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ABSTRACT: 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.
BJU International 01/2013; · 2.84 Impact Factor
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Tomas Kirchhoff,
Mia M Gaudet,
Antonis C Antoniou,
Lesley Mcguffog,
Manjeet K Humphreys,
Alison M Dunning,
Stig E Bojesen,
Børge G Nordestgaard,
Henrik Flyger,
Daehee Kang, [......],
Jackie Cook,
Fiona Douglas,
Shirley Hodgson,
D Gareth Evans,
Rosalind Eeles,
Bert Gold,
Paul D P Pharoah,
Kenneth Offit,
Georgia Chenevix-Trench,
Douglas F Easton
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ABSTRACT: AM), 9 Gene Environment Interaction and Breast Cancer in Germany (GENICA): Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University Tü bingen, Stuttgart and Tü bingen, Germany (HB, Christina Justenhoven); Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum, Heidelberg, Germany (UH); Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany (YDK,); Institute of Pathology, Medical Faculty of the University of Bonn, Bonn, Germany (Hans-Peter Fischer); Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Bochum, Germany (Thomas Brü ning, Beate Pesch, Volker Harth, Sylvia Rabstein), 10 Amsterdam Breast Cancer Study (ABCS): Netherlands Cancer Institute, Departments of Experimental Therapy, Epidemiology and Molecular Pathology, Amsterdam, The Netherlands (AB, MKS, LJVV, LMB), 11 British Breast Cancer Study (BBCS):
PLoS ONE 06/2012; 6(7). · 4.09 Impact Factor
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ABSTRACT: 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.
Ziel:
Wirksamkeit und Verträglichkeit der moderat dosierten stereotaktischen Einzeitbestrahlung (SRS) bei limitierten (ein bis vier)
Hirnmetastasen sollte am eigenen Patientenkollektiv untersucht und mit patienten- und behandlungsbezogenen Parametern verglichen
werden.
Patienten und Methodik:
Von 05/1998 bis 10/2006 erhielten 93 Patienten eine SRS von 142 Hirnmetastasen. Median wurde pro Patient eine Hirnmetastase
bestrahlt (Streubreite: ein bis vier). Bei 46 Patienten (49%) erfolgte die SRS als alleinige Primärtherapie, bei 13 Patienten
(14%) mit früher Ganzhirnbestrahlung (WBRT) und bei 34 Patienten (37%) wegen einer Rezidivmetastase nach WBRT. Die Dosis betrug
median 16 Gy (Streubreite: 10–20 Gy).
Ergebnisse:
Das Gesamtüberleben nach SRS lag bei median 7,5 Monaten. Nach 6 bzw. 12 Monaten betrugen das Gesamtüberleben (OS) aktuarisch
60% und 35%, die lokale Kontrolle (LBC) 87% und 79% sowie die distale zerebrale Kontrolle (DBC) 48% und 37%. Nur zehn von
46 Patienten (22%) mit alleiniger SRS erhielten später eine WBRT. Zehn Patienten hatten Krampfanfälle innerhalb von 3 Monaten
nach SRS, sechs davon zeigten im Magnetresonanztomogramm einen zerebralen Progress. 20 Patienten benötigten ein Wiedereinsetzen
von Steroiden nach der SRS, 16 davon wegen zerebralem Progress. Bei fünf Patienten wurde eine Positronenemissionstomographie
des Kopfes durchgeführt, bei zwei wurde eine Radionekrose diagnostiziert. In der uni- und multivariaten Analyse hatten nur
das Zeitintervall zwischen Diagnose von Primärtumor und Hirnmetastase (p = 0,031) und das Volumen der bestrahlten Metastase
(p = 0,02) signifikanten Einfluss auf das Überleben. Weder der frühe Einsatz der WBRT noch die Dosis beeinflussten die LBC
signifikant.
Schlussfolgerung:
Die moderat dosierte SRS bei limitierter Hirnmetastasierung war ausreichend wirksam und verträglich. Die alleinige primäre
SRS eignet sich für informierte Patienten, die zu MRT-basierten Verlaufskontrollen bereit sind.
Key Words:
Radiosurgery-Brain metastases-Moderate dose-Outcome data
Schlüsselwörter:
Stereotaktische Einzeitbestrahlung-Hirnmetastasen-Moderate Dosis-Behandlungsergebnisse
Strahlentherapie und Onkologie 04/2012; 186(2):76-81. · 3.56 Impact Factor
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Diether Lambrechts,
Therese Truong,
Christina Justenhoven,
Manjeet K Humphreys,
Jean Wang,
John L Hopper,
Gillian S Dite,
Carmel Apicella,
Melissa C Southey,
Marjanka K Schmidt, [......],
Daehee Kang,
Keun-Young Yoo,
Dong-Young Noh,
Annika Lindblom,
Sara Margolin,
Alison M Dunning,
Paul D P Pharoah,
Douglas F Easton,
Pascal Guénel,
Hiltrud Brauch
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ABSTRACT: A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P ≤ 3 × 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 × 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype.
Human Mutation 03/2012; 33(7):1123-32. · 5.69 Impact Factor
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ABSTRACT: The aim of this study is to determine prognostic factors that influence further outcome in patients with glioma.
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.
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.
We were able to recognize grade and use of chemotherapy as statistically significant prognostic determinants, but not time intervals or overall treatment time.
Clinical neurology and neurosurgery 01/2012; 114(6):617-21. · 1.30 Impact Factor
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Rebecca Hein,
Melanie Maranian,
John L Hopper,
Miroslaw K Kapuscinski,
Melissa C Southey,
Daniel J Park,
Marjanka K Schmidt,
Annegien Broeks,
Frans B L Hogervorst,
H Bas Bueno-de-Mesquit, [......],
Polly A Newcomb,
Linda Titus,
Kathleen M Egan,
Georgia Chenevix-Trench,
Antonis C Antoniou,
Manjeet K Humphreys,
Jonathan Morrison,
Jenny Chang-Claude,
Douglas F Easton,
Alison M Dunning
PLoS ONE 01/2012; 7(10). · 4.09 Impact Factor
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Maya Ghoussaini,
Olivia Fletcher,
Kyriaki Michailidou,
Clare Turnbull,
Marjanka K Schmidt,
Ed Dicks,
Joe Dennis,
Qin Wang,
Manjeet K Humphreys,
Craig Luccarini, [......],
Susan M Gerty,
Nikki J Graham,
Bruce A J Ponder,
Georgia Chenevix-Trench,
Paul D P Pharoah,
Mark Lathrop,
Alison M Dunning,
Nazneen Rahman,
Julian Peto,
Douglas F Easton
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ABSTRACT: Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.
Nature Genetics 01/2012; 44(3):312-8. · 35.53 Impact Factor
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Tomas Kirchhoff,
Mia M Gaudet,
Antonis C Antoniou,
Lesley McGuffog,
Manjeet K Humphreys,
Alison M Dunning,
Stig E Bojesen,
Børge G Nordestgaard,
Henrik Flyger,
Daehee Kang, [......],
Jackie Cook,
Fiona Douglas,
Shirley Hodgson,
D Gareth Evans,
Rosalind Eeles,
Bert Gold,
Paul D P Pharoah,
Kenneth Offit,
Georgia Chenevix-Trench,
Douglas F Easton
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ABSTRACT: 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.
PLoS ONE 01/2012; 7(6):e35706. · 4.09 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
Onkologie 01/2012; 35(7-8):408-12. · 0.87 Impact Factor
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Rebecca Hein,
Melanie Maranian,
John L Hopper,
Miroslaw K Kapuscinski,
Melissa C Southey,
Daniel J Park,
Marjanka K Schmidt,
Annegien Broeks,
Frans B L Hogervorst,
H Bas Bueno-de-Mesquit, [......],
Polly A Newcomb,
Linda Titus,
Kathleen M Egan,
Georgia Chenevix-Trench,
Antonis C Antoniou,
Manjeet K Humphreys,
Jonathan Morrison,
Jenny Chang-Claude,
Douglas F Easton,
Alison M Dunning
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ABSTRACT: The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 × 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 × 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 × 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 × 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 × 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 × 10(-7), p(heterogeneity) = 5.1 × 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.
PLoS ONE 01/2012; 7(8):e42380. · 4.09 Impact Factor
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ABSTRACT: 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.
Case reports in oncological medicine. 01/2012; 2012:789640.
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ABSTRACT: 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.
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.
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).
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.
Strahlentherapie und Onkologie 11/2011; 187(11):729-35. · 3.56 Impact Factor
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Roger L Milne,
Ellen L Goode,
Montserrat García-Closas,
Fergus J Couch,
Gianluca Severi,
Rebecca Hein,
Zachary Fredericksen,
Núria Malats,
M Pilar Zamora,
Jose Ignacio Arias Pérez, [......],
Elza Khusnutdinova,
Marina Bermisheva,
Darya Prokofieva,
Albina Farahtdinova,
Janet E Olson,
Xianshu Wang,
Manjeet K Humphreys,
Qin Wang,
Georgia Chenevix-Trench,
Douglas F Easton
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ABSTRACT: 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.
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.
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)].
5p12 is a breast cancer susceptibility locus for PR-positive, lower grade breast cancer.
Multicenter fine-mapping studies of this region are needed as a first step to identifying the causal variant or variants.
Cancer Epidemiology Biomarkers & Prevention 08/2011; 20(10):2222-31. · 4.12 Impact Factor
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Dirk Rades,
Katja Freundt,
Thekla Meyners,
Amira Bajrovic,
Hiba Basic, Johann H Karstens,
Irenaeus A Adamietz,
Ingeborg Wildfang,
Volker Rudat,
Steven E Schild,
Juergen Dunst
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ABSTRACT: Radiotherapy alone is the most common treatment for metastatic spinal cord compression (MSCC) from relatively radioresistant tumors such as renal cell carcinoma, colorectal cancer, and malignant melanoma. However, the results of the "standard" regimen 30 Gy/10 fractions need to be improved with respect to functional outcome. This study investigated whether a dose escalation beyond 30 Gy can improve treatment outcomes.
A total of 91 patients receiving 30 Gy/10 fractions were retrospectively compared to 115 patients receiving higher doses (37.5 Gy/15 fractions, 40 Gy/20 fractions) for motor function and local control of MSCC. Ten further potential prognostic factors were evaluated: age, gender, tumor type, performance status, number of involved vertebrae, visceral or other bone metastases, interval from tumor diagnosis to radiotherapy, pretreatment ambulatory status, and time developing motor deficits before radiotherapy.
Motor function improved in 18% of patients after 30 Gy and in 22% after higher doses (p = 0.81). On multivariate analysis, functional outcome was associated with visceral metastases (p = 0.030), interval from tumor diagnosis to radiotherapy (p = 0.010), and time developing motor deficits (p < 0.001). The 1-year local control rates were 76% after 30 Gy and 80% after higher doses, respectively (p = 0.64). On multivariate analysis, local control was significantly associated with visceral metastases (p = 0.029) and number of involved vertebrae (p = 0.043).
Given the limitations of a retrospective study, escalation of the radiation dose beyond 30 Gy/10 fractions did not significantly improve motor function and local control of MSCC in patients with relatively radioresistant tumors.
International journal of radiation oncology, biology, physics 08/2011; 80(5):1492-7. · 4.59 Impact Factor
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ABSTRACT: 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.
Breast Cancer Research and Treatment 07/2011; 130(3):1021-8. · 4.43 Impact Factor
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Annegien Broeks,
Marjanka K Schmidt,
Mark E Sherman,
Fergus J Couch,
John L Hopper,
Gillian S Dite,
Carmel Apicella,
Letitia D Smith,
Fleur Hammet,
Melissa C Southey, [......],
Chia-Ni Hsiung,
Jyh-Cherng Yu,
Shou-Tung Chen,
Giu-Cheng Hsu,
Ming-Feng Hou,
Chiun-Sheng Huang,
Hoda Anton-Culver,
Argyrios Ziogas,
Paul D P Pharoah,
Montserrat Garcia-Closas
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ABSTRACT: 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.
Human Molecular Genetics 06/2011; 20(16):3289-303. · 7.64 Impact Factor
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Dirk Rades,
Sarah Douglas,
Stefan Huttenlocher,
Volker Rudat,
Theo Veninga,
Lukas J A Stalpers,
Hiba Basic, Johann H Karstens,
Peter J Hoskin,
Irenaeus A Adamietz,
Steven E Schild
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ABSTRACT: A score predicting post-radiotherapy (RT) ambulatory status was developed based on 2,096 retrospectively evaluated metastatic spinal cord compression (MSCC) patients. This study aimed to validate the score in a prospective series.
The score included five factors associated with post-RT ambulatory status: tumor type, interval tumor diagnosis to MSCC, visceral metastases, pre-RT motor function, time developing motor deficits. Patients were divided into five groups: 21-28, 29-31, 32-34, 35-37, 38-44 points. In this study, 653 prospectively followed patients were divided into the same groups. Furthermore, the number of prognostic groups was reduced from five to three (21-28, 29-37, 38-44 points). Post-RT ambulatory rates from this series were compared with the retrospective series. Additionally, this series was compared with 104 patients receiving decompressive surgery plus RT (41 laminectomy, 63 laminectomy plus stabilization of vertebrae).
In this study, post-RT ambulatory rates were 10.6% (21-28 points), 43.5% (29-31 points), 71.0% (32-34 points), 89.5% (35-37 points), and 98.5% (38-44 points). Ambulatory rates from the retrospective study were 6.2%, 43.5%, 70.0%, 86.1%, and 98.7%. After regrouping, ambulatory rates were 10.6% (21-28 points), 70.9% (29-37 points), and 98.5% (38-44 points) in this series, and 6.2%, 68.4%, and 98.7% in the retrospective series. Ambulatory rates were 0%, 62.5%, and 90.9% in the laminectomy plus RT group, and 14.3%, 83.9%, and 100% in the laminectomy + stabilization plus RT group.
Ambulatory rates in the different groups in this study were similar to those in the retrospective study demonstrating the validity of the score. Using only three groups is simpler for clinical routine.
International journal of radiation oncology, biology, physics 04/2011; 79(5):1503-6. · 4.59 Impact Factor
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Andreas Meyer,
Irina Coinac,
Natalia Bogdanova,
Natalia Dubrowinskaja,
Nurzhan Turmanov,
Sabine Haubold,
Peter Schürmann,
Florian Imkamp,
Christoph von Klot,
Axel S Merseburger,
Stefan Machtens,
Michael Bremer,
Peter Hillemanns,
Markus A Kuczyk, Johann H Karstens,
Jürgen Serth,
Thilo Dörk
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ABSTRACT: 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.
Urologic Oncology 03/2011; · 3.22 Impact Factor
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Xiaohong R Yang,
Jenny Chang-Claude,
Ellen L Goode,
Fergus J Couch,
Heli Nevanlinna,
Roger L Milne,
Mia Gaudet,
Marjanka K Schmidt,
Annegien Broeks,
Angela Cox, [......],
John L Hopper,
Fleur Hammet,
Helen Tsimiklis,
Letitia D Smith,
Melissa C Southey,
Manjeet K Humphreys,
Douglas Easton,
Paul Pharoah,
Mark E Sherman,
Montserrat Garcia-Closas
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ABSTRACT: Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors.
We pooled tumor marker and epidemiological risk factor data from 35,568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided.
In case-case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR(-) than PR(+) tumors (P = .001). Nulliparity (P = 3 × 10(-6)) and increasing age at first birth (P = 2 × 10(-9)) were less frequent in ER(-) than in ER(+) tumors. Obesity (body mass index [BMI] ≥ 30 kg/m(2)) in younger women (≤50 years) was more frequent in ER(-)/PR(-) than in ER(+)/PR(+) tumors (P = 1 × 10(-7)), whereas obesity in older women (>50 years) was less frequent in PR(-) than in PR(+) tumors (P = 6 × 10(-4)). The triple-negative (ER(-)/PR(-)/HER2(-)) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6(+) and/or epidermal growth factor receptor [EGFR](+)) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER(+) or PR(+) tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors.
This study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.
CancerSpectrum Knowledge Environment 02/2011; 103(3):250-63. · 14.07 Impact Factor
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ABSTRACT: 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.
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).
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).
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.
International journal of radiation oncology, biology, physics 01/2011; 81(5):e861-8. · 4.59 Impact Factor
