Severe acute haemolytic transfusion reaction secondary to a plasma incompatible group B platelet transfusion.

OBJECTIVES: To report a rare case of acute hemolytic transfusion reaction (AHTR) following an ABO plasma incompatible group B platelet transfusion. BACKGROUND: AHTR is an uncommon, but potentially fatal event. Most reported cases of platelet transfusions associated with AHTR involve group O donors. CASE REPORT: A 34-year-old man, recipient of a group AB haploidentical haematopoietic stem cell transplantation (HSCT), had received re-induction chemotherapy for leukaemia relapse. A group B whole blood-derived buffy coat platelet pool was transfused. He developed rigours/fever, profound hemolytic anaemia, and hemodynamic instability. Serological investigations revealed AHTR from passive transfer of high titre anti-A (256 for IgM and 8192 for IgG). DISCUSSION: This case highlights the potential risks associated with ABO-mismatched transfusions, and the complexity associated with transfusing HSCT recipients and red cell transfusion recipients with dual populations of circulating red cells. The literature on minor ABO plasma incompatible transfusions, challenges in establishing local policies to limit the risks of AHTR and risk mitigation strategies are discussed. CONCLUSION: Clinicians must maintain a high level of suspicion for AHTR after ABO plasma incompatible platelet transfusions. Patients must be aware of the risks of AHTR, and early recognition and diagnosis of this complication may be lifesaving.

Severe Cystic Echinococcosis-Associated Immune Thrombocytopenic Purpura: A Case Report.

We present a case of immune thrombocytopenic purpura (ITP), which leads to the diagnosis of severe cystic echinococcosis. Our patient presented with platelets of 5 × 109/L, and investigations uncovered multiple large echinococcal hepatic cysts, the largest of which measured 19.4 × 15 × 12 cm, and peritoneal implants. While initially refractory to prednisone and immunoglobulins, the ITP responded to dexamethasone. The echinococcosis was treated with albendazole followed by surgical resection of all lesions. Our patient's disease course has evolved favorable since his initial treatment with an isolated episode of recurrent thrombocytopenia 2 years later, and has remained in remission for the past 2 years. While a causal association between echinococcosis and ITP cannot be confirmed, this case is a reminder of the importance of remaining inquisitive for atypical potential triggers of ITP. We also present a review of the limited literature on the association of parasitic infections and ITP.

Molecular Pathogenesis of Hodgkin Lymphoma: Past, Present, Future.

Our understanding of the tumorigenesis of classical Hodgkin lymphoma (cHL) and the formation of Reed-Sternberg cells (RS-cells) has evolved drastically in the last decades. More recently, a better characterization of the signaling pathways and the cellular interactions at play have paved the way for new targeted therapy in the hopes of improving outcomes. However, important gaps in knowledge remain that may hold the key for significant changes of paradigm in this lymphoma. Here, we discuss the past, present, and future of cHL, and review in detail the more recent discoveries pertaining to genetic instability, anti-apoptotic signaling pathways, the tumoral microenvironment, and host-immune system evasion in cHL.

Bone Marrow Immunohistochemistry and Flow Cytometry in the Diagnosis of Malignant Hematologic Diseases With Emphasis on Lymphomas: A Comparative Retrospective Study.

We aim to evaluate the degree of agreement between immunohistochemistry (IHC) and flow cytometry (FC) in the diagnosis of malignant hematologic diseases, mainly lymphomas. A total of 260 bone marrow biopsies, 255 bone marrow aspirates, and 5 other suspensions of 260 patients used for diagnosis of a hematologic malignancy between 2009 and 2012 with both, IHC and FC, were retrospectively analyzed. Overall there is a substantial degree of agreement (κ=0.69) between IHC and FC. Chronic lymphocytic leukemia/small lymphocytic lymphoma, mature T-cell neoplasms, acute leukemias, and myelodysplastic syndromes had the highest concurrence rates (>80%). In nonconcordant cases, an IHC provided diagnosis in 25.4%, and an FC in 4.6%. Lymphomas were diagnosed by an IHC only in 51% of the cases. Both methods have good concurrence rates and are complementary. An IHC has the advantage of combining markers, morphology, and tissue immunoarchitecture, which is beneficial in the diagnosis of lymphomas. An FC is required in leukemias as it is faster and plays an important role in minimal residual disease.

Low endoscopy bleeding risk in patients with congenital bleeding disorders.

INTRODUCTION: Haemophilia A and haemophilia B, von Willebrand disease (VWD), factor VII deficiency and factor XI deficiency are congenital bleeding disorders predisposing to bleeding during invasive procedures. The ageing population of people with congenital bleeding disorders will likely increasingly require gastrointestinal endoscopy. The bleeding risk postgastrointestinal endoscopy and optimal prophylactic treatment regimens are not well described. METHODS: We performed a retrospective chart review at the McGill University Health Centre. Adult patients with haemophilia A or B, VWD, FVII deficiency and FXI deficiency who underwent gastrointestinal endoscopic procedures were included. Bleeding prophylaxis included combinations of plasma-derived factor (VWD) or recombinant factor (haemophilia A and haemophilia B), desmopressin and/or tranexamic acid. Our primary outcome was the 72-hour postendoscopy bleeding rate. RESULTS: One hundred and four endoscopies were performed in 48 patients. Haemophilia A (45.3% of endoscopies) was the most common bleeding disorder, followed by VWD (38.5%), FXI deficiency (8.7%), haemophilia B (4.8%) and FVII deficiency (2.9%). All patients were reviewed by the Haemophilia Treatment Center with peri-procedure treatment protocols put in place as required. The overall 72-hour bleeding rate was 0.96%, confidence interval (CI) 95% (0.17%-5.25%). The colonoscopic postpolypectomy bleeding rate was 1/21 (4.8%, CI 95% (0.9%-22.7%)) in comparison with the general population rate of 0.3%-10% for high-risk endoscopy (including colonoscopic polypectomy). CONCLUSION: To the best of our knowledge, this is the largest study describing patients with inherited bleeding disorders undergoing gastrointestinal endoscopy. The bleeding risk is not significantly higher to the general population when haemostatically managed by a team experienced in bleeding disorders.

IκB-Kinase-epsilon (IKKε) over-expression promotes the growth of prostate cancer through the C/EBP-ß dependent activation of IL-6 gene expression.

The inflammatory cytokine IL-6 has been shown to induce the nuclear translocation of androgen receptors in prostate cancer cells and to activate the androgen receptors in a ligand-independent manner, suggesting it may contribute to the development of a castrate-resistant phenotype. Elevated IL-6 serum levels have also been associated with metastasis-related morbidity in prostate cancer patients. We have previously established that over-expression of I-kappa-B-kinase-epsilon (IKKε also named IKKi or IκBKε) in hormone-sensitive prostate cancer cell lines induces IL-6 secretion. We have also reported that prostate cancer cell lines lacking androgen receptor expression exhibit high constitutive IKKε expression and IL-6 secretion. In the present study, we validated the impact of IKKε depletion on the in vitro proliferation of castrate-resistant prostate cancer cells, and characterized how IKKε depletion affects tumor growth and IL-6 tumor secretion in vivo through a mouse xenograft-based approach. We observed a significant growth delay in IKKε-silenced PC-3 cells injected in SCID mice fed with a doxycycline-supplemented diet in comparison with mice fed with a normal diet. We also found a decrease in IL-6 secretion levels that strongly correlated with tumor growth inhibition. Finally, using constructs with various IL-6-mutated promoters, we demonstrated that IKKε over-expression induces a NF-κB-independent stimulation of the IL-6 gene promoter through the activation and nuclear accumulation of the transcription factor C/EBP-ß. Our study demonstrates the pro-proliferative role of the oncogene IKKε in castrate-resistant prostate cancer cell lines, involving the phosphorylation and nuclear translocation of C/EBP-ß that initiates IL-6 gene expression.

Erectile function recovery after robotic-assisted radical prostatectomy (RARP): long term exhaustive analysis across all preoperative potency categories.

INTRODUCTION: To evaluate erectile function recovery following robotic-assisted radical prostatectomy (RARP) according to preoperative sexual health inventory for men (SHIM) score stratification. MATERIALS AND METHODS: We prospectively collected data on 250 consecutive patients who underwent RARP by a single surgeon between October 2006 and October 2012. Thirty-six patients were excluded because of lack of preoperative SHIM score. All patients had a minimum follow up of 2 years. Patients were divided into four groups according to their preoperative SHIM score: group 1 with normal potency (SHIM 22-25), group 2 with mild ED (SHIM 17-21), group 3 with mild-moderate ED (SHIM 12-16) and group 4 with moderate-severe ED (SHIM 1-11). Patients were followed at 3, 6, 9, 12, 18, 24 months intervals and twice yearly thereafter. SHIM questionnaire and erection hardness scale (EHS) score were collected at each visit. Potency was defined as successful penetration during intercourse (EHS score 3-4) with or without phosphodiesterase type 5-inhibitor (PDE5-I). RESULTS: After exclusion, 214 patients were evaluated. The number of patients in group 1, 2, 3 and 4 were 95, 59, 26 and 34, respectively. At 3, 6, 9, 12, 18, 24 months, SHIM scores and potency rates were statistically different between groups 1 versus 2 versus 3 versus 4 (p < 0.01, at each time point). Patients in each group 1, 2 and 3 showed a statistically significant improvement in potency rates and SHIM scores at consecutive follow up visits up to 24 months (p < 0.01, for each potency group). Potency rates at 24 months for groups 1 to 4 were 83.3%, 54.5%, 50.0%, and 20.7%, respectively (p < 0.001). CONCLUSION: For proper patient counseling and better prediction of erectile function recovery after RARP, it is important to stratify patients according to preoperative SHIM scores. Setting realistic expectations may increase patient satisfaction.

Microcirculatory response during on-pump versus off-pump coronary artery bypass graft surgery.

OBJECTIVES: The use of cardiopulmonary bypass (CPB) during coronary artery bypass graft surgery (CABG) is associated with a systemic inflammatory response, resulting in altered microcirculation. The aim of this study was to evaluate whether beating heart surgery can preserve the microcirculation. METHODS: Sublingual microcirculation was characterized by a Sidestream Darkfield Imaging Microscope during off-pump (OPCABG) and on-pump (ONCABG) surgery. Microcirculatory parameters were evaluated during eight precise perioperative time points. RESULTS: The quality of the microcirculation decreased during early ONCABG. OPCABG resulted in a significantly better microcirculation compared to ONCABG for three of six parameters during surgery. However, by the end of surgery and postoperatively, the microcirculatory parameters were no different between the groups. CONCLUSIONS: While the results do not show a marked preservation of the microcirculation during and after OPCABG compared to ONCABG, they coincide with the body temperature fluctuations of each group during and after surgery. Our work suggests that active warming could impact the microcirculation parameters.

Prevalence and risk factors of contralateral extraprostatic extension in men undergoing radical prostatectomy for unilateral disease at biopsy: A global multi-institutional experience.

INTRODUCTION: We assessed the incidence of contralateral prostate cancer (cPCa), contralateral EPE (cEPE) and contralateral positive surgical margins (cPSM) in patients diagnosed preoperatively with unilateral prostate cancer and evaluated risk factors predictive of contralateral disease extension. METHODS: The occurrence of cPCa, cEPE and cPSM and the side-specific nerve-sparing technique performed were collected postoperatively from 327 men diagnosed with unilateral prostate cancer at biopsy. Parameters, such as the localization, proportion, and percentage of cancer in positive cores, were prospectively collected. RESULTS: Overall, 50.5% of patients had bilateral disease, and were at higher risk when associated with a positive biopsy core at the apex (p = 0.016). The overall incidence of ipsilateral EPE and cEPE were 21.4% and 3.4%, respectively (p < 0.001). Compared to cPCa, ipsilateral disease was at an almost 4-fold higher risk of extending out of the prostate (p < 0.001). None of the criteria tested were identified as useful predictors for cEPE. The low incidence of cEPE in our cohort could limit our ability to detect significance. The overall incidence of ipsilateral PSM and cPSM were 15.3% and 5.8%, respectively (p < 0.001). More aggressive nerve-sparing was not associated with a higher incidence of PSM. Prostate sides selected for more aggressive nerve-sparing were associated with younger patients (p < 0.001), a smaller prostate (p = 0.006), and a lower percentage of cancer in biopsy material (p = 0.008). CONCLUSION: Although the risk of cPCa is high in patients diagnosed with unilateral prostate cancer at biopsy, the risk of cEPE and cPSM is low, yet not insignificant. Contralateral aggressive nerve-sparing should be used with caution and should not compromise oncological outcome.

Management of bone metastases in prostate cancer: a review.

PURPOSE OF REVIEW: Bone metastases in the advanced stages of prostate cancer have a detrimental effect on the quality of life, resulting in skeletal-related events and pain and place a significant burden on healthcare resources. Improvements in prostate cancer treatment have led to a longer survival of patients. Therefore, quality of life is of growing interest and importance. Successful management and prevention of the complications of bone metastasis in those patients remains, however, clinically challenging. RECENT FINDINGS: Recently, radium-223 was approved as a treatment for bone metastasis in patients with prostate cancer, joining zoledronic acid, denosumab and other radiopharmaceuticals in the clinical armamentarium. Radium-223 has shown to improve overall survival in patients with bone metastasis. SUMMARY: This review focuses on the recent landmark studies on zoledronic acid, denosumab and radium-223 for patients with metastatic prostate cancer and gives a comprehensive overview of their mechanism of action, efficacy, dosage and safety profile.

Uroflow Stop Test and Potency Recovery: A Surrogate for Pelvic Floor Integrity Post Robotic-Assisted Radical Prostatectomy?

OBJECTIVE: To study the relation between uroflow Stop Test and early recovery of potency following robot-assisted radical prostatectomy (RARP). We recently showed that the ability to completely stop urine flow during voiding, measured objectively by uroflowmetry at the time of catheter removal (uroflow Stop Test) can predict early urinary continence recovery following RARP. MATERIALS AND METHODS: In this prospective observational cohort, data were collected on 108 patients operated by a single surgeon (AEH). Eighty patients had a positive uroflow Stop Test (group one) and 28 had a negative Stop Test (group two). Patients were followed for a minimum of 2 years. Covariates included age, body mass index, international prostate symptom score and sexual health inventory for men scores, prostate-specific antigen, tumor stage, prostate volume, nerve sparing status, and estimated blood loss. RESULTS: Preoperative characteristics were comparable between both groups except nerve sparing and prostate-specific antigen which were statistically higher in group one (P <.05). Early 3- and 6-months recovery of erectile function was significantly higher in group one. Potency rates in group one and two at 1, 3, 6, 9, 12, 18, and 24 months were 25% vs 14.3% (P = .241), 54.5% vs 18.5% (P = .001), 55.4% vs 18.5% (P = .001), 56.4% vs 36% (P = .084), 66.6% vs 50% (P = .141), 65.5% vs 56% (P = .404) and 73.2% vs 57.7% (P = .160) respectively. Uroflow Stop Test was independent predictor of early potency recovery on multivariate regression analysis at 6 months [odds ratio 6.042 (confidence interval 95% 1.496-24.413) P = .012]. CONCLUSION: Uroflow Stop Test is simple and can help predict early potency recovery following RARP.

Androgen-deprivation therapy and bone loss in prostate cancer patients: a clinical review.

Androgen-deprivation therapy (ADT) has become a standard of care in the management of advanced prostate cancer or as an adjunct therapy. However, ADT is associated with a well-known deleterious effect on bone health, resulting in a decrease in bone-mass density (BMD) and increased risk for fracture. With the longer life expectancy of prostate cancer patients, improvement of the quality of life has become increasingly important. Therefore, adequate screening, prevention and treatment of BMD loss is paramount. Zoledronic acid and denosumab have shown promising results in recent studies, which has led to the Food and Drug Administration approval of these treatment options in various settings throughout the course of the disease, including the prevention of ADT-associated bone loss. This review focuses on the various parameters that impact BMD loss in men initiating ADT, on the specific effect of ADT on bone health and on various lifestyle modifications and treatment options such as bisphosphonates, osteoclast-targeted therapy and selective estrogen-receptor modulators that have shown promising results in recent studies.

Photoselective Vaporization of the Prostate for Benign Prostatic Hyperplasia Using the 180 Watt System: Multicenter Study of the Impact of Prostate Size on Safety and Outcomes.

PURPOSE: We evaluated photoselective vaporization of the prostate using the GreenLight™ XPS™ 180 W system for benign prostatic hyperplasia treatment in a large multi-institutional cohort at 2 years. We particularly examined safety, outcomes and the re-treatment rate in larger prostates, defined as a prostate volume of 80 cc or greater, to assess the potential of photoselective vaporization of the prostate as a size independent procedure. MATERIALS AND METHODS: A total of 1,196 patients were treated at 6 international centers in Canada, the United States, France and England. All parameters were collected retrospectively, including complications, I-PSS, maximum urinary flow rate, post-void residual urine, prostate volume, prostate specific antigen and the endoscopic re-intervention rate. Subgroup stratified comparative analysis was performed according to preoperative prostate volume less than 80 vs 80 cc or greater on transrectal ultrasound. RESULTS: Median prostate size was 50 cc in 387 patients and 108 cc in 741 in the prostate volume groups less than 80 and 80 cc or greater, respectively. The rate of conversion to transurethral prostate resection was significantly higher in the 80 cc or greater group than in the less than 80 cc group (8.4% vs 0.6%, p <0.01). I-PSS, quality of life score, maximum urinary flow rate and post-void residual urine were significantly improved compared to baseline at 6, 12 and 24 months of followup without significant differences between the prostate size groups. The re-treatment rate at 2 years reported in 5 of 411 patients was associated with the delivery of decreased energy density (2.1 vs 4.4 kJ/cc) in the group without re-treatment. CONCLUSIONS: Photoselective vaporization of the prostate using the XPS 180 W system is safe and efficacious, providing durable improvement in functional outcomes at 2 years independent of prostate size when treated with sufficient energy.

Predictors of early continence following robot-assisted radical prostatectomy.

INTRODUCTION: Functional outcomes after robot-assisted radical prostatectomy (RARP) greatly influence patient quality of life. Data regarding predictors of early continence, especially 1 month following RARP, are limited. Previous reports mainly address immediate or 3-month postoperative continence rates. We examine preoperative predictors of pad-free continence recovery at the first follow-up visit 1 month after RARP. METHODS: Between January 2007 and January 2013, preoperative and follow-up data were prospectively collected for 327 RARP patients operated on by 2 fellowship-trained surgeons (AEH and KCZ). Patient and operative characteristics included age, body mass index (BMI), staging, preoperative prostate-specific antigen (PSA), prostate weight, International Prostate Symptom Score (IPSS), Sexual Health Inventory for Men (SHIM) score and type of nerve-sparing performed. Continence was defined by 0-pad usage at 1 month follow-up. Univariate and multivariate logistic regression models were used to assess for predictors of early continence. RESULTS: Overall, 44% of patients were pad-free 1 month post-RARP. In multivariate regression analysis, age (odds ratio [OR] 0.946, confidence interval [CI] 95%: 0.91, 0.98) and IPSS (OR: 0.953, CI 95%: 0.92, 0.99) were independent predictors of urinary continence 1 month following RARP. Other variables (BMI, staging, preoperative PSA, SHIM score, prostate weight and type of nerve-sparing) were not statistically significant predictors of early continence. Limitations of this study include missing data for comorbidities, patient use of pelvic floor exercises and patient maximal activity. Moreover, patient-reported continence using a 0-pad usage definition represents a semiquantitative and subjective measurement. CONCLUSION: In a broad population of patients who underwent RARP at our institution, 44% of patients were pad-free at 1 month. Age and IPSS were independent predictors of early continence after surgery. Men of advanced age and those with significant lower urinary tract symptoms prior to RARP should be counselled on the increased risk of urinary incontinence in the early stages.

Oncological and functional outcomes of 722 robot-assisted radical prostatectomy (RARP) cases: The largest Canadian 5-year experience.

INTRODUCTION: While RARP (robotic-assisted radical prostatectomy) has become the predominant surgical approach to treat localized prostate cancer, there is little Canadian data on its oncological and functional outcomes. We describe the largest RARP experience in Canada. METHODS: Data from 722 patients who underwent RARP performed by 7 surgeons (AEH performed 288, TH 69, JBL 23, SB 17, HW 15, QT 7, and KCZ 303 patients) were collected prospectively from October 2006 to December 2013. Preoperative characteristics, as well as postoperative surgical and pathological outcomes, were collected. Functional and oncological outcomes were also assessed up to 72 months postoperative. RESULTS: The median follow-up (Q1-Q3) was 18 months (9-36). The D'Amico risk stratification distribution was 31% low, 58% intermediate and 11% high-risk. The median operative time was 178 minutes (142-205), blood loss was 200 mL (150-300) and the postoperative hospital stay was 1 day (1-23). The transfusion rate was only 1.0%. There were 0.7% major (Clavien III-IV) and 10.1% minor (Clavien I-II) postoperative complications, with no mortality. Pathologically, 445 men (70%) were stage pT2, of which 81 (18%) had a positive surgical margin (PSM). In addition, 189 patients (30%) were stage pT3 and 87 (46%) with PSM. Urinary continence (0-pads/day) returned at 3, 6, and 12 months for 68%, 80%, and 90% of patients, respectively. Overall, the potency rates (successful penetration) for all men at 6, 12, and 24 months were 37%, 52%, and 59%, respectively. Biochemical recurrence was observed in 28 patients (4.9%), and 14 patients (2.4%) were referred for early salvage radiotherapy. In total, 49 patients (8.4%) underwent radio-therapy and/or hormonal therapy. CONCLUSIONS: This study shows similar results compared to other high-volume RARP programs. Being the largest RARP experience in Canada, we report that RARP is safe with acceptable oncologic outcomes in a Canadian setting.

Comparison of fracture risk assessment tool score to bone mineral density for estimating fracture risk in patients with advanced prostate cancer on androgen deprivation therapy.

OBJECTIVE: To estimate the risk of fracture (Fracture Risk Assessment Tool [FRAX] algorithm) because of the development of osteoporosis in prostate cancer patients undergoing androgen deprivation therapy (ADT) for patients who would otherwise not have been identified for treatment by the T score. METHODS: This study includes men undergoing ADT for prostate cancer at our urology group. Clinical data were collected via chart review. Subjects were evaluated for fracture risk using country specific (for the United States of America) World Health Organization's FRAX. The FRAX calculations were then compared to fracture risk as determined by T score, for a subset of our cohort that received dual-energy X-ray absorptiometry. RESULTS: Our cohort consisted of 613 patients on ADT, 94 of which had a dual-energy X-ray absorptiometry scan. The FRAX algorithm identified 61.6% patients requiring therapy without bone mass density (BMD), 46.8% with BMD, and 19.14% with T score alone. In addition, positive correlation was found between FRAX with and without BMD as well as T score and FRAX with BMD and without BMD. CONCLUSION: Our data indicate that many patients who were not found at significant risk for fracture with T score were in fact found to be at risk with the FRAX calculation. The largest proportion of patients was found to be at risk through the FRAX calculation without BMD, followed by FRAX with BMD, followed by T score alone. The utility of FRAX is beneficial in identifying patients that may benefit from effective bone-tropic treatment modalities.

Accuracy of transrectal ultrasonography to evaluate pathologic prostate weight: correlation with various prostate size groups.

OBJECTIVE: To report the accuracy of transrectal ultrasonography (TRUS) to measure prostate size before robotic-assisted radical prostatectomy using the prolate ellipsoid formula and its correlation to the weight of the postoperative prostate specimen, for different prostate size groups. METHODS: Preoperative prostate size estimated by TRUS and the weight of postoperative prostate specimens were collected from 440 men undergoing robotic-assisted radical prostatectomy. Patients were grouped according to preoperative prostate size: <30, 30-60, 60-80, and ≥80 g. To evaluate accuracy, the mean absolute percentage of error was used. The mean percentage of error was used to indicate whether the estimation of TRUS had a tendency to overestimate or underestimate prostate size. The correlation between both measurements was analyzed for each size group. RESULTS: Accuracy of TRUS estimation was associated with increased prostate size. TRUS estimation was more accurate for larger prostates. The mean absolute percentage of error of each group was 38.64% (<30 g), 21.33% (30-60 g), 13.23% (60-80 g), and 14.96% (≥80 g). Correlation followed a similar size-dependent trend, with a stronger r coefficient for larger prostates: 0.174 (<30 g), 0.327 (30-60 g), 0.457 (60-80 g), and 0.839 (≥80 g). Interestingly, smaller prostates were underestimated, whereas larger glands (≥80 g) had a tendency to be overestimated by TRUS. CONCLUSION: This study demonstrates that the accuracy of the prolate ellipsoid formula for TRUS varies according to prostate size. Although this formula is fairly accurate for assessing larger prostates, it shows some limitations for smaller prostates. This must be taken into account when evaluating treatment modalities such as transurethral incision of the prostate and brachytherapy.