Irradiation before and donor splenocyte infusion immediately after transplantation induce tolerance to lung, but not heart allografts in miniature swine.

Solid organs may differ in their potential to induce and maintain a state of donor-specific tolerance. Previously, we induced stable immunological tolerance in a lung transplantation model in miniature swine. Here, we wished to transfer this established protocol into a heart transplantation model in miniature swine. Heterotopic heart transplantation (HTX) was performed in four and left-sided lung transplantation (LTX) in seven minipigs from gender- and SLA-mismatched donors. All recipients received nonmyeloablative irradiation, donor splenocyte infusion and intravenous pharmacologic immunosuppression for 28 postoperative days. All transplanted hearts were rejected within 95 days. In contrast, four animals of the LTX group developed stable tolerance surviving beyond 500 days, and three further animals rejected 119, 239 and 360 days post-transplantation. In both groups, peripheral blood donor leucocyte chimerism peaked 1 h after reperfusion of the allograft. Importantly, the early chimerism level in the LTX group was significantly higher compared to the HTX group and remained detectable throughout the entire observation period. In conclusion, lungs and hearts vary in their potential to induce a state of tolerance after transplantation in a protocol with pre-operative recipient irradiation and donor splenocyte co-transplantation. This could be due to differential early levels of passenger leucocyte chimerism.

A new instrument for estimating the survival of patients with metastatic epidural spinal cord compression from esophageal cancer.

BACKGROUND: This study was initiated to create a predictive instrument for estimating the survival of patients with metastatic epidural spinal cord compression (MESCC) from esophageal cancer. METHODS: In 27 patients irradiated for MESCC from esophageal cancer, the following nine characteristics were evaluated for potential impact on survival: age, gender, Eastern Cooperative Oncology Group (ECOG) performance score, histology, number of involved vertebrae, ambulatory status before irradiation, further bone metastases, visceral metastases, and dynamic of developing motor deficits before irradiation. In addition, the impact of the radiation regimen was investigated. According to Bonferroni correction, p-values of < 0.006 were significant representing an alpha level of < 0.05. RESULTS: ECOG performance score (p < 0.001), number of involved vertebrae (p = 0.005), and visceral metastases (p = 0.004) had a significant impact on survival and were included in the predictive instrument. Scoring points for each characteristic were calculated by dividing the 6-months survival rates (in %) by 10. The prognostic score for each patient was obtained by adding the scoring points of the three characteristics. The prognostic scores were 4, 9, 10, 14 or 20 points. Three prognostic groups were formed, 4 points (n = 11), 9-14 points (n = 12) and 20 points (n = 4). The corresponding 6-months survival rates were 0%, 33% and 100%, respectively (p < 0.001). Median survival times were 1 month, 5 months and 16.5 months, respectively. CONCLUSIONS: This new instrument allows the physician estimate the 6-months survival probability of an individual patient presenting with MESCC from esophageal cancer. This is important to know for optimally personalizing the treatment of these patients.

Predicting survival of patients with metastatic epidural spinal cord compression from cancer of the head-and-neck.

AIM: To develop an instrument for estimating survival after irradiation for metastatic epidural spinal cord compression (MESCC) from head and neck cancer. PATIENTS AND METHODS: In 58 patients, eleven factors were evaluated for influence on survival: age, gender, performance status, tumor site, time from cancer diagnosis until MESCC, affected vertebrae, walking ability, further osseous lesions, organ metastases, time developing motor deficits and radiation regimen. Factors with significant association with survival or a trend (multivariate analysis) were used for scoring. RESULTS: Walking ability, visceral metastases and time to developing motor deficits were included in the score. Scoring points were calculated by dividing 6-month survival rates by 10. Patients' scores were obtained from adding the points of the three factors. Four groups were created, 7-10, 12-15, 16-18 and 21 points. Six-month survival rates were 0%, 27%, 71% and 100% (p<0.001). CONCLUSION: With this new instrument, one can estimate 6-month survival probabilities of patients with MESCC from head-and-neck cancer.

A validated score estimating ambulatory status following radiotherapy of elderly patients for metastatic spinal cord compression.

BACKGROUND: This study was performed to develop a validated score predicting ambulatory status after radiotherapy (RT) alone for metastatic spinal cord compression (MSCC) in elderly patients. METHODS: 1,129 elderly patients (≥65 years) were assigned to the test (N = 565) or validation group (N = 564). In the test group, nine pre-treatment factors (age, gender, tumor type, number of involved vertebrae, pre-RT ambulatory status, other bone metastases, visceral metastases, interval cancer diagnosis to RT, time developing motor deficits) and fractionation regimen were investigated. Factors significantly associated with post-RT ambulatory status on multivariate analysis were included in the score. The score for each factor was determined by dividing the post-RT ambulatory rate at 1 month (%) by 10. The total score represented the sum of these scores. RESULTS: In the multivariate analysis of the test group, age, primary tumor type, pre-RT ambulatory status, visceral metastases, and time developing motor deficits were significantly associated with post-RT ambulatory status. Total scores were 19 to 41 points. In the test group, post-RT ambulatory rates were 5% for 19-25 points, 35% for 26-30 points, 80% for 31-34 points, and 98% for 35-41 points (p < 0.001). 6-month survival rates were 11%, 21%, 59% and 76%, respectively. In the validation group, post-RT ambulatory rates were 4%, 33%, 77% and 98%, respectively (p < 0.001). CONCLUSIONS: Patients achieving 19-25 points had very poor functional outcomes and survival, and may receive single-fraction RT for pain relief. Selected patients with 26-34 points may benefit from additional surgery. Patients achieving ≥35 points achieved favorable results after RT alone.

Number of extraspinal organs with metastases: a prognostic factor of survival in patients with metastatic spinal cord compression (MSCC) from non-small cell lung cancer (NSCLC).

BACKGROUND/AIM: In patients irradiated for MSCC from NSCLC, the number of extraspinal organs involved by metastases was investigated for associations with survival. PATIENTS AND METHODS: The data of 131 patients irradiated with 10×3 Gy in two weeks for MSCC were evaluated. The number of involved extraspinal organs plus eight other factors were retrospectively analyzed. RESULTS: The 6-month survival rates were 72%, 57%, 20%, and 11% for the involvement of 0, 1, 2, and ≥3 extraspinal organs, respectively (p<0.001). On multivariate analysis, the number of involved extraspinal organs remained significant (risk ratio 1.60; 95% CI 1.28-2.00; p<0.001). Gender (p=0.028), ECOG performance score (p=0.001), histology (p=0.014), ambulatory status (p=0.002), and time to developing motor deficits (p=0.041) were also independent prognostic factors for survival. CONCLUSION: The number of extraspinal organs with metastases is an independent prognostic factor for the survival of NSCLC patients presenting with MSCC and should be considered in future studies.

Metastatic spinal cord compression: a validated survival score for elderly patients.

BACKGROUND AND PURPOSE: This study aimed to develop a validated survival score for elderly patients with metastatic spinal cord compression (MSCC). PATIENTS AND METHODS: In all, 1,128 patients were randomly assigned to the test (n = 564) or validation group (n = 564). In the test group, ten pretreatment factors (age, gender, performance status, primary tumor, number of involved vertebrae, ambulatory status, other bone metastases, visceral metastases, interval from cancer diagnosis to radiotherapy of MSCC, time to developing motor deficits) plus the radiation regimen were retrospectively evaluated. Factors significantly associated with survival on multivariate analysis were included in the survival score. The score for each factor was determined by dividing the 6-month survival rate (%) by 10. The prognostic score represented the sum of the scores for each factor. RESULTS: In the multivariate analysis of the test group, age, performance status, primary tumor type, ambulatory status, other bone metastases, visceral metastases, interval from cancer diagnosis to radiotherapy of MSCC, and time to developing motor deficits were significantly associated with survival. Total scores ranged from 25 to 57 points. In the test group, 6-month survival rates were 11 % for 25-39 points, 56 % for 40-48 points, and 97 % for 49-57 points (p < 0.001). In the validation group, 6-month survival rates were 10, 53, and 94 %, respectively (p < 0.001). CONCLUSION: Based on the survival scores of the test group, three prognostic groups were identified. The survival rates of the validation group were similar to the test group. This score appears reproducible and can help select the appropriate treatment for elderly patients with MSCC.

Prognostic role of the number of involved extraspinal organs in patients with metastatic spinal cord compression.

OBJECTIVE: This study was investigated the prognostic role of the number of involved extraspinal organs in the survival of patients with metastatic spinal cord compression (MSCC). METHODS: Data of 552 patients treated with 30Gy in 10 fractions of radiotherapy (RT) alone for MSCC were retrospectively analyzed. In addition to the number of involved extraspinal organs, eight potential prognostic factors were investigated including age, gender, Eastern Cooperative Oncology Group performance score (ECOG-PS), primary tumor type, number of involved vertebrae, interval from cancer diagnosis to RT, pre-RT ambulatory status, and time developing motor deficits. RESULTS: The 6-month survival rates for the involvement of 0, 1, 2, 3, and ≥4 extraspinal organs were 88%, 55%, 30%, 13%, and 12%, respectively (P<0.001). In the multivariate analysis, number of involved extraspinal organs maintained significance (risk ratio 1.61; 95%-confidence interval 1.47-1.77; P<0.001). On multivariate analysis, gender (P=0.017), ECOG-PS (P<0.001), primary tumor type (P<0.001), interval from cancer diagnosis to RT (P<0.001), pre-RT ambulatory status (P<0.001), and time developing motor deficits (P<0.001) were also independent predictors for survival. CONCLUSIONS: The number of involved extraspinal organs is a new and independent prognostic factor in patients with MSCC and should be considered in future clinical trials.

Vestibular schwannoma microsurgery for recurrent tumors after radiation therapy or previous surgical resection.

OBJECTIVE: The purpose of this study is to compare the outcomes in patients who underwent microsurgical resection for recurrent vestibular schwannoma after microsurgical resection and previous radiation therapy. STUDY DESIGN: Retrospective study. SETTING: University hospital. PATIENTS: Fifteen patients, who underwent microsurgical resection for recurrent vestibular schwannoma after previous surgery (group A), and 5 patients, who underwent microsurgical resection after previous radiation therapy (group B) were included. INTERVENTION: Surgical resection after radiation therapy or previous surgical resection. MAIN OUTCOME MEASURES: Intraoperative findings and postoperative facial nerve function were investigated in groups A and B. RESULTS: Mean tumor volumes were 18.4 ± 2.44 cm3 in group A and 19.0 ± 1.53 cm3 in group B. Total resection was achieved in 10 patients (67%) of group A and in 3 patients (60.0%) of group B. The tumor was more difficult to resect because of severe adhesions to the facial nerve. Anatomic facial nerve preservation could be achieved in 19 patients. Mean follow-up time was 80 months for group A and 28 months for group B. At last follow-up, 7 patients (53.8%) of group A had a good facial nerve function. In 3 patients (75.0%) of group B, the preoperative facial nerve function was preserved postoperatively. Preexistent facial paresis, large tumor with extrameatal growth and brainstem compression correlated with poor postoperative facial nerve function. CONCLUSION: Surgical outcome of recurrent vestibular schwannoma is more unsatisfactory than after primary surgery. It remains to be clarified whether previous surgery may implicate a higher risk for postoperative facial nerve function than previous radiation therapy upon surgery for tumor recurrence.

Survival in patients with metastatic spinal cord compression from prostate cancer is associated with the number of extra-spinal organs involved.

BACKGROUND/AIM: To investigate the predictive value of the number of extra-spinal organs involved by metastases for survival in metastatic spinal cord compression (MSCC) from prostate cancer. PATIENTS AND METHODS: In 95 patients irradiated with 10 × 3 Gy for MSCC from prostate cancer, seven factors were investigated: Age, performance score, number of involved vertebrae, interval from prostate cancer diagnosis to MSCC, pre-radiotherapy ambulatory status, time to motor deficits development, number of involved extra-spinal organs. RESULTS: Six-month survival rates for 0, 1 and ≥ 2 involved extra-spinal organs, were 81, 53 and 33%, respectively (p<0.001). On multivariate analysis, the number of involved extra-spinal organs maintained significance (risk ratio 1.88, p=0.023). Better performance score (p<0.001), longer interval from prostate cancer diagnosis to radiotherapy of MSCC (p<0.001), and being ambulatory prior to radiotherapy (p=0.001) were also positively associated with survival. CONCLUSION: The number of extra-spinal organs involved by metastases predicts survival in patients with MSCC from prostate cancer.

Segmental dosimetry, toxicity and long-term outcome in patients with prostate cancer treated with permanent seed implants.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The development of side effects characteristic for the different treatment methods with impact on the patients' quality of life plays a growing role for individual patients with early stage prostate cancer. Using permanent brachytherapy a high dose to the prostate can be applied with a steep dose gradient to the normal tissue. However, small partial volumes of normal tissue may be exposed to high doses inducing special side effects including lower urinary tract symptoms and/or erectile dysfunction. In the literature there are only few publications so far regarding segmental dosimetry and its influence on side effects and the results are conflicting. We could not identify any dosimetric parameter in segmental dosimetry that may have an influence at certain time intervals on the development of side effects such as lower urinary tract symptoms or erectile dysfunction. However, we could state clearly that the preoperative situation is the most important factor for postoperative outcome. OBJECTIVE: To report on the side effects of patients with low to low-intermediate risk prostate cancer treated with permanent interstitial brachytherapy with special emphasis on segmental dosimetry. PATIENTS AND METHODS: A series of 186 consecutive patients treated for early stage prostate cancer receiving definitive I-125 brachytherapy (permanent seed implantation) between November 2001 and April 2005 at our institution were examined for the development of side effects. Morbidity was assessed prospectively using the International Prostate Symptom Score (IPSS) and the International Index of Erectile Function (IIEF-5) in a mean follow-up interval of 30 months. The scores were correlated with segmental dosimetry performed 6 weeks after the implantation. RESULTS: The mean postoperative dose to 90% of the prostate volume (D90) was 180.2 Gy, the mean preoperative IPSS 7.2 and the mean IIEF-5 14.35, with all scores showing a maximum deterioration after 6 weeks with normalization after 24 months. After correlating the segmental dosimetry and the scores at different time intervals, only the baseline scores remained statistically significant in multivariate regression analysis at all time intervals (P < 0.00). CONCLUSIONS: We could not demonstrate a correlation of segmental dosimetry with induction of side effects. There is no relationship between dose exposure of partial volumes and the development of radiation-induced toxicities. The preoperative situation regarding lower urinary tract symptoms and erectile function are the most important factors for postoperative outcome.

Apoptosis gene polymorphisms and risk of prostate cancer: a hospital-based study of German patients treated with brachytherapy.

BACKGROUND AND OBJECTIVES: Prostate cancer has a genetic component, and single nucleotide polymorphisms (SNPs) can contribute to the risk. We aimed to investigate the role of polymorphisms in 10 candidate genes with a key function in apoptosis. METHODS AND MATERIALS: Eight coding SNPs were chosen in ATM (Ser49Cys), BID (Ser56Cys), CASP8 (Asp302His), CASP10 (Val410Ile), LGALS3 (Pro64His), RASSF1 (Ser133Ala), TP53 (Arg72Pro), and TP53AIP1 (Ala7Val), and two non-coding SNPs were selected in BCL2 (-938C/A) and HDM2 (SNP309). A hospital-based case-control series of 510 prostate cancer patients and 490 healthy males from Northern Germany were genotyped for these polymorphisms. RESULTS: SNP rs4644 in LGALS3 showed evidence for a protective effect of the minor allele, encoding the His64 variant (OR 0.82, 95% CI 0.69;0.99, P = 0.04). Carriers were underrepresented among cases under a dominant model (OR 0.71; 95% CI 0.54;0.92; P = 0.01), and the effect appeared more pronounced in patients diagnosed before the age of 60 years (OR 0.52; 95% CI 0.31;0.85, P = 0.01). The other nine polymorphisms did not vary significantly between cases and controls, though subtle trends were noted for BCL2 (P = 0.07) and CASP10 (P = 0.08). The Asp302His variant of CASP8 tended to associate with a protective effect in the group with higher Gleason score under a dominant model (P = 0.03). Carriers of either the CASP8 or the CASP10 variants were underrepresented in the prostate cancer series (P = 0.02). CONCLUSIONS: These results provide first evidence to implicate the functional Pro64His variant of galectin-3 (LGALS3) in the genetic susceptibility towards prostate cancer. The potential role of polymorphisms in BCL2, CASP8, and CASP10 merits further investigation.

Langerhans cell histiocytosis of the cranial base: is low-dose radiotherapy effective?

Introduction. Langerhans cell histiocytosis (LCH) is a rare disease of unknown etiology with different clinical features. A standardised treatment has not been established so far. Case Report. We report a case of a 28-year-old patient who initially presented with hypesthesia of the fifth cranial nerve and pain of the left ear. Diagnosis showed a tumour localised in the cranial base with a maximum diameter of 4.1 cm. The diagnosis of LCH was confirmed histologically by biopsy. Diagnostic workup verified the cranial lesion as the sole manifestation of LCH. A total dose of 9 Gy (single dose 1.8 Gy) was delivered. The symptoms dissolved completely within 6 months after radiation; repeated CT and MRI scans revealed a reduction in size of the lesion and a remineralisation of the bone. After a followup of 13 years the patient remains free of symptoms without relapse or any side effects from therapy. Discussion. Due to the indolent course of the disease with a high rate of spontaneous remissions the choice of treatment strongly depends on the individual clinical situation. In the presented case low-dose radiotherapy was sufficient to obtain long-term local control in a region with critical structures and tissues.

Image-guided hypofractionated small volume radiotherapy of non-small cell lung cancer - feasibility and clinical outcome.

PURPOSE: Local hypofractionated stereotactic radiation treatment (hfSRT) of early stage non-small cell lung cancer (NSCLC) represents a highly effective treatment alternative in medically inoperable patients. METHOD: Between June 2007 and December 2010, 65 patients with NSCLC were treated with image-guided hypofractionated radiotherapy. The Union Internationale Contre le Cancer (UICC) stage distribution was: IA, n = 19; IB, n = 15; IIB, n = 5; IIIA, n = 10; IIIB, n = 6; and IV, n = 10. The fractionation schedule used was 3 × 12.5 Gy (n = 36) prescribed to the encompassing 67% isodose line for peripheral primary tumours, and 8 × 6 Gy (n = 26) or 8 × 5 Gy (n = 3) prescribed to the encompassing 80% isodose line for centrally located tumours. RESULTS: Mean follow-up was 13.8 months (range 1-41 months). Until now 6 patients developed a local recurrence, 2 of them in combination with mediastinal lymph node failure. The 1-year actuarial local control rate was 93% and overall survival 79%. Pneumonitis was seen in 14 patients (21.5%) (Common Terminology Criteria for Adverse Events (CTCAE) grade I: n = 12, and II: n = 2) after a median time period of 9.5 months. No patient developed pneumonitis of CTCAE grade III or higher. CONCLUSION: Image-guided hfSRT is effective and feasible in patients with non-operable NSCLC, even in higher stages, whenever local control is crucial and there are contraindications against systemic therapy.

Breast cancer risk and 6q22.33: combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2.

Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.

Malignant glioma grade 3 and 4: how relevant is timing of radiotherapy?

AIMS AND BACKGROUND: The aim of this study is to determine prognostic factors that influence further outcome in patients with glioma. METHODS: Between 01/2002 and 08/2008, 153 patients with malignant gliomas of WHO-grade 3 or 4 who were treated with external beam radiotherapy with or without chemotherapy. RESULTS: In univariate analysis, following factors were ascertained as statistically significant prognostic parameters: grade (p = 0.000), time between operation and radiotherapy >24 days (p = 0.044) for progression-free survival; grade (p = 0.000), age<58 years (p = 0.001), extent of surgery (p = 0.011), time between operation and radiotherapy >24 days (p = 0.009), overall treatment time >68 days (p = 0.003), use of chemotherapy (p = 0.015) for overall survival. A longer time period between resection and start of radiotherapy showed to be associated with improved outcome. After multivariate analysis, only grade (p = 0.000) remained a statistically significant factor for progression-free and grade (p = 0.000) and use of chemotherapy (p = 0.031) for overall survival. CONCLUSIONS: We were able to recognize grade and use of chemotherapy as statistically significant prognostic determinants, but not time intervals or overall treatment time.

Dose escalation of radiotherapy for metastatic spinal cord compression (MSCC) in patients with relatively favorable survival prognosis.

BACKGROUND AND PURPOSE: Local control of metastatic spinal cord compression (MSCC) is particularly important for long-term survivors. Radiotherapy alone is the most common treatment for MSCC. The most frequently used schedule world wide is 30 Gy/10 fractions. This study investigated whether patients with favorable survival prognoses benefit from a dose escalation beyond 30 Gy. PATIENTS AND METHODS: Data from 191 patients treated with 30 Gy/10 fractions were matched to 191 patients (1:1) receiving higher doses (37.5 Gy/15 fractions or 40 Gy/20 fractions). All patients had favorable survival prognoses based on a validated scoring system and were matched for age, gender, tumor type, performance status, number of involved vertebrae, visceral or other bone metastases, interval from tumor diagnosis to radiotherapy, ambulatory status, and time developing motor deficits. Both groups were compared for local control, progression-free survival, overall survival, and functional outcome. RESULTS: Local control rates at 2 years were 71% after 30 Gy and 92% after higher doses (p=0.012). Two-year progression-free survival rates were 68% and 90%, respectively (p=0.013). Two-year overall survival rates were 53% and 68%, respectively (p=0.032). Results maintained significance in the multivariate analyses (Cox proportional hazards model; stratified model) with respect to local control (p=0.011; p=0.012), progression-free survival (p=0.010; p=0.018), and overall survival (p=0.014; p=0.015). Functional outcome was similar in both groups. Motor function improved in 40% of patients after 30 Gy and 41% after higher doses (p=0.98). CONCLUSION: Escalation of the radiation dose beyond 30 Gy resulted in significantly better local control, progression-free survival, and overall survival in patients with favorable survival prognoses.

Mutation analysis of the SLX4/FANCP gene in hereditary breast cancer.

SLX4 coordinates three structure-specific endonucleases in the DNA damage response. One subtype of Fanconi anaemia, FA-P, has recently been attributed to biallelic SLX4 gene mutations. To investigate whether monoallelic SLX4 gene defects play some role in the inherited component of breast cancer susceptibility, in this study we resequenced the whole SLX4 coding region and flanking untranslated sections in genomic DNA samples obtained from a total of 52 German or Byelorussian patients with familial breast cancer. Selected variants were subsequently screened by RFLP or TaqMan-based assays in an extended set of 965 German breast cancer cases and 985 healthy female controls. The resequencing study uncovered four new SLX4 missense substitutions, each of them in a single breast cancer patient. Three missense substitutions (p.V197A, p.G700R and p.R1034H) were not found in a subsequent screening of 240 additional breast cancer patients, while one missense substitution (p.R237Q) was more common and was detected in a total of 12 cases (1.3%) and seven controls (0.7%) in the Hannover breast cancer study. The rare missense substitution, p.G700R, resides in the conserved BTB domain and was in silico predicted to be pathogenic. Seven additional missense polymorphisms were correlated and formed one haplotype which was, however, neither associated with breast cancer risk nor with survival from breast cancer. In summary, this study did not reveal truncating or clearly pathogenic mutations, but unravelled four new unclassified missense variants at a low frequency. We conclude that there is no evidence for a major role of SLX4 coding variants in the inherited susceptibility towards breast cancer in German and Byelorussian patients, although very rare mutations such as the p.G700R substitution could make a minor contribution.

Confirmation of 5p12 as a susceptibility locus for progesterone-receptor-positive, lower grade breast cancer.

BACKGROUND: The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium. METHODS: Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS), and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry. Associations overall and by tumor invasiveness and histopathology were assessed using logistic regression. RESULTS: For white Europeans, the per-allele OR associated with 5p12-rs10941679 was 1.11 (95% CI = 1.08-1.14, P = 7 × 10(-18)) for invasive breast cancer and 1.10 (95% CI = 1.01-1.21, P = 0.03) for DCIS. For Asian women, the estimated OR for invasive disease was similar (OR = 1.07, 95%CI = 0.99-1.15, P = 0.09). Further analyses suggested that the association in white Europeans was largely limited to progesterone receptor (PR)-positive disease (per-allele OR = 1.16, 95% CI = 1.12-1.20, P = 1 × 10(-18) vs. OR = 1.03, 95% CI = 0.99-1.07, P = 0.2 for PR-negative disease; P(heterogeneity) = 2 × 10(-7)); heterogeneity by ER status was not observed (P = 0.2) once PR status was accounted for. The association was also stronger for lower grade tumors [per-allele OR (95% CI) = 1.20 (1.14-1.25), 1.13 (1.09-1.16), and 1.04 (0.99-1.08) for grade 1, 2, and 3/4, respectively; P(trend) = 5 × 10(-7)]. CONCLUSION: 5p12 is a breast cancer susceptibility locus for PR-positive, lower grade breast cancer. IMPACT: Multicenter fine-mapping studies of this region are needed as a first step to identifying the causal variant or variants.

Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium.

Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER+ than ER- tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 × 10(-18)), rs3803662 (16q12) (P = 3.7 × 10(-5)), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 × 10(-6) and P = 4.1 × 10(-4), respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P ≤ 0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P ≤ 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment.

Surgery followed by radiotherapy versus radiotherapy alone for metastatic spinal cord compression from unfavorable tumors.

PURPOSE: Despite a previously published randomized trial, controversy exists regarding the benefit of adding surgery to radiotherapy for metastatic spinal cord compression (MSCC). It is thought that patients with MSCC from relatively radioresistant tumors or tumors associated with poor functional outcome after radiotherapy alone may benefit from surgery. This study focuses on these tumors. METHODS AND MATERIALS: Data from 67 patients receiving surgery plus radiotherapy (S+RT) were matched to 134 patients (1:2) receiving radiotherapy alone (RT). Groups were matched for 10 factors and compared for motor function, ambulatory status, local control, and survival. Additional separate matched-pair analyses were performed for patients receiving direct decompressive surgery plus stabilization of involved vertebrae (DDSS) and patients receiving laminectomy (LE). RESULTS: Improvement of motor function occurred in 22% of patients after S+RT and 16% after RT (p=0.25). Posttreatment ambulatory rates were 67% and 61%, respectively (p=0.68). Of nonambulatory patients, 29% and 19% (p=0.53) regained ambulatory status. One-year local control rates were 85% and 89% (p=0.87). One-year survival rates were 38% and 24% (p=0.20). The matched-pair analysis of patients receiving LE showed no significant differences between both therapies. In the matched-pair analysis of patients receiving DDSS, improvement of motor function occurred more often after DDSS+RT than RT (28% vs. 19%, p=0.024). Posttreatment ambulatory rates were 86% and 67% (p=0.30); 45% and 18% of patients regained ambulatory status (p=0.29). CONCLUSIONS: Patients with MSCC from an unfavorable primary tumor appeared to benefit from DDSS but not LE when added to radiotherapy in terms of improved functional outcome.