Postnatal risk factors for testicular cancer: The EPSAM case-control study.

Testicular cancer is considered to originate from an impaired differentiation of fetal germ cells, but puberty could represent another time window of susceptibility. Our study aimed at investigating the association between environmental exposures acting during puberty/adolescence (13-19 years of age) and the risk of testicular cancer. We used data of the EPSAM study, a case-control study on germ-cell testicular cancer conducted in the province of Turin, Italy, involving cases diagnosed between 1997 and 2008. Histologically confirmed cases (n = 255) and controls (n = 459) completed a postal questionnaire focusing in particular on the pubertal period (namely age 13 years) with questions on physical activity (competitive sports, gardening), lifestyle (alcohol consumption, smoking), occupational history and medical conditions. All analyses were adjusted for the matching variables, cryptorchidism and educational level. Having done at least one competitive sport during puberty (odds ratio [OR]: 0.72, 95% confidence interval: 0.52-1.00), gardening activities during puberty (OR: 0.62, 0.42-0.94) and having a lower weight than peers during puberty (OR: 0.64, 0.42-0.97) were all inversely associated with the risk of testicular cancer. No evidence of association between smoking or alcohol consumption during puberty and the risk of testicular cancer was observed. Regarding agriculture-related occupations, we found an association with the risk of testicular cancer both for occasional jobs during puberty (OR: 2.40, 95% CI: 1.08-5.29) and ever employment in adolescence (OR: 2.59, 95% CI: 0.83-8.10). Our results suggest that postnatal exposures could play a role in testicular cancer aetiology, at least when acting in puberty or adolescence.

Lifetime growth and risk of testicular cancer.

Adult height is associated with testicular cancer risk. We studied to what extent this association is explained by parental height, childhood height and age at puberty. We conducted a case-control study on germ-cell testicular cancer patients diagnosed in 1997-2008 and resident in the Province of Turin. Information was collected using mailed questionnaires in 2008-2011. Specifically, we asked for adult height (in cm), height at age 9 and 13 (compared to peers) and age at puberty (compared to peers). We also asked for paternal and maternal height (in cm) as indicators of genetic components of adult height. The analysis included 255 cases and 459 controls. Odds ratios (ORs) of testicular cancer were estimated for the different anthropometric variables. Adult height was associated with testicular cancer risk [OR: 1.16, 95% confidence interval (CI): 1.03-1.31 per 5-cm increase]. The risk of testicular cancer was only slightly increased for being taller vs. shorter than peers at age 9 (OR: 1.55, 95% CI: 0.91-2.64) or age 13 (OR: 1.26, 95% CI: 0.78-2.01), and parental height was not associated with testicular cancer risk. The OR for adult height was 1.32 (95% CI: 1.12-1.56) after adjustment for parental height. Among participants with small average parental height (<167 cm or less), the OR of testicular cancer for tall (>180 cm) vs. short (<174 cm) subjects was 3.47 (95% CI: 1.60-7.51). These results suggest that the association between height and testicular cancer is likely to be explained by environmental factors affecting growth in early life, childhood and adolescence.

Inferior vena cava prosthetic replacement in a patient with horseshoe kidney and metastatic testicular tumor: technical considerations and review of the literature.

BACKGROUND: Seminomatous and non-seminomatous Germ Cell Tumors (GCT) of the testis are a rare cancer, with an estimated incidence of 56.3 per million white males and 10 per million black males in the United States.The association between non-seminomatous GCT and horseshoe kidney is a rare event and is seen in about 1.3% of patients requiring retroperitoneal lymph node dissection. To our knowledge, no cases have been reported in which replacement of the IVC was also necessary. CASE PRESENTATION: We report the case of a 22-year-old man with horseshoe kidney and metastatic non-seminomatous germ cell tumor involving the wall of the inferior vena cava.Following post-chemotherapy retroperitonal lymph node dissection, the inferior vena cava was replaced with an expanded polytetrafluoroethylene graft.At 2-years follow-up, the patient was in good health and the graft was patent. No clinical or diagnostic signs of renal impairment or recurrence of neoplastic disease were noted. CONCLUSION: Radical surgery is warranted in patients with non-seminomatous germ cell tumor metastasizing to the retroperitoneal lymph nodes. When vena cava replacement is required, and the situation is further complicated by horseshoe kidney, as in this case, surgical technique will rely on multidisciplinary surgical treatment planning by a team composed of urologists, vascular surgeons and oncologists.

Caveolin-1 expression predicts favourable outcome and correlates with PDGFRA mutations in gastrointestinal stromal tumours (GISTs).

AIMS: Novel prognostic markers are warranted for gastrointestinal stromal tumours. Caveolin-1 is a multifunctional protein that proved to be associated with outcome in multiple tumour types. Aim of this study was to investigate Caveolin-1 expression and prognostic efficacy in a series of gastrointestinal stromal tumours. METHODS: Caveolin-1 expression was assessed by immunohistochemistry in a retrospective series of 66 gastrointestinal stromal tumours representative of the different molecular subtypes. Correlations with clinical, histopathological and molecular features were investigated. Statistical analyses were performed as appropriate. RESULTS: Thirty-five cases out of 66 (53.0%) expressed Caveolin-1. Presence of Caveolin-1 expression correlated with favourable histopathologic and clinical traits, including a lower mitotic count (p=0.003) and lower relapse rate (p=0.005). Caveolin-1 expression also resulted associated with the presence of PDGFRA mutations (p=0.010). Outcome analyses showed a favourable prognostic significance of Caveolin-1 expression in terms of relapse-free survival (HR=0.14; 95% CI=0.03 to 0.63) and overall survival (HR=0.29; 95% CI=0.11 to 0.74), even after adjusting for the mutational subgroup (relapse-free survival: HR=0.14, 95% CI=0.04 to 0.44; overall survival: HR=0.29, 95% CI=0.11 to 0.51) and imatinib treatment (relapse-free survival: HR=0.14, 95% CI=0.02 to 0.81; overall survival: HR=0.29, 95% CI=0.17 to 0.48). CONCLUSION: Caveolin-1 represents a novel prognostic marker in gastrointestinal stromal tumours. Further studies are warranted to validate these results and to explore the mechanisms linking Caveolin-1 expression with the PDGFRA oncogenic pathway.

Association Study between Polymorphisms in DNA Methylation-Related Genes and Testicular Germ Cell Tumor Risk.

BACKGROUND: Testicular germ cell tumors (TGCT), histologically classified as seminomas and nonseminomas, are believed to arise from primordial gonocytes, with the maturation process blocked when they are subjected to DNA methylation reprogramming. SNPs in DNA methylation machinery and folate-dependent one-carbon metabolism genes have been postulated to influence the proper establishment of DNA methylation. METHODS: In this pathway-focused investigation, we evaluated the association between 273 selected tag SNPs from 28 DNA methylation-related genes and TGCT risk. We carried out association analysis at individual SNP and gene-based level using summary statistics from the Genome Wide Association Study meta-analysis recently conducted by the international Testicular Cancer Consortium on 10,156 TGCT cases and 179,683 controls. RESULTS: In individual SNP analyses, seven SNPs, four mapping within MTHFR, were associated with TGCT risk after correction for multiple testing (q ≤ 0.05). Queries of public databases showed that three of these SNPs were associated with MTHFR changes in enzymatic activity (rs1801133) or expression level in testis tissue (rs12121543, rs1476413). Gene-based analyses revealed MTHFR (q = 8.4 × 10-4), methyl-CpG-binding protein 2 (MECP2; q = 2 × 10-3), and ZBTB4 (q = 0.03) as the top TGCT-associated genes. Stratifying by tumor histology, four MTHFR SNPs were associated with seminoma. In gene-based analysis MTHFR was associated with risk of seminoma (q = 2.8 × 10-4), but not with nonseminomatous tumors (q = 0.22). CONCLUSIONS: Genetic variants within MTHFR, potentially having an impact on the DNA methylation pattern, are associated with TGCT risk. IMPACT: This finding suggests that TGCT pathogenesis could be associated with the folate cycle status, and this relation could be partly due to hereditary factors.

Squamous cell carcinoma of the umbilicus: management of an unusual localization.

We describe the case of a squamous cell carcinoma spreading to the skin and regional lymph nodes from the umbilicus. Bilateral inguinal lymphadenectomy and a session of electrochemotherapy with bleomycin 15 mg/m2 were performed. However, because of the development of new cutaneous nodules in the abdominopelvic region, we performed targeted palliative therapy with erlotinib 150 mg/day. Targeted adjuvant therapy was preferred to the use of a major cytotoxic agent because of the high risk of superinfection and heart failure. Erlotinib produced a partial clinical response with reduction of the number and size of the skin nodules. CT scan performed after 60 days of treatment did not show any new lesions. To our knowledge, this is the first report of an umbilical metastatic squamous cell carcinoma treated with modern targeted therapy. This therapeutic strategy can be considered a valid palliative option in the management of metastatic cutaneous nodules of this rare primary site.

Quality of life among germ-cell testicular cancer survivors: The effect of time since cancer diagnosis.

INTRODUCTION: Testicular cancer is one of the most treatable cancers, with a 10-year survival of more than 95%. Many patients will be long-term survivors and this disease strikes men in an important phase of their lives, therefore the quality of life (QoL) among these patients is an area of particular interest. We aimed to study whether QoL in testicular cancer survivors depends on the time since cancer diagnosis. METHODS: Data were collected from the EPSAM (Esposizioni postnatali e salute maschile) study, a case-control study on patients with testicular cancer, diagnosed between 1997 and 2008 in the province of Turin, Northern Italy, and interviewed between 2008 and 2010 (response rate among cases 57%). Patients were contacted through their oncologist at the San Giovanni Batista Hospital in Turin or through their general practitioner (GP) in the rest of the Province of Turin. QoL was assessed cross-sectionally using the short form 12 (SF-12) questionnaire, a generic short-form health survey that produces two summary scores, PCS (physical component score) and MCS (mental component score), to evaluate physical and mental health, respectively. RESULTS: Out of 234 study patients, 125 cases were seminomas and 109 cases were nonseminomas. The mean age at diagnosis was 34.5 years. After adjusting for age, time since diagnosis was not associated with PCS and MCS scores. Among nonseminomas, the median PCS slightly increased (adjusted OR (odds ratio) for 5+ vs < 2 years since cancer diagnosis: 1.78 (1.17-2.73), p = 0.008) and MCS slightly decreased (adjusted OR per 1-year increase since cancer diagnosis: 0.92, 95% CI: 0.82-1.05, p = 0.23) with time. Similar findings of no association between time since diagnosis and PCS and MCS were found when the analyses were restricted to the subgroup of cancer patients contacted through their oncologist, whose response proportion was 82%. CONCLUSION: In a study of testicular cancer patients interviewed cross-sectionally at 1 to more than 10 years since diagnosis, time since cancer diagnosis was not associated with QoL when we considered all germ-cell testicular cancer patients together. When stratified by histology type, we found certain evidence that nonseminoma cases report higher PCS over time since cancer diagnosis.

Different quality of treatment in retroperitoneal sarcomas (RPS) according to hospital-case volume and surgeon-case volume: a retrospective regional analysis in Italy.

BACKGROUND: Retroperitoneal sarcomas (RPS) should be surgically managed in specialized sarcoma centers. However, it is not clearly demonstrated if clinical outcome is more influenced by Center Case Volume (CCV) or by Surgeon Case Volume (SCV). The aim of this study is to retrospectively explore the relationship between CCV and SCV and the quality of surgery in a wide region of Northern Italy. METHODS: We retrospectively collected data about patients M0 surgically treated for RPSs in 22 different hospitals from 2006 to 2011, dividing them in two hospital groups according to sarcoma clinical activity volume (HCV, high case volume or LCV, low case volume hospitals). The HCV group (> 100 sarcomas observed per year) included a Comprehensive Cancer Center (HVCCC) with a high sarcoma SCV (> 20 cases/year), and a Tertiary Academic Hospital (HVTCA) with multiple surgeon teams and a low sarcoma SCV (≤ 5 cases/year for each involved surgeon). All other hospitals were included in the LCV group (< 100 sarcomas observed per year). RESULTS: Data regarding 138 patients were collected. Patients coming from LCV hospitals (66) were excluded from the analysis as prognostic data were frequently not available. Among the 72 remaining cases of HCV hospitals 60% of cases had R0/R1 margins, with a more favorable distribution of R0/R1 versus R2 in HVCCC compared to HVTCA. CONCLUSIONS: In HCV hospitals, sarcoma SCV may significantly influence RPS treatment quality. In low-volume centers surgical reports can often miss important prognostic issues and surgical quality is generally poor.

Long-term survival after multidisciplinary management of a metastatic sarcomatoid porocarcinoma with repeated exeresis, radiotherapy, chemotherapy and cetuximab: case report and review of literature.

Eccrine porocarcinoma is a rare and aggressive skin neoplasm; only two cases of sarcomatoid differentiation have been reported. Whereas surgery is effective as first line treatment, optimal management of recurrent or metastatic porocarcinoma is not defined and needs multidisciplinary approach. Here we described the first reported case of metastatic sarcomatoid porocarcinoma. Our patient experienced multiple recurrences, mainly loco-regional, and was treated with a multidisciplinary treatment, involving surgery, radiotherapy, chemotherapy and target therapy, leading to a more than 4 years survival, from the first recurrence. We conclude that multidisciplinary approach in metastatic porocarcinoma must involve surgeon, radiotherapist and medical oncologist. The combination of local and systemic treatments can delay recurrence and prolong survival also in very aggressive cases.

Subfertility and Risk of Testicular Cancer in the EPSAM Case-Control Study.

BACKGROUND/OBJECTIVES: It has been suggested that subfertility and testicular cancer share genetic and environmental risk factors. We studied both subfertility and the strongest known testicular cancer susceptibility gene, the c-KIT ligand (KITLG), whose pathway is involved in spermatogenesis. METHODS: The EPSAM case-control study is comprised of testicular cancer patients from the Province of Turin, Italy, diagnosed between 1997 and 2008. The present analysis included 245 cases and 436 controls from EPSAM, who were aged 20 years or older at diagnosis/recruitment. The EPSAM questionnaire collected information on factors such as number of children, age at first attempt to conceive, duration of attempt to conceive, use of assisted reproduction techniques, physician-assigned diagnosis of infertility, number of siblings, and self-reported cryptorchidism. Genotyping of the KITLG single nucleotide polymorphism (SNP) rs995030 was performed on the saliva samples of 202 cases and 329 controls. RESULTS: Testicular cancer was associated with the number of children fathered 5 years before diagnosis (odds ratio (OR) per additional child: 0.78, 95% confidence interval (CI): 0.58-1.04) and sibship size (OR per additional sibling: 0.76, 95% CI: 0.66-0.88). When considering the reproductive history until 1 year before diagnosis, attempting to conceive for at least 12 months or fathering a child using assisted reproduction techniques was not associated with the risk of testicular cancer, nor was age at first attempt to conceive or physician-assigned diagnosis of infertility. The SNP rs995030 was strongly associated with risk of testicular cancer (per allele OR: 1.83; 95%CI: 1.26-2.64), but it did not modify the association between number of children and the risk of testicular cancer. CONCLUSION: This study supports the repeatedly reported inverse association between number of children and risk of testicular cancer, but it does not find evidence of an association for other indicators of subfertility.

Role of multidimensional assessment of frailty in predicting short-term outcomes in hospitalized cancer patients: results of a prospective cohort study.

AIMS AND BACKGROUND: The study analyzed the value of physical and psychosocial frailty assessment in predicting the need for supportive care and the risk of short-term failures after discharge in hospitalized cancer patients. METHODS AND STUDY DESIGN: Frailty was assessed in 350 consecutive patients using a multidimensional tool. Patients were followed for 4 months after discharge to record the occurrence of chemotherapy interruption, urgent hospital readmission or death. The association between patient characteristics and the outcomes were analyzed with either logistic or Cox multivariable models. RESULTS: About 40% of patients were classified as frail, with a higher prevalence of clinical frailty (alone or together with psychosocial frailty). Psychosocial frailty was positively associated with the need for supportive care at discharge (adjusted OR, 3.46; 95% CI, 1.55-7.76) but did not predict a worse prognosis when other important clinical factors were considered. However, the need for supportive care at discharge, in addition to advanced disease and reduced performance status, was a strong predictor of short-term hospital readmission or death (HR 7.50; 95% CI, 3.12-18.02). CONCLUSIONS: A more comprehensive assessment of frailty in cancer patients can aid in the timely identification of the need for supportive care after hospital discharge and improves the prediction of the short-term risk of hospital readmission or death.

Complete response of metastatic cutaneous squamous cell carcinoma to cetuximab plus paclitaxel.

BACKGROUND AND METHODS: Cetuximab therapy results strongly active in advanced cutaneous squamous cell carcinoma (cSCC). A patient affected by a rapidly progressing, already irradiated and cisplatin-refractory cSCC, with lung, pleura and thoracic lymph nodes metastasis, was treated with weekly cetuximab and paclitaxel. RESULTS: Treatment was well tolerated and a partial response was obtained after four months of cetuximab plus paclitaxel therapy. Then we continued maintenance cetuximab for another seven months with tumor shrinkage until complete response, maintained after six months. CONCLUSIONS: Cetuximab was safely associated with paclitaxel, obtaining a rapid tumor response in cisplatin-refractory metastatic cSCC. Single-agent cetuximab maintenance sustained tumor shrinkage until complete response.

KIT and PDGFRA mutations and PDGFRA immunostaining in gastrointestinal stromal tumors.

In the present study, we investigated the association of PDGFRA and KIT mutations as well as PDGFRA immunohistochemical expression with clinicopathologic features and prognosis in a series of gastrointestinal stromal tumors (GISTs). Tumor DNA from 40 GISTs was sequenced for the presence of mutations in KIT exons 9, 11, 13 and 17, and in PDGFRA exons 12 and 18. Tissue sections were stained with polyclonal anti-PDGFRA antibody. KIT mutations occurred in 26 cases. There were 13 deletions, 6 substitutions, 3 deletion-substitutions, 3 duplications and 1 insertion. Tumors with KIT deletions/insertion were large with a high mitotic index (MI), and were associated with a high rate of symptoms at diagnosis, invasion into adjacent organs, distant metastasis, relapse and a short disease-free survival (DFS). PDGFRA mutations occurred in 6 gastric GISTs. There were 4 deletions and 2 substitutions. Tumors with PDGFRA mutations were small, with a low MI and Ki67 score, and were associated with a very low rate of symptoms at diagnosis, invasion into adjacent organs and distant metastasis. PDGFRA immunopositivity was found in 23 cases: a peculiar 'dotlike' staining was found in 5 out of 6 PDGFRA mutated cases. Patients with positive PDGFRA immunostaining had a longer DFS than those with negative staining. Our data confirm that the type of KIT mutation is associated with various clinicopathologic features of GISTs, and indicate that PDGFRA mutations are associated with rather indolent tumors. PDGFRA immunopositivity reflects PDGFRA mutational status and is associated with a favorable outcome.

Thymoma: inter-relationships among World Health Organization histology, Masaoka staging and myasthenia gravis and their independent prognostic significance: a single-centre experience.

OBJECTIVE: In thymomas, World Health Organization (WHO) histology, Masaoka stage and myasthenia gravis (MG) have long been considered important for patient management and outcome. Their role has been independently investigated in the past. Few studies, however, focussed on the correlations among these variables. The aim of the present study was to retrospectively evaluate, in our patient population of resected thymomas, the inter-relationships among MG, WHO histology and Masaoka stage, and to look at how and to what extent one variable is associated with the other two in terms of clinical presentation and survival. METHODS: From January 1990 to October 2008, 255 patients received resection of thymoma. MG was present in 105 cases (41%). Histology by WHO was: 25 A (10%), 72 AB (28%), 65 B1 (25%), 69 B2 (27%) and 24 B (9%). Masaoka staging was stage I, 54 cases (21%), stage II, 86(34%), stage III 79 (31%), and stage IVA 36 (14%). Ordinal and logistic regression models were undertaken to analyse correlations among ordinal (WHO histology and Masaoka stage) and categorical (MG, A vs B WHO types) variables. Univariate and multivariate survival analysis were also performed using the same covariates. Overall survival (OS) and disease-free survival (DFS) were calculated. RESULTS: MG was associated with early Masaoka stages (odds ratio (OR) 0.45, 95% confidence interval (CI) 0.33-0.62) and B-type thymomas (OR 1.59, 95% CI 1.23-2.05). B-type thymomas were associated with high Masaoka stage (OR 0.46, 95% CI 0.36-0.60). High Masaoka stage was associated with non-MG (OR 3.27; 95% CI 2.00-5.34). In univariate survival analysis, MG (p = 0.01) and Masaoka stage (p = 0.0001) were significant prognostic indicators using OS. Using DFS, WHO histology (A/AB vs B1/B2/B3 types) (p = 0.05) and Masaoka stage (p = 0.0001) had a prognostic significance. In multivariate analysis, only Masaoka stage was an independent prognostic covariate using OS (hazard ratio (HR) 2.57, 95% CI 1.46-4.52, p = 0.001) and DFS (HR 3.18, 95% CI 1.56-6.52, p = 0.001). CONCLUSIONS: In thymomas, MG, WHO histology and Masaoka stage are inter-related. MG has an influence on histology and stage at presentation, while two clinical/histologic patterns are more likely: early Masaoka stage A/AB WHO type and high Masaoka stage/B WHO type. Among the three factors, only Masaoka stage had a prognostic significance on OS and DFS. Our results suggest that a consistent staging system for thymomas should take into account all three variables.

Hemolytic uremic syndrome induced by infusion of oxaliplatin: a case report.

INTRODUCTION: Oxaliplatin is a third-generation platinum compound with proven antitumor activity in the treatment of colorectal cancer. The occurrence of life-threating hemolitic uremic syndrome has been observed after oxaliplatin therapy. The kind of tumor and treatment modalities seem to influence the onset of hemolitic uremic syndrome. METHODS: The clinical course of the case is reviewed and compared with reports of other similar cases in the literature. RESULTS: We describe the development of hemolitic uremic syndrome as a result of prolonged oxaliplatin treatment of a colon cancer patient. CONCLUSIONS: Although this rare event requires the concurrence of other unknown factors, it should be considered in a decision-making setting.

Procalcitonin as a predictive marker of infections in chemoinduced neutropenia.

PURPOSE: This study was designed to determine the usefulness of procalcitonin (PCT) as a predictive marker of infections in neutropenic patients following chemotherapeutic treatments. METHODS: Over a 6-month period, 65 patients (34 affected by a solid tumor, 31 by a hematological disorder) were enrolled. Serum PCT concentrations were measured by an automated immunoassay on the leucocytes nadir and on the third day, when patients were checked for any sign of infection. RESULTS: Procalcitonin values were not affected by gender, age, therapeutic approach, use of G-CSF or performance status and did not differ between patients who subsequently developed a localized infection and those who did not. PCT concentrations resulted higher in patients affected by hematological disorders than in those affected by solid tumors (mean value 0.09 vs. 0.05 microg/L; p < 0.0015) and in those who were hospitalized than in the outpatient group (0.10 vs. 0.05 microg/L; p < 0.0013). PCT levels correlated with the type of neoplastic disease (p = 0.016), the highest concentrations being detected in patients affected by acute leukemia. CONCLUSIONS: These findings suggest that PCT is not a useful predictive marker of infection in oncohematologic neutropenic patients, even though higher serum PCT concentrations are associated with hematological tumors as well as in-hospital admission.