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.

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.

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.

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.

Computed tomography-guided retroperitoneal biopsies.

A retrospective review was performed on consecutive patients who had a computed tomographic (CT) biopsy of the retroperitoneum at University Hospitals of Cleveland. Biopsies were performed using a 20-gauge Chiba needle (University Medical Instruments Corp, Ballston Spa, NY) and a 14-gauge Tru-Cut needle (Baxter Pharmaseal, Valencia, CA). The results included success rate, failure, and complications, and were determined by a review of patient charts, surgical results, and autopsy results. The 20-gauge needle aspirations were accurate in suggesting the diagnosis in 20 of 22 cases of metastatic disease and ten of 15 cases of lymphoma. Using the 20-gauge needle, it was not possible to make a specific diagnosis in any of the lymphoma patients or for unusual benign disorders. With the 14-gauge Tru-Cut needle, the correct diagnosis was made in 13 of 13 cases of metastatic disease, ten of 11 cases of lymphoma, and two of 2 cases of unusual benign disorders. It was also possible to make the specific diagnosis of the lymphoma type in ten of 11 cases. The only complication was a small subcutaneous hematoma following a biopsy with a 20-gauge Chiba needle.

Modulation of O6-alkylguanine alkyltransferase-directed DNA repair in metastatic colon cancers.

PURPOSE: Carmustine (BCNU) resistance has been correlated with tumor expression of the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AT). It has been shown that streptozotocin will deplete AT activity of human colon cancer cells in vitro and potentiate BCNU cytotoxicity. This clinical trial was conducted to determine whether streptozotocin can be used as a modulator of AT in metastatic colorectal cancers and thereby overcome clinical resistance to BCNU. PATIENTS AND METHODS: Fifteen patients with fluorouracil-resistant metastatic colon or rectal cancers were treated sequentially with 2 g/m2 of streptozotocin followed 5 1/2 hours later by BCNU. Sequential biopsies of metastases before and after streptozotocin were conducted to determine whether streptozotocin depletes tumor AT. Peripheral-blood mononuclear cells (PBMCs) were evaluated as a surrogate tissue for prediction of baseline AT levels and streptozotocin posttreatment modulation of the AT in metastases. RESULTS: Streptozotocin treatment led to a 78% (range, 69% to 89%) decrease in the AT levels in colon cancer metastases; however, myelosuppression and hepatic toxicity limited the BCNU dose to 130 mg/m2. A similar decrease in AT levels of PBMCs was found; however, the absolute levels of AT in PBMCs at baseline and following streptozotocin were not predictive of the levels expressed in metastases from the same patient. Despite the decrease in tumor levels of AT, no clinical responses were observed. CONCLUSION: Streptozotocin decreases but does not fully deplete AT activity in metastatic colorectal cancers and the residual AT level in metastases is sufficient to maintain clinical resistance to BCNU. We have also demonstrated that sequential computed tomography (CT)-directed biopsies of colorectal cancer metastases can be used to evaluate strategies to investigate modulators of AT-directed repair. AT levels of PBMCs do not predict for the AT level or degree of modulation achieved in the metastatic tumor.

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.

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.

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.

Multiple microaerophilic streptococcal lung abscesses after orthodontic treatment.

An immunocompetent 12-year-old boy developed multiple microaerophilic streptococcal lung abscesses after application of orthodontic bands ("braces"). The dental work was done in the supine position. The data suggest that the patient aspirated the organisms and, possibly, flecks of dental cement, during orthodontic treatment. "Rubber dams" should be used to help prevent aspiration in children who receive dental work in the supine position. When a rubber dam cannot be used, as with orthodontic treatment, physicians should advise patients who are at risk for developing pulmonary infection (eg, patients with neuromuscular diseases which compromise cough and/or gag, cystic fibrosis, sickle cell anemia, primary immunodeficiency, etc) to have this dental work, including orthodontic treatment, performed in the erect position.

Use of fibrinolytic agents to coat wire implants to decrease infection. An animal model.

RATIONALE AND OBJECTIVES: Infection is a serious complication of metallic prosthesis implantation and may necessitate removal of the prosthesis. This study uses an animal model to evaluate the effects of coating stainless steel wire implants with fibrinolytic agents to prevent infection after bacterial contamination. METHODS: Three types of steel wire implants were used: plain stainless steel, heparin-coated steel, and urokinase-heparin-coated steel. Wire implants were incubated in a known concentration of Staphylococcus epidermidis and placed into the subcutaneous tissues of three groups of anesthetized hamsters. The implants and surrounding tissues were excised after 1 week and submitted for quantitative cultures. RESULTS: Using 100 organisms as the upper allowable limit to categorize abscesses as noninfected, the following rates of noninfectivity were observed: group 1 (control), 0% noninfected; group 2 (heparin-coated wire), 40% noninfected; and group 3 (urokinase-heparin-coated wire), 50% noninfected. The noninfectivity rates of groups 2 and 3 were significantly higher than the rate of group 1 (P < 0.001). There was no significant difference between groups 2 and 3 (P = 0.19). CONCLUSIONS: Both the heparin-coated and urokinase-heparin-coated wire exhibited significantly decreased infection rates compared with uncoated wire; the heparin coating may inhibit bacterial adherence. The urokinase coating of the heparin-coated wire appears to further decrease the infection rate, but not to a statistically significant degree.

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.

Functional electrical stimulation and respiration during sleep.

During obstructive sleep apnea (OSA), respiratory activation of upper airway muscles, particularly genioglossus, is ineffective during sleep. Functional electrical stimulation (FES) of muscles reportedly reduces the number and length of OSAs. Our goals were to examine the effect of FES on sensation during wakefulness and on OSA events. Studies were performed in 11 subjects: 4 healthy asymptomatic subjects and 7 patients with OSA. Surface electrodes placed on the submental region produced discomfort; however, during sleep, the stimulus intensity producing arousal was significantly greater than that producing barely tolerable discomfort during wakefulness. Additionally, we developed a protocol for placement of fine-wire electrodes into the neurovascular bundle of the hypoglossal nerve, using recognizable radiographic features and computerized axial tomography as guides. In these patients, while awake, optimal wire placement was associated with visible tongue protrusion without discomfort. With both surface stimulation and fine-wire FES, during sleep the stimulus intensity required to produce obvious electroencephalographic arousal was significantly greater than that producing a barely tolerable sensation while awake. During apneic events, the application of surface stimulation had an inconsistent effect, terminating 22% of the apneas, and fine-wire FES also had a limited impact, terminating 23% of the apneic events. We conclude from our studies that subjects tolerate surface and fine-wire FES to higher stimulus parameters during sleep than during wakefulness but that both approaches have an inconsistent effect on apneas during sleep.

Staging renal carcinoma. What is sufficient?

We retrospectively reviewed the roentgenographic and pathologic staging of 64 patients with renal cell carcinoma to assess the role of the various staging modalities (ie, angiography, venacavography, bone scanning, ultrasound, computed tomography [CT], and magnetic resonance imaging). Specific attention was directed at detecting vena cava thrombus and metastatic bone disease, factors with a significant impact on the therapeutic approach. The findings support the role of CT as the principle tool for overall staging and the observation that venacavography is not indicated if CT has excluded caval thrombus. Similarly, routine bone scans are not warranted in the absence of an elevated alkaline phosphatase level or bone pain. The key to the more efficient utilization of imaging resources is understanding the capabilities of the technology available.

Role of surgical and percutaneous drainage in the treatment of abdominal abscesses.

Reviewing our experience with 32 surgically and 13 percutaneously drained abdominal abscesses, we propose the following criteria for computed tomography (CT)-assisted percutaneous drainage: (1) the absence of more than two abscess cavities or loculations; (2) drainage route not traversing bowel, uncontaminated organs, or uncontaminated peritoneal or pleural spaces; (3) the absence of a source of continuous contamination; and (4) the absence of fungi as causative organisms. Of nine abscesses that met these criteria, seven were successfully drained percutaneously. In all abscesses that did not meet the criteria, percutaneous drainage resulted in complications. Of the 32 surgical patients, six would have been candidates for percutaneous drainage according to these criteria. Two of those patients experienced technical complications that might have been prevented by the use of percutaneous drainage. Surgical intervention is the preferred treatment in the majority of patients; however, in properly selected patients, CT-assisted percutaneous drainage is highly successful and can prevent unnecessary morbidity and mortality.

Foreign body localization and removal utilizing computerized axial tomography.

In this preliminary report, computerized tomography guidance was instrumental in allowing the safe and rapid removal of a metallic foreign body from paravesical soft tissues deep within the male pelvis. Hopefully, expanded future experience with this technique will further clarify its value in the management of retained foreign bodies.

Magnetic resonance imaging of the pancreas.

In this article, the author discusses his experience using a superconducting magnet for evaluation of the pancreas. The discussion includes evaluation of neoplastic and inflammatory disease of the pancreas and comparison of MRI with CT scanning.

Magnetic resonance imaging of the liver.

In this article, the author discusses his experience with a 0.30-T superconducting magnet for evaluation of the liver. This discussion includes evaluation of malignant and benign disease and comparison of MRI with CT scanning.

Clinical comparison of computed tomography and lymphangiography for detection of retroperitoneal lymphadenopathy.

The advantages of CT scan over lymphangiography are numerous and significant. The accuracy of CT scan was virtually identical to lymphogram for the detection of para-aortic lymph node involvement; however, CT provides a better means of assessing the true extent of disease. In such cases it is possible to determine whether the neoplastic process involves retroperitoneal structures such as the kidneys, ureters, pancreatic region, hilum of the liver, or the major vessels. Moreover, this excellent definition permits accurate follow-up assessment of therapy. Finally, CT is a noninvasive examination and does not require significant technical expertise, and the examination is easily reproducible following any time period from the initial examination. Finally, although we have not specifically discussed biopsy procedures, the CT scan is an excellent means for guiding biopsy procedures even for retroperitoneal abnormalities, perhaps precluding the necessity for laparotomy in order to provide histologic diagnosis of disease (Fig. 11). The disadvantages of CT are several. Of course, the acquisition of CT equipment is expensive and the cost effectiveness has not yet been proven. The most significant disadvantage is its inability to resolve or detect neoplastic disease within normal-sized lymph nodes. This was not a significant problem in our series, because our series contained only a few cases of suspected metastatic disease as opposed to lymph node neoplasms. The advantages of lymphography have been discussed by other authors. Because of the better spatial resolution of lymphograms, it is possible by proper interpretation to distinguish between neoplastic disease and lipogranulomatous changes. In a few cases in our series, this did not prove to be true; however, this may have been due to deficiencies in our interpretations (two cases of lymphoma were called positive for neoplasm, but proved to be lipogranulomatous changes by biopsy). Secondly, surveillance films may be easily and cheaply obtained to detect recurrences of disease. In addition, lymphography also provides the opportunity for biopsy of lymphoma masses, but to date this has only been accomplished by skinny-needle biopsy aspirations and not by large core biopsy techniques. After reviewing the literature and evaluating our data, we believe that several recommendations are appropriate with respect to the roles of computed tomography and lymphography. We agree with the previously stated concept that CT should be used for screening for lymphoma; however, we disagree that lymphograms have a greater advantage over CT in the biopsy-proven cases of lymphoma. Rather we believe that CT is better suited than lymphography for those cases with biopsy proven lymphoma. CT is better able to accurately localize the lymph node masses for surgeons if the surgical approach is desired and better able to define the extent of the disease throughout the abdomen. As a result of this it is capable of providing a better follow-up for therapy...

Computed body tomography.

Only the surface of the diagnostic possibilities inherent in CT imaging has been scratched. Solic organ pathology is readily visible in most instances by computed tomography. With further extension of present knowledge and development of newer contrast agents, the ability of computed body tomography to image a wide range of diseases appears almost limitless.