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Biomedical subjects

M L Sherman

Publications and source records attributed to M L Sherman.

At least 19 recordsLinked to original sources
PubMed2001

Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse.

PURPOSE: Three open-label, multicenter trials were conducted to evaluate the efficacy and safety of single-agent Mylotarg (gemtuzumab ozogamicin; CMA-676; Wyeth Laboratories, Philadelphia, PA), an antibody-targeted chemotherapy agent, in patients with CD33-positive acute myeloid leukemia (AML) in untreated first relapse. PATIENTS AND METHODS: The study population comprised 142 patients with AML in first relapse with no history of an antecedent hematologic disorder and a median age of 61 years. All patients received Mylotarg as a 2-hour intravenous infusion, at a dose of 9 mg/m(2), at 2-week intervals for two doses. Patients were evaluated for remission, survival, and treatment-emergent adverse events. RESULTS: Thirty percent of patients treated with Mylotarg obtained remission as characterized by 5% or less blasts in the marrow, recovery of neutrophils to at least 1,500/microL, and RBC and platelet transfusion independence. Although patients treated with Mylotarg had relatively high incidences of myelosuppression, grade 3 or 4 hyperbilirubinemia (23%), and elevated hepatic transaminase levels (17%), the incidences of grade 3 or 4 mucositis (4%) and infections (28%) were relatively low. There was a low incidence of severe nausea and vomiting (11%) and no treatment-related cardiotoxicity, cerebellar toxicity, or alopecia. Many patients received Mylotarg on an outpatient basis (38% and 41% of patients for the first and second doses, respectively). Among the 142 patients, the median total duration of hospitalization was 24 days; 16% of patients required 7 days of hospitalization or less. CONCLUSION: Administration of the antibody-targeted chemotherapy agent Mylotarg to patients with CD33-positive AML in first relapse induces complete remissions with what appears to be a favorable safety profile.

Acute Disease↗
PubMed2001

Chemical orientation of brown bullheads, Ameiurus nebulosus, under different flow conditions.

The spatiotemporal information in chemical signals provides critical information for organisms during chemical orientation. Information in chemical signals is influenced by the hydrodynamic conditions of the environment. Hydrodynamically distinct environments will contain different types of information, which will influence how organisms orient. This study was designed to examine how the orientation behavior of the brown bullhead (Ameiurus nebulosus) is influenced by flow regime. The experiment was conducted in a flume under two different flow conditions. Treatments consisted of control (no odor) and plain gelatin (odor). Percent success, swimming speed, turning angle, heading angle, heading angle upstream, and net-to-gross ratio were analyzed. Brown bullheads were 100% successful in finding the odor source under no flow and 57% successful in flow. Bullheads swam differently in the no-flow condition when compared to the flow condition. Since, these fish did not orient the same under different flow conditions, it appears that hydrodynamics plays a role in shaping their behavior.

Animals↗
PubMed2001

The role for interleukin-12 therapy of cutaneous T cell lymphoma.

Recent phase I and phase II trials using recombinant human interleukin-12 (rhIL-12) for cutaneous T cell lymphoma (CTCL) have been completed. Observations on 32 evaluable patients revealed an overall response rate approaching 50 percent. Biopsy of regressing lesions revealed an increase in numbers of CD8+ and/or TIA-1+ T cells. These results suggest that rhIL-12 may induce lesion regression by augmenting antitumor cytotoxic T cell responses. Future trials will be focused on strategies for further immune enhancement by the concomitant use of additional immune augmenting cytokines with rhIL-12.

Antigens, Differentiation, T-Lymphocyte↗
PubMed2000

Bilateral eventration of the diaphragm with perforated gastric volvulus in an adolescent.

Bilateral congenital eventration of the diaphragm almost uniformly presents in infancy with respiratory compromise and is associated with a high mortality rate. Delayed presentation of diaphragmatic eventration in older children and adults may be associated with acute gastric volvulus. Thus, any patient with abdominal pain, vomiting, or nonspecific gastrointestinal symptoms in association with abnormal diaphragmatic findings on chest x-ray should undergo further diagnostic workup with upper gastrointestinal series or computed tomography (CT) scan. Treatment of gastric volvulus requires immediate surgical repair to prevent subsequent necrosis and perforation. The authors describe a case report of bilateral congenital diaphragmatic eventration complicated by a perforated gastric volvulus in a 13-year-old boy. Emergent reduction of the volvulus, closure of the perforated stomach, plication of the diaphragm, and placement of gastrostomy was performed successfully.

Adolescent↗
PubMed1999

Interleukin-12 therapy of cutaneous T-cell lymphoma induces lesion regression and cytotoxic T-cell responses.

Progression of cutaneous T-cell lymphoma (CTCL) is associated with profound defects in cell-mediated immunity and depressed production of cytokines, which support cell-mediated immunity. Because we have observed marked defects in interleukin-12 (IL-12) production in CTCL and because IL-12 is critical for antitumor cytotoxic T-cell responses, we initiated a phase I dose escalation trial with recombinant human IL-12 (rhIL-12) where patients received either 50, 100, or 300 ng/kg rhIL-12 twice weekly subcutaneously or intralesionally for up to 24 weeks. Ten patients were entered: 5 with extensive plaque, 3 with Sezary syndrome, and 2 with extensive tumors with large cell transformation. One patient with Sezary syndrome dropped out after 1 week for personal reasons. Subcutaneous dosing resulted in complete responses (CR) in 2 of 5 plaque and partial responses (PR) in 2 of 5 plaque, and 1 of 2 Sezary syndrome (overall response rate CR+PR 5 of 9, 56%). A minor response also occurred in 1 of 5 plaque patients. Intralesional dosing resulted in individual tumor regression in 2 of 2 patients. Biopsy of regressing lesions showed a significant decrease in the density of the infiltrate in all cases and complete resolution of the infiltrate among those with clinical lesion resolution. An increase in numbers of CD8-positive and/or TIA-1-positive T cells were observed on immunohistochemical analysis of skin biopsy specimens obtained from regressing skin lesions. Adverse effects of rhIL-12 on this regimen were minor and limited and included low-grade fever and headache. One patient discontinued rhIL-12 at week 6 because of depression. These results suggest that rhIL-12 may augment antitumor cytotoxic T-cell responses and may represent a potent and well-tolerated therapeutic agent for CTCL.

Adult↗
PubMed1999

Immunological effects of interleukin 12 administered by bolus intravenous injection to patients with cancer.

The immunological effects of recombinant human interleukin 12 (rhIL-12) administration were examined during the conduct of a Phase I clinical trial. Forty patients with advanced cancer received bolus i.v. injections of rhIL-12 in doses ranging between 3 and 1000 ng/kg. Dose-dependent increases in serum IFN-gamma levels were seen during rhIL-12 therapy. Significant lymphopenia was observed 24 h after single i.v. injections of rhIL-12 at each dose level. The degree of lymphopenia was dose dependent, and a plateau effect was seen with rhIL-12 doses of 100 ng/kg and higher. Lymphocyte counts reached nadir levels at approximately 10 h after rhIL-12 injection and returned to baseline within 14 days postinjection. Rebound lymphocytosis, as seen after interleukin 2 therapy, was not observed after recovery from rhIL-12-induced lymphopenia. rhIL-12-induced lymphopenia involved all major lymphocyte subsets, although natural killer (NK) cell numbers were the most profoundly affected, and CD4 T-cell numbers were the least affected. CD2, LFA-1, and CD56 were transiently up-regulated on the surface of NK cells exposed to rhIL-12 in vivo. Peripheral blood mononuclear cells obtained from cancer patients before rhIL-12 therapy exhibited defective NK cell cytotoxicity and T-cell-proliferative responses. Peripheral blood mononuclear cells obtained after lymphocyte recovery following the administration of a single 500 ng/kg dose of rhIL-12 displayed augmented NK cell cytolytic activity in four of four patients tested and enhanced T-cell proliferation in three of four patients tested. These studies confirm that doses of rhIL-12 resulting in significant immunological activity can be administered with acceptable toxicity to cancer patients. Furthermore, rhIL-12 therapy can reverse defects in NK cell and T-cell function that are associated with advanced cancer in humans.

Antineoplastic Agents↗
PubMed1997

Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-gamma production.

Interleukin-12 (IL-12) is a key regulator of cell-mediated immunity that has therapeutic potential in cancer and infectious disease. In a previous Phase 1 dose escalation study of a single test dose of recombinant human IL-12 (rhIL-12) followed 14 days later by cycles of five consecutive daily intravenous injections every 3 weeks, we showed that a dose level up to 500 ng/kg could be administered with acceptable levels of safety. Based on these results, a Phase 2 study was conducted. In the Phase 2 study, however, administration of rhIL-12 at this same dose level resulted in severe toxicities with some patients unable to tolerate more than two successive doses. Of the 17 patients receiving rhIL-12 in the Phase 2 study, 12 patients were hospitalized and two patients died. A thorough scientific investigation to determine the cause of this unexpected toxicity failed to identify any difference in the drug products used or the patient populations enrolled in the Phase 1 and Phase 2 studies that could have accounted for the profound difference in toxicity. The focus of the investigation therefore shifted to the schedule of rhIL-12 administration. We determined that a single injection of rhIL-12 2 weeks before consecutive dosing included in the Phase 1 study, but not in the schedule of administration in the Phase 2 study, has a profound abrogating effect on IL-12-induced interferon-gamma (IFN-gamma) production and toxicity. This observation of schedule-dependent toxicity of IL-12 has been verified in mice, as well as nonhuman primates. In this regard, a single injection of IL-12 before consecutive daily dosing protected mice and cynomolgus monkeys from acute toxicity including mortality and was associated with an attenuated IFN-gamma response. Because of this unique biologic response, careful attention to the schedule of administration is required to assure safe and effective clinical development of this highly promising cytokine.

Adult↗
PubMed1997

Quality control for DNA contamination in laboratories using PCR-based class II HLA typing methods.

Quality control (QC) in laboratories performing molecular histocompatibility class II typing often includes a polymerase chain reaction (PCR) approach for monitoring DNA contamination. An oligonucleotide primer set was designed, (RBQBf/RBQBr), which is specific for nonpolymorphic regions of the DR-B, DQ-B, and DP-B consensus sequences with an expected PCR product size of 81 bp. RBQBf/RBQBr detected genomic DNA from reference cell lines LWAGS and BM21 (50 to 100 picograms) as well as DR-B, DP-B, and DQ-B amplicon (1 copy). Additionally, RBQBf/RBQBr detected SSP products from routine DR-B and DQ-B typings. Validation studies employing controlled DNA contamination of laboratory surfaces revealed that increasing amounts of wipe test samples (5% to 20% v/v) were inhibitory to the wipe test PCR, whereas lower amounts (1% to 2%), or alternatively, a diluted wipe test sample, increased the sensitivity of the test and optimized the results. Collectively, this study describes a primer set, RBQBf/RBQBr, which detects both genomic DNA and DR-B, DQ-B, or DP-B amplicon and furthermore illustrates the necessity of routine testing for potential inhibitory factors that may be introduced into the wipe test PCR.

Base Sequence↗
PubMed1997

Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies.

A Phase I dose escalation trial of i.v. administered recombinant human interleukin 12 (rhIL-12) was performed to determine its toxicity, maximum tolerated dose (MTD), pharmacokinetics, and biological and potential antineoplastic effects. Cohorts of four to six patients with advanced cancer, Karnofsky performance >/=70%, and normal organ function received escalating doses (3-1000 ng/kg/day) of rhIL-12 (Genetics Institute, Inc.) by bolus i.v. injection once as an inpatient and then, after a 2-week rest period, once daily for five days every 3 weeks as an outpatient. Therapy was withheld for grade 3 toxicity (grade 4 hyperbilirubinemia or neutropenia), and dose escalation was halted if three of six patients experienced a dose-limiting toxicity (DLT). After establishment of the MTD, eight more patients were enrolled to further assess the safety, pharmacokinetics, and immunobiology of this dose. Forty patients were enrolled, including 20 with renal cancer, 12 with melanoma, and 5 with colon cancer; 25 patients had received prior systemic therapy. Common toxicities included fever/chills, fatigue, nausea, vomiting, and headache. Fever was first observed at the 3 ng/kg dose level, typically occurred 8-12 h after rhIL-12 administration, and was incompletely suppressed with nonsteroidal anti-inflammatory drugs. Routine laboratory changes included anemia, neutropenia, lymphopenia, hyperglycemia, thrombocytopenia, and hypoalbuminemia. DLTs included oral stomatitis and liver function test abnormalities, predominantly elevated transaminases, which occurred in three of four patients at the 1000 ng/kg dose level. The 500 ng/kg dose level was determined to be the MTD. This dose, administered by this schedule, was associated with asymptomatic hepatic function test abnormalities in three patients and an onstudy death due to Clostridia perfringens septicemia but was otherwise well tolerated by the 14 patients treated in the dose escalation and safety phases. The T1/2 elimination of rhIL-12 was calculated to be 5.3-9.6 h. Biological effects included dose-dependent increases in circulating IFN-gamma, which exhibited attenuation with subsequent cycles. Serum neopterin rose in a reproducible fashion regardless of dose or cycle. Tumor necrosis factor alpha was not detected by ELISA. One of 40 patients developed a low titer antibody to rhIL-12. Lymphopenia was observed at all dose levels, with recovery occurring within several days of completing treatment without rebound lymphocytosis. There was one partial response (renal cell cancer) and one transient complete response (melanoma), both in previously untreated patients. Four additional patients received all proposed treatment without disease progression. rhIL-12 administered according to this schedule is biologically and clinically active at doses tolerable by most patients in an outpatient setting. Nonetheless, additional Phase I studies examining different schedules and the mechanisms of the specific DLTs are indicated before proceeding to Phase II testing.

Adult↗
PubMed1996

Randomized investigation of antimicrobials for the prevention of preterm birth.

OBJECTIVE: Occult amniotic fluid infection has emerged as a possible cause of many heretofore unexplained preterm births. We sought to determine whether antimicrobial therapy is effective in preventing preterm delivery. STUDY DESIGN: A double-blind, placebo-controlled, randomized trial was conducted to study the efficacy of ampicillin-sulbactam and amoxicillin-clavulanic acid in women hospitalized for preterm labor between 24 and 34 weeks' gestation. During this investigation no tocolytics or steroids were used. RESULTS: Thirty-nine women with preterm labor received antimicrobial therapy and 39 received placebos. The mean gestational ages at study entry were 29.8 +/- 0.4 weeks (SEM) and 30.6 +/- 0.3 weeks in the antimicrobial and placebo groups, respectively (not significant). Similarly, the mean gestational ages at delivery were 34.2 +/- 0.7 and 34.1 +/- 0.6 weeks, respectively (not significant). Other index values of pregnancy outcome, for example, birth weight, neonatal morbidity, and prenatal death, were not significantly improved by antimicrobial therapy given to the mother in preterm labor. CONCLUSION: We find that antimicrobial therapy given to women in preterm labor is ineffective in the prevention of preterm birth.

Amoxicillin↗
PubMed1996

Phase I study of continuous-infusion recombinant macrophage colony-stimulating factor in patients with metastatic melanoma.

Macrophage colony-stimulating factor (M-CSF) is a lineage-specific, homodimeric growth factor that supports the proliferation and maturation of bone marrow progenitors and the survival and function of mononuclear/macrophage cells. In vitro studies have demonstrated antitumor activity of macrophage colony-stimulating factor-treated monocytes against melanoma target cells. A Phase I study was conducted by administering the glycosylated form of the protein to patients with metastatic melanoma as two 7-day continuous i.v. infusions separated by a 2-week rest. Cohorts of three patients per dose level received escalating doses of 10-160 microgram/kg/day. Safety, clinical, and biological effects were evaluated. The infusions were well tolerated with occasional maximum grade 2 nonhematological toxicity. Rapidly reversible thrombocytopenia was the major hematological adverse effect. Its etiology may in part be explained by proliferation and activation of monocyte/macrophage cells in bone marrow samples. Evidence for a biological effect on tumors was suggested by the delayed, complete disappearance of multiple lesions in one patient and a decrease in the size of one marker lesion in a second patient with a mixed response. Fasting serum cholesterol levels decreased during the infusions and may represent an additional therapeutic application for this growth factor.

Adult↗
PubMed1995

Association between workers' compensation and outcome following multidisciplinary treatment for chronic pain: roles of mediators and moderators.

OBJECTIVE: To determine whether the tendency for chronic pain patients who receive Workers' Compensation to show a poorer response than non-compensated patients to pain treatment can be accounted for by mediating factors; to assess whether moderating factors can distinguish subgroups of Workers' Compensation recipients who react very poorly to treatment from compensated patients who respond well. DESIGN: Outcome study based on archives. SETTING: Multidisciplinary pain treatment center. PATIENTS: Of 214 patients, 158 had complete data. OUTCOME MEASURE: Blind ratings of narrative discharge summaries written by the Pain Treatment Center staff. RESULTS: A significant negative relationship between receiving Workers' Compensation and outcome was mediated by a pessimistic belief in the ability to return to former occupation. Moderator effects showed that Workers' Compensation recipients with high initial pain and a history of pain-related surgery fared worse than any other group. Moreover, Workers' Compensation recipients not characterized by high pain and a history of surgery responded as well as noncompensated patients. CONCLUSIONS: The inadequate response to pain programs shown by Workers' Compensation recipients may be partly understood in terms of well-defined mediating factors, which may admit to amelioration via clinical intervention. Moreover, Workers' Compensation patients should not be considered high risks for failure by sole virtue of their compensation status. Multifactor assessment methods may be needed to identify that portion of compensation recipients who are actually at appreciable risk for treatment failure so that appropriate adjustments in treatment regimen may be made.

Adult↗
PubMed1994

Maternal youth and pregnancy outcomes: middle school versus high school age groups compared with women beyond the teen years.

OBJECTIVE: We sought to measure and compare pregnancy complications in middle school versus high school versus older maternal age groups. STUDY DESIGN: From January 1988 through December 31, 1991, maternal and infant data from 16,512 consecutive nulliparous women were collected and electronically stored. These women were divided into three study groups: middle school (11 to 15 years old), high school (16 to 19 years old), and women 20 to 22 years old at delivery. Statistical analysis included logistic regression to control for potentially confounding demographic variables. RESULTS: Middle school-aged mothers were disproportionately black (50% vs 36% Hispanic vs 14% white), and very low birth weight (4% vs. 2%, p = 0.003) was increased in these youthful mothers. First births to high school-aged mothers were not found to be compromised compared with those of women 20 to 22 years old, and, indeed, cesarean birth was less frequent in these women compared with those > or = 20 years old. CONCLUSIONS: We conclude that the health hazard associated with school-age pregnancy is predominantly prematurity and is increased only in middle school-aged mothers. High school-aged mothers do not experience excess medical complications of pregnancy compared with older women. We suggest that middle school pregnancy, particularly for inner-city teenagers, should be a special focus for pregnancy prevention and intervention.

Adolescent↗
PubMed1994

Meconium: a 1990s perspective on an old obstetric hazard.

OBJECTIVE: To quantify the current perinatal consequences associated with intrapartum detection of meconium in the amniotic fluid (AF). METHODS: We compared retrospectively the outcomes in 8136 term singleton cephalic pregnancies with meconium and 34,573 similar pregnancies with clear AF. RESULTS: Virtually all measures of adverse fetal-neonatal outcomes were significantly increased with meconium. For example, perinatal mortality increased from 0.3 per 1000 births with clear AF to 1.5 deaths per 1000 with meconium (P < .001). Most of these deaths resulted from meconium aspiration. Other unwanted outcomes also increased; eg, severe fetal acidemia at birth (umbilical artery blood pH 7.00 or less) increased from three per 1000 to seven per 1000 when meconium was diagnosed (P < .001). Delivery by cesarean also increased with meconium, from 7 to 14% (P < .001). CONCLUSION: Meconium in the AF is an obstetric hazard with small but significantly increased risks of adverse fetal-neonatal outcomes.

Adolescent↗
PubMed1994

High-dose oxytocin: 20- versus 40-minute dosage interval.

OBJECTIVE: To determine whether an increase in the oxytocin dosing interval would decrease the incidence of uterine hyperstimulation. METHODS: This study included 1801 consecutive pregnancies receiving high-dose oxytocin. Oxytocin was used for labor augmentation in 1167 and induction in 634 women. Twenty- and 40-minute dosage intervals were compared. The study period was based on an 80% likelihood of detecting 5 and 10% differences in the cesarean and hyperstimulation rates, respectively. Statistics were analyzed with chi 2, Fisher, and Wilcoxon rank-sum tests where appropriate. Multivariate logistic regression and analysis of covariance were used to control for confounding demographic variables. RESULTS: Comparison of the 20- and 40-minute regimens for labor induction yielded no differences in the rates of cesarean delivery for dystocia (16 versus 19%) or fetal distress (5 versus 6%). The 20-minute regimen for augmentation was associated with a significant reduction in cesarean for dystocia (8 versus 12%; P = .05). The incidence of uterine hyperstimulation was greater with the 20-minute than the 40-minute regimen for induction (40 versus 31%; P = .02), but not for augmentation (31 versus 28%). Neonatal outcomes were unaffected by the dosage interval for both augmentation and induction. CONCLUSION: A 40-minute dosing interval for high-dose oxytocin offers no clear advantage over a 20-minute interval. Both regimens were safe and efficient, with no differences in perinatal outcome. The 20-minute interval was associated with fewer cesareans for dystocia when used for labor augmentation, whereas the 40-minute interval resulted in less hyperstimulation when used for labor induction.

Adult↗
PubMed1993

Down-regulation of tumor necrosis factor expression by pentoxifylline in cancer patients: a pilot study.

The wasting syndrome (cachexia) characterized by anorexia, malaise, and weight loss is observed in many patients with cancer or chronic infection. The excessive levels of tumor necrosis factor-alpha (TNF)/cachectin reported in 50% of cancer patients exhibiting clinically active disease may therefore mediate, at least in part, the cachexia associated with malignancy. Pentoxifylline, a substituted methylxanthine approved for treatment of intermittent claudication, has been shown in preclinical studies to down-regulate TNF RNA expression as well as TNF activity. We report that pentoxifylline suppressed TNF RNA levels on all three occasions in patients with initially elevated levels of TNF RNA. Pentoxifylline did not suppress TNF RNA to subnormal levels in all five patients with initially normal TNF RNA levels. Four patients reported an increased sense of well-being, improved appetite and ability to perform the activities of daily living. Two of these five patients with normal TNF levels each had a weight gain of more than 5% after 3 weeks of pentoxifylline therapy suggesting that, although TNF may be important in the pathogenesis of cancer cachexia, other anorexia-producing cytokines that are potentially affected by pentoxifylline may also be involved. No severe adverse effects were observed. Taken together these findings suggest that pentoxifylline can down-regulate TNF expression and improve the sense of well-being in cancer patients. A larger study with a randomized, double-blind, placebo-controlled design and more sophisticated estimates of quality of life will be needed to confirm these observations.

Adult↗