Standardizing Electronic Health Record Data on AD/ADRD to Accelerate Health Equity in Prevention, Detection, and Treatment.

Improving the prevention, detection, and treatment of Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD) across racial, ethnic, and other diverse populations is a national priority. To this end, this paper proposes the development of the Standard Health Record for Dementia (SHRD, pronounced "shared") for collecting and sharing AD/ADRD real-world data (RWD). SHRD would replace the current unstandardized, fragmented, or missing state of key RWD with an open source, consensus-based, and interoperable common data standard. This paper describes how SHRD could leverage the best practices of the Minimal Common Oncology Data Elements (mCODETM) initiative to advance prevention, detection, and treatment; gain adoption by clinicians and electronic health record (EHR) vendors; and establish sustainable business and governance models. It describes a range of potential use cases to advance equity, including strengthening public health surveillance by facilitating AD/ADRD registry reporting; improving case detection and staging; and diversifying participation in clinical trials.

Monte Carlo simulations of patch models with applications to soft matter.

Patch models have been employed to describe anisotropic interactions in disparate soft matter systems. In this work, we present a unified study of a patch model to explore particle self-assembly in both monodisperse and polydisperse systems, with applications to both proteins and colloids. In the first case, we obtained a temperature-density phase diagram for a model of the protein polyglutamine from Monte Carlo simulations. These simulations evinced clusters in the gas phase and, via a comparison with the corresponding coarse-grained PLUM model for this system, we verified that dense clustering in the gas phase falls into the supersaturation region of the saturation curve. In the second case, we have investigated the effect of size polydispersity on the phase behavior of binary colloidal mixtures. It was found that the width of gas-liquid phase coexistence increases with increasing polydispersity and that, in addition to the aforementioned particle clustering, small particles decorate patches on large particles, thereby creating large-particle bridges. Our aim is to compare and contrast self-assembly in these two prototypical systems.

Semiquantitative imaging measurement of baseline and vasomodulated normal prostatic blood flow using sildenafil.

The physiologic variability of blood flow to the prostate has not been studied until this time. We report the vasoactive effects of sildenafil and phenylephrine on blood flow of the normal prostate. Sildenafil increases prostate blood flow by approximately 75% and phenylephrine reduces the flow incrementally. Administration of these drugs with dynamic contrast-enhanced magnetic resonance imaging may improve the diagnosis of cancerous tissue because according to the literature, tumor angiogenic vessels lack the vasoactive physiologic response of the normal tissue.

Local carboplatin delivery and tissue distribution in livers after radiofrequency ablation.

This study investigated the local drug pharmacokinetics of intralesional drug delivery after radiofrequency ablation of the liver. We hypothesized that the tissue architecture damaged by the ablation process facilitates the drug penetration in the liver and potentially enlarges the therapeutic margin in the local treatment of cancer. The delivery rate and tissue distribution of carboplatin, an anticancer agent, released from poly(D,L-lactide-co-glycolide) implants into rat livers after radiofrequency ablation were quantified by atomic absorption spectroscopy. Results showed that carboplatin clearance through blood perfusion was significantly slower in the ablated livers, leading to a more extensive tissue retention and distribution of the drug. The concentration of Pt at the implant-tissue interface ranged from 234 to 1440 microg Pt/(g liver) in the ablated livers over 144 h versus 56 to 177 microg Pt/(g liver) in the normal tissue. The maximum penetration distance at which Pt level reached above 6 microg/g (calculated based on a reported IC90 value for carboplatin) was 8-10 mm and 4-6 mm in ablated and normal liver, respectively. Histological analysis of the necrotic lesions showed widespread destruction of tissue structure and vasculature, supporting the initial hypothesis. This study demonstrated that intralesional drug delivery could provide a sustained, elevated concentration of anticancer drug at the ablation boundary that has the potential to eliminate residual cancer cells surviving radiofrequency ablation.

Sequential tumor biopsies in early phase clinical trials of anticancer agents for pharmacodynamic evaluation.

PURPOSE: In the setting of target-based anticancer drug development, it is critical to establish that the observed preclinical activity can be attributed to modulation of the intended target in early phase trials in human subjects. This paradigm of target modulation allows us to determine a Phase II or III dose (optimal biochemical/biological modulatory dose) that may not necessarily be the maximum tolerated dose. A major obstacle to target-based (often cytostatic) drug development has been obtaining relevant tumor tissue during clinical trials of these novel agents for laboratory analysis of the putative marker of drug effect. EXPERIMENTAL DESIGN: From 1989 to present, we have completed seven clinical trials in which the end point was a biochemical or biological modulatory dose in human tumor tissues (not surrogate tissue). Eligibility enrollment required that patients have a biopsiable lesion either with computerized tomography (CT) guidance or direct visualization and consent to sequential (pre and posttreatment) biopsies. RESULTS: A total of 192 biopsies were performed in 107 patients. All but 8 patients had sequential pre and posttreatment biopsies. Seventy-eight (73%) of the 107 patients had liver lesion biopsies. In eight patients, either one or both biopsies contained insufficient viable tumor tissue or no tumor tissue at all for analysis. Of a total of 99 patients in whom we attempted to obtain paired biopsies, a total of 87 (88%) were successful. Reasons for failure included patient refusal for a second biopsy (n = 2), vasovagal reaction with first biopsy precluding a second biopsy (n = 1), subcapsular hepatic bleeding (n = 1), and most commonly obtaining necrotic tumor, fibrous, or normal tissue in one of the two sequential biopsies (n = 8). CONCLUSIONS: This is the first and largest reported series demonstrating that with adequate precautions and experience, sequential tumor biopsies are feasible and safe during early phase clinical trials.

Differential degradation rates of inactivated alkyltransferase in blood mononuclear cells and tumors of patients after treatment with O(6)-benzylguanine.

O(6)-Alkylguanine-DNA alkyltransferase (AGT) repairs O(6)-alkylating DNA adducts generated by alkylating therapeutic agents. Therefore, AGT activity may be an important marker of tumor and normal tissue sensitivity to chemotherapeutic agents and a predictor for the success of chemotherapeutic regimens. It is rapidly inactivated by O(6)-benzylguanine (BG) that mimics its substrates, O(6)-methylguanine and O(6)-chloroethylguanine DNA adducts. In a Phase I clinical trial, BG was given in increasing doses (from 10 to 120 mg/m(2)) by 1-h infusion. We previously reported depletion of AGT activity, and in this report, we demonstrate the relationship between degradation of BG-inactivated AGT protein and the depletion of AGT activity in peripheral blood mononuclear cells (PBMCs) and tumor samples obtained by computed tomography-guided cutting needle biopsy from patients prior to BG and either 2 or 18 h after BG. In PBMCs, BG inactivated AGT activity by over 95-100% at the end of a 1-h infusion, and depletion was maintained for 18 h. In contrast, AGT protein remained almost unchanged for up to 18 h after BG, suggesting that inactivated AGT proteins remain immunoreactive and are not rapidly degraded in PBMCs. In patient tumor biopsies, AGT activity was depleted approximately 90% 2 h after BG. Tumor AGT protein levels were reduced to approximately 40% of pretreatment values when detected by either Western blot or immunohistochemistry staining. In tumor samples obtained 18 h after BG, >95% inactivation of tumor AGT activity was observed at BG doses of 36-80 mg/m(2), and complete depletion of tumor AGT activity occurred at 120 mg/m(2) BG. However, residual AGT protein (5-10% of baseline) was detectable in all tumor samples. Therefore, the degradation of BG-inactivated AGT protein appeared to be much more rapid in tumors than that in PBMCs, which may impact on AGT regeneration rates as well. Because degradation of BG-inactivated AGT takes place slowly, antibody-based measurements of AGT protein correlate poorly with depletion of AGT activity immediately after BG. Thus, biochemical activity measurements remain the appropriate monitor of AGT during therapeutic modulation. These data provide the first and conclusive evidence of differential degradation rates of inactivated AGT in PBMCs and tumors of patients after treatment with BG and suggest that immunoreactive AGT measurements in PBMCs are a poor surrogate for AGT activity in tumor tissue.

Temozolomide: the effect of once- and twice-a-day dosing on tumor tissue levels of the DNA repair protein O(6)-alkylguanine-DNA-alkyltransferase.

Temozolomide (TMZ) is a methylating agent of the imidotetrazine class, whose cytotoxic product is O(6)-methylguanine DNA adducts, which initiate a futile recycling of the mismatch repair pathway causing DNA strand breaks and apoptotic cell death in mismatch repair proficient cells. The DNA repair protein O(6)-alkylguanine DNA alkyltransferase (AGT) repairs these adducts in a suicide manner and reduces the cytotoxic action of TMZ. An antitumor threshold is reached when sufficient adducts are formed by TMZ to inactivate AGT. In this study, we evaluated the relation between TMZ dosing and AGT depletion in patients with deep visceral tumors and in peripheral blood mononuclear cells (PBMCs) to determine whether the dose of TMZ was sufficient to inactivate AGT and lead to therapeutic efficacy. To do so, we compared single dose therapy with a novel twice daily regimen in a laboratory correlate-driven Phase I dose escalation study. p.o. bolus dose TMZ 200 mg/m(2) daily times five was compared with the same bolus on day 1 followed by nine doses at 12-h intervals of 50, 75, 90, or 100 mg/m(2). Dose-limiting toxicity in the bid regimen (grade IV thrombocytopenia and neutropenia) was seen at 100 mg/m(2), cumulative dose 1100 mg/m(2), and the maximum tolerated dose was 1010 mg/m(2). The degree of tumor tissue AGT activity depletion measured in biopsies before and on day 5 of therapy varied widely, between 0 (in 3 patients) and 99% (in 1), with the majority of patients (10 of 15) having 52-84% tumor AGT depletion. In contrast, AGT activity in PBMCs fell rapidly during TMZ administration to undetectable levels in all dosage groups on day 5 but did not correlate with tumor AGT depletion. TMZ pharmacokinetics were dose proportional; no accumulation occurred >5-day period in the bid regimen. Two partial responses were seen, lasting 3 and 4 months. Five additional patients achieved prolonged stabilization of disease for 4-6 monthly cycles. This is the first study to document that at maximum tolerated doses, TMZ depletes PBMC AGT but only partially and variably depletes visceral tumor AGT in most patients, even during twice daily dosing. Drug combinations or schedules designed to maximally deplete tumor AGT might improve TMZ efficacy.

Greater collaboration across the disciplines: challenges and opportunities.

This paper reports a panel discussion--Opportunities for and Limitations to Greater Collaboration Across the Disciplines--held at the conference. It highlights the need for greater collaboration between demographers and epidemiologists and notes the institutional and disciplinary challenges to and opportunities for promoting greater cooperation.

CT-integrated robot for interventional procedures: preliminary experiment and computer-human interfaces.

Pre-operative planning and intra-operative computer interfaces for minimally invasive interventions were investigated with an active robot integrated with a CT scanner. To test the robotic system, a biopsy study was performed using a pig. For pre-operative planning, a virtual needle was superimposed on axial slices and multiplanar reformatted views in correlation with the interventional field. The path of the virtual needle was sent to the robot's controller, and the robot's needle gripper moved into a position congruent with the planned path. Intra-operative controls were then used to drive the needle while keeping the interventionalist's hands out of the direct X-ray beam during CT fluoroscopy. After needle insertion, the imaged and virtual needles were shown to be sufficiently congruent.

Intracavitary urokinase for enhancement of percutaneous abscess drainage: phase II trial.

OBJECTIVE: To evaluate the effectiveness of urokinase as an abscess-cavity irrigant during percutaneous abscess drainage. SUBJECTS AND METHODS: In a prospective study, approved by the Food and Drug Administration and the review board at our institution, urokinase and saline were used as abscess-cavity irrigants. In the study group of 42 patients, half the patients were randomly placed into the urokinase group and the other half were placed into the control saline group. Doses used varied with the size of the abscess. Data collected from patient charts were evaluated with standard statistical methods. RESULTS: The results indicate definite benefits of the urokinase treatment. The length of stay (p = 0.0025) and treatment costs (p = 0.0021) were significantly less for the urokinase group. Other clinical parameters, including the febrile course, elevated WBC, and days of drainage, trended in a favorable fashion. CONCLUSION: Urokinase injected intracavitarily is an effective technique for shortening the treatment time and improves the clinical course for patients treated with percutaneous drainage techniques.

Complications of "dropped" gallstones after laparoscopic cholecystectomy: technical considerations and imaging findings.

New laparoscopic techniques have revolutionized the practice of surgery. Laparoscopic cholecystectomy has become one of the most commonly performed surgeries worldwide. Although shorter hospital stays and patient comfort have offered clear advantages over open cholecystectomy, the technique has resulted in several specific complications, including bile duct injury and gallbladder perforation. Although rarely clinically significant, intraperitoneal gallstone spillage can cause abscess formation and adhesions. Although these patients can present with a confusing clinical picture, their characteristic radiologic features should be recognized. We present two cases of complicated intraperitoneal gallstone spillage radiologically diagnosed and treated with laparoscopic and interventional radiologic techniques.

MR imaging-guided radio-frequency thermal ablation in the pancreas in a porcine model with a modified clinical C-arm system.

PURPOSE: To test the hypotheses that (a) magnetic resonance (MR) imaging-guided radio-frequency (RF) thermal ablation in the pancreas is safe and feasible in a porcine model and (b) induced thermal lesion size can be predicted with MR imaging monitoring. MATERIALS AND METHODS: MR imaging-guided RF ablation was performed in the pancreas of six pigs. A 17-gauge monopolar RF probe was inserted into the pancreas with MR imaging guidance, and RF was applied for 10 minutes. After postprocedural imaging (T2-weighted, short inversion time inversion-recovery [STIR], and T1-weighted imaging before and after intravenous administration of gadodiamide), the pigs were observed for 7 days and follow-up MR images were acquired. The pigs were sacrificed, and pathologic examination was performed. RESULTS: Successful RF probe placement was accomplished in all pigs; the interventional procedure took 46-80 minutes. Thermal lesions were 12-15 mm perpendicular to the probe track and were best seen on STIR and contrast material-enhanced T1-weighted images with a radiologic and/or pathologic mean difference in RF lesion diameter of 1.7 mm +/- 1.0 (SD) and 0.8 mm +/- 1.2, respectively. Diarrhea was the only side effect during the 1-week follow-up; no clinical signs of pancreatitis occurred. CONCLUSION: MR imaging-guided RF thermal ablation in the pancreas is feasible and safe. Induced thermal lesion size can best be monitored with STIR and contrast-enhanced T1-weighted images. In the future, RF ablation may offer an alternative treatment option for pancreatic cancer.

Complications of no biopsy.

OBJECTIVE: We present three cases in which complications occurred after CT-guided procedures were not carried out, supporting the contention that some complications occurring after CT-guided procedures may not be true procedural complications. CONCLUSION: Although most complications after CT-guided procedures are indeed caused by the antecedent procedure, some complications may be unrelated to the procedure and may in fact occur without any procedure being performed at all.

O6-benzylguanine: a clinical trial establishing the biochemical modulatory dose in tumor tissue for alkyltransferase-directed DNA repair.

Early phase evaluation of anticancer drugs has traditionally used toxicity (usually hematological) rather than efficacy end points to establish appropriate dosing schedules. To establish a biochemical efficacy end point for overcoming alkylguanine DNA alkyltransferase (AGT)-mediated tumor cell resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea, we performed a novel dose escalation clinical trial for the AGT-depleting agent O6-benzylguanine (BG). The dose of BG required to deplete AGT to undetectable levels (BMD(T)) in sequential computed tomography-guided tumor tissue biopsies before BG and 18 h after BG was determined. Thirty patients received doses of BG ranging from 10 to 120 mg/m2. In tumor tissue, AGT depletion >86% of baseline was demonstrated at all doses tested. Residual tumor AGT activity, present 18 h after BG doses of 10-80 mg/m2, was eliminated at the 120 mg/m2 dose and is thus the BMD(T) of BG. BG pharmacokinetics are characterized by the rapid, dose-independent clearance of BG from plasma Metabolism of BG to its biologically active metabolite, 8-oxo-benzylguanine (8-oxo-BG), was found. The t(1/2) of 8-oxo-BG is longer than BG. Plasma concentrations of 8-oxo-BG well above 200 ng/ml 18 h after the end of the BG infusion were observed at the highest dose levels tested and appeared to correlate with depletion of AGT activity to undetectable levels in tumor tissue. AGT activity in peripheral blood mononuclear cells at baseline did not correlate with tumor tissue AGT activity. Depletion of AGT activity to undetectable levels in peripheral blood mononuclear cells occurred at lower doses and was not a reliable predictor for tumor tissue depletion. No serious side effects were observed with administration of BG alone or in combination with 13 mg/m2 1,3-bis(2-chloroethyl)-1-nitrosourea. This is the first clinical study in which biochemical analyses from pre- and posttreatment tumor biopsies have been used as an efficacy end point for the clinical development of an anticancer agent. From our tumor tissue biopsy data, we have established that a BG dose of 120 mg/m2 infused over 1 h should be used in Phase II clinical trials.

Interactive MR imaging-guided biopsy and aspiration with a modified clinical C-arm system.

OBJECTIVE: This investigation was performed to test the hypotheses that interactive guidance of MR image acquisition during needle-directed procedures using a clinical 0.2-T C-arm open MR imaging system integrated with a frameless optically linked stereotaxy system is feasible, and that procedure times can be sufficiently short to be well tolerated by the patient. SUBJECTS AND METHODS: One hundred six MR-guided procedures were performed in 86 patients (ranging in age from 5 months to 88 years) using a clinical C-arm imaging system supplemented with an in-room RF-shielded liquid crystal display monitor, a frameless stereotaxy system, rapid gradient-echo sequences for needle guidance, and MR-compatible monitoring and surgical lighting equipment. We performed 50 biopsies and aspirations of the head and neck in 37 patients, 23 biopsies of musculoskeletal lesions in 22 patients, 16 biopsies of abdominal sites in 10 patients, six biopsies of the thoracolumbar spine or sacrum in six patients, and 11 shoulder joint injections for MR arthrography in 11 patients, in addition to 38 MR arthrographic injections on the same imaging system described in a previous report. Tissue sampling included fine-needle aspiration (n = 90) and cutting needle core biopsy (n = 41). Thirty-five patients underwent both procedures. Procedures were evaluated for success of needle placement, procedure time, and complications. RESULTS: Needle placement was successful in all cases, and no complications occurred. Tissue was sufficient for pathologic diagnosis for all but eight patients. Passes per patient averaged 2.1. For fine-needle aspiration, instrument time averaged 7 min 42 sec per pass, cutting needle core biopsy averaged 6 min 24 sec, and shoulder injection averaged 8 min. CONCLUSION: MR imaging guidance for needle procedures on a clinical 0.2-T C-arm system with supplemental interventional accessories is feasible, with relatively rapid needle placement.

MR monitoring of MR-guided radiofrequency thermal ablation of normal liver in an animal model.

The purpose of this study was to determine the suitability of MRI to accurately detect radiofrequency (RF) thermoablative lesions created under MR guidance. In vivo RF lesions were created in the livers of six New Zealand White rabbits using a 2-mm-diameter titanium alloy RF electrode with a 20-mm exposed tip and a 50-W RF generator. This was performed using a 0.2T clinical C-arm MR imager for guidance and monitoring. Each animal was sacrificed and gross evaluation was performed. Histologic correlation was performed on the first two animals. The MR-compatible RF electrode was easily identified on rapid gradient-echo images used to guide electrode placement. A single lesion was created in each rabbit liver. Lesions ranged from approximately 10 to 17 mm in diameter (mean, 13.5 mm). T2-weighted and short T1 inversion recovery (STIR) images demonstrated lesions ranging in diameter from 12 to 18 mm (mean, 14.6 mm). Lesion dimensions determined from images closely correlated with those determined at gross examination with the discrepancy never exceeding 2 mm, for an r2 value of .87. MRI performed at the time of MR-guided RF ablation accurately demonstrated created lesions. This modality may provide a new option for the treatment of local and regional neoplastic disease.