RNA-sequencing predicts a role of androgen receptor and aldehyde dehydrogenase 1A1 in osteosarcoma lung metastases.

One-third of pediatric patients with osteosarcoma (OS) develop lung metastases (LM), which is the primary predictor of mortality. While current treatments of patients with localized bone disease have been successful in producing 5-year survival rates of 65-70%, patients with LM experience poor survival rates of only 19-30%. Unacceptably, this situation that has remained unchanged for 30 years. Thus, there is an urgent need to elucidate the mechanisms of metastatic spread in OS and to identify targetable molecular pathways that enable more effective treatments for patients with LM. We aimed to identify OS-specific gene alterations using RNA-sequencing of extremity and LM human tissues. Samples of extremity and LM tumors, including 4 matched sets, were obtained from patients with OS. Our data demonstrate aberrant regulation of the androgen receptor (AR) pathway in LM and predicts aldehyde dehydrogenase 1A1 (ALDH1A1) as a downstream target. Identification of AR pathway upregulation in human LM tissue samples may provide a target for novel therapeutics for patients with LM resistant to conventional chemotherapy.

Secretion of Sphinganine by Drug-Induced Cancer Cells and Modified Mimetic Sphinganine (MMS) as c-Src Kinase Inhibitor.

BACKGROUND: Cancer cells exhibit selective metabolic reprogramming to promote proliferation, invasiveness, and metastasis. Sphingolipids such as sphingosine and sphinganine have been reported to modulate cell death processes in cancer cells. However, the potential of extracellular sphinganine and its mimetic compounds as inducers of cancer cell death has not been thoroughly investigated. METHODS: We obtained extracellular conditioned medium from HCT-116 cells treated with the previously reported anticancer composition, goat urine DMSO fraction (GUDF). The extracellular metabolites were purified using a novel and in-house developed vertical tube gel electrophoresis (VTGE) technique and identified through LC-HRMS. Extracellular metabolites such as sphinganine, sphingosine, C16 sphinganine, and phytosphingosine were screened for their inhibitory role against intracellular kinases using molecular docking. Molecular dynamics (MD) simulations were performed to study the inhibitory potential of a novel designed modified mimetic sphinganine (MMS) (Pubchem CID: 162625115) upon c-Src kinase. Furthermore, inhibitory potential and ADME profile of MMS was compared with luteolin, a known c-Src kinase inhibitor. RESULTS: Data showed accumulation of sphinganine and other sphingolipids such as C16 sphinganine, phytosphingosine, and ceramide (d18:1/14:0) in the extracellular compartment of GUDF-treated HCT-116 cells. Molecular docking projected c-Src kinase as an inhibitory target of sphinganine. MD simulations projected MMS with strong (-7.1 kcal/mol) and specific (MET341, ASP404) binding to the inhibitory pocket of c-Src kinase. The projected MMS showed comparable inhibitory role and acceptable ADME profile over known inhibitors. CONCLUSION: In summary, our findings highlight the significance of extracellular sphinganine and other sphingolipids, including C16 sphinganine, phytosphingosine, and ceramide (d18:1/14:0), in the context of drug-induced cell death in HCT-116 cancer cells. Furthermore, we demonstrated the importance of extracellular sphinganine and its modified mimetic sphinganine (MMS) as a potential inhibitor of c-Src kinase. These findings suggest that MMS holds promise for future applications in targeted and combinatorial anticancer therapy.

Essentials of Computed Tomography Imaging of Hematuria.

Hematuria is defined usually as the presence of blood in the urine, either on voiding or in a catheterized specimen. Hematuria is broadly divided into microscopic and gross hematuria and may be symptomatic or asymptomatic. The causes of hematuria include a very wide spectrum of conditions. However, here, we have filtered the causes causing gross hematuria, including calculus, trauma, tumors, vascular, and miscellaneous causes. Plain X-rays of the kidney, ureter, and bladder; ultrasound; intravenous urography; computed tomography (CT); magnetic resonance imaging; retrograde ureterography and pyelography (RGP); cystoscopy; and ureteroscopy are techniques that are useful for diagnosis. In the past, one or a combination of several techniques was used to evaluate hematuria but recently, advances in CT urography mean that it can be used alone for this task. This article briefly reviews the common causes of gross hematuria in adults and their evaluation by CT-based urography. Gross hematuria is evaluated well with CT scan urography which includes an unenhanced scan, the nephrographic phase, and the excretory phase. Unenhanced scans are routinely performed to evaluate the basic parameters such as the size, shape, position, and outline of the kidneys and calculus disease, which is the most common cause of hematuria. Renal parenchymal diseases including masses are best visualized in the nephrographic phase along with other abdominal organs. Delayed excretory phases including the kidneys, ureters, and bladder are useful for detecting urothelial diseases. CT urography's protocol permits evaluations of hematuria through a single examination.

Preoperative Risk Stratification in Arthroscopic Rotator Cuff Repair: Aspartate Aminotransferase-to-Platelet Ratio Index as an Estimate of Liver Dysfunction.

BACKGROUND: Aspartate Aminotransferase-to-Platelet Ratio Index (APRI) is a cost-effective and noninvasive measure of liver function, an alternative to the gold standard liver biopsy which is resource-intensive and invasive. This study investigates the association between various degrees of liver dysfunction based on APRI and 30-day postoperative complications following arthroscopic rotator cuff repair (aRCR). METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried for all patients who underwent aRCR between 2015 and 2021. The study population was divided into four groups based on preoperative APRI: normal/reference (APRI ≤ 0.5), mild fibrosis (0.5 < APRI ≤ 0.7), significant fibrosis (0.7 < APRI ≤ 1), and cirrhosis (APRI > 1). Multivariate logistic regression analysis was conducted to investigate the connection between preoperative APRI and postoperative complications. RESULTS: Compared to normal liver function, mild fibrosis was significantly associated with male gender, lower BMI, American Society of Anesthesiologists (ASA) classification ≥ 3, and comorbid diabetes, hypertension, chronic obstructive pulmonary disease, and bleeding disorders. Significant fibrosis was significantly associated with male gender, greater BMI, ASA classification ≥ 3, and comorbid diabetes, hypertension, and bleeding disorders. Cirrhosis was significantly associated with younger age, ASA classification ≥ 3, smokers, and comorbid diabetes and bleeding disorders. Compared to normal liver function, fibrosis was not associated with complications, significant fibrosis was associated with myocardial infarction, and cirrhosis was associated with major complications, sepsis, non-home discharge, and mortality. However, mild fibrosis, significant fibrosis, and cirrhosis were independently associated with any adverse 30-day postoperative complications following aRCR. CONCLUSION: Among those with predicted liver damage based on preoperative APRI, 30-day postoperative complications following aRCR were not found to be independently associated with preoperative mild fibrosis, significant fibrosis, or cirrhosis. Our results suggest that APRI predictive of liver dysfunction may be a weaker deterrent to undergoing aRCR compared to other orthopedic surgeries.

The effect of reduced bone mineral density on elective total hip arthroplasty outcomes.

INTRODUCTION: Reduced bone mineral density (BMD) and disruption of normal bony architecture are the characteristics of osteopenia and osteoporosis and in patients undergoing total hip arthroplasty (THA) may cause failure of trabecular ingrowth. The purpose of this study is to evaluate the impact of reduced BMD on outcomes following primary elective THA. METHODS: A retrospective chart review of 650 elective THAs with a DEXA scan in their electronic health record (EHR) from 2011 to 2020 was conducted at an urban, academic center and a regional, health center. Patients were separated into three cohorts based on their t-score and the World Health Organizations definitions: normal (t-score ≥ - 1), osteopenia (t-score < - 1.0 and > - 2.5), and osteoporosis (t-score ≤ - 2.5). Demographic and outcome data were assessed. Subsidence was assessed for patients with non-cemented THAs. Regression models were used to account for demographic differences. RESULTS: 650 elective THAs, of which only 11 were cemented, were included in the study. Patients with osteopenia and osteoporosis were significantly older than those without (p = 0.002 and p < 0.0001, respectively) and had a lower BMI (p < 0.0001 and p < 0.0001, respectively). PFx was significantly greater in patients with osteoporosis when compared to those with normal BMD (6.5% vs. 1.0%; p = 0.04). No such difference was found between osteoporotic and osteopenic patients. The revision rate was significantly higher for osteoporotic patients than osteopenic patients (7.5% vs. 1.5%; p = 0.04). No such difference was found between the other comparison groups. CONCLUSION: Patients with osteoporosis were older with reduced BMI and had increased PFx after non-cemented elective THA. Understanding this can help surgeons formulate an appropriate preoperative plan for the treatment of patients with osteoporotic bone undergoing elective THA.

Nipple-Sparing Mastectomy and Immediate Reconstruction: A Propensity Score-Matched Analysis of Satisfaction and Quality of Life.

BACKGROUND: Although it is intuitive that nipple-sparing mastectomy in selected patients would result in excellent cosmetic outcomes and high patient satisfaction, studies of clinical outcomes and health-related quality of life are limited and show mixed results. This study aimed to use a propensity score-matching analysis to compare satisfaction and health-related quality-of-life outcomes in patients who underwent implant-based reconstruction following bilateral nipple-sparing mastectomy or skin-sparing mastectomy. METHODS: A propensity score-matching analysis (1:1 matching, no replacement) was performed comparing patients undergoing nipple-sparing or skin-sparing mastectomy with immediate bilateral implant-based breast reconstruction. Patients with a history of any radiation therapy were excluded. Matched covariates included age, body mass index, race, smoking history, neoadjuvant chemotherapy, bra size, and history of psychiatric diagnosis. Outcomes of interest included BREAST-Q scores and complications. RESULTS: The authors examined 1371 patients for matching and included 460 patients (nipple-sparing mastectomy, n = 230; skin-sparing mastectomy, n = 230) in the final analyses. The authors found no significant differences in baseline, cancer, and surgical characteristics between matched nipple-sparing and skin-sparing mastectomy patients, who also had similar profiles for surgical complications. Interestingly, the authors found that postoperative Satisfaction with Breasts scores and all other health-related quality-of-life domains were stable over a 3-year period and did not differ significantly between the two groups. CONCLUSIONS: Compared with skin-sparing mastectomy, bilateral nipple-sparing mastectomy did not improve patient-reported or clinical outcomes when combined with immediate implant-based reconstruction. The impact that nipple-sparing mastectomy may have on breast aesthetics and the ability of the BREAST-Q to gauge an aesthetic result following nipple-sparing mastectomy warrant further investigation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Percutaneous ablation of renal tumors versus surgical ablation and partial nephrectomy: Medicare trends and reimbursement cost comparison from 2010 to 2018.

PURPOSE: The purpose of this study is to analyze trends in Medicare volume and reimbursement for percutaneous and surgical ablation as well as laparoscopic and open partial nephrectomy for treatment of small renal tumors from 2010 to 2018. METHODS: Claims from the Medicare Part B Physician/Supplier Procedure Summary from 2010 to 2018 were extracted using CPT codes for percutaneous and surgical renal ablation and surgical and laparoscopic partial nephrectomy. Facility reimbursement and relative value units (RVUs) were obtained using the Centers for Medicare & Medicaid Services physician fee schedule look-up tool. RESULTS: Volume of percutaneous ablation increased from 2539 to 4571 procedures (80.0%). Specifically, percutaneous cryoablation became the dominant technique, increasing from 1434 to 2981 procedures (107.9%). Overall, volume of partial nephrectomy also increased by 40.4%, driven by an increase in laparoscopic partial nephrectomy from 3227 to 7770 procedures (140.8%) with a decrease in open partial nephrectomy from 3489 to 1661 (- 52.4%). Volume of surgical ablations also decreased 72.7% from 1260 to 344 procedures. In 2018, reimbursement was $358.56 for percutaneous radiofrequency ablation, $481.32 for percutaneous cryoablation, $1216.43 for surgical radiofrequency ablation, $1269.35 for surgical cryoablation, $1381.67 for open partial nephrectomy, and $1552.66 for laparoscopic partial nephrectomy. CONCLUSION: There has been a trend toward minimally invasive techniques for treatment of small renal tumors among Medicare patients. Laparoscopic partial nephrectomy has become the dominant treatment. In the setting of evidence showing comparable outcomes with surgery as well as lower costs to insurers, the volume of percutaneous ablation has also markedly increased.

Effects of health beliefs, social support, and self-efficacy on sun protection behaviors among medical students: testing of an extended health belief model.

Sun protection behaviors (SPB) are important modifiable risk factors for skin cancer. As the most common malignancies in the world, skin cancers account for significant morbidity, mortality, and economic burden. Physicians play a key role in educating patients about proper SPB. Medical education provides the foundation for physician understanding of SPB and future patient education. The Health Belief Model (HBM) is a theoretical model that offers constructs to help explain health behaviors. This cross-sectional study examined a convenience sample of 186 medical student to assess their engagement in SPB through the lens of the 6 HBM constructs and social support. Overall, we found engagement in SPB among our cohort to be low. About 70.4% report never using wide-brimmed hats and only 44.6% often or always use sunscreen. Hierarchical multiple regressions were performed in three blocks to analyze the relationship between the independent variables (HBM constructs and social support) and dependent variable (SPB) after controlling for the influence of demographic covariates. In our health constructs model, beliefs about susceptibility, benefits minus barriers, and self-efficacy were found to be significant predictors of engaging in SPB. Addition of social support in the final model did not significantly improve prediction of SPB engagement. These findings support use of educational programs based on HBM for the improvement of SPB among medical students.

Loss of Estrogen Receptors is Associated with Increased Tumor Aggression in Laryngeal Squamous Cell Carcinoma.

Laryngeal squamous cell carcinoma (LSCC) responds to 17ß-estradiol via estrogen-receptor (ER, transcribed from ESR1) dependent mechanisms, but is not recognized as a hormonally responsive cancer. 17ß-estradiol production by LSCC cell lines UM-SCC-11A and UM-SCC-12 was examined. Wild type (WT) and ESR1-silenced LSCC cultures and xenografts were examined for 17ß-estradiol responsiveness in vivo. 14 LSCC and surrounding epithelial samples at various pathological stages were obtained from patients; ERα and ERß expression were verified using data from the total cancer genome atlas. UM-SCC-11A and UM-SCC-12 both produce 17ß-estradiol, but only UM-SCC-12, not UM-SCC-11A, xenograft tumors grow larger in vivo in response to systemic 17ß-estradiol treatments. ERα66 and ERα36 expression inversely correlated with clinical cancer stage and tumor burden. LSCC ERα66 expression was higher compared to surrounding epithelia in indolent samples but lower in aggressive LSCC. ERß expression was highly variable. High ESR1 expression correlated with improved survival in LSCC. Loss of ERα66 expression inversely correlated with prognosis in LSCC. ERα66 may be a histopathological marker of aggression in LSCC.

Non-narcotic Perioperative Pain Management in Prosthetic Breast Reconstruction During an Opioid Crisis: A Systematic Review of Paravertebral Blocks.

BACKGROUND: Alternatives to postoperative, narcotic pain management following implant-based, postmastectomy breast reconstruction (IBR) must be a focus for plastic surgeons and anesthesiologists, especially with the current opioid epidemic. Paravertebral blocks (PVBs) are a regional technique that has demonstrated efficacy in patients undergoing a variety of breast cancer-related surgeries. However, a specific understanding of PVB's efficacy in pain management in patients who undergo IBR is lacking. METHODS: A systematic search of PubMed, EMBASE, and Cochrane Library electronic database was conducted to examine PVB administration in mastectomy patients undergoing IBR. Data were abstracted regarding: authors, publication year, study design, patient demographics, tumor laterality, tumor stage, type, and timing of reconstruction. The primary outcome was PVB efficacy, represented as patient-reported pain scores. Secondary outcomes of interest include narcotic consumption, postoperative nausea and vomiting, antiemetic use, and length of stay. RESULTS: The search resulted in 1,516 unique articles. After title and abstract screening, 29 articles met the inclusion criteria for full-text review. Only 7 studies were included. Of those, 2 studies were randomized control trials and 5 were retrospective cohort studies. Heterogeneity of included studies precluded a meta-analysis. Overall, PVB patients had improved pain control, and less opioid consumption. CONCLUSION: PVBs are a regional anesthesia technique which may aid in pain management in the breast reconstructive setting. Evidence suggests that PVBs aid in controlling acute postoperative pain, reduce opioid consumption, and improve patient length of stay. However, some conflicting findings demonstrate a need for continued research in this area of pain control.

Effect of 17ß-estradiol on estrogen receptor negative breast cancer cells in an osteolytic mouse model.

17ß-Estradiol (E2) promotes metastasis of triple negative breast cancer cells to bone. Recent studies show many triple negative breast cancer cell lines lacking the 66 kDa estrogen receptor (ER) alpha (ERα66) or its splice variant ERα46, express another splice variant, ERα36 associated with membrane-mediated rapid actions of the hormone. qPCR and western blot confirmed that MCF7 cells possessed ERα splice variants ERα66, ERα46 and ERα36, while ER-negative breast cancer cells MDA-MB-231 possessed only ERα36. MDA-MB-231 breast cancer cells were implanted into medullary canals of ovariectomized female athymic nude mice femurs (N = 8 mice/treatment). To examine the effect of E2 on osteolysis, mice were treated with 0.72 mg E2 or placebo via 60 day release osmotic pumps implanted subcutaneously. Legs were examined by Faxitron through the course of the study, and by microCT and histology after 8 weeks. Greater occurrence of osteolysis and pathologic fracture was observed in E2-treated animals compared to placebo, and microCT demonstrated less bone volume remaining in MDA-MB-231 treated legs compared to contralateral control legs, as well as E2-treated animals compared to placebo. E2-treated animals had significantly greater tumor volume compared to placebo. Large nests of anaplastic tumor cells with eroded cortical margin were observed in E2-treated animals compared to placebo. MDA MB 231 breast cancer cells positive for ERα36 but negative for ERα46/66 had enhanced osteolysis, pathologic fractures, and tumor volume in an in vivo osteolytic mouse model when treated with 17ß-estradiol compared to placebo, demonstrating a role for ERα36 in bone tumor progression.

Intratarsal keratinous cysts of the meibomian gland (a sebaceous duct cyst): report of 2 cases.

Intratarsal keratinous cyst of the meibomian gland is a recently described entity that recurs if not completely excised. Herein, we report 2 cases and discuss their diagnosis and management: (1) A 57-year-old man with a recurrent mass of the upper eyelid treated with incision and drainage as a chalazion for more than 5 years and (2) An 85-year-old man presented with a slow growing nodule of the upper eyelid. Exploration via the eyelid crease approach revealed cysts fixed to the tarsus that were completely excised with a portion of the anterior tarsus. Histologically, these cysts exhibited a keratinizing squamous epithelium without a granular layer (trichilemmal keratinization), were lined by an eosinophilic undulating cuticle, contain string-like keratin debris, and had a fibrous wall without sebaceous lobules. All epithelial components strongly expressed high-molecular weight keratins, whereas the lining, cuticle, and keratin contents strongly expressed carcinoembryonic antigen. No recurrence has occurred 7 and 12 months postoperatively. The location and clinicopathologic findings of intratarsal keratinous cysts distinguish it from sebaceous tumors, steatocystoma simplex, epidermoid cyst, and dermoid cyst. However, like steatocystomas, intratarsal keratinous cysts exhibit a sebaceous duct phenotype. The anterior lid crease approach with partial tarsectomy seems to be an effective treatment.