Ubiquinone does not rescue acute myeloid leukemia cells from growth inhibition by statins.
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Acute Disease↗
Biomedical subjects
R P Perez
Publications and source records attributed to R P Perez.
Phase I study of twice-weekly gemcitabine and concomitant external-beam radiotherapy in patients with adenocarcinoma of the pancreas.
PURPOSE: To determine the maximum tolerated dose and dose-limiting toxicity associated with twice-weekly gemcitabine and concomitant external-beam radiotherapy in patients with adenocarcinoma of the pancreas. METHODS AND MATERIALS: Twenty-one patients with biopsy-proven adenocarcinoma of the pancreas were treated with external-beam radiotherapy to a dose of 50.4 Gy in 28 fractions, concurrent with gemcitabine, infused over 30 min before irradiation on a Monday and Thursday schedule. The dose of gemcitabine was escalated in 5 cohorts of 3--6 patients each. Initial gemcitabine dose was 10 mg/m(2), with dose escalation until dose-limiting toxicity was observed. RESULTS: The maximum tolerated dose of gemcitabine was 50 mg/m(2), when given in a twice-weekly schedule with radiation. Dose-limiting toxicity was seen in 2 patients at 60 mg/m(2), and consisted of severe upper gastrointestinal bleeding approximately 1 month after completion of treatment. Six patients had radiographic evidence of response to treatment, and 5 of these underwent complete surgical resection. Three patients who underwent complete resection had been deemed to have unresectable tumors before enrollment on trial. Four patients are alive, including 2 without evidence of disease more than 1 year after resection. CONCLUSION: The combination of external-beam radiation and twice-weekly gemcitabine at a dose of 50 mg/m(2) is well tolerated and shows promising activity for the treatment of pancreatic cancer. Our data suggest a higher maximum tolerated dose and different dose-limiting toxicity than previously reported. Further investigation of this regimen is warranted.
Adenocarcinoma↗
Credentialing residents for intraoperative cystoscopy.
OBJECTIVE: To determine whether incorporation of routine intraoperative cystoscopy for evaluation of potential urinary tract injury into gynecologic residency training provides sufficient experience to justify hospital credentials after graduation. METHODS: We developed a curriculum to train residents in intraoperative cystoscopic evaluation of potential lower urinary tract injury. Cystoscopy was performed when indicated with hysterectomy and routinely in conjunction with pelvic reconstruction. Faculty members evaluated conceptual and technical proficiency by oral examination and direct observation in the operating room. Once the resident demonstrated a thorough understanding and proficiency in performing intraoperative cystoscopy, a competency certification document was issued by the Program Director. This certification was transmitted to the postresidency hospital credentials committee to justify granting privileges. RESULTS: Since 1994 over 400 transurethral cystoscopic evaluations have been done in conjunction with major gynecologic abdominal and vaginal surgeries, and since 1997 an additional 50 transvesical microcystoscopies have been done in selected abdominal cases. Twenty-five residency graduates have been certified as fully trained in intraoperative diagnostic cystoscopy. All these graduates have been granted intraoperative cystoscopy privileges at their subsequent hospital practice. CONCLUSION: Incorporation of cystoscopic urinary tract evaluation into routine gynecologic surgical training is good medical practice and provided a mechanism whereby obstetrics and gynecology residents could obtain intraoperative cystoscopy hospital privileges after graduation. (Obstet Gynecol 2000;96:1014-7.)
Credentialing↗
Expression of melanoma inhibitory activity in melanoma and nonmelanoma tissue specimens.
Melanoma inhibitory activity (MIA) is a small soluble protein secreted by malignant melanoma cells and chondrocytes. Prior studies suggested that MIA expression was relatively tissue-specific, making it a potentially useful marker for melanoma. The current investigations sought to more clearly define the range of tumor/tissue-types where MIA is expressed, compared with expression of 4 other potential melanoma marker genes (tyrosinase melanoma antigen recognized by T cells [MART-1/MelanA], gp100, and melanoma growth-stimulatory activity [MGSA/Gro alpha]). Expression of these genes was assayed by reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry in 23 melanoma tumor specimens and in 25 additional nonmelanoma or nonmalignant specimens. MIA, tyrosinase, and MGSA were expressed in most melanoma specimens. Specificity was highest for MART-1, followed by MIA and tyrosinase. Increasing the number of cycles of amplification from 35 to 40 increased sensitivity but decreased specificity of most markers, though MIA was relatively robust. MIA mRNA was also detected in carcinomas of the colon, ovary, kidney, and head/neck, as well as in normal laryngeal epithelium. Although MIA discriminated melanoma from nonmelanoma at least as well as tyrosinase, no single mRNA marker had accuracy greater than 71%, raising potential concern about application of these particular mRNA markers to the minimal disease setting. HUM PATHOL 31:1381-1388.
Adult↗
Detection of EWS-WT1 fusion mRNA in ascites of a patient with desmoplastic small round cell tumor by RT-PCR.
Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive malignancy characterized cytogenetically by a unique translocation of chromosomes 11 and 22 [t(11:22)(p13:ql2)], resulting in fusion of the EWS and WT1 genes. The presence of a unique fusion mRNA in DSRCT allows disease detection and diagnosis by reverse transcription polymerase chain reaction (RT-PCR), as previously described in fixed paraffin-embedded material. In this report, EWS WT1 fusion mRNA was detected in ascites from a patient with DSRCT by RT-PCR. RT-PCR results confirmed the diagnoses of DSRCT and of malignant ascites at the molecular level. RT-PCR assays for specific molecular markers, such as EWS-WT1 fusion mRNA, are potentially powerful methods that can complement routine histological, cytological, and/or immunohistologic assays.
Adult↗
Development of a core curriculum in professional growth: practice management military model.
Military medicine has faced some big challenges in recent years. Military treatment facilities have not been exempt from these alterations, as the American public has sought to reinvent government practices with regard to medicine. Until recently, professional education consisted almost entirely of emphasis in the particular content of the chosen field. Obstetrics and gynecology was one of the first medical specialties to recognize the importance of practice management, professional growth and development, and to require exposure to it as part of the residency process. The Department of Obstetrics and Gynecology's instructional objectives dealing with professional growth and development originated as part of the military-unique curriculum for physicians implemented at Tripler Army Medical Center in Hawaii. Later, these objectives were used at Madigan Army Medical Center in Tacoma, Washington. Recent changes in the health care environment, coupled with an increasing awareness of professional liability and the newer specter of managed care, force physicians to learn the cost of each health encounter and to be more familiar with the business aspects of health care. As medicine in general is changing, the curricula have been revised and tailored to the needs of our physicians with the addition of ethics, managed care, utilization, and practice management.
Curriculum↗
Female circumcision: the prevalence and nature of the ritual in Eritrea.
This study evaluates the prevalence, complications, and attitudes concerning the practice of female circumcision among the women of Eritrea. Four hundred thirty-six Eritrean women from rural and urban environments were questioned about their perceptions and beliefs concerning female circumcision. Eighty-eight percent of those interviewed had undergone some form of female circumcision. Those who favored the continuation of the practice were more likely to be rural dwellers with little formal education, and they did so primarily out of tradition or cultural conformity. The direct and indirect consequences of this practice to the health of women and infants are considerable and as complex as the social, religious, and traditional factors that have led to its preservation.
Adult↗
Enhancing advanced surgical laparoscopy. Combined, routine use of microlaparoscopes and macrolaparoscopes.
OBJECTIVE: To describe a variety of techniques for using the microlaparoscope in conjunction with a standard-sized laparoscope for simplifying and enhancing advanced laparoscopic surgery. STUDY DESIGN: Descriptive study of microlaparoscopic techniques for enhancing macrolaparoscopic procedures. RESULTS: The microlaparoscope facilitates macrolaparoscopy by permitting: (1) specimen removal and use of 10-mm instruments without secondary, large ports; (2) performance of laparoscopic vaginal hysterectomy with the endoscopic stapler using only one 12-mm port; (3) lysis of difficult pelvic and periumbilical adhesions; (4) enhancement of visual access to difficult operative sites; (5) closure of large umbilical and secondary port sites under direct monitoring; (6) visualization from the left upper quadrant when umbilical adhesions are suspected; and (7) use as the initial entry laparoscope when extensive surgery is not anticipated. CONCLUSION: The routine, combined use of the microlaparoscope and 10-mm laparoscope significantly expands the capabilities of the advanced laparoscopic surgeon. Procedures are simplified, facilitated and made less invasive.
Endoscopes↗
Cellular and molecular determinants of cisplatin resistance.
Cisplatin and carboplatin are among the most active and widely used cytotoxic anticancer drugs. However, the acquisition or presence of resistance significantly undermines the curative potential of these drugs against many malignancies. Multiple potential mechanisms of resistance have been identified at the cellular and molecular levels. Alterations in cellular pharmacology, including decreased drug accumulation, increased cellular thiol levels and increased repair of platinum-DNA damage, have been observed in numerous model systems. More recently, it has become apparent that an enhanced capacity to tolerate cisplatin-induced damage may also contribute to resistance. Alterations in proteins that recognise cisplatin-DNA damage (mismatch repair and high-mobility group (HMG) family proteins) and in pathways that determine sensitivity to apoptosis may contribute to damage tolerance. It remains to be determined whether any of these mechanisms contribute significantly to resistance in the clinical setting. Ongoing biochemical modulation and translational correlative trials should clarify which specific mechanisms are most relevant to clinical cisplatin resistance. Such investigations have the potential to improve the ability to predict likelihood of response and should identify potential targets for pharmacological or molecular intervention.
Antineoplastic Agents↗
Fine needle aspiration of palpable breast masses performed in a military obstetrics/gynecology clinic: a follow-up report.
Evaluation of breast disease has increasingly become more integrated into the routine gynecology care of women seen in the obstetrics/gynecology (OB/GYN) clinic. Patients expect their obstetrician-gynecologist to have expertise in evaluation and diagnosis of breast problems that arise from self examination, routine mammography, unusual breast symptoms, or clinical findings during annual gynecology examinations. In 1993, Tripler Army Medical Center Department of Obstetrics and Gynecology initiated a Breast Evaluation Clinic to better serve its patients with breast problems and to train military OB/GYN resident physicians in evaluation and diagnosis of breast disease. A preliminary report of the first 40 patients evaluated in this Breast Evaluation Clinic was previously published in Military Medicine. The patient evaluation, the technique of performing fine needle aspiration (FNA) of breast masses, and the cytologic slide preparation was described in the preliminary report. This follow-up report presents a total of 245 patients who underwent FNA of palpable breast masses in the Tripler Army Medical Center OB/GYN Department Breast Evaluation Clinic between December 1, 1993, and December 8, 1995. Patients found to have suspicious breast masses or abnormal mammography reports at the time of evaluation were immediately referred to the Department of General Surgery for evaluation rather than be subjected to FNA in the OB/GYN Department Breast Evaluation Clinic. Of the 245 patients who underwent FNA, 26 (11%) were referred to the Department of General Surgery for treatment or open biopsy based on cytologic diagnosis and evaluation in the OB/GYN Breast Evaluation Clinic. No major complications from the FNA procedures occurred during this 2-year study period.
Adolescent↗
Increased DT-diaphorase expression and cross-resistance to mitomycin C in a series of cisplatin-resistant human ovarian cancer cell lines.
In a series of ovarian carcinoma cell lines selected in vitro for resistance to cisplatin by continuous exposure to increasing drug concentrations, the level of resistance is proportional to the expression of gamma-glutamylcysteine synthetase (gamma-GCS). To determine if other detoxicating genes are coordinately expressed, we measured the activity of DT-diaphorase and cytochrome P450 reductase. The specific activity of DT-diaphorase, but not that of cytochrome P450 reductase, increased with increasing resistance to cisplatin. Steady-state mRNA levels for DT-diaphorase correlated with enzyme activity and hence with cisplatin resistance. Since the activity of DT-diaphorase has been associated with sensitivity to quinones, we studied the cytotoxicity of mitomycin C under oxic conditions. Unexpectedly, resistance to mitomycin C increased proportionally with that to cisplatin (r = 0.997). Pretreatment with buthionine sulfoximine, which inhibits glutathione (GSH) synthesis, failed to sensitize either the sensitive or the resistant lines to mitomycin C. Thus, the basis for collateral resistance to mitomycin C in the cisplatin-resistant lines under oxic conditions is unrelated to overproduction of GSH. Under hypoxia, the toxicity of mitomycin C to the most sensitive (A2780) cell line was unchanged. However, the most resistant (C200) line was 2-fold more resistant to mitomycin C under hypoxic conditions. The coordinate overexpression of DT-diaphorase and gamma-GCS in the resistant cell lines is thus associated with hypoxic cell resistance, and supports the involvement of shared mechanisms of gene regulation in the observed resistant phenotype.
Antineoplastic Agents↗
Early phase studies with paclitaxel/low-dose carboplatin in patients with solid tumors.
In preparation for the design of phase II studies in lung cancer, low-dose carboplatin, fixed at a target area under the concentration-time curve (AUC) of 4.0 or 4.5 mg x min/mL, has been combined with escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in a series of studies to establish the maximum tolerated dose of the combination. In patients who had received prior chemotherapy, the maximum tolerated paclitaxel dose was 135 mg/m2 (carboplatin target AUC 4.0); the dose-limiting toxicity was febrile neutropenia. Without granulocyte colony-stimulating factor support in chemotherapy-naive patients (carboplatin target AUC 4.5), and with granulocyte colony-stimulating factor in chemotherapy-pretreated patients, the current paclitaxel dose is 290 mg/m2. The maximum tolerated dose has not been defined. In a study in which paclitaxel was given by 1-hour infusion with carboplatin (target AUC 4.5), a 205 mg/m2 dose was poorly tolerated. No evidence of pharmacokinetic interactions between paclitaxel and carboplatin was found. Twenty-one evaluable patients with lung cancer have been treated to date. There have been two partial responses, one minor response, and 10 patients with stable disease at paclitaxel doses of 100 to 270 mg/m2.
Antineoplastic Agents, Phytogenic↗
Daily subcutaneous injection of low-dose interleukin 2 expands natural killer cells in vivo without significant toxicity.
We aimed to determine the toxicity and immunological effects of daily s.c. administered low-dose interleukin (IL) 2. Adult cancer patients received a single daily s.c. injection of IL-2 as outpatients for 90 consecutive days. Cohorts of four to nine patients were treated at escalating IL-2 dose levels until the maximum tolerated dose (MTD) was defined. Peripheral blood mononuclear cell phenotyping, IL-2 serum levels, and the presence of anti-IL-2 antibodies were investigated. Thirty-eight patients were treated at seven IL-2 dose levels ranging from 0.4 to 1.75 million International Units (mIU)/m2 daily. The MTD was 1.25 mIU/m2, with constitutional side effects, vomiting, and hyperglycemia dose limiting. Severe toxicity did not occur at or below the MTD, although mild local skin reaction and mild constitutional side effects were common. Objective tumor regressions were not observed during this Phase I trial. Low-dose IL-2 resulted in natural killer (NK) cell (CD3(-) CD56(+)) expansion at all dose levels. This effect was dose dependent (P < 0.01), ranging from a 154 to 530% increase over baseline. Peak NK levels were achieved at 6-8 weeks and sustained through 12 weeks of therapy. As predicted by in vitro studies of IL-2 receptor structure-activity relationships, the subset of NK cells that constitutively express high-affinity IL-2 receptors (CD3(-)CD56(bright+)) showed more profound dose-dependent expansion, with increases ranging from 368 to 2763% (P = 0.015). NK expansion occurred at peak IL-2 levels <10 pM (2.3 IU/ml). Three patients developed nonneutralizing anti-IL-2 antibodies. Thus, we concluded that selective expansion of NK cells may be achieved in vivo with daily s.c. injections of low-dose IL-2 with minimal toxicity.
Adult↗
Malignancy-related pericardial effusion. 127 cases from the Roswell Park Cancer Institute.
BACKGROUND: Malignancy-related pericardial effusions may represent a terminal event in patients with therapeutically unresponsive disease. However, select patients with malignancies sensitive to available therapies may achieve significant improvement in palliation and long term survival with prompt recognition and appropriate intervention. METHODS: From 1968 to 1994, 150 invasive procedures were performed for the treatment or diagnosis of pericardial effusion in 127 patients with underlying malignancies. These cases were reviewed retrospectively to best identify the clinical features, appropriate diagnostic workup, and optimal therapy for this complication of malignancy. RESULTS: Dyspnea (81%) and an abnormal pulsus paradoxus (32%) were the most common symptoms. Echocardiography had a 96% diagnostic accuracy. Cytology and pericardial biopsy had sensitivities of 90% and 56%, respectively. Fifty-five percent of all effusions were malignant comprising 71% of adenocarcinomas of the lung, breast, esophagus, and unknown primary site. In 57 patients, a malignant effusion could not be determined, and no definitive etiology could be established for 74% of these effusions. Radiation-induced, infectious, and hemorrhagic pericarditis each were identified in fewer than 5% of cases. CONCLUSIONS: Subxyphoid pericardiotomy proved to be a safe and effective intervention that successfully relieved pericardial effusions in 99% of cases with recurrence and reoperation rates of 9% and 7%, respectively. Survival most closely was related to the extent of disease and its inherent chemo-/radiosensitivity, with 72% of the patients who survived longer than 1 year having breast cancer, leukemia, or lymphoma.
Adolescent↗
Determinants of cisplatin sensitivity in normal versus spontaneously transformed rat ovarian surface epithelial cells.
The chemosensitivity of spontaneously transformed rat ovarian surface epithelial (ROSE) cell lines was compared to that of the parental cells from which they were derived. Cisplatin cytotoxicity was determined in three nontransformed (early passage) and three transformed (late passage) ROSE cell lines. Transformed cells were uniformly more sensitive to cisplatin than parental cells (1.5- to 2.6-fold) and grew more rapidly (doubling time range 15-22 hr) than parental cells (28-37 hr). Increased doubling time correlated with decreased cisplatin sensitivity (rho = 0.771). Cisplatin accumulation did not correlate with cisplatin sensitivity. Glutathione (GSH) levels were higher in two of three early passage cell lines, but the correlation between GSH and decreased cisplatin sensitivity in the overall panel of cell lines was modest (rho = 0.549). No statistically significant differences in DNA-platinum binding were observed between early and late passage cell lines. However, initial levels of DNA-bound platinum correlated with cisplatin sensitivity (rho = 0.812) in the six-cell-line panel. GSH levels were inversely correlated with cisplatin accumulation (rho = -0.829) and DNA platination (rho = -0.786). Increased cisplatin sensitivity in spontaneously transformed ROSE cell lines showed a weak, inverse relationship with GSH levels, but more strongly correlated with their increased growth kinetics and to DNA platination.
Animals↗
Role of platinum-DNA adduct formation and removal in cisplatin resistance in human ovarian cancer cell lines.
A series of cisplatin-resistant cell lines were used to examine the formation and removal of platinum-DNA adducts from the overall genome and the formation and removal of cisplatin-interstrand cross-links from specific genomic regions. Cisplatin accumulation and DNA platination levels, which correlated linearly, were similar in three of the resistant cell lines despite differences in their primary cisplatin resistance. Increased platinum removal from total genomic DNA was found to be associated with increased resistance. Interstrand cross-link levels were found to be 2- to 4-fold lower in the 28S ribosomal RNA gene and a non-coding genomic region of the resistant cell lines as compared with the parental A2780 cell line. In addition, 1.2- to 2.7-fold more cross-links were formed in the non-coding region than in the ribosomal RNA gene in all of the cell lines. Interstrand cross-links were removed more rapidly from both regions of the highly cisplatin-resistant C80 and C200 cells and from the ribosomal RNA gene only in the cell lines of lower resistance. The results support a role for DNA repair and alterations in interstrand cross-link formation in cisplatin resistance and provide evidence for heterogeneous interstrand cross-link formation in the genome.
Cisplatin↗
Phase I and pharmacokinetic study of ormaplatin (tetraplatin, NSC 363812) administered on a day 1 and day 8 schedule.
Ormaplatin (tetraplatin, NSC 363812) is a platinum(IV) analogue that is active against cisplatin-resistant cell lines in preclinical models. A schedule previously shown to be active and well tolerated for cisplatin was evaluated in 26 patients. Ormaplatin was administered over a dose range of 4.4-60.8 mg/m2 i.v. given over 30 min on a day 1 and day 8 schedule every 28 days. Twenty-three patients had received prior chemotherapy, and the median performance status was 1. Nausea/vomiting (> or = grade 2) occurred in 40% of patients but was well controlled with standard antiemetic therapy. One patient had grade 2 renal toxicity and 1 patient had grade 3 hepatotoxicity (grade 2 pretreatment). No toxicity limited the dose given during the first course. With repeated drug administration delayed severe neurotoxicity developed in 4 patients, manifested as a sensory polyneuropathy in 3 patients and a possible autonomic neuropathy in one. Prospective nerve conduction studies did not detect subclinical neuropathy prior to the onset of symptoms. Patients who received cumulative doses above 200 mg/m2 were at increased risk for developing neurotoxicity. Plasma elimination of ultrafilterable platinum (measured by atomic absorption spectrometry) was biphasic with a harmonic mean terminal half-life of 15.8 h. The mean total body clearance and renal clearance of ultrafilterable platinum were 173 and 29.8 ml/min/m2, respectively. Thus, renal clearance accounted for 16% of total clearance suggesting that extensive protein/tissue binding was responsible for the majority of platinum clearance. Approximately 60% of the platinum is protein bound (one-half irreversibly) at the end of the infusion. Pharmacokinetic parameters were not dose dependent. No pharmacokinetic parameters were more predictive of neurotoxicity than the cumulative ormaplatin dose. A phase II dose cannot be recommended on this schedule because severe and unpredictable neurotoxicity precludes the administration of more than three cycles at the three highest doses levels tested.
Adult↗
Transformation of rat ovarian epithelial and Rat-1 fibroblast cell lines by RAST24 does not influence cisplatin sensitivity.
Recent reports suggest that expression of an activated c-Ha-ras oncogene is associated with cisplatin resistance in NIH-3T3 fibroblasts. To investigate the generality of these observations, cisplatin cytotoxicity was determined in a series of clonal Rat-1 fibroblast and rat ovarian surface epithelial (ROSE) cell lines carrying a zinc-inducible metallothionein-RAST24 fusion gene, MTRAST24. Cisplatin sensitivity in RAS-transformed fibroblast sublines did not differ from parental controls. Induction of mutant RAST24 expression by zinc sulfate did not affect the cisplatin sensitivity of individual cell lines. Expression of mutant p21Ha-RAS varied more than 40-fold in these fibroblast sublines. Similarly, there was no difference in cisplatin sensitivity between parental ROSE controls, neomycin phosphotransferase transfected controls, or MTRAST24 transfectants. Finally, the cisplatin sensitivity of RAS-transformed ROSE cells was similar to that of spontaneously transformed ROSE cells. Overall, these observations suggest that there is little relationship between mutant ras expression and cisplatin sensitivity in rat epithelial and fibroblast cell lines.
Animals↗