Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis.

Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P < 5 × 10-8) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 (TERT), 5q35.2 (FGFR4) and 11q22.3 (ATM). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis.

Estimation of the risk for radiation-induced liver disease following photon- or proton-beam radiosurgery of liver metastases.

BACKGROUND: Radiotherapy of liver metastases is commonly being performed with photon-beam based stereotactic body radiation therapy (SBRT). The high risk for radiation-induced liver disease (RILD) is a limiting factor in these treatments. The use of proton-beam based SBRT could potentially improve the sparing of the healthy part of the liver. The aim of this study was to use estimations of normal tissue complication probability (NTCP) to identify liver-metastases patients that could benefit from being treated with intensity-modulated proton therapy (IMPT), based on the reduction of the risk for RILD. METHODS: Ten liver metastases patients, previously treated with photon-beam based SBRT, were retrospectively planned with IMPT. A CTV-based robust optimisation (accounting for setup and range uncertainties), combined with a PTV-based conventional optimisation, was performed. A robustness criterion was defined for the CTV (V95% > 98% for at least 10 of the 12 simulated scenarios). The NTCP was estimated for different endpoints using the Lyman-Kutcher-Burman model. The ΔNTCP (NTCPIMPT - NTCPSBRT) for RILD was registered for each patient. The patients for which the NTCP (RILD) < 5% were also identified. A generic relative biological effectiveness of 1.1 was assumed for the proton beams. RESULTS: For all patients, the objectives set for the PTV and the robustness criterion set for the CTV were fulfilled with the IMPT plans. An improved sparing of the healthy part of the liver, right kidney, lungs, spinal cord and the skin was achieved with the IMPT plans, compared to the SBRT plans. Mean liver doses larger than the threshold value of 32 Gy led to NTCP values for RILD exceeding 5% (7 patients with SBRT and 3 patients with the IMPT plans). ΔNTCP values (RILD) ranging between - 98% and - 17% (7 patients) and between 0 and 2% (3 patients), were calculated. CONCLUSIONS: In this study, liver metastases patients that could benefit from being treated with IMPT, based on the NTCP reductions, were identified. The clinical implementation of such a model-based approach to select liver metastases patients to proton therapy needs to be made with caution while considering the uncertainties involved in the NTCP estimations.

No evidence of association of oxytocin polymorphisms with breastfeeding in 2 independent samples.

Oxytocin has an important function in breastfeeding via its role in the milk ejection reflex and in attachment and bonding processes. Genetic factors account for a significant part of the individual differences in breastfeeding behavior. OXT and OXTR have been proposed as gene candidates for breastfeeding. Previous studies have focused on certain single-nucleotide polymorphisms (SNPs) within these genes, finding null or inconsistent results. The present study analyses the associations between a wide coverage of polymorphisms in OXT and OXTR and breastfeeding duration from 2 large and independent unselected samples comprising a total of 580 and 2112 female twin mothers from the Murcia Twin Registry (Spain) and QIMR Berghofer Medical Research Institute (Australia), respectively. A total of 19 SNPs in OXT and 137 in OXTR SNPs were covered in both samples. Effects of the OXT and OXTR polymorphisms on breastfeeding duration were calculated by means of linear regression controlling for age at survey time, educational level, interaction between age and educational level and principal components of genetic ancestry. The analyses were conducted independently in the 2 samples and also meta-analyzed. Although some SNPs were associated at an alpha level of .05 with breastfeeding, they did not survive multiple testing correction. We conclude that SNPs within or nearby OXT and OXTR are unlikely to have large effects on breastfeeding behavior.

Genome-wide association study of pathological gambling.

BACKGROUND: Pathological gambling is a behavioural addiction with negative economic, social, and psychological consequences. Identification of contributing genes and pathways may improve understanding of aetiology and facilitate therapy and prevention. Here, we report the first genome-wide association study of pathological gambling. Our aims were to identify pathways involved in pathological gambling, and examine whether there is a genetic overlap between pathological gambling and alcohol dependence. METHODS: Four hundred and forty-five individuals with a diagnosis of pathological gambling according to the Diagnostic and Statistical Manual of Mental Disorders were recruited in Germany, and 986 controls were drawn from a German general population sample. A genome-wide association study of pathological gambling comprising single marker, gene-based, and pathway analyses, was performed. Polygenic risk scores were generated using data from a German genome-wide association study of alcohol dependence. RESULTS: No genome-wide significant association with pathological gambling was found for single markers or genes. Pathways for Huntington's disease (P-value=6.63×10(-3)); 5'-adenosine monophosphate-activated protein kinase signalling (P-value=9.57×10(-3)); and apoptosis (P-value=1.75×10(-2)) were significant. Polygenic risk score analysis of the alcohol dependence dataset yielded a one-sided nominal significant P-value in subjects with pathological gambling, irrespective of comorbid alcohol dependence status. CONCLUSIONS: The present results accord with previous quantitative formal genetic studies which showed genetic overlap between non-substance- and substance-related addictions. Furthermore, pathway analysis suggests shared pathology between Huntington's disease and pathological gambling. This finding is consistent with previous imaging studies.

Survival benefit and additional value of preoperative chemoradiotherapy in resectable gastric and gastro-oesophageal junction cancer: a direct and adjusted indirect comparison meta-analysis.

Several phase I/II studies of chemoradiotherapy for gastric cancer have reported promising results, but the significance of preoperative radiotherapy in addition to chemotherapy has not been proven. In this study, a systematic literature search was performed to capture survival and postoperative morbidity and mortality data in randomised clinical studies comparing preoperative (chemo)radiotherapy or chemotherapy versus surgery alone, or preoperative chemoradiotherapy versus chemotherapy for gastric and/or gastro-oesophageal junction (GOJ) cancer. Hazard ratios (HRs) for overall mortality were extracted from the original studies, individual patient data provided from the principal investigators of eligible studies or the earlier published meta-analysis. The incidences of postoperative morbidities and mortalities were also analysed. In total 18 studies were eligible and data were available from 14 of these. The meta-analysis on overall survival yielded HRs of 0.75 (95% CI 0.65-0.86, P < 0.001) for preoperative (chemo)radiotherapy and 0.83 (95% CI 0.67-1.01, P = 0.065) for preoperative chemotherapy when compared to surgery alone. Direct comparison between preoperative chemoradiotherapy and chemotherapy resulted in an HR of 0.71 (95% CI 0.45-1.12, P = 0.146). Combination of direct and adjusted indirect comparisons yielded an HR of 0.86 (95% CI 0.69-1.07, P = 0.171). No statistically significant differences were seen in the risk for postoperative morbidity or mortality between preoperative treatments and surgery alone, or preoperative (chemo)radiotherapy and chemotherapy. Preoperative (chemo)radiotherapy for gastric and GOJ cancer showed significant survival benefit over surgery alone. In comparisons between preoperative chemotherapy and (chemo)radiotherapy, there is a trend towards improved survival when adding radiotherapy, without increased postoperative morbidity or mortality.

Quality of life in patients with advanced gastric cancer sequentially treated with docetaxel and irinotecan with 5-fluorouracil and folinic acid (leucovin).

With a median overall survival of only 9-13 months in patients with advanced gastric cancer (GC), the quality of life (QoL) during the palliative treatment remains a key issue. Furthermore, when combinations of two or three drugs are used, the impact on QoL should be carefully evaluated. This was studied within the GATAC trial in patients sequentially treated with docetaxel and irinotecan with 5-fluorouracil and leucovorin (5-Fu/Lv). Patients with previously untreated advanced GC were randomly assigned to start with docetaxel 45 mg/m(2) (arm T) or irinotecan 180 mg/m(2) (arm C) with bolus and 44 h infusion of 5-Fu/Lv (D1, q2 weeks). After four courses, there was a prescheduled crossover to the alternative regimen for four additional courses. QoL was measured with the EORTC QLQ-C30 questionnaire at the start of the treatment, at crossover and after completing treatment with both regimens. Eighty-one patients were randomized, and 78 patients started treatment. A total of 191 completed QoL questionnaires were collected. There were no statistically significant differences in QoL scores between the two treatment groups and no changes in mean scores during the 16 weeks of treatment. During the last 8 weeks of treatment, a significantly larger portion of patients with radiological response reported sustained or better QoL scores than those with no radiological response (82 vs. 50%, p = 0.007). Chemotherapy in advanced GC did not affect QoL average scores. Patients with non-responding tumours reported more often a decline in the global QoL score. The concept of the pre-scheduled switch of chemotherapy regimens prior to progression should be further studied in this disease, as it appears effective, tolerable and not to negatively affect QoL.

Dyslexia and DYX1C1: deficits in reading and spelling associated with a missense mutation.

The status of DYX1C1 (C15q21.3) as a susceptibility gene for dyslexia is unclear. We report the association of this gene with reading and spelling ability in a sample of adolescent twins and their siblings. Family-based association analyses were carried out on 13 single-nucleotide polymorphisms (SNPs) in DYX1C1, typed in 790 families with up to 5 offspring and tested on 6 validated measures of lexical processing (irregular word) and grapheme-phoneme decoding (pseudo-word) reading- and spelling-based measures of dyslexia, as well as a short-term memory measure. Significant association was observed at the misssense mutation rs17819126 for all reading measures and for spelling of lexical processing words, and at rs3743204 for both irregular and nonword reading. Verbal short-term memory was associated with rs685935. Support for association was not found at rs3743205 and rs61761345 as previously reported by Taipale et al., but these SNPs had very low (0.002 for rs3743205) minor allele frequencies in this sample. These results suggest that DYX1C1 influences reading and spelling ability with additional effects on short-term information storage or rehearsal. Missense mutation rs17819126 is a potential functional basis for the association of DYX1C1 with dyslexia.

Variation in the dysbindin gene and normal cognitive function in three independent population samples.

The association between DTNBP1 genotype and cognitive abilities was investigated in three population samples (1054 Scottish, 1806 Australian and 745 English) of varying age. There was evidence in each of the cohorts for association (P < 0.05) to single nucleotide polymorphisms (SNPs) and haplotypes previously shown to relate to cognition. By comparison with previous findings, these associations included measures of memory, and there was at best equivocal evidence of association with general cognitive ability. Of the SNPs typed in all three cohorts, rs2619528 and rs1011313 showed significant association with measures of executive function in two cohorts, rs1018381 showed significant association with verbal ability in one cohort and rs2619522 showed significance/marginal significance with tests of memory, speed and executive function in two cohorts. For all these SNPs, the direction and magnitude of the allelic effects were consistent between cohorts and with previous findings. In the English cohort, a previously untested SNP (rs742105) located in a distinct haplotype block upstream of the other SNPs showed the strongest significance (P < 0.01) for measures of memory but weaker significance for general cognitive ability. Our results therefore support involvement of the dysbindin gene in cognitive function, but further work is needed to clarify the specific functional variants involved and the cognitive abilities with which they are associated.

Replication of the association of common rs9939609 variant of FTO with increased BMI in an Australian adult twin population but no evidence for gene by environment (G x E) interaction.

OBJECTIVE: To further investigate a common variant (rs9939609) in the fat mass- and obesity-associated gene (FTO), which recent genome-wide association studies have shown to be associated with body mass index (BMI) and obesity. DESIGN: We examined the effect of this FTO variant on BMI in 3353 Australian adult male and female twins. RESULTS: The minor A allele of rs9939609 was associated with an increased BMI (P=0.0007). Each additional copy of the A allele was associated with a mean BMI increase of approximately 1.04 kg/m(2) (approximately 3.71 kg). Using variance components decomposition, we estimate that this single-nucleotide polymorphism accounts for approximately 3% of the genetic variance in BMI in our sample (approximately 2% of the total variance). By comparing intrapair variances of monozygotic twins of different genotypes we were able to perform a direct test of gene by environment (G x E) interaction in both sexes and gene by parity (G x P) interaction in women, but no evidence was found for either. CONCLUSIONS: In addition to supporting earlier findings that the rs9939609 variant in the FTO gene is associated with an increased BMI, our results indicate that the associated genetic effect does not interact with environment or parity.

LRRTM1 on chromosome 2p12 is a maternally suppressed gene that is associated paternally with handedness and schizophrenia.

Left-right asymmetrical brain function underlies much of human cognition, behavior and emotion. Abnormalities of cerebral asymmetry are associated with schizophrenia and other neuropsychiatric disorders. The molecular, developmental and evolutionary origins of human brain asymmetry are unknown. We found significant association of a haplotype upstream of the gene LRRTM1 (Leucine-rich repeat transmembrane neuronal 1) with a quantitative measure of human handedness in a set of dyslexic siblings, when the haplotype was inherited paternally (P=0.00002). While we were unable to find this effect in an epidemiological set of twin-based sibships, we did find that the same haplotype is overtransmitted paternally to individuals with schizophrenia/schizoaffective disorder in a study of 1002 affected families (P=0.0014). We then found direct confirmatory evidence that LRRTM1 is an imprinted gene in humans that shows a variable pattern of maternal downregulation. We also showed that LRRTM1 is expressed during the development of specific forebrain structures, and thus could influence neuronal differentiation and connectivity. This is the first potential genetic influence on human handedness to be identified, and the first putative genetic effect on variability in human brain asymmetry. LRRTM1 is a candidate gene for involvement in several common neurodevelopmental disorders, and may have played a role in human cognitive and behavioral evolution.

Pulmonary complications following different radiotherapy techniques for breast cancer, and the association to irradiated lung volume and dose.

PURPOSE: This study investigates the incidence of short-term pulmonary complications following radiotherapy (RT) for breast cancer (BC) with different treatment techniques/incidentally irradiated lung volumes and the importance of confounding factors on RT-induced pulmonary complications. PATIENTS AND METHODS: Prospectively, 475 patients with BC were followed for pulmonary complications 1, 4 and 7 months post-RT. Mean lung dose volume histograms (MDVH) were constructed and compared for the different RT-techniques. Among a subset of the mastectomized patients treated with loco-regional (LR-) RT, who had undergone complete three-dimensional (3-D) dose planning (n = 43), MDVH for asymptomatic patients was compared with MDVH for patients experiencing both radiological and clinical pulmonary side-effects. RESULTS: Moderate pulmonary complications, that is requiring treatment with corticosteroids, were rare following local RT (< 1%), but were diagnosed among 11% of the patients treated with LR-RT. A correlation between increasing irradiated lung volumes at the >20 Gy-level (V20), based on MDVH for the RT-techniques, and pulmonary complications was found (P < 0.001). Furthermore, increasing age and reduced pre-RT functional level were independently associated with a higher rate of pulmonary complications (P = 0.005 and P = 0.018). Among the subgroup of mastectomized patients treated with LR-RT, who had undergone complete 3-D dose planning, a difference in mean V20 was found between patients experiencing both clinical and radiological pulmonary side-effects compared to patients experiencing neither of the two side-effects (P = 0.007). CONCLUSION: Moderate pulmonary complications following local RT for BC are rare. The incidence of short-term moderate pulmonary complications in LR-RT is, however, clinically significant and to define quality assurance guidelines for these RT-techniques, 3-D RT planning can be used.

Radiation-induced pulmonary toxicity: a dose-volume histogram analysis in 201 patients with lung cancer.

PURPOSE: To relate lung dose-volume histogram-based factors to symptomatic radiation pneumonitis (RP) in patients with lung cancer undergoing 3-dimensional (3D) radiotherapy planning. METHODS AND MATERIALS: Between 1991 and 1999, 318 patients with lung cancer received external beam radiotherapy (RT) with 3D planning tools at Duke University Medical Center. One hundred seventeen patients were not evaluated for RP because of <6 months of follow-up, development of progressive intrathoracic disease making scoring of pulmonary symptoms difficult, or unretrievable 3D dosimetry data. Thus, 201 patients were analyzed for RP. Univariate and multivariate analyses were performed to test the association between RP and dosimetric factors (i.e., mean lung dose, volume of lung receiving >or=30 Gy, and normal tissue complication probability derived from the Lyman and Kutcher models) and clinical factors, including tobacco use, age, sex, chemotherapy exposure, tumor site, pre-RT forced expiratory volume in 1 s, weight loss, and performance status. RESULTS: Thirty-nine patients (19%) developed RP. In the univariate analysis, all dosimetric factors (i.e., mean lung dose, volume of lung receiving >or=30 Gy, and normal tissue complication probability) were associated with RP (p range 0.006-0.003). Of the clinical factors, ongoing tobacco use at the time of referral for RT was associated with fewer cases of RP (p = 0.05). These factors were also independently associated with RP according to the multivariate analysis (p = 0.001). Models predictive for RP based on dosimetric factors only, or on a combination with the influence of tobacco use, had a concordance of 64% and 68%, respectively. CONCLUSIONS: Dosimetric factors were the best predictors of symptomatic RP after external beam RT for lung cancer. Multivariate models that also include clinical variables were slightly more predictive.

A practical and easy method to locate the first three internal mammary lymph node-bearing areas.

PURPOSE: To assess the distance from a clinically recognized anatomic landmark to the different costocondral interspaces in female patients to facilitate the design of radiation fields intended to include specific internal mammary nodal areas. METHODS AND MATERIALS: The distance from the suprasternal notch (SSN) to the caudal portion of the first through fourth interspace was measured on a computer display of the chest skeleton of 65 female patients with left-sided breast cancer. The relationship between these distances and bone size (sternal length and standing height) was assessed via linear regression. In 21 of the 65 patients where myocardial perfusion imaging of the heart was available, the relationship between the location of the 3rd costochondral interspace and the left ventricle was assessed. RESULTS: In 90% of patients (59/65), the first, second, third, and fourth interspace were within 5, 8.5, 11, and 14 cm of the SSN, respectively. The SSN-interspace distances did not correlate well with sternal length (r = 0.28) or standing height (r = 0.31). In 20 of 21 patients (95%), the third interspace "shadowed" the cephalad aspect of the left heart ventricle. Median "shadowing" was 3 cm (range 0.5-6 cm). CONCLUSION: The caudal portion of the third costochondral interspace is < or = 11 cm caudal to the SSN in 90% of patients. These measurements can be used to clinically design radiation therapy fields intended to treat the upper three interspaces. The distance from the SSN to the 1st through 4th interspaces is not related to sternal length or to standing height. In patients with left-sided breast cancer, radiation treatment fields designed to include the internal mammary lymph nodes in the upper three interspaces may incidentally include a portion of the heart.

Abnormalities on chest radiographs following radiation therapy for breast cancer.

The aim of this study was to study pulmonary radiological abnormalities with chest radiography following different radiotherapy (RT) techniques for breast cancer with respect to regions and density, and their association with pulmonary complications and reduction in vital capacity (VC). Chest radiographs were performed 5 months following local or loco-regional RT in 167 breast cancer patients. The radiological abnormalities were analysed with a classification system originally proposed by Arriagada and evaluated according to increasing density (0-3) and affected lung regions (apical-lateral, basal-lateral, central-parahilar). The highest-density grades in each region were added together to form scores ranging from 0 to 9. The patients were monitored for RT-induced pulmonary complications. The VC was measured prior to and 5 months following RT. An independent evaluation of 51 patients was performed by a second radiologist to control the reproducibility of the classification system. Increasing scores were associated with loco-regional RT and pulmonary complications (P < 0.001). The mean reduction of VC for patients scoring 0-3 (-30 ml) vs 4-9 (-161 ml) was not statistically significant (P = 0.10). Scores of 4-9 were more frequently observed in older patients (P < 0.001). The independent evaluations by two radiologists revealed good agreement (P < 0.001) and no systematic inter-observer variation. Radiological abnormalities on chest radiographs, scored according to Arriagada, can be used as an objective end point for RT-induced pulmonary side effects in breast cancer.

Abnormalities by pulmonary regions studied with computer tomography following local or local-regional radiotherapy for breast cancer.

PURPOSE: To study pulmonary radiological abnormalities with computer tomography (CT) following different radiotherapy (RT) techniques for breast cancer with respect to regions and density, and their correlation to pulmonary complications and reduction in vital capacity (VC). METHODS AND MATERIALS: CT scans of the lungs were performed prior to and 4 months following RT in 105 breast cancer patients treated with local or local-regional RT. The radiological abnormalities were analyzed with a CT-adapted modification of a classification system originally proposed by Arriagada, and scored according to increasing density (0-3) and affected lung regions (apical-lateral, central-parahilar, basal-lateral). The highest density grade in each region were added together to form scores ranging from 0-9. The patients were monitored for RT-induced pulmonary complications. VC was measured prior to and 5 months following RT. RESULTS: Increasing CT scores were correlated with both local-regional RT and pulmonary complications (p < 0.001). The mean reduction of VC for patients scoring 4-9 (-202 ml) was larger than for patients scoring 0-3 (-2 ml) (p = 0.035). The effect of confounding factors on the radiological scoring was tested in the local-regional RT group. Scores of 4-9 were less frequently seen in the patients who had received adjuvant chemotherapy prior to RT. The importance of the respective lung regions on the outcome of pulmonary complications was tested. Only radiological abnormalities in the central-parahilar and apical-lateral regions were significantly correlated to pulmonary complications. DISCUSSION: Radiological abnormalities detected on CT images and scored with a modification of Arriagada's classification system can be used as an objective endpoint for pulmonary side effects in breast cancer. The described model should, however, be expanded with information about the volume of lung affected in each region before definite conclusions can be drawn concerning each region's relative importance for the development of pulmonary complications. The negative association between sequential chemotherapy and radiological abnormalities should be confirmed in future studies.

Pulmonary function following adjuvant chemotherapy and radiotherapy for breast cancer and the issue of three-dimensional treatment planning.

BACKGROUND AND PURPOSE: The frequency and grade of pulmonary complications following adjuvant radiotherapy for breast cancer are still debated. This study focuses on loss of pulmonary function. MATERIALS AND METHODS: We have measured the reduction of pulmonary function 5 months following radiotherapy in 144 node-positive stage II breast cancer patients by using pulmonary function tests. RESULTS: No deterioration of pulmonary function was detected among the patients who were treated with local radiotherapy. On the contrary, there was a mean increase in diffusion capacity by 7% (P = 0.004) following radiotherapy, which most likely was explained by the adjuvant chemotherapy administered prior to the baseline pulmonary function tests. Patients undergoing loco-regional radiotherapy showed a mean reduction in diffusion capacity by 5% (P < 0.001) and in vital capacity by 3% (P = 0.001). The subset of patients (9%) who were diagnosed with severe pulmonary complications needing cortisone treatment had significantly larger mean paired differences in vital capacity (-0.446 L, -15% (equivalent to 15 years of normal ageing or the loss of 3/4 of a lung lobe)) compared to the patients who were asymptomatic (-0.084 L) (P < 0.05). When the effects of potential confounding factors and different radiotherapy techniques were tested on the reduction of pulmonary function by stepwise multiple regression analysis, a significant correlation was found only to locoregional radiotherapy including the lower internal mammary lymph nodes. CONCLUSIONS: We conclude that a clinically important reduction of pulmonary function is seen in the subset of patients who are diagnosed with severe pulmonary complication following loco-regional radiotherapy for breast cancer. The results of this study warrant further studies based on individual lung dose volume histograms.

A descriptive study of pulmonary complications after postoperative radiation therapy in node-positive stage II breast cancer.

This study was conducted to assess the frequencies of symptomatic pulmonary complications following adjuvant postoperative radiotherapy using different treatment techniques in patients with Stage II node-positive breast cancer. During 1991-1993, 177 patients were referred to the Radiotherapy Department of Stockholm Söder Hospital; 144 after modified radical mastectomy and 33 after partial mastectomy. The records of these patients were studied retrospectively for clinically diagnosed radiotherapy-induced lung complications 1-7 months after treatment. Thirty-three of 138 patients (24%) irradiated after modified radical mastectomy developed pulmonary complications and 20 (14%) of these were diagnosed as severe, i.e. needing medical treatment with corticosteroids. No statistically significant difference could be found between the different electron energies used for treating the chest wall and the frequency of respiratory side-effects. Eighteen of 33 patients completed the prescribed treatment after partial mastectomy. Nine of these 18 patients (50%) developed pulmonary complications and 4 (22%) developed severe reactions. Fifteen patients received alternative treatments. With the techniques used after partial mastectomy the median central lung distance was 32 mm among the patients who experienced respiratory side-effects compared with 25 mm among the patients who were not affected (p = 0.03). This study identifies acute/subacute pulmonary side-effects as a clinically significant problem. Prospective follow-up with lung function tests, identification of risk factors, and individual lung dose volume histograms is warranted to assess the long-term implications.