Biomedical subjects

E Frei

Publications and source records attributed to E Frei.

At least 37 records · Page 2Linked to original sources

PubMed2000

Comparative analysis of methotrexate polyglutamates in lymphoblast preparations from bone marrow and blood, and the contribution of residual red blood cells.

PURPOSE: Blasts isolated from bone marrow aspirates or blood samples of patients with acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) were compared for uptake of methotrexate (MTX) and formation of MTX polyglutamates (MTX-Glu(n)). Red blood cells (RBC) from the same patient samples were also analyzed. METHODS: Blasts were isolated by standard density centrifugation. RBC were prepared from the pellet of the same centrifugation. MTX-Glu(n) were analyzed by means of HPLC and radiochemical quantification. RESULTS: In lymphoblasts isolated from blood, the distribution patterns of MTX-Glu(n) were the same as in bone marrow lymphoblasts, but the total amount of MTX-Glu(n) accumulated in blood lymphoblasts was reduced by 41% 51% when compared to the same number of bone marrow lymphoblasts of the same patient. RBC accumulated MTX but no formation of MTX-Glu(n) occurred. CONCLUSIONS: The determination of MTX and MTX-Glu(n) in lymphoblasts isolated from blood samples of patients with common ALL provides qualitative information on the capacity of the blasts to form MTX-Glu(n) since distribution patterns of MTX and MTX-Glu(n) parallel that of bone marrow lymphoblasts. The amounts of MTX-Glu(n) accumulated, however, were much lower in blood lymphoblasts. Blood lymphoblasts are therefore not useful for a quantitative analysis of MTX-Glu(n). The contribution of RBC to MTX and MTX-Glu(n) in vitro is only marginal and residual RBC in lymphoblast preparations from bone marrow can therefore be ignored.

Adolescent↗

PubMed2000

Double high-dose chemotherapy with stem cell rescue (HD-SCR) in patients with breast cancer - effect of sequence.

INTRODUCTION: A preliminary analysis of our double high-dose chemotherapy with stem cell rescue (HD-SCR) clinical trial for breast cancer, and preclinical cross-resistant studies, suggested that melphalan (M) adversely affected response to subsequent chemotherapy, i.e., that the sequence of alkylating agents (AAs) might affect response. We, therefore, constructed and examined preclinical models to determine whether prior exposure to M, in fact, adversely affected response to other therapy. PURPOSE: The purpose of the study was to determine whether the sequence of AAs, specifically the prior use of M, adversely affected response to subsequent treatment. METHODS: The methods employed were the following: (1) Human tumor cell lines rendered resistant by in vitro sequential exposure to five different AAs were developed. The resistant cell lines were examined for cross-resistance to alkylating and other agents. (2) In vivo studies in the p388 mouse leukemia for resistance and cross-resistance among the AAs. (3) In vivo studies of the effect of sequence of AAs on response in mice bearing EMT6 breast cancer. (4) The double transplant model was developed in the mouse and the sequence of high-dose AAs was studied. (5) Biochemical and reverse transcriptase-polymerase chain reaction (RT-PCR) studies of the various resistant tumor cell lines. RESULTS: (1) The in vitro human tumor cells resistant to M were cross-resistant in 57% of tests to other AAs. In contrast, resistance for other AAs crossed to other agents in only 10 to 20% of tests. (2) The in vivo studies of p388 indicated that resistance to M commonly crossed to other AAs and many non-AAs. (3) The results for the mouse breast cancer (EMT6) studies of the sequence of AAs again indicated that M employed first markedly reduced responsiveness to subsequent treatment, particularly with AAs. (4) The double transplant model: again, M first markedly reduced response to other agents. (5) The in vitro resistant human tumor cell lines, particularly the breast cancer cell line MCF7, were found to contain high concentrations of glutathione S1 transferase gamma, which is consistent with that mechanism being responsible for resistance. CONCLUSION: The sequence of alkylating agent treatment may substantially influence response. Melphalan, particularly, produces resistance that commonly crosses to the other AAs. Mechanistic studies indicate significant changes in glutathione S1 transferase, a known mechanism for broadly based resistance to AAs.

Alkylating Agents↗

PubMed2000

Oxidation of xenobiotics by plant microsomes, a reconstituted cytochrome P450 system and peroxidase: a comparative study.

The microsomal fraction from tulip bulbs (Tulipa fosteriana, L.) contains cytochrome P450 (CYP3, EC 1.14.14.1) and peroxidase (EC 1.11.1.7.) enzymes catalyzing the NADPH--and hydrogen peroxide--dependent oxidation of the xenobiotic substrates, N-nitrosodimethylamine (NDMA), N-nitrosomethylaniline (NMA), aminopyrine and 1-phenylazo 2-hydroxynaphthalene (Sudan I), respectively. Oxidation of these model xenobiotics has also been assessed in a reconstituted electron-transport chain with a partially purified CYP fraction, phospholipid and isolated tulip NADPH:CYP reductase (EC 1.6.2.4.). Peroxidase isolated from tulip bulbs (isoenzyme C) oxidizes these xenobiotics, too. Values of kinetic parameters (Km, Vmax), requirements for cofactors (NADPH, hydrogen peroxide), the effect of inhibitors and identification of products formed from the xenobiotics by the microsomal fraction, partially purified CYP and peroxidase C were determined. These data were used to estimate the participation of the CYP preparation and peroxidase C in oxidation of two out of the four studied xenobiotics (NMA, Sudan I) in tulip microsomes. Using such detailed study, we found that the CYP-dependent enzyme system is responsible for the oxidation of these xenobiotics in the microsomal fraction of tulip bulbs. The results demonstrate the progress in resolving the role of plant CYP and peroxidase enzymes in oxidation of xenobiotics.

Cytochrome P-450 Enzyme System↗

PubMed2000

Laparoscopic appendectomy in Switzerland: a prospective audit of 2, 179 cases.

BACKGROUND/AIMS: Since its introduction in 1983, laparoscopic appendectomy (LA) has not replaced the conventional open procedure. The patient benefit seems limited to a decreased wound infection rate, and the overall morbidity and mortality rates remain equal to those of open appendectomy. METHODS: The data (collected by the Swiss Association of Laparoscopic and Thoracoscopic Surgery) from 2, 179 patients undergoing LA at 84 surgical institutions in Switzerland between January 1995 and December 1997 were retrospectively analyzed. RESULTS: More than 90% of all patients had no intra- or postoperative complications. However, perforated appendicitis was associated with more complications, in particular a threefold increased wound infection rate (9.2 vs 3.5%). Furthermore, the conversion and reoperation rates of perforated appendicitis were significantly increased compared to 'simple' acute appendicitis (25. 5 and 10.4% vs 4.8 and 2.1%, respectively). LA performed with a stapling device is superior to LA performed with loops, although the difference is not significant. CONCLUSION: Therefore, LA is a safe and effective procedure. The postoperative morbidity and mortality rates are comparable to those of open appendectomy, which is still the most commonly used procedure in Switzerland. The question of whether perforated appendicitis is better treated laparoscopically or by the open procedure cannot be answered with our data.

Adolescent↗

PubMed1999

Prostaglandin H synthase-medicated oxidation and binding to DNA of a detoxication metabolite of carcinogenic Sudan I, 1-(phenylazo)-2,6-dihydroxynaphthalene.

The metabolite of the carcinogenic azo dye Sudan I, 1-(phenylazo)-2,6-dihydroxynaphthalene (6-OH-Sudan I), which is considered to be the detoxification product of this dye is metabolized by prostaglandin H synthase (PHS) in the presence of arachidonic acid or H2O2 in vitro. The apparent Michaelis constant value for 6-OH-Sudan I as a substrate is 98.9 microM. 1-(Phenylazo)-2,6-naphthoquinone is a principal product of the 6-OH-Sudan I oxidation. This oxidation is inhibited by radical scavengers nitrosobenzene, ascorbate, glutathione and NADH. This indicates that PHS metabolizes 6-OH-Sudan I through a one-electron oxidation mechanism, giving rise to free radicals. During the PHS-mediated reaction, 6-OH-Sudan I is activated to metabolites binding to protein and DNA. The 32P-postlabeling analysis of DNA modified by activated 6-OH-Sudan I provides evidence that covalent binding to DNA is the principal type of DNA modification. The PHS-mediated binding of 6-OH-Sudan I to DNA presumably proceeds through formation of 1-(phenylazo)-2,6-naphthoquinone. The results suggest strongly that the C-hydroxylated derivative of Sudan I (6-OH-Sudan I) should be evaluated as a proximate carcinogenic metabolite, which may participate in the initiation of Sudan I-carcinogenesis in the urinary bladder.

Animals↗

PubMed1999

Direct evidence for the formation of deoxyribonucleotide adducts from carcinogenic N-nitroso-N-methylaniline revealed by the 32P-postlabeling technique.

N-Nitroso-N-methylaniline (NMA) is an esophageal carcinogen in the rat. NMA forms a benzenediazonium ion (BDI) during microsomal cytochrome P-450 2B1 (CYP2B1) catalyzed metabolism. Using the nuclease P1-enhanced version of the 32P-postlabeling assay we investigated the formation of adducts by NMA with deoxyadenosine 3'-monophosphate (dAp) and deoxyguanosine 3'-monophosphate (dGp). 32P-postlabeling analysis of dAp and dGp, which were modified by NMA activated with microsomes of rats pretreated with phenobarbital (PB), and directly labeled resulted in each case in the appearance of one single adduct spot. Quantitative analysis of adducts revealed that the extent of dGp modification by activated NMA was more than 23 times greater than the extent of modification of dAp. The results suggest strongly that BDI, derived from NMA by CYP2B1 present in PB microsomes, participates in the formation of dAp and dGp adducts.

Carcinogens↗

PubMed1999

The profile of urinary metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in rats is determined by its pulmonary metabolism.

Metabolism of the tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in rats was compared to metabolism in primary lung and liver cells. Untreated rats and rats pretreated with phenobarbital, acetone or phenethyl isothiocyanate (PEITC) were used for all experiments. Also the influence of [-]-1-methyl-2-[3-pyridyl]-pyrrolidine (nicotine) administered concomitantly with NNK, or incubated with isolated cells, upon NNK metabolism was investigated and found to be only marginal upon alpha-hydroxylation and pyridine N-oxidation in vivo. In hepatocytes nicotine inhibited NNK pyridine N-oxidation, alpha-hydroxylation and glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), whereas in lung cells the influence of nicotine was not as pronounced. In vivo phenobarbital induced alpha-hydroxylation and pyridine N-oxidation. In vitro the effects of the modulators were most pronounced upon hepatocytes, where phenobarbital greatly induced pyridine N-oxidation and PEITC inhibited alpha-hydroxylation. NNAL was conjugated to its beta-glucuronide in lung cells at four times higher rates than in hepatocytes. The ratios of the sum of N-oxides to the sum of alpha-hydroxylation products in vivo were similar to those in lung cells, especially at low NNK concentrations (1 microM), while in hepatocytes alpha-hydroxylation was more pronounced. The same correlation of metabolism in isolated lung cells with whole rats was observed if oxidative NNAL metabolism was related to oxidative NNK metabolism. Here hepatocytes showed a much higher formation of NNAL oxidation products than either lung cells formed, or rats excreted in urine. This was true despite a lower rate of metabolism in the lung than in liver if based on cell number, the rate based on mg protein was four times higher in lung than liver. Only after phenobarbital treatment was the contribution of hepatic metabolism to excreted metabolites important. In conclusion the lung which is also the target of NNK carcinogenesis, and not the liver, is the organ with the most important contribution to NNK and NNAL metabolism at concentrations relevant to human exposure.

Animals↗

PubMed1999

Aristolactam I a metabolite of aristolochic acid I upon activation forms an adduct found in DNA of patients with Chinese herbs nephropathy.

Aristolochic acid (AA) a naturally occuring nephrotoxin and carcinogen is implicated in a unique type of renal fibrosis, designated Chinese herbs nephropathy (CHN). We identified AA-specific DNA adducts in kidneys and in a ureter obtained from CHN patients after renal transplantation. AA is a plant extract of aristolochia species containing AA I as the major component. Aristolactams are the principal detoxication metabolites of AA, which were detected in urine and faeces from animals and humans. They are activated by cytochrome P450 (P450) and peroxidase to form DNA adducts. Using the 32P-postlabelling assay we investigated the formation of DNA adducts by aristolactam I in these two activation systems. A combination of two independent chromatographic systems (ion-exchange chromatography TLC and reversed-phase HPLC) with reference compounds was used for the identification of adducts. Aristolactam I activated by peroxidase led to the formation of several adducts. Two major adducts were identical to adducts previously observed in vivo. 7-(deoxyguanosin-N2-yl)aristolactam I (dG-AAI) and 7-(deoxyadenosin-N6-yl)aristolactam I (dA-AAI) were formed in DNA during the peroxidase-mediated one-electron oxidation of aristolactam I. Aristolactam I activated by P450 led to one major adduct and four minor ones. Beside the principal AA-DNA adducts identified recently in the ureter of one patient with CHN, an additional minor adduct was detected, which was found to have indistinguishable chromatographic properties on TLC and HPLC from the major adduct formed from aristolactam I by P450 activation. Thus, this minor AA-adduct might be evolved from the AAI detoxication metabolite (aristolactam I) by P450 activation. These results indicate a potential carcinogenic effect of aristolactam I in humans.

Animals↗

PubMed1999

One step isolation of bovine asialoglycoprotein receptor and its characterization by sequence analysis and MALDI mass spectrometry.

The asialoglycoprotein receptor (ASGP-R), which is responsible for the uptake of partially deglycosylated serum glycoproteins was isolated from bovine liver. The receptor was purified in one step from solubilized plasma membranes by affinity chromatography on 6-(beta-D-lactosyl)-n-hexylamine coupled to N-hydroxysuccinimide activated Sepharose with a coupling degree of 7.6 micromol/ml gel. The preparation yielded two distinct polypeptides with apparent molecular weights of 48 and 43 kDa as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. A polyclonal antibody raised against the human ASGP-R recognized the bovine 43 kDa protein in Western blot analysis. The 48 and 43 kDa polypeptides were digested by trypsin and the digests were subsequently analyzed by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Sequence analysis of four tryptic fragments, two each of the 48 kDa and of the 43 kDa polypeptides revealed that these were highly homologous to ASGP-R subunits from man, mouse and rat.

Amino Acid Sequence↗

PubMed1999

The interval between courses of high-dose chemotherapy with stem cell rescue: therapeutic hypotheses.

The interval between courses of chemotherapy have classically been kept to a minimum in order to maximize dose intensity. Certain clinical observations suggest that longer intervals, particularly in the high-dose setting, may be more effective. This is based in part on the evidence that resistance is reversible over time and that the interval should be sufficient to allow for such a reversal. Clinical evidence for such reversibility include the following. In metastatic breast cancer, double or double high-dose stem cell rescue (HD-SCR) studies involving a minimal interval, have not, at least as yet, been shown to be superior to single HD-SCR. In Hodgkin's disease, response after relapse correlates directly with duration of time to relapse. In a comparative study of metastatic breast cancer, early HD-SCR preceded by daunorubicin induction was inferior to delayed HD-SCR. The latter was not preceded by induction chemotherapy. In a comparative study of childhood ALL, patients randomized to delayed (4 month interval) intensification had a significantly superior survival as compared to patients randomized to immediate (1 month interval) intensification. Taken together, these clinical observations indicate that resistance is reversible and that optimization of the interval must take this into account. Cytokinetic modeling of those clinical studies also found that delayed HD-SCR could result in a superior effect. Cytokinetic models of minimal residual tumor which were also examined included the Skipper exponential model, the Norton-Simon model which emphasizes the Gompertzian effect, the clonal evolution model, and the Retsky-Demisheli model which derives from a bimodal relapse pattern above. Biological and clinical data have resulted in a clinical protocol in the CALGB wherein patients with metastatic breast cancer are randomly allocated to (1) a single HD-SCR arm; (2) a double HD-SCR with a 5-week interval; and (3) a double HD-SCR arm with a 16 week interval.

Antineoplastic Agents↗

PubMed1999

Analysis of the inhibition of N-nitroso-dimethylamine activation in the liver by N-nitro-dimethylamine using a new non-linear statistical method.

N-nitro-dimethylamine (NTDMA) is carcinogenic to rats: it induces nasal cavity tumours. It can be demethylated to N-nitromethylamine and formaldehyde and reduced to N-nitroso-dimethylamine (NDMA): a potent liver carcinogen and also of the nasal cavity if activation in the liver is blocked. To explain the mechanism of NTDMA carcinogenicity we compared its demethylation with that of NDMA in liver microsomes from female and male rats, untreated, fasted or treated with ethanol to induce cytochrome P450 2E1 (CYP2E1). Kinetic parameters were analysed by nonlinear statistical methods, which yielded unbiased parameter estimates for the calculated Km and Vmax values. Km for both compounds was very similar in females (24-47 microM) whereas Vmax for NTDMA was consistently higher than for NDMA as substrate: 1.07-4.70 nmol formaldehyde/mg microsomal protein x min and 0.52-2.76 nmol, respectively. In liver microsomes from induced male rats NTDMA was found to be a much more effective inhibitor of NDMA activation (KEI 39.6-73.6 microM) than NDMA of NTDMA demethylation (KEI 224-286 microM). Nasal microsomes can demethylate both NDMA and NTDMA but the kinetics are vastly different. NTDMA is demethylated at a linear rate and approximately 10-fold more effectively than NDMA. The mechanism of carcinogenicity of ingested NTDMA, we propose, is a partial reduction to NDMA in the liver and inhibition of NDMA activation in the liver by residual NTDMA, which enables NDMA to reach the nasal mucosa where it is activated to DNA-alkylating species and the observed tumours are formed.

Animals↗

PubMed1999

Dose-intensive therapy for limited-stage small-cell lung cancer: long-term outcome.

PURPOSE: To determine progression-free survival (PFS) and overall long-term survival for limited-stage small-cell lung cancer (SCLC) patients aged 60 years or younger who respond to first-line chemotherapy followed by high-dose combination alkylating agents (cyclophosphamide 5,625 mg/m(2), cisplatin 165 mg/m(2), and carmustine 480 mg/m(2)) with hematologic stem-cell support and chest and prophylactic cranial radiotherapy. PATIENTS AND METHODS: Patients were selected on the basis of their continued response to first-line therapy, their relative lack of significant comorbidity, and their ability to obtain financial clearance. RESULTS: Of 36 patients with stage III SCLC, nine patients (25%) had achieved a complete response (CR), 20 had achieved a near-CR, and seven had achieved a partial response before undergoing high-dose therapy. Toxicity included three deaths (8%). For all patients, the median PFS was 21 months. The 2- and 5-year survival rates after dose intensification were 53% (95% confidence interval [CI], 39% to 72%), and 41% (95% CI, 28% to 61%). Of the 29 patients who were in or near CR before undergoing high-dose therapy, 14 remain continuously progression-free a median of 61 months (range, 40 to 139 months) after high-dose therapy. Actuarial 2- and 5-year PFS rates were 57% (95% CI, 41% to 79%) and 53% (95% CI, 38% to 76%). By multivariate analysis, short intensive induction chemotherapy was associated with favorable outcome (P <.05). CONCLUSION: Use of high-dose systemic therapy with intensive local-regional radiotherapy was associated with manageable treatment-related morbidity and mortality. Patients who were in or near CR before intensification are enjoying an unmaintained 5-year PFS rate of 53%. Late complications were infrequent, and most patients returned to full-time work and activity. A randomized comparison of this approach and conventional-dose therapy should define the use of dose intensification with hematopoietic support in patients with responding limited-stage SCLC.

Adult↗

PubMed1999

Safety and efficacy of using a single agent or a phase II agent before instituting standard combination chemotherapy in previously untreated metastatic breast cancer patients: report of a randomized study--Cancer and Leukemia Group B 8642.

PURPOSE: We undertook a prospective, randomized phase III trial to evaluate the safety and efficacy of using a phase II agent before initiating therapy with standard combination chemotherapy in metastatic breast cancer patients. PATIENTS AND METHODS: A total of 365 women with measurable metastatic breast cancer, previously untreated with chemotherapy for their metastatic disease, were randomized to receive either immediate chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) or up to four cycles of one of five sequential cohorts of single-agent drugs: trimetrexate, melphalan, amonafide, carboplatin, or elsamitrucin, followed by CAF. RESULTS: The toxicity of each single agent followed by CAF was comparable to that of CAF alone. The cumulative response rates for the single agent followed by CAF were not statistically different from those of CAF alone (44% v 52%; P = .24). However, in the multivariate analysis, patients with visceral disease had a trend toward lower response rates on the phase II agent plus CAF arm (P = .078). Although survival and response duration also were not statistically significantly different between the two study arms (P = .074 and P = .069, respectively), there was a suggestion of benefit for the CAF-only arm. CONCLUSION: The brief use of a phase II agent, regardless of its efficacy, followed by CAF resulted in response rates, toxicities, durations of response, and survival statistically equivalent to those seen with the use of CAF alone. These findings support the use of a new paradigm for the evaluation of phase II agents in the treatment of patients with metastatic breast cancer.

Adenine↗

PubMed1999

double-time is identical to discs overgrown, which is required for cell survival, proliferation and growth arrest in Drosophila imaginal discs.

We have isolated the discs overgrown gene of Drosophila and shown that it encodes a homolog of the Casein kinase I(delta)/(epsilon) subfamily and is identical to the double-time gene. However, in contrast to the weak double-time alleles, which appear to affect only the circadian rhythm, discs overgrown alleles, including bona fide null alleles, show strong effects on cell survival and growth control in imaginal discs. Analysis of their phenotypes and molecular lesions suggests that the Discs overgrown protein is a crucial component in the mechanism that links cell survival during proliferation to growth arrest in imaginal discs. This work provides the first analysis in a multicellular organism of Casein kinase I(delta)/(epsilon) functions necessary for survival. Since the amino acid sequences and three-dimensional structures of Casein kinase I(delta)/(epsilon) enzymes are highly conserved, the results suggest that these proteins may also function in controlling cell growth and survival in other organisms.

Amino Acid Sequence↗

PubMed1999

Phase I trial of methotrexate-albumin in a weekly intravenous bolus regimen in cancer patients. Phase I Study Group of the Association for Medical Oncology of the German Cancer Society.

Methotrexate-albumin conjugate (MTX-HSA) is a novel human albumin-based prodrug conjugate of methotrexate (MTX). A low MTX loading rate provided optimal tumor targeting and therapeutic efficacy during preclinical testing. The objectives of this first Phase I study of MTX-HSA were to determine dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) in a weekly regimen. Seventeen cancer patients who were no longer amenable to standard treatment were enrolled and were evaluable for DLT. Up to eight injections were performed in weekly intervals. Dose escalation was as follows: 20, 40, 50, and then 60 mg/m2 MTX-HSA (based on the amount of MTX bound to albumin). Additional MTX-HSA courses were feasible in case of tumor response. DLT (mainly stomatitis, Common Toxicity Criteria grade 3) occurred, beginning at the 50 mg/m2 dose level after repeated administrations; in one case, thrombocytopenia was dose-limiting. Two events of DLT occurred at the 60 mg/m2 dose level within the first two administrations. Mild anemia, transaminitis, and one case of skin toxicity were found. No significant leukopenia, nausea, renal toxicity, or other toxicities were observed. MTX-HSA was well tolerated. Drug accumulation occurred on the weekly schedule. The half-life of the drug was estimated to be up to 3 weeks. Tumor responses were seen in three patients: (a) a partial response was seen in one patient with renal cell carcinoma (response duration, 30 months, ongoing); (b) a minor response was seen in one patient with pleural mesothelioma (response duration, 31 months, ongoing); and (c) a minor response was seen in one patient with renal cell carcinoma (response duration, 14 months until progression). Poststudy treatment was administered at 2-4-week intervals. No signs of toxicity or drug accumulation were seen. Altered pharmacological properties of MTX-HSA such as plasma half-life, tumor targeting, or intracellular metabolism might have contributed to these responses. The MTD for weekly administration was 4 x 50 mg/m2 MTX-HSA during short-term treatment. A regimen with MTX-HSA injections of 50 mg/m2 every 2 weeks was recommended for a further clinical Phase I study.

Adolescent↗

PubMed1998

Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B.

BACKGROUND: Both total dose and dose intensity of adjuvant chemotherapy are postulated to be important variables in the outcome for patients with operable breast cancer. The Cancer and Leukemia Group B study 8541 examined the effects of adjuvant treatment using conventional-range dose and dose intensity in female patients with stage II (axillary lymph node-positive) breast cancer. METHODS: Within 6 weeks of surgery (radical mastectomy, modified radical mastectomy, or lumpectomy), 1550 patients with unilateral breast cancer were randomly assigned to one of three treatment arms: high-, moderate-, or low-dose intensity. The patients received cyclophosphamide, doxorubicin, and 5-fluorouracil on day 1 of each chemotherapy cycle, with 5-fluorouracil administration repeated on day 8. The high-dose arm had twice the dose intensity and twice the drug dose as the low-dose arm. The moderate-dose arm had two thirds the dose intensity as the high-dose arm but the same total drug dose. Disease-free survival and overall survival were primary end points of the study. RESULTS: At a median follow-up of 9 years, disease-free survival and overall survival for patients on the moderate- and high-dose arms are superior to the corresponding survival measures for patients on the low-dose arm (two-sided P<.0001 and two-sided P = .004, respectively), with no difference in disease-free or overall survival between the moderate- and the high-dose arms. At 5 years, overall survival (average +/- standard error) is 79% +/- 2% for patients on the high-dose arm, 77% +/- 2% for the patients on the moderate-dose arm, and 72% +/- 2% for patients on the low-dose arm; disease-free survival is 66% +/- 2%, 61% +/- 2%, and 56% +/- 2%, respectively. CONCLUSION: Within the conventional dose range for this chemotherapy regimen, a higher dose is associated with better disease-free survival and overall survival.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

Spilled gallstones after laparoscopic cholecystectomy. A relevant problem? A retrospective analysis of 10,174 laparoscopic cholecystectomies.

BACKGROUND: Spilled gallstones after laparoscopic cholecystectomy may cause abscess formation, but the exact extent of this problem remains unclear. METHOD: The data (collected by the Swiss Association of Laparoscopic and Thoracoscopic Surgery) on 10,174 patients undergoing laparoscopic cholecystectomy at 82 surgical institutions in Switzerland between January 1992 and April 1995 were retrospectively analyzed with special interest in spilled gallstones and their complications. RESULTS: In 581 cases (5.7%) spillage of gallstones occurred; 34 of these cases were primarily converted to an open procedure for stone retrieval. Of the remaining 547 cases only eight patients (0.08%) developed postoperatively abscess formation requiring reoperation. CONCLUSIONS: Spillage of gallstones after laparoscopic cholecystectomy is fairly common and occurs in about 6% of patients. However, abscess formation with subsequent surgical therapy remains a minor problem. Removal of spilled gallstones is therefore not recommended for all patients, but an attempt at removal should be performed whenever possible.

Adolescent↗

PubMed1998

Complications of laparoscopic cholecystectomy in Switzerland. A prospective 3-year study of 10,174 patients. Swiss Association of Laparoscopic and Thoracoscopic Surgery.

BACKGROUND: We set out to analyze the technical aspects, intraoperative complications, morbidity, and mortality of laparoscopic cholecystectomy in a multi-institutional study representative of Switzerland. METHODS: Data were collected from 10,174 patients from 82 surgical services. A total of 353 different parameters per patient were included. RESULTS: We found intraoperative complications in 34.4% of patients and had a conversion rate of 8.2%. This rate was significantly increased in patients with complicated cholelithiasis and in those with previous upper-but not lower-abdominal surgery. In most cases, conversions to open procedures were required because of technical difficulties due to inflammatory changes and/or unclear anatomical findings at the time of operation. Bleeding was a common intraoperative complication, that significantly increased the risk of conversion. Patients with loss of gallstones in the peritoneal cavity had increased rates of abscesses. The rate of common bile duct injuries was 0.31%, but it decreased significantly as the laparoscopic experience of the surgeon increased. The rate of common bile duct injuries was not increased in patients with acute cholecystitis or in the 1.32% of patients undergoing laparoscopic common bile duct exploration. Intraoperative cholangiography did not reduce the risk of common bile duct injuries, but it allowed them to be diagnosed intraoperatively in 75% of patients. Local complications were recorded in 4.79% of patients, and systemic complications were seen in 5.59%. The mortality rate was 0.2%. CONCLUSIONS: Although laparoscopic cholecystectomy is a safe procedure, the rate of conversion to open cholecystectomy is still substantial. The conversion rate depends both on the indication and intraoperative complications. There is still a 10.38% morbidity associated with the procedure; however, the incidence of common bile duct injuries, which decreases with growing laparoscopic experience, was relatively low.

Cholangiography↗