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J Haaga

Publications and source records attributed to J Haaga.

At least 19 recordsLinked to original sources
PubMed2001

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.

Animals↗
PubMed2001

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.

Demography↗
PubMed2001

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.

Adult↗
PubMed2001

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.

Biopsy↗
PubMed2001

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.

Animals↗
PubMed1999

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.

Adult↗
PubMed1994

Twelve-year follow-up of respondents in a sample survey in Peninsular Malaysia.

"This note reports the experience of an attempt to find and re-interview in late 1988 and early 1989, as part of the Second Malaysian Family Life Survey (MFLS-2), the female respondents to the 1976-77 Malaysian Family Life Survey (MFLS-1) and a sample of their adult children aged 18 or older.... We discuss the field methods used to track the panel members and their adult children, report follow-up rates and analyze the selectivity of attrition from the panel, using data from the MFLS-1 on characteristics of both the missing and the re-interviewed respondents and their families. We then discuss the degree to which these results might be generalized to other such attempts at re-contacting survey respondents."

Asia↗
PubMed1993

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.

Adult↗
PubMed1993

Self-reported drug use data: what do they reveal?

The purpose of this study is to examine self-reported marijuana and cocaine use responses from two nationally representative surveys. We compared prevalence rates across birth cohorts for multiple years of the National Household Survey of Drug Abuse (NHSDA) and also analyzed longitudinal inconsistencies in self-reported drug use between two waves of the National Longitudinal Survey Youth Cohort (NLS-Y). We found the percentages of respondents admitting use within the past month, year, and lifetime were comparable to other findings and were consistent with the declining trend in drug use in the late 1980s. A comparison of lifetime prevalence rates revealed seemingly inconsistent reports between 1985 respondents and their birth cohorts in 1990. Using the longitudinal NLS-Y data, we found that roughly one-fifth of the people who had admitted using marijuana or cocaine in their lifetime on the 1984 survey subsequently denied ever having used in 1988. The majority of these cases were people who reported having used infrequently. The subsample of women had similar patterns. In addition, we discovered that women who had been pregnant between the two surveys were more likely to inconsistently deny having ever used, while those who were currently pregnant responded more honestly about their past use. Overall, we found that although most people are willing to provide accurate accounts of their use, the researcher should be aware that under-reporting or complete denial does occur. Most importantly, external factors appear to contribute to the rate of inaccurate reporting.

Adolescent↗
PubMed1989

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.

Biopsy, Needle↗
PubMed1986

Children's seatbelt usage: evidence from the National Health Interview Survey.

Data from the 1981 Child Health Supplement to the National Health Interview Survey were used to examine relationships between family and child characteristics and regular use of seatbelts or child restraints. Only for a third of children less than seven years old was regular seatbelt use reported. They were more likely to be used for infants and younger children than for older children; for a given child's age, older mothers were more likely to report seatbelt use by their children. Hispanics and Blacks reported lower rates of seatbelt use than White non-Hispanics, and usage rates were higher when mothers had more education. In a multivariate analysis, the effects of race, ethnicity, family income, urban residence, and child's age remained. A positive association with reported seatbelt use was found for such health-promoting behaviours as breastfeeding and abstinence from smoking during pregnancy.

Adult↗
PubMed1978

Urological applications of computerized axial tomography: a preliminary report.

Computerized tomography scanning of the chest and abdomen has been used as a diagnostic technique in more than 4,500 patients since 1974, 190 of whom had histologically proved disorders of the genitourinary system and retroperitoneum. On the basis of this experience computerized tomography scanning has been found to be safe and effective, and offers certain advantages over conventional techniques. The number, extent and content of renal mass lesions can be determined with relatively great accuracy. The presence and extent of metastases into the retroperitoneum, liver and chest can often be shown by computerized tomography scanning when other tests are negative. Placement of needles for aspiration, biopsy, injection of contrast medium or insertion of drainage tubes can be done more accurately under computerized tomography control. Computerized tomography in itself is non-invasive, carries a low radiation exposure comparable to other radiographic procedures and therefore, can be valuable in following the course of patients with various diseases during and after therapy. While scanning will not replace other diagnostic procedures it should lead to a more judicious selection of potentially hazardous tests in selected cases, such as angiography, aspiration and open biopsy.

Adrenal Gland Neoplasms↗
PubMed1978

Urological applications of computerized axial tomography.

Computerized tomography (CT scanning) of the chest and abdomen has been used as a diagnostic technique in more than 7,200 patients since 1974, 250 of whom had histological proved disorders of the genitourinary system and retroperitoneum. On the basis of this experience CT scanning has been found to be safe and effective, and offers certain advantages over conventional techniques. The number, extent and content of adrenal and renal mass lesions can be determined with relatively great accuracy. The presence and extent of metastases into the retroperitoneum, liver and chest often can be shown by CT scanning when other tests are negative. Placement of needles for aspiration, biopsy, injection of contrast medium or insertion of drainage tubes can be done accurately under computerized tomographic control. Air contrast scanning of the bladder can be of real help in staging bladder tumors, espically in obese patients. Computerized tomography in itself is non-invasive, carries a low radiation exposure comparable to other radiographic procedures and therefore, can, be valuable in following the course of patients with various diseases during and after therapy. While CT scanning will not replace other diagnostic procedures it should lead to a more judicious selection of potentially hazardous tests, such as angiography, aspiration and open biopsy.

Adenocarcinoma↗