Radioactive seed localization is a safe and effective tool for breast cancer surgery: an evaluation of over 25,000 cases.

Radioactive seed localization (RSL) provides a precise and efficient method for removing non-palpable breast lesions. It has proven to be a valuable addition to breast surgery, improving perioperative logistics and patient satisfaction. This retrospective review examines the lessons learned from a high-volume cancer center's RSL program after 10 years of practice and over 25 000 cases. We provide an updated model for assessing the patient's radiation dose from RSL seed implantation and demonstrate the safety of RSL to staff members. Additionally, we emphasize the importance of various aspects of presurgical evaluation, surgical techniques, post-surgical management, and regulatory compliance for a successful RSL program. Notably, the program has reduced radiation exposure for patients and medical staff.

Impact of shield location on staff and caregiver dose rates for I-131 radiopharmaceutical therapy patients.

The goal of this study is to investigate the effect of the location and width of a single lead shield on the dose rate of staff and caregivers in a hospital room with an I-131 patient. The best orientation of the patient and caregiver relative to the shield was determined based on minimizing staff and caregiver radiation dose rates. Shielded and unshielded dose rates were simulated using a Monte Carlo computer simulation and validated using real-world ionisation chamber measurements. Based on a radiation transport analysis using an adult voxel phantom published by the International Commission on Radiological Protection, placing the shield near the caregiver yielded the lowest dose rates. However, this strategy reduced the dose rate in only a tiny area of the room. Furthermore, positioning the shield near the patient in the caudal direction provided a modest dose rate reduction while shielding a large room area. Finally, increased shield width was associated with decreasing dose rates, but only a four-fold dose-rate reduction was observed for standard width shields. The recommendations of this case study may be considered as potential candidate room configurations where radiation dose rates are minimized, however these findings must be weighed against additional clinical, safety, and comfort considerations.

TRAF3IP2-IL-17 Axis Strengthens the Gingival Defense against Pathogens.

Recent genome-wide association studies have suggested novel risk loci associated with periodontitis, which is initiated by dysbiosis in subgingival plaque and leads to destruction of teeth-supporting structures. One such genetic locus was the tumor necrosis factor receptor-associated factor 3 interacting protein 2 (TRAF3IP2), a gene encoding the gate-keeping interleukin (IL)-17 receptor adaptor. In this study, we first determined that carriers of the lead exonic variant rs13190932 within the TRAF3IP2 locus combined with a high plaque microbial burden was associated with more severe periodontitis than noncarriers. We then demonstrated that TRAF3IP2 is essential in the IL-17-mediated CCL2 and IL-8 chemokine production in primary gingival epithelial cells. Further analysis suggested that rs13190932 may serve a surrogate variant for a genuine loss-of-function variant rs33980500 within the same gene. Traf3ip2 null mice (Traf3ip2-/-) were more susceptible than wild-type (WT) mice to the Porphyromonas gingivalis-induced periodontal alveolar bone loss. Such bone loss was associated with a delayed P. gingivalis clearance and an attenuated neutrophil recruitment in the gingiva of Traf3ip2-/- mice. Transcriptomic data showed decreased expression of antimicrobial genes, including Lcn2, S100a8, and Defb1, in the Traf3ip2-/- mouse gingiva in comparison to WT mice prior to or upon P. gingivalis oral challenge. Further 16S ribosomal RNA sequencing analysis identified a distinct microbial community in the Traf3ip2-/- mouse oral plaque, which was featured by a reduced microbial diversity and an overabundance of Streptococcus genus bacteria. More P. gingivalis was observed in the Traf3ip2-/- mouse gingiva than WT control animals in a ligature-promoted P. gingivalis invasion model. In agreement, neutrophil depletion resulted in more local gingival tissue invasion by P. gingivalis. Thus, we identified a homeostatic IL-17-TRAF3IP2-neutrophil axis underpinning host defense against a keystone periodontal pathogen.

Evidence of Small Airways Disease and the Immediate Effects of Lumacaftor/Ivacaftor in Children with Cystic Fibrosis.

Aim The aim of this study was to explore risk factors for acute changes in lung function following initiation of lumacaftor/ivacaftor (LUM/IVA) in children with cystic fibrosis. Methods Retrospective review of all children commenced on LUM/IVA treatment over a one-year period. CT Thorax images were reviewed for evidence of air trapping using the Brody score. Results Data was collected from 15 children. A transient decline in ppFEV1 was observed after initiation of LUM/IVA in 93% (n=14) of patients with an absolute mean decline of -10.8%. There was a statistically significant inverse relationship between ΔFEV1 and baseline ppFEV1. There was no relationship between air trapping score and ΔFEV1 (p=0.41). Conclusion Pre-existing small airways disease is not a risk factor for acute changes in lung function following initiation of LUM/IVA. Our results suggest that a LUM/IVA-related decline in lung function is more significant in CF children with higher baseline FEV1.

Artificial Intelligence Tool for Optimizing Eligibility Screening for Clinical Trials in a Large Community Cancer Center.

PURPOSE: Less than 5% of patients with cancer enroll in clinical trials, and 1 in 5 trials are stopped for poor accrual. We evaluated an automated clinical trial matching system that uses natural language processing to extract patient and trial characteristics from unstructured sources and machine learning to match patients to clinical trials. PATIENTS AND METHODS: Medical records from 997 patients with breast cancer were assessed for trial eligibility at Highlands Oncology Group between May and August 2016. System and manual attribute extraction and eligibility determinations were compared using the percentage of agreement for 239 patients and 4 trials. Sensitivity and specificity of system-generated eligibility determinations were measured, and the time required for manual review and system-assisted eligibility determinations were compared. RESULTS: Agreement between system and manual attribute extraction ranged from 64.3% to 94.0%. Agreement between system and manual eligibility determinations was 81%-96%. System eligibility determinations demonstrated specificities between 76% and 99%, with sensitivities between 91% and 95% for 3 trials and 46.7% for the 4th. Manual eligibility screening of 90 patients for 3 trials took 110 minutes; system-assisted eligibility determinations of the same patients for the same trials required 24 minutes. CONCLUSION: In this study, the clinical trial matching system displayed a promising performance in screening patients with breast cancer for trial eligibility. System-assisted trial eligibility determinations were substantially faster than manual review, and the system reliably excluded ineligible patients for all trials and identified eligible patients for most trials.

Intra-operative fluoroscopy time and radiation dose during suprapatellar tibial nailing versus infrapatellar tibial nailing.

BACKGROUND: Fractures of the tibial shaft are routinely managed with intramedullary nailing. An increasingly accepted technique is the suprapatellar extended leg method. The aim of this study was to investigate whether the suprapatellar tibial nailing technique offers shorter intraoperative fluoroscopy times and lower radiation doses when compared to the traditional infrapatellar technique. STUDY DESIGN AND METHODS: Data from 200 consecutive intramedullary tibial nailing operations in our level 1 Major Trauma Centre were retrospectively collected from a prospective database (January 2014-December 2017). Only acute diaphyseal nailing procedures were included. The operations were performed by seven senior trauma consultants experienced in both suprapatellar and infrapatellar tibial nailing. The operations were divided into two groups: infrapatellar and suprapatellar. Intraoperative radiation time and dose data were collected. RESULTS: A total of 90 cases were included and analysed. The majority of the patients were male (82%). 37 operations were infrapatellar and 53 were suprapatellar. Independent samples t-test revealed lower radiation time and dose for the suprapatellar group. The infrapatellar group had a mean radiation time of 129.7 ±â€¯56.6 s versus 94.4 ±â€¯47.9 s for the suprapatellar group. The infrapatellar group had a mean radiation dose (Dose Area Product) 53.6 ±â€¯34.2 cGY cm2 versus 38.2 ±â€¯26.7 cGY cm2 for the suprapatellar group. The difference in mean radiation time and mean radiation dose were both significant (p = 0.002 and p = 0.02 respectively). CONCLUSIONS: Suprapatellar tibial nailing is an increasingly accepted technique in the management of tibial fractures. It is shown here that amongst surgeons experienced in both suprapatellar and infrapatellar nailing techniques, the suprapatellar approach trends towards lower use of intra-operative fluoroscopy as measured by time and dose and thus potentially lower radiation exposure to the operating surgeon, assistants and patient.

Immediate weight bearing after plate fixation of fractures of the tibial plateau.

BACKGROUND: Proximal articular fractures of the tibia are commonly stabilised with internal fixation using plates and screws. There is a lack of evidence and conflicting guidelines as to the most suitable post-operative rehabilitation regime including weight bearing status. There are numerous physiological and socioeconomic benefits of early weight bearing after orthopaedic surgery, but concerns remain around loss of fracture reduction. Therefore, the aim of this study is to investigate whether the weight bearing status after tibial plateau plate fixation is associated with any loss of reduction or articular collapse. METHODS: We retrospectively analysed data from our prospectively collected major trauma centre database. All tibial plateau fractures that required open reduction and internal fixation with plate and screws were included. The immediate post-operative weight bearing status of these patients was recorded. Group I consisted of those patients that were either non-weight bearing or touch weight bearing for the first six post-operative weeks. Group II consisted of patients who were instructed to weight bear fully (as tolerated) immediately after the operation. Radiographs were taken on day one post-operation, at six weeks and at three months and analysed for fracture displacement and joint depression or loss of fixation. RESULTS: A total of 90 patients were included in the study. Group I (non-weight bearing or touch weight bearing) consisted of 60 patients (67%). Group II (full weight bearing as tolerated) consisted of 30 patients (33%). The follow up radiographs demonstrated no failure of fixation in either study group. One patient from the weight bearing group had >1 mm joint depression (4 mm) identified at the first follow up, which did not progress. CONCLUSIONS: This study shows immediate post-operative full weight bearing does not affect the fixation or cause articular collapse up to three months after surgery and thus we propose that patients should be allowed to weight bear immediately after surgical stabilisation of tibial plateau fractures. This will enable patients to benefit from the positive effects on fracture healing of early weight bearing post-surgery and avoid the complications of non-weight bearing without loss of fixation or articular collapse.

Radiotherapeutic implications of the updated ICRP thresholds for tissue reactions related to cataracts and circulatory diseases.

Radiation therapy of cancer patients involves a trade-off between a sufficient tumour dose for a high probability of local control and dose to organs at risk that is low enough to lead to a clinically acceptable probability of toxicity. The International Commission on Radiological Protection (ICRP) reviewed epidemiological evidence and provided updated estimates of 'practical' threshold doses for tissue injury, as defined at the level of 1% incidence, in ICRP Publication 118. Particular attention was paid to cataracts and circulatory diseases. ICRP recommended nominal absorbed dose threshold for these outcomes as low as 0.5 Gy. Threshold doses for tissue reactions can be reached in some patients during radiation therapy. Modern treatment planning systems do not account for such low doses accurately, and doses to therapy patients from associated imaging procedures are not generally accounted for. While local control is paramount, the observations of ICRP Publication 118 suggest that radiation therapy plans and processes should be examined with particular care. The research needs are discussed in this paper.

Plexin-B1 signalling promotes androgen receptor translocation to the nucleus.

Semaphorins and their receptors plexins have diverse roles in many cancers affecting tumour growth, metastasis and angiogenesis. Plexin-B1, the receptor for semaphorin4D (Sema4D), has been implicated in prostate cancer where mutation of the gene and overexpression of the protein occur. It is not clear, however, as to which of the several Sema4D-activated signalling pathways downstream of plexin-B1 function in prostate cancer progression. We show here that Sema4D/plexin-B1 increases the expression of androgen-responsive genes and activates the transcriptional activity of the androgen receptor (AR). Activation of plexin-B1 results in phosphorylation of AR at Serine 81, a site that is phosphorylated by nuclear kinases. Cell fractionation and immunocytochemistry studies demonstrated that the proportion of cells with AR in the nucleus increases significantly upon Sema4D treatment. The N-terminal (AF-1) domain of AR, which contains binding sites for transcription regulators, is not required for this response. Depletion of AR suppressed Sema4D-induced anchorage-independent growth of LNCaP and LNCaP-LN3 cells, demonstrating the functional significance of these findings. These results show that Sema4D/plexin-B1 signalling promotes the translocation of AR to the nucleus and thereby enhances AR transcriptional activity. Plexin-B1 is therefore a promising target for cancer therapy, especially in low androgen situations such as those imposed by androgen deprivation therapy.

SU-E-T-262: Treatment Room Activation after 15 MV Single Fraction Radiation Treatments Delivered Using Varian's TrueBeam and Trilogy Linear Accelerators.

PURPOSE: To measure radiation levels in treatment room due to activation after 15MV single fraction radiation treatment (SFRT) delivered to a solid water phantom. METHODS: We performed radiation surveys of two LINAC treatment rooms immediately after 15 MV SFRT. We delivered a sequence of two 15 MV single fraction IMRT treatments to a phantom at the end of a typical treatment day. The first treatment delivered was 6201MU (about 12 Gy) and the second one, 15 minutes later was 12711 MU (24 Gy). Both were delivered to the pelvic region of a solid water anthropomorphic phantom. In a second technique, a 15 MV VMAT SFRT (4326 MU) was delivered using the Varian TrueBeam LINAC. Radiation measurements were recorded repetitively at four locations using a thin windowed Geiger Muller detector, a sodium iodide photon spectrometer and a pressurized ionization chamber. The four locations surveyed were: the top of the collimator head, the collimator window surface, the isocenter, and the inferior end of the patient support assembly. RESULTS: Radiation levels at the isocenter at the end of the treatment day and before the two IMRT SFRTs varied from 0.06 to 0.1 mR/h. Within 2-3 minutes after finishing the second IMRT SFRT the radiation levels were approximately 10 and 1.4 mR/h at isocenter for the TrueBeam and Trilogy rooms respectively and around 0.6 mR/h for the TrueBeam VMAT SFRT. Closing the MLC and the jaws significantly reduces the radiation level at isocenter. The average half life of the mixture of radionuclides produced is about 10 minutes. CONCLUSIONS: High dose single fraction IMRT treatments with 15 MV photons produce elevated treatment room activation as compared to conventional IMRT. In addition, activation levels varied between the TrueBeam and Trilogy for similar SFRT schemes. There is no funding support, disclosures, or conflict of interest.

Ovarian-sparing surgery for ovarian teratoma in children.

BACKGROUND: Ovarian teratoma (OT) is the most common ovarian neoplasm in children. Oophorectomy has been the standard treatment but may impair fertility. The aim of this study was to investigate the feasibility and outcome of ovarian-sparing surgery (OSS) for OT. PROCEDURE: We retrospectively studied all children treated for OT at a pediatric teaching hospital in Paris, France, between March 1992 and July 2006. OSS was performed when deemed technically feasible in patients who had no lymphadenopathy by preoperative imaging or surgical exploration, normal tumor marker levels, and calcifications on radiographs. RESULTS: We identified 30 patients, including 29 with unilateral OT and 1 with synchronous bilateral OT. Emergent surgery was performed in five patients, among whom four had ovarian torsion requiring oophorectomy and one underwent OSS. Of the 26 OTs in the 25 remaining patients, 10 were managed with OSS and 16 with oophorectomy. Subsequently, ultrasound monitoring detected OT development in the contralateral ovary in 4 (14%) patients, after a median of 3 years (range, 1-14 years); OSS was performed in all four cases. The patient with bilateral synchronous OT, managed by OSS initially, underwent unilateral oophorectomy 3 years later for a recurrence. Overall OSS was performed for 15 (42%) OTs. CONCLUSIONS: Our results suggest recommendations for preserving fertility whenever possible without compromising the oncological prognosis. In particular, OSS should be reserved for patients who meet all criteria for localized mature teratoma. Long-term follow-up is crucial.

A role for class 3 semaphorins in prostate cancer.

BACKGROUND: Class 3 semaphorins are secreted proteins that act as guidance cues for migrating cells via their transmembrane receptors plexins and neuropilins. Semaphorins have a role in cancer affecting tumor progression both directly, and indirectly by affecting angiogenesis. METHODS: The expression of semaphorins and their receptors in prostate cancer cell lines and tissue was determined by RT-PCR, Western blotting and immunohistochemistry. The effect of Sema3E on prostate cancer cell lines was determined by adhesion assays and transwell migration assays. RESULTS: Semaphorins and their receptors, plexins and neuropilins, are widely co-expressed in prostate cancer cell lines and tissue with a significant overexpression of Sema3E in tumor tissue. Sema3E affected integrin-mediated adhesion to fibronectin of prostate cancer cells, and inhibited their motility. Expression of Sema3C was upregulated and Sema3A and Sema3E were down regulated in prostate cells by hypoxia, consistent with an additional role for Sema3A and 3E as anti-angiogenic factors in prostate cancer. CONCLUSIONS: Semaphorin 3E is aberrantly expressed in prostate cancer and affects adhesion and motility of prostate cancer cells, indicating a role for the Sema3E/PlexinD1 signaling pathway in prostate cancer and identifying a new possible target for therapy.

Binding of topotecan to a nicked DNA oligomer in solution.

Topotecan (TPT) is in clinical use as an antitumor agent. It acts by binding to the covalent complex formed between nicked DNA and topoisomerase I, and inserts itself into the single-strand nick, thereby inhibiting the religation of the nick and acting as a poison. A crystal structure analysis of the ternary complex has shown how the drug binds (B. L. Staker, K. Hjerrild, M. D. Feese, C. A. Behnke, A. B. Burgin, L. Stewart, Proc. Natl. Acad. Sci. U.S.A., 2002, 99, 15 387-15 392), but has left a number of unanswered questions. Herein, we use NMR spectroscopy and molecular modeling to show that the solution structure of a complex of TPT with nicked natural DNA is similar, but not identical to the crystal conformation, and that other geometries are of very low population. We also show that the lactone form of TPT binds approximately 40 times more strongly than the ring-opened carboxylate.

Hypomethylation of WNT5A, CRIP1 and S100P in prostate cancer.

Oligoarray analysis of a matched pair of prostate cancer and normal cell lines derived from the same radical prostatectomy specimen identified 113 candidate hypomethylated genes that were overexpressed in the cancer cells and contained CpG islands. Hypomethylation of wingless-related MMTV integration site 5A (WNT5A), S100 calcium-binding protein P (S100P) and cysteine-rich protein 1(CRIP1) was confirmed in the cancer cells by bisulfite sequencing. Treatment of the corresponding normal prostate epithelial cells 1542-NPTX with the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-aza-CdR) induced higher levels of mRNA expression and partial loss of methylation on these genes. Primary prostate cancers were tested using methylation-specific polymerase chain reaction. WNT5A was hypomethylated in 11/17 (65%) tumors, S100P in 8/16 (50%) and CRIP1 in 13/20 (65%). Bisulfite sequencing of a section of the 5' untranslated region (UTR) of WNT5A revealed that three CpG sites (15, 24 and 35) were consistently methylated (93%) in the normal cell line and normal tissues, but not in the prostate cancer cell line and eight primary prostate cancers. Multiple putative binding sites for the transcription factors SP1 and AP-2 were found adjacent to CpG sites 15 and 24. A putative c-Myb binding site was located within the CpG site 35. Anti-c-Myb antibody co-precipitation with WNT5A was methylation-sensitive in 1542-NPTX cells. It is likely that an epigenetic mechanism regulates WNT5A expression in prostate cancer.

Artery calcification in uremic rats is increased by a low protein diet and prevented by treatment with ibandronate.

The present experiments investigate medial artery calcification in adult rats made uremic by feeding a synthetic diet containing 0.75% adenine for 4 weeks. Calcification was assessed by Alizarin red staining of intact aortas, by von Kossa staining of carotid artery sections, and by calcium and phosphate incorporated into the thoracic aorta. The major conclusions are as follows: Lowering the protein content of the diet from 25 to 2.5% dramatically increases the frequency and extent of medial artery calcification in uremic rats without significantly affecting the elevation in serum creatinine, phosphate, or parathyroid hormone. This observation suggests that low dietary protein intake could be a risk factor for medial artery calcification in uremic patients. Medial artery calcification in uremic rats is prevented by a dose of ibandronate that inhibits bone resorption. The observation suggests that bone resorption inhibitors could prevent artery calcification in uremic patients. Medial artery calcification in uremic rats correlates with increased serum bone Gla protein (BGP; osteocalcin), but not with serum matrix Gla protein or fetuin. This finding indicates that it could be of interest to examine the relation between serum BGP and artery calcification in uremic patients. Each of these conclusions lends support for our hypothesis that medial artery calcification is linked to bone resorption. Future investigations of the as yet unknown biochemical basis for this link will be facilitated by the present discovery that a synthetic, 2.5% protein diet containing 0.75% adenine produces consistent and dramatic medial calcification in adult rats within just 4 weeks.

Both estrogen receptor alpha and estrogen receptor beta agonists enhance cell proliferation in the dentate gyrus of adult female rats.

This study investigated the involvement of estrogen receptors alpha and beta in estradiol-induced enhancement of hippocampal neurogenesis in the adult female rat. Subtype selective estrogen receptor agonists, propyl-pyrazole triol (estrogen receptor alpha agonist) and diarylpropionitrile (estrogen receptor beta agonist) were examined for each receptor's contribution, individual and cooperative, for estradiol-enhanced hippocampal cell proliferation. Estradiol increases hippocampal cell proliferation within 4 h [Ormerod BK, Lee TT, Galea LA (2003) Estradiol initially enhances but subsequently suppresses (via adrenal steroids) granule cell proliferation in the dentate gyrus of adult female rats. J Neurobiol 55:247-260]. Therefore, animals received s.c. injections of estradiol (10 microg), propyl-pyrazole triol and diarylpropionitrile alone (1.25, 2.5, 5.0 mg/0.1 ml dimethylsulfoxide) or in combination (2.5 mg propyl-pyrazole triol+2.5 mg diarylpropionitrile/0.1 ml dimethylsulfoxide) and 4 h later received an i.p. injection of the cell synthesis marker, bromodeoxyuridine (200 mg/kg). Diarylpropionitrile enhanced cell proliferation at all three administered doses (1.25 mg, P<0.008; 2.5 mg, P<0.003; 5 mg, P<0.005), whereas propyl-pyrazole triol significantly increased cell proliferation (P<0.0002) only at the dose of 2.5 mg. Our results demonstrate both estrogen receptor alpha and estrogen receptor beta are individually involved in estradiol-enhanced cell proliferation. Furthermore both estrogen receptor alpha and estrogen receptor beta mRNA was found co-localized with Ki-67 expression in the hippocampus albeit at low levels, indicating a potential direct influence of each receptor subtype on progenitor cells and their progeny. Dual receptor activation resulted in reduced levels of cell proliferation, supporting previous studies suggesting that estrogen receptor alpha and estrogen receptor beta may modulate each other's activity. Our results also suggest that a component of estrogen receptor-regulated cell proliferation may take place through alternative ligand and/or cell-signaling mechanisms.

Allelic imbalance and biochemical outcome after radical prostatectomy.

OBJECTIVE: To compare the incidence of allelic imbalance (AI) in men with rapid disease progression with those who remained disease free after radical prostatectomy, with the aim of identifying genetic markers to predict prognosis and guide further treatment. PATIENTS AND METHODS: Tumour and normal DNA were extracted from two matched groups of 31 men with extracapsular node-negative (pT3N0) prostate cancer who had undergone radical prostatectomy. One group comprised men who developed biochemical recurrence within 2 years of surgery and one group were prostate-specific antigen (PSA) free for at least 3 years. Men were matched for Gleason grade, preoperative PSA and pathological stage. Analysis was performed by genotyping. RESULTS: Allelic imbalance was analysed using 30 markers, and was seen in at least one marker in 57 (92%) of the cases. Deletion at marker D10S211 (10p12.1) was significantly more common in the relapse group than the non-relapse group (35 vs 5%, P=0.03). CONCLUSIONS: This study demonstrates significant association between AI on chromosome 10 and biochemical progression after radical prostatectomy.