Infection after prostatic transrectal fiducial marker implantation for image guided radiation therapy.

PURPOSE: The aim of this retrospective study is to assess the risk of infection after transrectal ultrasound-guided fiducial marker insertion for image-guided radiotherapy of prostate cancer. MATERIAL AND METHODS: Between January 2016 and December 2020, 829 patients scheduled for intensity-modulated radiotherapy for prostate cancer had an intraprostatic fiducial marker transrectal implantation under ultrasound guidance by radiation-oncologists specialized in brachytherapy. Patients received standard oral prophylactic antibiotic with quinolone. If Gram negative bacteria resistant to quinolone were detected at the time of the prostate cancer biopsies, the antibioprophylaxis regimen was modified accordingly. The resistance to quinolone screening test was not repeated before fiducial marker insertion. Infectious complications were assessed with questionnaires at the time of CT-planning and medical record reviewed. Toxicity was evaluated according to CTCAE v5.0. RESULTS: The median time between fiducial marker implantation and evaluation was 10 days (range: 0-165 days). Four patients (0.48%) developed urinary tract infection related to the procedure, mostly with Gram-negative bacteria resistant to quinolone (75%). Three had a grade 2 infection, and one patient experienced a grade 3 urosepsis. The quinolone-resistance status was known for two patients (one positive and one negative) and was unknown for the other two patients prior to fiducial marker implantation. CONCLUSION: Intraprostatic transrectal fiducial marker implantation for image-guided radiotherapy is well tolerated with a low rate of infection. With such a low rate of infection, there is no need to repeat the search of Gram-negative bacteria resistant to quinolone before fiducial marker implantation if it was done at the time of prostate biopsies. Optimal antibioprophylaxis should be adapted to the known status of Gram-negative bacteria resistant to quinolone.

Comparison of four-year toxicities and local control of ultra-hypofractionated vs moderate-hypofractionated image guided prostate radiation with HDR brachytherapy boost: A phase I-II single institution trial.

Purpose/Objectives: To analyze the long term efficacy and safety of an ultra-hypofractionated (UHF) radiation therapy prostate treatment regimen with HDR brachytherapy boost (BB) and compare it to moderate-hypofractionated regimens (MHF). Materials/Methods: In this single arm, prospective monocentric study, 28 patients with intermediate risk prostate cancer were recruited in an experimental treatment arm of 25 Gy in 5 fractions plus a 15 Gy HDR BB. They were then compared to two historical control groups, treated with either 36 Gy in 12 fractions or 37.5 Gy in 15 fractions with a similar HDR BB. The control groups included 151 and 311 patients respectively. Patient outcomes were reported using the International Prostate Symptom Score (IPSS) and Expanded Prostate Index Composite (EPIC-26) questionnaires at baseline and at each follow-up visit. Results: Median follow-up for the experimental arm was 48.5 months compared to 47 months and 60 months compared to the 36/12 and 37,5/15 groups respectively. The IPSS and EPIC scores did not demonstrate any significant differences in the gastrointestinal or genitourinary domains between the three groups over time. No biochemical recurrence occurred in the UHF arm as defined by the Phoenix criterion. Conclusion: The UHF treatment scheme with HDR BB seems equivalent to standard treatment arms in terms of toxicities and local control. Randomized control trials with larger cohorts are ongoing and needed to further confirm our findings.

Clinical applications of high dose rate endorectal brachytherapy for patients with rectal cancer.

With the establishment of total mesorectal excision for the treatment of rectal cancer, local recurrence rates have significantly decreased. The addition of preoperative external beam irradiation further reduces this risk to less than 6%. As the local treatment becomes successful and more widely used, the associated treatment-related toxicity is becoming clinically important. If 4 to 6% of the patients are to benefit from neo-adjuvant therapy before total mesorectal excision, the acute and the long-term toxicity burden must be reasonable. With the introduction of better-quality imaging for tumour visualization and treatment planning, a new-targeted radiation treatment was introduced with high dose rate endorectal brachytherapy. The treatment concept was tested in phase I and II studies first in the preoperative setting, then as a boost after external beam radiation therapy as a dose escalation study to achieve higher tumour local control in a radical treatment setting with no surgery. High dose rate endorectal brachytherapy is safe and effective in achieving high tumour regression rate and was well tolerated. It is presently explored in a phase III dose escalation study in the non-operative management of patients with operable rectal cancer.

Time-Dependent Mechanical Properties in Polyetherimide 3D-Printed Parts Are Dictated by Isotropic Performance Being Accurately Predicted by the Generalized Time Hardening Model.

The Fused-Deposition Modelling (FDM) technique has transformed the manufacturing discipline by simplifying operational processes and costs associated with conventional technologies, with polymeric materials being indispensable for the development of this technology. A lack of quantification of viscoelastic/plastic behavior has been noted when addressing FDM parts with Polyetherimide (PEI), which is currently being investigated as a potential material to produce functional end-products for the aerospace and health industry. Primary and secondary creep along with stress relaxation tests have been conducted on FDM PEI specimens by applying stresses from 10 to 40 MPa for 100 to 1000 min. Specimens were 3D printed by varying the part build orientation, namely XY, YZ, and XZ. Creep results were fitted to the Generalized Time Hardening equation (GTH), and then this model was used to predict stress relaxation behavior. FDM PEI parts presented an isotropic creep and stress relaxation performance. The GTH model was proven to have a significant capacity to fit viscoelastic/plastic performances for each single build orientation (r > 0.907, p < 0.001), as well as a tight prediction of the stress relaxation behavior (r > 0.998, p < 0.001). Averaged-orientation coefficients for GTH were also closely correlated with experimental creep data (r > 0.958, p < 0.001) and relaxation results data (r > 0.999, p < 0.001). FDM PEI parts showed an isotropic time-dependent behavior, which contrasts with previous publications arguing the significant effect of part build orientation on the mechanical properties of FDM parts. These findings are strengthened by the high correlation obtained between the experimental data and the averaged-coefficient GTH model, which has been proven to be a reliable tool to predict time-dependent performance in FDM parts.

Stereotactic Ablative Radiotherapy Versus Low Dose Rate Brachytherapy or External Beam Radiotherapy: Propensity Score Matched Analyses of Canadian Data.

AIMS: To compare biochemical failure-free survival (BFFS) and overall survival for prostate cancer treated with stereotactic ablative radiotherapy (SABR), low dose rate (LDR) brachytherapy or external beam radiotherapy (EBRT) using a large Canadian multi-institutional database. MATERIALS AND METHODS: Patients with low risk localised prostate cancer treated with SABR, LDR or EBRT and no androgen deprivation therapy were selected. Propensity score matching was used to create two sets of matched cohorts with LDR and EBRT serving as control groups. Kaplan-Meier survival analysis and Cox proportional hazards regression were used to compare differences in BFFS and overall survival between treatment groups. RESULTS: The pre-matched cohort contained 602 patients; the median follow-up was >5.0 years. There were no significant differences in BFFS before or after matching for SABR versus LDR but the prostate-specific antigen (PSA) nadir was lower after LDR. For the SABR versus EBRT, SABR had a BFFS trend before matching (P = 0.08), which became significant after matching (P < 0.001). CONCLUSIONS: Using the Genitourinary Radiation Oncologists of Canada Prostate Cancer Risk Stratification database, low risk prostate cancer patients receiving SABR had similar BFFS compared with patients receiving LDR but better BFFS than EBRT patients. Further comparative studies of efficacy, quality of life and economic outcomes using a broader risk of patients are warranted.

Evaluating competing and emerging technologies for stereotactic body radiotherapy and other advanced radiotherapy techniques.

Stereotactic body radiotherapy (SBRT) refers to the precise irradiation of an image-defined extracranial lesion, using a high total radiation dose delivered in a small number of fractions. A significant proportion of SBRT treatment has been successfully delivered using conventional gantry-based linear accelerators with appropriate image guidance and motion management techniques, although a number of specialist systems are also available. Evaluating the competing SBRT technologies is difficult due to frequent refinements to all major platforms. Comparison of geometric accuracy or treatment planning performance can be hard to interpret and may not provide much useful information. Nevertheless, a general specification overview can provide information that may help radiotherapy providers decide on an appropriate system for their centre. A number of UK randomised controlled trials (RCTs) have shown that better radiotherapy techniques yield better results. RCTs should play an important part in the future evaluation of SBRT, especially where there is a smaller volume of existing data, and where outcomes from conventional radiotherapy are very good. RCT comparison of SBRT with surgery is more difficult due to the radically different treatment arms, although successful recruitment can be possible if the lessons from previous failed trials are learned. The evaluation of new technology poses a number of challenges to the conventional RCT methodology, and there may be situations where it is genuinely not possible, with careful observational studies or decision modelling being more appropriate. Further development in trial design may have an important role in providing clinical evidence in a more timely manner.

RTOG 0518: randomized phase III trial to evaluate zoledronic acid for prevention of osteoporosis and associated fractures in prostate cancer patients.

BACKGROUND: RTOG 0518 evaluated the potential benefit of zoledronic acid therapy in preventing bone fractures for patients with high grade and/or locally advanced, non-metastatic prostate adenocarcinoma receiving luteinizing hormone-releasing hormone (LHRH) agonist and radiotherapy (RT). METHODS: Eligible patients with T-scores of the hip (<-1.0, but >-2.5 vs >-1.0) and negative bone scans were prospectively randomized to either zoledronic acid, 4 mg, concurrently with the start of RT and then every six months for a total of 6 infusions (Arm 1) or observation (Arm 2). Vitamin D and calcium supplements were given to all patients. Secondary objectives included quality of life (QOL) and bone mineral density (BMD) changes over a period of three years. RESULTS: Of 109 patients accrued before early closure, 96 were eligible. Median follow-up was 36.3 months for Arm 1 and 34.8 months for Arm 2. Only two patients experienced a bone fracture (one in each arm) resulting in no difference in freedom from any bone fracture (P=0.95), nor in QOL. BMD percent changes from baseline to 36 months were statistically improved with the use of zoledronic acid compared to observation for the lumbar spine (6% vs -5%, P<0.0001), left total hip (1% vs -8%, P=0.0002), and left femoral neck (3% vs -8%, P=0.0007). CONCLUSIONS: For patients with advanced, non-metastatic prostate cancer receiving LHRH agonist and RT, the use of zoledronic acid was associated with statistically improved BMD percent changes. The small number of accrued patients resulted in decreased statistical power to detect any differences in the incidence of bone fractures or QOL.

CD133 expression in normal skin and in epithelial cutaneous tumors.

BACKGROUND: Expression of human CD133 (human prominin-1) in cancer cells has been postulated to be a marker of stemness and is considered as a putative marker of cancer stem cells (CSCs). We designed a study to describe the expression pattern of CD133 in normal skin and in epithelial cutaneous neoplasms. METHODS: The CD133 immunohistochemical expression of forty-three eccrine and apocrine tumors was compared to that observed in other epithelial tumors of the skin. In addition, flow cytometry was used to detect the CD133 expression of four epithelial skin neoplasms, including one porocarcinoma. RESULTS: CD133 immunoreactivity at the apical or at the apicolateral surface of cells forming glandular structures was observed. Cells from solid areas of benign or malignant tumors were not stained. The porocarcinoma derived culture cells showed a 22% of CD133 positive cells using flow cytometry, while squamous cell carcinoma cultures contained less than 0.1%. CONCLUSIONS: These observations indicate that CD133 is a specific marker of glandular differentiation that could be included in the diagnostic panel of cutaneous tumors with possible eccrine or apocrine differentiation. However, the use of CD133 expression as a marker of CSCs should be interpreted with caution in experiments of skin.

(Stereotactic) radiosurgery XIX: spinal radiosurgery--two year experience in a UK centre.

INTRODUCTION: Modern radiotherapy image guidance enables the treatment of extracranial targets with the required accuracy for safe delivery of radiosurgical treatments. The first two years' experience of spinal radiosurgery in a UK radiotherapy centre is reported. MATERIALS AND METHODS: Patients with primary or metastatic spinal lesions were treated using the CyberKnife stereotactic radiotherapy system. Xsight Spine (fiducial-free) tumour tracking software was used in all cases. Treatment was delivered using either a single or a three-fraction schedule, between February 2009 and March 2011. RESULTS: Fifty-three spinal lesions were treated, comprising 14 primary lesions in 12 patients, and 39 metastases in 29 patients. The prescription dose ranged from 8 to 30 Gy in 1-3 fractions. Fifty-nine percent of patients experienced no acute side effects from treatment. There were three cases of acute grade 3 back or nerve root pain, all of which responded to a short course of oral corticosteroids. At a median follow-up of 11.1 months, local control and overall survival were 91 and 65%, respectively. Pain improvement was seen in 75% of symptomatic metastases at 6 months post treatment. CONCLUSIONS: Early UK experience confirms that radiosurgery is well tolerated with excellent local control rates. Longer-term prospective data are needed to clarify the role of spinal radiosurgery for patients in this country.

Sox2 expression in breast tumours and activation in breast cancer stem cells.

The cancer stem cell (CSC) model does not imply that tumours are generated from transformed tissue stem cells. The target of transformation could be a tissue stem cell, a progenitor cell, or a differentiated cell that acquires self-renewal ability. The observation that induced pluripotency reprogramming and cancer are related has lead to the speculation that CSCs may arise through a reprogramming-like mechanism. Expression of pluripotency genes (Oct4, Nanog and Sox2) was tested in breast tumours by immunohistochemistry and it was found that Sox2 is expressed in early stage breast tumours. However, expression of Oct4 or Nanog was not found. Mammosphere formation in culture was used to reveal stem cell properties, where expression of Sox2, but not Oct4 or Nanog, was induced. Over-expression of Sox2 increased mammosphere formation, effect dependent on continuous Sox2 expression; furthermore, Sox2 knockdown prevented mammosphere formation and delayed tumour formation in xenograft tumour initiation models. Induction of Sox2 expression was achieved through activation of the distal enhancer of Sox2 promoter upon sphere formation, the same element that controls Sox2 transcription in pluripotent stem cells. These findings suggest that reactivation of Sox2 represents an early step in breast tumour initiation, explaining tumour heterogeneity by placing the tumour-initiating event in any cell along the axis of mammary differentiation.

Analysis of patient information leaflets provided by a district general hospital by the Flesch and Flesch-Kincaid method.

INTRODUCTION: Patient information leaflets (PILs) remain the most frequently used sources of medical information. There is a concern that the reading age of these leaflets may exceed patient comprehension, thus negating their beneficial effect. The 'Flesch Reading Ease' and the 'Flesch-Kincaid grade level' are established methods for providing reliable and reproducible scores of readability. METHOD: All available hospital PILs (171) were assessed and divided into 21 departments. Microsoft Word was used to provide Flesch and Flesch-Kincaid readability statistics and compared against the national reading age and the recommended level for provision of medical information. RESULTS: The average Flesch readability of all of the hospital's PILs is 60, with a Flesch-Kincaid grade of 7.8 (12-13 years old). There is considerable variation in the average readability between departments (Flesch readability 43.8-76.9, Flesch-Kincaid 5.4-10.2). The average scores of two departments have PILs scores suitable for patient information. CONCLUSION: Although our PILs were well laid out and easy to read, the majority would have exceeded patient comprehension. The current advice for provision of NHS information does not highlight the importance of a recommended reading level when designing a PIL. Potentially a wide group of patients are being excluded from the benefits of a PIL.

Assessing the readability statistics of national consent forms in the UK.

INTRODUCTION: When obtaining consent for an invasive procedure, the patient needs to understand what is happening to them in broad terms. Best medical practice advocates that written consent is given to acknowledge patient agreement. Across the UK, the Department of Health has provided standard consent forms for obtaining consent in all situations. Potentially these written sources of information may not be comprehended by patients and thus invalidate consent. METHOD: Consent forms were assessed by the Flesch readability and Flesch-Kincaid grade formulae and compared with the national reading age, the recommended level for patient medical information, three newspaper articles and a journal article. RESULTS: The consent forms have acceptable statistics [average Flesch readability 61.1 (range 57.2-66.1) and Flesch-Kincaid grade 7 (range 6.3-8)]. This grade, however, is above the recommended level of patient health information (Flesch-Kincaid grade 6). When the patient statements are isolated the reading statistics worsen [average Flesch readability 52.6 (range 41-62.6) and Flesch-Kincaid grade 9.6 (range 7.9-11.1)]. CONCLUSION: Consent forms should be used as adjuncts to detailed conversations, describing what a procedure involves to ensure that a patient understands, in broad terms, what is happening to them. The patient's statement section of the form may be being written at a level above patient comprehension currently and thus could invalidate any consent given. We would advocate a documented conversation with patients to ensure they have a broad understanding of the procedure and using the consent form as an adjunct to this discussion. The patient's statement section should be re-written to avoid invalidating consent.

[Clinical outcome of intermediate risk prostate cancer treated with iodine 125 monotherapy: The Hotel-Dieu of Quebec experience]. / Evolution clinique des patients atteints d'un cancer prostatique de risque intermédiaire traités par implants permanents d'iode-125 : l'expérience de l'Hôtel-Dieu de Québec.

PURPOSE: To describe the biochemical failure-free survival (BFFS), GU toxicity and erectile dysfunction in intermediate risk prostate cancer treated with iodine 125 monotherapy (I125). PATIENTS AND METHODS: Between October 1994 and October 2007, 1282 patients were treated with I125 at the Hotel Dieu de Quebec. Two hundred patients were intermediate risk prostate cancer. One hundred and fifty-seven had enough follow-up to be evaluated in this study. Biochemical failure-free survival is reported using Phoenix definition. Acute and late GU toxicity was described using the International Prostate Symptoms Score (IPSS) as well as with the rate of bladder catheter. Erectile dysfunction was also reported. RESULTS: The mean age of the patients was 65.6 years (S.D.=6 years) and the mean pretreatment PSA was 8.7ng/ml. About half of the patients (51%) were T2b/T2c. About 44.6% had a PSA greater than 10 and 4.5% had Gleason score of 7/10. More than half of the patients received a short course of hormones of less than 6 months for cytoreduction (57.4%). The median follow-up was 60 months. Biochemical failure-free survival at 60-month and 96-month were 87.1% and 81% according to Phoenix definition. The mean IPSS rose from 5 immediately after the implant to 15 1 month after and then slowly decreased to 8 at 24 months. Acute urinary retention with bladder catheter occurred in 10.9% of patients. Only 4.3% presented erectile dysfunction at 5 months post-implant. CONCLUSION: I125 monotherapy for intermediate risk prostate implant gives biochemical failure-free survivals at 5 years and 8 years comparable to those obtained with high dose external beam radiotherapy. GU toxicity and erectile dysfunction were low and acceptable. Therefore, the use of I125 alone in this group of patients could be presented and discussed with the patient in the waiting of phase III validation.

The 'pulseless pink' hand after supracondylar fracture of the humerus in children: the predictive value of nerve palsy.

We compared two management strategies for the perfused but pulseless hand after stabilisation of a Gartland type III supracondylar fracture. We identified 19 patients, of whom 11 were treated conservatively after closed reduction (group 1). Four required secondary exploration, of whom three had median and/or anterior interosseus nerve palsy at presentation. All four were found to have tethering or entrapment of both nerve and vessel at the fracture site. Only two regained patency of the brachial artery, and one patient has a persistent neurological deficit. In six of the eight patients who were explored early (group 2) the vessel was tethered at the fracture site. In group 2 four patients also had a nerve palsy at presentation and were similarly found to have tethering or entrapment of both the nerve and the vessel. The patency of the brachial artery was restored in all six cases and their neurological deficits recovered completely. We would recommend early exploration of a Gartland type III supracondylar fracture in patients who present with a coexisting anterior interosseous or median nerve palsy, as these appear to be strongly predictive of nerve and vessel entrapment.

[The impact of 3D image guided prostate brachytherapy on therapeutic ratio: the Quebec University Hospital experience]. / Le rôle de la curiethérapie prostatique guidée par imagerie 3D sur le ratio thérapeutique: l'expérience du CHU de Québec.

PURPOSE: To evaluate the impact of adaptative image-guided brachytherapy on therapeutic outcome and toxicity in prostate cancer. MATERIALS AND METHODS: The 1,110 first patients treated at the CHUQ-l'Hôtel-Dieu de Québec were divided in five groups depending on the technique used for the implantation, the latest being intra operative treatment planning. Biochemical disease free survival (5-bDFS), toxicities and dosimetric parameters were compared between the groups. RESULTS: 5-bDFS (ASTRO+Houston) were of 88.5% and 90.5% for the whole cohort. The use of intra operative treatment planning resulted in better dosimetric parameters. Clinically, this resulted in a decreased use of urethral catheterism, from 18.8% in group 1 to 5.2% in group 5, and in a reduction in severe acute urinary side effects (21.3 vs 33.3% P=0.01) when compared with preplanning. There was also less late gastrointestinal side effects (groups 5 vs 1: 26.6 vs 43.2% P<0.05). Finally, when compared with preplanning, intra operative treatment planning was associated with a smaller reduction between planned D90 and the dose calculated at the CT scan 1 month after the implant (38 vs 66 Gy). CONCLUSION: The evolution of prostate brachytherapy technique toward intra operative treatment planning allowed dosimetric gains which resulted in significant clinical benefits by increasing the therapeutic ratio mainly through a decreased urinary toxicity. A longer follow-up will answer the question whether there is an impact on 5-bDFS.

Common patterns of response to the head-up tilt test in children and adolescents.

Testing using the head-up tilt table is performed regularly as a diagnostic tool in the evaluation of syncope. Recommendations for protocols, and interpretation of the results, however, are mainly based on experience in adults. We evaluated the results of tilt table testing in 100 consecutive children and adolescents aged from 6 to 18 years and referred for investigation of syncope. Over half the patients, 55%, proved impossible to classify using the criterions established by the European Society of Cardiology. Based on our data, we propose a modified classification for responses to tilt table testing in the young.

Small molecule inhibitors of Apaf-1-related caspase- 3/-9 activation that control mitochondrial-dependent apoptosis.

Apoptosis is a biological process relevant to human disease states that is strongly regulated through protein-protein complex formation. These complexes represent interesting points of chemical intervention for the development of molecules that could modulate cellular apoptosis. The apoptosome is a holoenzyme multiprotein complex formed by cytochrome c-activated Apaf-1 (apoptotic protease-activating factor), dATP and procaspase-9 that link mitochondria disfunction with activation of the effector caspases and in turn is of interest for the development of apoptotic modulators. In the present study we describe the identification of compounds that inhibit the apoptosome-mediated activation of procaspase-9 from the screening of a diversity-oriented chemical library. The active compounds rescued from the library were chemically optimised to obtain molecules that bind to both recombinant and human endogenous Apaf-1 in a cytochrome c-noncompetitive mechanism that inhibits the recruitment of procaspase-9 by the apoptosome. These newly identified Apaf-1 ligands decrease the apoptotic phenotype in mitochondrial-mediated models of cellular apoptosis.