Biomedical subjects

S Mani

Publications and source records attributed to S Mani.

At least 55 records · Page 3Linked to original sources

PubMed1999

A Phase I study of raltitrexed and paclitaxel given every 3 weeks to patients with solid tumors.

BACKGROUND: Raltitrexed is a novel thymidylate synthase inhibitor with single agent activity in colorectal, nonsmall cell lung, and breast carcinomas. The recommended Phase II dose of raltitrexed administered as a single agent is 3 mg/m2 every 3 weeks. Paclitaxel also has a broad spectrum of activity. A Phase I study of both agents in combination therapy was conducted. METHODS: Eligible patients had refractory solid tumors and a Cancer and Leukemia Group B performance status of 0 to 2. Cohorts of patients were treated with escalating doses of raltitrexed as a 15-minute intravenous infusion immediately followed by 175 mg/m2 of paclitaxel administered over 3 hours. Dose-limiting toxicity was defined as World Health Organization Grade 4 neutropenia with fever, Grade 4 thrombocytopenia requiring platelet transfusion, a nonhematologic toxicity of Grade 3 or higher (excluding nausea, emesis, and alopecia), or failure of toxicities to recover to Grade 1 or lower within 21 days after causing a dose delay. RESULTS: A total of 33 patients enrolled in the study. Raltitrexed was escalated in increments of 0.5 mg/m2, from 0.5 mg/m2 to the recommended Phase II dose of 3 mg/m2. Dose-limiting toxicity first was observed at a raltitrexed dose of 2 mg/m2. At a dose of 3 mg/m2, dose-limiting neutropenia was observed in 2 of 12 patients. Diarrhea was the other dose-limiting toxicity. Two patients achieved a partial response (one patient with carcinoma of the head and neck and another with gallbladder carcinoma). CONCLUSIONS: The authors conclude that raltitrexed and paclitaxel may be administered in combination at their respective single agent Phase II doses. Phase II testing of this combination is indicated.

Adult↗

PubMed1999

The preoptic area/anterior hypothalamus of different strains of mice: sex differences and development.

While sex differences in neural morphology in the preoptic area/anterior hypothalamus (POA/AH) have been demonstrated in many species, their existence in mice have been controversial. Given the increased use of transgenic and gene-disrupted mice, we characterized sex differences using Nissl stains, and the immunocytochemical location of estrogen receptor-alpha (ER-alpha) and galanin in the POA/AH of two widely used strains, C57BL/6 and 129SvEv, and a mixed strain (C57BL/6x129Sv); the wild-type littermates of steroidogenic factor-1 (SF-1) gene-disrupted mice. Cell grouping was not a reliable marker of sex. In adults, cells located beneath the anterior commissure (AC) were reliably larger in females than males in 129SvEv, but not in the other strains. Caudally, cells in a group medial to the medial extension of the bed nucleus of the stria terminalis (BST) were significantly larger in males than females in C57BL/6J and SF-1 gene-disrupted wild-types. Cell groups discernible by embryonic day (E) 18 were not sexually dimorphic for cell size in C57BL/6J mice at E18 or postnatal day (P) 4. The pattern of distribution of cells containing ER-alpha was similar among the strains, reduced in the group medial to the BST; a pattern established by P0. Galanin-containing cells and fibers were seen from E15 to adulthood ventral to the AC. Caudally, a smaller group ventromedial to the BST was found only in 129SvEv adults. Sex differences in neural morphology which develop within the POA/AH depend upon multiple factors, particularly including genetic background.

Animals↗

PubMed1999

A phase I study of oral uracil/ftorafur (UFT) plus leucovorin and bis-acetato-ammine-dichloro-cyclohexylamine-platinum IV (JM-216) each given over 14 days every 28 days.

PURPOSE: To determine the feasibility, maximal tolerated doses, and response rates for a combined regimen of the platinum and 5-fluorouracil oral analogues bis-acetato-ammine-dichloro-cyclohexyl-amine platinum(IV) (JM-216) and uracil/ftorafur (UFT) coadministered as a 14 consecutive-day every 28-day schedule. METHODS: Of 20 patients enrolled in this investigation, 17 on the following dose escalation scheme were evaluable for toxicity and/or response: I UFT 300 mg/day, JM-216 5 mg/day (three patients), II UFT 300 mg/day, JM-216 10 mg/day (four patients), III UFT 300 mg/day, JM-216 20 mg/day (ten patients). RESULTS: All 17 evaluable patients were evaluable for toxicity. At dose level III dose-limiting nausea and emesis were observed in one patient despite maximal antiemetic support. Importantly, neurotoxicity and nephrotoxicity were not observed at the JM-216 dose levels examined in this study. This observation is consistent with results seen with single agent JM-216. CONCLUSION: For JM-216 and UFT administered at 20 mg/day and 300 mg/day over 14 days, nausea and emesis were observed as the principal dose-limiting toxicities. These doses are considerably below the maximally tolerated doses of single agent JM-216 and UFT. Shorter administration schedules should be explored in an attempt to increase the dose intensity and minimize the toxicity of this combination oral regimen.

Administration, Oral↗

PubMed1999

Two-Stage Machine Learning model for guideline development.

We present a Two-Stage Machine Learning (ML) model as a data mining method to develop practice guidelines and apply it to the problem of dementia staging. Dementia staging in clinical settings is at present complex and highly subjective because of the ambiguities and the complicated nature of existing guidelines. Our model abstracts the two-stage process used by physicians to arrive at the global Clinical Dementia Rating Scale (CDRS) score. The model incorporates learning intermediate concepts (CDRS category scores) in the first stage that then become the feature space for the second stage (global CDRS score). The sample consisted of 678 patients evaluated in the Alzheimer's Disease Research Center at the University of California, Irvine. The demographic variables, functional and cognitive test results used by physicians for the task of dementia severity staging were used as input to the machine learning algorithms. Decision tree learners and rule inducers (C4.5, Cart, C4.5 rules) were selected for our study as they give expressive models, and Naive Bayes was used as a baseline algorithm for comparison purposes. We first learned the six CDRS category scores (memory, orientation, judgement and problem solving, personal care, home and hobbies, and community affairs). These learned CDRS category scores were then used to learn the global CDRS scores. The Two-Stage ML model classified as well as or better than the published inter-rater agreements for both the category and global CDRS scoring by dementia experts. Furthermore, for the most critical distinction, normal versus very mildly impaired, the Two-Stage ML model was 28.1 and 6.6% more accurate than published performances by domain experts. Our study of the CDRS examined one of the largest, most diverse samples in the literature, suggesting that our findings are robust. The Two-Stage ML model also identified a CDRS category, Judgment and Problem Solving, which has low classification accuracy similar to published reports. Since this CDRS category appears to be mainly responsible for misclassification of the global CDRS score when it occurs, further attribute and algorithm research on the Judgment and Problem Solving CDRS score could improve its accuracy as well as that of the global CDRS score.

Algorithms↗

PubMed1999

Phase II trial of uracil/tegafur (UFT) plus leucovorin in patients with advanced biliary carcinoma.

PRECIS: UFT 300 mg/m2/day and leucovorin 90 mg/day could be administered safely to patients with advanced biliary cancer with good performance status; however, this combination and schedule of 28-day administration has no activity in this disease. PURPOSE: To determine the activity and evaluate the toxicity of uracil and tegafur in a 4:1 molar concentration ratio (UFT; Bristol-Myers Squibb, Wallingford, CT) plus oral calcium leucovorin in the treatment of patients with advanced biliary (gallbladder and bile duct) carcinoma. PATIENTS AND METHODS: Thirteen patients with advanced measurable biliary carcinoma were enrolled onto the trial. All patients had a Karnofsky performance status > or = 60%, platelet count > or = 75,000/microL, total bilirubin < or = 2.0x institutional upper limit of normal but otherwise normal liver and kidney function profile and bidimensionally measurable disease by CT scan or ultrasound examination. None of these patients previously received cytotoxic chemotherapy or radiation therapy for advanced disease. Patients received 300 mg/m2/d UFT plus 90 mg/d leucovorin administered orally in divided daily doses every 8 hours for 28 days repeated every 35 days. Objective tumor response, the primary endpoint of this trial, was evaluated after two courses of therapy. Other endpoints included toxicity, time to progression, and overall survival. RESULTS: All patients were evaluable for response and toxicity. No complete or partial responses were observed in this trial. Four patients had stable disease lasting 17, 30, 33, and 35 weeks, respectively. The median (range) time to progression and survival were 9 (1-35) and 28 (1-61) weeks, respectively. Treatment-related toxicity was mild with severe (grade 3 or 4) diarrhea seen in 2 (15%). Grade 3-4 hyperbilirubinemia (31%) and nausea/vomiting (31%) were observed and likely related to the underlying disease. Grade 1 and 2 toxic effects included mainly anorexia and fatigue. CONCLUSION: UFT 300 mg/m2/d plus oral leucovorin 90 mg/d administered for 28 days repeated every 35 days is ineffective in the treatment of advanced biliary carcinoma.

Aged↗

PubMed1999

Antisense therapeutics in oncology: points to consider in their clinical evaluation.

Novel therapeutics in oncology stem from a rational design of drugs targeting selective pathways that stimulate and maintain tumor cell growth. Many of these agents are cytostatic in action and also have a limited toxicity profile. However, some can be cytotoxic if they successfully modulate molecular pathways of apoptosis, such as bcl-2. This article discusses points to consider in the design of one class of cytostatic agents, antisense therapy. Our purpose is to stimulate designs that answer the question specifically with regard to proof-of-concept, and the concepts proposed should be viewed as ideas in development rather than firm recommendations.

Apoptosis↗

PubMed1999

A study in causal discovery from population-based infant birth and death records.

In the domain of medicine, identification of the causal factors of diseases and outcomes, helps us formulate better management, prevention and control strategies for the improvement of health care. With the goal of exploring, evaluating and refining techniques to learn causal relationships from observational data, such as data routinely collected in healthcare settings, we focused on investigating factors that may contribute causally to infant mortality in the United States. We used the U.S. Linked Birth/Infant Death dataset for 1991 with more than four million records and about 200 variables for each record. Our sample consisted of 41,155 records randomly selected from the whole dataset. Each record had maternal, paternal and child factors and the outcome at the end of the first year--whether the infant survived or not. For causal discovery we used a modified Local Causal Discovery (LCD2) algorithm, which uses the framework of causal Bayesian Networks to represent causal relationships among model variables. LCD2 takes as input a dataset and outputs causes of the form variable X causes variable Y. Using the infant birth and death dataset as input, LCD2 output nine purported causal relationships. Eight out of the nine relationships seem plausible. Even though we have not yet discovered a clinically novel causal link, we plan to look for novel causal pathways using the full sample after refining the algorithm and developing a more efficient implementation.

Algorithms↗

PubMed1998

Phase I clinical and pharmacokinetic study of oral 9-aminocamptothecin (NSC-603071).

PURPOSE: 9-Aminocamptothecin (9-AC) is a topoisomerase I inhibitor with high antitumor activity but poor solubility in conventional vehicles. The purpose of this study was to evaluate the toxicities and pharmacokinetics of a colloidal dispersion (CD) formulation of 9-AC when administered orally on a 5 days per week every 2 weeks schedule. METHOD: This formulation, which was developed for intravenous administration, was orally administered in 20 ml orange juice. A group of 16 cancer patients were treated at doses of 0.2-0.68 mg/m2 daily. RESULTS: Grade 1-2 nausea (n = 9) was common, usually occurring during the last 2 days of dosing. No objective responses or cumulative toxicities were observed. Pharmacokinetic analysis of total 9-AC showed highly variable apparent oral 9-AC clearance and half-life. There was marked interpatient variability at each dose level in the 9-AC AUC and Cmax, and these parameters showed a poor correlation with dose (r2 = 0.07 and 0.38, respectively). CONCLUSIONS: We conclude that this formulation is not suitable for further clinical development because of poor bioavailability and highly variable and/or saturable absorption or elimination. Another formulation developed for oral administration is under study elsewhere.

Adult↗

PubMed1998

Phase II trial of uracil/tegafur (UFT) plus leucovorin in patients with advanced pancreatic carcinoma: a University of Chicago phase II consortium study.

BACKGROUND/OBJECTIVES: Uracil and tegafur in a 4:1 molar concentration ratio (UFT; Bristol-Myers Squibb, Wallingford, CT) has broad anti-tumor activity for cancers arising from the gastrointestinal tract. However, there are no published data regarding the efficacy of leucovorin-modulated UFT in patients with pancreatic cancer. The objective of this trial was to determine the activity and evaluate the toxicity of UFT plus oral calcium leucovorin in patients with advanced pancreatic adenocarcinoma. PATIENTS AND METHODS: Fourteen patients with advanced measurable adenocarcinoma of the pancreas were enrolled onto the trial. Patients received 300 mg/m2/d UFT plus 90 mg/d leucovorin administered orally in divided doses every eight hours for 28 days repeated every 35 days. Objective tumor response was evaluated after two courses of therapy. RESULTS: Fourteen patients were evaluable for response and toxicity. No objective responses were seen. The median (range) time to progression and survival were 14 (1.6-37), and 15 (1.9-62) weeks, respectively. Toxicity was mild with severe (grade 3 or 4) hyperbilirubinemia, pain, diarrhea, transaminitis, venous thrombus, weakness, renal failure, confusion, and edema/ascites seen in three (21%), one (7%), two (14%), one (7%), one (7%), one (7%), one (7%), one (7%), and two (14%) patients, respectively. CONCLUSION: In the 14 patients evaluable, UFT 300 mg/m2/d plus oral leucovorin 90 mg/d administered for 28 days did not demonstrate anti-tumor activity against advanced pancreatic adenocarcinoma; however, this oral regimen was well tolerated and devoid of neutropenia, significant oral mucositis or diarrhea.

Adenocarcinoma↗

PubMed1998

Adult duodenal web.

An 18-year-old male presented with persistent vomiting and epigastric fullness of 8 months' duration. Barium examination revealed an abrupt cutoff at the third part of the duodenum. Duodenotomy revealed a web at the third part of the duodenum. Following web excision, the patient experienced marked symptomatic relief and remains well 6 months after surgery.

Adolescent↗

PubMed1998

Primary pleomorphic sarcoma of the liver.

A 35-year-old woman presented with abdominal distension and a palpable liver mass. Ultrasonography and computed tomography revealed a large well-delineated liver mass with bilobar involvement. Based on autopsy and immunohistochemical findings, a final diagnosis of primary pleomorphic liver sarcoma with myogenic differentiation was established.

Adult↗

PubMed1998

Phase II and pharmacodynamic studies of pyrazine diazohydroxide (NSC 361456) in patients with advanced renal and colorectal cancer.

Pyrazine diazohydroxide (PZDH) is a novel antitumor agent that forms DNA adducts via the reactive pyrazine diazonium ion. In a recent Phase I study of PZDH, we identified a recommended Phase II dose of 100 mg/m2/day x 5, given as a 5-min i.v. bolus with the cycles repeated every 42 days (N. J. Vogelzang, et al, Cancer Res., 54: 114-119, 1994). There was a moderate negative correlation between serum chloride concentration and logarithm platelet nadir, suggesting the hypothesis that PZDH is activated in an acidic environment, leading to more toxicity in acidotic patients. Therefore, the University of Chicago Phase II cooperative network conducted two Phase II studies of PZDH in renal cancer (15 patients, 2 with liver metastases) and in 5-fluorouracil-refractory colorectal cancer (14 patients, 13 with liver metastases) to determine efficacy in each disease and to correlate safety and tolerance of the drug with PZDH pharmacokinetics/pharmacodynamics and with arterial blood gas measurements. There were no responses seen in either tumor type. The primary toxicity of PZDH was myelosuppression with neutropenia (absolute neutrophil count, < 1000/microl) and thrombocytopenia (<50,000 cells/microl), seen in 41 and 24% of all cycles, respectively. Other grade 3 and 4 toxicities were rare. Pharmacodynamic analysis revealed no significant correlation between plasma levels at 5, 60, and 120 min; WBCs; absolute neutrophil and platelet count nadirs; and initial serum chloride or blood pH levels. The colorectal patients experienced significantly more thrombocytopenia than did the renal cancer patients (median platelet nadir after cycle 1 was 151 x 10(3)/microl for renal patients versus 76 x 10(3)/microl for colon patients; P = 0.04), suggesting either that prior 5-fluorouracil and leucovorin reduced bone marrow reserve or that colorectal patients with liver metastases experienced more PZDH toxicity. Regression analyses revealed a possible relationship (P = 0.06) between serum pH and thrombocytopenia (i.e., for each increase of 0.03 in pH, there was a 34% increase in the platelet nadir), but there was no relationship between serum chloride and thrombocytopenia. Curiously, an increase in alkaline phosphatase was associated with an increase in the platelet nadir (P = 0.02). If PZDH continues to be developed as an antineoplastic agent, further studies of these relationships are suggested.

Adult↗

PubMed1998

Guideline generation from data by induction of decision tables using a Bayesian network framework.

Decision tables can be used to represent practice guidelines effectively. In this study we adopt the powerful probabilistic framework of Bayesian Networks (BN) for the induction of decision tables. We discuss the simplest BN model, the Naive Bayes and extend it to the Two-Stage Naive Bayes. We show that reversal of edges in Naive Bayes and Two-stage Naive Bayes results in simple decision table and hierarchical decision table respectively. We induce these graphical models for dementia severity staging using the Clinical Dementia Rating Scale (CDRS) database from the University of California, Irvine, Alzheimer's Disease Research Center. These induced models capture the two-stage methodology clinicians use in computing the global CDR score by first computing the six category scores of memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care, and then the global CDRS. The induced Two-Stage models also attain a clinically acceptable performance when compared to domain experts and could serve as useful guidelines for dementia severity staging.

Algorithms↗

PubMed1997

Background suppression with multiple inversion recovery nulling: applications to projective angiography.

We have developed a technique to accurately null the longitudinal magnetization (Mz) of background material. This suppression involves first saturating the longitudinal magnetization (Mz) of a region, and then applying several nonselective inversions. The inversions are timed relative to the saturation such that Mz is nulled across a broad range of T1 at a predetermined time after the initial saturation. B1 and B0 inhomogeneity, which could lead to inaccurate suppression, are dealt with by the combination of a multiple tip saturation sequence and four adiabatic inversion pulses. The suppression sequence can be used to form projective angiograms by selectively tagging the imaging region with the saturation pulse. After the inversions are played out, a projection taken through the tag region when Mz is nulled will only contain signal from blood that has flown into the region after the saturation. Since only two dimensions are acquired, the technique can acquire gated projection angiograms in reasonable scan times. Representative inflow MIR angiograms of the carotid arteries and renal arteries show excellent background suppression.

Carotid Arteries↗

PubMed1997

Sonographic evaluation of biliary ascariasis.

In a prospective 6-month study, sonographic diagnosis of biliary ascariasis was made in 14 patients; in nine patients, the diagnosis was confirmed by endoscopic retrograde cholangiopancreatography and bile analysis, while in five patients, confirmation was obtained by proven intestinal infestation. No false-positive or false-negative cases were encountered. Ascariasis of the biliary tract was seen on ultrasound as echogenic, non-shadowing images, either as single or multiple strips, with visualization of the digestive tract of the worm as an anechoic inner tube, or as amorphous fragments. Follow-up sonograms helped in detection of worm expulsion following medical therapy in five patients, while endoscopic extraction of the worm was performed in four patients. In three patients, disappearance of the worm from the biliary tract was noted following a therapeutic sphincterotomy, and two patients detected to have a worm within the gall-bladder were operated on. In all patients, serial sonograms revealed disappearance of the worm, and the regression of biliary tract dilatation.

Animals↗

PubMed1997

Control of tubercular haemoptysis by bronchial artery embolization.

Thirty-seven patients presenting with massive or recurrent haemoptysis secondary to tuberculous aetiology were subjected to bronchial artery angiography. Of these, failure, to catheterize the bleeding vessel occurred in two patients while embolization was withheld in two patients due to the presence of anterior spinal artery arising from a common intercosto-bronchial trunk. Immediate arrest of bleeding was performed in the remaining 33 patients by selective embolization of the abnormal bronchial arteries with a resorbable material (Gelfoam). Regular follow up for a duration of 6 months after the procedure revealed relapse of haemoptysis in four patients; three were treated by re-embolization of the abnormal bleeding vessels while one patient died due to aspiration immediately on admission. No recurrence of bleeding was seen in the remaining 29 patients. It is concluded that bronchial artery embolization is an effective treatment for immediate control of life-threatening haemoptysis.

Acute Disease↗

PubMed1997

New phase I trial methodology.

Phase I trial design is constantly evolving to adapt to deficiencies in traditional methods and to accommodate newer rationally designed agents. This article discusses some of the important aspects of the design of phase I studies with particular reference to identifying new methods of safer but rapid dose escalation and reproducible end points such as maximum tolerated dose and recommended phase II dose. Given the explosion of rationally designed drugs capable of pathway specific inhibition, we also discuss potential strategies in designing trials with these agents. It is hoped that future strategies incorporate the existing methodologies with newer dose titration examples to complete phase I trials in a rapid and timely fashion.

Clinical Trials, Phase I as Topic↗

PubMed1997

UFT plus leucovorin in advanced hepatobiliary tumors and pancreatic adenocarcinomas.

UFT (tegafur and uracil) has been studied extensively in Japan, with documented efficacy in hepatobiliary and pancreatic cancer. In the United States, UFT with or without leucovorin has not undergone phase II testing in these malignancies. Our current trial is designed primarily to assess the efficacy in terms of response rates to UFT with leucovorin in patients with advanced hepatobiliary and pancreatic cancer. Secondary objectives include determining response duration, time to disease progression, overall survival, quality of life, and toxicity.

Adenocarcinoma↗