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PubMed1996

[Mammalian phosphoribosylpyrophosphate synthetase].

PRPP synthetase from rat liver exists as large molecular weight aggregates composed of at least four different components, i.e., two isoforms of 34 kDa catalytic subunits, PRSI and PRSII, and two associated proteins of 39 kDa and 41 kDa (PAP39 and PAP41). The four proteins have remarkably similar amino acid sequences and form a relatively large group of PRS family. PAPs, however, have extra regions of 40 to 50 amino acid residues, totally dissimilar to sequences of the catalytic subunits and thus form a subfamily. PAPs suppress the catalytic activity of PRS. They are very likely to be enzymatically inactive. The relative amounts of the mRNAs of the four components vary with the tissues, hence composition and properties of PRPP synthetase would also differ. Future studies on the physiology and pathology of PAPs are critical in elucidation of pathogenesis of some types of hyperuricemia.

Amino Acid Sequence↗
PubMed1997

Metabolism of apolipoprotein B-100 in a kindred with familial hypobetalipoproteinemia without a truncated form of apoB.

Familial hypobetalipoproteinemia (FHBL) exists in three forms: a) FHBL genetically linked to truncated forms of apolipoprotein B (apoB); b) FHBL linked to the apoB gene but with no apoB truncations; and c) FHBL not linked to the apoB gene. Mean production rate (PR) of apoB-100 in FHBL subjects heterozygous for apoB truncations is approximately 30% of normal. In a 49-member D-kindred (FHBL phenotype defined as apoB < 40 mg/dl), no apoB truncations were detectable either by immunoblotting of plasma or by sequencing of relevant stretches of the apoB gene. Herein we report on the kinetic parameters of apoB-100-containing lipoproteins in four affected members of the D-kindred, and compare their kinetic values to 14 normal subjects, and 8 previously reported FHBL subjects heterozygous for various truncated forms of apoB. After an 8-h primed intravenous infusion of [13C]-leucine, enrichments of apoB-100 were assessed by gas chromatography-mass spectrometry and kinetic parameters were calculated by multicompartmental modeling. The affected members of the D-kindred had similar very low, intermediate, and low density lipoprotein (VLDL, IDL, and LDL) PRs as normal controls, but their fractional catabolic rates (FCR) for VLDL and LDL were approximately 2 and 3 times higher, respectively, than those of normals. By contrast in apoB truncation subjects, apoB-100 PRs were uniformly reduced, while apoB-100 FCRs were similar to normals. Thus, diverse physiologic mechanisms are responsible for the low apoB levels in these two different, genetically determined forms of FHBL.

Adolescent↗
PubMed1997

[Botulinum toxin in spastic infantile cerebral palsy: results in 27 cases during one year].

INTRODUCTION AND OBJECTIVES: Positive outcome of patients with spastic cerebral palsy treated with botulinum toxin reported in the last three years has led us to perform this study with the aim to show our experience in the management of spastic cerebral palsy with the toxin, determine its indications, analyze the results and propose new possible indications in the future. MATERIAL AND METHODS: We include 10 hemiplegic and 17 diplegic patients with an average age of 6 years and 7 months, followed up between 5 and 17 months. Clinical improvement was monitored using the PRS and EVFEL scales and articular motion range was measured 6 months before and after the injection while continuing physiotherapy. The injected muscles were adductor, hamstrings, triceps and posterior tibialis, and the doses were 1-2 U/muscle/kg body weight. RESULTS: The values on PRS improved an average of 24%, adductor angle 66% (p < 0.01), knee angle 40% (p = 0.05) and ankle angle 52% (p < 0.01); 96% of patients could get more physiological static or walking patterns because of the decrease of spasticity and those persisted after the effect of the toxin had worn off. It was maximum at 2 months, stabilized 4 to 6 months later and decreased during further 2 months. CONCLUSIONS: This experience leads us to propose higher starting dosage and to take into account the stability of postural pattern of each patient to choice the muscle to be injected. Other therapeutic possibilities are also proposed in children with fixed shortening e.g. combining the toxin with stretching casts.

Adolescent↗
PubMed1997

Paclitaxel (Taxol) for the treatment of lymphoma.

Paclitaxel (Taxol) was recently tested in patients with relapsed and refractory lymphoma in two phase II clinical trials using two different infusion schedules. The first, reported from the NCI (USA), used a 96-hour intravenous continuous infusion schedule, and the second, from our group, used a 3-hour infusion. In the NCI trial, 29 evaluable patients were treated with 140 mg/m2 every three weeks, which achieved a 17% response rate (all PRs); while we treated 96 evaluable patients with 200 mg/m/ every three weeks, which achieved a 25% response rate (10 CRs and 14 PRs, 95% CI: 17%-35%). In our trial, patients with relapsed (not primary refractory) intermediate-grade lymphoma had a response rate of 50%, and those with relapsed low-grade lymphoma had a response rate of 31%. In a follow-up trial, 12 patients who failed to respond to 3-hour infusion of paclitaxel were crossed over to receive paclitaxel by 96-hour infusion. None of the 12 evaluable patients achieved a major clinical response. Similarly, of 25 patients treated with cyclosporine A and paclitaxel after failing therapy with single-agent paclitaxel, only one patient (4%) responded. We conclude that paclitaxel has a promising single-agent activity, most prominently in patients with relapsed intermediate-grade lymphoma. Paclitaxel-based combination programs are currently being evaluated in our institution.

Antineoplastic Agents, Phytogenic↗
PubMed1997

Better survival in women with resected hepatocellular carcinoma is not related to tumor proliferation or expression of hormone receptors.

OBJECTIVE: There is a well known male predominance in hepatocellular carcinoma (HCC). Moreover, female patients with HCC have better survival and lower recurrence rates after surgical resection. We previously showed that the better prognosis in female patients is related to a higher incidence of tumor encapsulation and less invasive tumors. However, the underlying mechanism is still obscure. METHODS: In this study, we examined the cell proliferative indices (expression of proliferative cell nuclear antigen (PCNA) and Ki-67 antigen using MIB1 antibody) and expression of the estrogen and progesterone receptors (ERs and PRs, respectively) in 71 patients with resected HCC. These were correlated with the pathological features of the tumors and the survival rates of patients. RESULTS: Female patients with HCC had significantly better actuarial and disease-free survival rates than male patients (p = 0.010 and 0.004, respectively). Tumor PCNA scores, represented by positively stained nuclei per 1000 tumor cells, were significantly higher in tumors showing venous permeation (p = 0.034), positive resection margins (p = 0.011), and absence of bile production (p = 0.008). Higher tumor MIB1 scores were seen in tumors that had poorer cellular differentiation (p = 0.002) and no tumor capsules (p = 0.042). However, both tumor PCNA and MIB1 scores did not differ significantly between female and male patients. ERs were detected in the tumor cells in 23.9% of tumors, and PRs were detected in 14.3%. Expression of both ER and PR was not influenced by gender. CONCLUSIONS: Women with HCC had significantly better survival and lower tumor recurrence rates. However, significant differences in cellular proliferation indices and expression of ER and PR were not observed between men and women to explain the difference in survival rate.

Adult↗
PubMed1997

Treatment of patients with upper gastrointestinal carcinomas.

Carcinomas of the stomach and esophagus are a major health problem worldwide. Cancer remains incurable when it is metastatic or unresectable, and new active agents are needed to improve the outcome for these patients. Three phase II studies of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) are described here. The first, at M.D. Anderson Cancer Center, examined the role of single-agent paclitaxel in untreated patients with advanced gastric carcinoma. Thirty-three patients were accrued. The starting dose of paclitaxel was 200 mg/m2 and it was repeated every 21 days. The first 15 patients received paclitaxel administered over 3 hours, and the subsequent 18 patients received paclitaxel administered over 24 hours. Three patients were not evaluable. Among the first 15 patients (two not evaluable) receiving paclitaxel over 3 hours, there was one partial response (PR) (8%) and three minor responses (MRs) (23%). Among the 18 patients (one not evaluable) receiving paclitaxel over 24 hours, however, there were four PRs (24%) and three MRs (18%). The overall PR rate was 17% (five of 30 patients). The median duration of PR was 6.5 months (range, 2.3 to 11.3+ months). Myelosuppression was more severe with the 24-hour schedule than with the 3-hour schedule. Our data suggest that paclitaxel is active against gastric carcinoma, albeit to a lesser degree than in esophageal adenocarcinoma. Paclitaxel should be investigated further in combination therapy with other active agents. In the second phase II study, paclitaxel was administered via a 24-hour intravenous infusion in chemotherapy-naive patients with unresectable locoregional or metastatic carcinoma of the esophagus. The starting dose of paclitaxel was 250 mg/m2, repeated every 21 days. In addition, patients received granulocyte colony-stimulating factor (5 microg/kg/d subcutaneously) 24 hours after the completion of treatment. Thirty-three patients had adenocarcinoma and 18 had squamous cell carcinoma. Sixteen patients (31%) achieved a response (one complete response [CR] and 15 PRs), and 11 (22%) achieved an MR. Of the 33 patients with adenocarcinoma, 12 (36%) achieved either a CR (one patient) or a PR (11 patients); six patients had an MR. Four of 18 patients (22%) with squamous cell carcinoma had a PR and four (22%) had an MR. Paclitaxel was well tolerated. Granulocytopenia was frequent, resulting in 11 hospitalizations in nine patients. Thus, paclitaxel is active against both adenocarcinoma and squamous cell carcinoma of the esophagus. In a subsequent phase II trial, paclitaxel has been studied in combination with cisplatin and 5-fluorouracil in 30 patients with advanced adenocarcinoma and 22 patients with squamous cell carcinoma of the esophagus. The doses are paclitaxel 175 mg/m2 administered over 3 hours on day 1, cisplatin 20 mg/m2 on days 1 to 5, and S-fluorouracil 1,000 mg/m2/d (in the first 10 patients, but then reduced to 750 mg/m2/d as continuous infusion on days 1 to 5) given every 28 days. Among the 47 patients evaluated for response so far, four have had a CR and 17 have had a PR (overall response rate, 45%). Toxicity with this combination has been moderate, and there have been no treatment-related deaths. With the reduced starting dose of 5-fluorouracil, the tolerance of this combination has improved substantially both in the inpatient and outpatient settings, resulting in a low frequency of grade 3 or 4 nonhematologic toxicity. Response has been higher in patients with squamous cell carcinoma.

Adult↗
PubMed1998

[Parry-Romberg syndrome: a form of focal vasculitis].

The Parry-Romberg syndrome (PRS), which was described many years ago, is a process of unknown etiology which evolves with invalidating lesions in one half of the face to which different neurologic, cutaneous or analytical abnormalities may be associated. A clinical, analytical and radiologic study of 5 patients in whom intracranial lesions were shown are herein presented. These findings, together with alterations in the cutaneous biopsies reported in the literature lead to the hypothesis that PRS may be due to a neurovascular alteration of immunologic basis, indicating antiinflammatory or immunosuppressive treatment.

Adolescent↗
PubMed2026

Selphi, a tool for improving genotype imputation accuracy.

Genotype imputation is a powerful tool for inferring missing genotype data in large-scale genetic studies. Over the last two decades, multiple imputation algorithms have been developed, steadily improving in speed and overall accuracy. However, accurate imputation of rare and infrequent variants remains a challenge, largely because existing methods rely on local haplotype matching within genomic windows and do not fully exploit the extended patterns of haplotype sharing that span entire chromosomes. Here we present Selphi, a new genotype imputation algorithm that combines the Positional Burrows-Wheeler Transform (PBWT) with a multi-stage haplotype selection heuristic operating across entire chromosomes. When compared to state-of-the-art methods Beagle 5.4, IMPUTE5, and Minimac4, Selphi showed higher accuracy on the 1000 Genomes Project and TOPMed datasets, across all super-populations and allele frequencies. Similarly, Selphi achieved higher accuracy than Beagle 5.4 on the UK Biobank dataset, which translated into improved concordance with hc-WGS GWAS summary statistics at known trait-associated loci and more accurate polygenic risk scores (PRS). Selphi outputs standard VCF files with genotype dosages (DS), haplotype-specific allele probabilities (AP1, AP2), and a per-variant dosage R-squared quality score (DR2), enabling direct integration with downstream analytical pipelines including standard post-imputation quality filtering.

Genome-Wide Association Study↗
PubMed1999

The disease burden associated with overweight and obesity.

CONTEXT: Overweight and obesity are increasing dramatically in the United States and most likely contribute substantially to the burden of chronic health conditions. OBJECTIVE: To describe the relationship between weight status and prevalence of health conditions by severity of overweight and obesity in the US population. DESIGN AND SETTING: Nationally representative cross-sectional survey using data from the Third National Health and Nutrition Examination Survey (NHANES III), which was conducted in 2 phases from 1988 to 1994. PARTICIPANTS: A total of 16884 adults, 25 years and older, classified as overweight and obese (body mass index [BMI] > or =25 kg/m2) based on National Institutes of Health recommended guidelines. MAIN OUTCOME MEASURES: Prevalence of type 2 diabetes mellitus, gallbladder disease, coronary heart disease, high blood cholesterol level, high blood pressure, or osteoarthritis. RESULTS: Sixty-three percent of men and 55% of women had a body mass index of 25 kg/m2 or greater. A graded increase in the prevalence ratio (PR) was observed with increasing severity of overweight and obesity for all of the health outcomes except for coronary heart disease in men and high blood cholesterol level in both men and women. With normal-weight individuals as the reference, for individuals with BMIs of at least 40 kg/m2 and who were younger than 55 years, PRs were highest for type 2 diabetes for men (PR, 18.1; 95% confidence interval [CI], 6.7-46.8) and women (PR, 12.9; 95% CI, 5.7-28.1) and gallbladder disease for men (PR, 21.1; 95% CI, 4.1-84.2) and women (PR, 5.2; 95% CI, 2.9-8.9). Prevalence ratios generally were greater in younger than in older adults. The prevalence of having 2 or more health conditions increased with weight status category across all racial and ethnic subgroups. CONCLUSIONS: Based on these results, more than half of all US adults are considered overweight or obese. The prevalence of obesity-related comorbidities emphasizes the need for concerted efforts to prevent and treat obesity rather than just its associated comorbidities.

Adult↗
PubMed1999

Randomized trial of treatment with cisplatin and interleukin-2 either alone or in combination with interferon-alpha-2a in patients with metastatic melanoma: a Federation Nationale des Centres de Lutte Contre le Cancer Multicenter, parallel study.

BACKGROUND: The objective of the current study was to evaluate the response rate, survival, and toxicity of treatment with cisplatin and high dose intravenous continuous infusion interleukin-2 (IL-2) with or without interferon-alpha-2a (IFN) in patients with metastatic melanoma. METHODS: One hundred and seventeen patients with metastatic melanoma randomly were assigned to receive cisplatin, 100 mg/m2, followed after a 3-day rest period by IL-2, 18 x 10(6) IU/m2, on Days 3-6 and Days 17-21 (Arm 1) or cisplatin and IL-2 using an identical schedule plus subcutaneous IFN, 9 x 10(6) U, 3 times a week during IL-2 administration (Arm 2). In the absence of disease progression or undue toxicity, the cycle could be repeated on Day 29. Patients who responded after two cycles eventually could receive a third cycle. One hundred and one patients were evaluable for toxicity and efficacy. RESULTS: On treatment Arm 1, 3 patients (6%) achieved a complete response (CR) and 5 patients (10%) achieved a partial response (PR) with a median response duration of 3.8 months for the CRs and 8.7 months for the PRs. On treatment Arm 2, 2 patients (3%) achieved a CR (durations of 5.9 and 33.1 months, respectively) and 11 patients (21%) a PR with a median response duration of 8.3 months. The median durations of overall survival were 10.4 months (range, 1.1-39.7+ months) and 10.9 months (range, 0.5-38.1+ months) for treatment Arms 1 and 2, respectively. The toxicity profile was consistent with the known side effects of this IL-2 intravenous regimen combined with cisplatin chemotherapy and IFN. Toxicity was more pronounced in treatment Arm 2 compared with treatment Arm 1. There were 2 and 4 patients, respectively, in treatment Arms 1 and 2 who died within 28 days after completion of treatment. CONCLUSIONS: The observed overall response rates of 16% and 25% in treatment Arms 1 and 2, respectively, is lower than that expected with biochemotherapy; despite the fact that the objective of the trial was not to show any difference between the 2 treatment arms, our results indicate that the addition of IFN, at the dose and schedule used in this trial, fails to improve the activity of a cisplatin/IL-2 regimen significantly in patients with metastatic melanoma. Although response rates were relatively low, the median overall survival was nearly 1 year in both groups.

Adolescent↗
PubMed2000

Coronary stenting without predilatation (SWOP): applicable technique in everyday practice.

To evaluate the feasibility of stenting without predilatation, we registered all interventional procedures over a 6-month period. Six hundred patients were registered, and 684 lesions were treated. Interventions were divided into four groups: stenting without predilatation (SWOP), 221 lesions (32.4%); primary stenting with predilatation (PDS), 161 lesions (23.5%); provisional stenting (PRS), 131 lesions (19.2%); and plain-old balloon angioplasty (POBA), 171 lesions (25%). Interventional strategy was at the discretion of the operator based on few simple angiographic criteria and his clinical judgment. Procedural success was similar in all stent groups. We conclude that when primary stenting is planned, about 60% of lesions can be treated by SWOP effectively with excellent procedural results and considerable cost saving.

Adult↗
PubMed2000

Ovarian steroid action in the serotonin neural system of macaques.

The serotonin neural system plays an important role in cognitive, emotional and endocrine processes. If the ovarian hormones, oestrogen and progesterone, alter serotonin neural transmission, then functional changes in all of these systems would follow. Therefore, information on the effects of oestrogen and progesterone at a molecular level in the serotonin neural system was sought using non-human primates. Serotonin neurons express nuclear oestrogen receptor beta (ER beta) and progesterone receptors (PRs) which are gene transcription factors. Within serotonin neurons, the regulation of three genes related to serotonin neurotransmission was examined. The mRNA for tryptophan hydroxylase (TPH), the committal enzyme in serotonin synthesis, increased significantly with oestrogen treatment and remained elevated when progesterone was added to the oestrogen regimen. Serotonin reuptake transporter (SERT) mRNA decreased significantly with oestrogen treatment and addition of progesterone had no further effect. 5-HT1A autoreceptor mRNA decreased significantly with oestrogen treatment and addition of progesterone caused a further decrease. Little or no regulation of postsynaptic 5-HT1A, 5-HT2A or 5-HT2C receptor mRNAs was observed in hypothalamic target neurons. TPH protein is increased by oestrogen treatment and remains elevated with addition of progesterone in a manner similar to TPH mRNA. Medroxyprogesterone (MPA) blocked the stimulatory effect of oestrogen on TPH protein and tamoxifen reduced TPH protein levels below that observed in spayed monkeys. Together these data indicate that ovarian hormones and their synthetic analogues could modify cognitive and autonomic neural functions by acting on the serotonin neural pathway.

Animals↗
PubMed2001

Oral combination chemotherapy in conjunction with filgrastim (G-CSF) in the treatment of AIDS-related non-Hodgkin's lymphoma: evaluation of the role of G-CSF; quality-of-life analysis and long-term follow-up.

In 1993 we reported the efficacy and toxicity profile of an oral combination regimen administered to 18 patients with AIDS-related lymphoma (NHL-1 study). We observed a 61% response rate; 39% one-year survival rate; nearly two-thirds of patients developed > or = grade 3 leukopenia; and 28% of cycles were associated with febrile neutropenia. These results prompted us to shorten the duration of therapy and to add G-CSF to ameliorate the myelosuppression. Twenty patients with biopsy-proven AIDS-related lymphoma were treated with three 6-week cycles of oral chemotherapy consisting of lomustine (CCNU) 100 mg/m2 on day 1, cycles no. 1 and 3; etoposide 200 mg/m2 days 1-3; cyclophosphamide and procarbazine both 100 mg/m2 days 22-31; and G-CSF 5 microg/kg subcutaneously days 5-21 and days 33-42 (NHL-2 study). The following analyses were undertaken: (1) evaluation of toxicity and efficacy parameters for patients in the current (NHL-2) study; (2) analysis of the clinical role of G-CSF by (historical) comparison with the NHL-1 study of the same regimen without G-CSF; (3) quality-of-life assessments using the Functional Living Index-Cancer (FLIC) and Brief Symptom Inventory (BSI) instruments for all 38 patients (NHL-1+2); and (4) long-term follow-up for all 38 patients. In the current study the overall objective response using ECOG criteria was 70% (95% CI, 50-90%) with 6 CRs (30%) and 8 PRs (40%). The median survival duration was 7.3 months (range: 0.5-51+ months). One patient developed CNS relapse. There were no significant differences with respect to demographics or prognostic factors between the patient populations of the NHL-1 study and the current study (P > 0.2 for each factor). Myelosuppression was the major toxicity in both studies. In the current study versus the NHL-1 study, although the lower incidences of grade 3/4 myelosuppression (51% vs. 64%) and febrile neutropenia (17% vs. 28%) on a per cycle basis were not statistically significant, fewer patients (40% vs. 60%) were affected. However, the severity of myelotoxicity was lessened with the addition of G-CSF, measured in terms of the discontinuation of therapy, myelotoxic deaths, and freedom from grade 3/4 myelotoxicity ( P < 0.02). The number of hospitalizations for febrile neutropenia (7 in the NHL-2 study vs. 13 in the NHL-1 study) was also significantly different (P < 0.05). Quality-of-life analysis confirmed no significant functional or psychological deterioration during therapy except for patients experiencing febrile neutropenia, whose functional capacity deteriorated (P < 0.04). The 1-year, 18-month, and 2-year survival rates for the combined studies (38 patients) were 32%, 21%, and 13%, respectively. At time of death 49% of patients were free from progression of their lymphoma. Administration of the oral regimen has resulted in 13% of patients surviving two years, and half of patients surviving free from progression of their lymphoma. This regimen is efficacious and considerate of patient quality-of-life issues. The addition of G-CSF to the regimen decreases the frequency of hospitalization for febrile neutropenia.

Adult↗
PubMed2000

Estrogen-regulated progestin receptors are found in the midbrain raphe but not hippocampus of estrogen receptor alpha (ER alpha) gene-disrupted mice.

Estrogen and progesterone may modulate serotonergic function through intracellular receptors, alpha (ER alpha) and/or beta (ER beta), and the progestin receptor (PR). Studies in macaque and rat suggest species differences in steroid action. Presently, we examined the mouse. To identify whether ER alpha is involved in estrogen induction of PR in midbrain raphe, we studied the ER alpha gene-disrupted (alpha ERKO) mouse. The hippocampus was examined as another estrogen/progestin-sensitive brain area reported to express ER alpha, ER beta, and PR. Female and male homozygous alpha ERKO and wildtype mice were gonadectomized and given estradiol benzoate or vehicle. Dual-label immunocytochemistry was performed for PR or ER alpha and the serotonin-synthesizing enzyme, tryptophan hydroxylase (TPH). Cells exhibiting PR immunoreactivity (PR-ir) or ER alpha-ir were observed in dorsal and median raphe and hippocampus in both sexes. No ER alpha-ir cells were observed in alpha ERKO brains. In raphe, PR-ir or ER alpha-ir often colocalized with TPH-ir. Thus, estrogen and progesterone may directly modulate gene expression in select serotonergic neurons via ER alpha and PR in female and male mice. Estrogen significantly increased the number of PR-ir cells, and the percentage of PR-ir cells colocalizing TPH-ir in both raphe nuclei, regardless of sex and genotype. Although less among alpha ERKO mice, the significant estrogen induction of PRs implicates the involvement of another ER, perhaps ER beta. In hippocampus, distinct estrogen-induced PR-ir cells were observed only in wildtype animals, demonstrating an ER alpha-mediated event in this forebrain region. Collectively, these findings suggest that estrogen can regulate the expression of one gene (the PR) via multiple mechanisms, based upon brain region.

Animals↗
PubMed1980

Comparison of sex steroid receptor analyses and carcinoembryonic antigen with clinical response to hormone therapy.

This study corroborates previous reports which suggested the efficacy of estrogen receptor (ER) analysis in predicting responses of patients with metastatic mammary carcinoma to hormonal therapeutic manipulation. The predictive value of multiconcentration titration and sucrose density gradient analyses of ERs and progesterone receptors (PRs) are compared. The predictive value of ER analyses can be improved by the discrimination of 8S versus 4S binding species or by the use of PR analysis in combination with ER analysis. The tumor-associated antigen, carcinoembryonic antigen (CEA), is evolving as an important quantitative aid in evaluating the clinical responses to patients receiving hormonal therapy.

Adrenalectomy↗
PubMed1981

VAB-4 combination chemotherapy in the treatment of metastatic testis tumors.

Forty-two patients with advanced testis carcinoma without previous chemotherapy were treated with VAB-4, and 41 were evaluable. The program consisted of three in-hospital inductions 16 weeks apart, and outpatient treatments every three weeks. Of the patients, 80% achieved complete remissions (CR). Chemotherapy alone induced CR in 61%, partial remissions (PR), in 24% and minor response (MR), in 15%. An additional 20% of patients (six PRs and 2 MRs) achieved CR following resection of residual tumor deposits. With a median follow-up of 27 months, the median duration of CR has not been reached. Of those achieving CR to chemotherapy alone, 12% had relapses. Bulk and extent of metastatic disease, histology of primary tumor, and tumor markers at the beginning of therapy influenced the frequency of CR. Of those with minimal disease, 90% achieved CR. The CR rate was 67% for those with advanced thoracic disease and 29% for those with advanced abdominal disease. Patients who had embryonal carcinoma and those who had no elevation of alpha-fetoprotein had a higher frequency of CRs. Myelosuppression with a leukocyte count drop less than 1000/mm3 occurred in three patients, and no patient had chronic renal failure or pulmonary fibrosis. One patient died from sepsis while in complete remission.

Adolescent↗
PubMed1982

Nodular histiocytic lymphoma: factors influencing prognosis and implications for aggressive chemotherapy.

Twenty-five patients with Stage III and IV nodular histiocytic lymphoma (NH), entered on three different Eastern Cooperative Oncology Group protocols from 1972-78, were analyzed for response and survival. A complete response (CR) rate of 44% was observed, with 40% partial responders (PR). Four of the 11 CRs are continuing in their original remission. Median survival for CRs was 52 months; for PRs it was 30 months. The six patients treated with cyclophosphamide-prednisone had a median survival of 18 months versus 51 months for the 19 patients treated with more aggressive combination chemotherapy programs. No significant difference in survival was noted between those patients with both nodular and diffuse histology and those with a pure nodular pattern. The median survival of the 25 NH patients was 47 months and is similar to a group of 101 patients with nodular mixed lymphoma (NM) entered on the same ECOG protocols during this time. This survival is intermediate between the nodular lymphocytic poorly differentiated subtype and diffuse histiocytic lymphoma. It suggests that patients with NH histologies be treated with aggressive combination chemotherapy programs designed to achieve complete remission and prolonged disease-free survival.

Antineoplastic Agents↗
PubMed1984

A phase II trial of teniposide (VM 26) in advanced non-Hodgkin's lymphoma, with emphasis on the treatment of elderly patients.

Fifty-four patients entered a phase II trial of teniposide (VM 26) in Stage III (35 patients) and stage IV (19 patients) non-Hodgkin's lymphoma (NHL) classified according to modified Rappaport system. The median age was 71 years (range, 19-85). Thirty-two patients were previously treated at least with combination chemotherapy and radiotherapy, whereas 22 were elderly (range, 70-85 years) untreated patients with a median Karnofsky score of 70. VM 26 was given by IV infusion at 100 mg/m2 weekly for at least 3 doses in "unfavorable" histologic subtypes, and for at least 6 to 9 doses in "favorable" subtypes, prior to the evaluation of response. The overall objective response rate was 43% in the 51 evaluable patients. The median duration of the 12 complete responses (CRs) was 7+ months (26+ to 2). According to the histology, VM 26 was very effective in the six patients with diffuse "histiocytic" (DH) subtype (four CRs, one partial response [PR]), and in the 8 patients with mycosis fungoides (MF) (two CRs, two PRs). Diffuse lymphocytic poorly differentiated and lymphoblastic NHL were less sensitive subtypes to VM 26. Among the 20 evaluable elderly patients a 50% objective response rate was obtained with five CRs. Four CRs and one PR were obtained in the five patients with DH subtype; no response was obtained in the only patient with MF. Toxicity, usually hematologic, was mild, even in elderly patients; neurotoxicity occurred in four instances. VM 26 seemed to be an effective and well-tolerated drug in advanced NHL; this drug should be further evaluated as first line chemotherapy in elderly (greater than or equal to 70 years) previously untreated patients with poor general conditions and DH histology.

Adult↗