Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design.

BACKGROUND: Current standard of care for metastatic castration-sensitive prostate cancer supplements androgen deprivation therapy with either docetaxel, second-generation hormonal therapy, or radiotherapy. We aimed to evaluate the efficacy and safety of abiraterone plus prednisone, with or without radiotherapy, in addition to standard of care. METHODS: We conducted an open-label, randomised, phase 3 study with a 2 × 2 factorial design (PEACE-1) at 77 hospitals across Belgium, France, Ireland, Italy, Romania, Spain, and Switzerland. Eligible patients were male, aged 18 years or older, with histologically confirmed or cytologically confirmed de novo metastatic prostate adenocarcinoma, and an Eastern Cooperative Oncology Group performance status of 0-1 (or 2 due to bone pain). Participants were randomly assigned (1:1:1:1) to standard of care (androgen deprivation therapy alone or with intravenous docetaxel 75 mg/m2 once every 3 weeks), standard of care plus radiotherapy, standard of care plus abiraterone (oral 1000 mg abiraterone once daily plus oral 5 mg prednisone twice daily), or standard of care plus radiotherapy plus abiraterone. Neither the investigators nor the patients were masked to treatment allocation. The coprimary endpoints were radiographic progression-free survival and overall survival. Abiraterone efficacy was first assessed in the overall population and then in the population who received androgen deprivation therapy with docetaxel as standard of care (population of interest). This study is ongoing and is registered with ClinicalTrials.gov, NCT01957436. FINDINGS: Between Nov 27, 2013, and Dec 20, 2018, 1173 patients were enrolled (one patient subsequently withdrew consent for analysis of his data) and assigned to receive standard of care (n=296), standard of care plus radiotherapy (n=293), standard of care plus abiraterone (n=292), or standard of care plus radiotherapy plus abiraterone (n=291). Median follow-up was 3·5 years (IQR 2·8-4·6) for radiographic progression-free survival and 4·4 years (3·5-5·4) for overall survival. Adjusted Cox regression modelling revealed no interaction between abiraterone and radiotherapy, enabling the pooled analysis of abiraterone efficacy. In the overall population, patients assigned to receive abiraterone (n=583) had longer radiographic progression-free survival (hazard ratio [HR] 0·54, 99·9% CI 0·41-0·71; p<0·0001) and overall survival (0·82, 95·1% CI 0·69-0·98; p=0·030) than patients who did not receive abiraterone (n=589). In the androgen deprivation therapy with docetaxel population (n=355 in both with abiraterone and without abiraterone groups), the HRs were consistent (radiographic progression-free survival 0·50, 99·9% CI 0·34-0·71; p<0·0001; overall survival 0·75, 95·1% CI 0·59-0·95; p=0·017). In the androgen deprivation therapy with docetaxel population, grade 3 or worse adverse events occurred in 217 (63%) of 347 patients who received abiraterone and 181 (52%) of 350 who did not; hypertension had the largest difference in occurrence (76 [22%] patients and 45 [13%], respectively). Addition of abiraterone to androgen deprivation therapy plus docetaxel did not increase the rates of neutropenia, febrile neutropenia, fatigue, or neuropathy compared with androgen deprivation therapy plus docetaxel alone. INTERPRETATION: Combining androgen deprivation therapy, docetaxel, and abiraterone in de novo metastatic castration-sensitive prostate cancer improved overall survival and radiographic progression-free survival with a modest increase in toxicity, mostly hypertension. This triplet therapy could become a standard of care for these patients. FUNDING: Janssen-Cilag, Ipsen, Sanofi, and the French Government.

The degradation of single-use plastics and commercially viable bioplastics in the environment: A review.

Plastics have become an integral part of human life. Single-use plastics (SUPs) are disposable plastics designed to be used once then promptly discarded or recycled. This SUPs range from packaging and takeaway containers to disposable razors and hotel toiletries. Synthetic plastics, which are made of non-renewable petroleum and natural gas resources, require decades to perpetually disintegrate in nature thus contribute to plastic pollution worldwide, especially in marine environments. In response to these problems, bioplastics or bio-based and biodegradable polymers from renewable sources has been considered as an alternative. Understanding the mechanisms behind the degradation of conventional SUPs and biodegradability of their greener counterpart, bioplastics, is crucial for appropriate material selection in the future. This review aims to provide insights into the degradation or disintegration of conventional single-use plastics and the biodegradability of the different types of greener-counterparts, bioplastics, their mechanisms, and conditions. This review highlights on the biodegradation in the environments including composting systems. Here, the various types of alternative biodegradable polymers, such as bacterially biosynthesised bioplastics, natural fibre-reinforced plastics, starch-, cellulose-, lignin-, and soy-based polymers were explored. Review of past literature revealed that although bioplastics are relatively eco-friendly, their natural compositions and properties are inconsistent. Furthermore, the global plastic market for biodegradable plastics remains relatively small and require further research and commercialization efforts, especially considering the urgency of plastic and microplastic pollution as currently critical global issue. Biodegradable plastics have potential to replace conventional plastics as they show biodegradation ability under real environments, and thus intensive research on the various biodegradable plastics is needed to inform stakeholders and policy makers on the appropriate response to the gradually emerging biodegradable plastics.

Structural Basis for Receptor Activity-Modifying Protein-Dependent Selective Peptide Recognition by a G Protein-Coupled Receptor.

Association of receptor activity-modifying proteins (RAMP1-3) with the G protein-coupled receptor (GPCR) calcitonin receptor-like receptor (CLR) enables selective recognition of the peptides calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) that have diverse functions in the cardiovascular and lymphatic systems. How peptides selectively bind GPCR:RAMP complexes is unknown. We report crystal structures of CGRP analog-bound CLR:RAMP1 and AM-bound CLR:RAMP2 extracellular domain heterodimers at 2.5 and 1.8 Å resolutions, respectively. The peptides similarly occupy a shared binding site on CLR with conformations characterized by a ß-turn structure near their C termini rather than the α-helical structure common to peptides that bind related GPCRs. The RAMPs augment the binding site with distinct contacts to the variable C-terminal peptide residues and elicit subtly different CLR conformations. The structures and accompanying pharmacology data reveal how a class of accessory membrane proteins modulate ligand binding of a GPCR and may inform drug development targeting CLR:RAMP complexes.

Malignant peripheral nerve sheath tumours in a patient with Neurofibromatosis-1.

Malignant peripheral nerve sheath tumour (MPNST) is an uncommon type of soft tissue tumour which most commonly arises in the setting of Neurofibromatosis-1 (NF-1) or in the presence of another nerve sheath tumour. NF-1 is an autosomal dominant syndrome which is diagnosed based on clinical criteria. People suffering from NF-1 are at a higher risk of developing tumours, especially MPNST. MPNST can occur anywhere along the distribution of nerve roots but most commonly involves the limbs and trunk. The prognosis of MPNST in the setting of NF-1 is grave as the distant metastasis develops earlier than non-syndromic cases. Pre-operative diagnosis is difficult as there is no gold standard radiologic technique or characteristic radiological features. The diagnosis is established after histological evaluation supplemented by immunohistochemistry of the tumour tissue. We present a case of a 38-year-old female, a known case of NF-1, who presented with a single, irregular, cystic swelling in the left flank which was increasing in size. The patient underwent complete surgical excision of a 6cm tumour which was diagnosed as MPNST after histopathological examination. The rare nature of this tumour makes the diagnosis and treatment extremely hard. Awareness regarding this disease should be increased so that proper treatment plans can be made.

Recurrent radiation recall dermatitis 40 years after radiation therapy for breast cancer.

Radiation recall dermatitis is an inflammatory reaction of the skin, which occurs at previously irradiated areas, usually following a subsequent exposure to an aggravating factor. Recall dermatitis can occur weeks to months after radiation, and the longest duration between radiation and dermatitis has been reported to be about 25 years. Here, we report a case of recurrent radiation recall dermatitis that developed spontaneously after 40 years following radiation for breast cancer. This case suggests that radiation recall dermatitis can occur much later than previously reported. In spite of this late presentation, topical anti-inflammatory agents managed the condition well.

Anaplastic thyroid cancer: outcomes of trimodal therapy.

BACKROUND: The purpose of this study is to assess the impact of trimodal therapy [surgery, chemotherapy and external beam radiotherapy (EBRT)] in patients with anaplastic thyroid cancer (ATC) treated with curative intent. MATERIALS AND METHODS: Retrospective review of patients with ATC treated at a tertiary referral centre between January 2009 and June 2020. Data were collected regarding demographics, histology, staging, treatment and outcomes. RESULTS: Seven patients (4 female) were identified. Median age was 58 years (range 52-83 years). All patients received EBRT with concurrent doxorubicin. Six patients received surgery followed by chemoradiotherapy (CRT), and one underwent neoadjuvant CRT followed by surgery. Median radiological tumour size was 50mm (range 40-90 mm). Six patients had gross extrathyroidal extension and three had N1b disease. Prescribed radiotherapy schedules were 46.4 Gy in 29 bidaily fractions (n = 2, treated 2010), 60 Gy in 30 daily fractions (n = 2), 66 Gy in 30 fractions (n = 2) and 70 Gy in 35 fractions (n = 1; patient received neoadjuvant CRT). CRT was discontinued early for two patients due to toxicities. At median follow up of 5.8 months, 42.9% (3/7) patients were alive and disease-free. Only one patient developed a local failure. Three patients died from distant metastases without locoregional recurrence. CONCLUSIONS: Despite poor prognosis of ATC, selected patients with operable tumours may achieve high locoregional control rates with trimodal therapy, with possibility of long-term survival in select cases.

Proteomic Profile of Human Schwann Cells.

Schwann cells (SC) are essential for the growth, maintenance, and regeneration of peripheral nerves, but the proteome of normal human SC is poorly defined. Here, a proteomic analysis by LC-MS/MS is performed to define the protein expression profile of primary human SC. A total of 19 557 unique peptides corresponding to 1553 individual proteins are identified. Ingenuity Pathway Analysis (IPA), Gene Ontology (GO), and Database for Annotation, Visualization, and Integrated Discovery (DAVID) are used to assign protein localization and function, and to define enriched pathways. EIF2, mTOR, and integrin signaling are among the most enriched pathways and the most enriched biological function is cell-cell adhesion, which is in agreement with the supportive role of SC in peripheral nerves. In addition, several nociceptors and synaptic proteins are identified and may contribute to the recently discovered role of SC in pain sensation and cancer progression. This proteome analysis of normal human SC constitutes a reference for future molecular explorations of physiological and pathological processes where SC are involved.

Proteomic Analysis of Stromal and Epithelial Cell Communications in Human Endometrial Cancer Using a Unique 3D Co-Culture Model.

Epithelial and stromal communications are essential for normal uterine functions and their dysregulation contributes to the pathogenesis of many diseases including infertility, endometriosis, and cancer. Although many studies have highlighted the advantages of culturing cells in 3D compared to the conventional 2D culture system, one of the major limitations of these systems is the lack of incorporation of cells from non-epithelial lineages. In an effort to develop a culture system incorporating both stromal and epithelial cells, 3D endometrial cancer spheroids are developed by co-culturing endometrial stromal cells with cancerous epithelial cells. The spheroids developed by this method are phenotypically comparable to in vivo endometrial cancer tissue. Proteomic analysis of the co-culture spheroids comparable to human endometrial tissue revealed 591 common proteins and canonical pathways that are closely related to endometrium biology. To determine the feasibility of using this model for drug screening, the efficacy of tamoxifen and everolimus is tested. In summary, a unique 3D model system of human endometrial cancer is developed that will serve as the foundation for the further development of 3D culture systems incorporating different cell types of the human uterus for deciphering the contributions of non-epithelial cells present in cancer microenvironment.

Solid-Phase Thiol-Ene Lipidation of Peptides for the Synthesis of a Potent CGRP Receptor Antagonist.

We report a new method herein coined SP-CLipPA (solid-phase cysteine lipidation of a peptide or amino acid) for the synthesis of mono-S-lipidated peptides. This technique utilizes thiol-ene chemistry for conjugation of a vinyl ester to a free thiol of a semiprotected, resin-bound peptide. Advantages of SP-CLipPA include: ease of handling, conversions of up to 91 %, by-product removal by simple filtration, and a single purification step. Additionally, the desired lipidated products show high chromatographic separation from impurities, thus facilitating RP-HPLC purification. To showcase the utility of SP-CLipPA, we synthesized a potent calcitonin gene-related peptide (CGRP) receptor antagonist peptide in excellent yield and purity. This peptide, selected from a series of lipidated analogues of CGRP8-37 and CGRP7-37 , has potential for the treatment of migraine.

Mixed disulfide formation in vitro between a glycoprotein substrate and yeast oligosaccharyltransferase subunits Ost3p and Ost6p.

Oligosaccharyltransferase (OTase) glycosylates selected asparagine residues in secreted and membrane proteins in eukaryotes, and asparagine (N)-glycosylation affects the folding, stability and function of diverse glycoproteins. The range of acceptor protein substrates that are efficiently glycosylated depends on the action of several accessory subunits of OTase, including in yeast the homologous proteins Ost3p and Ost6p. A model of Ost3p and Ost6p function has been proposed in which their thioredoxin-like active site cysteines form transient mixed disulfide bonds with cysteines in substrate proteins to enhance the glycosylation of nearby asparagine residues. We tested aspects of this model with a series of in vitro assays. We developed a whole protein mixed disulfide interaction assay that showed that Ost6p could form mixed disulfide bonds with selected cysteines in pre-reduced yeast Gas1p, a model glycoprotein substrate of Ost3p and Ost6p. A complementary peptide affinity chromatography assay for mixed disulfide bond formation showed that Ost3p could also form mixed disulfide bonds with cysteines in selected reduced tryptic peptides from Gas1p. Together, these assays showed that the thioredoxin-like active sites of Ost3p and Ost6p could form transient mixed disulfide bonds with cysteines in a model substrate glycoprotein, consistent with the function of Ost3p and Ost6p in modulating N-glycosylation substrate selection by OTase in vivo.

Hyperbilirubinaemia a predictive factor for complicated acute appendicitis: a study in a tertiary care hospital.

OBJECTIVE: To study the role of hyperbilirubinaemia as a predictive factor for appendiceal perforation in acute appendicitis. METHODS: The prospective, descriptive study was conducted at the Abbasi Shaheed Hospital and the Karachi Medical and Dental College, Karachi, from January 2010 to June 2012. It comprised all patients coming to the surgical outpatient department and emergency department with pain in the right iliac fossa with duration less than seven days. They were clinically assessed for signs and symptoms of acute appendicitis and relevant tests were conducted. Patients were diagnosed as a case of acute appendicitis on the basis of clinical and ultrasound findings, and were prepared for appendicectomy. Per-operative findings were recorded and specimens were sent for histopathology to confirm the diagnosis. SPSS version 10 was used to analyse the data. RESULTS: Of the 71 patients, 37 (52.10%) were male and 34 (47.90%) were female. The age range was 3-57 years, and most of the patients (n = 33; 46.5%) were between 11 and 20 years. Besides, 63 (89%) patients had pain in the right iliac fossa of less than four-days duration, while 8 (11%) had pain of longer duration.Total leukocyte count was found to be elevated in 33 (46.5%) patients, while total serum bilirubin was elevated in 41 (57.70%). Ultrasound of abdomen showed 9 (12.70%) patients having normal appearance of appendix and 59 (83.30%) had inflamed appendix. Four (5.60%) patients had no signs of inflammation on naked eye appearance per operatively. Histopathology of appendix showed 10 (14.10%) patients had non-inflammatory appendix. CONCLUSION: Patients with signs and symptoms of acute appendicitis and a raised total serum bilirubin level indicated a complication of acute appendicitis requiring an early intervention to prevent peritonitis and septicaemia. A raised serum bilirubin level is a good indicator of complicated acute appendicitis, and should be included in the assessment of patients with suspected complicated acute appendicitis.

Validation of the bladder neck as an important organ at risk in prostate seed brachytherapy based on D2cc: A single-institution, retrospective review.

Purpose: International guidelines recommend urethral dose volume constraints to minimize the risk of urinary toxicity after prostate brachytherapy. An association between dose to the bladder neck (BN) and toxicity has previously been reported, and we sought to evaluate the impact of this organ at risk on urinary toxicity, based on intra-operative contouring. Material and methods: Rates of acute and late urinary toxicity (AUT and LUT, respectively) were graded according to CTCAE version 5.0 for 209 consecutive patients who underwent low-dose-rate (LDR) brachytherapy monotherapy, with approximately equal numbers treated before and after we began routinely contouring the BN. AUT and LUT were compared in patients treated before and after we began contouring the OAR, and also for those treated after we began contouring who had a D2cc of greater than or less than 50% prescription dose. Results: AUT and LUT fell after intra-operative BN contouring was instituted. Rates of grade ≥ 2 AUT fell from 15/101 (15%) to 9/104 (8.6%), p = 0.245. Grade ≥ 2 LUT decreased from 32/100 (32%) to 18/100 (18%), p = 0.034. Grade ≥ 2 AUT was observed in 4/63 (6.3%) and 5/34 (15%) of those with a BN D2cc >/≤ 50%, respectively, of prescription dose. Corresponding rates for LUT were 11/62 (18%) and 5/32 (16%). Conclusions: There were lower urinary toxicity rates for patients treated after we commenced routine intra-operative contouring of the BN. No clear relationship was observed between dosimetry and toxicity in our population.

LncRNA LIMp27 Regulates the DNA Damage Response through p27 in p53-Defective Cancer Cells.

P53 inactivation occurs in about 50% of human cancers, where p53-driven p21 activity is devoid and p27 becomes essential for the establishment of the G1/S checkpoint upon DNA damage. Here, this work shows that the E2F1-responsive lncRNA LIMp27 selectively represses p27 expression and contributes to proliferation, tumorigenicity, and treatment resistance in p53-defective colon adenocarcinoma (COAD) cells. LIMp27 competes with p27 mRNA for binding to cytoplasmically localized hnRNA0, which otherwise stabilizes p27 mRNA leading to cell cycle arrest at the G0/G1 phase. In response to DNA damage, LIMp27 is upregulated in both wild-type and p53-mutant COAD cells, whereas cytoplasmic hnRNPA0 is only increased in p53-mutant COAD cells due to translocation from the nucleus. Moreover, high LIMp27 expression is associated with poor survival of p53-mutant but not wild-type p53 COAD patients. These results uncover an lncRNA mechanism that promotes p53-defective cancer pathogenesis and suggest that LIMp27 may constitute a target for the treatment of such cancers.

Analysis of congenital disorder of glycosylation-Id in a yeast model system shows diverse site-specific under-glycosylation of glycoproteins.

Asparagine-linked glycosylation is a common post-translational modification of proteins in eukaryotes. Mutations in the human ALG3 gene cause changed levels and altered glycan structures on mature glycoproteins and are the cause of a severe congenital disorder of glycosylation (CDG-Id). Diverse glycoproteins are also under-glycosylated in Saccharomyces cerevisae alg3 mutants. Here we analyzed site-specific glycosylation occupancy in this yeast model system using peptide-N-glycosidase F to label glycosylation sites with an asparagine-aspartate conversion that creates a new endoproteinase AspN cleavage site, followed by proteolytic digestion, and detection of peptides and glycopeptides by LC-ESI-MS/MS. We used this analytical method to identify and measure site-specific glycosylation occupancy in alg3 mutant and wild type yeast strains. We found decreased site-specific N-glycosylation occupancy in the alg3 knockout strain preferentially at Asn-Xaa-Ser sequences located in secondary structural elements, features previously associated with poor glycosylation efficiency. Furthermore, we identified 26 previously experimentally unverified glycosylation sites. Our results provide insights into the underlying mechanisms of disease in CDG-Id, and our methodology will be useful in site-specific glycosylation analysis in many model systems and clinical applications.

Pharmacological characterisation of mouse calcitonin and calcitonin receptor-like receptors reveals differences compared with human receptors.

BACKGROUND AND PURPOSE: The calcitonin (CT) receptor family is complex, comprising two receptors (the CT receptor [CTR] and the CTR-like receptor [CLR]), three accessory proteins (RAMPs) and multiple endogenous peptides. This family contains several important drug targets, including CGRP, which is targeted by migraine therapeutics. The pharmacology of this receptor family is poorly characterised in species other than rats and humans. To facilitate understanding of translational and preclinical data, we need to know the receptor pharmacology of this family in mice. EXPERIMENTAL APPROACH: Plasmids encoding mouse CLR/CTR and RAMPs were transiently transfected into Cos-7 cells. cAMP production was measured in response to agonists in the absence or presence of antagonists. KEY RESULTS: We report the first synthesis and characterisation of mouse adrenomedullin, adrenomedullin 2 and ßCGRP and of mouse CTR without or with mouse RAMPs. Receptors containing m-CTR had subtly different pharmacology than human receptors; they were promiscuous in their pharmacology, both with and without RAMPs. Several peptides, including mouse αCGRP and mouse adrenomedullin 2, were potent agonists of the m-CTR:m-RAMP3 complex. Pharmacological profiles of receptors comprising m-CLR:m-RAMPs were generally similar to those of their human counterparts, albeit with reduced specificity. CONCLUSION AND IMPLICATIONS: Mouse receptor pharmacology differed from that in humans, with mouse receptors displaying reduced discrimination between ligands. This creates challenges for interpreting which receptor may underlie an effect in preclinical models and thus translation of findings from mice to humans. It also highlights the need for new ligands to differentiate between these complexes. LINKED ARTICLES: This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary).. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc.

Identification of Small-Molecule Positive Modulators of Calcitonin-like Receptor-Based Receptors.

Class B G protein-coupled receptors are highly therapeutically relevant but challenges remain in identifying suitable small-molecule drugs. The calcitonin-like receptor (CLR) in particular is linked to conditions such as migraine, cardiovascular disease, and inflammatory bowel disease. The CLR cannot act as a cell-surface receptor alone but rather must couple to one of three receptor activity-modifying proteins (RAMPs), forming heterodimeric receptors for the peptides adrenomedullin and calcitonin gene-related peptide. These peptides have extended binding sites across their receptors. This is one reason why there are few small-molecule ligands that can modulate these receptors. Here we describe small molecules that are able to positively modulate the signaling of the CLR with all three RAMPs but are not active at the related calcitonin receptor. These compounds were selected from a ß-arrestin recruitment screen, coupled with rounds of medicinal chemistry to improve their activity. Translational potential is shown as the compounds can positively modulate cAMP signaling in a vascular cell line model. Binding experiments do not support an extracellular domain binding site; however, molecular modeling reveals potential allosteric binding sites in multiple receptor regions. These are the first small-molecule positive modulators described for the CLR:RAMP complexes.

Initial clinical assessment of "center-specific" automated treatment plans for low-dose-rate prostate brachytherapy.

PURPOSE: To report results of an initial pilot study assessing iodine-125 prostate implant treatment plans created automatically by a new seed-placement method. METHODS AND MATERIALS: A novel mixed-integer linear programming method incorporating spatial constraints on seed locations in addition to standard dose-volume constraints was used to place seeds. The approach, described in detail elsewhere, was used to create treatment plans fully automatically on a retrospective basis for 20 patients having a wide range of prostate sizes and shapes. Corresponding manual plans used for patient treatment at a single institution were combined with the automated plans, and all 40 plans were anonymized, randomized, and independently evaluated by five clinicians using a common scoring tool. Numerical and clinical features of the plans were extracted for comparison purposes. RESULTS: A full 51% of the automated plans were deemed clinically acceptable without any modification by the five practitioners collectively versus 90% of the manual plans. Automated plan seed distributions were for the most part not substantially different from those for the manual plans. Two observed shortcomings of the automated plans were seed strands not intersecting the prostate and strands extending into the bladder. Both are amenable to remediation by adjusting existing spatial constraints. CONCLUSIONS: After spatial and dose-volume constraints are set, the mixed-integer linear programming method is capable of creating prostate implant treatment plans fully automatically, with clinical acceptability sufficient to warrant further investigation. These plans, intended to be reviewed and refined as necessary by an expert planner, have the potential to both save planner time and enhance treatment plan consistency.

Clinical factors and dosimetry associated with the development of prostate brachytherapy-related urethral strictures: A matched case-control study.

PURPOSE: Urethral strictures are a rare complication of prostate brachytherapy (BXT), with prior studies showing radiation dose to the bulbomembranous urethra as being associated with stricture formation. This retrospective case-control study explored clinical and dosimetric parameters associated with the development of BXT-related urethral strictures. METHODS AND MATERIALS: A cohort of 34 patients developed urethral strictures after BXT at our institution for the period of 2008-2014. Each case was matched with two controls (68 controls) that had not developed a urethral stricture according to similar baseline clinical and dosimetric parameters. Stricture development was compared with clinical (i.e., age, smoking status, diabetes, hypertension, vascular disease, International Prostate Symptom Score, hormones) and dosimetric (i.e., prostate, urethra, urethral segments [base, midgland, apex, extraprostatic, and 5 mm margin]) variables. Statistical modeling approaches such as univariate, multivariate, and subset selection methods for risk prediction were applied to identify parameter(s) with best predictive ability of toxicity. The performances of models were ranked according to Akaike information criterion score. RESULTS: The results show that the R2 statistic increases from 6%, when only one parameter is included in the model, to almost 33%, when all the parameters are included. The best-fit subset of parameters included pretreatment International Prostate Symptom Score sum, urethra D30 Gy, urethra D5 Gy, and intraprostatic urethra with 5-mm margin V200 at the apex having the highest ability to predict the development of urinary strictures. CONCLUSIONS: This study used statistical modeling, a novel approach in prostate BXT dosimetric studies, to identify a subset of parameters with predictive ability in identifying patients who develop urethral strictures.

Quantifying 125I placement accuracy in prostate brachytherapy using postimplant transrectal ultrasound images.

PURPOSE: The quality of a prostate brachytherapy implant depends on the accurate placement of sources. This study quantifies the misplacement of 125I sources from the intended location using intraoperative ultrasound images. METHODS AND MATERIALS: 125I sources were manually identified in the postimplant ultrasound images and compared to the preoperative plan. Due to the subjective nature of the identifying sources, only sources identified with high confidence were included in the analysis. Misplacements from the original intended coordinate were measured along the X, Y, and Z axes and were stratified between overall misplacements and regions of the prostate gland. RESULTS: A total of 1619 125I sources using 357 strands were implanted in 15 patients' prostate glands, with 1197 (74%) confidently identified for misplacement analysis. The overall mean displacement was 0.49 cm and in the X, Y, and Z direction was 0.13, 0.15, and 0.38 cm, respectively. Greater source misplacement occurred in the anterior part of the prostate gland than the posterior part of the prostate gland by a factor 1.33 (p < 0.0001). Comparing sources in the lateral vs. medial regions of the prostate, no statistically significant differences on source misplacement were observed. Comparing misplacement in the base vs. midgland vs. apex identified the greatest difference between the base and midgland by a factor of 1.29 (p < 0.0001). CONCLUSIONS: This study has identified significant misplacement of 125I sources from their intended locations with the greatest error misplacement occurring in the Z direction. Source misplacement tends to occur more commonly in the anterior gland and in the base of the prostate.