Accelerator-Based Production of Scandium Radioisotopes for Applications in Prostate Cancer: Toward Building a Pipeline for Rapid Development of Novel Theranostics.

In the field of nuclear medicine, the ß+ -emitting 43Sc and ß- -emitting 47Sc are promising candidates in cancer diagnosis and targeted radionuclide therapy (TRT) due to their favorable decay schema and shared pharmacokinetics as a true theranostic pair. Additionally, scandium is a group-3 transition metal (like 177Lu) and exhibits affinity for DOTA-based chelators, which have been studied in depth, making the barrier to implementation lower for 43/47Sc than for other proposed true theranostics. Before 43/47Sc can see widespread pre-clinical evaluation, however, an accessible production methodology must be established and each isotope's radiolabeling and animal imaging capabilities studied with a widely utilized tracer. As such, a simple means of converting an 18 MeV biomedical cyclotron to support solid targets and produce 43Sc via the 42Ca(d,n)43Sc reaction has been devised, exhibiting reasonable yields. The NatTi(γ,p)47Sc reaction is also investigated along with the successful implementation of chemical separation and purification methods for 43/47Sc. The conjugation of 43/47Sc with PSMA-617 at specific activities of up to 8.94 MBq/nmol and the subsequent imaging of LNCaP-ENZaR tumor xenografts in mouse models with both 43/47Sc-PSMA-617 are also presented.

Current Landscape of Targeted Therapies for Hormone-Receptor Positive, HER2 Negative Metastatic Breast Cancer.

The majority of deaths from MBC are in patients with hormone receptor (HR) positive, HER2 negative disease. Endocrine therapy (ET) remains the backbone of treatment in these cases, improving survival and quality of life. However, treatment can lose effectiveness due to primary or acquired endocrine resistance. Analysis of mechanisms of ET resistance has led to the development of a new generation of targeted therapies for advanced breast cancer. In addition to anti-estrogen therapy with selective estrogen receptor modulators, aromatase inhibitors, and/or selective estrogen receptor degraders, combinations with cyclin dependent kinase (CDK) 4/6 inhibitors have led to substantial progression free survival (PFS) improvements in the first and second line settings. While the PI3K/AKT/mTOR pathway is known to be an important growth pathway in HR positive breast cancer, PI3K inhibitors have been disappointing due to modest effect sizes and significant toxicity. The mTOR inhibitor everolimus significantly improves progression free survival when added to ET, and recent studies have improved supportive care allowing less toxicity. While these combination targeted therapies improve outcomes and often delay initiation of chemotherapy, long term overall survival data are lacking and data for the ideal strategy for sequencing these agents remains unclear. Ongoing research evaluating potential biomarkers and mechanisms of resistance is anticipated to continue to improve outcomes for patients with HR positive metastatic breast cancer. In this review, we will discuss management and ongoing challenges in the treatment of advanced HR positive, HER2 negative breast cancer, highlighting single agent and combination endocrine therapies, targeted therapies including palbociclib, ribociclib, abemaciclib, and everolimus, and sequencing of therapies in the clinic.

Improving efficiency and safety in external beam radiation therapy treatment delivery using a Kaizen approach.

INTRODUCTION: Modern external beam radiation therapy treatment delivery processes potentially increase the number of tasks to be performed by therapists and thus opportunities for errors, yet the need to treat a large number of patients daily requires a balanced allocation of time per treatment slot. The goal of this work was to streamline the underlying workflow in such time-interval constrained processes to enhance both execution efficiency and active safety surveillance using a Kaizen approach. METHODS AND MATERIALS: A Kaizen project was initiated by mapping the workflow within each treatment slot for 3 Varian TrueBeam linear accelerators. More than 90 steps were identified, and average execution times for each were measured. The time-consuming steps were stratified into a 2 × 2 matrix arranged by potential workflow improvement versus the level of corrective effort required. A work plan was created to launch initiatives with high potential for workflow improvement but modest effort to implement. Time spent on safety surveillance and average durations of treatment slots were used to assess corresponding workflow improvements. RESULTS: Three initiatives were implemented to mitigate unnecessary therapist motion, overprocessing of data, and wait time for data transfer defects, respectively. A fourth initiative was implemented to make the division of labor by treating therapists as well as peer review more explicit. The average duration of treatment slots reduced by 6.7% in the 9 months following implementation of the initiatives (P = .001). A reduction of 21% in duration of treatment slots was observed on 1 of the machines (P < .001). Time spent on safety reviews remained the same (20% of the allocated interval), but the peer review component increased. CONCLUSIONS: The Kaizen approach has the potential to improve operational efficiency and safety with quick turnaround in radiation therapy practice by addressing non-value-adding steps characteristic of individual department workflows. Higher effort opportunities are identified to guide continual downstream quality improvements.

Analysis of the transcriptome of the Indonesian coelacanth Latimeria menadoensis.

BACKGROUND: Latimeria menadoensis is a coelacanth species first identified in 1997 in Indonesia, at 10,000 Km of distance from its African congener. To date, only six specimens have been caught and just a very limited molecular data is available. In the present work we describe the de novo transcriptome assembly obtained from liver and testis samples collected from the fifth specimen ever caught of this species. RESULTS: The deep RNA sequencing performed with Illumina technologies generated 145,435,156 paired-end reads, accounting for ~14 GB of sequence data, which were de novo assembled using a Trinity/CLC combined strategy. The assembly output was processed and filtered producing a set of 66,308 contigs, whose quality was thoroughly assessed. The comparison with the recently sequenced genome of the African congener Latimeria chalumnae and with the available genomic resources of other vertebrates revealed a good reconstruction of full length transcripts and a high coverage of the predicted full coelacanth transcriptome. CONCLUSION: Given the high genomic affinity between the two coelacanth species, the here described de novo transcriptome assembly can be considered a valuable support tool for the improvement of gene prediction within the genome of L. chalumnae and a valuable resource for investigation of many aspects of tetrapod evolution.

3D photography in the objective analysis of volume augmentation including fat augmentation and dermal fillers.

The authors present quantitative and objective 3D data from their studies showing long-term results with facial volume augmentation. The first study analyzes fat grafting of the midface and the second study presents augmentation of the tear trough with hyaluronic filler. Surgeons using 3D quantitative analysis can learn the duration of results and the optimal amount to inject, as well as showing patients results that are not demonstrable with standard, 2D photography.

Quantitative evaluation of volume augmentation in the tear trough with a hyaluronic Acid-based filler: a three-dimensional analysis.

BACKGROUND: Despite the prevalent use of hyaluronic acid-based filling materials for facial soft-tissue augmentation and favorable reports of durability in the infraorbital region, no quantitative data exist on the long-term durability of these products following injection. This study represents the first attempt to use three-dimensional imaging to quantify augmentation achieved and duration of effect with one hyaluronic acid product in the tear trough. METHODS: The authors conducted a prospective, blinded case series in a clinical setting. One non-animal stabilized hyaluronic acid material was used to augment 20 tear troughs to address cosmetic deficiency in this region. Patients were followed long term with three-dimensional imaging. Posttreatment and pretreatment images were compared, volume change was calculated at each time point, and percentage change between immediate and long-term posttreatment was evaluated. All measurements and calculations were performed independent of the injector. RESULTS: Residual effect from the hyaluronic acid product was demonstrable on three-dimensional imaging in 100 percent of tear troughs augmented in this study at the final follow-up visit. Average follow-up was 14.4 months (range, 8.5 to 22.75 months). Average initial augmentation measured by three-dimensional imaging was 0.21 cc per site. Average maintenance of effect for patients at the final follow-up visit was 85 percent. CONCLUSIONS: The long-term durability of a small gel particle-based hyaluronic acid in the tear trough is substantiated for the first time in an objective, quantitative fashion using three-dimensional imaging for evaluation of volumetric facial rejuvenation. Three-dimensional photographic imaging offers clinicians a precise and expeditious method for quantitatively evaluating volumetric changes in the face, and represents a significant advance in technology for studying the effects of facial aging.

Structure-based drug design: from nucleic acid to membrane protein targets.

The in silico methods for drug discovery are becoming increasingly powerful and useful. That, in combination with increasing computer processor power, in our case using a novel distributed computing grid, has enabled us to greatly enhance our virtual screening efforts. Herein we review some of these efforts using both receptor and ligand-based virtual screening, with the goal of finding new anti-cancer agents. In particular, nucleic acids are a neglected set of targets, especially the different morphologies of duplex, triplex, and quadruplex DNA, many of which have increasing biological relevance. We also review examples of molecular modeling to understand receptors and using virtual screening against G-protein coupled receptor membrane proteins.

Autologous fat grafting: long-term evidence of its efficacy in midfacial rejuvenation.

OBJECTIVE: To provide quantitative objective data demonstrating the longevity and amount of volume augmentation in the midface obtained with autologous fat grafting. METHODS: A prospective analysis of all patients who underwent autologous fat transfer to the midface region at our private practice and were followed up for at least 1 year. Three-dimensional imaging was performed with a Canfield Scientific Vectra camera and software, with quantitative volume measurements evaluating the amount of postoperative volume change. RESULTS: Thirty-three patients (66 hemiface-midface regions) were included in the study. The mean follow-up time was 16 months. The mean amount of autologous fat injected into each midface region was 10.1 mL. Overall, the mean absolute volume augmentation measured at their last postoperative visit was 3.3 mL (31.8% take). There was variability between patients in the volume amount and percentage that remained. Touch-up procedures were performed in 8 patients. CONCLUSIONS: To our knowledge, this study is the first clinical quantification of autologous fat transfer and/or grafting in the literature that provides definitive evidence on the amount as well as the resultant longevity in the midface. Autologous fat transfer to the midface has definite long-term volume augmentation results. On average, approximately 32% of the injected volume remains at 16 months. However, some variability exists in the percentage of volume that remains that may require a touch-up procedure.

A novel, macrophage migration inhibitory factor suicide substrate inhibits motility and growth of lung cancer cells.

Although chemokine and growth factor receptors are attractive and popular targets for cancer therapeutic intervention, structure-based targeting of the ligands themselves is generally not considered practical. New evidence indicates that a notable exception to this is macrophage migration inhibitory factor (MIF). MIF, an autocrine- and paracrine-acting cytokine/growth factor, plays a pivotal role in both the initiation and maintenance of neoplastic diseases. MIF possesses a nonphysiologic enzymatic activity that is evolutionarily well-conserved. Although small molecule antagonists of MIFs enzymatic active site have been reported to inhibit biological activities of MIF, universally high IC(50)s have limited their clinical appeal. Using a computational virtual screening strategy, we have identified a unique small molecule inhibitor that serves as a suicide substrate for MIF, resulting in the covalent modification of the catalytically active NH(2)-terminal proline. Our studies further reveal that this compound, 4-iodo-6-phenylpyrimidine (4-IPP), is approximately 5x to 10x times more potent in blocking MIF-dependent catalysis and lung adenocarcinoma cell migration and anchorage-independent growth than the prototypical MIF inhibitor, ISO-1. Finally, using an in silico combinatorial optimization strategy, we have identified four unique congeners of 4-IPP that exhibit MIF inhibitory activity at concentrations 10x to 20x lower than that of parental 4-IPP.

Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth.

6-phosphofructo-1-kinase, a rate-limiting enzyme of glycolysis, is activated in neoplastic cells by fructose-2,6-bisphosphate (Fru-2,6-BP), a product of four 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isozymes (PFKFB1-4). The inducible PFKFB3 isozyme is constitutively expressed by neoplastic cells and required for the high glycolytic rate and anchorage-independent growth of ras-transformed cells. We report herein the computational identification of a small-molecule inhibitor of PFKFB3, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), which suppresses glycolytic flux and is cytostatic to neoplastic cells. 3PO inhibits recombinant PFKFB3 activity, suppresses glucose uptake, and decreases the intracellular concentration of Fru-2,6-BP, lactate, ATP, NAD+, and NADH. 3PO markedly attenuates the proliferation of several human malignant hematopoietic and adenocarcinoma cell lines (IC50, 1.4-24 micromol/L) and is selectively cytostatic to ras-transformed human bronchial epithelial cells relative to normal human bronchial epithelial cells. The PFKFB3 enzyme is an essential molecular target of 3PO because transformed cells are rendered resistant to 3PO by ectopic expression of PFKFB3 and sensitive to 3PO by heterozygotic genomic deletion of PFKFB3. Importantly, i.p. administration of 3PO (0.07 mg/g) to tumor-bearing mice markedly reduces the intracellular concentration of Fru-2,6-BP, glucose uptake, and growth of established tumors in vivo. Taken together, these data support the clinical development of 3PO and other PFKFB3 inhibitors as chemotherapeutic agents.

Endoscopic management of recurrent congenital tracheoesophageal fistula: a review of techniques and results.

OBJECTIVE: Recurrent tracheoesophageal fistula (TEF) is a difficult problem in both diagnosis and management. Revision open repair with thoracotomy is challenging and has a significant associated morbidity. Because of the technical difficulty and the substantial morbidity, several authors have suggested and implemented endoscopic management. This paper reviews and describes the endoscopic techniques and management of recurrent TEF. METHODS: This retrospective study evaluates three patients who underwent endoscopic (bronchoscopic) management of recurrent TEF at Children's Memorial Hospital in Chicago, Illinois. Median follow-up is 48 months. A current literature review is presented with a synthesis of the data on techniques and results. RESULTS: Two of the three patients had successful bronchoscopic closure using fibrin adhesive. The mean number of procedures required was two. Including these patients, 62 patients with endoscopic closure of congenital TEF have been reported in the literature. The overall success rate is 60% with a mean of 2.1 procedures per patient. Of the obliterating agents described, tissue adhesive and fibrin adhesive have been employed most frequently with success rates of 48 and 55%, respectively. CONCLUSION: Endoscopic repair of recurrent TEF is an effective and safe alternative to second thoracotomy and open surgical repair. More than one endoscopic procedure is usually necessary for successful closure.

Continuous intraoperative facial nerve monitoring in predicting postoperative injury during parotidectomy.

OBJECTIVES/HYPOTHESIS: To assess whether the use of continuous intraoperative facial nerve monitoring correlates to postoperative facial nerve injury during parotidectomy. STUDY DESIGN: A retrospective analysis. METHODS: Forty-five consecutive parotidectomies were performed using an electromyograph (EMG)-based intraoperative facial nerve monitor. Of those, 37 had complete data for analysis. Intraoperative findings and final interpretation of the EMGs were analyzed by a senior neurologist and neurophysiologist. All patients were analyzed, including those with preoperative weakness and facial nerve sacrifice. RESULTS: The overall incidence of facial paralysis (House-Brackmann scale > 1) was 43% for temporary and 22% for permanent deficits. This includes an 11% incidence of preoperative weakness and 14% with intraoperative sacrifice. An abnormal EMG occurred in only 16% of cases and was not significantly associated with permanent or temporary facial nerve paralysis (chi, P < 1.0; Fisher's exact P < .68). Of the eight patients with permanent paralysis, only two had abnormalities on the facial nerve monitor. Also, only one of five patients with intraoperative sacrifice of the facial nerve had an abnormal EMG. Factors significantly associated with the incidence of facial paralysis include malignancy, advanced age, extent of parotidectomy, and dissection beyond the parotid gland (chi and Fisher's, P < .05). CONCLUSIONS: The results suggest that abnormalities on the intraoperative continuous facial nerve monitor during parotidectomy do not predict facial nerve injury. The incidence of permanent and temporary facial nerve paralysis compare favorably with the literature given that this study includes patients with revision surgery, intraoperative sacrifice, and preoperative paralysis. Standard of care implications will be discussed.

Altered pigment epithelium-derived factor and vascular endothelial growth factor levels in lymphangioma pathogenesis and clinical recurrence.

OBJECTIVE: To determine the role of angiogenesis in the clinical behavior and pathogenesis of lymphangioma tumors. DESIGN: A retrospective study. Median follow-up period was 44.5 months. SETTING: Children's Memorial Hospital, Chicago, Ill. PATIENTS: Tumor specimens from 12 pediatric patients who underwent surgical excision of cervicofacial lymphangioma were examined for expression of angiogenic inducer vascular endothelial growth factor (VEGF) and angiogenic inhibitor pigment epithelium-derived factor (PEDF) using immunohistochemical analysis. Specimens were divided into recurrent and nonrecurrent tumors based on clinical information. MAIN OUTCOME MEASURES: Staining patterns of VEGF and PEDF were evaluated in lymphangioma specimens. Staining patterns were then compared in both recurrent and nonrecurrent groups and graded in a blinded fashion. Histological evidence of increased angiogenesis including microvascular density, stromal fibrosis, and inflammation were graded in each group and correlated with recurrence. RESULTS: Lymphangioma specimens demonstrated histological evidence of increased angiogenic activity including multiple areas of increased VEGF staining combined with little PEDF staining. Sex, age at onset, or tumor location did not correlate with recurrence. Furthermore, recurrent specimens had increased histological evidence of angiogenesis as well as increased VEGF and decreased PEDF activity compared with nonrecurrent lesions. CONCLUSIONS: Lymphangiomas exhibit tumorlike pathogenesis owing to the high expression of angiogenic inducers compared with the low expression of inhibitors. Recurrence may be influenced by this imbalance of angiogenic mediators. Further research with antiangiogenic therapy using agents such as PEDF analogues or anti-VEGF receptor antibodies is indicated because they may stabilize or suppress the growth of these neoplasms.