Natural history of visceral branch artery dissections and the influence of concurrent aortic dissection on overall and intervention-free survival.

OBJECTIVE: Visceral branch artery dissection (VBAD) is uncommon and may occur with or without an associated aortic dissection (AD). We hypothesized that isolated VBAD would have a more benign clinical course than those with concurrent AD and compared survival outcomes stratified based on aortic involvement. METHODS: VBAD over a 5-year period were identified using International Classification of Diseases codes. Data related to patient demographics, comorbid conditions, clinical presentation, management (including procedural interventions), and survival were obtained from medical records. Anatomic imaging studies were reviewed to characterize anatomy, including the presence or absence of concurrent AD. Overall survival and intervention-free survival were evaluated using Kaplan-Meier and Cox proportional hazards models. RESULTS: A total of 299 VBAD were identified, 174 of which were isolated VBAD and 125 were associated with concurrent AD. Seventy-one percent of patients were men, 77% were White, and 85% were non-Hispanic. The mean age was 61.1 ± 14.4 years. The mean follow-up was 53.2 ± 50.0 months. The estimated overall survival was 88.2% and the estimated overall intervention-free survival was 55.6% at 12 months. Isolated VBAD had better overall survival than those with concurrent AD (69.2% vs 32.4%; P < .001). Concurrent AD was also associated with inferior intervention-free survival (57.5% vs 7.3%; P < .001). Acute presentation was associated with decreased intervention-free survival (86.1% vs 13.4%; P < .001). Acute presentation was also associated with decreased overall survival in patients with isolated VBAD (60.8% vs 80.0% at 180 months; P < .001) and inferior intervention-free survival (48.4% vs 69.5% at 180 months; P < .001) in the subgroup of patients with isolated VBAD. Multivariable Cox models identified that age (hazard ratio [HR]: 1.05, standard deviation [SD]: 0.02; P = .001) was associated with inferior survival and renal dissections (HR: 3.08, SD: 0.99; P = .001) or mesenteric and renal dissections (HR: 3.39, SD: 1.44; P = .004) were associated with inferior intervention-free survival. CONCLUSIONS: Isolated VBAD has superior overall and intervention-free survival to those associated with concurrent AD. The absence vs presence of aortic involvement is useful for risk stratification and may support tailored approaches to the frequency of imaging surveillance.

Synthetic biology approaches for enhancing safety and specificity of CAR-T cell therapies for solid cancers.

CAR-T cell therapies have been successful in treating numerous hematologic malignancies as the T cell can be engineered to target a specific antigen associated with the disease. However, translating CAR-T cell therapies for solid cancers is proving more challenging due to the lack of truly tumor-associated antigens and the high risk of off-target toxicities. To combat this, numerous synthetic biology mechanisms are being incorporated to create safer and more specific CAR-T cells that can be spatiotemporally controlled with increased precision. Here, we seek to summarize and analyze the advancements for CAR-T cell therapies with respect to clinical implementation, from the perspective of synthetic biology and immunology. This review should serve as a resource for further investigation and growth within the field of personalized cellular therapies.

Characterizing patient-reported claudication treatment goals to support patient-centered treatment selection and measurement strategies.

OBJECTIVE: Patient-reported outcomes (PRO) have been increasingly emphasized for peripheral artery disease (PAD). Patient-defined treatment goals and expectations, however, are poorly understood and might not be achievable or aligned with guidelines or clinical outcomes. We evaluated the patient-reported treatment goals among patients with claudication and the associations between patient characteristics, goals, and PAD-specific PRO scores. METHODS: Patients with a diagnosis of claudication were prospectively recruited. Patient-defined treatment goals and outcomes related to walking distance, duration, and speed were quantified using multiple-choice survey items. Free-text items were used to identify activities other than walking distance, duration, or speed associated with symptoms and treatment goals. The peripheral artery disease quality of life and walking impairment questionnaire instruments were included as PRO. The treatment goal categories were compared with the PRO percentile scores using 95% confidence intervals (CIs), categorical tests, and logistic regression models. Associations between the patient characteristics and PRO were evaluated using linear and ordinal logistic regression models. RESULTS: A total of 150 patients meeting the inclusion criteria were included in the present study. Of these 150 patients, 144 (96%) viewed the entire survey. Their mean age was 70.0 ± 11.3 years, and 32.9% were women. Most of the respondents had self-reported their race as White (n = 135), followed by Black (n = 3), Asian (n = 2), Native American (n = 2), and other/unknown (n = 2). Two participants self-reported Hispanic ethnicity. The primary treatment goals were an increased walking distance or duration without stopping (62.0%), the ability to perform a specific activity or task (23.0%), an increased walking speed (8.0%), or other/none of the above (7.0%). The specific activities associated with symptoms or goals included outdoor recreation (38.5%), labor-related tasks (30.7%), sports (26.9%), climbing stairs (23.1%), uphill walking (19.2%), and shopping (6%). Among the patients choosing an increased walking distance and duration as the primary goals, 64% had indicated that a distance of ≥0.5 mile (2640 ft) and 59% had indicated a duration of ≥30 minutes would be a minimum increase consistent with meaningful improvement. Increasing age was associated with lower odds of a distance improvement goal of ≥0.5 mile (odds ratio [OR], 0.68 per 5 years; 95% CI, 0.51-0.92; P = .012) or duration improvement goal of ≥30 minutes (OR, 0.76 per 5 years; 95% CI, 0.58-0.99; P = .047). Patient characteristics associated with PAD Quality of Life percentile scores included age, ankle brachial index, and gender. Ankle brachial index was the only patient characteristic associated with the walking impairment questionnaire percentile scores. CONCLUSIONS: Patients define treatment goals according to their desired activities and expectations, which may influence their goals and perceived outcomes. Patients' expectations of minimum increases in walking distance and duration consistent with meaningful improvement exceeded reported minimum important difference criteria for many patients and would not be captured using common clinic-based walking tests. Patient age was associated with both treatment goals and PRO scores, and the related floor and ceiling effects could influence sensitivity to PRO changes for younger and older patients, respectively. Heterogeneity in treatment goals supports consideration of tailored decision-making and outcomes informed by patient characteristics and perspectives.

Factors associated with successful median arcuate ligament release in an international, multi-institutional cohort.

OBJECTIVE: Prior research on median arcuate ligament syndrome has been limited to institutional case series, making the optimal approach to median arcuate ligament release (MALR) and resulting outcomes unclear. In the present study, we compared the outcomes of different approaches to MALR and determined the predictors of long-term treatment failure. METHODS: The Vascular Low Frequency Disease Consortium is an international, multi-institutional research consortium. Data on open, laparoscopic, and robotic MALR performed from 2000 to 2020 were gathered. The primary outcome was treatment failure, defined as no improvement in median arcuate ligament syndrome symptoms after MALR or symptom recurrence between MALR and the last clinical follow-up. RESULTS: For 516 patients treated at 24 institutions, open, laparoscopic, and robotic MALR had been performed in 227 (44.0%), 235 (45.5%), and 54 (10.5%) patients, respectively. Perioperative complications (ileus, cardiac, and wound complications; readmissions; unplanned procedures) occurred in 19.2% (open, 30.0%; laparoscopic, 8.9%; robotic, 18.5%; P < .001). The median follow-up was 1.59 years (interquartile range, 0.38-4.35 years). For the 488 patients with follow-up data available, 287 (58.8%) had had full relief, 119 (24.4%) had had partial relief, and 82 (16.8%) had derived no benefit from MALR. The 1- and 3-year freedom from treatment failure for the overall cohort was 63.8% (95% confidence interval [CI], 59.0%-68.3%) and 51.9% (95% CI, 46.1%-57.3%), respectively. The factors associated with an increased hazard of treatment failure on multivariable analysis included robotic MALR (hazard ratio [HR], 1.73; 95% CI, 1.16-2.59; P = .007), a history of gastroparesis (HR, 1.83; 95% CI, 1.09-3.09; P = .023), abdominal cancer (HR, 10.3; 95% CI, 3.06-34.6; P < .001), dysphagia and/or odynophagia (HR, 2.44; 95% CI, 1.27-4.69; P = .008), no relief from a celiac plexus block (HR, 2.18; 95% CI, 1.00-4.72; P = .049), and an increasing number of preoperative pain locations (HR, 1.12 per location; 95% CI, 1.00-1.25; P = .042). The factors associated with a lower hazard included increasing age (HR, 0.99 per increasing year; 95% CI, 0.98-1.0; P = .012) and an increasing number of preoperative diagnostic gastrointestinal studies (HR, 0.84 per study; 95% CI, 0.74-0.96; P = .012) Open and laparoscopic MALR resulted in similar long-term freedom from treatment failure. No radiographic parameters were associated with differences in treatment failure. CONCLUSIONS: No difference was found in long-term failure after open vs laparoscopic MALR; however, open release was associated with higher perioperative morbidity. These results support the use of a preoperative celiac plexus block to aid in patient selection. Operative candidates for MALR should be counseled regarding the factors associated with treatment failure and the relatively high overall rate of treatment failure.

Community-based organization perspectives on participating in state-wide community canvassing program aimed to reduce COVID-19 vaccine disparities in California.

BACKGROUND: Inequities in COVID-19 vaccine accessibility and reliable COVID-related information disproportionately affected marginalized racial and ethnic communities in the U.S. The Get Out the Vaccine (GOTVax) program, an innovative statewide government-funded COVID-19 vaccine canvassing program in California, aimed to reduce structural barriers to COVID-19 vaccination in high-risk communities with low vaccination rates. GOTVax consisted of a community-academic-government partnership with 34 local trusted community-based organizations' (CBOs) to conduct COVID-19 vaccine outreach, education, and vaccine registration. The purpose of this qualitative evaluation study was to explore the barriers and facilitators of using local CBOs to deploy a geographically, racially, and ethnically diverse state-wide COVID-19 vaccine outreach program. METHODS: Semi-structured online interviews were conducted with participating GOTVax CBO leaders from November 2021 to January 2022. Transcripts were analyzed using reflexive thematic analysis. RESULTS: Thirty-one of 34 CBOs participated (91% response rate). Identified themes encompassed both facilitators and barriers to program participation. Key facilitators included leveraging trust through recognized entities; promoting empathetic, tailored outreach; and flexibility of milestone-based CBO funding contracts for rapid program implementation. Barriers included navigating community sociopolitical, geographic, and cultural factors; managing canvassers' safety; desiring metrics for self-evaluation of outreach success; mitigating canvassing technology challenges; and concerns of program infrastructure initially limiting outreach. CBOs problem-solved barriers with academic and government partners. CONCLUSIONS: Between May and December 2021, the GOTVax program reached over 2 million California residents and registered over 60,000 residents for COVID-19 vaccination. Public health campaigns may improve benefits from leveraging the expertise of community-trusted CBOs and universities by providing flexible infrastructure and funding, allowing CBOs to seamlessly tailor outreach most applicable to local minoritized communities.

A review of vascular endothelial growth factor and its potential to improve functional outcomes following spinal cord injury.

Spinal cord injuries (SCI) are traumatic events with limited treatment options. Following injury, the lesion site experiences a drastic change to both its structure and vasculature which reduces its ability for tissue regeneration. Despite the lack of clinical options, researchers are investigating therapies to induce neuronal regeneration. Cell-based therapies have long been assessed in the context of SCI to promote neuronal protection and repair. Vascular endothelial growth factor (VEGF) not only demonstrates this ability, but also demonstrates angiogenic potential to promote blood vessel formation. While there have been numerous animal studies investigating VEGF, further research is still warranted to pinpoint its role following SCI. This review aims to discuss the literature surrounding the role of VEGF following SCI and its potential in promoting functional recovery.

Selective reactivation of STING signaling to target Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a lethal skin cancer that metastasizes rapidly. Few effective treatments are available for patients with metastatic MCC. Poor intratumoral T cell infiltration and activation are major barriers that prevent MCC eradication by the immune system. However, the mechanisms that drive the immunologically restrictive tumor microenvironment remain poorly understood. In this study, we discovered that the innate immune regulator stimulator of IFN genes (STING) is completely silenced in MCCs. To reactivate STING in MCC, we developed an application of a human STING mutant, STINGS162A/G230I/Q266I, which we found to be readily stimulated by a mouse STING agonist, DMXAA. This STING molecule was efficiently delivered to MCC cells via an AAV vector. Introducing STINGS162A/G230I/Q266I expression and stimulating its activity by DMXAA in MCC cells reactivates their antitumor inflammatory cytokine/chemokine production. In response to MCC cells with restored STING, cocultured T cells expressing MCPyV-specific T cell receptors (TCRs) show increased cytokine production, migration toward tumor cells, and tumor cell killing. Our study therefore suggests that STING deficiency contributes to the immune suppressive nature of MCCs. More importantly, DMXAA stimulation of STINGS162A/G230I/Q266I causes robust cell death in MCCs as well as several other STING-silenced cancers. Because tumor antigens and DNA released by dying cancer cells have the potential to amplify innate immune response and activate antitumor adaptive responses, our finding indicates that targeted delivery and activation of STINGS162A/G230I/Q266I in tumor cells holds great therapeutic promise for the treatment of MCC and many other STING-deficient cancers.

Reliability of hospital-level mortality in abdominal aortic aneurysm repair.

OBJECTIVE: The relationship between volume and surgical outcomes has been shown for a variety of surgical procedures. The effects in abdominal aortic aneurysm repair have continued to be debated. Reliability adjustment has been used as a method to remove statistical noise from hospital-level outcomes. However, its impact on aortic aneurysm repair is not well understood. METHODS: We used prospectively collected data from the Vascular Quality Initiative to identify all patients who had undergone abdominal aortic aneurysm repair from 2003 to 2019. We first calculated the hospital-level risk-adjusted 30-day mortality rates. We subsequently used hierarchical logistic regression modeling to adjust for measurement reliability using empirical Bayes techniques. The effect of volume on risk- and reliability-adjusted mortality rates was then assessed using linear regression. RESULTS: Between 2003 and 2019, 67,073 abdominal aortic aneurysms were repaired, of which 11,601 (17.3%) were repaired with an open approach. The median annual volume was 7.4 (interquartile range, 3.0-13.3) for open repairs and 35.4 (interquartile range, 18.8-59.8) for endovascular repairs. Of the 223 hospitals that had performed open repairs during the study period, only 11 (4.9%) had performed ≥15 open repairs annually, and the risk-adjusted mortality rates varied from 0% to 75% across all centers. After reliability adjustment, the variability of the risk-adjusted mortality rates had decreased significantly to 1.3% to 8.2%. The endovascular repair risk-adjusted mortality rate variability had decreased from 0% to 14.3% to 0.3% to 2.8% after reliability adjustment. A decreasing trend in mortality was found with increasing an annual case volume for open repair with each additional annual case associated with a 0.012% decrease in mortality (P = .05); however, the relationship was not significant for endovascular repair (P = .793). CONCLUSIONS: We found that most hospitals do not perform a sufficient number of annual cases to generate a reliable center-specific mortality rate for open aneurysm repair. Center-specific mortality rates for low-volume centers should be viewed with caution, because a substantial proportion of the variation for these outcomes will be statistical noise rather than true center-level differences in the quality of care.

Focus group study of factors relevant to treatment decisions and experiences among patients with symptomatic peripheral artery disease.

BACKGROUND: Clinical guidelines recommend shared decision-making for treatment of peripheral artery disease (PAD), which requires understanding of patient perspectives and preferences. We conducted a focus group study of patients with symptomatic PAD to identify factors important and relevant to treatment choices, and to characterize aspects of the health care process that contribute to positive vs negative experiences apart from the specific treatment(s) received. METHODS: Participants were recruited from an academic medical center over 2 years using a purposeful sampling approach based on a clinical diagnosis of symptomatic PAD (either claudication or chronic limb-threatening ischemia [CLTI]) confirmed by the abnormal ankle or toe brachial index. Focus groups were led by a nonphysician moderator, consisted of 5 to 12 participants, and were conducted separately for patients with CLTI and claudication. Audio recordings converted to verbatim transcripts were used for qualitative analysis. RESULTS: A total of 51 patients (26 with CLTI and 25 with claudication) were enrolled and participated in focus groups. Major themes identified related to treatment preferences and decisions included specific interventions under consideration, the chance of technical success versus failure, anticipated degree of symptom improvement, outcome durability, and risk. Major themes related to the process of care included decision-making input, provider communication and trust, the timeline from diagnosis to definitive treatment, and compartmentalized care (including different venues of care). CONCLUSIONS: The results provide insights into patient preferences, perspectives, and experiences related to PAD treatment. These observations can be used to inform patient-centered approaches to shared decision-making, communication, and assessment of PAD treatment outcomes.

Exploring the rapid expansion of office-based laboratories and peripheral vascular interventions across the United States.

OBJECTIVE: To characterize the relationship between office-based laboratory (OBL) use and Medicare payments for peripheral vascular interventions (PVI). METHODS: Using the Centers for Medicare and Medicaid Services Provider Utilization and Payment Data Public Use Files from 2014 to 2017, we identified providers who performed percutaneous transluminal angioplasty, stent placement, and atherectomy. Procedures were aggregated at the provider and hospital referral region (HRR) level. RESULTS: Between 2014 and 2017, 2641 providers performed 308,247 procedures. The mean payment for OBL stent placement in 2017 was $4383.39, and mean payment for OBL atherectomy was $13,079.63. The change in the mean payment amount varied significantly, from a decrease of $16.97 in HRR 146 to an increase of $43.77 per beneficiary over the study period in HRR 11. The change in the rate of PVI also varied substantially, and moderately correlated with change in payment across HRRs (R2 = 0.40; P < .001). The majority of HRRs experienced an increase in rate of PVI within OBLs, which strongly correlated with changes in payments (R2 = 0.85; P < .001). Furthermore, 85% of the variance in change in payment was explained by increases in OBL atherectomy (P < .001). CONCLUSIONS: A rapid shift into the office setting for PVIs occurred within some HRRs, which was highly geographically variable and was strongly correlated with payments. Policymakers should revisit the current payment structure for OBL use and, in particular atherectomy, to better align the policy with its intended goals.

Industry Compensation to Physician Vascular Specialist Authors of Highly-referenced Aortic Aneurysm Studies.

BACKGROUND: Industry payments to physicians may influence their attitudes toward medical devices and products. Disclosure of industry compensation by authors of scientific manuscripts usually occurs at the authors' discretion and is seldom audited as part of the peer review process. The purpose of this analysis was to characterize industry compensation among highly cited research articles related to aortic aneurysm. METHODS: A Web of Science search for English language articles published from 2013-2017 using the search term "aortic aneurysm" identified publications for this study. The top 99 most-cited publications were abstracted by author. Physician authors with reported industry compensation from 2013-2016 were identified using the ProPublica Dollars for Docs search tool (linked to Centers for Medicare and Medicaid Services Open Payments data), based on provider name, medical specialty, and geographic location. Statistical analysis included descriptive statistics and categorical tests. RESULTS: The 99 articles had 1,264 unique authors, of whom 105 physicians (8.3%) received industry compensation during the study period. Fourteen of the 105 authors self-reported having received industry compensation. The remaining 91 authors (86.7%) did not disclose their industry-reported compensation. Industry payments during the study period totaled $6,082,574 paid through 13,489 transactions from 169 different manufacturers. In-kind items and services were the most common form of payment (65.3%). The median transaction amount was $58.32. [$138.34]. Food and beverage accounted for the largest number of transactions (N=9653), followed by travel and lodging (N=2365), consulting (N=513), and promotional speaking (N=436). Consulting accounted for the most total dollars over the study period ($1,970,606), followed by travel and lodging ($1,122,276), promotional speaking ($972,894), food and beverage ($568,251), royalty or license ($504,631), honoraria ($452,167), and education ($428,489). Royalty and license payments had the highest median transaction amount ($15,418. [$29,049]), and was the only category with a median transaction amount greater than $5,000. In contrast, several categories had median transaction amounts under $50, including food and beverage ($32. [$77]), gifts ($34. [$86]), and entertainment ($30. [$69]). No significant difference in payment amounts by medical specialty was identified (P=0.071). CONCLUSIONS: Only 8.3% of physician authors of highly cited aortic aneurysm studies received industry compensation, but 86.7% of those physician authors receiving payments did not disclose industry compensation within the manuscripts. Potential bias associated with industry compensation may be underestimated and conservatively biased based on author self-reporting.

Cannabis Use During Lactation: Literature Review and Clinical Recommendations.

Cannabis is the most commonly used psychoactive substance in Canada. The prevalence of cannabis use both during pregnancy and in the postpartum period has been estimated at 5% of the population. Women who use the drug during lactation place their infants at risk of exposure to cannabis and its metabolites in breast milk. This article provides a systematic review of infant outcomes associated with cannabis use by women during lactation followed by clinical recommendations. A review of the literature was conducted using Medline, Embase, and PsychInfo from their start to July 2018. Inclusion criteria consisted of articles addressing the impact of postpartum cannabis use by lactating women and providing developmental outcomes for infants. Two articles met these criteria and were included in our systematic review. Results indicate conflicting outcomes regarding the risk of exposure to cannabis in breast milk. Women should be advised to abstain from cannabis use during lactation or reduce consumption if abstinence is not possible. Furthermore, women should be advised to avoid breastfeeding within 1 hour of inhaled use to reduce exposure to highest concentration of cannabis in breast milk. Despite some evidence regarding health risks of post-natal exposure to cannabis, further research is needed to determine its impact on infant neurodevelopmental outcomes beyond the first year of life.

Aggressive Phenotype of Intravascular Lymphoma Relative to Other Malignant Intraabdominal Tumors Requiring Vascular Reconstruction.

BACKGROUND: Safe resection of intraabdominal and retroperitoneal malignancies with a goal of negative margins may require vascular surgical assistance with grafting of the aorta and/or vena cava. The current report reviews malignancies associated with major vascular reconstructions at a single tertiary referral center. METHODS: Adults with abdominal or retroperitoneal tumors involving the aorta, vena cava, or iliac arteries that underwent reconstruction with vascular grafts at the University of Michigan from 2010 to 2016 were reviewed retrospectively. The initial presentation, surgical management, and outcomes were analyzed. RESULTS: Twelve patients with tumors involving the abdominal aorta, vena cava, or iliac arteries underwent major vascular reconstruction in this seven-year study period. Tumor pathology included solid tumors (leiomyosarcoma [n = 7], germ cell tumor [n = 3], and intravascular lymphoma [n = 2]). Surgical treatment included grafting of the vena cava (n = 6), aorta (n = 3), iliac artery (n = 4), or both the aorta and vena cava (n = 1). Patients with intravascular lymphoma were identified incidentally during treatment of abdominal aortic aneurysm or on pathological analysis of thromboembolism from an aortic source. Other patients had planned resection. Follow-up ranged from 9 to 86 months (median: 28.9). There were no graft occlusions. Tumor metastasized or recurred in patients with sarcoma (n = 2; 28.6%), germ cell tumor (n = 1; 33.3%), and intravascular lymphoma (n = 2; 100%). Both patients with lymphoma had multiple anastomotic or tumor-embolic pseudoaneurysms for <14 months after vascular reconstruction. Both lymphoma patients died during follow-up. CONCLUSIONS: This single-center review suggests that sarcoma and germ cell tumors may be safely resected in conjunction with major vascular reconstruction in carefully selected patients. In comparison, intravascular lymphoma identified incidentally at the time of aortic reconstruction resulted in a more malignant course with pseudoaneurysm formation of anastomoses or native vessels, cancer recurrence, and 100% mortality. Aneurysm contents and emboli should be carefully reviewed perioperatively by pathologists.

From Cancer Immunoediting to New Strategies in Cancer Immunotherapy: The Roles of Immune Cells and Mechanics in Oncology.

For the last three decades, the concept of immunoediting has evolved to characterize our increasing understanding of the interactions between cells from the immune system and cancer development. Elucidating the role of immune cells in the progression of cancer has been very challenging due to their dual role; the immune system can either suppress tumor formation by killing cancer cells, or it can also promote tumor growth. Revealing how immune cells are hampered by the tumor microenvironment and how they aid tumor progression has signaled strategies to reverse these effects and control cancer cell growth; this has been the advent of immunotherapy design. More recently, the role of physical forces in the process of immunoediting has been highlighted by multiple studies focusing on understanding how force changes in the stiffness of the extracellular matrix and fluid flow shear stress contribute to tumor development. Using models in vitro that incorporate biomechanical components, it has been shown that these physical aspects are not only important during the formation and growth of primary tumors, but in the metastatic process as well. In this way, we have also gained insight into the interactions occurring within the vascular system, which are highly affected by the dynamics of physical collisions between cells and by shear forces. Here, we review the concept of cancer immunoediting with an emphasis on biomechanics and conclude with a summary on current immunotherapies and potential new strategies.

Immune Cell-Mediated Biodegradable Theranostic Nanoparticles for Melanoma Targeting and Drug Delivery.

Although tremendous efforts have been made on targeted drug delivery systems, current therapy outcomes still suffer from low circulating time and limited targeting efficiency. The integration of cell-mediated drug delivery and theranostic nanomedicine can potentially improve cancer management in both therapeutic and diagnostic applications. By taking advantage of innate immune cell's ability to target tumor cells, the authors develop a novel drug delivery system by using macrophages as both nanoparticle (NP) carriers and navigators to achieve cancer-specific drug delivery. Theranostic NPs are fabricated from a unique polymer, biodegradable photoluminescent poly (lactic acid) (BPLP-PLA), which possesses strong fluorescence, biodegradability, and cytocompatibility. In order to minimize the toxicity of cancer drugs to immune cells and other healthy cells, an anti-BRAF V600E mutant melanoma specific drug (PLX4032) is loaded into BPLP-PLA nanoparticles. Muramyl tripeptide is also conjugated onto the nanoparticles to improve the nanoparticle loading efficiency. The resulting nanoparticles are internalized within macrophages, which are tracked via the intrinsic fluorescence of BPLP-PLA. Macrophages carrying nanoparticles deliver drugs to melanoma cells via cell-cell binding. Pharmacological studies also indicate that the PLX4032 loaded nanoparticles effectively kill melanoma cells. The "self-powered" immune cell-mediated drug delivery system demonstrates a potentially significant advancement in targeted theranostic cancer nanotechnologies.

New predictors of complications in carotid body tumor resection.

OBJECTIVE: This study examined the relationship between two new variables, tumor distance to base of skull (DTBOS) and tumor volume, with complications of carotid body tumor (CBT) resection, including bleeding and cranial nerve injury. METHODS: Patients who underwent CBT resection between 2004 and 2014 were studied using a standardized, multi-institutional database. Demographic, perioperative, and outcomes data were collected. CBT measurements were determined from computed tomography, magnetic resonance imaging, and ultrasound examination. RESULTS: There were 356 CBTs resected in 332 patients (mean age, 51 years; 72% female); 32% were classified as Shamblin I, 43% as Shamblin II, and 23% as Shamblin III. The mean DTBOS was 3.3 cm (standard deviation [SD], 2.1; range, 0-10), and the mean tumor volume was 209.7 cm3 (SD, 266.7; range, 1.1-1642.0 cm3). The mean estimated blood loss (EBL) was 257 mL (SD, 426; range, 0-3500 mL). Twenty-four percent of patients had cranial nerve injuries. The most common cranial nerves injured were the hypoglossal (10%), vagus (11%), and superior laryngeal (5%) nerves. Both Shamblin grade and DTBOS were statistically significantly correlated with EBL of surgery and cranial nerve injuries, whereas tumor volume was statistically significantly correlated with EBL. The logistic model for predicting blood loss and cranial nerve injury with all three variables-Shamblin, DTBOS, and volume (R2 = 0.171, 0.221, respectively)-was superior to a model with Shamblin alone (R2 = 0.043, 0.091, respectively). After adjusting for Shamblin grade and volume, every 1-cm decrease in DTBOS was associated with 1.8 times increase in risk of >250 mL of blood loss (95% confidence interval, 1.25-2.55) and 1.5 times increased risk of cranial nerve injury (95% confidence interval, 1.19-1.92). CONCLUSIONS: This large study of CBTs demonstrates the value of preoperatively determining tumor dimensions and how far the tumor is located from the base of the skull. DTBOS and tumor volume, when used in combination with the Shamblin grade, better predict bleeding and cranial nerve injury risk. Furthermore, surgical resection before expansion toward the base of the skull reduces complications as every 1-cm decrease in the distance to the skull base results in 1.8 times increase in >250 mL of blood loss and 1.5 times increased risk of cranial nerve injury.

Sample size requirements for one-year treatment effects using deep gray matter volume from 3T MRI in progressive forms of multiple sclerosis.

OBJECTIVE: The subcortical deep gray matter (DGM) develops selective, progressive, and clinically relevant atrophy in progressive forms of multiple sclerosis (PMS). This patient population is the target of active neurotherapeutic development, requiring the availability of outcome measures. We tested a fully automated MRI analysis pipeline to assess DGM atrophy in PMS. DESIGN/METHODS: Consistent 3D T1-weighted high-resolution 3T brain MRI was obtained over one year in 19 consecutive patients with PMS [15 secondary progressive, 4 primary progressive, 53% women, age (mean±SD) 50.8±8.0 years, Expanded Disability Status Scale (median, range) 5.0, 2.0-6.5)]. DGM segmentation applied the fully automated FSL-FIRST pipeline ( http://fsl.fmrib.ox.ac.uk ). Total DGM volume was the sum of the caudate, putamen, globus pallidus, and thalamus. On-study change was calculated using a random-effects linear regression model. RESULTS: We detected one-year decreases in raw [mean (95% confidence interval): -0.749 ml (-1.455, -0.043), p = 0.039] and annualized [-0.754 ml/year (-1.492, -0.016), p = 0.046] total DGM volumes. A treatment trial for an intervention that would show a 50% reduction in DGM brain atrophy would require a sample size of 123 patients for a single-arm study (one-year run-in followed by one-year on-treatment). For a two-arm placebo-controlled one-year study, 242 patients would be required per arm. The use of DGM fraction required more patients. The thalamus, putamen, and globus pallidus, showed smaller effect sizes in their on-study changes than the total DGM; however, for the caudate, the effect sizes were somewhat larger. CONCLUSIONS: DGM atrophy may prove efficient as a short-term outcome for proof-of-concept neurotherapeutic trials in PMS.