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.

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.

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.

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.

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.

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.

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.

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.

Outcome of moderately dosed radiosurgery for limited brain metastases. Report of a single-center experience.

PURPOSE: Efficacy and safety of the own single-center experience with moderately dosed radiosurgery (SRS) for limited (one to four) brain metastases were analyzed and correlated with patient- and treatment-related variables. PATIENTS AND METHODS: Between 05/1998 and 10/2006, 93 patients received SRS for a total of 142 brain metastases. The median number of brain metastases treated per patient was one (range, one to four). 46 patients (49%) received initial SRS alone, 13 patients (14%) SRS with up-front whole-brain radiotherapy (WBRT), and 34 patients (37%) SRS for recurrent metastases after WBRT. Median dose was 16 Gy (range, 10-20 Gy). RESULTS: Median overall survival (OS) was 7.5 months. The actuarial 6- and 12-month data for OS were 60% and 35%, for local brain control (LBC) 87% and 79%, and for distant brain control (DBC) 48% and 37%, respectively. Only ten of 46 patients (22%) with initial SRS alone ultimately received WBRT. Ten patients suffered from seizures within 3 months after SRS, six of them showed brain progression on magnetic resonance imaging (MRI). 20 patients required reinstitution of steroids following SRS, 16 of these due to brain progression. Five patients received positron emission tomography scan of the brain revealing radionecrosis in two patients. In uni- and multivariate analysis, only time interval between diagnosis of primary and brain metastases (p = 0.031) and volume of treated metastasis (p = 0.02) were significant predictors of OS. Neither up-front WBRT nor dose had a significant influence on LBC. CONCLUSION: Moderately dosed SRS of limited brain metastases was found to be both effective and safe. Initial SRS only may be offered to informed patients complying with MRI-based follow-up.

Radiotherapy for oligometastatic disease in patients with spinal cord compression (MSCC) from relatively radioresistant tumors.

BACKGROUND: Radiotherapy alone is the most common treatment for metastatic spinal cord compression (MSCC). Patients with relatively radioresistant tumors and oligometastatic disease may benefit from more intensive therapies (surgery, high-precision radiotherapy). If such therapies are not available, one can speculate whether patients benefit from dose escalation beyond the standard regimen 30 Gy in ten fractions. PATIENTS AND METHODS: Of 206 patients with MSCC from relatively radioresistant tumors (renal cell carcinoma, colorectal cancer, malignant melanoma), 51 had oligometastatic disease (no visceral or other bone metastases, involvement of only one to three vertebrae). In this subset, 21 patients receiving 30 Gy in ten fractions were retrospectively compared to 30 patients receiving higher doses. Seven further potential prognostic factors were investigated: age, gender, tumor type, performance status, interval from tumor diagnosis to radiotherapy of MSCC, pretreatment ambulatory status, and time developing motor deficits before radiotherapy. RESULTS: Motor function improved in 52% of patients after 30 Gy and 40% after higher doses (p = 0.44). On multivariate analysis, functional outcome was associated with interval from tumor diagnosis to radiotherapy (p = 0.020). 1-year local control rates were 84% after 30 Gy and 82% after higher doses (p = 0.75). No factor was associated with local control. 1-year survival rates were 76% after 30 Gy and 63% after higher doses (p = 0.52). On multivariate analysis, survival was associated with performance status (p = 0.022) and interval from tumor diagnosis to radiotherapy (p = 0.039), and almost with pretreatment ambulatory status (p = 0.069). CONCLUSION: Dose escalation beyond 30 Gy in ten fractions did not improve motor function, local control, and survival in MSCC patients with oligometastatic disease from relatively radioresistant tumors.

TOPBP1 missense variant Arg309Cys and breast cancer in a German hospital-based case-control study.

The DNA double strand break repair gene TOPBP1 has been suggested as a breast cancer susceptibility gene and a missense variant Arg309Cys was observed at elevated frequency in familial breast cancer cases compared to healthy controls from Finland. We found the Arg309Cys allele at a 13% carrier frequency in a hospital-based series of 1064 German breast cancer patients and at a 14% carrier frequency in 1014 population controls (OR 0.89, 95%CI 0.69-1.15; p = 0.4). Arg309Cys carriers were not enriched among patients with a family history of breast cancer (OR = 0.87, 95%CI 0.53-1.43, p = 0.6) and were slightly underrepresented in patients with bilateral disease (OR = 0.49, 95%CI = 0.24-0.99; p = 0.047). In the latter group, the mean age at diagnosis was 62 years in carriers and 54 years in non-carriers (p = 0.004). We conclude that there is no evidence for the TOPBP1*Arg309Cys variant to confer an increased risk for breast cancer in the German population.

Long-term renal toxicity in children following fractionated total-body irradiation (TBI) before allogeneic stem cell transplantation (SCT).

PURPOSE: To retrospectively assess the incidence and time course of renal dysfunction in children (< or = 16 years) following total- body irradiation (TBI) before allogeneic stem cell transplantation (SCT). PATIENTS AND METHODS: Between 1986 and 2003, 92 children (median age, 11 years; range, 3-16 years) underwent TBI before allogeneic SCT. 43 of them had a minimum follow-up of 12 months (median, 51 months; range, 12-186 months) and were included into this analysis. Conditioning regimen included chemotherapy and fractionated TBI with 12 Gy (n = 26) or 11.1 Gy (n = 17). In one patient, renal dose was limited to 10 Gy by customized renal shielding due to known nephropathy prior to SCT. Renal dysfunction was defined as an increase of serum creatinine > 1.25 times the upper limit of age-dependent normal. RESULTS: Twelve children (28%) experienced an episode of renal dysfunction after a median of 2 months (range, 1-10 months) following SCT. In all but one patient renal dysfunction was transient and resolved after a median of 8 months (range, 3-16 months). One single patient developed persistent renal dysfunction with onset at 10 months after SCT. None of these patients required dialysis. The actuarial 3-year freedom from persistent renal toxicity for children surviving > 12 months after SCT was 97.3%. CONCLUSION: The incidence of persistent renal dysfunction after fractionated TBI with total doses < or = 12 Gy was very low in this analysis.

TGFB1 gene polymorphism Leu10Pro (c.29T>C), prostate cancer incidence and quality of life in patients treated with brachytherapy.

OBJECTIVES: Transforming growth factor beta1 gene (TGFB1) variant Leu10Pro (L10P) has previously been implicated in prostate cancer risk and radiation-induced side-effects. We investigated whether prevalence of this polymorphism is increased in prostate cancer patients and whether carriers are at increased risk for treatment-related side effects. METHODS: A series of 445 consecutive patients treated for early-stage prostate cancer receiving definitive I-125 brachytherapy (permanent seed implantation) between 10/2000 and 10/2007 at our institution and a comparison group of 457 healthy male control individuals were screened for TGFB1 L10P (869T>C) polymorphism. Morbidity was assessed prospectively and compared between carriers versus non-carriers using International Prostate Symptom Score (IPSS), disease-specific Quality-of-Life single question added to the IPSS and International Index of Erectile Function with its subgroups. RESULTS: The Leu/Leu genotype was found in 150 patients (34%) versus 180 controls (39%), the Pro/Pro genotype in 75 patients (17%) versus 65 controls (14%) and the Leu/Pro genotype in 220 patients (49%) versus 212 controls (46%) without any statistically significant differences between the two groups. There was a trend towards an increased prevalence of the L10P substitution among patients with a per allele odds ratio of 1.19 (95% CI 0.99-1.44; P = 0.08). After a median follow-up of 18 months (range 1-60 months) there were no statistically significant differences regarding morbidity. CONCLUSIONS: TGFB1 polymorphism L10P is not strongly associated with prostate cancer risk. After 18 months, there was no evidence for increased adverse radiotherapy responses in heterozygote or rare homozygote carriers. Longer follow-up may be necessary to detect a statistically significant difference.

Nijmegen Breakage Syndrome mutations and risk of breast cancer.

Mutations in the NBS1 gene have been identified as disease-causing mutations in patients with Nijmegen Breakage Syndrome (NBS), but their clinical impact on breast cancer susceptibility has remained uncertain. We determined the frequency of 2 NBS mutations, 657del5 and R215W, in two large series of breast cancer cases and controls from Northern Germany and from the Republic of Belarus. The 5-bp-deletion 657del5 was identified in 15/1,588 cases (0.9%) from Belarus and in 1/1,076 cases (0.1%) from Germany but in only 1/1,014 population controls from Belarus and 0/1017 German controls (p < 0.01). The missense substitution R215W was observed in 9/1,588 Byelorussian and 9/1,076 German patients (0.6% and 0.8%, respectively) but was also present in 5/1,014 Byelorussian and 2/1,017 German control individuals (adjusted OR = 1.9, 95%CI 0.8-4.6, p = 0.18). Studies of lymphoblastoid cell lines revealed that NBS1/p95 protein levels were reduced to 70% in cells from a heterozygous breast cancer patient carrying R215W and to 15% in cells from a NBS patient compound heterozygous for 657del5/R215W suggesting that the R215W substitution may be associated with protein instability. Levels of radiation-induced phosphorylation of Nbs1/p95(Ser343) were reduced to 60% and 35% of wildtype, respectively. Neither age at diagnosis nor family history of breast cancer differed significantly between carriers and noncarriers of NBS mutations. The combined data are in line with an about 3-fold increase in breast cancer risk for female NBS heterozygotes (OR 3.1; 95%CI 1.4-6.6) and indicate that the 657del5 deletion and perhaps the R215W substitution contribute to inherited breast cancer susceptibility in Central and Eastern Europe.

Mutation analysis of the MDM4 gene in German breast cancer patients.

BACKGROUND: MDM4 is a negative regulator of p53 and cooperates with MDM2 in the cellular response to DNA damage. It is unknown, however, whether MDM4 gene alterations play some role in the inherited component of breast cancer susceptibility. METHODS: We sequenced the whole MDM4 coding region and flanking untranslated regions in genomic DNA samples obtained from 40 German patients with familial breast cancer. Selected variants were subsequently screened by RFLP-based assays in an extended set of breast cancer cases and controls. RESULTS: Our resequencing study uncovered two MDM4 coding variants in 4/40 patients. Three patients carried a silent substitution at codon 74 that was linked with another rare variant in the 5'UTR. No association of this allele with breast cancer was found in a subsequent screening of 133 patients with bilateral breast cancer and 136 controls. The fourth patient was heterozygous for the missense substitution D153G which is located in a less conserved region of the MDM4 protein but may affect a predicted phosphorylation site. The D153G substitution only partially segregated with breast cancer in the family and was not identified on additional 680 chromosomes screened. CONCLUSION: This study did not reveal clearly pathogenic mutations although it uncovered two new unclassified variants at a low frequency. We conclude that there is no evidence for a major role of MDM4 coding variants in the inherited susceptibility towards breast cancer in German patients.

Prediction of prognosis regarding fractionation schedule and survival in patients with whole-brain radiotherapy for metastatic disease.

AIM: To look at differences between fractionation schedules regarding established prognostic factors in patients treated with whole-brain radiotherapy (WBRT) for metastasis and actual survival. PATIENTS AND METHODS: One hundred and forty-six patients with brain metastases treated with WBRT with three different fractionation schedules with respect to the single dose (SD) 20 x 2.0 Gy (SD2), 15 x 2.5 Gy (SD2.5) and 10 x 3 Gy (SD3) were included. RESULTS: The median overall survival in the SD2, SD2.5 and SD3 groups was 10.3, 10.3 and 5.5 months (p = 0.005) while in recursive partitioning analysis (RPA) classes I, II and III it was 16.7, 8.1 and 3.7 months, respectively (p < 0.0001). Statistically significant variables for overall survival were age (< 60 years, p < 0.0001) and primary site (breast, p = 0.049) in the univariate analysis, and age (p = 0.003) and RPA class (p < 0.0001) in the multivariate analysis. CONCLUSION: The dose fractionation schedule for WBRT of metastases adequately reflected the clinical estimate of more favourable prognosis. Reduced single doses due to neurocognitive decline may be considered in patients with RPA class I.

Preoperative versus postoperative chemoradiotherapy for rectal cancer.

BACKGROUND: Postoperative chemoradiotherapy is the recommended standard therapy for patients with locally advanced rectal cancer. In recent years, encouraging results with preoperative radiotherapy have been reported. We compared preoperative chemoradiotherapy with postoperative chemoradiotherapy for locally advanced rectal cancer. METHODS: We randomly assigned patients with clinical stage T3 or T4 or node-positive disease to receive either preoperative or postoperative chemoradiotherapy. The preoperative treatment consisted of 5040 cGy delivered in fractions of 180 cGy per day, five days per week, and fluorouracil, given in a 120-hour continuous intravenous infusion at a dose of 1000 mg per square meter of body-surface area per day during the first and fifth weeks of radiotherapy. Surgery was performed six weeks after the completion of chemoradiotherapy. One month after surgery, four five-day cycles of fluorouracil (500 mg per square meter per day) were given. Chemoradiotherapy was identical in the postoperative-treatment group, except for the delivery of a boost of 540 cGy. The primary end point was overall survival. RESULTS: Four hundred twenty-one patients were randomly assigned to receive preoperative chemoradiotherapy and 402 patients to receive postoperative chemoradiotherapy. The overall five-year survival rates were 76 percent and 74 percent, respectively (P=0.80). The five-year cumulative incidence of local relapse was 6 percent for patients assigned to preoperative chemoradiotherapy and 13 percent in the postoperative-treatment group (P=0.006). Grade 3 or 4 acute toxic effects occurred in 27 percent of the patients in the preoperative-treatment group, as compared with 40 percent of the patients in the postoperative-treatment group (P=0.001); the corresponding rates of long-term toxic effects were 14 percent and 24 percent, respectively (P=0.01). CONCLUSIONS: Preoperative chemoradiotherapy, as compared with postoperative chemoradiotherapy, improved local control and was associated with reduced toxicity but did not improve overall survival.

Escalation of radiation dose beyond 30 Gy in 10 fractions for metastatic spinal cord compression.

PURPOSE: In many centers worldwide, radiotherapy for metastatic spinal cord compression (MSCC) is performed with 30 Gy in 10 fractions. This study investigated the potential benefit of dose escalation. METHODS AND MATERIALS: Data from 922 patients with carcinomas causing MSCC were retrospectively evaluated. The outcome of 345 patients treated with 10 fractions of 3 Gy in 2 weeks was compared with the outcomes of 577 patients treated with 37.5 Gy in 15 fractions within 3 weeks or 40 Gy in 20 fractions within 4 weeks. Additionally, 10 potential prognostic factors were investigated: age, gender, performance status, tumor type, interval between cancer diagnosis and MSCC, number of involved vertebrae, other bone and visceral metastases, ambulatory status, and the interval to the development of motor deficits before radiotherapy. RESULTS: Motor function improved in 19% of patients after 30 Gy in 10 fractions and in 22% after greater doses (p = 0.31). The local control (p = 0.28) and survival (p = 0.85) rates were not significantly different with doses >30 Gy. Better functional outcome was associated with the absence of visceral metastases, an interval between tumor diagnosis and MSCC of >12 months, ambulatory status, and an interval to the development of motor deficits of >7 days. Improved local control was significantly associated with no visceral metastases, improved survival with favorable histologic features (breast or prostate cancer), no visceral metastases, ambulatory status, an interval between cancer diagnosis and MSCC of >12 months, and an interval to the development of motor deficits of >7days. CONCLUSION: Escalation of the radiation dose to >30 Gy in 10 fractions did not improve the outcomes in terms of motor function, local control, or survival but did increase the treatment time for these frequently debilitated patients. Therefore, doses >30 Gy in 10 fractions are not recommended.

Improved posttreatment functional outcome is associated with better survival in patients irradiated for metastatic spinal cord compression.

PURPOSE: To evaluate the potential prognostic impact of the effect of radiotherapy (RT) on motor function and of the post-RT ambulatory status on survival in metastatic spinal cord compression (MSCC) patients. METHODS AND MATERIALS: Of 1,852 patients irradiated for MSCC, 778 patients (42%) received short-course RT and 1,074 (58%) received long-course RT. The effect of RT on motor function (improvement vs. no change vs. deterioration) and the ambulatory status after RT (ambulatory vs. nonambulatory) were evaluated with respect to survival. RESULTS: The actuarial survival rate of the entire cohort was 56% at 6 months, 43% at 12 months, and 32% at 24 months. The patients in whom motor function improved after RT had a significantly better 1-year survival rate than those who had no change or deterioration of motor function (75% vs. 40% and 3%, p < 0.001). The 1-year survival rate of the patients who were ambulatory after RT was significantly better than for those who were not ambulatory (63% vs. 4%, p < 0.001). The results were confirmed in multivariate analysis. CONCLUSIONS: The response to RT and the post-RT ambulatory status are important predictors for survival in MSCC patients. This finding can be used by physicians to stratify future studies, plan further therapy, and improve follow-up strategy in these patients.