Confrontation, passion, and personalization. Emil J. Freireich.
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
E Frei
Publications and source records attributed to E Frei.
Metabolism of carcinogenic N-nitroso-N-methylaniline by purified cytochromes P450 2B1 and P450 2B2.
N-Nitroso-N-methylaniline (NMA) is an esophageal carcinogen in the rat. The in vitro enzymatic metabolism of NMA was investigated using cytochromes P450 2B1 and P450 2B2, isolated from liver microsomes of rats pretreated with phenobarbital (PB), reconstituted with NADPH-cytochrome P450 reductase and dilauroylphosphatidylcholine. Formaldehyde is produced by both cytochromes P450 (P450). NMA is a better substrate for P450 2B1 than for P450 2B2. The maximal velocity (Vmax) values are 3.3 and 1.6 nmol HCHO/min per nmol P450 for P450 2B1 and P450 2B2, respectively. Beside formation of formaldehyde, aniline and p-aminophenol (p-AP) are found to be metabolites formed from NMA by both P450 isoenzymes. P450 2B1 also affords phenol, while none was found with the P450 2B2 isoenzyme. Phenol formation presumably arose from direct alpha-C-hydroxylation of NMA via a benzenediazonium ion (BDI) intermediate. The results suggest strongly that P450 2B1 catalyzes both alpha-C-hydroxylation and denitrosation of NMA while P450 2B2 catalyzes only denitrosation. Therefore, the P450 2B1 isoenzyme participates in the activation of NMA to the ultimate carcinogenic BDI.
Aniline Compounds↗
Cross-reactivity of T cell lines and clones to beta-lactam antibiotics.
To clarify on a molecular level the specific T cell response to haptens like penicillin G, we generated T cell lines and clones from penicillin-allergic patients. Two types of beta-lactam reactivity of T cells could be delineated: one group of patients showed a rather restricted specificity, as the penicillin-elicited T cell lines generated from such donors proliferated only to the stimulating penicillin, but not to other beta-lactam antibiotics nor to cephalosporines, even if the side chain was identical. This indicates that the penicilloyl structure together with the side chain was recognized by these T cells. The second group comprised patients with more broadly reactive T cells, as they were restimulated by penicillin G as well as by related penicillins like amoxicillin or ampicillin, but not cephalosporines. This indicates that the penicilloyl structure, a common motif of penicillins, was important for T cell recognition. Clones generated from a broadly reactive patient confirmed this heterogeneity, as either monospecific or broadly specific T cell clones could be identified. This broad or very restricted pattern of T cell reactivity was reflected in the use of TCR Vbeta-chains: while the broadly reactive T cell lines showed a heterogenous TCR usage, the highly restricted T cell lines showed an up-regulation of one TCR Vbeta-chain. Thus, our data suggest that the outgrowth of T cells bearing a certain TCR Vbeta may be a sign of a limited cross-reactivity.
Anti-Bacterial Agents↗
High-dose therapy/stem cell support: comparison of mice and humans.
A murine high-dose therapy/stem cell support model is described using female BALB/c mice bearing the EMT-6 mammary carcinoma. Peripheral blood cells were prepared in syngeneic donor animals mobilized by treatment with cyclophosphamide and rhG-CSF. The most effective support regimen includes administration of fluid by gavage, rhG-CSF twice per day for 12 days and peripheral blood cells administered i.v. on the day after cytotoxic therapy. Dose escalations of 2.2- to 13-fold over the usual conventional dose were possible in mice treated with single doses of cyclophosphamide, carmustine, melphalan, thiotepa, carboplatin or total body radiation, which compare favorably with dose escalations achievable in humans. Depletion and recovery rates of white blood cells and granulocytes in the mice were similar to those seen in humans. Rapid weight loss is a major factor in limiting further dose escalation. Single high-dose therapy with cyclophosphamide, melphalan, thiotepa and carboplatin, but not 5-fluorouracil, produced longer tumor growth delays than standard regimens of the same drugs. For melphalan and thiotepa, there was a direct correlation between drug dose, tumor growth delay and tumor surviving fraction. With cyclophosphamide, the tumor growth delay with high-dose therapy was greater than expected from the dose increase and the tumor surviving fraction data.
Animals↗
Controlled multicenter trial of laparoscopic transabdominal preperitoneal hernioplasty vs Shouldice herniorrhaphy. Early results.
BACKGROUND: In February 1993 a prospective randomized multicenter trial was initiated to compare laparoscopic transabdominal preperitoneal hernioplasty to Shouldice herniorrhaphy as performed by surgeons of nonspecialized clinics. METHODS: Until January 1994, 87 patients with 108 hernias took part in the trial (43 Shouldice and 44 laparoscopic repairs). RESULTS: The laparoscopic procedure took significantly longer than did the open operation but caused less pain as measured by pain analogue score and consumption of paracetamol and narcotics. The postoperative complication rate was 26% in the open and 16% in the laparoscopic group. The patients in the laparoscopic group were discharged earlier and their convalescence was shorter than after open hernia repair. There has been one early recurrence in the laparoscopic and two in the open group to date with a mean follow-up of 201 days. CONCLUSIONS: Laparoscopic hernia repair causes less pain than the conventional operation and enables the patient to return to full work and usual activities earlier. The recurrence rate will not be known for 5 years.
Abdomen↗
Postlabeling detection of DNA adducts of antitumor alkylating agents.
The sensitivity for DNA adduct formation by antitumor alkylating agents (mechlorethamine, cisplatin and adozelesin) of the postlabeling technique and thin-layer chromatography was studied. Three DNAs were used: a double-stranded 20-bp oligonucleotide of defined sequence, calf thymus DNA and murine leukemia L1210 cellular DNA. With high concentrations of mechlorethamine, there was a marked decrease in normal dGp, a lesser decrease in dAp and dCp and no change in dTp. Using 2D mapping PEI-cellulose thin-layer chromatography analyses, it was found that six mechlorethamine: DNA adducts were produced after a short exposure to mechlorethamine. After an extended time at relatively high drug concentrations there was an alteration in the mechlorethamine: DNA adduct pattern that may reflect the conversion of monoadducts to crosslinked adducts. Similar observations were made with cisplatin and adozelesin. When murine leukemia L1210 cells were treated with 50 microM mechlorethamine or 50 microM cisplatin for 1 h, six or more mechlorethamine: DNA adducts and five cisplatin: DNA adducts were detected. After allowing 6 h. for repair of potentially lethal damage, several adducts were no longer detectable and others appeared with diminished intensity. Nuclease P(1) dephosphorylates normal nucleotides at relatively low enzyme concentrations with variation depending upon the nucleotide. In general, considerably lower concentrations of nuclease P1 were required to dephosphorylate the normal nucleotides than to dephosphorylate the antitumor alkylating agent: nucleotide adducts, thus allowing increased sensitivity of the postlabeling assay. The sensitivity of detection of antitumor alkylating agent: DNA adducts in DNA from treated L1210 cells approached one adduct per 10(7)-10(8) nucleotides. These results suggest that the postlabeling technique may be sufficiently sensitive and specific for the study of the clinically effective levels of antitumor alkylating agents.
Animals↗
Re-isolated extra sex combs (esc) gene of Drosophila.
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Animals↗
Inhibition of syncytia-inducing (SI) virus by autologous serum from HIV-1-infected individuals.
BACKGROUND: Progression from HIV infection to AIDS is often accompanied or even predicted by a switch of the virus to a more pathogenic or syncytia-inducing (SI) phenotype concomitant with the development of HIV variants escaping neutralizing antibodies. OBJECTIVE: Here we studied the capacity of sera to neutralize autologous SI-HIV or the laboratory strain III(B) and compared these data to the viral load in HIV-1-infected patients. METHODS: The SI phenotype of HIV was detected by co-cultivation of peripheral blood mononuclear cells (PBMCs) with MT2 cells in 112 patients stratified by their CD4 cell counts. Sera at dilutions of 1 : 15 and 1 : 75 were added to MT2 co-cultures with autologous PBMCs as well as with HIV-1/IIIB-infected H9 cells to study the inhibitory capacity. The p24 antigenemia was detected by enzyme-linked immunosorbent assay (ELISA) and the circulating HIV RNA was determined using the polymerase chain reaction (PCR). RESULTS: The SI virus was detected in PBMCs from 31/65 patients with < or = 200 CD4+ cells, 8/28 patients with 201-499 CD4+ cells, and 1/19 patients with > or = 500 CD4+ cells. Sera from 16/40 patients inhibited the autologous SI-HIV. In sera from patients with < or = 200 CD4+ cells, p24 antigen could be detected in 17/34 (50%) patients with non-syncytia-inducing (NSI) phenotype and in 7/19 (37%) patients carrying SI-HIV without serum inhibition. In contrast, all 12 sera with inhibitory activity to the autologous SI-HIV were negative for p24 antigen. A similar tendency was seen in patients with higher CD4+ T-cell counts. The mean load of circulating HIV RNA did not differ among groups of patients. Independently of their neutralizing activity to the autologous SI virus, the majority of sera were able to neutralize the laboratory HIV-1/III(B). CONCLUSIONS: While most of the patients' sera neutralized the laboratory HIV-1/III(B) strain, only some sera were able to inhibit the autologous SI-HIV. In these cases, the detectable SI-HIV may still be controlled by the immune system in vivo, which is consistent with a low p24 antigenemia.
Journal Article↗
Time course of methotrexate polyglutamate formation and degradation in the pre-B-leukaemia cell line Nalm6 and in lymphoblasts from children with leukaemia.
With the aim of investigation, the mechanisms of resistance to methotrexate (MTX) in children refractory to leukaemia-treatment, we established a method of analysing MTX metabolism in Nalm6 cells (human pre-B). The optimal extracellular concentration for MTX uptake and MTX polyglutamate (MTXPG2-6) formation at a density of 5 x 10(6) cells/ml was 1 microM 3H-MTX. After 15 h incubation at this concentration, a plateau of 5 pmol/10(6) cells of total MTX accumulated in the form of equal amounts of polyglutamates 3, 4 and 5 and low amounts of MTX and polyglutamates 2 and 6. MTX preloaded cells rapidly lost MTX and MTXPG2 in MTX-free medium, while MTXPG5 was still formed and then degraded very slowly. After 8 h in medium without MTX, 40% of total MTXPG was lost, after 24 h, 70%. The method is feasible for patient blasts. The number of blasts isolated from bone marrow after diagnosis is enough to perform small kinetic studies. The uptake of MTX into patient blasts is about 1/10 of that in Nalm6 cells.
Antimetabolites, Antineoplastic↗
The impact of regulations, tradition, and experimental design on clinical cancer trials: report and recommendations resulting from Washington Cancer Trials Conference.
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Antineoplastic Agents↗
Colorectal intussusception: an unusual gastrointestinal complication of hereditary angioedema.
A 21-year-old man with a history of hereditary angioedema presented with protracted abdominal pain which failed to respond to infusion of C1 inhibitor concentrate. Evaluation by CT scan revealed extensive colorectal intussusception requiring surgical intervention. Under replacement therapy with C1 inhibitor concentrate, both the operation under general anesthesia and the postoperative phase were uneventful. The intraoperative examination suggested initiation of intussusception by local mucosal edema in the transverse colon.
Adult↗
Double dose-intensive chemotherapy with autologous stem-cell support for metastatic breast cancer: no improvement in progression-free survival by the sequence of high-dose melphalan followed by cyclophosphamide, thiotepa, and carboplatin.
PURPOSE: Twenty-one percent of responding metastatic breast cancer patients remain progression-free a median 50 months following one intensification cycle of cyclophosphamide (6,000 mg/m2), thiotepa (500 mg/ m2), and carboplatin (800 mg/m2) (CTCb) with autologous bone marrow transplantation (ABMT). This trial studied whether the sequence of high-dose melphalan followed by CTCb resulted in improved disease response and duration. METHODS: Women with at least partial responses (PRS) to induction received melphalan (140 or 180 mg/ m2) with peripheral-blood progenitor cell (PBPC) and granulocyte colony-stimulating factor (G-CSF) support. They were monitored as outpatients. After recovery, patients were hospitalized for CTCb with marrow, PBPC, and G-CSF support. RESULTS: Data on 67 women, at a median of 25 months from CTCb, were examined. After melphalan, 49 (73%) required admission for fever (89%), mucositis (35%), or infection (15%) (median stay, 8 days). All received CTCb. For the first 33 patients, the median days from start of melphalan to CTCb was 24. After liver toxicity (one death from venoocclusive disease [VOD]) developed in 11 patients during CTCb, the interval between intensifications was increased to 35 days without incident. Twenty-three patients (34%) are progression-free a median of 16 months post-CTCb. The median progression-free survival (PFS) and survival times for the whole group are estimated at 11 and 20 months, respectively. CONCLUSION: Treatment with this sequence of high-dose melphalan followed by CTCb has not resulted in superior PFS to date, when compared with single-intensification CTCb. This report discusses factors related to patient selection, the role of induced drug resistance, and the schedule of administration of alkylating agenting that may adversely influence outcome.
Adolescent↗
Taiwanese-German workshop on tumour prevention.
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Apoptosis↗
[Technique and results of laparoscopic rectum resection].
The general principles of oncologic operations for colorectal cancer are the same for both open and laparoscopic surgery. Isolation of the tumor by occlusion of the intestinal lumen, early blockage of venous outflow, complete resection of the lymph node bearing mesenterium, high ligation of the artery and prevention of tumor cell dissemination during extirpation of the specimen are the most important factors. We present our technique for laparoscopic abdominoperineal resection, which fulfills the above mentioned criteria. From June 1993 to October 1994 we operated on 19 patients (median age 68 [47-91] years; male/female ratio 10/9). Laparoscopic abdominoperineal resection of the rectum was palliative in 3 patients and curative in 16. Tumors were located 3 (1-8) cm from the anal verge. In 3 patients the operation was converted to open surgery. Intraoperative complications were encountered in 3 patients. Median operation time was 300 (200-400) minutes and postoperative morbidity 8/19 (42%) leading to reoperation in one patient. 30-day mortality was nil. Three patients died 5, 8, and 14 months postoperatively due to metastatic disease (all 3 after initial palliation). One patient had local recurrence and liver metastasis and died 14 months after operation. Another patient died from liver metastases. In one patient a single liver metastasis was successfully removed. 14 patients were tumor-free after a median follow-up of 10 (3-14) months. There was no implantation metastasis on a trocar site. Laparoscopic abdominoperineal resection of the rectum is feasible and the results are comparable with those of open surgery. Local recurrence rate and incidence of liver metastases are comparable with open surgery after this short follow-up. However, 5-year survival is needed to judge the oncological radicality of laparoscopic abdominoperineal resection of the rectum.
Adenocarcinoma↗
Laparoscopic management of nonparasitic symptom-producing solitary hepatic cysts.
BACKGROUND: In 1991, the first laparoscopic treatment of a nonparasitic solitary hepatic cyst was published. We now report a series of eight cases and describe a standardized minimally invasive technique. STUDY DESIGN: Between October 1992 and December 1995, eight patients underwent laparoscopic surgical treatment for nonparasitic solitary hepatic cysts. Patients with polycystic hepatic disease were not included in our study. RESULTS: Cyst diameters varied from 12 to 15 cm. The mean operation time was 114 minutes, and the mean postoperative hospital stay was 8.5 days. There was no morbidity or mortality. During the mean follow-up time of 12.6 months, one asymptomatic recurrence was noted. CONCLUSIONS: The treatment of choice for solitary hepatic cysts that produce symptoms is laparoscopic fenestration and wide resection (deroofing) of the external part of the cyst followed by the transposition of an omental flap into the remaining cyst cavity to prevent recurrences. Laparoscopic deroofing of solitary hepatic cysts is a safe and effective procedure. This technique allows ample access for surgical treatment of solitary cysts in segments II, III, IVb, V, and VIII of the liver; however, the posterior segments, VI and VII, and segment IVa are difficult to approach laparoscopically. Hemorrhage and bile leakage can be controlled by applying a running suture to the resection margin. A cholecystectomy should be performed if gallstones are present or if the cyst is located in the right hepatic lobe adjacent to the gallbladder wall.
Aged↗
Cytochromes P450 2B1 and P450 2B2 demethylate N-nitrosodimethylamine and N-nitrosomethylaniline in vitro.
The demethylation of carcinogenic N-nitrosodimethylamine (NDMA) and N-nitrosomethylaniline (NMA) is catalyzed by purified rat liver cytochromes P450 2B1 and 2B2 reconstituted with NADPH-P450 reductase and dilauroylphosphatidylcholine. A molar P450 to reductase ratio of about 1.0 is the most appropriate for the catalysis. NMA is a better substrate for both P450 enzymes than NDMA, with K(m) values of 0.34 and 0.43 mmol/l for P450 2B1 and P450 2B2, respectively. For NDMA as the substrate, the K(m) values were approx. ten times higher than those for NMA. With each isoenzyme only one K(m) for NDMA or NMA was observed, whereas with liver microsomes of PB-pretreated rats, multiple K(m) values were obtained. The results strongly suggest that both P450 isoenzymes can be involved in the metabolism of nitrosamines.
Animals↗
The Polycomb-group gene, extra sex combs, encodes a nuclear member of the WD-40 repeat family.
We have delimited the extra sex combs (esc) gene to < 4 kb that include a single transcript and are able to rescue both the maternal and zygotic esc phenotypes. Several mutations have been identified within the esc transcript. In agreement with earlier genetic studies, esc is expressed maternally and its product is most abundant during the early embryonic stages. It encodes a protein of the WD-40 repeat family, which localizes predominantly to the nucleus. During germ band extension, it is expressed in a stereotypic pattern of neuroblasts. We propose a model in which Esc is recruited by gap proteins both to act as a corepressor that competes with the TAFII80 coactivator to block transcription and also to mediate the transition to permanent repression by Polycomb-group proteins.
Amino Acid Sequence↗
[Early results of the initial 100 laparoscopic hernia operations under peridural anesthesia].
From November 1992 to March 1994 we performed 100 transabdominal laparoscopic herniographies in 84 patients. The mean age was 54.6 years. 83% of all hernias were primary, 17% recurrent and 16% bilateral. All hernias were classified according to Nyhus and individually repaired. Except in type 2 hernias, a large polypropylene mesh was inserted (15 x 12 cm) and the peritoneum closed with a running suture. During a mean follow-up time of 14 months no recurrent hernias, infections or bowel adhesions were observed. The mean postoperative hospital stay was 4.1 days and the mean time off work 16.4 days. Intraoperative complications were found in 11.9%, early postoperative complications in 25% and late postoperative complications in 3.6%.
Adult↗