Search

An entry point medial to the tip of the greater trochanter is considered optimal for antegrade femur nailing. The deforming forces in a subtrochanteric fracture often make it difficult to establish a perfect entry point during antegrade cephalomedullary nailing. To overcome this problem, we report a simple technique of making a retrograde entry portal for select difficult subtrochanteric fractures. The technique was used in 12 subtrochanteric fractures. Our indications were morbid obesity, revision nailing and atypical fractures. The technique involves creating a nail entry portal through the fracture from distal to proximal taking advantage of the abducted proximal fragment. Fracture reduction and nail insertion then proceeds in a standard manner. Additional reaming of the thick endosteal lateral cortex through the fracture was performed in atypical fractures. Satisfactory fracture reduction was achieved in all patients and 11 out of the 12 fractures united in the series. 1 patient developed an infected nonunion and was considered failure of treatment. The retrograde entry portal is a valuable alternative method that can be considered in nailing of difficult subtrochanteric fractures to establish an ideal entry point and nail trajectory.

Objectives To report surgical outcomes, palliative durability, and quality of life (QOL) after palliative robotic cystectomy (RC) for symptomatic advanced prostate cancer (PC). Methods Retrospective review of patients who underwent RC (n=10) at our institution from 2013-2018. European Organization for Research and Treatment of Cancer (EORTC) Functional Assessment of Cancer Therapy – Bladder Cystectomy (FACT-BL-CYS) questionnaire was administered to assess QOL. Patient characteristics, peri-operative outcomes, changes in pre-operative symptoms, and FACT-BL-CYS scores were assessed post-operatively. Results Mean age was 70 years (IQR, 64-72), and median follow up was 505 days. Five patients (50%) had prior radiation therapy (RT). Rates of perioperative and delayed complications were 30% and 30%, respectively. There were no cases of rectal injury. At latest follow up, there were no cases of urinary obstruction, hematuria, or pelvic pain, and 80% of patients remained symptom free. Six of ten patients responded to the questionnaire and completed the FACT-BL-CYS. Individual sub-domain scores (physical, social, functional, emotional, bladder specific) and overall scores were similar to post-operative radical cystectomy populations in other studies. 100% of responding patients would repeat RC. Conclusion RC appears to be a safe and effective option for advanced PC refractory to other interventions. The majority of patients would repeat the procedure. However, given the differences in goals of care for patients undergoing surgery for curative intent vs for palliation, we lack the ability to make true inferences regarding measurable improvements in quality of life; this highlights the need for high quality multi-institutional studies to better understand the impact of RC on QOL.

INTRODUCTION: Altered lipid metabolism and subsequent changes in cellular lipid composition have been observed in prostate cancer cells, are associated with poor clinical outcome, and are promising targets for metabolic therapies. This study reports for the first time on the synthesis of a phospholipid radiotracer based on the phospholipid 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine (PC44:12) to allow tracking of polyunsaturated lipid tumor uptake via PET imaging. This tracer may aid in the development of strategies to modulate response to therapies targeting lipid metabolism in prostate cancer. METHODS: Lipidomics analysis of prostate tumor explants and LNCaP tumor cells were used to identify PC44:12 as a potential phospholipid candidate for radiotracer development. Synthesis of phosphocholine precursor and non-radioactive standard were optimised using click chemistry. The biodistribution of a fluorine-18 labeled analogue, N-{[4-(2-[18F]fluoroethyl)-2,3,4-triazol-1-yl]methyl}-1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine ([18F]2) was determined in LNCaP prostate tumor-bearing NOD SCID gamma mice by ex vivo biodistribution and PET imaging studies and compared to biodistribution of [18F]fluoromethylcholine. RESULTS: [18F]2 was produced with a decay-corrected yield of 17.8 ± 3.7% and an average radiochemical purity of 97.00 ± 0.89% (n = 6). Molar activity was 85.1 ± 3.45 GBq/μmol (2300 ± 93 mCi/μmol) and the total synthesis time was 2 h. Ex vivo biodistribution data demonstrated high liver uptake (41.1 ± 9.2%ID/g) and high splenic uptake (10.9 ± 9.1%ID/g) 50 min post-injection. Ex vivo biodistribution showed low absolute tumor uptake of [18F]2 (0.8 ± 0.3%ID/g). However, dynamic PET imaging demonstrated an increase over time of the relative tumor-to-muscle ratio with a peak of 2.8 ± 0.5 reached 1 h post-injection. In contrast, dynamic PET of [18F]fluoromethylcholine demonstrated no increase in tumor-to-muscle ratios due to an increase in both tumor and muscle over time. Absolute uptake of [18F]fluoromethylcholine was higher and peaked at 60 min post injection (2.25 ± 0.29%ID/g) compared to [18F]2 (1.44 ± 0.06%ID/g) during the 1 h dynamic scan period. CONCLUSIONS AND ADVANCES IN KNOWLEDGE: This study demonstrates the ability to radiolabel phospholipids and indicates the potential to monitor the in vivo distribution of phospholipids using fluorine-18 based PET. ispartof: NUCLEAR MEDICINE AND BIOLOGY vol:93 pages:37-45 ispartof: location:United States status: published

Background Metaphyseal fracture healing in the distal femur requires a stable biomechanical environment. The presence of arthritis-induced coronal-plane knee deformities can cause deviation of the mechanical axis, which results in asymmetric loading and increased bending forces in fractures of the distal femur metaphysis. This predisposes patients to nonunions or loss of fixation. Concurrent TKA during revision osteosynthesis might facilitate fracture healing, owing to its ability to correct coronal alignment, thereby restoring normal loading patterns at the fracture site, but to our knowledge, this has not been studied. Questions/purposes (1) Does TKA with concurrent revision internal fixation achieve fracture union in patients with coronal-plane deformity from knee arthritis and nonunion or loss of fixation in distal metaphyseal femoral fractures? (2) What is the survivorship and what are the short-term functional outcomes after these reconstructions? (3) What complications occur after these reconstructions? Methods Between 2015 and 2018, one surgeon treated 16 patients with a distal metaphyseal femur fracture nonunion and/or loss of fixation using concurrent TKA plus revision internal fixation. Autologous iliac crest bone grafting was performed in five patients with evident gaps at the fracture site. The indications for the procedure included patients older than 55 years of age presenting with a nonunion and/or loss of fixation of a distal metaphyseal femur fracture in the setting of painful Ahlback Grade III to V knee arthritis with an associated coronal-plane deformity. All patients meeting these indications were treated with this approach during the study period. Fracture union assessed by radiological bridging of at least three cortices, TKA survival free from revision due to any reason, coronal-plane correction using tibiofemoral angle, and patient mobility status assessed presurgery and at follow-up using the Parker mobility score (scored 0-9 points, with 9 indicating best mobility) were assessed by two surgeons who were not involved in the care of the study patients. Immediate and delayed complications were recorded. Patients were followed for a minimum of 24 months. The median (range) follow-up was 38 months (27 to 52 months). Results All fractures united after concurrent TKA plus revision internal fixation. In all, 14 of 16 fractures healed before 5 months, while the remaining two fractures united by 6 months. Survivorship analysis revealed a TKA component survival of 94% (95% CI 63% to 99%) at 52 months. The median (range) preoperative Parker mobility score of 5 points (3 to 8) improved to 7 points (2 to 9) at 12 months postoperatively and was maintained at last follow-up (p = 0.001). Four patients experienced complications; these were (1) prolonged surgical wound drainage resulting in debridement and polyethylene liner exchange, (2) deep knee infection needing a staged revision, (3) popliteal vein thrombosis, and (4) prolonged graft site pain. Conclusion Concurrent TKA plus revision internal fixation is effective for achieving union in patients with distal metaphyseal femur nonunion and loss of fixation in the setting of coronal-plane deformity induced by knee arthritis. Short-term TKA survival and improvement in patient mobility are excellent, although 4 of 16 patients in this report experienced complications, as one might expect with a procedure of this magnitude. Based on our results, correction of arthritis-induced coronal-plane knee malalignment can be considered part of the surgical strategy when treating such distal metaphyseal femur nonunions. Better preoperative evaluation of the deformity and control-based comparative studies can further validate the utility of this technique. Level of evidence Level II, therapeutic study.

Introduction: It is well known that the SARS-CoV-2 virus that causes COVID-19 could enter the human host through the oral cavity. In patients with periodontal disease, there is an increase of Furin, Cathepsin, and CD14+ CD16+ monocytes. The hypothesis stated here sheds light on the regular need of periodontal management to reduce inflammation and the levels of deleterious host enzymes and cytokines, which could pave the way for deadly viral diseases such as COVID-19. The Hypothesis: Patients with periodontal disease are at increased risk of SARS-CoV-2 infection due to elevated levels of Furin and Cathepsin in oral cavity and COVID-19 complications like cytokine storm could occur with increased frequency in patients with periodontal disease due to the significant increase of CD14+ CD16+ monocytes in blood. Evaluation of the Hypothesis: Oral and periodontal examination of patients with mild, moderate, and severe SARS-CoV-2 infection could shed light on the significant role played by periodontal disease in making an individual more prone to get SARS-CoV-2 infection by elevation of Furin and Cathepsin and the elevation of CD14+CD16+ monocytes and proinflammatory cytokines in the blood that could consequently worsen COVID-19 complications like cytokine storm. The blood counts of CD14+CD16+ monocytes need to be assayed in SARS-CoV-2 patients with and without periodontal disease to observe if periodontal disease as a coexisting condition elevates the proportion of CD14 CD16+ monocytes in SARS-CoV-2 patients. In fact, assessment of monocyte subsets in peripheral blood could be used as an immunosurveillance marker in SARS-CoV-2 patients. Hence, SARS-CoV-2 positive patients with chronic periodontal disease should be closely monitored for potential signs of a cytokine storm and its related complications.

Background In the setting of intra-articular distal radius fractures, the volar lunate facet (VLF) is the only articular segment that resists volar carpal subluxation. So, it is important to achieve a stable fixation of this key fragment. The VLF, when small (also called as volar marginal fragment, VMF) is located distal to the watershed line making fixation with the conventional volar locking plates difficult or impossible. Methods 18 patients with either an AO: 2R3B3 or a C3 fracture consisting of a VMF underwent surgical repair through a volar approach. The VMF was stabilised using a anatomical volar hook plate. Remaining fracture components were stabilised using 2.4/ 2.0 mm locked plates. Fracture healing, ability of the hook plate to maintain reduction of the VMF and complications were assessed during follow up. Functional outcome was evaluated using Mayo score and patient rated wrist evaluation questionnaires. Results All fractures united at follow up. Reduction of the VMF was maintained through healing with a stable radiocarpal and distal radioulnar joint. The mean flexion - extension wrist arc was 105° ± 10.2° The mean grip strength reached 74.6 ± 6% of the opposite side. The mean Mayo wrist score was 75 ± 5.3 and the mean patient rated wrist evaluation (PRWE) score was 15.2 ± 4.3 indicating recovery of wrist function. Conclusion It is important to identify VMFs in intra-articular distal radius fractures. Anatomically designed volar hook plate achieves excellent low-profile stable fixation of this key fragment to allow early mobilisation without fearing loss of reduction and volar carpal subluxation.

Accurate component positioning is the key for successful outcome after total hip arthroplasty (THA). Positioning acetabular and femoral components in a safe zone of 25°–50° on the basis of combined anteversion (CA) has shown to reduce instability and impingement. This safe zone was described for THAs performed through the posterior approach and has not been validated for other surgical approaches. Seventy patients who underwent unilateral uncemented THA were included in the study; 35 patients—using posterior approach and the remaining 35—using trans-gluteal approach. All patients included had a stable and impingement-free THA at a mean follow-up of 39.2 ± 9.5 months. CT scan was performed to assess component positioning by calculating CA. The values were compared between the two groups to study possible differences. CA in the trans-gluteal group was significantly lower (32° ± 3.7° vs 38.4° ± 4.6°, P

The paper confers the use of phytochemicals in resisting of several diseases caused by different microbes/pathogen. In the current scenario, there is a high demand for proven plant therapies, herbal drugs, and other natural products, as well as their therapeutic application, which are often found to be more effective than synthetic pharmaceuticals in chronic diseases. In many cases, plant extracts, herbal formulations, and phytochemicals perfectly supplement the typical therapy and at the same time do not cause side effects for example skin irritation, gastrointestinal problems. It is an urgent demand to find out complete therapeutic potential and adverse effects, of these phytochemical compounds because of the continued rise of drug‐resistant bacterial infections.

The 17q23 amplicon is associated with poor outcome in ER+ breast cancers, but the causal genes to endocrine resistance in this amplicon are unclear. Here, we interrogate transcriptome data from primary breast tumors and find that among genes in 17q23, PRR11 is a key gene associated with a poor response to therapeutic estrogen suppression. PRR11 promotes estrogen-independent proliferation and confers endocrine resistance in ER+ breast cancers. Mechanistically, the proline-rich motif-mediated interaction of PRR11 with the p85α regulatory subunit of PI3K suppresses p85 homodimerization, thus enhancing insulin-stimulated binding of p110-p85α heterodimers to IRS1 and activation of PI3K. PRR11-amplified breast cancer cells rely on PIK3CA and are highly sensitive to PI3K inhibitors, suggesting that PRR11 amplification confers PI3K dependence. Finally, genetic and pharmacological inhibition of PI3K suppresses PRR11-mediated, estrogen-independent growth. These data suggest ER+/PRR11-amplified breast cancers as a novel subgroup of tumors that may benefit from treatment with PI3K inhibitors and antiestrogens., The 17q23 amplicon is associated with poor outcome in ER+ breast cancers, but the causal genes responsible endocrine resistance in this region are unclear. In this study, the authors demonstrate that PRR11 located at 17q23, is critical for conferring endocrine resistance through activation of PI3K signalling and therefore propose PI3K inhibition as a treatment for PRR11-amplified breast cancers.

Guar gum was hydrophobically modified by microwave assisted condensation with dimer acid (DA, a dimer of ricinoleic acid derived from castor oil) under “green” conditions. The condensation product (HMG) was then blended with polyvinyl alcohol and cast into films abbreviated as HMGF (hydrophobically modified guar gum film). FTIR and UV–visible spectroscopies, X-ray diffractometry, swelling, permeability and tensile strength measurements were used to evaluate the properties of HMG and HMGF. HMGF exhibits optimal mechanical strength with UV protective effect and restricted entry of chemical contaminants. HMGF could be easily disposed by burying in soil. HMGF may be a potential eco-friendly food packaging material.

Radiation dose intensification improves outcome in men with high-risk prostate cancer (HR-PCa). A prospective trial was conducted to determine safety, feasibility, and maximal tolerated dose of multilevel magnetic resonance imaging (MRI)-based 5-fraction SABR in patients with HR-PCa.This phase I clinical trial enrolled patients with HR-PCa with grade group ≥4, prostate-specific antigen (PSA) ≥20 ng/mL, or radiographic ≥T3, and well-defined prostatic lesions on multiparametric MRI (mpMRI) into 4 dose-escalation cohorts. The initial cohort received 47.5 Gy to the prostate, 50 Gy to mpMRI-defined intraprostatic lesion(s), and 22.5 Gy to pelvic lymph nodes in 5 fractions. Radiation doses were escalated for pelvic nodes to 25 Gy and mpMRI lesion(s) to 52.5 Gy and then 55 Gy. Escalation was performed sequentially according to rule-based trial design with 7 to 15 patients per cohort and a 90-day observation period. All men received peri-rectal hydrogel spacer, intraprostatic fiducial placement, and 2 years of androgen deprivation. The primary endpoint was maximal tolerated dose according to a 90-day acute dose-limiting toxicity (DLT) rate33%. DLT was defined as National Cancer Institute Common Toxicity Criteria for Adverse Events ≥grade 3 treatment-related toxicity. Secondary outcomes included acute and delayed gastrointestinal (GI)/genitourinary (GU) toxicity graded with Common Toxicity Criteria for Adverse Events.Fifty-five of the 62 enrolled patients were included in the analysis. Dose was escalated through all 4 cohorts without observing any DLTs. Median overall follow-up was 18 months, with a median follow-up of 42, 24, 12, and 7.5 months for cohorts 1 to 4 respectively. Acute and late grade 2 GU toxicities were 25% and 20%, while GI were 13% and 7%, respectively. Late grade 3 GU and GI toxicities were 2% and 0%, respectively.SABR dose for HR-PCa was safely escalated with multilevel dose painting of 47.5 Gy to prostate, 55 Gy to mpMRI-defined intraprostatic lesions, and 25 Gy to pelvic nodal region in 5 fractions. Longer and ongoing follow-up will be required to assess late toxicity.

Histone deacetylase inhibitors (HDACi) are identified as novel therapeutic agents, however, recent clinical studies suggested that they are marginally effective in treating triple negative breast cancer (TNBC). Here, we show that first-in-class Leukemia Inhibitory Factor Receptor (LIFRα) inhibitor EC359 could enhance the therapeutic efficacy of HDACi against TNBC. We observed that both targeted knockdown of LIFR with CRISPR or treatment with EC359 enhanced the potency of four different HDACi in reducing cell viability, cell survival, and enhanced apoptosis compared to monotherapy in TNBC cells. RNA-seq studies demonstrated oncogenic/survival signaling pathways activated by HDACi were attenuated by the EC359 + HDACi therapy. Importantly, combination therapy potently inhibited the growth of TNBC patient derived explants, cell derived xenografts and patient-derived xenografts in vivo. Collectively, our results suggest that targeted inhibition of LIFR can enhance the therapeutic efficacy of HDACi in TNBC., Li, Viswanadhapalli et al utilized multiple in vitro, ex vivo and in vivo models of TNBC to investigate LIFR inhibition. The authors reported that HDAC inhibition in TNBC cells led to an increase of LIFR expression and over activation of the downstream signaling elements (e.g., STAT3, mTOR, AKT), enhancing the aggressive potential of TNBC cells, and an LIFR inhibitor, EC359, synergistically enhanced the efficacy of HADC inhibitors in suppressing TNBC in vitro and in vivo.

The androgen receptor (AR) plays a central role in prostate cancer. Development of castration resistant prostate cancer (CRPC) requires androgen-independent activation of AR, which involves its large N-terminal domain (NTD) and entails extensive epigenetic changes depending in part on histone lysine demethylases (KDMs) that interact with AR. The AR-NTD is rich in low-complexity sequences, including a polyQ repeat. Longer polyQ sequences were reported to decrease transcriptional activity and to protect against prostate cancer, although they can lead to muscular atrophy. However, the molecular mechanisms underlying these observations are unclear. Using NMR spectroscopy, here we identify weak interactions between the AR-NTD and the KDM4A catalytic domain, and between the AR ligand-binding domain and a central KDM4A region that also contains low-complexity sequences. We also show that the AR-NTD can undergo liquid-liquid phase separation in vitro, with longer polyQ sequences phase separating more readily. Moreover, longer polyQ sequences hinder nuclear localization in the absence of hormone and increase the propensity for formation of AR-containing puncta in the nucleus of cells treated with dihydrotestosterone. These results lead us to hypothesize that polyQ-dependent liquid-liquid phase separation may provide a mechanism to decrease the transcriptional activity of AR, potentially opening new opportunities to design effective therapies against CRPC and muscular atrophy.

Background: ESR1 mutations are acquired following ERα targeted therapies and are a major determinant of therapy-resistance. These ESR1 mutations maintain ESR1 signaling, albeit in a ligand-independent manner. Effective drugs targeting these mutant (MT) ERα proteins represent a significant unmet clinical need. We had previously shown that ERX-11, an ESR1-coregulator binding inhibitor, could block the function of these MT ERα proteins. In this study, we sought to leverage recently published structures of MT ERα to develop more potent analogues of ERX-11. Methods: Virtual screening of >250,000 derivatives of ERX-11 was performed with simulated docking on the MT ERα to identify and design analogues of ERX-11. Several hundred analogues were synthesized and tested in vitro using multiple BC model cells that express wild type (WT) ESR1 or mutant (MT) ESR1 (Y537S or D538G). Mechanistic studies were performed using RNA-Seq, Western blotting, qRT-PCR and reporter gene assays. The in vivo efficacy of the most potent ERX-11 analogue ERX-245 was examined using xenograft, PDX and metastatic models of MT-ER driven BC. Results: From our virtual and functional screen, we identified an ERX-11 analogue, ERX-245 as the most potent hit to target MT-ERα. Docking studies modeled a better fit of ERX-245 into the ligand binding domain of both the Y537S and D538G MT-ERα. ERX-245 potently reduced (IC50 ~250 nM) the cell viability of both WT-ERα and MT-ERα driven BC cells but not ERα negative BC cells. ERX-245 significantly reduced the growth (colony formation, clonogenic and mammosphere assays) of MT-ERα BC cells. ERX-245 exhibited synergistic activity in combination with CDK4/6 inhibitors. In distinction to classic SERDs like fulvestrant (which degrade ERα with in 4h), ERX-245 treatment decreased MT-ERα protein levels over 24 hours. PK studies indicated that ERX-245 is more polar and has better solubility and pharmacokinetic properties than ERX-11. ERX-245 reduced tumor growth of subcutaneous xenograft and PDX models driven by MT-ERα as well as the proliferation of xenograft derived MT-ERα explant models. ERX-245 significantly reduced the invasive capability of MT-ERα BC cells in vitro and inhibited both the metastatic capability and growth of metastatic tumors derived from MT-ERα BC cells injected by intracardiac or intratibial routes. Conclusions: Taken together, these results indicate that ERX-245 is a potent and pharmacologically translatable analog of ERX-11, with activity against both primary and metastatic tumors driven by MT-ERα. Citation Format: Ganesh V Raj, Suryavathi Viswanadhapalli, Karla Parra, Shihong Ma, Tae-Kyung Lee, Xihui Liu, Kara Kassees, Weiwei Tang, Junhao Liu, Zexuan Liu, Uday P Pratap, Behnam Ebrahimi, Rajeshwar Rao Tekmal, Jung-Mo Ann, Ratna K Vadlamudi. Development of a potent mutant-ESR1 targeted agent, ERX-245, for treating metastatic therapy-resistant breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-09.

Introduction: Giant cell tumor (GCT) most commonly involves distal femoral condyles, distal end of radius, proximal tibial plateau, and proximal humerus. GCT is uncommon to occur in small bones of hand and feet. 2% of GCT occur in hand. The incidence of GCT in foot is 1.2–1.8%. Only a few cases have been reported in literature worldwide. GCT is the most common cause of secondary ABC. We report a case of GCT of intermediate cuneiform in a 25-year-old female evolving into aneurysmal bone cyst (ABC). Case Report: A 25-year-old female presented to us with complaints of pain and swelling over the dorsum of right foot for a period of 1 year. On examination, there was a localized ovoid-shaped swelling of 2 by 2 cm over the dorsum of right foot. Radiographs revealed a well-defined osteolytic lesion in the intermediate cuneiform. T2 MRI showed hyper-intense lesion in intermediate cuneiform. The patient was taken up for surgery, and the intermediate cuneiform was excised completely. Removed bone was sent for histopathological examination which confirmed it to be GCT evolving into secondary ABC. The patient was followed for 1 year and had no complaints. The patient was able to weight bear and walk without any difficulty. There was no recurrence of lesion. Conclusion: GCT of the cuneiform evolving into ABC is a very rare presentation. The treatment of choice is excision of the tumor with or without bone grafting. Any osteolytic lesion in the small bones must be evaluated and should be intervened in the early stage. Keywords: Giant cell tumor, osteolytic lesion, surgical resection, intermediate cuneiform.

INTRODUCTION AND OBJECTIVE:Radical nephroureterectomy (RNU) and cystectomy (RC) are commonly performed in urologic oncology, but their concurrent use is rare. Here, we report the perioperative and ...

Purpose: Protein kinases are known to play a prominent role in oncogenic progression across multiple cancer subtypes, yet their role in prostate cancer progression remains underexplored. The purpose of this study was to identify kinases that drive prostate cancer progression. Experimental Design: To discover kinases that drive prostate cancer progression, we investigated the association between gene expression of all known kinases and long-term clinical outcomes in tumor samples from 545 patients with high-risk disease. We evaluated the impact of genetic and pharmacologic inhibition of the most significant kinase associated with metastatic progression in vitro and in vivo. Results: DNA-dependent protein kinase (DNAPK) was identified as the most significant kinase associated with metastatic progression in high-risk prostate cancer. Inhibition of DNAPK suppressed the growth of both AR-dependent and AR-independent prostate cancer cells. Gene set enrichment analysis nominated Wnt as the top pathway associated with DNAPK. We found that DNAPK interacts with the Wnt transcription factor LEF1 and is critical for LEF1-mediated transcription. Conclusions: Our data show that DNAPK drives prostate cancer progression through transcriptional regulation of Wnt signaling and is an attractive therapeutic target in aggressive prostate cancer.

Introduction: Fulvestrant is currently the only selective estrogen receptor degrader (SERD) that is approved for clinical use in estrogen receptor (ER) positive advanced breast cancer (ABC). The drug is approved as single-agent therapy in the first and second-line setting of metastatic ER-positive breast cancer. Areas covered: In this review, the authors review the preclinical studies that were pivotal in the development of fulvestrant, the pharmacologic properties of the drug, and the key clinical trials that resulted in its approval for clinical use. The authors discuss mechanisms of endocrine resistance and potential targets for endocrine refractory disease while highlighting ongoing studies that assess fulvestrant use with novel agents. Expert opinion: While fulvestrant has limited use in the first-line setting in advanced breast cancer, it is most frequently used in the second line after progression with aromatase inhibitors. The combination of fulvestrant with CDK4/6 inhibitors has shown a clear benefit over monotherapy in patients who progress on prior endocrine therapy. Further study is necessary to assess if patient outcomes can be enhanced by optimizing the sequence of endocrine therapies, targeting resistance pathways with novel agents, and development of new agents in the SERD class.

Alternative donor allogeneic hematopoietic cell transplants (HCTs), such as double umbilical cord blood transplants (dUCBT) and haploidentical related donor transplants (haplo-HCT), have been shown to be safe and effective in adult patients who do not have an HLA-identical sibling or unrelated donor available. Most transplant centers have committed to 1 of the 2 alternative donor sources, even with a lack of published randomized data directly comparing outcomes and comparative data on the cost-effectiveness of dUCBT versus haplo-HCT. We conducted a retrospective study to evaluate and compare the early costs and charges of haplo-HCT and dUCBT in the first 100 days at 2 US transplant centers. Forty-nine recipients of haplo-HCT (at 1 center) and 37 with dUCBT (at another center) were included in the analysis. We compared graft acquisition, inpatient/outpatient, and total charges in the first 100 days. The results of the analysis showed a significantly lower cost of graft acquisition and lower total charges (for 100-day HCT survivors) in favor of haplo-HCT. Importantly, to control for the obvious shortcomings of comparing costs at 2 different transplant centers, adjustments were made based on the current (2018) local wage index and inflation rate. In the absence of further guidance from a prospective study, the cost analysis in this study suggests that haplo-HCT may result in early cost savings over dUCBT and may be preferred by transplant centers and for patients with more limited resources.

Femoral neck nonunion in young patients has always been a difficult problem to deal with for surgeons. Numerous surgical procedures to address either the biological or mechanical issues at the nonunion have been described and most of them have been associated with variable results. Isolated biological augmentation is often associated with poor results and some techniques like vascularized grafting may require not so commonly available expertise. Valgus osteotomy is aimed to correct the abnormal fracture biomechanics associated with femoral neck fractures. By altering the nature of force transmission across the nonunion, shear forces are converted into compressive forces that lead to rapid osseous union without the need for bone grafting. Though the principles are sound and were described a long time ago, the technical aspects have evolved over time. Various modifications have been described to overcome shortcomings such as limb length discrepancy, reduction of femoral offset, alteration in mechanical axis, and the overall proximal femur anatomy. In this review, we look back at the fundamental principles and recent literature on the results of valgus intertrochanteric osteotomy for femoral neck pseudoarthrosis. We also highlight the important need for accurate preoperative planning and surgical execution. Lastly, we elaborate on the technical improvisations that have happened over time in order to improve functional results and to minimize complications and poor outcome after a valgus osteotomy.

IFNγ, a potent cytokine known to modulate tumor immunity and tumoricidal effects, is highly elevated in patients with prostate cancer after radiation. In this study, we demonstrate that IFNγ can induce epithelial-to-mesenchymal transition (EMT) in prostate cancer cells via the JAK–STAT signaling pathway, leading to the transcription of IFN-stimulated genes (ISG) such as IFN-induced tetratricopeptide repeat 5 (IFIT5). We unveil a new function of IFIT5 complex in degrading precursor miRNAs (pre-miRNA) that includes pre-miR-363 from the miR-106a-363 cluster as well as pre-miR-101 and pre-miR-128, who share a similar 5′-end structure with pre-miR-363. These suppressive miRNAs exerted a similar function by targeting EMT transcription factors in prostate cancer cells. Depletion of IFIT5 decreased IFNγ-induced cell invasiveness in vitro and lung metastasis in vivo. IFIT5 was highly elevated in high-grade prostate cancer and its expression inversely correlated with these suppressive miRNAs. Altogether, this study unveils a prometastatic role of the IFNγ pathway via a new mechanism of action, which raises concerns about its clinical application. Significance: A unique IFIT5–XRN1 complex involved in the turnover of specific tumor suppressive microRNAs is the underlying mechanism of IFNγ-induced epithelial-to-mesenchymal transition in prostate cancer. See related commentary by Liu and Gao, p. 1032

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer and represents a disproportional share of the breast cancer mortality, primarily due to a lack of targeted therapies. There is a major unmet need for rationally designed novel therapies that can extend survival of patients with TNBC. TNBCs are characterized by a high basal level of endoplasmic reticulum stress, due to high protein turnover and need for proliferation. Recent studies revealed the role of several members of the Nuclear Receptor (NR) superfamily as molecular drivers in TNBC, including the androgen receptor (AR), glucocorticoid receptor (GR) and the orphan NR tailless (TLX). Methods: Recently, using peptidomimetics, we have developed small molecules that specifically target and block interactions of multiple coregulators with oncogenic NRs. We performed a screen of our 500+ compound peptidomimetic library derived from our ERX-11 oligobenzamide (that was rationally designed to target ERα) for anti-proliferative activity in TNBC cell lines. Identified leads were then validated in multiple TNBC cell lines. In vitro activity was tested using Cell titer glo, MTT, matrigel invasion, and apoptosis assays. Mechanistic studies were conducted using Western blot, reporter gene assays, CRISPR/Cas9 KO and RNA-seq analysis. Xenograft, patient derived xenograft (PDX), patient derived explant (PDE) and xenograft derived explant (XDE) TNBC models were used for preclinical evaluation and toxicity. Results: We have identified a first-in-class drug (ERX-41) that has potent activity (IC50 = 50-250nM) against all six molecular subtypes of TNBC. Systematic evaluation using CRISPR/Cas9 KO screen and overexpression screen comprising 48 NRs identified TLX as a preferred target of ERX-41. Analyses of primary breast tumors revealed TLX was highly expressed in TNBC. Further, TLX was amplified in nearly 50% of TNBC xenografts (cbioportal.org). Modelling, mechanistic and biochemical studies showed that ERX-41 interact with TLX and selectively blocks its interactions with coregulators. Gene expression analyses revealed both significant reduction of TLX-activated genes (CCND1, WNT7A) and significant activation of TLX-repressed genes (p21) upon treatment with ERX-41 in TNBC models. Gene ontogeny pathway analyses of RNA-seq data in TNBC cells showed that ERX-41 treatment positively correlated with apoptosis. Our ultrastructural studies indicated that ERX-41 enhances endoplasmic reticulum stress in TNBC inducing autophagic flux and subsequent apoptosis. ERX-41 has significant potency against multiple TNBC xenografts and PDXs in vivo, PDEs and XDEs ex vivo, indicating its potential for clinical translation. Pharmacologically, ERX-41 exhibited high oral bioavailability and associated with minimal toxicity upon oral gavage for up to 120 days in animal studies. Conclusions: We believe that the ability of ERX-41 to block NR signaling and target a critical molecular vulnerability in TNBC and its ability to enhance endoplasmic reticulum stress in TNBC, will revolutionize the therapeutic landscape of TNBC. ERX-41 is oral bioavailable, potent against multiple TNBC molecular subtypes, and is associated with minimal systemic side effects. (supported by NIH grant RO1 CA223828-01) Citation Format: Liu X, Viswanadhapalli S, Ma S, Lee T-K, Sareddy GR, Ekoue DN, Blatt EM, Zhou M, Li M, Tekmal RR, Ahn J-m, Vadlamudi RK, Raj GV. A small molecule inhibitor (ERX-41) induces endoplasmic reticulum stress in triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-07-01.

The treatment and management of prostate cancer continues to evolve; newer classes of agents and combination therapies are being developed and some are being investigated in early phase clinical trials.We discuss investigational hormonal agents for the treatment of prostate cancer and focus primarily on luteinizing hormone releasing hormone (LHRH) agonists in early stage trials. We look at agents that target the hormonal axis, including anti-androgens, gonadotropins, estrogenic agents and progestogenic agents and other non-hormonal agents often used in combination with LHRH agonists. We review these candidates in the specific clinical niche in which they might find utility.Of all candidate compounds being evaluated in clinical trials, very few will receive FDA approval. Few, if any of the investigational agents discussed here will be used routinely in clinical practice for treating prostate cancer. Recognizing the reasons for the failure of agents to advance to later stage trials is important. Furthermore, a thorough understanding of the mechanisms underlying prostate cancer pathogenesis, including various points in the HGPA and parallel pathways, will help identify potentially actionable targets.

Objectives To determine the implications of different prostate sampling schemes on the diagnosis of clinically significant prostate cancer (csPCA, ISUP group 2–5) and clinically insignificant prostate cancer (ciPCA, ISUP group 1) in men with abnormal multiparametric magnetic resonance imaging (mpMRI) undergoing MRI-transrectal ulrasound fusion targeted biopsies. Materials and Methods This is a retrospective analysis of a cohort including all men who had a single lesion on mpMRI of the prostate performed between January 2016 and June 2017. All men underwent an MRI-transrectal ulrasound fusion biopsy and systematic (SBx) sampling of the prostate, which combined and were considered the standard of reference. The hypothetical 3 biopsy sampling schemes were defined as follows: Targeted biopsy only (TBx), TBx + ipsilateral SBx (ipsi-SBx) and TBx + contralateral SBx (contra-SBx) and were evaluated for the detection of csPCA and ciPCA. Sensitivity and 95% intervals were calculated, McNemar test was used to compare sensitivities between the various sampling schemes. Results TBx + SBx detected csPCa in 47% (55 of 116) of the 116 men who met eligibility criteria. Sensitivity and 95% confidence intervals for csPCa detection was 85.5% (73.3%–93.5%), 96.4% (87.5%–99.6%), and 92.7 (82.4%–98%) for TBx alone, TBx + ipsi-SBx and TBx + contra-SBx, respectively. csPCa detection rates were higher for both TBx + ipsi-SBx and TBx + contra-SBx compared to TBx alone. Clinically insignificant cancers alone were detected in 7.7% (9 of 116), 10.3% (12 of 116), and 14.6% (17 of 116) of the cohort by TBx only and TBx + ipsi-SBx, and TBx + contra-SBx, respectively. Conclusions TBx + ipsi-SBx may increase the detection of csPCa while limiting overdiagnosis of indolent cancers.

Summary Background We report the clinical efficacy against COVID-19 infection of BBV152, a whole virion inactivated SARS-CoV-2 vaccine formulated with a toll-like receptor 7/8 agonist molecule adsorbed to alum (Algel-IMDG) in Indian adults. Methods We did a randomised, double-blind, placebo-controlled, multicentre, phase 3 clinical trial in 25 Indian hospitals or medical clinics to evaluate the efficacy, safety, and immunological lot consistency of BBV152. Adults (age γ18 years) who were healthy or had stable chronic medical conditions (not an immunocompromising condition or requiring treatment with immunosuppressive therapy) were randomised 1:1 with a computer-generated randomisation scheme (stratified for the presence or absence of chronic conditions) to receive two intramuscular doses of vaccine or placebo administered 4 weeks apart. Participants, investigators, study coordinators, study-related personnel, the sponsor, and nurses who administered the vaccines were masked to treatment group allocation; an unmasked contract research organisation and a masked expert adjudication panel assessed outcomes. The primary outcome was the efficacy of the BBV152 vaccine in preventing a first occurrence of laboratory-confirmed (RT-PCR-positive) symptomatic COVID-19 (any severity), occurring at least 14 days after the second dose in the per-protocol population. We also assessed safety and reactogenicity throughout the duration of the study in all participants who had received at least one dose of vaccine or placebo. This report contains interim results (data cutoff May 17, 2021) regarding immunogenicity and safety outcomes (captured on days 0 to 56) and efficacy results with a median of 99 days for the study population. The trial was registered on the Indian Clinical Trials Registry India, CTRI/2020/11/028976, and ClinicalTrials.gov, NCT04641481 (active, not recruiting). Findings Between Nov 16, 2020, and Jan 7, 2021, we recruited 25 798 participants who were randomly assigned to receive BBV152 or placebo; 24 419 received two doses of BBV152 (n=12 221) or placebo (n=12 198). Efficacy analysis was dependent on having 130 cases of symptomatic COVID-19, which occurred when 16 973 initially seronegative participants had at least 14 days follow-up after the second dose. 24 (0·3%) cases occurred among 8471 vaccine recipients and 106 (1·2%) among 8502 placebo recipients, giving an overall estimated vaccine efficacy of 77·8% (95% CI 65·2–86·4). In the safety population (n=25 753), 5959 adverse events occurred in 3194 participants. BBV152 was well tolerated; the same proportion of participants reported adverse events in the vaccine group (1597 [12·4%] of 12 879) and placebo group (1597 [12·4%] of 12 874), with no clinically significant differences in the distributions of solicited, unsolicited, or serious adverse events between the groups, and no cases of anaphylaxis or vaccine-related deaths. Interpretation BBV152 was highly efficacious against laboratory-confirmed symptomatic COVID-19 disease in adults. Vaccination was well tolerated with no safety concerns raised in this interim analysis. Funding Bharat Biotech International and Indian Council of Medical Research.

The stiffness of large arteries, measured locally from a small segment or regionally over a long trajectory, has a highly clinically relevant role in cardiovascular hemodynamics. A comprehensive measure of vascular stiffness accounting for both the local and regional stiffness indices has strong potential in stratifying risks of future events. Existing technologies are not amenable for such combined measurements, especially with provisions for easy-to-use, minimal operator dependency, portability, and field deployability. In this work, we report a novel device with these features that perform simultaneous measurement of local and regional stiffness indices. The device uses a single-element ultrasound transducer to measure carotid diameter waveforms in an image-free manner. It estimates the carotid local stiffness indices such as stiffness index (β), pressure-strain elastic modulus (EP), and one-point local pulse wave velocity (PWV β ). A bladder-type thigh cuff enabled the synchronized acquisition of femoral pressure pulse wave, and was used to measure the carotid-femoral pulse wave velocity (cfPWV) – the gold-standard regional aortic stiffness index. An in-vivo study on 35 subjects verified the functionality and measurement reliability of the ARTSENS®. The measured beat-by-beat carotid β (range: 2.71 – 11.15), EP (range: 32.31 – 153.65 kPa), and PWV β (range: 3.50 – 7.72 m/s) were repeatable with variability < 8.7%. The cfPWV measurements were in agreement with that provided by SphygmoCor device (R = 0.93, p < 0.001, and mean absolute error = 4.82%). The association between local and regional stiffness indices was further investigated. This study demonstrated a strong potential of using ARTSENS® to easily evaluate local and regional stiffness for screening in clinical and resource-constrained settings.

The heterogeneity of cancer necessitates developing a multitude of targeted therapies. We propose the view that cancer drug discovery is a low rank tensor completion problem. We implement this vision by using heterogeneous public data to construct a tensor of drug-target-disease associations. We show the validity of this approach computationally by simulations, and experimentally by testing drug candidates. Specifically, we show that a novel drug candidate, SU11652, controls melanoma tumor growth, including BRAFWT melanoma. Independently, we show that another molecule, TC-E 5008, controls tumor proliferation on ex vivo ER+ human breast cancer. Most importantly, we identify these chemicals with only a few computationally selected experiments as opposed to brute-force screens. The efficiency of our approach enables use of ex vivo human tumor assays as a primary screening tool. We provide a web server, the Cancer Vulnerability Explorer (accessible at https://cavu.biohpc.swmed.edu), to facilitate the use of our methodology.

Prostate cancer (PCa) and breast cancer (BCa) are both hormone-dependent cancers that require the androgen receptor (AR) and estrogen receptor (ER, ESR1) for growth and proliferation, respectively. Endocrine therapies that target these nuclear receptors (NRs) provide significant clinical benefit for metastatic patients. However, these therapeutic strategies are seldom curative and therapy resistance is prevalent. Because the vast majority of therapy-resistant PCa and BCa remain dependent on the augmented activity of their primary NR driver, common mechanisms of resistance involve enhanced NR signaling through overexpression, mutation, or alternative splicing of the receptor, coregulator alterations, and increased intracrine hormonal synthesis. In addition, a significant subset of endocrine therapy-resistant tumors become independent of their primary NR and switch to alternative NR or transcriptional drivers. While these hormone-dependent cancers generally employ similar mechanisms of endocrine therapy resistance, distinct differences between the two tumor types have been observed. In this review, we compare and contrast the most frequent mechanisms of antiandrogen and antiestrogen resistance, and provide potential therapeutic strategies for targeting both advanced PCa and BCa.

The study of DNA damage repair response (DDR) in prostate cancer is restricted by the limited number of prostate cancer cell lines and lack of surrogates for heterogeneity in clinical samples. Here, we sought to leverage our experience with patient derived explants (PDEs) cultured ex vivo to study dynamics of DDR in primary tumors following application of clinically relevant doses of ionizing radiation (IR) to tumor cells in their native 3-dimensional microenvironment. We compared DDR dynamics between prostate cancer cell lines, PDEs and xenograft derived explants (XDEs) following treatment with IR (2Gy) either alone or in combination with pharmacological modulators of DDR. We have shown that following treatment with 2Gy, DDR can be consistently detected in PDEs from multiple solid tumors, including prostate, kidney, testes, lung and breast, as evidenced by γ-H2AX, 53BP1, phospho-ATM and phospho-DNA-PKcs foci. By examining kinetics of resolution of IR-induced foci, we have shown that DDR in prostate PDEs (complete resolution in 8 h) is much faster than in prostate cancer cell lines (, Highlights • IR induces distinct DNA damage repair kinetics in prostate cancer PDEs and cell lines. • IR induces a distinct transcriptional program in prostate cancer PDE and cell lines. • DNA-PKcs inhibition blocks IR-induced DDR in prostate cancer PDE. • Inhibition of AR impairs NHEJ in prostate cancer PDEs.

Background: Ultrasonographic imaging to record changes in peripheral arterial diameter associated with Flow mediated dilatation or Low flow mediated constriction is routinely used to assess various facets of vascular endothelial function. Imaging poses many challenges including requirement of costly ultrasound machines, trained manpower to perform imaging and effort-intensive steps to analyse the images subsequently using manual or automated methods. We tested the feasibility and validity of using an imaging-free technology to record resting arterial diameters of brachial and radial arteries. Methods: Eight healthy volunteers initially underwent ultrasonographic imaging (M7, Mindray; Shenzhen, P.R. China) of brachial artery and proximal radial artery. The brachial and radial artery ‘zones’ thereby identified through imaging were surface marked on subject’s arm. Imaging-free ARTSENS® Pen device [1] (Healthcare Technology Innovation Centre, IIT Madras, India) consisting of highly integrated hardware for operating a single element broadband ultrasound transducer (centre-frequency = 5 MHz, spatial half angle

Background: Arterial stiffness index (β) is a clinically accepted vascular metric, calculated from arterial pressure and diameter obtained simultaneously from a single arterial site [1]. Hence, accurate measurement of β can only be performed on arteries where pressure can be recorded along with the diameter. We present a method to evaluate β from superficial arteries using arterial force (F) and diameter (D) waveforms, employing mathematical models (shown below) exploiting the non-linear pressure-diameter relationship [2], without requiring absolute pressure. Methods: Pilot functionality assessment was performed on eight participants (24 ± 5 years). A custom-developed frequency-matched system, combining single-element ultrasound and force-sensing transducers, was used to measure D and F waveforms from the common carotid artery. A hemodynamic-loop was formed from these measures and optimised to eliminate viscous components, and evaluate the elastic stiffness index β. Traditional β-formula [2] yielded reference values for comparison. fe(t)=fmx×(eβ(D(t)Dd−1)−1eβ(DsDd−1)−1) fe(t): Viscosity eliminated arterial force fmx: Maxima of viscosity eliminated arterial force β : Stiffness index D(t): Arterial diameter Ds: Systolic diameter Dd: Diastolic diameter Results: The system captured high fidelity D and F waveforms, adequate for reliable β evaluation. Measured group-average β (4.7 ± 0.8) was concurrent with literature. The measured β values statistically agreed (LoA = ±0.83 and bias = –0.32; non-significant p > 0.05) and strongly correlated (r = 0.93, p < 0.001) with the reference values. Further, they exhibited acceptable beat-to-beat repeatability (variation

OBJECTIVE To evaluate the legacy of endocrinologist Jean Wilson, whose discovery in 1969 of 5 alpha-reductase (5AR) and description of dihydrotestosterone (DHT) as the primary hormone associated with prostatic growth ushered in a golden age of collaboration between endocrinologists, oncologists, and urologists that led to some of the critical discoveries in the understanding and treatment of prostatic pathology. MATERIALS AND METHODS A review of the medical literature between 1969 and 2020 was conducted and multiple authors interviewed. RESULTS In 1969, Gloyna and Wilson demonstrated the reduction of testosterone to DHT in the prostate. With Bruchovsky, Wilson established that DHT was the primary hormone associated with prostatic growth. Wilson went on to show that androgens are involved in every aspect of prostate development, growth, and function. Wenderoth and Wilson then showed that a 5AR inhibitor blocked the prostatic growth. Subsequently, clinical trials with therapies targeting 5AR were led by Roehrborn and McConnell. Tilley and Wilson with Marcelli and McPhaul cloned the human androgen receptor at UT Southwestern in 1989 and provided the first evidence that androgen receptor was a transcriptional factor that could regulate its own expression in prostate cancer. Androgen receptor mutations explaining the molecular basis of androgen resistance syndromes were first described by Wilson, McPhaul, et al in the early 1990s. CONCLUSION Basic, translational, and clinical research has played a pivotal role in our current understanding of prostatic disease. Much of this legacy is credited to Jean Wilson and the cross-pollination of world-class scientists across fields, whom he inspired.

Safe surgical dislocation with a trochanteric flip osteotomy has been shown to be a reliable technique that provides excellent exposure for treating femoral-head fractures with minimal complications. This technique also allows associated labral injuries and acetabular fractures to be treated through the same approach. DESCRIPTION: The procedure is performed with use of a conventional Kocher-Langenbeck exposure with the patient in the lateral position. The trochanteric flip is performed, allowing exposure of the anterior capsule, which is incised to dislocate the head anteriorly. Fracture fixation is performed with use of mini-fragment screws followed by relocation of the head, closure of the capsulotomy, and fixation of the osteotomy. ALTERNATIVES: Fixation of femoral-head fractures can also be performed with use of alternate surgical approaches. Anterior-based surgical approaches like the Hueter approach or the Smith-Petersen approach are preferred with the goal of preserving the posterior extraosseous blood supply to the femoral head. The posterior Kocher-Langenbeck approach can also be utilized because there is no clear evidence suggesting that a properly performed posterior approach affects the blood supply of the femoral head. RATIONALE: Surgical hip dislocation is 1 of the preferred techniques for operative treatment of femoral-head fractures and is a versatile approach that provides circumferential exposure of the femoral head and acetabulum through an anterior dislocation. A compromised blood supply to the femoral head is much less likely with use of this approach compared with posterior-based surgical approaches. Compared with anterior-based surgical approaches, which are often restrictive, surgical dislocation is extensile and provides adequate exposure to treat associated injuries to the acetabulum and the labrum of the hip. EXPECTED OUTCOMES: Outcomes following surgical dislocation for femoral-head fractures are reportedly good to excellent in >80% patients. Urgent reduction of the hip joint followed by anatomical reduction of the fracture and stable fixation of the fracture and osteotomy leads to predictably good results. Notable complications include heterotopic ossification, which has been reported in up to 60% patients, as well as osteonecrosis of the femoral head (often related to the initial injury rather than the approach) and degenerative arthritis of the hip joint. IMPORTANT TIPS: The Gibson interval may be utilized to preserve the gluteus maximus. Identify all of the posterior structures starting proximally from the posterior border of the gluteus medius, and continuing to the piriformis, triceps coxae, quadratus femoris, and the vastus lateralis. Aim for a thickness of 1 to 1.5 cm when performing the osteotomy; an osteotomy that is either too thick or too thin can negatively affect outcomes. The osteotomy should begin just anterior to the posterior fibers of the gluteus medius to ensure that the osteotomy is anterior to the piriformis tendon. It should exit distally to the vastus lateralis origin. Carefully elevate the posterior margin of the gluteus minimis from the capsule to avoid the tethering effect during anterior translation of the osteotomized fragment. Capsular tears during the initial dislocation are common and should be incorporated into the anterior capsulotomy. Repair of large posterosuperior labral tears may improve outcomes. Fixation of the fracture can be performed with mini-fragment screws or headless screws. Non-fixable small fragments can be excised. The osteotomy should be reduced and fixed in a stable manner to prevent trochanteric nonunion and preserve abductor function.

PURPOSE Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services. METHODS A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider). RESULTS Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing—initial testing of priority genes followed by expanded testing—was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches. CONCLUSION This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

BackgroundResistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer remains a significant clinical problem. Riluzole is FDA-approved for the treatment of amyotrophic lateral sclerosis. A benzothiazole-based glutamate release inhibitor with several context-dependent mechanism(s) of action, Riluzole has shown anti-tumor activity in multiple malignancies, including melanoma, glioblastoma, and breast cancer. We previously reported that the acquisition of Tamoxifen resistance in a cellular model of invasive lobular breast cancer is accompanied by the upregulation of GRM mRNA expression and growth inhibition by Riluzole.MethodsWe tested the ability of Riluzole to reduce cell growth, alone and in combination with endocrine therapy, in a diverse set of ER+ invasive ductal and lobular breast cancer-derived cell lines, primary breast tumor explant cultures, and the estrogen-independent,ESR1-mutated invasive lobular breast cancer patient-derived xenograft model HCI-013EI.ResultsSingle-agent Riluzole suppressed the growth of ER+ invasive ductal and lobular breast cancer cell linesin vitro, inducing a histologic subtype-associated cell cycle arrest (G0-G1 for ductal, G2-M for lobular). Riluzole induced apoptosis and ferroptosis and reduced phosphorylation of multiple pro-survival signaling molecules, including Akt/mTOR, CREB, and Src/Fak family kinases. Riluzole, in combination with either Fulvestrant or 4-hydroxytamoxifen, additively suppressed ER+ breast cancer cell growthin vitro. Single-agent Riluzole significantly inhibited HCI-013EI patient-derived xenograft growthin vivo, and the combination of Riluzole plus Fulvestrant significantly reduced proliferation in primary breast tumor explant cultures.ConclusionsRiluzole, alone or combined with endocrine therapy, may offer therapeutic benefits in diverse ER+ breast cancers, including lobular breast cancer.

OBJECTIVES To compare outcomes after surgical treatment of Pipkin I and II femoral head fractures treated with either a surgical dislocation (SD) or a direct anterior approach (the modified Heuter approach). STUDY DESIGN Retrospective, multicentre. SETTING Three Level I trauma care centers. PATIENTS Fourty-nine patients operated for Pipkin types I or II femoral head fractures. Twenty-seven using SD and 22 using the modified Heuter approach. INTERVENTIONS Initial closed reduction of the joint followed by open reduction and internal fixation of the fracture/fragment excision. Fixation was performed using headless or countersunk mini fragment screws. OUTCOME MEASUREMENTS The 2 groups were compared for (1) perioperative measures: blood loss, surgical time, pain [visual analog scale (VAS)], and length of hospital stay; (2) radiological outcome in terms of fracture union, occurrence of posttraumatic hip arthritis, and femoral head osteonecrosis; and (3) functional outcome using the modified Merle d' Aubigne score and Oxford hip scores. RESULTS Surgical time, blood loss, and VAS at 24 hours were significantly lower in the modified Heuter group. The VAS at discharge and length of stay were similar in both groups. All fractures had united. No cases of osteonecrosis were observed. Functional outcome and complications were similar in both groups. CONCLUSIONS Both SD and the modified Heuter approach are effective in treating patients with Pipkin I and II femoral head fractures with comparable radiological and functional outcomes. LEVEL OF EVIDENCE Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Estrogen receptor-positive (ER+) breast cancer is the most commonly diagnosed form of this malignancy. Aromatase inhibitors and selective estrogen receptor modulators or degraders (SERMS, SERDs) can be highly effective in treating ER+ breast cancer, but de novo and acquired resistance to these interventions is a persistent clinical problem. Endocrine therapy resistant breast cancer cells rewire their metabolism to support cellular demands associated with rapid proliferation and/or increased invasion and metastasis. An important feature of this metabolic flexibility is conversion of glutamine to glutamate, an amino acid integral to protection of cells from oxidative stress. Consistent with this, we show multiple cellular models of ER+, endocrine resistant breast cancer cells markedly increase glutamate release and upregulate expression of essential glutamine/glutamate metabolic enzymes and transporters, including the glutamate/cystine antiporter xCT, glutamate dehydrogenase (GLUD1/2), and/or the glutamine importer SLC1A5. Riluzole (RIL) is FDA-approved for the treatment of amyotrophic lateral sclerosis (ALS), and has several proposed mechanisms of action, including suppression of glutamate release and increased glutamate uptake. We show ER+, endocrine responsive and resistant breast cancer cells are growth-inhibited by RIL. This is due to an increase in cell death, particularly in endocrine resistant breast cancer cells, and cell cycle arrest. Interestingly, histologic subtype confers a different cell cycle arrest profile, with invasive ductal cancer (IDC) models arresting in G1 but invasive lobular cancer (ILC) models arresting in G2/M. Isobologram analysis of RIL plus SERMs or SERDs shows additive-to-synergistic activity in a subset of ER+ cell line models, and preliminary studies show combination activity in patient-derived explants (PDEs). Mechanistically, we tested whether signaling through metabotropic glutamate receptors (mGluRs, GRMs) and/or cystine import contribute to RIL’s growth-inhibitory phenotype. Antagonists of mGluRs/GRMs don’t phenocopy the effects of RIL, suggesting extracellular glutamate signaling through these receptors is not a key mechanism. Rescue experiments with β-mercaptoethanol to promote cystine uptake through transporters other than xCT show partial reversal of RIL-mediated cell cycle arrest in some cells, suggesting xCT may contribute to RIL-induced growth inhibition. In summary, we show RIL may be a viable addition to endocrine therapy in ER+ breast cancer. Ongoing studies will test additional mechanism(s) by which RIL may attenuate the growth of ER+ breast cancer models in vitro, including inhibition of protein kinase C and casein kinase 1 delta. We are further testing RIL efficacy alone and in combination with a SERD in primary tumors and lung metastases in a ER+ patient-derived xenograft (PDX) model.

Background: Radiofrequency probes have been used extensively in various arthroscopic procedures. Measurable cartilage damage occurs after radiofrequency probe application. However, the histological changes of cartilage damage following radiofrequency chondroplasty have not been extensively studied. Materials & Methods: Articular cartilage specimens were obtained from patients undergoing total knee replacement surgeries. Radiofrequency probes were applied at 1, 3 and 5 seconds and samples were sent to histopathology laboratory. The histological changes of cartilage damage were analyzed using the International Cartilage Repair Society (ICRS) assessment scale. Safranin O staining was done to assess the proteoglycan content. Results: Histologically measurable articular cartilage damage occurs after radiofrequency probes Conclusions: The time of application of radiofrequency probes should be optimized so as to minimize cartilage damage.

Background: Breast cancer is a heterogeneous group of disease, and recently, intrinsic sub-typing on the basis of gene expression profiling is found to be a predictor of breast cancer clinical course. The St. Gallen has released surrogate classification for breast cancer sub-types depending on immunohistochemistry (IHC) markers. Aim: The aim of our study was to analyze the distribution of sub-types using IHC surrogate markers in our patient population and to assess the clinico-pathological factors in different sub-types. Materials and Methods:A total of 635 non-metastatic patients who underwent radical intend treatment from January 2011 to December 2013 were included for this retrospective analysis. A statistical analysis was done by Windows SPSS version 20. The Chi-square test was used to examine the correlations of these sub-types with clinico-pathological parameters. The Kaplan-Meier method estimates were used for survival analysis. Results: The median follow-up was 42.77 months (5 months to 112 months). Luminal B was the predominant group. Disease free survival (DFS) at 5 years was 95% in luminal A, 78% in luminal B HER-2 negative, 80% in luminal B HER-2 positive, 72% in triple negative, and 79% in HER-2/neu non-luminal. Tumor size, Ki67, T stage, N stage, and grade were significantly associated with DFS in all biological type with a P value of less than 0.05. Conclusion: Surrogate classification was successfully applied in our patient cohort. Luminal B and triple negative sub-groups were more prevalent in our patients, and this finding is at variance with published international data. Biological sub-type also emerged as an important predictor of survival.

T cell–replete post-transplant cyclophosphamide (PTCy)-based protocols have led to increasing use of haploidentical allogeneic hematopoietic cell transplantation (haploHCT). With this approach, bidirectional alloreactivity causing nonengraftment or severe graft-versus-host disease (GVHD) is no a longer major barrier to haploHCT. PTCy eliminates alloreactive lymphocytes but spares CD34+ stem cells and regulatory T lymphocytes, resulting in reliable hematopoietic recovery with relatively low incidence of GVHD. The immediate post-haploHCT course, usually before PTCy administration, is often complicated by cytokine release syndrome (CRS). The predictors of CRS and its effect on outcomes post-transplant have not been fully ascertained. We analyzed the outcomes of 66 patients who received haploHCT at our institution. Using published CRS criteria we identified 48 patients who developed CRS. In multivariate analysis peripheral blood grafts were significantly associated with grade ≥ 2 CRS, compared with bone marrow. Grade ≥ 2 CRS (compared with grade

BACKGROUND: Recently,CDK4/6 inhibitors in combination with endocrine therapy (AE/AI/SERDs) is approved for the treatment of ER+ advanced breastcancer (BCa). However, not all patients benefit from CDK4/6 inhibitors therapy. Emerging studies indicate many therapy-resistant tumors retainER signaling, via interaction with critical oncogenic coregulatorproteins. Considering complex signaling interplay of ER and CDK4/6 axis, combination therapy of CDK inhibitor with other potent ER-targeted agents that block ER coregulatory signaling may extend the efficacy and may prevent the development of resistance to the CDK4/6 inhibitors. We recently developed a small organic molecule, ER coregulator binding modulator ERX-11 (EtiraRx-11). The objective of this study is to test the utility of novel combination therapy of ERX-11 with CDK4/6 inhibitor palbociclib in treating therapy resistant advanced BCa. METHODS: We have utilized multiple therapy sensitive and therapy-resistant BCa models with various genetic backgrounds. We tested efficacy using both acquired resistance and engineered models that express ER mutations or oncogenes. Efficacy of combination therapy was tested using established in vitro assays including, MTT, colony formation, apoptosis, and cell cycle progression. Mechanistic studies were conducted using reporter gene assays, gene expression, RNA-seq analysis and signaling alterations. Patient-derived BCa explant and Xenograft studies were used to determine the in vivo efficacy of the combination therapy. RESULTS: ERX-11 effectively blocked ER-mediated and ER-coregulator mediated oncogenic signaling and has potent anti-proliferative activity against both endocrine therapy-sensitive and therapy-resistant BCa cells. Mechanistic studies using IP-Mass spectrometry showed that ERX-11 blocks the interaction between a subset of coregulators with ER in resistant BCa models. ERX-11 exhibited potent anti-proliferative activity against therapy-sensitive and therapy-resistant ER-driven BCa cells in vitro, in xenograft models in vivo and in patient-derived breast tumor explants ex vivo. Co-treatment of ERX-11 with palbociclib synergistically reduced cell viability and induced apoptosis of therapy sensitive and resistant BCa model cells. Importantly, combination therapy of ERX-11 and the palbociclib synergistically reduced the growth and induced apoptosis of tamoxifen and letrozole resistant xenograft tumors compared to either drug alone. RNA-seq studies revealed that combinational treatment with ERX-11 and palbociclib uniquely activated p53 and unfolded response mediated apoptotic pathways and suppressed E2F and Myc target genes. Biochemical studies confirmed combination therapy significantly altered E2F1 and ER signaling pathways and promoted apoptosis. CONCLUSIONS: Our data support a critical role of blocking ER coregulator signaling in treating therapy resistance in advanced ER+ BCa. Combinational treatment with ERX-11 and palbociclib may overcome/delay endocrine therapy resistance. Citation Format: Viswanadhapalli S, Sareddy GR, Zhou M, Ali E, Li X, Ma S-H, Lee T-K, Tekmal RR, Ahn J-M, Raj GV, Vadlamudi RK. Blocking ER coregulator signaling enhances CDK4/6 inhibitor palbociclib therapy in ER-positive advanced breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-09-06.

Objective To describe epidemiologic patterns, stage at presentation, histology, and treatment differences associated with Hispanic men diagnosed with testicular germ cell tumor (TGCT). Hispanics are the fastest growing demographic in the United States and reports suggest that the incidence of TGCT is rising most rapidly in this demographic, yet little is known about TGCTs in Hispanic patients. Materials and Methods We compared patient factors, tumor characteristics, treatment patterns, and outcomes of non-Hispanic white (NHW) vs Hispanic patients at our own institution in North Texas from 2010 to 2016. The findings were corroborated by analyzing the National Cancer Database testicular cancer registry from 2004 to 2014. Results We identified 154 patients with TGCT at our institution, of which 89 were NHW (56.0%) and 65 were Hispanic (40.9%). A review of the National Cancer Database identified 49,607 NHW patients (81.5%) and 6724 Hispanic patients (11.0%) diagnosed with TGCT. At presentation, Hispanic patients were approximately 5 years younger than NHW patients, delay seeking care for testicular cancer, were more likely to have nonseminomatous histology, had a larger tumor size, and had a higher disease burden at presentation. Additionally, we identified differences in treatment patterns at the national level. Conclusion Differences in outcomes and treatment patterns of Hispanic and NHW patients with TGCT may represent underlying socioeconomic issues and access to care; however, discrepancies in age of onset and histology of TGCT between Hispanic and NHW patients may signify differences in tumor biology or risk factors. We suggest that this possibility be explored further as we embark upon the genomic classification of TGCT.

The proposed study examined the preparation of chitosan (CS)–polyvinylpyrrolidone (PVP)–bovine serum albumin (BSA)-coated magnetic iron oxide (Fe3O4) nanoparticles (Fe3O4–CS–PVP–BSA) to use as potential drug delivery carriers for delivery of tamoxifen drug (TAM) . The anticancer drug selected in this study was tamoxifen which can be used for the human breast cancer treatment. These prepared nanoparticles were characterized by FTIR, XRD, SEM, AFM, TEM, CD and VSM techniques. The swelling studies have been measured at different (10, 20, 30, 40, 50%) drug loading. The mean particle size of the tamoxifen-loaded nanoparticles system (Fe3O4–CS–TAM, Fe3O4–CS–TAM–PVP and Fe3O4–CS–TAM–PVP–BSA) as measured by Malvern Zetasizer ranged between 350 ± 2.3 and 601 ± 1.7 nm. As well as these drug-loaded nanoparticles were positively charged. The zeta potential was in the range of 28.9 ± 3.5 and 50.8 ± 3.9 mV. The encapsulation efficiency was between 63.60 ± 2.11 and 96.45 ± 2.12%. Furthermore, in vitro release and drug loading efficiency from the nanoparticles were investigated. The cytotoxicity of prepared nanoparticles was verified by MTT assay. In vitro release studies were executed in 4.0 and 7.4 pH media to simulate the intestinal and gastric conditions and different temperature (37 and 42 °C). Hence, the prepared tamoxifen-loaded nanoparticles system (Fe3O4–CS–TAM, Fe3O4–CS–TAM–PVP and Fe3O4–CS–TAM–PVP–BSA) could be a promising candidate in cancer therapy.

The overall recurrence rate of T1 renal cell carcinoma is low. We evaluated abdominal imaging after partial nephrectomy based on current guidelines for T1 renal cell carcinoma surveillance.We retrospectively reviewed the records of patients with T1 renal cell carcinoma who underwent partial nephrectomy between 2006 and 2012 followed by abdominal imaging at our institution. Primary and secondary outcomes were the incidence and timing, respectively, of imaging diagnosed abdominal recurrences. A literature review was performed to summarize prior reports of recurrence incidence and timing after partial nephrectomy for T1 disease.A total of 160 patients with stage T1a and 37 with T1b underwent partial nephrectomy. Seven patients had an abdominal recurrence, including 3 with local and distant recurrences, and 4 with a metachronous contralateral kidney recurrence. The incidence of abdominal recurrence detected by imaging was higher in the T1b than in the T1a group (10.8% vs 1.9%, p = 0.024). Although it was not significant, median time to recurrence was earlier in T1b vs T1a cases (13 vs 37 months, p = 0.480). In each group recurrences developed after 3 years of suggested guideline surveillance. In the literature combined with the current study the time to median recurrence for T1b vs T1a was 24 vs 29 months (p = 0.226).Recurrences detected by abdominal imaging developed earlier and more frequently in T1b than in T1a cases. Future recommendations for surveillance strategies after partial nephrectomy should distinguish T1a from T1b with less intense frequency of imaging for T1a. A longer period of surveillance should be considered since recurrences can develop beyond 3 years.