Maternal smoking and testicular germ cell tumors.

Testicular germ cell tumors (TGCT) are the most common cancer among men ages 15 to 35 years in the United States. The well-established TGCT risk factors cryptorchism, prior diagnosis of TGCT, and family history of testicular cancer indicate that exposures in early life and/or in the familial setting may be critical to determining risk. Previous reports of familial clustering of lung cancer in mothers and testicular cancers in sons suggest that passive smoking in childhood may be such an exposure. To clarify the relationship of passive smoking exposure to TGCT risk, data from 754 cases and 928 controls enrolled in the Servicemen's Testicular Tumor Environmental and Endocrine Determinants study were analyzed. Data from 1,086 mothers of the cases and controls were also examined. Overall, there was no relationship between maternal [odds ratio (OR), 1.1; 95% confidence interval (95% CI), 0.9-1.3] or paternal smoking (OR, 1.0; 95% CI, 0.8-1.3) and TGCT risk. Although living with a non-parent smoker was marginally related to risk (OR, 1.4; 95% CI, 1.0-2.1), there was no relationship with number of smokers, amount smoked, or duration of smoking. Responses from both case-control participants and mothers also revealed no relationship between either maternal smoking while pregnant or while breast-feeding. Results did not differ by TGCT histology (seminoma, non-seminoma). These results do not support the hypothesis that passive smoking, either in utero or in childhood, is related to risk of TGCT. Other early life exposures, however, may explain the familial clustering of lung cancer in mothers and TGCT in sons.     

Risk of second malignant neoplasms in women and girls with germ cell tumors

BackgroundWhile an elevated risk of second malignant neoplasms (SMNs) has been observed in men treated for germ cell tumors (GCTs), risk of SMNs have not been quantified in adult women or in girls treated for GCTs.Patients and methodsOne-year survivors of primary GCTs diagnosed between January 1980 and December 2012 were identified from Surveillance, Epidemiology, and End Results (SEER 9) registries. Risk of SMNs was calculated using SEER*Stat.ResultsAmong 1507 patients, a total of 47 SMNs were identified. The overall risk of SMNs was not elevated in females overall or in females treated for GCT during adulthood although SMN sites (pancreas, soft tissue, bladder, kidney, and thyroid) and trends were comparable with those in men. There were too few childhood GCT cases with SMNs for further analysis.ConclusionsUnlike men, women treated for GCTs did not have a statistically significant elevated risk of SMNs [standardized incidence ratio = 1.11; 95% confidence interval (CI) = 0.81–1.47]. The fact that SMNs in women occur in sites similar to those observed in men indicate that long-term follow-up of a larger cohort of females treated for GCT is warranted.     

Risk of childhood leukemia associated with parental smoking and alcohol consumption prior to conception and during pregnancy: the cross-Canada childhood leukemia study

Objective As part of a larger case–control study, the authors evaluated risk of childhood leukemia relative to parental self-reported smoking and alcohol consumption. Methods Children 0–14 years of age diagnosed with leukemia between 1990 and 1994 were ascertained through population-based sources at the time of diagnosis. For each participating case, an age, gender, and area-matched control was randomly selected from provincial government health insurance rolls. Risk factor information was obtained through personal interviews with each child’s parents. Conditional logistic regression models were used to examine risk of leukemia associated with parental smoking and drinking. Results Maternal alcohol consumption prior to conception (OR = 1.37, 95% CI, 0.99–1.90) and during pregnancy (OR = 1.39, 95% CI, 1.01–1.93) was associated with an excess risk of childhood leukemia, with a positive dose-response trend for increasing weekly consumption (p < 0.05). Similar results were observed for children diagnosed with acute lymphoblastic leukemia (ALL). Odds ratios for maternal cigarette smoking before and during pregnancy were consistently elevated above one, but not statistically significant. No relationship was observed with paternal drinking or smoking in the perinatal period. Conclusions Our study suggests that maternal alcohol drinking before or during pregnancy may contribute to an increased risk of childhood leukemia.     

Bax mutation and overexpression inversely correlate with immature phenotype and prognosis of childhood germ cell tumors

Primary childhood germ cell tumors (GCTs) represent a rare and heterogeneous group of tumors that varies in histologic differentiation, age of presentation and clinical outcome. In malignant neoplasms, apoptosis is a prognostic marker and a predictive factor of response to therapy. Therefore, the study of the expression and mutation of molecules involved in the regulation of apoptosis could be useful in order to both predict the clinical outcome and design self-tailored therapeutic approaches. We retrospectively analysed tissue samples of 54 childhood GCTs. The expression of p53 and BAX protein was assessed by immunohistochemistry (IHC). Moreover, we investigated the presence of mutations in the BAX and p53 genes SSCP-PCR and direct sequencing. IHC analysis of BAX protein expression showed that 14 out of 54 tumors (26%) had no BAX protein expression, in the remaining 40 patients (74%) the intensity of BAX was low in 20 patients (37%) and high/intermediate in 20 (37%). BAX was mutated in 6 patients. p53 was expressed in 43 patients (79.6%), was not detectable in the remaining 11 (20.4%) and mutated in only 3 patients. p53 mutational status and expression were not correlated to the overall survival (OS). On the other hand, both IHC score and mutations for BAX were correlated to sacrococcygeal primary localization. BAX mutations were inversely correlated with OS (p=0.0419) while BAX IHC intensity was directly correlated with OS (p=0.0376). The stratification for histotype showed a direct correlation between BAX IHC and OS in both immature teratoma (p=0.045) and mixed malignant GCT (p=0.010) while the correlation was lost in mature teratoma (p=0.300). These results indicate that both mutations and BAX protein levels are useful molecular biological markers for prognosis and clinical management of pediatric GCT.     

Ifosfamide in germ cell tumors

Ifosfamide has always had significant single-agent activity in patients with germ cell tumors. We first began studies of cisplatin + ifosfamide combination chemotherapy as salvage chemotherapy in 1982. The regimen of etoposide (VP-16) + ifosfamide + cisplatin (VIP) was initially utilized as third-line chemotherapy. Even in this refractory setting, we were able to cure a small cohort of patients. Ifosfamide-cisplatin combination chemotherapy then became a standard second-line chemotherapy program, and achieved a 25% cure rate. Subsequent phase III studies compared VIP to bleomycin + etoposide + cisplatin (BEP) as initial chemotherapy. Although the results of the ifosfamide-based regimen were slightly better, there was no statistically significant difference and BEP was less toxic. However, for individual patients with concern for bleomycin-induced pulmonary fibrosis, VIP remains an attractive first-line regimen.     

Pediatric germ cell tumors

Malignant germ cell tumors are relatively uncommon, accounting for approximately 3% of all childhood malignancies. Occurring with an incidence of approximately 4 per million among children less than 15 years of age, they account for approximately 225 new cases per year in the United States. Germ cell tumors occur in both gonadal and extragonadal sites, with extragonadal and testicular tumors predominating in children less than 3 years of age and with the gonads being the main location of tumors during and after puberty. They occur more frequently in girls than boys. Germ cell tumors are interesting for several reasons: (1) abnormal migration of primordial germ cells account for many of the childhood germ cell tumors; (2) markers exist to allow evaluation of the extent of resection and the development of recurrence for many of the tumors; and (3) the introduction of platinum-based chemotherapy has markedly improved the survival rate for germ cell tumors, as well as the salvage rate for recurrent or metastatic disease.     

Testicular germ cell tumors

PURPOSE OF REVIEW: Preclinical and clinical developments in germ cell tumors over the past year are summarized. RECENT FINDINGS: Attenuations in the rising incidence of testicular germ cell tumors are beginning to be observed in certain European populations. Additional data on predisposing factors related to race, estrogenic exposure, cryptorchidism, and infertility are becoming available. Significant work on the genetic and molecular alterations in tissue specimens and cell culture models of germ cell tumors continues. Additional treatment strategies for advanced stages of the disease are being evaluated. Cardiovascular and metabolic consequences of therapies in long-term testicular germ cell tumor survivors are being further clarified. Late relapses of successfully treated patients are also being increasingly recognized. SUMMARY: More effective treatments for intermediate risk, poor risk, and recurrent germ cell tumors need to be developed, while long-term toxicities of therapies need to be further modified. Given these challenges, active research on these fronts continues and remains a priority.     

Intracranial germ cell tumors

Intracranial germ cell tumors are a heterogeneous group of lesions which occur in children and adults. Within the classification of intracranial germ cell tumors, there are a variety of different tumor types which carry different prognoses. The diagnosis of an intracranial germ cell tumor usually requires histological information, but a subgroup of tumors will secrete specific tumor markers, including alpha-fetoprotein and beta-human chorionic gonadotropin, which may obviate the need for surgical intervention. The management of intracranial germ cell tumors in both children and adults remains unsettled. Germinomas have a good prognosis, as over 90% of patients can be effectively treated with radiation therapy. The dose and volume of radiation therapy needed for disease control is not well established, and controversy exists concerning the need for whole brain or craniospinal radiation therapy for localized tumors. Germinomas are also chemosensitive and recent reports suggest that the dose and volume of radiation therapy required for disease control can be lessened with the addition of adjuvant chemotherapy. The outcome for patients with nongerminomatous germ cell tumors is less favorable. Radiation therapy alone will result in disease control in 40%-60% of patients. The addition of chemotherapy to radiation therapy may improve the rate of survival.     

Pediatric germ cell tumors

Pediatric germ cell tumors are a diverse group of neoplasms with variable clinical behaviors, depending upon the age and site of presentation. Most result from sporadic mutations, although environmental exposures and other genetic aberrations may play a role. Platinum-based chemotherapy has dramatically improved the event-free and overall survival outcomes of pediatric patients with malignant germ cell tumors over the past two decades. Prognosis is dependent on tumor stage and location. Patients with gonadal germ cell tumors have at least a 95% 5-year survival for early stage disease and at least a 85% 5-year survival for advanced stages. In general, extragonadal germ cell tumors carry a poorer prognosis with mediastinal location having the worst outcomes (70% 4-year survival). Current trials are focused on maintaining similar excellent outcomes while reducing morbidity by reducing the dose and duration of chemotherapy. Cytogenetic research studies have found chromosomal aberrations specific to some of these tumors that may serve as prognosticators and even direct therapy.     

Retroperitoneal germ cell tumors in childhood. A clinical and pathologic study of 11 cases

During the last 54 years at the Children's Hospital 11 children (10 female, 1 male) had been treated for an extragonadal germ cell tumor arising in the retroperitoneum. There were eight teratomas (five mature, three immature), two endodermal sinus tumors and one tumor with a mixture of both components. Abdominal pain or discomfort was the usual presenting complaint, with the average age at diagnosis being 18 months. On physical examination, each child had a palpable abdominal mass usually localized in the upper quadrants. The finding of calcification, bone or teeth, on radiologic study was most helpful in establishing a preoperative diagnosis of teratoma. The preferred treatment for children with mature and immature teratomas is complete surgical resection; decisions regarding adjuvant therapy for patients with immature tumors must be evaluated on an individual basis. The prognosis remains guarded for children with unresectable primaries or those with endodermal sinus tumor. Of three tumor-related deaths, two were due to metastatic endodermal sinus tumor and one resulted from extensive local growth by immature teratoma. Successful management of children with endodermal sinus tumor requires surgery aimed at debulking or complete resection in combination with aggressive adjuvant chemotherapy.     

Risk of germ cell tumors among men with HIV/acquired immunodeficiency syndrome.

BACKGROUND: Men with HIV/acquired immunodeficiency syndrome (AIDS) are reported to be at increased risk for germ cell tumors (GCT), particularly testicular seminoma. We investigated correlates of this association to improve understanding of GCTs. METHODS: Testicular and extratesticular seminoma and nonseminoma cases were found by linking population-based cancer and HIV/AIDS registry data for 268,950 men who developed AIDS in 1980 to 2003. Standardized incidence ratios (SIR) with 95% confidence intervals (95% CI) were used to compare these cases with the number of cases expected in the demographically matched population. RESULTS: Overall, seminoma risk (161 cases: SIR, 1.9; 95% CI, 1.6-2.2) was increased significantly with HIV/AIDS, whereas nonseminoma risk was not (56 cases: SIR, 1.3; 95% CI, 0.96-1.7). Extratesticular GCT risk also was increased (11 cases: SIR, 2.1; 95% CI, 1.1-3.7). Seminoma risk was elevated regardless of age, race, or HIV/AIDS transmission group. It was highest for disseminated disease (SIR, 4.7; 95% CI, 2.9-7.2) and within 9 months of AIDS onset (SIR, 7.6; 95% CI, 5.8-9.6), but it was unrelated to CD4 count and duration of HIV/AIDS. The excess risk of seminoma declined in more recent calendar periods, and it was no longer elevated (SIR, 1.4; 95% CI, 0.9-1.9) in the highly active antiretroviral treatment era. CONCLUSIONS: Men with HIV/AIDS had an increased risk of seminoma, but this risk may have attenuated with improving anti-HIV/AIDS treatments. Although detection bias could partly explain the excess of this cancer, various lines of evidence support a causal relationship. Possible mechanisms underlying this association include impaired tumor immunosurveillance or AIDS-related testicular atrophy.     

Therapy-associated secondary tumors in patients with non-germinomatous malignant germ cell tumors

We report three patients with non-germinomatous malignant germ cell tumor (NGMGCT) who developed therapy-associated secondary tumors. They were diagnosed as having NGMGCT by elevated serum levels of α-fetoprotein (AFP), human chorionic gonadotropin (HCG), or β-HCG. Preoperatively, all patients received a combination of etoposide and platinum-based chemotherapy and radiotherapy; neo-adjuvant therapy (NAT) was followed by complete excision of the residual tumor. Postoperatively, all underwent maintenance chemotherapy and all remained free of NGMGCT without recurrence. However, they developed therapy-associated secondary tumors, i.e. glioblastoma, meningioma, or cavernous angioma after 10.1, 9.8, and 8.2 years, respectively. The patient with gliobastoma died one year after its detection. The other two patients are currently alive; the meningioma was completely removed and the cavernous angioma is being monitored without additional treatment. To the best of our knowledge, therapy-associated secondary tumors in patients treated for NGMGCT are rare.     

Biology of germ cell tumors

Testicular cancer has been a model for a curable malignancy. The existence of an array of potential new therapies is the result of a prodigious effort in the researching and defining of the molecular components of the cancer phenotype and the subsequent rational design of agents to target candidate pathways. A better understanding of the molecular biology of cancer may also aid in guiding the most appropriate use of existing therapies, such as conventional chemotherapy.     

Parental smoking and risk of childhood brain tumors

Childhood brain tumors (CBT) are the leading cause of cancer death in children, yet their etiology remains largely unknown. Tobacco smoke contains 61 known carcinogens and increases the risk of several adult cancers. This study investigated associations between parental smoking and risk of CBT in a population‐based case–control study conducted between 2005 and 2010. Cases were identified through all ten Australian pediatric oncology centers, controls via nationwide random‐digit dialing, frequency matched to cases on age, sex and state of residence. Parental smoking information was obtained for 302 cases and 941 controls through mailed questionnaires that requested average daily cigarette use in each calendar year from age 15 to the child's birth, linked to residential and occupational histories. Data were analyzed using unconditional logistic regression, adjusting for frequency matching variables and potential confounders. Overall, parental smoking before or during pregnancy showed no association with CBT risk. The odds ratios for maternal smoking before and during pregnancy were 0.99 (95% CI: 0.70, 1.40) and 0.89 (95% CI: 0.61, 1.21), respectively, and those for paternal smoking before and during pregnancy were 0.99 (95% CI: 0.71, 1.38) and 1.04 (95% CI: 0.74, 1.46), respectively. In children under 24 months of age, the odds ratios for maternal smoking preconception and during pregnancy were 5.06 (95% CI 1.35–19.00) and 4.61 (95% CI: 1.08, 19.63), although these results were based on modest numbers. Future studies should investigate the associations between maternal smoking and risk of CBT by the child's age of diagnosis.     

Chemotherapeutic intensification in germ cell tumors

Chemotherapy has dramatically improved the prognosis of non-seminomatous germ cell tumors (NSGCT). However, some patients relapse and others are refractory to first line chemotherapy. We studied a salvage chemotherapeutic regimen with etoposide 75 gm/m2/day, and cisplatin 40 mg/m2/day, days 1-5 and Ifosfamide 3 g/m2/day, days 1 and 2 (VIhP regimen) in 32 patients. We observed 8 complete remissions with 4 long-term NED patients. Hematological, neurological and renal complications were frequent. In 16 other cases, a protocol using high dose chemotherapy, followed by autologous bone marrow rescue was studied. We observed 8 complete remissions with 4 long-term NED patients. These observations support a dose/effect relationship. A French randomized trial testing high dose chemotherapy, followed in some cases by an autologous marrow graft in poor risk advanced NSGCT, has recently been activated.     

Extragonadal germ cell tumors in Japan

Extragonadal germ cell tumors (EGCT) represent only 2–5% of adult germ cell malignancies. Some publications from Asia have reported inferior treatment outcomes compared to data from an international study group. To ascertain whether this is generally the case, here we analyze treatment outcomes for 30 Japanese patients with EGCT. The medical records of 30 patients (25 non-seminomas and 4 pure seminomas) treated from 1992 to 2002 were reviewed retrospectively. All patients with seminoma achieved long survival except one who died of chemotherapy-related sepsis. Ten and 11 patients with EGCT presented with mediastinal and retroperitoneal primary sites, respectively. The 5-year overall survival (OS) and progression-free survival (PFS) for non-seminoma was 71% and 42%, respectively. The 5-year OS and PFS was 60% and 44%, respectively, for 10 patients with mediastinal nonseminoma, and 91% and 48%, respectively, for patients with retroperitoneal nonseminoma. Tumor marker values on day 7 were available for 19 patients. Among the 19 patients in whom AFP or β-HCG were measured on day 7, the values had declined in 12 patients and were transiently elevated in 7 patients compared to pretreatment values. The transient elevations of tumor markers were significantly associated with poor OS ( P =0.02) and PFS ( P =0.008). The treatment outcome of Japanese patients with EGCT seemed to be comparable to that reported from international studies, suggesting no difference between ethnic groups. Transient tumor marker elevations on day 7 predict poor survival in EGCT patients and may be a useful parameter for identifying patients requiring more aggressive treatment.