Té Vuong

Magneto-aerotactic bacteria deliver drug-containing nanoliposomes to tumour hypoxic regions

Oxygen depleted hypoxic regions in the tumour are generally resistant to therapies1. Although nanocarriers have been used to deliver drugs, the targeting ratios have been very low. Here, we show that the magneto-aerotactic migration behaviour2 of magnetotactic bacteria3, Magnetococcus marinus strain MC-14, can be used to transport drug-loaded nanoliposomes into hypoxic regions of the tumour. In their natural environment, MC-1 cells, each containing a chain of magnetic iron-oxide nanocrystals5, tend to swim along local magnetic field lines and towards low oxygen concentrations6 based on a two-state aerotactic sensing system2. We show that when MC-1 cells bearing covalently bound drug-containing nanoliposomes were injected near the tumour in SCID Beige mice and magnetically guided, up to 55% of MC-1 cells penetrated into hypoxic regions of HCT116 colorectal xenografts. Approximately 70 drug-loaded nanoliposomes were attached to each MC-1 cell. Our results suggest that harnessing swarms of microorganisms exhibiting magneto-aerotactic behaviour can significantly improve the therapeutic index of various nanocarriers in tumour hypoxic regions.

Conformal preoperative endorectal brachytherapy treatment for locally advanced rectal cancer: early results of a phase I/II study.

AbstractPURPOSE: Downstaging rectal carcinoma by preoperative radiotherapy decreases local recurrence, and recent phase II studies suggest that, in the lower one-third lesions, sphincter-preserving surgery can be considered. The purpose of the current study was to assess the efficacy and the toxicity of endorectal high dose-rate brachytherapy as a preoperative downstaging treatment modality. METHODS: Patients with newly diagnosed invasive rectal adenocarcinoma, T2 to very early T4, operable tumors were eligible. A dose of 26 Gy was given over four consecutive daily treatments of 6.5 Gy prescribed at the tumor radial margin using endorectal brachytherapy with high dose-rate delivery system. Surgery as planned initially was done four to eight weeks later to allow for tumor downstaging. Patients found to have pathologic positive nodes received postoperative external beam (45 Gy/25 fractions) to the pelvis and systemic 5-fluorouracil-leucovorin chemotherapy. RESULTS: Forty-nine patients entered the study. Tumors were in the lower one-third in 24 patients, middle one-third in 22, and upper one-third in 3. With preoperative endorectal ultrasound and magnetic resonance imaging, the clinical staging of the tumors was: 3 T2, 42 T3, 4 T4, and 16 N1–2. Acute toxicity related to brachytherapy was limited to a moderate proctitis (Radiation Therapy Oncology Group acute toxicity scoring system, Grade 2) in all patients, with two patients with tumors extending into the anal canal having Grade 3 dermatitis. Forty-seven patients underwent surgery. Two patients refused their operation based on a normal endoscopic rectal ultrasound after treatment. A complete clinical response was obtained in 32 of 47 (68 percent) patients with 32 percent pathologically pT0N0–1, and 36 percent had only residual microfoci of carcinoma. The surgical approaches did not yield more complications than expected. CONCLUSION: Preoperative high dose-rate endorectal brachytherapy seems to be safe, because acute toxicity was mainly local, with moderate proctitis (Grade 2) and occasional dermatitis (Grade 3) for very low tumors. Finally, this modality, by providing high rate of tumor downstaging and downsizing especially for patients with lesions in the lower one-third of the rectum, represents a definite potential for sphincter-preserving surgery for investigation in future studies.

Absence of toxicity with hypofractionated 3-dimensional radiation therapy for inoperable, early stage non-small cell lung cancer.

PurposeHypofractionated radiotherapy may overcome repopulation in rapidly proliferating tumors such as lung cancer. It is more convenient for the patients and reduces health care costs. This study reports our results on patients with medically inoperable, early stage, non-small cell lung cancer (NSCLC) treated with hypofractionation.Materials and methodsStage T1-2N0 NSCLC patients were treated with hypofractionation alone, 52.5 Gy/15 fractions, in 3 weeks, with 3-dimensional conformal planning. T1-2N1 patients with the hilar lymphnode close to the primary tumor were also eligible for this treatment. We did not use any approach to reduce respiratory motion, but it was monitored in all patients. Elective nodal radiotherapy was not performed. Routine follow up included assessment for acute and late toxicity and radiological tumor response. Median follow up time was 29 months for the surviving patients.ResultsThirty-two patients with a median age of 76 years, T1 = 15 and T2 = 17, were treated. Median planning target volume (PTV) volume was 150cc and median V16 of both lungs was 13%. The most important finding of this study is that toxicity was minimal. Two patients had grade ≤ 2 acute pneumonitis and 3 had mild (grade 1) acute esophagitis. There was no late toxicity. Actuarial 1 and 2-year overall survival rates are 78% and 56%, cancer specific survival rates (CSS) are 90% and 74%, and local relapse free survival rates are 93% and 76% respectively.Conclusion3-D planning, involved field hypofractionation at a dose of 52.5 Gy in 15 daily fractions is safe, well tolerated and easy radiation treatment for medically inoperable lung cancer patients. It shortens by half the traditional treatment. Results compare favorably with previously published studies. Further studies are needed to compare similar technique with other treatments such as surgery and stereotactic radiotherapy.

Advantages of inflatable multichannel endorectal applicator in the neo‐adjuvant treatment of patients with locally advanced rectal cancer with HDR brachytherapy

High‐dose rate endorectal brachytherapy (HDR‐EBT) is mainly used as a palliative treatment modality. In this paper, we compare dosimetry distributions for a single‐channel catheter (Miami) applicator with distributions of the inflatable multichannel (Novi Sad) endorectal applicator. The comparisons were made with respect to dose coverage to the clinical tumor volume as well as to the bladder, rectal wall, prostate, and bone marrow. Our results suggest that a multichannel applicator provides better sparing of the bone marrow by 50%, clinically uninvolved parts of the rectal wall by 70%, and bladder and prostate (in the case of male patients) by 100% in terms of ratio of median doses to critical organ volume for single‐ and multichannel endorectal applicators. Our results justify the advantage of using a multichannel endorectal brachytherapy applicator as a neo‐adjuvant treatment of patients with locally advanced rectal cancer. PACS numbers: 87.53.Jw, 87.53.Tf

Reporting Late Rectal Toxicity in Prostate Cancer Patients Treated With Curative Radiation Treatment

PURPOSE Long-term rectal toxicity is a concern for patients with prostate cancer treated with curative radiation. However, comparing results of late toxicity may not be straightforward. This article reviews the complexity of reporting long-term side effects by using data for patients treated in our institution with hypofractionated irradiation. METHODS AND MATERIALS Seventy-two patients with localized prostate cancer treated with hypofractionated radiotherapy alone to a dose of 66 Gy in 22 fractions were prospectively assessed for late rectal toxicity according to the Common Toxicity Criteria, Version 3, scoring system. Ninety percent of patients had more than 24 months of follow-up. Results are compared with data published in the literature. RESULTS We found an actuarial incidence of Grade 2 or higher late rectal toxicity of 27% at 30 months and a crude incidence of Grade 2 or higher late rectal toxicity of 18%. This was mostly severe toxicity documented during follow-up. The incidence of Grade 3 rectal toxicity at the last visit was 3% compared with 13% documented at any time during follow-up. CONCLUSION Comparison of late toxicity after radiotherapy in patients with prostate cancer must be undertaken with caution because many factors need to be taken into consideration. Because accurate assessment of late toxicity in the evaluation of long-term outcome after radiotherapy in patients with localized prostate cancer is essential, there is a need to develop by consensus guidelines for assessing and reporting late toxicity in this group of patients.

Image-guided high dose rate endorectal brachytherapy

Fractionated high dose rate endorectal brachytherapy (HDR-EBT) using CT-based treatment planning is an alternative method for preoperative down-sizing and down-staging of advanced rectal adeno-carcinomas. The authors present an image guidance procedure that was developed to ensure daily dose reproducibility for the four brachytherapy treatment fractions. Since the applicator might not be placed before each treatment fraction inside the rectal lumen in the same manner as it was placed during the 3D CT volume acquisition used for treatment planning, there is a shift along the catheter axis that may have to be performed. The required shift is determined by comparison of a daily radiograph with the treatment planning digitally-reconstructed radiograph (DRR). A procedure is developed for DRR reconstruction from the 3D data set used for the treatment planning, and two possible daily longitudinal shifts are illustrated: above and below the planning dose distribution. The authors also describe the procedure for rotational alignment illustrated on a clinical case. Reproduction of the treatment planned dose distribution on a daily basis is crucial for the success of fractionated 3D based brachytherapy treatments. Due to the cylindrical symmetry of the applicator used for preoperative HDR-EBT, two types of adjustments are necessary: applicator rotation and dwell position shift along the applicators longitudinal axis. The impact of the longitudinal applicator shift prior to treatment delivery for 62 patients treated in our institution is also assessed.

An alternative mantle irradiation technique using 3D CT- based treatment planning for female patients with Hodgkin’s disease

PURPOSE For female patients, radiotherapy treatment for Hodgkins disease invariably results in the irradiation of breast tissue that may lead to radiation induced secondary cancers. The risk for secondary breast cancer is correlated with dose. We have developed a technique in an attempt to increase breast sparing during mantle field irradiation for female patients. MATERIAL AND METHODS To minimize the irradiated breast volume, a virtual simulation technique making use of a Styrofoam breast immobilization board has been developed whereby the patient lies prone with the breasts positioned in grooves within the board. The breast position is adjusted using Styrofoam wedges, and breast placement is verified using an AP CT-pilot view. A CT scan of the neck and thoracic regions is taken, and the lymph nodes, breast volume and critical structures are outlined. Virtual simulation of the mantle fields (typically AP/PA isocentric beams) is performed, and beam blocks are drawn on the digitally reconstructed radiographs (DRR) generated by the virtual simulation package. The shielding is designed to allow adequate margins around the lymph nodes while maximizing shielding of the lung and breast tissues. The para-aortic fields are also easily determined through virtual simulation, where multi-planar reconstructions (MPR) and 3D renderings of the patients CT data are used to determine the field limits and beam gaps. In addition to allowing for the geometric optimization of the positioning of the breasts under the lung shields, the virtual simulation technique provides the necessary information for a 3D dosimetric analysis, including dose-volume histograms (DVHs) of the irradiated breast volume. RESULTS The 3D breast sparing technique was qualitatively and quantitatively compared to non-CT-based techniques and other 3D techniques currently available to assess the protection of the breasts. In a preliminary analysis, virtual simulation images (DRRs, 3D rendering and multi-planar reconstruction) demonstrated the advantage of using the breast sparing technique. A further analysis of DVHs showed a reduction of at least 50% in the volume of breast tissue irradiated when using the breast positioning board and virtual simulation as compared to the conventional simulation techniques where a breast immobilization board was not used. CONCLUSIONS The use of a breast immobilization board and of a virtual simulation technique is recommended for the planning and treatment of female patients with Hodgkins disease. DVH analysis has shown that this leads to a decrease in the volume of breast irradiated. It is hoped that this approach will reduce the risk of secondary breast malignancies in female patients with Hodgkins disease.

Comparative skin dose measurement in the treatment of anal canal cancer: Conventional versus conformal therapy

The subject of this work was to compare the effect of Conventional and Conformal techniques, used for anal canal cancer treatments, on the skin dose deposition. Skin dose was measured on a Rando phantom using XR-T GAFCHROMIC film. A skin surface dose histogram was constructed and a skin dose profile in the sagittal direction of the perineal region was measured, for both techniques. The measured skin dose in the anterior and posterior region of the skin exposed to radiation is from two to ten times higher when using a conventional technique. In the perineal region, an 85% of the prescription isodose line spreads over 25% of the perineum for conformal technique as compared to 65% with conventional techniques. In addition, conformal technique dose profiles confine better the anatomical position of the anal verge than conventional techniques. Results presented in this work confirm clinically observed improvement in the radiation-induced dermatitis when using the conformal technique.

Predicting residual rectal adenocarcinoma in the surgical specimen after preoperative brachytherapy with endoscopic ultrasound

BACKGROUND AND STUDY AIMS A novel brachytherapy (BT) protocol evaluated at McGill University has shown promise in terms of downstaging and achieving high tumour sterilization rates in rectal cancer. Endoscopic ultrasound (EUS) has emerged as the imaging modality of choice for local staging of rectal cancer. However, external beam radiotherapy appears to decrease the accuracy of EUS from 85% to 40%. The aim of the present study was to prospectively evaluate the accuracy of EUS in assessing the response of rectal cancer to BT. PATIENTS AND METHODS Thirty-three patients with locally advanced (stage T2 or T3) operable rectal carcinomas were included in an experimental protocol involving a novel conformal technique, using three-dimensional planning, to administer high-dose rate preoperative BT. The 18 patients who were able to have a post-BT EUS exam arranged within two weeks before surgery (eg, four to eight weeks post-BT) were included in this study. Tumour (T)- and lymph node (N)-staging on radial EUS, as well as interpretation of the residual tumour, were assessed prospectively. Pathologists were blinded to the post-BT EUS results. RESULTS The mean age was 70 years (SD +/- 11; range, 52 to 93 years) and 78% of the patients were male. Pre-BT EUS indicated that 16 patients (89%) were stage T3, and two were stage T2. Five patients (28%) had positive nodes (N1) by ultrasound. With BT, the mean maximal wall thickness on EUS decreased from 14 mm to 9.4 mm (P<0.001). At the time of surgery, seven of the 18 patients (39%) had no detectable tumour in the resected specimen; one had carcinoma in situ, one was stage T1, one was stage T2, and eight were stage T3. Eleven patients (61%) underwent an abdominoperineal resection, including four of the 11 (36%) with no ultimate evidence of residual carcinoma. Eight patients (44%) were node-positive. The sensitivity, specificity, and positive and negative predictive values of post-BT EUS in predicting residual tumour were 82%, 29%, 64% and 50%, respectively. The post-BT EUS accurately predicted the T-stage in eight (44%) patients; most errors were due to overstaging. CONCLUSIONS Rectal cancer T-staging by EUS post-BT is inaccurate, and although it appears sensitive in predicting the presence or absence of residual tumor in rectal adenocarcinoma after preoperative BT, the low predictive values in this setting limit its utility at this time.

Neurocognitive function and psychological distress in young adults (YA) with cancer.

199 Background: Cancer treatment is associated with neurocognitive sequelae and changes in structural and functional brain imaging in older adults, even if they do not receive central nervous system directed therapy. Because the brain continues to develop into the 3rd decade of life, YA (age 18-39 yrs) may also be vulnerable to neurocognitive dysfunction. In YA, cancer disrupts acquisition of developmental milestones and is associated with psychological distress. This study aims to characterize neurocognitive functions and its relation to psychological distress in YA. Here we present baseline results of our longitudinal study. METHODS In this prospective, inception-cohort study, we recruited 3 groups of YA from ambulatory oncology clinics: YA with cancers (YAC; lymphoma, breast, gynecology, gastrointestinal, genitourinary, sarcoma) who required chemotherapy (YAC+, n = 55), YAC who do not require it (YAC-, n = 31), and healthy YA (HYA, n = 54). Participants completed a 2-hr battery of standardized neurocognitive tests and validated self-report questionnaires. YAC were assessed within 3 months of diagnosis, and YAC+prior to chemotherapy. Test scores were converted to age-corrected scaled scores and transformed to z-scores (mean 0, SD 1). A global neurocognitive function score and 6 domain scores were evaluated. RESULTS There were no group differences in neurocognitive domains (ANOVA, all p-values > .1), or in the number of impaired test scores (defined as z < -1). YAC+ reported greater symptoms of somatic distress (p = .001) and anxiety (p = .004) than both HYA and YAC-. Symptoms were unrelated to neurocognitive performance (ρ < .16 for all). However, each group had poorer memory compared to population norms (1-sample t-tests: YAC+ p = .007; YAC- p = .047; HYA p = .023). CONCLUSIONS Prior to treatment, neurocognitive functions of YAC were not different from HYA, suggesting that cancer itself is not a neurocognitive risk factor in YA. It is important to use appropriate control groups, rather than relying on normative data for comparison. We continue to follow this cohort to document neurocognitive function and distress over time, and to identify risk factors that contribute to outcomes in YA.