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Purpose: The abnormal function of tumor blood vessels causes tissue hypoxia, promoting disease progression and treatment resistance. Although tumor microenvironment normalization strategies can alleviate hypoxia globally, how local oxygen levels change is not known because of the inability to longitudinally assess vascular and interstitial oxygen in tumors with sufficient resolution. Understanding the spatial and temporal heterogeneity should help improve the outcome of various normalization strategies. Experimental Design: We developed a multiphoton phosphorescence quenching microscopy system using a low-molecular-weight palladium porphyrin probe to measure perfused vessels, oxygen tension, and their spatial correlations in vivo in mouse skin, bone marrow, and four different tumor models. Further, we measured the temporal and spatial changes in oxygen and vessel perfusion in tumors in response to an anti-VEGFR2 antibody (DC101) and an angiotensin-receptor blocker (losartan). Results: We found that vessel function was highly dependent on tumor type. Although some tumors had vessels with greater oxygen-carrying ability than those of normal skin, most tumors had inefficient vessels. Further, intervessel heterogeneity in tumors is associated with heterogeneous response to DC101 and losartan. Using both vascular and stromal normalizing agents, we show that spatial heterogeneity in oxygen levels persists, even with reductions in mean extravascular hypoxia. Conclusions: High-resolution spatial and temporal responses of tumor vessels to two agents known to improve vascular perfusion globally reveal spatially heterogeneous changes in vessel structure and function. These dynamic vascular changes should be considered in optimizing the dose and schedule of vascular and stromal normalizing strategies to improve the therapeutic outcome.

Over the past few years, the NCCN Guidelines for Melanoma: Cutaneous have been expanded to include pathways for treatment of microscopic satellitosis (added in v2.2020), and the following Principles sections: Molecular Testing (added in v2.2019), Systemic Therapy Considerations (added in v2.2020), and Brain Metastases Management (added in v3.2020). The v1.2021 update included additional modifications of these sections and notable revisions to Principles of: Pathology, Surgical Margins for Wide Excision of Primary Melanoma, Sentinel Lymph Node Biopsy, Completion/Therapeutic Lymph Node Dissection, and Radiation Therapy. These NCCN Guidelines Insights discuss the important changes to pathology and surgery recommendations, as well as additions to systemic therapy options for patients with advanced disease.

Closed-loop insulin delivery systems have the potential to address suboptimal glucose control in children and adolescents with type 1 diabetes. We compared safety and efficacy of the Cambridge hybrid closed-loop algorithm with usual care over 6 months in this population.In a multicentre, multinational, parallel randomised controlled trial, participants aged 6-18 years using insulin pump therapy were recruited at seven UK and five US paediatric diabetes centres. Key inclusion criteria were diagnosis of type 1 diabetes for at least 12 months, insulin pump therapy for at least 3 months, and screening HbAOf 147 people initially screened, 133 participants (mean age 13·0 years [SD 2·8]; 57% female, 43% male) were randomly assigned to either the closed-loop group (n=65) or the control group (n=68). Mean baseline HbAThe Cambridge hybrid closed-loop algorithm had an acceptable safety profile, and improved glycaemic control in children and adolescents with type 1 diabetes. To ensure optimal efficacy of the closed-loop system, usage needs to be consistently high, as demonstrated with CamAPS FX.National Institute of Diabetes and Digestive and Kidney Diseases.

Objective To determine whether central venous oxygen saturation (ScvO2) measurements could be used interchangeably with mixed venous oxygen saturation (SvO2) measurements in adult cardiac surgery patients. Design A single-center prospective observational study. Setting A university hospital. Participants Eighty-five adult patients undergoing cardiac surgery. Interventions The study authors compared the oxygen saturations in 590 pairs of venous blood samples drawn from the pulmonary artery catheter (PAC) at three different time points during surgery and four different time points in the intensive care unit. They compared samples obtained from the distal pulmonary artery line (SvO2) to those drawn from the proximal central venous line of the PAC (ScvO2) with the Bland-Altman test and the four-quadrant method. Measurements and main results The mean bias between SvO2 and ScvO2 was -1.9 (95% confidence interval [CI], -2.3 to -1.5) and the limits of agreement (LOA) were -11.5 to 7.6 (95% CI, -12.5 to -10.7 and 6.8-8.5, respectively). The percentage error (PE) was 13.2%. Based on the four-quadrant plot, only 50% of the measurement pairs were in agreement, indicating deficient trending ability. Conclusion ScvO2 values showed acceptable accuracy as the mean bias was low. The precision was inadequate; although the PE was acceptable, the LOA were wide. Trending ability was inadequate. The authors cannot recommend the use of ScvO2 values interchangeably with SvO2 measurements in the management of adult cardiac surgery patients.

Background Cancers of the head and neck region are associated with high symptom burden and elevated levels of psychological distress. Radiotherapy (RT) is a common treatment for patients with head and neck cancer (HNC) that is associated with psychological distress related to the immobilizing nature of the treatment, frequency of treatment delivery, and side effects. Guided imagery is a relaxation technique that is beneficial in reducing psychological distress in patients with other cancer diagnoses but has not been studied in this patient population. The purpose of this study is to evaluate the feasibility and acceptability of a brief guided imagery intervention (guided imagery for treatment, GIFT) to reduce RT-related anxiety and depression in patients with HNC relative to treatment as usual (TAU). Methods Patients with HNC planning to receive RT will be recruited to participate in a randomized controlled trial evaluating a brief, two-session guided imagery intervention (GIFT) relative to TAU alone. Primary aims include acceptability and feasibility evaluated through quantitative and qualitative methods. Measures of anxiety and depression, symptom burden, health-related quality of life, and anxiolytic medication use will be collected at baseline, during treatment, and at 1-month follow-up. Discussion There are no published interventions of guided imagery for anxiety and depression in patients with HNC despite its efficacy in other populations of patients with cancer. This proposed project evaluates the feasibility and acceptability of an intervention that has the potential to reduce psychological distress in a vulnerable population. Additionally, we will preliminarily examine the impact of behavioral intervention on psychological distress and the use of anxiolytic medication, a novel area of study. Trial registration Clinicaltrials.gov NCT03662698; registered on 9/6/2018.

Perception of sounds occurs in the context of surrounding sounds. When spectral properties differ between earlier (context) and later (target) sounds, categorization of later sounds becomes biased through spectral contrast effects (SCEs). Past research has shown SCEs to bias categorization of speech and music alike. Recent studies have extended SCEs to naturalistic listening conditions when the inherent spectral composition of (unfiltered) sentences biased speech categorization. Here, we tested whether natural (unfiltered) music would similarly bias categorization of French horn and tenor saxophone targets. Preceding contexts were either solo performances of the French horn or tenor saxophone (unfiltered; 1 second duration in Experiment 1, or 3 seconds duration in Experiment 2) or a string quintet processed to emphasize frequencies in the horn or saxophone (filtered; 1 second duration). Both approaches produced SCEs, producing more “saxophone” responses following horn / horn-like contexts and vice versa. One-second filtered contexts produced SCEs as in previous studies, but 1-second unfiltered contexts did not. Three-second unfiltered contexts biased perception, but to a lesser degree than filtered contexts did. These results extend SCEs in musical instrument categorization to everyday listening conditions.

Radiotherapy (RT) to the primary nasopharyngeal tumor is frequently offered to patients with metastatic nasopharyngeal carcinoma (mNPC). However, only limited data exist to support RT in this setting. We used the National Cancer Database (NCDB) to evaluate outcomes for mNPC patients receiving chemotherapy with and without local RT.The NCDB was queried for patients with mNPC with synchronous metastatic disease at diagnosis who received chemotherapy. Overall survival (OS) was analyzed using the Kaplan-Meier method, Cox proportional hazards models, and propensity score-matched analyses.From 2004 to 2013, 718 cases were identified (39% chemotherapy-alone, 61% chemotherapy+RT). At a median follow-up of 4.4years, RT was associated with improved survival on univariate analysis (median OS 21.4 vs 15.5months; 5-year OS 28% vs 10%; p0.001) and multivariate analyses (HR, 0.61; CI, 0.51-0.74; p0.001). Propensity score analysis with matched baseline characteristics demonstrated a similar OS advantage with RT (HR, 0.68; CI, 0.55-0.84; p0.001). The benefits of RT remained consistent in models controlling for single vs multi-organ metastases and anatomic sites of metastatic involvement. RT dose was an independent prognostic factor as both a continuous and categorical variable, with OS benefits observed among patients receiving ≥50Gy. Long-term survival of10years was only observed in the RT cohort.This analysis supports strategies incorporating local RT with chemotherapy for mNPC. Prospective trials evaluating RT integration for mNPC are warranted.

Background Recurrence rates for atypical and anaplastic meningiomas range between 9% and 50% after gross total resection and between 36% and 83% after subtotal resection. Optimal treatment of recurrent meningiomas exhibiting atypical/anaplastic histology is complicated because they are often refractory to both surgery and radiation. Objective To evaluate clinical determinants of recurrence and treatment-specific outcomes in patients with recurrent meningiomas exhibiting atypical/anaplastic histology at our institution. Methods A cohort study was conducted using clinical data of all patients treated for meningiomas with atypical/anaplastic histology at first recurrence between January 1985 and July 2014 at a tertiary cancer center. Predictors of second recurrence were analyzed using competing risks regression models. Results Nine hundred eighteen patients with meningioma were screened, of whom 60 (55% female) had recurrent disease with atypical/anaplastic histology at a median age of 58.1 yr at diagnosis. The median follow-up from the time of first recurrence was 36.7 mo, with 32 (53%) patients alive at last follow-up. There was no effect of extent of resection at first recurrence on time to a subsequent recurrence. Inclusion of radiation as primary or adjuvant therapy at first recurrence reduced the risk of progression or subsequent recurrence compared to surgery alone (P = .07). Conclusion Treatment of recurrent meningiomas with atypical/anaplastic histology remains challenging. Our data, from one of the largest cohorts, suggest better tumor control with the addition of radiation and challenges the importance of extent of resection at first recurrence. A multicenter effort is needed to confirm these findings and propose treatment guidelines.

BACKGROUND Sinonasal malignancies are a rare and heterogeneous group of tumors for which there is a paucity of robust data with which to guide management decisions. The authors used the National Cancer Data Base to better understand the presenting characteristics of these tumors and to compare outcomes by treatment modality. METHODS The National Cancer Data Base was queried for sinonasal malignancies diagnosed between 2004 and 2012. Overall survival was assessed using multivariate analyses and propensity score matching. RESULTS A total of 11,160 patients were identified for the initial analysis. The majority were male, aged 40 to 69 years, with tumors of the nasal cavity or maxillary sinus. Squamous cell histology was most common. The majority of patients presented with advanced tumor stage but without locoregional lymph node or distant metastases. Treatment modalities were compared for squamous cell carcinomas. In multivariate analysis, compared with surgery alone, patients who received adjuvant radiotherapy (hazard ratio [HR], 0.658 [P

Purpose To report on the single-catheter high-dose-rate brachytherapy treatment of a 21-month-old girl child with an embryonal, botryoid-type, rhabdomyosarcoma limited to the external auditory canal (EAC). Methods and Materials A 2.4-mm diameter catheter was inserted into the right EAC and placed against the tympanic membrane. A computed tomography simulation scan was acquired. A brachytherapy treatment plan, in which 21 Gy in seven fractions was prescribed to a 1-mm depth along the distal 2 cm of the catheter, was generated. Treatments were delivered under anesthesia without complication. A dosimetric comparison between this plan and an intensity-modulated radiation therapy (IMRT) plan was then conducted. A clinical target volume (CTV), which encompassed a 1-mm margin along the distal 2 cm of the catheter, was delineated for both plans. Given positioning uncertainty under image guidance, a planning target volume (PTV = CTV + 3-mm margin) was defined for the IMRT plan. The IMRT plan was optimized for maximal CTV coverage but subsequently normalized to the same CTV volume receiving 100% of the prescription dose ( V 100 ) of the brachytherapy plan. Results The IMRT plan was normalized to the brachytherapy CTV V 100 of 82.0%. The PTV V 100 of this plan was 34.1%. The PTV exhibited dosimetric undercoverage within the middle ear and toward the external ear. Mean cochlea doses for the IMRT and brachytherapy plans were 26.7% and 10.5% of prescription, respectively. Conclusions For rhabdomyosarcomas limited to the EAC, a standard brachytherapy catheter can deliver a highly conformal radiation plan that can spare the nearby cochlea from excess radiation.

The treatment of rectal cancer is evolving and the role of radiotherapy (RT) continues to be refined. Treatment options and regimens often depend upon the stage of disease, imaging findings, or surgical pathology. Radiation therapy is used in the treatment of locally advanced rectal cancer in the neoadjuvant setting or as post-operative therapy for tumors with high-risk histopathologic features. In the modern era of total mesorectal excision and induction or adjuvant chemotherapy, the primary benefit of radiation is local control. Rectal cancer is unique in that locally recurrent lesions can cause significant symptoms of pain, bowel obstruction and rectal bleeding. Additionally, locally recurrent disease often requires significant surgery such as a pelvic exenteration. Neoadjuvant RT can also reduce the extent and morbidity of surgery and increase the rates of sphincter preservation.

Purpose To report a small substudy of an ongoing large, multi-arm study using functional imaging to assess pre-/intratreatment hypoxia for all head and neck cancer, in which we hypothesized that pre- and early-treatment hypoxia assessment using functional positron emission tomography (PET) imaging may help select which human papillomavirus (HPV)-positive (HPV + ) oropharyngeal cancer (OPC) patients can safely receive radiation de-escalation without jeopardizing treatment outcomes. Methods and Materials Patients with HPV + oropharyngeal carcinoma were enrolled on an institutional review board–approved prospective study of which de-escalation based on imaging response was done for node(s) only. Pretreatment 18 F-fluorodeoxyglucose and dynamic 18 F-FMISO (fluoromisonidazole) positron emission tomography (PET) scans were performed. For patients with pretreatment hypoxia on 18 F-FMISO PET (defined as a >1.2 tumor to muscle standard uptake value ratio), a repeat scan was done 1 week after chemoradiation. Patients without pretreatment hypoxia or with resolution of hypoxia on repeat scan received a 10-Gy dose reduction to metastatic lymph node(s). The 2-year local, regional, distant metastasis–free, and overall survival rates were estimated using the Kaplan-Meier product-limit method. A subset of patients had biopsy of a hypoxic node done under image guidance. Results Thirty-three HPV + OPC patients were enrolled in this pilot study. One hundred percent showed pretreatment hypoxia (at primary site and/or node[s]), and among these, 48% resolved (at primary site and/or node[s]); 30% met criteria and received 10-Gy reduction to the lymph node(s). At the median follow-up of 32 months (range, 21-61 months), the 2-year locoregional control rate was 100%. One patient failed distantly with persistence of hypoxia on 18 F-FMISO PET. The 2-year distant metastasis–free rate was 97%. The 2-year OS rate was 100%. Hypoxia on imaging was confirmed pathologically. Conclusions Hypoxia is present in HPV + tumors but resolves within 1 week of treatment in 48% of cases either at the primary site and/or lymph node(s). Our 100% locoregional control rate suggests that intratreatment functional imaging used to selectively de-escalate node(s) to 60 Gy was confirmed safe using our stringent imaging criteria. Intratreatment functional imaging warrants further study to determine its ultimate role in de-escalation treatment strategies.

Nonaqueous-phase liquid (NAPL) contaminants are difficult to eliminate from natural aquifers due, in part, to the heterogeneous structure of the soil. Chemotaxis enhances the mixing of bacteria with contaminant sources in low-permeability regions, which may not be readily accessible by advection and dispersion alone. A microfluidic device was designed to mimic heterogeneous features of a contaminated groundwater aquifer. NAPL droplets (toluene) were trapped within a fine pore network, and bacteria were injected through a highly conductive adjacent macrochannel. Chemotactic bacteria (Pseudomonas putida F1) exhibited greater accumulation near the pore network at 0.5 m/day than both the nonchemotactic control and the chemotactic bacteria at a higher groundwater velocity of 5 m/day. Chemotactic bacteria accumulated in the vicinity of NAPL droplets, and the accumulation was 15% greater than a nonchemotactic mutant. Indirect evidence showed that chemotactic bacteria were retained within the contaminated low-permeability region longer than nonchemotactic bacteria at 0.25 m/day. This retention was diminished at 5 m/day. Numerical solutions of the bacterial-transport equations were consistent with the experimental results. Because toluene is degraded by P. putida F1, the accumulation of chemotactic bacteria around NAPL sources is expected to increase contaminant consumption and improve the efficiency of bioremediation.

This paper presents a new cognitive assistive technology, nonlinear contextually aware prompting system (N-CAPS) that uses advanced sensing and artificial intelligence to monitor and provide assistance to workers with cognitive disabilities during a factory assembly task.The N-CAPS system was designed through the application of various computer vision and artificial intelligence algorithms that allows the system to track a user during a specific assembly task, and then provide verbal and visual prompts to the worker as needed. A pilot study was completed with the N-CAPS solution in order to investigate whether it was an appropriate intervention. Four participants completed the required assembly task five different times, using the N-CAPS system.The participants completed all of the trials that they attempted with 85.7% of the steps completed without assistance from the job coach. Of the 85.7% of steps completed independently, 32.5% of these were completed in response to prompts given by N-CAPS. Overall system accuracy was 83.3%, the overall sensitivity was 86.2% and the overall specificity was 82.4%.The results from the study were positive in that they showed that this type of technology does have merit with this population. Implications for Rehabilitation It provides a concise summary of the importance of work in the lives of people with intellectual disabilities and how technology can support this life goal. It describes the first artificially intelligent system designed to support workers with intellectually disabilities. It provides evidence that individuals with intellectual disabilities can perform a work task in response to technology.

Among patients with T2N0M0 glottic larynx cancer undergoing definitive radiotherapy, recent retrospective and prospective data have suggested improved outcomes with altered fractionation over conventional fractionation (CFxn). We sought to characterize national fractionation patterns and to compare outcomes among them.We queried the National Cancer Database for T2N0M0 squamous cell carcinomas of the glottis diagnosed from 2004-2014 and managed with definitive radiotherapy. Dose-per-fraction and duration of radiotherapy were used to define cohorts undergoing CFxn, hypofractionation (HypoFxn), and hyperfractionation (HyperFxn). Logistic regression was performed to identify predictors of receiving altered fractionation. Cox regression and propensity-score matching (PSM) analyses were used to compare survival between schedules.We abstracted 2 006 CFxn patients, 1 166 HypoFxn patients, and 161 HyperFxn patients. Fractionation patterns changed significantly from 2004 to 2014, with use of HyperFxn decreasing from 6.3% to 1.8% and use of HypoFxn increasing from 23.9% to 54.1% (p0.001). Receipt of altered fractionation was independently associated with later year of diagnosis and higher facility volume. On Cox regression, both HypoFxn (hazard ratio [HR] for mortality 0.84, 95% confidence interval [95%CI] 0.73-0.97) and HyperFxn (HR 0.74, 95%CI 0.56-0.99) were associated with improved survival over CFxn. The survival advantage of each altered fractionation schedule over CFxn was redemonstrated on comparison of PSM groups.Increasing utilization of HypoFxn for T2N0M0 glottic cancer is driving national practice patterns away from CFxn. Our findings support the use of altered fractionation, particularly HypoFxn, for patients undergoing definitive radiotherapy, although HyperFxn remains understudied in a prospective fashion.

Purpose To characterize practice patterns, including temporal trends, in fractionation schedules among patients in the United States undergoing definitive radiotherapy for early-stage glottic cancer and to compare overall survival outcomes between fractionation schedules. Methods and Materials We queried the National Cancer Database for patients with TisN0M0, T1N0M0, or T2N0M0 squamous cell carcinoma of the glottic larynx diagnosed between 2004 and 2012 and undergoing definitive radiotherapy. Dose per fraction was calculated to define cohorts undergoing conventional fractionation (CFxn) and hypofractionation (HFxn). Logistic regression was performed to identify predictors of receiving HFxn, and Cox regression was used to determine predictors of mortality. One-to-one propensity-score matching (PSM) was then employed to compare survival between fractionation schedules. Results 10,539 patients were included, with 6,576 undergoing CFxn and 3,963 undergoing HFxn. T1 patients comprised a majority of each cohort. Use of HFxn increased significantly over the period studied ( p p =0.008), a finding redemonstrated on univariate Cox regression among a well-matched PSM cohort (HR 0.88, 95%CI 0.80-0.96, p =0.003). Subgroup Cox multivariate analysis demonstrated a significant survival advantage with HFxn among T1 patients (HR 0.90, 95%CI 0.81-0.99; p =0.042), but a nonsignificant benefit among those with Tis (HR 0.86, 95%CI 0.57-1.30; p =0.472) or T2 disease (HR 0.88, 95%CI 0.76-1.02; p =0.099). Conclusions Utilization of HFxn is increasing and is associated with improved survival over CFxn. Our findings support the broadened use of HFxn for patients with early-stage glottic cancer undergoing definitive radiotherapy.

Perception of sounds occurs in the context of surrounding sounds. When spectral properties differ between earlier (context) and later (target) sounds, categorization of later sounds becomes biased through spectral contrast effects (SCEs). Past research has shown SCEs to bias categorization of speech and music alike. Additionally, the magnitudes of SCEs are not all-or-none but vary continuously in both speech and music categorization. Recently, the natural spectral composition of (unfiltered) sentences biased speech categorization via SCEs (Stilp and Assgari, under review). Here, we tested whether natural (unfiltered) music would similarly bias categorization of French horn and tenor saxophone targets. Preceding contexts were either solo performances of the French horn or tenor saxophone (unfiltered) or a string quintet processed to emphasize frequencies in the horn or saxophone (filtered). Categorization was influenced by SCEs in both unfiltered and filtered conditions, with more “saxophone” responses following horn / horn-like contexts and vice versa. Since unfiltered music produced SCEs in musical instrument categorization, this extends their influence to everyday listening conditions. Perception of sounds occurs in the context of surrounding sounds. When spectral properties differ between earlier (context) and later (target) sounds, categorization of later sounds becomes biased through spectral contrast effects (SCEs). Past research has shown SCEs to bias categorization of speech and music alike. Additionally, the magnitudes of SCEs are not all-or-none but vary continuously in both speech and music categorization. Recently, the natural spectral composition of (unfiltered) sentences biased speech categorization via SCEs (Stilp and Assgari, under review). Here, we tested whether natural (unfiltered) music would similarly bias categorization of French horn and tenor saxophone targets. Preceding contexts were either solo performances of the French horn or tenor saxophone (unfiltered) or a string quintet processed to emphasize frequencies in the horn or saxophone (filtered). Categorization was influenced by SCEs in both unfiltered and filtered conditions, with more “saxophone” responses fo...

Sinonasal malignancies are a rare and heterogeneous group of tumors for which there is a paucity of robust data with which to guide management decisions. The authors used the National Cancer Data Base to better understand the presenting characteristics of these tumors and to compare outcomes by treatment modality.The National Cancer Data Base was queried for sinonasal malignancies diagnosed between 2004 and 2012. Overall survival was assessed using multivariate analyses and propensity score matching.A total of 11,160 patients were identified for the initial analysis. The majority were male, aged 40 to 69 years, with tumors of the nasal cavity or maxillary sinus. Squamous cell histology was most common. The majority of patients presented with advanced tumor stage but without locoregional lymph node or distant metastases. Treatment modalities were compared for squamous cell carcinomas. In multivariate analysis, compared with surgery alone, patients who received adjuvant radiotherapy (hazard ratio [HR], 0.658 [P.001]), adjuvant chemoradiotherapy (HR, 0.696 [P = .002]), or neoadjuvant therapy (HR, 0.656 [P = .007]) had improved overall survival. Patients who received radiotherapy alone (HR, 1.294 [P = .001]) or chemotherapy alone (HR, 1.834 [P.001]) had worse outcomes. These findings were validated in propensity score matching. It is important to note that neoadjuvant chemoradiotherapy was associated with achieving a negative surgical margin (odds ratio, 2.641 [P = .045]).Surgery is the mainstay of therapy for patients with sinonasal malignancies, but multimodality therapy is associated with improved overall survival. Cancer 2017;123:3040-49. © 2017 American Cancer Society.

Swimming bacteria sense and respond to chemical signals in their environment. Chemotaxis is the directed migration of a bacterial population toward increasing concentrations of a chemical that they perceive to be beneficial to their survival. Bacteria that are indigenous to groundwater environments exhibit chemotaxis toward chemical contaminants such as hydrocarbons, which they are also able to degrade. This phenomenon may facilitate bioremediation processes by bringing bacteria into closer proximity to these contaminants. A microfluidic device was assembled to study chemotaxis transverse to advective flow. Using a T-shaped channel design (T-sensor), two fluid streams were brought into contact by impinging flow. They then flowed adjacent to each other along a transparent channel. An advantage to this design is that it allows real-time visualization of bacterial distributions within the channel. Under laminar flow conditions a chemotactic driving force was created perpendicular to the direction of flow by diffusion of the chemical attractant from one input stream to the other. A comparison of the chemotactic band behavior in the absence and presence of flow showed that fluid velocity did not significantly impede chemotactic migration in the transverse direction.

A ratiometric fluorescent pH sensor based on CdSe/CdZnS nanocrystal quantum dots (NCs) has been designed for biological pH ranges. The construct is formed from the conjugation of a pH dye (SNARF) to NCs coated with a poly(amido amine) (PAMAM) dendrimer. The sensor exhibits a well-resolved ratio response at pH values between 6 and 8 under linear or two-photon excitation, and in the presence of a 4% bovine serum albumin (BSA) solution.

Background and Purpose— Through 2-way live video and audio communication, telestroke enhances urgent treatment of patients with acute stroke in emergency departments (EDs) without immediate access to on-site specialists. To assess for opportunities to shorten the door to thrombolysis time, we measured multiple time intervals in a telestroke system. Methods— We retrospectively analyzed 115 records of consecutive acute stroke patients treated with intravenous thrombolysis during a 20-month period via a statewide telestroke system in 17 EDs in Georgia. On the basis of times documented in the telestroke system, we calculated the time elapsed between the following events: ED arrival, telestroke patient registration, start of specialist consultation, head computed tomography, thrombolysis recommendation, and thrombolysis initiation. Results— The most conspicuous delay was from ED arrival to telestroke patient registration (median, 39 minutes; interquartile range, 21–56). Median time from ED arrival to thrombolysis initiation was 88 minutes, interquartile range 75 to 105. Thrombolysis was initiated within 60 minutes from ED arrival in 13% of patients. Conclusions— The greatest opportunity to expedite acute thrombolysis via telestroke is by shortening the time from ED arrival to telestroke patient registration.

We present a combined near-infrared diffuse optical spectroscopy (DOS) and Magnetic Resonance Imaging (MRI) system for the study of animal model tumors. Acombined broadband steady-state and frequency domain optical spectroscopy apparatus was integrated with the MRI. The physiological properties of tissue rendered by MRI, including vascular volume fraction and water, were compared with chromophore concentrations as determined from the parameters obtained by optical measurements. DOS measurements provided oxyhemoglobin, deoxy-hemoglobin, and water concentration locally in tumors. A method for coregistration of the information obtained by both modalities was developed. Using Monte Carlo simulations, the optically sampled volume was superimposed on the MR images, illustrating which tissue structure was probed optically. Finally, two optical contrast agents, indocyanine green (ICG) and methylene blue (MB), were employed and their kinetics were measured by DOS system from different locations on the tumor and compared with Gd-DTPA enhancement maps obtained from MRI.

Successful implementation of bioremediation clean-up strategies depends on accurate predictions of the transport of bacteria within the subsurface. In this study, etched flat-plate glass micromodels were used to examine bacterial transport in a homogenous network. These networks were created by acid-etching interconnected channels into a glass plate and then fusing it to an unetched plate forming semi-cylindrical pores. The transparent nature of the micromodel allows for both qualitative observations of the bacteria within the pores and quantitative measurements of their concentration. The micromodels are designed to allow establishment of a well-characterized step change in bacterial concentration (Escherichia coli NR50) within the network. During the experiments, bacteria are dispersed through the network by flow. Light scattering is used to detect the change in turbidity within the pores as the bacteria travel through the network. The change in turbidity is used to construct breakthrough curves and spatial concentration profiles of bacteria within the network. The breakthrough curves are fit to the one-dimensional advection/dispersion equation to determine dispersion coefficients at different interstitial fluid velocities. From the breakthrough curves, dispersion coefficients were reproducible for replicate experiments over a range of velocities in the advection-dominated regime. The dispersivity values for two network designs resembling an interconnecting capillary network and a spatially periodic network of cylinders were 0.28 and 0.33 cm respectively, which are slightly greater than the literature values found for other pore networks. Experiments were also conducted within the diffusion-dominated regime to examine the effects of bacterial motility on dispersion. The accumulation of bacteria on the pore walls became significant at the low flow rates and extended experimental times thereby rendering the use of light scattering to determine concentrations ineffective. Bacterial chemotaxis, created by a self-imposed oxygen gradient, was also observed in the micromodel under stagnant fluid conditions.

Rationale: The CA19-9 antigen is frequently overexpressed in pancreatic and other GI tumors. MVT-5873 (HuMab-5B1), a fully human monoclonal antibody currently in phase I study, targets the sialyl Lewis A (sLea) epitope on CA19-9, and is a promising platform for development of a targeted radioimmunotherapy (RIT). MVT-5873 was conjugated with the chelator CHX-A″-DTPA and radiolabeled with the beta-emitting isotopes Lutetium -177 (177Lu) or Yttrium-90 (90Y) to form the RIT agents MVT-1075 (177Lu- CHX-A″-DTPA-HuMAb-5B1) and MVT-1916 (90Y- CHX-A″-DTPA-HuMAb-5B1), respectively. The antitumor efficacy of each of the constructs was studied in nude mice bearing BxPC3 human pancreatic tumor xenografts, known to express CA19-9. Methods: The initial dose-finding studies utilized doses of MVT-1075 of 75-450 μCi and MVT-1916 of 25-250 μCi, administered to groups of mice (n = 8) bearing subcutaneous (subQ) BxPC3 tumors (~ 150 mm3). Further studies focused on MVT-1075 and assessed antitumor effect in an orthotopic xenograft model, the effect of dose fractionation, and biodistribution in nontumor bearing (normal) and BxPC3 tumor-bearing mice. Results: A single dose of MVT-1075 at 75, 150, 300, or 450 μCi significantly inhibited subQ BxPC3 tumor growth at all dose levels, with sustained suppression with higher doses. MVT-1916 produced similar results. MVT-1075 was selected based on the favorable half-life of 177Lu (6.7 d) and its utility for clinical biodistribution assessments. In an orthotopic BxPC3 tumor model, treatment with a single dose of MVT-1075 at 300 μCi significantly inhibited tumor growth, with Day 20 tumor volume approximately 50% that of the initial starting volume. A third BxPC3 xenograft study evaluated fractionated dosing schedules, (150 μCi x 1, 75 μCi x 2, 50 μCi x3), with both single-dose and fractionated schedules effectively inhibiting subQ BxPC3 tumor growth. Biodistribution studies in normal mice showed an expected gradually decreasing activity in blood, heart, and lungs, with low uptake in normal pancreas. In subQ BxPC3 tumor-bearing mice, tumor uptake was rapid, reaching 69% ID/g by 24 h and 86% ID/g by 120 h. Otherwise, the biodistribution pattern paralleled that of normal mice, with relative %ID/g values within about ± 25% of normal mice across all time points comparing blood, heart, lungs, kidneys, and pancreas, with slightly higher uptake in liver and slightly lower uptake in spleen. Conclusions: MVT-1075 demonstrates promising antitumor activity in a human pancreatic cancer xenograft model, with efficacy shown in both single dose and fractionated schedules. Biodistribution shows rapid and substantial tumor uptake, with much lower uptake in normal organs. These findings support the phase I clinical trial of MVT-1075 in patients with CA19-9 positive pancreatic cancers planned to begin in early 2017. Citation Format: Jacob L. Houghton, Ryan Lanning, Dayla Abdel-atti, Toni Jun, Christine M. Kearns, Michael Schlosser, Wolfgang Scholz, Jason S. Lewis, Paul W. Maffuid. Preclinical development of MVT-1075 as radioimmunotherapy for pancreatic cancer and other CA19-9 positive malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5204. doi:10.1158/1538-7445.AM2017-5204

Human epidermal growth factor receptor 2 (HER2) overexpression was associated with locoregional recurrence (LRR) in the preadjuvant trastuzumab era. This study aimed to examine the effect of trastuzumab on LRR in mastectomy patients and whether it varied with postmastectomy radiation (PMRT). From the authors’ institutional database, 501 women with stages I–III HER2-positive breast cancer who underwent mastectomy from 1998 to 2007 were identified. A landmark analysis was performed to compare two cohorts: 170 women who received trastuzumab and 281 who did not. Kaplan–Meier methods were used to estimate locoregional recurrence-free survival (LRRFS). A propensity score analysis was used to balance the treatment groups with respect to multiple covariates. Analogous methods were used to study the effect of PMRT. The women in the trastuzumab group were more likely to be node positive and to receive systemic therapy or PMRT (p

The purpose of the study was to find out the prevalence of osteonecrosis in children with acute lymphoblastic leukemia (ALL) in complete bone marrow remission at the end of the treatment. Twenty-eight children with ALL underwent MRI of the upper and/or lower extremities. Bone marrow signal intensity was analyzed on T1-weighted images, where circumscribed lesions with a rim of low signal intensity were considered typical of osteonecrosis. Osteonecrosis was found in 9 of the 28 children (32%, 95% CI 16% to 52%). Five of them were asymptomatic. They had been treated with high risk and intermediate risk protocols, both of which include a delayed intensification phase with dexamethasone. None of the patients with standard risk ALL were found to have developed osteonecrosis. Osteonecroses occurred unexpectedly in symptomless patients and in patients with mild transient symptoms treated with high risk and intermediate risk protocols. Our study suggests that the intensification phase of the treatment protocols with intensive dexamethasone medication might be responsible for the development of osteonecrosis.

Acidity, hypoxia, and glucose levels characterize the tumor microenvironment rendering pH, pO2, and pGlucose, respectively, important indicators of tumor health. To this end, understanding how these parameters change can be a powerful tool for the development of novel and effective therapeutics. We have designed optical chemosensors that feature a quantum dot and an analyte-responsive dye. These noninvasive chemosensors permit pH, oxygen, and glucose to be monitored dynamically within the tumor microenvironment by using multiphoton imaging., National Cancer Institute (U.S.) (Grant R01-CA126642)

Tumor markers CA 125 and CA 19-9 are elevated in a variety of malignancies in adult patients, but only little is known of their biology during gestation or infancy. We have addressed the developmental pattern of these carbohydrate antigens in pediatric patients by measuring their serum levels in 133 cord blood samples from the second through third trimester of gestation and in 39 infants aged less than 1.5 y. The serum concentrations of both markers revealed developmental changes, the levels being higher at earlier gestation (wk 24 through 37) than at term or during infancy. The clinical value of the markers was evaluated by monitoring 26 children with germ cell tumors; 14 benign and 2 immature teratomas, and 11 malignant germ cell tumors. Patients with immature sacrococcygeal teratomas showed constant and prolonged elevations of serum CA 125 and CA 19-9. In contrast, all but two children with mature teratomas had normal marker levels; these two patients with abnormally high serum CA 125 and CA 19-9 values for the first 4 postoperative weeks had a benign ovarian and ventricular teratoma, respectively. Of the 11 children with malignant germ cell tumors, serum CA 125 or CA 19-9 concentration was elevated in four patients at diagnosis and declined to normal within 2 wk after institution of therapy. Malignant recurrence in two patients was not associated with a reelevation of the CA 125 level. Taken together, our results demonstrate a developmentally regulated pattern of serum CA 125 and CA 19-9. The carbohydrate markers were usually inferior to alpha-fetoprotein in monitoring of germ cell tumors, but may be a useful adjunct in the follow-up of immature teratomas.

Forty patients (nine adults aged 20-54; 31 children aged 1-17) with Diamond-Blackfan anaemia (DBA) were treated with recombinant human interleukin-3 (IL-3) in a European multicentre compassionate-need study. IL-3 was given as a daily subcutaneous injection at a starting dose of 2.5 micrograms/kg, escalating at day 21 to 5 micrograms/kg, and then to 10 micrograms/kg if there was no response, for a total duration of 12 weeks. Three children achieved a significant response, achieving sustained remissions off all therapy. At the time of entry, one was steroid-responsive and transfusion-independent, and two were transfusion-dependent. Two adults had a transient reduction in transfusion requirements, but could not tolerate the complete course of therapy. Eosinophilia was common; neutrophil and platelet counts were unaffected except in three patients in whom previously noted mild thrombocytopenia was transiently exacerbated. Clinical response to IL-3 did not correlate with in vitro culture results. A comparison of individual patient characteristics of our study with previously reported series confirms earlier impressions that patients who have never achieved significant in vivo erythropoiesis in response to steroids or during a spontaneous remission are highly unlikely to respond to IL-3. In contrast, there may be a 50% chance of a sustained remission, off steroids, in children who are steroid-dependent and transfusion-independent at the time of IL-3 therapy, suggesting a possible role for a short course of IL-3 earlier in the treatment of children with steroid-responsive DBA.

e21699Background: To report the palliative response and early toxicity data of proton hypofractionated radiotherapy (RT) in incurable recurrent or metastatic malignancies of the head and neck using...

Molecular cancer therapy relies on interstitial diffusion for drug distribution in solid tumors. A mechanistic understanding of how tumor components affect diffusion is necessary to advance cancer drug development. Yet, because of limitations in current techniques, it is unclear how individual tissue components hinder diffusion. We developed multiscale fluorescence recovery after photobleaching (MS-FRAP) to address this deficiency. Diffusion measurements facilitated by MS-FRAP distinguish the diffusive hindrance of the interstitial versus cellular constituents in living tissue. Using multiscale diffusion measurements in vivo, we resolved the contributions of these two major tissue components toward impeding diffusive transport in solid tumors and subcutaneous tissue in mice. We further used MS-FRAP in interstitial matrix-mimetic gels and in vivo to show the influence of physical interactions between collagen and hyaluronan on diffusive hindrance through the interstitium. Through these studies, we show that interstitial hyaluronan paradoxically improves diffusion and that reducing cellularity enhances diffusive macromolecular transport in solid tumors.

Among a cohort of 981 children who were followed up 4.3-26.5 years after cessation of antileukemic therapy, eight patients in remission of acute lymphoblastic leukemia (ALL) developed a distinctively new malignant disease. The second malignant neoplasms (SMN) included brain tumors, basal cell carcinomas, thyroid cancer, leiomyosarcoma and finally rhabdomyosarcoma in a patient who also had suffered from Hodgkin's disease while still on antileukemic treatment. Cranial radiation had been given to 58.4% of the patients in the study group, which consisted of 895 ALL patients who had completed various chemotherapy protocols. With one exception, the SMN appeared after 7.5-16.5 years at a location previously exposed to radiotherapy (RT). The estimated cumulative risk of SMN appearing within 20 years after diagnosis was 2.9%, and the corresponding risk for cases with RT was 8.1% compared to 0.3% for those without (p = 0.05). In a Cox regression analysis, the incidence rate ratio of SMN between patients with and without RT was 6.7 (95% CI = 0.8, 57.7). Based on age-, year- and sex-specific cancer incidence figures for Norway, the overall standardized incidence rate ratio (SIR) of SMN after treatment for ALL was 5.9 (95% CI = 2.2, 12.9). The number of brain tumors among patients who had received cranial radiation was nearly 27 times greater than expected, whereas no such tumors were seen after chemotherapy. Individuals treated for childhood ALL are at increased risk of a new malignancy, and this seems mainly to be associated with previous irradiation.

The influence of magnetic resonance (MR) imaging on the integrity and function of an implantable, programmable drug infusion pump and the distortion of the image by this device were tested. Six identical pumps were tested in magnetic fields of 1.5 T. Pump memory was not affected by the procedure. The pump rotor stalled (no infusion) as long as the device was within the magnetic field. Drug delivery resumed as programmed after the pump was removed from the field. No structural damage to the electrical or mechanical pump components was detected. The pump caused a circular image artifact (a signal dropout) within 8-10 cm of the device. The authors conclude that MR imaging is accurate if the area of interest is at least 10 cm from the pump, and that with awareness of temporary infusion cessation, it is safe to perform MR imaging in patients with this implanted pump.

Tissue engineering requires formation of a de novo stable vascular network. Because of their ability to proliferate, differentiate into endothelial cells, and form new vessels, blood-derived endothelial progenitor cells (EPCs) are attractive source of cells for use in engineering blood vessels. However, the durability and function of EPC-derived vessels implanted in vivo are unclear. To this end, we directly compared formation and functions of tissue-engineered blood vessels generated by peripheral blood– and umbilical cord blood–derived EPCs in a model of in vivo vasculogenesis. We found that adult peripheral blood EPCs form blood vessels that are unstable and regress within 3 weeks. In contrast, umbilical cord blood EPCs form normal-functioning blood vessels that last for more than 4 months. These vessels exhibit normal blood flow, perm-selectivity to macromolecules, and induction of leukocyte-endothelial interactions in response to cytokine activation similar to normal vessels. Thus, umbilical cord blood EPCs hold great therapeutic potential, and their use should be pursued for vascular engineering.

CD1a, an antigen-presenting molecule related to major histocompatibility complex (MHC) class I, is frequently described as nonpolymorphic. In humans it is dimorphic, due to two linked amino acid substitutions in the alpha1 domain (Ile13Thr and Trp51Cys). The CD1a gene on chromosome 1 is not linked to MHC and may be mismatched between human leukocyte antigen-identical siblings. We analyzed 155 donor-recipient pairs of the Eurobank cohort, 141 matched for CD1a and 14 unmatched in the graft-versus-host disease (GVHD) direction. The burden of GVHD was not increased by CD1a mismatching. The incidence of GVHD in matched and unmatched groups was respectively: grade I-IV: 81% and 86% (P = 0.492); II-IV 61% and 57% (P = 0.495); III-IV 23% and 21% (P = 0.608). Adjusting for age, sex mismatch, GVHD prophylaxis, and conditioning did not reveal any significant difference. This suggests that, unlike conventional class I molecules, CD1a does not function as a transplantation antigen and does not require matching in hematopoietic stem cell transplantation.

Classically, nitric oxide (NO) formed by endothelial NO synthase (eNOS) freely diffuses from its generation site to smooth muscle cells where it activates soluble guanylyl cyclase (sGC), producing cGMP. Subsequently, cGMP activates both cGMP- and cAMP-dependent protein kinases [cGMP-dependent protein kinase (PKG) and cAMP-dependent protein kinase (PKA), respectively], leading to smooth muscle relaxation. In endothelial cells, eNOS has been localized to caveolae, small invaginations of the plasma membrane rich in cholesterol. Membrane cholesterol depletion impairs acetylcholine (ACh)-induced relaxation due to alteration in caveolar structure. Given the nature of NO to be more soluble in a hydrophobic environment than in water, and assuming that colocalization of components in a signal transduction cascade seems to be a critical determinant of signaling efficiency by eNOS activation, we hypothesize that sGC, PKA, and PKG activation may occur at the plasma membrane caveolae. In endothelium-intact rat aortic rings, the relaxation induced by ACh, by the sGC activator 3-(5'-hydroxymethyl-2'furyl)-1-benzyl indazole (YC-1), and by 8-bromo-cGMP was impaired in the presence of methyl-beta-cyclodextrin, a drug that disassembles caveolae by sequestering cholesterol from the membrane. sGC, PKG, and PKA were colocalized with caveolin-1 in aortic endothelium, and this colocalization was abolished by methyl-beta-cyclodextrin. Methyl-beta-cyclodextrin efficiently disassembled caveolae in endothelium. In summary, our results provide evidence of compartmentalization of sGC, PKG, and PKA in endothelial caveolae contributing to NO signaling cascade, giving new insights by which the endothelium mediates vascular smooth muscle relaxation.

We report coregistration of near-infrared diffuse optical spectroscopy (DOS) and magnetic resonance imaging (MRI) for the study of animal model tumors. A combined broadband steady-state and frequency-domain apparatus was used to determine tissue oxyhemoglobin, deoxyhemoglobin, and water concentration locally in tumors. Simultaneous MRI coregistration provided structural (T2-weighted) and contrast-enhanced images of the tumor that were correlated with the optical measurements. By use of Monte Carlo simulations, the optically sampled volume was superimposed on the MR images, showing precisely which tissue structure was probed optically. DOS and MRI coregistration measurements were performed on seven rats over 20 days and were separated into three tumor tissue classifications: viable, edematous, and necrotic. A ratio of water concentration to total hemoglobin concentration, as measured optically, was performed for each tissue type and showed values for edematous tissue to be greater than viable tissue (1.2 +/- 0.49 M/microM versus 0.48 +/- 0.15 M/microM). Tissue hemoglobin oxygen saturation (StO2) also showed a large variation between tissue types: viable tissue had an optically measured StO2 value of 61 +/- 5%, whereas StO2 determined for necrotic tissue was 43 +/- 6%.