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1.  The cost of cancer care is not related to its outcomes 
ecancermedicalscience  2016;10:687.
Solid tumours make up 90% of all proliferative diseases and the main action for cure remains surgery, removing the visible tumour as well as the surrounding tissue. Radiotherapy is an added value for eliminating local microscopic as well as regional disease. Systemic treatment has a small impact on the outcome but has a cost, which is as much as all the other actions such as diagnostic tools and treatments.
PMCID: PMC5130330  PMID: 27994643
cost-effectiveness; surgery; radiotherapy; systemic treatment
2.  Signal transducer and activator of transcription 3 in myeloid-derived suppressor cells: an opportunity for cancer therapy 
Oncotarget  2016;7(27):42698-42715.
Cancer progression is in part determined by interactions between cancer cells and stromal cells in the tumor microenvironment (TME). The identification of cytotoxic tumor-infiltrating lymphocytes has instigated research into immune stimulating cancer therapies. Although a promising direction, immunosuppressive mechanisms exerted at the TME hamper its success. Myeloid-derived suppressor cells (MDSCs) have come to the forefront as stromal cells that orchestrate the immunosuppressive TME. Consequently, this heterogeneous cell population has been the object of investigation. Studies revealed that the transcription factor signal transducer and activator of transcription 3 (STAT3) largely dictates the recruitment, activation and function of MDSCs in the TME. Therefore, this review will focus on the role of this key transcription factor during the MDSC's life cycle and on the therapeutic opportunities it offers.
PMCID: PMC5173167  PMID: 27029037
MDSC; STAT3; T cell; immunotherapy; radiotherapy
3.  Initial characterization, dosimetric benchmark and performance validation of Dynamic Wave Arc 
Dynamic Wave Arc (DWA) is a clinical approach designed to maximize the versatility of Vero SBRT system by synchronizing the gantry-ring noncoplanar movement with D-MLC optimization. The purpose of this study was to verify the delivery accuracy of DWA approach and to evaluate the potential dosimetric benefits.
DWA is an extended form of VMAT with a continuous varying ring position. The main difference in the optimization modules of VMAT and DWA is during the angular spacing, where the DWA algorithm does not consider the gantry spacing, but only the Euclidian norm of the ring and gantry angle. A preclinical version of RayStation v4.6 (RaySearch Laboratories, Sweden) was used to create patient specific wave arc trajectories for 31 patients with various anatomical tumor regions (prostate, oligometatstatic cases, centrally-located non-small cell lung cancer (NSCLC) and locally advanced pancreatic cancer-LAPC). DWA was benchmarked against the current clinical approaches and coplanar VMAT. Each plan was evaluated with regards to dose distribution, modulation complexity (MCS), monitor units and treatment time efficiency. The delivery accuracy was evaluated using a 2D diode array that takes in consideration the multi-dimensionality of DWA during dose reconstruction.
In centrally-located NSCLC cases, DWA improved the low dose spillage with 20 %, while the target coverage was increased with 17 % compared to 3D CRT. The structures that significantly benefited from using DWA were proximal bronchus and esophagus, with the maximal dose being reduced by 17 % and 24 %, respectively. For prostate and LAPC, neither technique seemed clearly superior to the other; however, DWA reduced with more than 65 % of the delivery time over IMRT. A steeper dose gradient outside the target was observed for all treatment sites (p < 0.01) with DWA. Except the oligometastatic cases, where the DWA-MCSs indicate a higher modulation, both DWA and VMAT modalities provide plans of similar complexity. The average ɣ (3 % /3 mm) passing rate for DWA plans was 99.2 ± 1 % (range from 96.8 to 100 %).
DWA proven to be a fully functional treatment technique, allowing additional flexibility in dose shaping, while preserving dosimetrically robust delivery and treatment times comparable with coplanar VMAT.
Electronic supplementary material
The online version of this article (doi:10.1186/s13014-016-0633-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4850693  PMID: 27130434
Dynamic Wave Arc; Noncoplanar delivery; 2D diode dosimeter
4.  Evaluation of a dedicated brain metastases treatment planning optimization for radiosurgery: a new treatment paradigm? 
To investigate the feasibility of a novel dedicated treatment planning solution, to automatically target multiple brain metastases with a single isocenter and multiple inversely-optimized dynamic conformal arcs (DCA), and to benchmark it against the well-established multiple isocenter DCA (MIDCA) and volumetric modulated arc therapy (VMAT) approaches.
Material and Methods
Ten previously treated patients were randomly selected, each representing a variable number of lesions ranging between 1 to 8. The original MIDCA treatments were replanned with both VMAT and the novel brain metastases tool. The plans were compared by means of Paddick conformity (CI) and gradient index (GI), and the volumes receiving 10 Gy (V10) and 12 Gy (V12).
The brain metastases software tool generated plans with similar CI (0.65 ± 0.08) as both established treatment techniques while improving the gradient (mean GI = 3.9 ± 1.4). The normal tissue exposure in terms of V10 (48.5 ± 35.9 cc) and V12 (36.3 ± 27.1 cc) compared similarly to the MIDCA technique and surpassed VMAT plans.
The automated brain metastases planning algorithm software is an optimization of DCA radiosurgery by increasing delivery efficiency to the level of VMAT approaches. Improving dose gradients and normal tissue sparing over VMAT, revives DCA as the paradigm for linac-based stereotactic radiosurgery of multiple brain metastases.
PMCID: PMC4736109  PMID: 26831367
Stereotactic radiosurgery; Brain metastases; Automated planning optimization; Single isocenter dynamic conformal arc
5.  Ex vivo generation of myeloid-derived suppressor cells that model the tumor immunosuppressive environment in colorectal cancer 
Oncotarget  2015;6(14):12369-12382.
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that accumulate in tumor-bearing subjects and which strongly inhibit anti-cancer immune responses. To study the biology of MDSC in colorectal cancer (CRC), we cultured bone marrow cells in conditioned medium from CT26 cells, which are genetically modified to secrete high levels of granulocyte-macrophage colony-stimulating factor. This resulted in the generation of high numbers of CD11b+ Ly6G+ granulocytic and CD11b+ Ly6C+ monocytic MDSC, which closely resemble those found within the tumor but not the spleen of CT26 tumor-bearing mice. Such MDSC potently inhibited T-cell responses in vitro, a process that could be reversed upon blocking of arginase-1 or inducible nitric oxide synthase (iNOS). We confirmed that inhibition of arginase-1 or iNOS in vivo resulted in the stimulation of cytotoxic T-cell responses. A delay in tumor growth was observed upon functional repression of both enzymes. These data confirm the role of MDSC as inhibitors of T-cell-mediated immune responses in CRC. Moreover, MDSC differentiated in vitro from bone marrow cells using conditioned medium of GM-CSF-secreting CT26 cells, represent a valuable platform to study/identify drugs that counteract MDSC activities.
PMCID: PMC4494944  PMID: 25869209
MDSC; CRC; arginase-1; inducible nitric oxide synthase; GM-CSF
6.  Breast Conserving Treatment for Breast Cancer: Dosimetric Comparison of Sequential versus Simultaneous Integrated Photon Boost 
BioMed Research International  2014;2014:827475.
Background. Breast conserving surgery followed by whole breast irradiation is widely accepted as standard of care for early breast cancer. Addition of a boost dose to the initial tumor area further reduces local recurrences. We investigated the dosimetric benefits of a simultaneously integrated boost (SIB) compared to a sequential boost to hypofractionate the boost volume, while maintaining normofractionation on the breast. Methods. For 10 patients 4 treatment plans were deployed, 1 with a sequential photon boost, and 3 with different SIB techniques: on a conventional linear accelerator, helical TomoTherapy, and static TomoDirect. Dosimetric comparison was performed. Results. PTV-coverage was good in all techniques. Conformity was better with all SIB techniques compared to sequential boost (P = 0.0001). There was less dose spilling to the ipsilateral breast outside the PTVboost (P = 0.04). The dose to the organs at risk (OAR) was not influenced by SIB compared to sequential boost. Helical TomoTherapy showed a higher mean dose to the contralateral breast, but less than 5 Gy for each patient. Conclusions. SIB showed less dose spilling within the breast and equal dose to OAR compared to sequential boost. Both helical TomoTherapy and the conventional technique delivered acceptable dosimetry. SIB seems a safe alternative and can be implemented in clinical routine.
PMCID: PMC4137720  PMID: 25162031
7.  Breast conserving treatment for breast cancer: dosimetric comparison of different non-invasive techniques for additional boost delivery 
Today it is unclear which technique for delivery of an additional boost after whole breast radiotherapy for breast conserved patients should be state of the art. We present a dosimetric comparison of different non-invasive treatment techniques for additional boost delivery.
For 10 different tumor bed localizations, 7 different non-invasive treatment plans were made. Dosimetric comparison of PTV-coverage and dose to organs at risk was performed.
The Vero system achieved an excellent PTV-coverage and at the same time could minimize the dose to the organs at risk with an average near-maximum-dose (D2) to the heart of 0.9 Gy and the average volume of ipsilateral lung receiving 5 Gy (V5) of 1.5%. The TomoTherapy modalities delivered an average D2 to the heart of 0.9 Gy for the rotational and of 2.3 Gy for the static modality and an average V5 to the ipsilateral lung of 7.3% and 2.9% respectively. A rotational technique offers an adequate conformity at the cost of more low dose spread and a larger build-up area. In most cases a 2-field technique showed acceptable PTV-coverage, but a bad conformity. Electrons often delivered a worse PTV-coverage than photons, with the planning requirements achieved only in 2 patients and with an average D2 to the heart of 2.8 Gy and an average V5 to the ipsilateral lung of 5.8%.
We present advices which can be used as guidelines for the selection of the best individualized treatment.
PMCID: PMC3907792  PMID: 24467916
Breast cancer; Tumor bed boost; Image guided radiation treatment (IGRT); Intensity modulated radiotherapy (IMRT); TomoTherapy; Vero
8.  Advances in radiotherapy and targeted therapies for rectal cancer 
The last decade witnessed a significant progress in understanding the biology and immunology of colorectal cancer alongside with the technical innovations in radiotherapy. The stepwise implementation of intensity-modulated and image-guided radiation therapy by means of megavolt computed tomography and helical tomotherapy enabled us to anatomically sculpt dose delivery, reducing treatment related toxicity. In addition, the administration of a simultaneous integrated boost offers excellent local control rates. The novel challenge is the development of treatment strategies for medically inoperable patient and organ preserving approaches. However, distant control remains unsatisfactory and indicates an urgent need for biomarkers that predict the risk of tumor spread. The expected benefit of targeted therapies that exploit the tumor genome alone is so far hindered by high cost techniques and pharmaceuticals, hence hardly justifying rather modest improvements in patient outcomes. On the other hand, the immune landscape of colorectal cancer is now better clarified with regard to the immunosuppressive network that promotes immune escape. Both N2 neutrophils and myeloid-derived suppressor cells (MDSC) emerge as useful clinical biomarkers of poor prognosis, while the growing list of anti-MDSC agents shows promising ability to boost antitumor T-cell immunity in preclinical settings. Therefore, integration of genetic and immune biomarkers is the next logical step towards effective targeted therapies in the context of personalized cancer treatment.
PMCID: PMC3885997  PMID: 24415852
Rectal cancer; Image-guided radiotherapy; Intensity-modulated radiotherapy; Biomarkers; Targeted therapies; Myeloid-derived suppressor cells
9.  Hypoxia Integration in the Serological Proteome Analysis Unmasks Tumor Antigens and Fosters the Identification of Anti-Phospho-eEF2 Antibodies as Potential Cancer Biomarkers 
PLoS ONE  2013;8(10):e76508.
The expression by tumor cells of proteins with aberrant structure, expression or distribution accounts for the development of a humoral immune response. Autoantibodies (aAb) directed against tumor-associated antigens (TAA) may thus be particularly relevant for early detection of cancer. Serological proteome analysis (SERPA) aims to identify such circulating aAb through the immunoblotting of 2D-separated tumor cell proteins with cancer patient serum and the consecutive MS identification of proteins in reactive spots. This method has the advantage to use post-translationally modified proteins as a source of potential TAA. Here, we applied this strategy by using colorectal tumor cells pre-exposed to hypoxia in order to promote the expression of a pattern of TAA more likely to represent in vivo conditions. We used two human HCT116 and HT29 colorectal cancer cell lines exposed for 48 hours to 1% O2. Spots positive after immunoblotting of 2D-separated lysates of hypoxic cells with the sera of tumor-bearing mice, were collected and analysed by MS for protein identification. Among the hypoxia-specific immunogenic proteins, we identified a phosphorylated form of eukaryotic translation elongation factor 2 (phospho-Thr56 eEF2). We confirmed the increased phosphorylation of this protein in hypoxic colorectal tumor cells as well as in mouse tumors. Using a specific immunoassay, we could detect the presence of corresponding anti-phospho-Thr56 eEF2 aAb in the serum of tumor-bearing mice (vs healthy mice). We further documented that the detection of these aAb preceded the detection of a palpable tumor mass in mice and validated the presence of anti-phospho-Thr56 eEF2 aAb in the serum of patients with adenomatous polyps and colorectal carcinoma. In conclusion, this study validates a phosphorylated form of eEF2 as a new TAA and more generally, provides evidence that integrating hypoxia upstream of SERPA offers a more relevant repertoire of TAA able to unmask the presence of circulating aAb.
PMCID: PMC3794947  PMID: 24130777
10.  A randomized hypofractionation dose escalation trial for high risk prostate cancer patients: interim analysis of acute toxicity and quality of life in 124 patients 
The α/β ratio for prostate cancer is postulated being in the range of 0.8 to 2.2 Gy, giving rise to the hypothesis that there may be a therapeutic advantage to hypofractionation. To do so, we carried out a randomized trial comparing hypofractionated and conventionally fractionated image-guided intensity modulated radiotherapy (IG-IMRT) in high-risk prostate cancer. Here, we report on acute toxicity and quality of life (QOL) for the first 124 randomized patients.
The trial compares 76 Gy in 38 fractions (5 fractions/week) (Arm 1) to 63 Gy in 20 fractions (4 fractions/week) (Arm 2) (IG-IMRT). Prophylactic pelvic lymph node irradiation with 46 Gy in 23 fractions sequentially (Arm 1) and 44 Gy in 20 fractions simultaneously (Arm 2) was applied. All patients had long term androgen deprivation therapy (ADT) started before RT. Both physician-rated acute toxicity and patient-reported QOL using EPIC questionnaire are described.
There were no differences in overall maximum acute gastrointestinal (GI) or genitourinary (GU) toxicity. Compared to conventional fractionation (Arm 1), GI and GU toxicity both developed significantly earlier but also disappeared earlier in the Arm 2, reaching significant differences from Arm 1 at week 8 and 9. In multivariate analyses, only parameter shown to be related to increased acute Grade ≥1 GU toxicity was the study Arm 2 (p = 0.049). There were no statistically significant differences of mean EPIC scores in any domain and sub-scales. The clinically relevant decrease (CRD) in EPIC urinary domain was significantly higher in Arm 2 at month 1 with a faster recovery at month 3 as compared to Arm 1.
Hypofractionation at 3.15 Gy per fraction to 63 Gy within 5 weeks was well tolerated. The GI and GU physician-rated acute toxicity both developed earlier but recovered faster using hypofractionation. There was a correlation between acute toxicity and bowel and urinary QOL outcomes. Longer follow-up is needed to determine the significance of these associations with late toxicity.
PMCID: PMC3846611  PMID: 24007322
11.  Health-related quality of life in survivors of stage I-II breast cancer: randomized trial of post-operative conventional radiotherapy and hypofractionated tomotherapy 
BMC Cancer  2012;12:495.
Health-related quality of life (HRQOL) assessment is a key component of clinical oncology trials. However, few breast cancer trials comparing adjuvant conventional radiotherapy (CR) and hypofractionated tomotherapy (TT) have investigated HRQOL. We compared HRQOL in stage I-II breast cancer patients who were randomized to receive either CR or TT. Tomotherapy uses an integrated computed tomography scanner to improve treatment accuracy, aiming to reduce the adverse effects of radiotherapy.
A total of 121 stage I–II breast cancer patients who had undergone breast conserving surgery (BCS) or mastectomy (MA) were randomly assigned to receive either CR or TT. CR patients received 25 × 2 Gy over 5 weeks, and BCS patients also received a sequential boost of 8 × 2 Gy over 2 weeks. TT patients received 15 × 2.8 Gy over 3 weeks, and BCS patients also received a simultaneous integrated boost of 15 × 0.6 Gy over 3 weeks. Patients completed the EORTC QLQ-C30 and BR23 questionnaires. The mean score (± standard error) was calculated at baseline, the end of radiotherapy, and at 3 months and 1, 2, and 3 years post-radiotherapy. Data were analyzed by the 'intention-to-treat' principle.
On the last day of radiotherapy, patients in both treatment arms had decreased global health status and functioning scores; increased fatigue (clinically meaningful in both treatment arms), nausea and vomiting, and constipation; decreased arm symptoms; clinically meaningful increased breast symptoms in CR patients and systemic side effects in TT patients; and slightly decreased body image and future perspective.
At 3 months post-radiotherapy, TT patients had a clinically significant increase in role- and social-functioning scores and a clinically significant decrease in fatigue. The post-radiotherapy physical-, cognitive- and emotional-functioning scores improved faster in TT patients than CR patients. TT patients also had a better long-term recovery from fatigue than CR patients. ANOVA with the Bonferroni correction did not show any significant differences between groups in HRQOL scores.
TT patients had a better improvement in global health status and role- and cognitive-functioning, and a faster recovery from fatigue, than CR patients. These results suggest that a shorter fractionation schedule may reduce the adverse effects of treatment.
PMCID: PMC3492203  PMID: 23098579
Health-related quality of life; Breast cancer; Hypofractionated radiotherapy; Adjuvant treatment; Randomized trial
12.  Early Contralateral Shoulder-Arm Morbidity in Breast Cancer Patients Enrolled in a Randomized Trial of Post-Surgery Radiation Therapy 
Shoulder/arm morbidity is a common complication of breast cancer surgery and radiotherapy (RT), but little is known about acute contralateral morbidity.
Patients were 118 women enrolled in a RT trial. Arm volume and shoulder mobility were assessed before and 1–3 months after RT. Correlations and linear regression were used to analyze changes affecting ipsilateral and contralateral arms, and changes affecting relative interlimb differences (RID).
Changes affecting one limb correlated with changes affecting the other limb. Arm volume between the two limbs correlated (R = 0.57). Risk factors were weight increase and axillary dissection. Contralateral and ipsilateral loss of abduction strongly correlated (R = 0.78). Changes of combined RID exceeding 10% affected the ipsilateral limb in 25% of patients, and the contralateral limb in 18%. Aromatase inhibitor therapy was significantly associated with contralateral loss of abduction.
High incidence of early contralateral arm morbidity warrants further investigations.
PMCID: PMC3418149  PMID: 22904635
early breast cancer; short-course radiation therapy; image-guided radiation therapy; shoulder/arm morbidity; breast cancer-related lymphedema
13.  Implementation of HybridArc treatment technique in preoperative radiotherapy of rectal cancer: dose patterns in target lesions and organs at risk as compared to helical Tomotherapy and RapidArc 
HybridArc is a novel treatment technique blending aperture-enhanced optimized arcs with discrete IMRT-elements, allowing selection of arcs with a set of static IMRT-beams. This study compared this new technique to helical Tomotherapy, and RapidArc, in preoperative radiotherapy of rectal cancer.
Material and methods
Twelve rectal cancer patients treated consecutively with Tomotherapy Hi-Art II system were simulated with HybridArc and RapidArc. Treatment plans were designed to deliver homogeneous dose of 46.0Gy to mesorectum and draining lymph nodes, with a simultaneous-integrated-boost to the primary tumor up to a total dose of 55.2Gy. Planning objectives were 95% of prescribed dose to 95% of PTVs, while minimizing the volume of small bowel receiving more than 15Gy (V15) and the mean bladder dose. Dose gradient towards simultaneous-integrated-boost (GI), calculated by dividing the volume receiving more then 52.4Gy (95% of PTV55.2Gy)to the volume of PTV55.2Gy, was kept below 1.5. Mean beam-on time and amount of MUs were also analyzed.
PTV swere adequately covered by all plans. Significant advantage was found for Tomotherapy in sparing small bowel (V15 = 112.7cm3SD73.4cm3) compared to RapidArc (133.4cm3SD75.3cm3) and HybridArc (143.7cm3SD74.4cm3) (p < 0.01). The mean bladder dose was better with RapidArc (20.6GySD2.2Gy) compared to HybridArc (24.2Gy SD4.3Gy) and Tomotherapy (23.0GySD4.7Gy) (p < 0.01). The mean beam-on time was significantly lower (p < 0.01) for HybridArc (2.7min SD0.8) and RapidArc (2.5min SD0.5) compared to Tomotherapy (11.0min SD0.7). The total amount of MUs was significantly (p < 0.01) lower for RapidArc (547SD44)compared to HybridArc (949 SD153).
HybridArc is a feasible solution for preoperative RT with a simultaneous-integrated-boost in rectal cancer patients. It achieved similar PTV coverage with significant lower beam-on time, but less efficient in sparing small bowel and bladder compared to Tomotherapy and RapidArc. The added value of HybridArc is that the treatment modality can be implemented on every LINAC equipped with Dynamic-Conform-Arc and IMRT treatment techniques, while maintaining the same QA-schemes.
PMCID: PMC3484057  PMID: 22849723
HybridArc; Helical Tomotherapy; RapidArc; Simultaneous integrated boost; Preoperative radiotherapy; IMRT rectal cancer
14.  Short course radiotherapy with simultaneous integrated boost for stage I-II breast cancer, early toxicities of a randomized clinical trial 
TomoBreast is a unicenter, non-blinded randomized trial comparing conventional radiotherapy (CR) vs. hypofractionated Tomotherapy (TT) for post-operative treatment of breast cancer. The purpose of the trial is to compare whether TT can reduce heart and pulmonary toxicity. We evaluate early toxicities.
The trial started inclusion in May 2007 and reached its recruitment in August 2011. Women with stage T1-3N0M0 or T1-2N1M0 breast cancer completely resected by tumorectomy (BCS) or by mastectomy (MA) who consented to participate were randomized, according to a prescribed computer-generated randomization schedule, between control arm of CR 25x2 Gy/5 weeks by tangential fields on breast/chest wall, plus supraclavicular-axillary field if node-positive, and sequential boost 8x2 Gy/2 weeks if BCS (cumulative dose 66 Gy/7 weeks), versus experimental TT arm of 15x2.8 Gy/3 weeks, including nodal areas if node-positive and simultaneous integrated boost of 0.6 Gy if BCS (cumulative dose 51 Gy/3 weeks). Outcomes evaluated were the pulmonary and heart function. Comparison of proportions used one-sided Fisher's exact test.
By May 2010, 70 patients were randomized and had more than 1 year of follow-up. Out of 69 evaluable cases, 32 were assigned to CR (21 BCS, 11 MA), 37 to TT (20 BCS, 17 MA). Skin toxicity of grade ≥1 at 2 years was 60% in CR, vs. 30% in TT arm. Heart function showed no significant difference for left ventricular ejection fraction at 2 years, CR 4.8% vs. TT 4.6%. Pulmonary function tests at 2 years showed grade ≥1 decline of FEV1 in 21% of CR, vs. 15% of TT and decline of DLco in 29% of CR, vs. 7% of TT (P = 0.05).
There were no unexpected severe toxicities. Short course radiotherapy of the breast with simultaneous integrated boost over 3 weeks proved feasible without excess toxicities. Pulmonary tests showed a slight trend in favor of Tomotherapy, which will need confirmation with longer follow-up of patients.
Trail registration NCT00459628
PMCID: PMC3432009  PMID: 22656865
Early breast cancer; Hypofractionation; Simultaneous integrated boost (SIB); Image guided radiation treatment (IGRT); Intensity modulated radiotherapy (IMRT)
15.  Scapula alata in early breast cancer patients enrolled in a randomized clinical trial of post-surgery short-course image-guided radiotherapy 
Scapula alata (SA) is a known complication of breast surgery associated with palsy of the serratus anterior, but it is seldom mentioned. We evaluated the risk factors associated with SA and the relationship of SA with ipsilateral shoulder/arm morbidity in a series of patients enrolled in a trial of post-surgery radiotherapy (RT).
The trial randomized women with completely resected stage I-II breast cancer to short-course image-guided RT, versus conventional RT. SA, arm volume and shoulder-arm mobility were measured prior to RT and at one to three months post-RT. Shoulder/arm morbidities were computed as a post-RT percentage change relative to pre-RT measurements.
Of 119 evaluable patients, 13 (= 10.9%) had pre-RT SA. Age younger than 50 years old, a body mass index less than 25 kg/m2, and axillary lymph node dissection were significant risk factors, with odds ratios of 4.8 (P = 0.009), 6.1 (P = 0.016), and 6.1 (P = 0.005), respectively. Randomization group was not significant. At one to three months’ post-RT, mean arm volume increased by 4.1% (P = 0.036) and abduction decreased by 8.6% (P = 0.046) among SA patients, but not among non-SA patients. SA resolved in eight, persisted in five, and appeared in one patient.
The relationship of SA with lower body mass index suggests that SA might have been underestimated in overweight patients. Despite apparent resolution of SA in most patients, pre-RT SA portended an increased risk of shoulder/arm morbidity. We argue that SA warrants further investigation. Incidentally, the observation of SA occurring after RT in one patient represents the second case of post-RT SA reported in the literature.
PMCID: PMC3488523  PMID: 22591589
Breast cancer; Surgery; Radiation treatment; Complications; Winged scapula; Scapular winging; Long thoracic nerve; Multiple outcomes; Shoulder/arm morbidity; Lymphedema
16.  Phase II study of helical tomotherapy in the multidisciplinary treatment of oligometastatic colorectal cancer 
Complete metastasectomy provides a real chance for long-term survival in patients with oligometastatic colorectal cancer (CRC). For inoperable patients, we evaluated in this study intensity-modulated and image-guided radiotherapy (IMRT-IGRT) by helical tomotherapy.
Twenty-four CRC patients with ≤ 5 metastases were enrolled, receiving a dose of 50 Gy in fractions of 5 Gy. No limitations concerning dimension or localization of the metastases were imposed. Whole body PET-CT was performed at baseline and 3 months after the initiation of RT to evaluate the metabolic response rate according to PET Response Criteria in Solid Tumors (PERCIST) version 1.0.
A total of 53 metastases were treated. Seventeen patients (71%) received previously ≥ 1 line of chemotherapy for metastatic disease, displaying residual (n = 7) or progressive (n = 10) metabolic active oligometastatic disease at time of inclusion. Most common sites were the lung, liver and lymphnodes. One patient (4%) experienced grade 3 dysphagia. Twenty-two patients were evaluated by post-treatment PET-CT. Twelve patients achieved a complete (n = 6) or partial (n = 6) metabolic response, resulting in an overall metabolic response rate of 55%. At a median follow-up of 10 months, 7 patients (29%) are in remission, of which 5 received previous chemotherapy with residual oligometastatic disease at time of inclusion. The actuarial 1-year local control, progression-free survival, and overall survival were 54%, 14% and 78%.
Helical tomotherapy delivering 10 fractions of 5 Gy resulted in a metabolic response rate of 55%, and appeared to be attractive as consolidation of inoperable oligometastatic disease after effective chemotherapy.
Trial registration
Eudract 2008-008300-40; NCT00807313
PMCID: PMC3355052  PMID: 22423615
Metastatic colorectal cancer; Oligometastases; Helical tomotherapy; IMRT-IGRT
17.  Current Status of Intensified Neo-Adjuvant Systemic Therapy in Locally Advanced Rectal Cancer 
The addition of 5-fluorouracil (5-FU) or its prodrug capecitabine to radiotherapy (RT) is a standard approach in the neo-adjuvant treatment of patients with rectal tumors extending beyond the muscularis propria (stage II) and/or with clinical evidence of regional lymph node metastases (stage III). According to European randomized trials, the combined treatment modality resulted in favorable local control rates as compared with radiotherapy (RT) alone, but no improvement was found regarding the occurrence of distant metastases or overall survival. In an effort to further enhance the response rates and to decrease the high incidence of distant metastases in locally advanced rectal cancer patients, the addition of other chemotherapeutical drugs and biologic agents as radiation sensitizers to neo-adjuvant 5-FU based chemoradiotherapy (CRT) has been recently investigated. The role of those agents is however questionable as first results from phase III data do not show improvement on pathologic complete remission and circumferential resection margin negative resection rates as compared to 5-FU based CRT, nevertheless an increased toxicity.
PMCID: PMC3360164  PMID: 22655273
rectal cancer; neo-adjuvant radiotherapy; chemoradiotherapy
18.  Prognostic value of histopathology and trends in cervical cancer: a SEER population study 
BMC Cancer  2007;7:164.
Histopathology is a cornerstone in the diagnosis of cervical cancer but the prognostic value is controversial.
Women under active follow-up for histologically confirmed primary invasive cervical cancer were selected from the United States Surveillance, Epidemiology, and End Results (SEER) 9-registries public use data 1973–2002. Only histologies with at least 100 cases were retained. Registry area, age, marital status, race, year of diagnosis, tumor histology, grade, stage, tumor size, number of positive nodes, number of examined nodes, odds of nodal involvement, extent of surgery, and radiotherapy were evaluated in Cox models by stepwise selection using the Akaike Information Criteria.
There were 30,989 records evaluable. From 1973 to 2002, number of cases dropped from 1,100 new cases/year to 900/year, but adenocarcinomas and adenosquamous carcinoma increased from 100/year to 235/year. Median age was 48 years. Statistically significant variables for both overall and cause-specific mortality were: age, year of diagnosis, race, stage, histology, grade, hysterectomy, radiotherapy, tumor size and nodal ratio. The histological types were jointly significant, P < 0.001. Cause-specific mortality hazard ratios by histological type relatively to non-microinvasive squamous cell carcinoma were: microinvasive squamous cell carcinoma 0.28 (95% confidence interval: 0.20–0.39), carcinoma not otherwise specified 0.91 (0.79–1.04), non-mucinous adenocarcinoma 1.06 (0.98–1.15), adenosquamous carcinoma 1.35 (1.20–1.51), mucinous adenocarcinoma 1.52 (1.23–1.88), small cell carcinoma 1.94 (1.58–2.39).
Small cell carcinoma and adenocarcinomas were associated with poorer survival. The incidental observation of increasing numbers of adenocarcinomas despite a general decline suggests the inefficiency of conventional screening for these tumors. Increased incidence of adenocarcinomas, their adverse prognosis, and the young age at diagnosis indicate the need to identify women who are at risk.
PMCID: PMC1994954  PMID: 17718897

Results 1-18 (18)