Real-world prevalence of microsatellite instability testing and related status in women with advanced endometrial cancer in Europe.

PURPOSE: To assess the real-world prevalence of microsatellite instability (MSI)/mismatch repair (MMR) testing and related tumor status in recurrent/advanced endometrial cancer patients in Europe. METHODS: Data were from two multi-center, retrospective patient chart review studies conducted in the United Kingdom, Germany, Italy, France and Spain: The Endometrial Cancer Health Outcomes-Europe-First-Line (ECHO-EU-1L) study and the ECHO-EU-Second-Line (ECHO-EU-2L) study. ECHO-EU-1L included recurrent/advanced endometrial cancer patients who received first-line systemic therapy between 1/JUN/2016 and 31/MAR/2020 after recurrent/advanced diagnosis. ECHO-EU-2L included patients with recurrent/advanced endometrial cancer who progressed between 1/JUN/2016 and 30/JUN/2019 following prior first-line systemic therapy. Data collected included patient demographics, MSI/MMR tumor testing and results, and clinical/treatment characteristics. RESULTS: ECHO-EU-1L included 242 first-line patients and ECHO-EU-2L included 475 s-line patients. For all patients, median age at recurrent/advanced diagnosis was 69 years, roughly half had endometrioid carcinoma histology and over 75% had Stage IIIB-IV disease at initial diagnosis. The prevalence of MSI/MMR testing in the first-line and second-line cohorts was similar (36.4 and 34.9%, respectively). Among those tested, a majority had non-MSI-high/MMR proficient tumors (80.7 and 74.7% among first- and second-line patients, respectively). About 15% had MSI-high/MMR deficient tumors in both cohorts, and a few patients had discordant results (3.4 and 10.8% among first- and second-line patients, respectively). CONCLUSION: Prior to the approvals of biomarker-directed therapies for recurrent/advanced endometrial cancer patients in Europe, there were low MSI/MMR testing rates for these patients of just over one-third. Given the availability of biomarker-directed therapies, increased MSI/MMR testing may help inform treatment decisions for recurrent/advanced endometrial cancer patients in Europe.

Real-world treatment patterns and clinical outcomes from a retrospective chart review study of patients with recurrent or advanced endometrial cancer who progressed following prior systemic therapy in Europe.

OBJECTIVE: To evaluate real-world treatment patterns and clinical outcomes in recurrent/advanced endometrial cancer patients who progressed following prior systemic therapy in clinical practice in Europe. DESIGN: Endometrial Cancer Health Outcomes-Europe (ECHO-EU) is a retrospective patient chart review study. SETTING: ECHO-EU is a multicentre study conducted in the UK, Germany, Italy, France and Spain. PARTICIPANTS: Patients with recurrent/advanced endometrial cancer who progressed between 1 July 2016 and 30 June 2019 following prior first-line systemic therapy were eligible and data were collected until last available follow-up through November 2021. PRIMARY AND SECONDARY OUTCOME MEASURES: Data collected included patient demographics, clinical and treatment characteristics, and clinical outcomes. Kaplan-Meier analyses were performed since initiation of second-line therapy to estimate time to treatment discontinuation, real-world progression-free survival (rwPFS) and overall survival (OS). RESULTS: A total of 475 patients were included from EU5 countries. Median age was 69 years at advanced endometrial cancer diagnosis, 78.7% had stage IIIB-IV disease, 45.9% had Eastern Cooperative Oncology Group status ≥2 at second-line therapy initiation. In second line, a majority of patients initiated either non-platinum-based chemotherapy (55.6%) or endocrine therapy (16.2%). Physician-reported real-world overall response rate (classified as complete or partial response) to second-line therapy was 34.5%, median rwPFS was 7.4 months (95% CI 6.2 to 8.0) and median OS was 11.0 months (95% CI 9.9 to 12.3). CONCLUSIONS: Patients had poor clinical outcomes with a median OS of <1 year and rwPFS of approximately 7 months, highlighting the significant unmet medical need in pretreated recurrent/advanced endometrial cancer patients. Novel therapies with potential to improve PFS and OS over conventional therapies could provide significant clinical benefit.

Treatment patterns and real-world clinical outcomes in patients with advanced endometrial cancer who are microsatellite instability (MSI)-high or are mismatch repair deficient (dMMR) in the United States.

OBJECTIVES: Microsatellite instability-high (MSI-H) and deficient DNA mismatch repair (dMMR) status have emerged as actionable biomarkers for advanced endometrial cancer (aEC). The objective of this study was to assess clinical outcomes and treatment patterns among MSI-H/dMMR aEC patients who had disease progression following prior systemic therapy (FPST) in the US. METHODS: Endometrial Cancer Health Outcomes (ECHO) was a retrospective, medical chart review study of patients with MSI-H/dMMR aEC who had disease progression between 07/01/2016 and 12/31/2018 FPST and were not candidates for curative surgery. Data on patient demographics, clinical and treatment characteristics, and clinical outcomes were collected. Kaplan-Meier analyses were performed to estimate real-world progression-free survival (rwPFS) and overall survival (OS), stratified by drug class. RESULTS: A total of 124 eligible patients who initiated second-line chemotherapy ± bevacizumab or immunotherapy were included. Mean age was 61.4 years at aEC diagnosis and 86.3% of patients were stage IIIB-IV. Median rwPFS and OS were 4.0 months (95% CI: 2.0-9.0) and 7.0 months (95% CI: 5.0-18.0), respectively, among 21 patients who received chemotherapy ± bevacizumab, and 29.0 months (95% CI: 18.0-NE) and not reached (95% CI: 30.0-NA), respectively, among 103 patients who received immunotherapy. Most patients (n = 92) received pembrolizumab; among these patients, rwPFS and OS were 29.0 months (95% CI: 18.0-NE) and 30 months (95% CI: 30.0-NA), respectively. CONCLUSIONS: Real-world evidence suggests that pembrolizumab monotherapy provides considerable clinical benefits and has become the standard of care for MSI-H/dMMR aEC patients FPST who are not candidates for curative surgery in real-world settings.

Real-world economic and clinical outcomes associated with current hemostatic matrix use in spinal surgery.

Aim: Bleeding during spine surgery is controlled using topical hemostatic agents. Studies have reported outcomes between Surgiflo® and Floseal, the most widely used flowable hemostatic matrices, but have not included the latest Surgiflo formulation which is more adherent to the bleeding surface than prior formulations. Materials & methods: A propensity score-matched analysis was conducted using the Premier Healthcare Database to compare economic and clinical outcomes of adults undergoing inpatient spinal surgery between 2013 and 2018 receiving current Surgiflo or Floseal. Results: This retrospective study included 28,910 patients in each group and found comparable outcomes for bleeding events, overall transfusion rate, inpatient mortality and readmissions between Surgiflo and Floseal. Surgiflo was associated with $430 (USD) lower hospitalization costs, shorter length of stay and shorter operating room time than Floseal.

Topical hemostatic agents such as Surgiflo^® and Floseal are used during invasive surgery to manage bleeding. We compared outcomes of spine surgeries that used either of two most frequently used topical hemostatic agents, Surgiflo or Floseal. This is the largest retrospective study presenting economic and clinical outcomes of patients receiving Surgiflo versus Floseal during spine surgery using the latest product formulations. The study suggests that clinical outcomes are comparable between Surgiflo and Floseal groups and that Surgiflo is associated with lower hospitalization costs, slightly shorter hospital stay and shorter operating room time among patients undergoing spine surgery.

Treatment patterns and real-world clinical outcomes in patients with advanced endometrial cancer that are non-microsatellite instability high (non-MSI-high) or mismatch repair proficient (pMMR) in the United States.

Objective: Microsatellite instability (MSI) due to defective DNA mismatch repair has emerged as an actionable biomarker in advanced endometrial cancer (aEC). Currently, there are no treatment patterns and outcomes data in non-MSI-high (non-MSI-H) or mismatch repair proficient (pMMR) aEC patients following prior systemic therapy (FPST). Our goal was to describe real-world data in this population in the US in 2019 and prior years. Methods: Endometrial Cancer Health Outcomes (ECHO) is a retrospective patient chart review study conducted in the US. Patients with non-MSI-H/pMMR aEC and progression between 06/01/2016-06/30/2019 FPST were eligible. Data collected included patient demographics, clinical and treatment characteristics, and clinical outcomes. Kaplan-Meier analyses were performed to estimate time to treatment discontinuation, real-world progression-free survival (rwPFS), and overall survival (OS), separately by treatment category. Results: A total of 165 eligible patients initiated second-line therapy with chemotherapy ± bevacizumab (n = 140) or hormonal therapy (n = 25). Median age was 66.0 years at aEC diagnosis, 70.2% were Stage IIIB-IV, 40.0% had ECOG ≥ 2 at second-line therapy initiation. Median rwPFS was 5.0 months (95% CI: 4.0-6.0) for patients receiving chemotherapy ± bevacizumab and 5.5 months (95% CI: 3.0-29.0) for those receiving hormonal therapy. Median OS was 10.0 months (95% CI: 8.0-13.0) and 9.0 months (95% CI: 6.0-NA) in these groups, respectively. Conclusions: Non-MSI-H/pMMR patients who initiated second-line therapy with chemotherapy ± bevacizumab or hormonal therapy had poor clinical outcomes with a median survival less than 1 year and rwPFS less than 6 months. This was the first study to define the clinical unmet need in patients with non-MSI-H/pMMR aEC with conventional therapy.

Real-world use of inhaled nitric oxide therapy in patients with COVID-19 and mild-to-moderate acute respiratory distress syndrome.

Background: Inhaled nitric oxide (iNO) has been studied in patients with severe acute respiratory distress syndrome (ARDS) due to COVID-19 when it may be too late to impact disease course. This article aims to describe real-world iNO use and outcomes in patients with COVID-19 with mild-to-moderate ARDS in the United States. Methods: This was a retrospective medical chart review study that included patients who were ≥18 years old, hospitalized for COVID-19, met the Berlin ARDS definition, received iNO for ≥24 hours continuously during hospitalization, and had a partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio (P/F ratio) of >100 to ≤300 mmHg at iNO initiation. Outcomes included oxygenation parameters, physician-rated Clinical Global Impression-Improvement (CGI-I) scale scores, and adverse events. Response to iNO was defined as >20% improvement in P/F ratio. Results: Thirty-seven patients at six sites were included. A P/F ratio of ≤100 was the most common reason for exclusion (n=146; 83% of excluded patients). The mean P/F ratio (SD) increased from 136.7 (34.4) at baseline to 140.3 (53.2) at 48 hours and 151.8 (50.0) at 72 hours after iNO initiation. The response rate was 62% (n=23). During hospitalization, no patient experienced adverse events, including methemoglobinaemia, airway injury, or worsening pulmonary oedema associated with iNO. At discharge, 54.0% (n=20) of patients improved or remained stable according to the CGI-I. Conclusion: In patients hospitalized with COVID-19 and mild-to-moderate ARDS, iNO was associated with improvement in the P/F ratio with no reported toxicity. This study provides additional evidence supporting a favourable benefit-risk profile for iNO in the treatment of mild-to-moderate ARDS in patients with COVID-19 infection.

Real-World Clinical and Economic Outcomes Associated with Surgiflo® vs Floseal in Cardiovascular Surgeries in the US.

Background: Topical hemostatic agents are an option for controlling bleeding during cardiovascular surgery. Previous studies comparing topical hemostatic agents in cardiovascular surgery predate the 2012 reformulation of Surgiflo®, which had been re-engineered to increase paste viscosity and thus be more adherent to the bleeding surface. Objective: To compare clinical and economic outcomes in patients receiving the current formulation of Surgiflo vs Floseal during cardiovascular surgeries. Methodology: A retrospective analysis was conducted using the Premier Healthcare Database. Eligible patients had an inpatient cardiovascular surgery between 1/1/2013 and 6/1/2018, were ≥18 years old and received the current formulation of Surgiflo or Floseal during surgery. Propensity score matching was performed, with exact matching on the surgery year and surgery type (aortic, coronary artery bypass grafting, valve, or other). Descriptive analysis and generalized estimating equations models compared outcomes between the Surgiflo and Floseal groups. Results: The matched sample included 5768 patients in each group (mean age: 66.5 years; 66.3% male). In the matched sample, rates of any documented bleeding event were similar in Surgiflo and Floseal groups (6.9% vs 7.2%; P = 0.576). Differences in transfusion rates between patients receiving Surgiflo vs Floseal varied by operational definition and timing of measurement but did not differ by >2 percentage points. Compared to Floseal, patients who received Surgiflo experienced longer surgery duration (306.0 vs 299.4 minutes), lower hospitalization cost ($44,146 vs $46,812), and lower odds of readmission at 30, 60, and 90 days post-discharge (all P < 0.05). Inpatient mortality and LOS were comparable between Surgiflo and Floseal (all P > 0.05). Conclusion: In this large study of real-world clinical and economic outcomes after cardiovascular surgery involving the current formulation of Surgiflo vs Floseal, Surgiflo was associated with mostly similar clinical outcomes as compared with Floseal. Differences in selected economic/resource use outcomes were also observed, for which root-cause analysis in future research would be informative.

Predictors and timing of response to teduglutide in patients with short bowel syndrome dependent on parenteral support.

BACKGROUND AND AIMS: This study aimed to identify predictors and estimate time to teduglutide response among adult patients with short bowel syndrome with intestinal failure (SBS-IF) dependent on parenteral support (PS). METHODS: Post-hoc analysis was performed on individual patient data from teduglutide-treated patients in the phase III teduglutide trial STEPS and the STEPS-2 extension. Response was defined as ≥20% PS volume reduction from baseline for two consecutive visits. Early responders experienced the reduction at 20 and 24 weeks during STEPS while late responders experienced the reduction during STEPS-2. Timing and predictors for response were assessed among the treated population using Cox proportional hazard model. Time to response was compared in aetiological subgroups using Kaplan-Meier analysis. Patient characteristics and time to response were compared between early vs. late responders. RESULTS: A total of 34 patients were included in this analysis; overall median time to response was 4.3 months. The presence of stoma predicted a positive response to teduglutide (hazard ratio [HR]: 5.6; 95% confidence interval [CI]: 1.4-21.9; p = 0.013). Vascular disease (vs. inflammatory bowel disease [IBD]) as cause of major intestinal resection (HR: 0.2; 95% CI: 0.0-0.8; p = 0.015), presence of ileocecal valve (HR: 0.1; 95% CI: 0.0-0.8; p = 0.047), and female sex (HR: 0.3; 95% CI: 0.1-1.0; p = 0.026) are negatively associated with response. In subgroup analyses, patients with IBD (vs. vascular disease), with (vs. without) a stoma, and without (vs. with) colon-in-continuity had a shorter time to response (all p < 0.05). The mean times to response were 3.6 (standard deviation (SD): 1.1) months for early responders (n = 27) and 10.0 (SD: 6.1) months for late responders (n = 7). Fewer early responders had colon-in-continuity (51.9%) and ileocecal valve (0.0%) compared to late responders (100% and 28.6%, respectively; both p < 0.05). Early responders had a lower mean percentage of colon remaining compared to late responders (24.6% vs. 57.1%, respectively; p = 0.016). CONCLUSIONS: Time to response to teduglutide depends on bowel anatomy and SBS-IF aetiology. IBD, presence of a stoma, and absence of ileocecal valve were associated with earlier response to teduglutide. These findings may enhance management of patients with SBS-IF; however, due to sample size limitations, additional studies are needed to confirm these findings.

Impact of Teduglutide on Quality of Life Among Patients With Short Bowel Syndrome and Intestinal Failure.

BACKGROUND: Teduglutide reduces or eliminates parenteral support (PS) dependency in patients with short bowel syndrome (SBS). Recent post hoc analyses demonstrated that effects are correlated with baseline PS volume. We assessed the SBS-related quality-of-life (QoL) impact of teduglutide, particularly whether improvements are greater among subgroups achieving more PS volume reduction. METHODS: Using phase 3 trial data of teduglutide in patients with SBS (NCT00798967), change in Short Bowel Syndrome-Quality of Life (SBS-QoL) scores from baseline were compared between teduglutide vs placebo in the overall population and subgroups classified by baseline PS volume requirement, disease etiology, and bowel anatomy. Generalized estimating equation models were fitted to assess impact of teduglutide on SBS-related QoL using data from all visits, adjusted for baseline characteristics. RESULTS: Of 86 patients, 43 each were randomized to teduglutide or placebo (mean age: 51 vs 50 years, respectively). In adjusted analyses, teduglutide had a nonsignificant reduction (improvement) of -8.6 points (95% CI: 2.6 to -19.8) in SBS-QoL sum score from baseline to Week-24 vs placebo. The impact of teduglutide varied by subgroup. Patients treated with teduglutide experienced significantly greater reductions in SBS-QoL sum score at Week-24 vs placebo in 2 subgroups, ie, the third (highest) tertile baseline PS volume (-27.3, 95% CI: -50.8 to -3.7) and inflammatory bowel disease (IBD; -29.6, 95% CI: -46.3 to -12.9). Results were similar for SBS-QoL subscale and item scores. CONCLUSIONS: The impact of teduglutide treatment on SBS-related QoL vs placebo varied among subgroups and was significant and most pronounced among patients with highest baseline PS volume requirement or IBD.

Medication use in adults with attention deficit/hyperactivity disorder in a commercially-insured population in the United States.

OBJECTIVE: To examine real-world prescription medication usage among commercially-insured adults with attention deficit/hyperactivity disorder (ADHD) in the US. METHODS: Adults with ADHD who received ≥1 ADHD medication during 2013 were identified from a large US claims database. Combination therapy was defined as an overlap of ≥30 days between the index (first treatment ≥30 days in 2013) and another medication(s). Patients were classified into six groups: long-acting (LA) monotherapy, short-acting (SA) monotherapy, LA + LA, SA + SA, LA + SA, and >2 therapies. Analyses compared baseline characteristics by regimen, ranked combination regimens, and estimated daily average consumption (DACON) for monotherapy users. RESULTS: Of 206,443 adults with ADHD (mean age = 32.9 years; 51.6% female), 56.9% used LA monotherapy, 30.7% SA monotherapy, and 12.5% used combination therapies (LA + SA: 10.3%; LA + LA: 1.3%; SA + SA: 0.4%; >2 therapies: 0.5%). Extended-release mixed amphetamine salts (MAS-XR, 39.2%) and lisdexamfetamine (LDX, 31.5%) were the most common LA monotherapies. Nearly all SA monotherapy patients received immediate-release mixed amphetamine salts (MAS-IR; 81.7%). The top three therapies among combination categories were: (a) LA + LA: branded MAS-XR + generic MAS-XR (13.7%), LDX + generic MAS-XR (10.8%), LDX + guanfacine ER (10.7%); (b) SA + SA: generic MAS-IR + clonidine IR (33.5%), generic MAS-IR + generic MPH SA (17.9%), branded MAS-IR + generic MAS-IR (11.1%); (c) LA + SA: generic MAS-XR+/-IR (39.2%), LDX + generic MAS-IR (16.7%), LA + SA generic MPH (12.6%). Among monotherapy users, DACON was 1.2 ± 0.6 (LA) and 2.1 ± 0.9 (SA) tablets. CONCLUSIONS: There is significant treatment heterogeneity among US adults with ADHD. A sizable proportion of patients received monotherapies at above the recommended dosages or combination therapies, suggesting existing single-tablet regimens may not meet patients' needs.

Characterization of a Murine Model of Bioequivalent Bladder Wound Healing and Repair Following Subtotal Cystectomy.

Previous work demonstrated restoration of a bioequivalent bladder within 8 weeks of removing the majority of the bladder (subtotal cystectomy or STC) in rats. The goal of the present study was to extend our investigations of bladder repair to the murine model, to harness the power of mouse genetics to delineate the cellular and molecular mechanisms responsible for the observed robust bladder regrowth. Female C57 black mice underwent STC, and at 4, 8, and 12 weeks post-STC, bladder repair and function were assessed via cystometry, ex vivo pharmacologic organ bath studies, and T2-weighted magnetic resonance imaging (MRI). Histology was also performed to measure bladder wall thickness. We observed a time-dependent increase in bladder capacity (BC) following STC, such that 8 and 12 weeks post-STC, BC and micturition volumes were indistinguishable from those of age-matched non-STC controls and significantly higher than observed at 4 weeks. MRI studies confirmed that bladder volume was indistinguishable within 3 months (11 weeks) post-STC. Additionally, bladders emptied completely at all time points studied (i.e., no increases in residual volume), consistent with functional bladder repair. At 8 and 12 weeks post-STC, there were no significant differences in bladder wall thickness or in the different components (urothelium, lamina propria, or smooth muscle layers) of the bladder wall compared with age-matched control animals. The maximal contractile response to pharmacological activation and electrical field stimulation increased over time in isolated tissue strips from repaired bladders but remained lower at all time points compared with controls. We have established and validated a murine model for the study of de novo organ repair that will allow for further mechanistic studies of this phenomenon after, for example, genetic manipulation.

Prevalence, clinical and economic burden of mucormycosis-related hospitalizations in the United States: a retrospective study.

BACKGROUND: Mucormycosis is a rare but devastating fungal infection primarily affecting immunocompromised patients such as those with hematological malignancy, bone marrow and solid organ transplantation, and patients with diabetes, and, even more rarely, immunocompetent patients. The objective of this study was to assess the prevalence and burden, both clinical and economic, of mucormycosis among hospitalized patients in the U.S. METHODS: This is a retrospective study using the Premier PerspectiveTM Comparative Database, with more than 560 participating hospitals covering 104 million patients (January 2005-June 2014). All hospitalizations in the database were evaluated for the presence of mucormycosis using either an ICD-9 code of 117.7 or a positive laboratory result for Mucorales. Hospitalizations were further required to have prescriptions of amphotericin B or posaconazole to be considered as mucormycosis-related hospitalizations. The prevalence of mucormycosis-related hospitalizations among all hospital discharges was estimated. Mortality rate at discharge, length of hospital stay, and readmission rates at 1 and 3 months were evaluated among mucormycosis-related hospitalizations. Cost per hospital stay and average per diem cost (inflated to 2014 USD) were reported. RESULTS: The prevalence of mucormycosis-related hospitalizations was estimated as 0.12 per 10,000 discharges during January 2005-June 2014. It increased to 0.16 per 10,000 discharges if the definition of mucormycosis was relaxed to not require the use of amphotericin B or posaconazole. The median length of stay was 17 days, with 23% dead at discharge; readmission rates were high, with 30 and 37% of patients readmitted within one and three months of discharge, respectively. The average cost per hospital stay was $112,419, and the average per diem cost was $4,096. CONCLUSIONS: The study provides a recent estimate of the prevalence and burden of mucormycosis among hospitalized patients. The high clinical and economic burden associated with mucormycosis highlights the importance of establishing active surveillance and optimizing prophylactic and active treatment in susceptible patients.

Near Infrared Fluorescent Nanoparticles Derived from Hyaluronic Acid Improve Tumor Contrast for Image-Guided Surgery.

Tumor tissue that remains undetected at the primary surgical site can cause tumor recurrence, repeat surgery, and treatment strategy alterations that impose a significant patient and healthcare burden. Intraoperative near infrared fluorescence (NIRF) imaging is one potential method to identify remaining tumor by visualization of NIR fluorophores that are preferentially localized to the tumor. This requires development of fluorophores that consistently identify tumor tissue in different patients and tumor types. In this study we examined a panel of NIRF contrast agents consisting of polymeric nanoparticle (NP) formulations derived from hyaluronic acid (HA), with either physically entrapped indocyanine green (ICG) or covalently conjugated Cy7.5. Using orthotopic human breast cancer MDA-MB-231 xenografts in nude mice we identified two lead formulations. One, NanoICGPBA, with physicochemically entrapped ICG, showed 2.3-fold greater tumor contrast than ICG alone at 24 h (p < 0.01), and another, NanoCy7.5100-H, with covalently conjugated Cy7.5, showed 74-fold greater tumor contrast than Cy7.5 alone at 24 h (p < 0.0001). These two lead formulations were then tested in immune competent BALB/c mice bearing orthotopic 4T1 breast cancer tumors. NanoICGPBA showed 2.2-fold greater contrast than ICG alone (p < 0.0001), and NanoCy7.5100-H showed 14.8-fold greater contrast than Cy7.5 alone (p < 0.0001). Furthermore, both NanoICGPBA and NanoCy7.5100-H provided strong tumor enhancement using image-guided surgery in mice bearing 4T1 tumors. These studies demonstrate the efficacy of a panel of HA-derived NPs in delineating tumors in vivo, and identifies promising formulations that can be used for future in vivo tumor removal efficacy studies.

Dual wavelength stimulation of polymeric nanoparticles for photothermal therapy.

BACKGROUND AND OBJECTIVE: Photothermal therapy (PTT) has several applications in the areas of wound healing, pain management, bacterial infection control, and cancer treatment dependent on the temperature that is generated. PTT is often used exclusively with near infrared (NIR) light and most nanoparticles (NP) used for PTT are designed to absorb within one narrow range of wavelengths. We have developed a dual-wavelength photothermal therapy by capitalizing on the dual absorption of nanoparticles in the blue and NIR range. MATERIALS AND METHODS: Our lab has previously developed NP based on the semiconducting, conjugated polymer poly[4,4-bis(2-ethylhexyl)-cyclopenta[2,1-b;3,4-b']dithiophene-2,6-diyl-alt-2,1,3-benzoselenadiazole-4,7-diyl] (PCPDTBSe). The NP have strong absorption in the blue and NIR regions. In this report, we have explored the heat generated by PCPDTBSe NP using simultaneous delivery of 450 and 800 nm light, either independently or together for photothermal ablation of mouse colorectal cancer cells. RESULTS: The heat generation studies indicated that the use of either 450 or 800 nm wavelengths at the same fluences produced approximately the same temperature change of deionized water. Fluences of 114.6 and 229.2 J/cm2 , utilizing 450 or 800 nm light applied individually resulted in temperatures of 8-47°C above ambient temperature, leading to a 90% reduction in cell viability. Simultaneous stimulation of the PCPDTBSe NP with 450 and 800 nm light effectively doubles the effective power delivered, resulting in temperatures 18-63°C above ambient and 100% photothermal ablation of the colorectal cancer cells. CONCLUSION: The results of this study demonstrate that PCPDTBSe polymer NP can be utilized as effective PTT agents by capitalizing on their dual absorption of both blue and NIR light. Lasers Surg. Med. 48:893-902, 2016. © 2016 Wiley Periodicals, Inc.

Near infrared fluorescent nanoparticles based on hyaluronic acid: Self-assembly, optical properties, and cell interaction.

UNLABELLED: Fluorescent imaging agents that can specifically highlight tumor cells could have a significant impact on image-guided tumor removal. Here, fluorescent nanoparticles (NPs) derived from hyaluronic acid (HA) are investigated. HA is a ligand for the receptor CD44, which is a common biomarker present on many primary tumor cells, cancer-initiating cells, and tumor-associated fibroblasts. In addition, a family of enzymes that degrade HA, called hyaluronidases (HYALs), are also overexpressed with increased activity in many tumors. We report the design and development of a panel of targeted imaging agents using the near-infrared (NIR) dye, Cy7.5, that was directly conjugated to hydrophobically-modified HA. Two different molecular weights of HA, 10kDa and 100kDa, and three different degrees of hydrophobic moiety conjugation (0, 10, and 30mol%) were utilized to develop a panel of NPs with variable size that ranged from 50 to 400nm hydrodynamic diameter (HD) depending HA molecular weight, extent of fluorescence quenching (25-50%), kinetics of cellular uptake, and targeting to CD44+ cells. The kinetics and energy-dependence of cellular uptake in breast and prostate cancer cell lines, MDA-MB 231 and PC-3 cells, respectively, showed increased uptake with longer incubation times (at 4 and 8h compared to 1h), as well as uptake at 37°C but not 4°C, which indicated energy-dependent endocytosis. NP uptake studies in the presence of excess free HA showed that pre-treatment of cells with excess high molecular weight (MW) free HA decreased NP uptake by up to 50%, while no such trend was observed with low MW HA. These data lay the foundation for selection of optimized HA-derived NPs for image-guided surgery. STATEMENT OF SIGNIFICANCE: Here, hyaluronic acid (HA), a well-studied biomacromolecule, is modified with a near infrared fluorophore and a hydrophobic moiety. The significance of this work, especially for imaging applications, is that the impact of HA molecular weight and the hydrophobic moiety conjugation degree on fluorescence and cell interaction can be predicted. With respect to existing literature, the eventual use of these HA-based NPs is image-guided surgery; thus, we focus on the dye, Cy7.5, for conjugation, which is more NIR than most existing HA literature. Furthermore, HA is a ligand for CD44, which is associated with cancer and tumor microenvironment cells. Systematic studies in this work highlight that HA can be tuned to maximize or minimize CD44 binding.

Development of a Self-Assembled Nanoparticle Formulation of Orlistat, Nano-ORL, with Increased Cytotoxicity against Human Tumor Cell Lines.

Fatty acid synthase (FASN), the enzyme that catalyzes de novo synthesis of fatty acids, is expressed in many cancer types. Its potential as a therapeutic target is well recognized, but inhibitors of FASN have not yet been approved for cancer therapy. Orlistat (ORL), an FDA-approved lipase inhibitor, is also an effective inhibitor of FASN. However, ORL is extremely hydrophobic and has low systemic uptake after oral administration. Thus, new strategies are required to formulate ORL for cancer treatment as a FASN inhibitor. Here, we report the development of a nanoparticle (NP) formulation of ORL using amphiphilic bioconjugates that are derived from hyaluronic acid (HA), termed Nano-ORL. The NPs were loaded with up to 20 wt % weight of ORL at greater than 95% efficiency. The direct inhibition of the human recombinant thioesterase domain of FASN by ORL extracted from Nano-ORL was similar to that of stock ORL. Nano-ORL demonstrated a similar ability to inhibit cellular FASN activity when compared to free ORL, as demonstrated by analysis of (14)C-acetate incorporation into lipids. Nano-ORL treatment also disrupted mitochondrial function similarly to ORL by reducing adenosine triphosphate turnover in MDA-MB-231 and LNCaP cells. Nano-ORL demonstrated increased potency compared to ORL toward prostate and breast cancer cells. Nano-ORL decreased viability of human prostate and breast cancer cell lines to 55 and 57%, respectively, while free ORL decreased viability to 71 and 79% in the same cell lines. Moreover, Nano-ORL retained cytotoxic activity after a 24 h preincubation in aqueous conditions. Preincubation of ORL dramatically reduced the efficacy of ORL as indicated by high cell viability (>85%) in both breast and prostate cell lines. These data demonstrate that NP formulation of ORL using HA-derived polymers retains similar levels of FASN, lipid synthesis, and ATP turnover inhibition while significantly improving the cytotoxic activity against cancer cell lines.

The direct and indirect costs of uterine fibroid tumors: a systematic review of the literature between 2000 and 2013.

This systematic literature review was conducted to summarize the direct and indirect costs per patient that are associated with uterine fibroid tumors in international studies. A search with predefined search terms was conducted in MEDLINE and EMBASE for studies that were published from January 2000 to November 2013. The review included primary studies that were in English and that reported either direct costs (drug costs, procedure costs, and medical service costs) or indirect costs (such as productivity loss) among patients with uterine fibroid tumors. A total of 26 studies that were identified and included in the data extraction included 19 studies in the United States, 2 studies in the Netherlands, 1 study each in Germany, China, Italy, and Canada, and 1 study reported data that were collected from 3 countries: Germany, France, and England. The studies differed substantially in perspectives that were adopted for analysis, research designs, data elements that were collected, setting, populations, and outcome measurements. Among 3 studies that reported total direct costs during the year after uterine fibroid tumor diagnosis, 2 studies reported an average of $9473 and $9319 per patient, respectively; 2 studies reported the excess costs over controls to be $6076 and $5427, respectively. The indirect costs per patient ranged from $2399-15,549, and the excess indirect cost per patient over control groups ranged from $323-4824 in the year after the diagnosis. The total costs, sum of direct and indirect costs, ranged from $11,717-25,023 per patient per year, after diagnosis or surgery among patients with uterine fibroid tumors. Compared with control subjects, the additional annual cost ranged from $2200-15,952 per patient. The results of this systematic literature review highlight the substantial direct and indirect costs that are associated with uterine fibroid tumors to health care payers and society. The large number and the variety of studies identified also emphasize the growing awareness of the significant economic impact of uterine fibroid tumors. Current gaps that were identified through this review warrant further investigation to elucidate fully the economic burden of uterine fibroid tumors, including, but not limited to, burden from the patient's perspective and the entirety of indirect costs.

Indocyanine green-loaded nanoparticles for image-guided tumor surgery.

Detecting positive tumor margins and local malignant masses during surgery is critical for long-term patient survival. The use of image-guided surgery for tumor removal, particularly with near-infrared fluorescent imaging, is a potential method to facilitate removing all neoplastic tissue at the surgical site. In this study we demonstrate a series of hyaluronic acid (HLA)-derived nanoparticles that entrap the near-infrared dye indocyanine green, termed NanoICG, for improved delivery of the dye to tumors. Self-assembly of the nanoparticles was driven by conjugation of one of three hydrophobic moieties: aminopropyl-1-pyrenebutanamide (PBA), aminopropyl-5ß-cholanamide (5ßCA), or octadecylamine (ODA). Nanoparticle self-assembly, dye loading, and optical properties were characterized. NanoICG exhibited quenched fluorescence that could be activated by disassembly in a mixed solvent. NanoICG was found to be nontoxic at physiologically relevant concentrations and exposure was not found to inhibit cell growth. Using an MDA-MB-231 tumor xenograft model in mice, strong fluorescence enhancement in tumors was observed with NanoICG using a fluorescence image-guided surgery system and a whole-animal imaging system. Tumor contrast with NanoICG was significantly higher than with ICG alone.

Lanthanide-containing polycations for monitoring polyplex dynamics via lanthanide resonance energy transfer.

Theranostic nanomaterials have emerged in the past decade that combine therapeutic delivery and diagnostic imaging into one package. Such materials offer the opportunity to aid diagnosis, track therapeutic biodistribution, and monitor drug release. We have developed a series of nucleic acid delivery polymers containing oligoethylene amines that are able to be protonated at physiological pH (for binding/compacting pDNA) and a lanthanide-chelating domain, which imparts diagnostic functionality. Diamine monomers (containing between 3 and 6 Boc-protected ethyleneamines) were prepared via a multistep procedure involving the selective protection and deprotection of primary and secondary amines. The polymer structures were then synthesized by step-growth polymerization of the oligoethylene diamines with a bisanhydride of diethylenetriamine pentaacetic acid (DTPA-BA), yielding degrees of polymerization between 18 and 24. Chelation of the polymers with gadolinium and terbium was performed to offer MRI contrast agent and luminescence properties, respectively. All of the polymer chelates were found to house approximately one water coordination site, as calculated by the Horrock's equation and possess longitudinal relaxivities (r1, on a per Gd basis) at least twice that of Magnevist, a clinical contrast agent. All the structures formed polyplexes with pDNA with highly positive zeta potentials and hydrodynamic diameters around 50-80 nm. Lanthanide resonance energy transfer (LRET) was used to monitor polyplex association and dissociation. Polyplexes were formed using the donor-acceptor pair comprising of terbium-chelated polymer with five ethyleneamines within the repeat unit (6c-Tb) and tetramethyl rhodamine (TMR)-labeled pDNA. Association/dissociation in the presence of heparin and NaCl was monitored. The effect of amine number along the polymer backbone on transfection efficiency and cytotoxicity was also investigated. None of the polymers revealed cytotoxic effects with cultured cells; however, the polymer with six ethyleneamines clearly offered the highest transfection efficiency. This preliminary study offers insight into the development of materials with the ability to monitor polyplex unpackaging over time within the cellular environment.