Genome-wide linkage screen for testicular germ cell tumour susceptibility loci

A family history of disease is a strong risk factor for testicular germ cell tumour (TGCT). In order to identify the location of putative TGCT susceptibility gene(s) we conducted a linkage search in 237 pedigrees with two or more cases of TGCT. One hundred and seventy-nine pedigrees were evaluated genome-wide with an average inter-marker distance of 10 cM. An additional 58 pedigrees were used to more intensively investigate several genomic regions of interest. Genetic linkage analysis was performed with the ALLEGRO software using two model-based parametric analyses and a non-parametric analysis. Six genomic regions on chromosomes 2p23, 3p12, 3q26, 12p13-q21, 18q21-q23 and Xq27 showed heterogeneity LOD (HLOD) scores of greater than 1, with a maximum HLOD of 1.94 at 3q26. Genome-wide simulation studies indicate that the observed number of HLOD peaks greater than one does not differ significantly from that expected by chance. A TGCT locus at Xq27 has been previously reported. Of the 237 pedigrees examined in this study, 66 were previously unstudied at Xq27, no evidence for linkage to this region was observed in this new pedigree set. Overall, the results indicate that no single major locus can account for the majority of the familial aggregation of TGCT, and suggests that multiple susceptibility loci with weak effects contribute to the diseas

Tumour volume and radiotherapy prolongation in locally advanced head and neck cancer patients treated with radical IMRT

Aims. The relationship of tumour volume, radiotherapy treatment time and other prognostic factors affecting prognosis was evaluated. Methods. 184 patients with locally advanced head and neck cancer were treated with radical intensity modulated radiotherapy (IMRT) and compared retrospectively. Results. In the multivariate analysis the overall survival was dependent on gross tumour volume (GTV), clinical stage (CS), radiotherapy treatment time (RTT) and p16 status. Local control was influenced by GTV, overall RTT and age. DFS was significantly affected by GTV, CS, RTT, p16 status and concomitant chemotherapy (CHT). Conclusions. The tumour volume and the radiotherapy treatment time were the most significant prognostic factors with the best outcomes in patients with GTV ≤ 55 cc and RTT ≤ 48 days (mean LC 8.1, DFS 7.1 and OS 6.4 years) and worst outcomes with GTV > 55 cc and RTT >48 days (mean LC 4.4, mean DFS 3.2 and mean OS 2.6 years)

Evaluation of 2 whole-brain radiotherapy schedules and prognostic factors for brain metastases in breast cancer patients

The majority of breast cancer patients with brain metastases receive whole-brain radiotherapy (WBRT) and have a survival of only a few months. A short WBRT regimen would be preferable if it provides survival that is similar to that achieved with longer programs. This retrospective study compared survival and local control within the brain resulting from short-course WBRT with longer programs in 207 breast cancer patients. Sixty-nine patients treated with 5 fractions of 4 grays (Gy) each given within 5 days were compared with 138 patients treated with 10 fractions of 3 Gy each given over 2 weeks or 20 fractions of 2 Gy each given over 4 weeks. Six additional potential prognostic factors were investigated: age, Karnofsky performance score (KPS), number of brain metastases, the presence of extracranial metastases, interval from tumor diagnosis to WBRT, and recursive partitioning analysis (RPA) class. On univariate analysis, the WBRT regimen was not found to be associated with survival (P=.254) or local control (P=.397). Improved survival was associated with a KPS>70 (P 70 (RR of 5.75; P <.001). Short-course WBRT with 5 fractions of 4 Gy each resulted in survival and local control that were similar to longer programs in breast cancer patients with brain metastases. The dose of 5 fractions of 4 Gy each appears preferable for the majority of these patients because it is less time consuming and more convenien

Comparison of short-course versus long-course whole-brain radiotherapy in the treatment of brain metastases

Whole-brain radiotherapy (WBRT) is the most common treatment for brain metastases. Most of these patients have a poor survival prognosis. Therefore, a short radiation program is preferred, if it provides a similar outcome as longer programs. This study compares 20 Gy in five fractions (treatment time: 1 week) to longer programs, with higher doses including 30 Gy in ten fractions (2 weeks) and 40 Gy in 20 fractions (4 weeks). Data regarding 1,085 patients treated with WBRT for brain metastases were retrospectively analyzed. 387 patients received 20 Gy in five fractions, and 698 patients received higher doses (30 Gy in ten fractions, n = 527, or 40 Gy in 20 fractions, n = 171). In addition, eight potential prognostic factors were investigated including age, sex, Karnofsky Performance Score (KPS), tumor type, interval from tumor diagnosis to WBRT, number of brain metastases, extracranial metastases, and recursive partitioning analysis (RPA) class. Subgroup analyses were performed for each RPA class individually. The WBRT schedule had no significant impact on survival (p = 0.415). On multivariate analysis, improved survival was significantly associated with age or = 70 (RR: 1.73; p = 0.002), lack of extracranial metastases (RR: 1.27; p = 0.007), interval from tumor diagnosis to WBRT > 8 months (RR: 1.19; p = 0.011), and lower RPA class (RR: 1.56; p < 0.001). The subgroup analyses for each RPA class did not reveal a significant association between WBRT schedule and survival. Short-course WBRT with 20 Gy in five fractions is preferable for most patients, because it is associated with similar survival as longer programs and is less time-consumin

Reduction of overall treatment time in patients irradiated for more than three brain metastases

Patients with multiple brain metastases usually receive whole brain radiotherapy (WBRT). A dose of 30 Gy in 10 fractions (10 x 3 Gy) in 2 weeks is the standard treatment in many centers. Regarding the poor survival of these patients, a shorter RT regimen would be preferable if it provides a similar outcome as that with 10 x 3 Gy. This study compared 20 Gy in five fractions (5 x 4 Gy) within 5 days to 10 x 3 Gy. Data from 442 patients treated with WBRT for multiple brain metastases were retrospectively analyzed. Survival and local control within the brain of 232 patients treated with 5 x 4 Gy were compared with the survival and local control within the brain of 210 patients treated with 10 x 3 Gy. Seven additional potential prognostic factors were investigated: age, gender, Karnofsky performance score, tumor type, interval from tumor diagnosis to RT, extracranial metastases, and recursive partitioning analysis class. On univariate analysis, the WBRT program was not associated with survival (p = 0.29) or local control (p = 0.07). On multivariate analyses, improved survival was associated with a lower recursive partitioning analysis class (p or=70 (p = 0.015), and the absence of extracranial metastases (p = 0.005). Improved local control was associated with a lower recursive partitioning analysis class (p or=70 (p <0.001), and breast cancer (p = 0.043). Grade 3 acute toxicity rates were not significantly different between 5 x 4 Gy and 10 x 3 Gy. Shorter course WBRT with 5 x 4 Gy was associated with similar survival and local control as "standard" WBRT with 10 x 3 Gy in patients with more than three brain metastases. The 5 x 4-Gy regimen appears preferable for most of these patients, because it is less time consuming and more convenient for patients than the 10 x 3-Gy regime

Whole-brain radiotherapy with 20 Gy in 5 fractions for brain metastases in patients with cancer of unknown primary (CUP)

Whole brain radiotherapy (WBRT) is the most common treatment for brain metastases. Survival of patients with cancer of unknown primary (CUP) presenting with brain metastases is extremely poor. A radiation program with a short overall treatment time (short-course RT) would be preferable to longer programs if it provides similar outcomes. This study compares short-course RT with 20 Gy in 5 fractions (5 x 4 Gy) given over 5 days to longer programs in CUP patients. Data regarding 101 CUP patients who received either short course WBRT (n=34) with 5 x 4 Gy or long-course WBRT (n=67) with 10 x 3 Gy given over 2 weeks or 20 x 2 Gy given over 4 weeks for brain metastases were analyzed retrospectively. Six additional potential prognostic factors were investigated: age, gender, Karnofsky performance score (KPS), number of brain metastases, extracranial metastases, RPA-(Recursive Partitioning Analysis-)class. On univariate analysis, the radiation program was not associated with survival (p=0.88) nor intracerebral control (p=0.36). Improved survival was associated with KPS >or= 70 (p <0.001), absence of extracranial metastases (p <0.001), and RPA-class 1 (p <0.001). On multivariate analyses, KPS (risk ratio [RR]: 4.55; p <0.001), extracranial metastases (RR: 1.70; p=0.018), and RPA-class (RR: 2.86; p <0.001) maintained significance. On univariate analysis, KPS (p <0.001) and RPA-class (p <0.001) were significantly associated with intracerebral control. On multivariate analyses, KPS (RR: 2.72; p <0.001) and RPA-class (RR: 2.09; p <0.001) remained significant. Short-course WBRT with 5 x 4 Gy provided similar intracerebral control and survival as longer programs for the treatment of brain metastases in CUP patients. 5 x 4 Gy appears preferable because it is more convenient for patient

The International Testicular Cancer Linkage Consortium:A clinicopathologic descriptive analysis of 461 familial malignant testicular germ cell tumor kindred

Objectives: Familial aggregation of testicular germ cell tumor (TGCT) has been reported, but it is unclear if familial TGCT represents a unique entity with distinct clinicopathologic characteristics. Here we describe a collection of familial TGCT cases from an international consortium, in an effort to elucidate any clinical characteristics that are specific to this population. Materials and methods: Families with >= 2 cases of TGCT enrolled at 18 of the sites participating in the International Testicular Cancer Linkage Consortium were included. We analyzed clinicopathologic characteristics of 985 cases from 461 families. Results: A majority (88.5%) of families had only 2 cases of TGCT. Men with seminoma (50% of cases) had an older mean age at diagnosis than nonseminoma cases (P = 0.001). Among individuals with a history of cryptorchidism. TGCT was more likely to occur in the ipsilateral testis (kappa = 0.65). Cousin pairs appeared to represent a unique group, with younger age at diagnosis and a higher prevalence of cryptorchidism than other families. Conclusions: Clinicopathologic characteristics in these familial TGCT cases were similar to those generally described for nonfamilial eases. However, we observed a unique presentation of familial TGCT among cousin pairs. Additional studies are needed to further explore this observation. Published by Elsevier Inc

Genome-wide linkage screen for testicular germ cell tumour susceptibility loci.

A family history of disease is a strong risk factor for testicular germ cell tumour (TGCT). In order to identify the location of putative TGCT susceptibility gene(s) we conducted a linkage search in 237 pedigrees with two or more cases of TGCT. One hundred and seventy-nine pedigrees were evaluated genome-wide with an average inter-marker distance of 10 cM. An additional 58 pedigrees were used to more intensively investigate several genomic regions of interest. Genetic linkage analysis was performed with the ALLEGRO software using two model-based parametric analyses and a non-parametric analysis. Six genomic regions on chromosomes 2p23, 3p12, 3q26, 12p13-q21, 18q21-q23 and Xq27 showed heterogeneity LOD (HLOD) scores of greater than 1, with a maximum HLOD of 1.94 at 3q26. Genome-wide simulation studies indicate that the observed number of HLOD peaks greater than one does not differ significantly from that expected by chance. A TGCT locus at Xq27 has been previously reported. Of the 237 pedigrees examined in this study, 66 were previously unstudied at Xq27, no evidence for linkage to this region was observed in this new pedigree set. Overall, the results indicate that no single major locus can account for the majority of the familial aggregation of TGCT, and suggests that multiple susceptibility loci with weak effects contribute to the disease