabdomyosarcoma

To gain insight concerning prognosis, we investigated seven cases of post-chemotherapy retroperitoneal lymph-node dissections from patients with testicular germ-cell tumors that contained sizable nodules of differentiated skeletal muscle, but that lacked both a primitive cellular component and mitotic activity. The patients were 18–28 years old at the time of retroperitoneal lymph-node dissection. All had a previous non-seminomatous germ-cell tumor of the testis, five of which had a teratoma component. In one the testicular tumor had foci of embryonal rhabdomyosarcoma. The retroperitoneal lymph-node dissections were performed 0.2–4.7 years after orchiectomy, all following cisplatin-based chemotherapy, and contained rhabdomyomatous tumors that ranged from 0.8–5 cm. These consisted of nodular to diffuse aggregates of fetal-type rhabdomyocytes with central to peripheral nuclei and abundant, eosinophilic, fibrillary cytoplasm with occasional cross striations. Elongated myotubes with multiple nuclei in a common sarcoplasm occurred at least focally in all cases. Mild to moderate nuclear atypia, including nuclear enlargement and nucleolar prominence, was present, but mitotic activity, necrosis, and a primitive cellular component were absent. All but one retroperitoneal lymph-node dissection also contained other teratomatous elements. Follow-up in six patients showed three were disease free at 2.2–3.4 years; two developed recurrent teratoma at 1.3–3.7 years; and a sixth developed recurrent teratoma at 0.5 and 2 years, followed at 17 years by progressive tumor with elevated α-fetoprotein. No patient with available follow-up developed progressive sarcoma. We conclude that rhabdomyomatous tumors in retroperitoneal lymph-node dissection specimens after chemotherapy for metastatic testicular germ-cell tumors show clinical behavior similar to teratoma rather than rhabdomyosarcoma. We believe the most likely explanation for the finding of pure rhabdomyomatous tumors in this setting, a phenomenon sometimes termed ‘cytodifferentiation,‘ is selective persistence of differentiated tumor cells because of chemotherapy.

The Effects of Chemotherapy on Metastatic Testicular Germ Cell Tumors

Modern chemotherapy combined with surgery can achieve complete cure in over 90% of all patients with malignant testicular germ cell tumors. Even tumors that have already metastasized at the time of orchidectomy are curable by platinum-based multidrug treatment. Chemotherapy related changes can be seen in the residual tumor tissue in metastatic sites. In patients fully responding to chemotherapy these changes include complete necrosis of the tumor cells, and inflammatory-phagocytic response, fibrosis replacing the necrotic tumor tissue, and residual benign somatic tissue tissues in form of teratoma. Epithelial and stromal cells of these teratomas may display nuclear atypia, which is however not a reason for concern and should not be considered an indication for additional chemotherapy. Less commonly the lymph nodes contain cystic trophoblastic tumors. In contrast to metastatic classical biphasic or monophasic choriocarcinoma, cystic trophoblastic tumors portend a favorable clinical outcome. Patients with an incomplete response to chemotherapy and those with recurrences of the malignant tumor contain in metastatic sites foci composed of embryonal carcinoma cells, yolk sac carcinoma, or choriocarcinoma. The latter two subtypes of germ cell neoplasia may recur in several microscopic variant forms. Somatic forms of malignancy (also known as non-germ cell malignancies) that develop occasionally in some treated patients include most often sarcomas and tumors resembling central primitive neuroectodermal neoplasms. These secondary malignancies are usually resistant to chemotherapy. The broad spectrum of morphologic findings in the lymph nodes of patients with treated metastatic testicular germ cell tumors clearly illustrates the importance of meticulous pathologic analysis of tissue changes related to chemotherapy.

Anti‐Ma2 paraneoplastic encephalitis associated with testicular germ cell tumor treated by carboplatin, etoposide and bleomycin

Anti-Ma2-associated encephalitis is a paraneoplastic disorder that predominantly affects the limbic system, diencephalon and brainstem, and is usually associated with tumors of the testis. We report a 35-year-old man with a right testicular mass who presented with multiple neurological complains, and clinical, serological and radiological features compatible with anti-Ma2-associated encephalitis. After three courses of carboplatin, etoposide and bleomycin for metastatic testicular germ-cell tumor, all elevated tumor markers normalized and the retroperitoneal metastases disappeared, but the neurological disorder deteriorated. To our knowledge, this is the first case in which orchiectomy followed by carboplatin, etoposide and bleomycin for a testicular tumor with anti-Ma2 encephalitis was performed.

Repeat retroperitoneal lymph‐node dissection after chemotherapy for metastatic testicular germ cell tumour

To examine the operative findings, histopathology and clinical outcome of patients undergoing repeat retroperitoneal lymph node dissection (RPLND) after initial chemotherapy and RPLND (PC-RPLND) for metastatic testicular germ cell tumour (GCT), as a small proportion relapse or have residual disease after incomplete resection in the lung, retrocrural or pelvic nodes, and retroperitoneum. Between September 1992 and May 2006, 359 patients had PC-RPLND under the care of one surgeon, 54 of which were repeat procedures. We compared the long-term outcome between those having primary and those having repeat PC-RPLND. The median (range) time from original to repeat surgery was 2.4 (0.25-26.5) years, and the median follow-up after the repeat procedure was 5.8 (0.08-12.9) years. There was no difference in survival between patients requiring only one PC-RPLND and those having a repeat procedure (P = 0.592). The most frequent sites of recurrent disease were: behind the great vessels/para-aortic areas (38, 46%), in the suprahilar region (18, 18%), in the retrocrural area (16, 19%), in the pelvic nodes (10, 12%) and in the lung (one, 1%). The most common pathological findings in the repeat PC-RPLNDs were differentiated teratoma (19, 35%), malignant teratoma undifferentiated (nine, 17%), adenocarcinoma (eight, 15%) and necrotic tissue (five, 9.2%). Although a small proportion of patients with metastatic GCT might require repeat PC-RPLND, there is no difference in survival between this group and those having one PC-RPLND. However, to avoid cancer recurrence and reoperation, it is crucial that the first PC-RPLND is careful and complete, preferably done in a centre with expertise in this procedure.

Molecular genetic evidence supporting the neoplastic nature of stromal cells in ‘fibrosis’ after chemotherapy for testicular germ cell tumours

A residual retroperitoneal mass containing only fibrosis and necrosis is present in 40-52% of patients with advanced testicular germ cell tumours after chemotherapy. The biological nature and genetic characteristics of the stromal cells in these residual masses have not been adequately investigated. Laser-microdissected stromal cells from 27 patients who underwent retroperitoneal lymph node dissection after chemotherapy for metastatic testicular germ cell tumour were analysed. Allelic loss in the stromal cells of fibrosis was present at one or more of the ten microsatellite DNA loci examined in 23 (85%) of the cases. Chromosome arm 12p anomalies, the hallmark of germ cell neoplasia, were present in nine (33%) cases. The high frequency of allelic losses and chromosome arm 12p anomalies in the stromal cells from residual retroperitoneal fibrous masses after chemotherapy for testicular germ cell tumours suggests that the stromal cells are derived from the same tumour progenitor cells as the pre-existing metastatic germ cell tumour.

Topoisomerase II Alpha Expression in Testicular Germ Cell Tumors

Inhibitors of topoisomerase II alpha (TopoIIalpha), an enzyme with a crucial role in DNA maintenance, are included in the chemotherapy protocols for testicular germ cell tumors (GCTs). Despite the success of current chemotherapy regimens, a significant number of patients experience relapse. We analyzed TopoIIalpha expression in primary and metastatic testicular GCTs because this enzyme is a target for some antineoplastic agents. Primary GCT specimens from 109 patients, including 57 seminomas and 52 mixed GCTs (41 embryonal carcinomas, 23 yolk sac tumors, 19 seminomas, 8 choriocarcinomas, 17 teratomas with immature elements, and 16 teratomas with mature elements), were obtained from our archives. The metastatic lesions from 11 of the patients with mixed GCTs included seven teratomas with mature components, five embryonal carcinomas, one yolk sac tumor, one choriocarcinoma, and one teratoma with immature components. Representative sections were subjected to immunohistochemistry with monoclonal antibody against TopoIIalpha, and the nuclear staining findings were evaluated. Most embryonal carcinoma (100%), yolk sac tumor (95%), seminoma (88%), and choriocarcinoma (62%) components of the GCTs were TopoIIalpha immunoreactive. None of the teratoma specimens with mature elements expressed TopoIIalpha. The results of our study have shown that TopoIIalpha is expressed in most seminomas, embryonal carcinomas, yolk sac tumors, and choriocarcinomas, suggesting a possible mechanism of sensitivity of these components to TopoIIalpha inhibitors. Teratomas with mature and immature elements expressed low levels of TopoIIalpha, which might contribute to their chemoresistance. These findings imply that the variable chemoresponsiveness of testicular GCTs could have an underlying molecular basis.

Clinical outcome following post‐chemotherapy retroperitoneal lymph node dissection in men with intermediate‐ and poor‐risk nonseminomatous germ cell tumour

To evaluate the outcome in patients treated with chemotherapy and retroperitoneal lymph node dissection (RPLND) after an initial diagnosis of International Germ Cell Cancer Collaborative Group (IGCCCG) intermediate- and poor-risk metastatic nonseminomatous testicular germ cell tumour (NSGCT), as the integration of chemotherapy and surgery in managing advanced NSGCT continues to develop. Between 1989 and 2003, 157 patients initially diagnosed with IGCCCG intermediate- and poor-risk NSGCT had RPLND after chemotherapy at the authors' institution, with a median follow-up of 36 months. Progression-free probability (PFP) and disease-specific survival (DSS) were estimated using the Kaplan-Meier method. Cox proportional hazards regression analysis was used to assess the prognostic significance of risk factors for disease progression after RPLND. In all, 68 (43%) and 89 (57%) patients were assigned as intermediate- and poor-risk, respectively. At the time of RPLND the median residual retroperitoneal mass was 3.0 cm and 29 (19%) men had elevated serum tumour markers (alpha-fetoprotein, human chorionic gonadotrophin, or both). Retroperitoneal residual masses were completely resected in 147 (94%) patients; retroperitoneal histology revealed fibrosis in 73 (47%), teratoma in 63 (40%) and viable GCT in 21 (13%). The 5-year overall DSS and PFP were 81% and 70%, respectively. Patients with poor-risk NSGCT were at no greater risk of disease progression than those with intermediate-risk NSGCT. In a multivariate analysis, residual mass size, incomplete surgical resection and the presence of teratoma and viable germ cell cancer independently predicted disease progression after RPLND. Patients with advanced NSGCT have long-term freedom from disease progression when chemotherapy is combined with resection of residual masses. Our data suggest that the tumour response to chemotherapy, coupled with complete resection of all residual masses, predicts long-term freedom from disease progression.

Pathologic findings and clinical outcome of patients undergoing retroperitoneal lymph node dissection after multiple chemotherapy regimens for metastatic testicular germ cell tumors

Postchemotherapy surgery is an essential component in the management of patients with metastatic germ cell tumors (GCT). The authors assessed their institutional experience of retroperitoneal lymph node dissection (RPLND) after multiple chemotherapy regimens for advanced GCT. By analyzing the institutional prospective surgical database from 1989 to 2004, 71 patients were identified who underwent RPLND after multiple chemotherapy regimens. Clinicopathologic and treatment trends were characterized, and predictors of disease-specific survival (DSS) were evaluated. The histologic findings at RPLND were fibrosis in 36 men (51%), GCT in 20 men (28%), and teratoma in 15 men (21%). Patients who underwent RPLND from 1989 to 1998 (n = 47), compared with patients who underwent RPLND from 1999 to 2004 (n = 24) were more likely to have GCT (36% vs 13%; P = .04). Patients who received taxane-containing chemotherapy regimens as salvage therapy had lower rates of GCT at RPLND (14% vs 42%; P = .01), higher rates of fibrosis (63% vs 39%; P = .04), and similar rates of teratoma (31% vs 33%; P = .9). The 5- and 10-year DSS rates were 74% (95% confidence interval [95% CI], 62-86%) and 70% (95% CI, 56-84%), respectively. Five-year DSS based on worst histology of RPLND and extraretroperitoneal specimens was 87% (95% CI, 75-99%) for fibrosis, 87% for teratoma (95% CI, 63-100%), and 47% for GCT (95% CI, 23-71%; P = .004). On multivariable analysis, retroperitoneal mass > or = 5 cm and GCT were predictors of worse DSS (P = .03 and P = .005, respectively). Taxane-based salvage chemotherapeutic regimens appear to have decreased the rate of GCT at RPLND. The current data support RPLND in select patients after salvage chemotherapy, because a considerable proportion has teratoma or GCT, and the 10-year DSS rate after resection is 70%.

Clonal Origin of Metastatic Testicular Teratomas

Testicular teratomas in adult patients are histologically diverse tumors that frequently coexist with other germ cell tumor (GCT) components. These mixed GCTs often metastasize to retroperitoneal lymph nodes where multiple GCT elements are frequently present in the same metastatic lesion. Neither the genetic relationships among the different components in metastatic lesions nor the relationships between primary and metastatic GCT components have been elucidated. We examined metastases from 31 patients who underwent primary retroperitoneal lymph node dissection for metastatic testicular GCT. All patients had metastatic mature teratoma with one or more other GCT components. This study included a total of 72 metastatic GCT components and 16 primary GCT components from 31 patients. Genomic DNA samples from each component were prepared from formalin-fixed, paraffin-embedded tissue sections using laser-assisted microdissection. Loss of heterozygosity (LOH) assays for seven microsatellite polymorphic markers on chromosomes 1p36 (D1S1646), 9p21 (D9S171 and IFNA), 9q21 (D9S303), 13q22-q31 (D13S317), 18q22 (D18S543), and 18q21 (D18S60) were done to assess clonality. Twenty-nine of 31 (94%) cases showed allelic loss in one or more components of the metastatic GCTs. Twenty-nine of 31 mature teratomas showed allelic loss in at least one of seven microsatellite polymorphic markers analyzed. The frequency of allelic loss in informative cases of metastatic mature teratoma was 27% (8 of 30) with D1S1646, 34% (10 of 29) with D9S171, 37% (10 of 27) with IFNA, 27% (8 of 30) with D9S303, 46% (13 of 28) with D13S317, 26% (7 of 27) with D18S543, and 36% (10 of 28) with D18S60. Completely concordant allelic loss patterns between the mature teratoma and all of the other metastatic GCT components were seen in 26 of 29 cases in which the mature teratoma component showed LOH. Nearly identical allelic loss patterns were seen in the three remaining cases. In six cases analyzed, LOH patterns of each metastatic component were compared with each GCT component of the primary testicular tumor. In all six cases, each primary and metastatic component showed an identical pattern of allelic loss. Our data support the common clonal origin of metastatic mature teratomas with other components of metastatic testicular GCTs and with each component of the primary tumor.

Short- and Long-Term Outcomes After Large Pulmonary Resection for Germ Cell Tumors After Bleomycin-Combination Chemotherapy

Abstract Background Treatment of nonseminomatous germ cell tumors frequently requires bleomycin-combination chemotherapy followed by resection of residual disease. Bleomycin administration however raises concerns with respect to postoperative respiratory complications, particularly for patients undergoing large pulmonary resections. We undertook an institutional review to determine the outcome of large pulmonary resections after bleomycin-combination chemotherapy. Methods Between 1981 and 2001, 530 patients presented to our institution for resection of residual intrathoracic disease for either metastatic testicular or primary mediastinal nonseminomatous germ cell tumors. We subsequently reviewed 32 of these patients who required pneumonectomy (n = 19; right=9, left=10) or bilobectomy (n = 13) after bleomycin-combination chemotherapy. Results There were four operative deaths (13%). All postoperative deaths occurred in patients undergoing right-sided resections (pneumonectomy, n=2; bilobectomy, n=2) as a consequence of pulmonary complications. Operative survivors had a pulmonary morbidity of 18%. Fourteen of 20 long-term survivors were found to have a satisfactory performance status at follow-up. Conclusions Otherwise young and healthy male nonseminomatous germ cell tumors patients requiring large pulmonary resections after bleomycin-combination chemotherapy appear to be at higher than anticipated risk for pulmonary-related morbidity and mortality. However long-term survivors report an acceptable functional status.

Recent advances in management of patients with platinum‐refractory testicular germ cell tumors

With the use of cisplatin-based combination chemotherapy, metastatic testicular germ cell tumors can be cured in 70-80% of patients, but patients refractory to cisplatin-based chemotherapy continue to have a very poor prognosis. Various chemotherapeutic agents have been evaluated in intensively pretreated or cisplatin-refractory patients, but as single agents, only orally administered etoposide, paclitaxel, gemcitabine, and, most recently, oxaliplatin have been shown to be active with selected patients achieving complete remissions. This has for the first time lead to clinical evaluation of combination chemotherapy regimens such as gemcitabine-paclitaxel or oxaliplatin-gemcitabine, demonstrating the feasibility of combination therapy in these heavily pretreated patients. High response rates of up to 45% were observed in particular with the latter combination. Salvage surgery remains a very important treatment option for patients with resectable disease. The molecular mechanisms of cisplatin resistance have been intensively studied, and several mechanisms have been discussed such as a decreased intracellular concentration of the drug, increased repair of the drug-induced damage, or an altered apoptotic response to this damage. This increasing knowledge may now allow design of new therapeutic options. Ongoing studies in refractory germ cell tumors are evaluating 3-drug regimens such as gemcitabine-paclitaxel-oxaliplatin but also biologic approaches such as inhibitors of the epidermal growth factor receptor or the vascular endothelial growth factor. This research may eventually allow the development of a noncross-resistant multidrug combination regimen that can be evaluated in an earlier line of therapy.

Postchemotherapy resections of residual masses from metastatic nonseminomatous testicular germ cell tumors. A Spanish Germ Cell Group study

4525 Background: After chemotherapy for metastatic testicular tumors masses may remain. We analyze factors influencing histology and long-term evolution of patients with post-chemotherapy residual masses. Methods: 352 patients with nonseminomatous germ cell tumors with postchemotherapy residual masses and negative tumor markers were selected from the database of the Spanish Germ Cell Group between December 94 and February 04. Our protocol recommends surgical resection of masses larger than 2 cm. Patients with masses between 1 and 2 cm were offered follow-up or surgical resection. Of them 292 were finally operated: IGCCCG class: 137 (47%), 72 and 83 (28%) for good, intermediate and bad prognosis group respectively. Results: Median follow-up: 4 yrs. Thirty patients need 2 resections, 8 patients 3 and 3 patients 4 surgical maneuvers. Histology of masses: necrosis in 116 (40%), teratoma in 135 (46%), malignant tumor in 41 (14%). IGCCCG and Royal Marsdem class, histology of the primary, age and prechemotherapy size were correlated (X2 test) with histology of the residual masses. Lesions >5 cm before chemo and intermediate or bad prognosis group of the IGCCCG significantly correlated with necrosis. Statistically significant factors predicting teratoma were primary containing teratomatous elements, patient belonging to the good prognosis group and lesions below 5 cm before treatment. We did not identify factors correlated to malignant tumor. Analysis for survival: both IGCCCG class and malignant tumor at surgery were statistically significant in the multivariate analysis (p<0.001), whereas size, Royal Marsdem Class or histology of the primary were not. Five-year survival was 75%, 93% and 95% if malignant tumor, teratoma or necrosis were found respectively. Good, intermediate and bad prognosis group had a 5-yr survival of 97, 87 and 81% respectively. Conclusions: Our results suggest that persistence of small lesions after chemotherapy together with teratomatous elements in the primary predicts teratoma at surgery. IGCCCG class and persistence of malignant cells at surgery are the strongest prognostic factors for survival after resection of residual masses. No significant financial relationships to disclose.

Hidden by HIPAA: The Costs of Cure

In the second half of the last century, there were dramatic improvements in the management of advanced cancers of the genitourinary tract, with particular progress in the management of germ cell tumors. The management of metastatic testicular germ cell tumors has become one of the paradigms of successful cancer treatment, reflecting progress in the development of chemotherapy and an improved understanding of the principles of tumor biology, and of the importance of multidisciplinary management. Withincreasingexperience,wehavecometorecognizethat theseapproachestotreatmenthavesomeflaws,particularly with respect to the creation of late iatrogenic effects, and this has become the focus of intense scrutiny. An increased understanding of risk factors has allowed us to tailor our treatments to the level of risk, such as reducing the number of cycles of chemotherapy required for good-risk metastatic disease, based on randomized trial data. We have attempted to avoid some of the late complications of treatment by modifying some treatment approaches. However, some of these attempts to improve treatmentoutcomesbyreducingtoxicityhavefailed,largely becauseofareductionintheinitialcurerate—forexample, the attempt to avoid the nephrotoxicity of cisplatin by the

Short- and Long-Term Outcomes after Large Pulmonary Resection for Germ Cell Tumors After Bleomycin-Combination Chemotherapy

Background Treatment of nonseminomatous germ cell tumors frequently requires bleomycin-combination chemotherapy followed by resection of residual disease. Bleomycin administration however raises concerns with respect to postoperative respiratory complications, particularly for patients undergoing large pulmonary resections. We undertook an institutional review to determine the outcome of large pulmonary resections after bleomycin-combination chemotherapy. Methods Between 1981 and 2001, 530 patients presented to our institution for resection of residual intrathoracic disease for either metastatic testicular or primary mediastinal nonseminomatous germ cell tumors. We subsequently reviewed 32 of these patients who required pneumonectomy (n = 19; right = 9, left = 10) or bilobectomy (n = 13) after bleomycin-combination chemotherapy. Results There were four operative deaths (13%). All postoperative deaths occurred in patients undergoing right-sided resections (pneumonectomy, n = 2; bilobectomy, n = 2) as a consequence of pulmonary complications. Operative survivors had a pulmonary morbidity of 18%. Fourteen of 20 long-term survivors were found to have a satisfactory performance status at follow-up. Conclusions Otherwise young and healthy male nonseminomatous germ cell tumors patients requiring large pulmonary resections after bleomycin-combination chemotherapy appear to be at higher than anticipated risk for pulmonary-related morbidity and mortality. However long-term survivors report an acceptable functional status.

637 Evaluation of spontaneous apoptosis and BCL-2, BAX, MCL-1 expressions for prognostic value in metastatic testicular germ cell tumour tissues

637 Evaluation of spontaneous apoptosis and BCL-2, BAX, MCL-1 expressions for prognostic value in metastatic testicular germ cell tumour tissues