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PubMed1996

Phase II study of mitonafide in non-small cell lung cancer (NSCLC).

BACKGROUND: The new intercalative agent Mitonafide was shown in early clinical trials to be toxic to the central nervous system when administered as a short intravenous infusion, but not when given as a 120-hour continuous infusion. Thus, clinical development in different tumor types was pursued using only this administration schedule. PATIENTS AND METHODS: Forty-nine patients with previously untreated non-small cell lung cancer (NSCLC) and at least one measurable site received Mitonafide as a 120-hour continuous (5 days) infusion every 3 weeks. The starting dose was 170 mg/m2/day x 5 in the first 26 patients and 200 mg/m2/day x 5 in the remainder. Patients were evaluated for toxicity after each course and for response every two courses and remained on treatment until excessive toxicity or disease progression were observed. A special test, the "Mini-mental state", was used to assess patients' cognitive functions. RESULTS: Of the 49 patients entered, 42 were evaluable for response and toxicity. Toxicity consisted mainly of myelosuppression and no neurologic side effects were observed. Only one patient presented a partial response. CONCLUSIONS: Although definitively safe with this schedule of administration, Mitonafide is not active in NSCLC.

Adult↗
PubMed1996

Phase II study of Mitonafide in advanced and relapsed colorectal cancer.

BACKGROUND: This study investigated the antitumoral activity in colorectal cancer and toxicity of a 5-day continuous infusion of a new cytostatic agent, Mitonafide, that had previously shown to be neurotoxic when administered as a short daily x 5 days infusion. PATIENTS AND METHODS: Seventeen chemotherapy-naive patients with advanced or relapsed colorectal cancer and measurable disease entered the study. All but one received a 120-hour (5-day) continuous infusion of Mitonafide at a starting dose of 200 mg/m2/day every 3 weeks. Toxicity evaluation was performed after each course and response assessment every 2 courses using the standard World Health Organization (WHO) criteria completed by the "Mini-mental state" test for cognitive status examination. RESULTS: Sixteen patients received a total of 41 courses of Mitonafide which resulted to be severely myelotoxic. In total, 13/16 patients had WHO grade 3-4 neutropenia, 7 of them with infection, and the treatment had to be stopped in 3 patients after only 1 course due to excessive toxicity. No central nervous system toxicity was observed. No objective responses were evidenced. CONCLUSIONS: At the dose and schedule of administration used, Mitonafide is not active in colorectal cancer and induces severe myelotoxicity thus not deserving further studies in this indication.

Aged↗
PubMed1996

The role of induction (neoadjuvant) chemotherapy in stage IIIA NSCLC.

Induction (neoadjuvant) chemotherapy has become an accepted treatment for stage IIIA (T1-3N2M0) non-small cell lung cancer. In two recent randomized trials, neoadjuvant chemotherapy plus surgery gave an increase in median survival at least fivefold greater than surgery alone. The Spanish Lung Cancer Group trial of preoperative chemotherapy, in which the cisplatin dose was randomized to either 50 mg/m2 or 100 mg/m2 plus 3 g/m2 ifosfamide and 6 mg/m2 mitomycin, examines the effect of K-ras gene mutations on tumor response and survival. Patients whose tumors contain K-ras gene mutations are more likely to develop distant metastases and have lower median survival than patients without such mutations. Microsatellite instability seems to be a frequent mechanism of genetic aberrations. Knowledge about these genetic alterations could have prognostic importance and may identify the patients who should receive the most aggressive additional treatment.

Carcinoma, Non-Small-Cell Lung↗
PubMed1995

Sequential methotrexate, 5-fluorouracil (5-FU), and high dose leucovorin versus 5-FU and high dose leucovorin versus 5-FU alone for advanced colorectal cancer. A multi-institutional randomized trial.

BACKGROUND: The primary objective of this study was to compare the single-biochemical modulation of 5-fluorouracil (5-FU) and leucovorin with that of the double-biochemical modulation of methotrexate and leucovorin. Because of the Martin et al. study in which an experimental model showed similar effects of 5-FU at maximum tolerated doses to the modulation with leucovorin at standard doses, a third treatment arm of 5-FU alone was also studied. METHODS: A randomized trial was performed using a 500-mg/m2 intravenous (i.v.) 1-hour infusion of methotrexate, and 12 hours later, a 600-mg/m2 i.v. bolus of 5-FU plus a 200-mg/m2 i.v. 1-hour infusion of leucovorin (MFL) every 2 weeks versus 5-FU plus leucovorin at an equal dose and schedule (FL), versus a 1200-mg/m2 i.v. dose of 5-FU every 2 weeks. Of 186 patients included in the study, 178 were evaluable. RESULTS: In a preliminary analysis with 94 evaluable patients, two significant statistical differences were shown. First, the toxicity rate of the 5-FU--alone (F) treatment arm was higher than that of the other arms (MFL vs. F, P = 0.0002; FL vs. F, P = 0.00001). Second, the median survival was worse in the F treatment arm with a rate of 12.6 months for the MFL and FL arms and 7.5 months for the F arm (P < 0.05). Considering these results, the F treatment arm was discontinued. The final results included 70 evaluable patients for MFL and 74 patients for FL. No difference was found in the distribution of prognostic factors. The response rates were 25.7% for MFL (95% CI, 16-37.5) and 14.8% for FL (95% CI, 7.6-25), (P = 0.1). The median survival was 14.3 months for patients treated with MFL and 12.3 months for those treated with FL. The hematologic toxicity was mild, with no grade 3/4 leukopenia in either treatment arm. The major nonhematologic toxicity in the MFL and FL treatment arms was ocular; nongrade 3/4 diarrhea also was observed. CONCLUSIONS: The results of MFL double-biochemical modulation failed to show a significant statistical difference from that of single-biochemical modulation for this dose and schedule.

Adenocarcinoma↗
PubMed1995

Mutated K-ras gene analysis in a randomized trial of preoperative chemotherapy plus surgery versus surgery in stage IIIA non-small cell lung cancer.

The observation that the proteins encoded by ras genes play a central role in the signalling pathways used by cells to respond to growth factors and the fact that mutated ras proteins are constantly promoting cell division have led to a PCR-based hunt for additional clinical information. In the present study, K-ras analysis draws the following conclusions: (1) K-ras point mutation frequency was higher in the surgery group (10 of 24 patients) than in the chemotherapy-surgery group (3 of 20 patients). (2) Mutated K-ras was predominantly observed at codon 12 but five mutations appeared at codon 61. (3) Mutations were identified in the squamous cell carcinoma histological NSCLC subtype except in four cases corresponding to adenocarcinoma. (4) A multifarious pattern of substitutions, especially at codon 12, were noted with aspartic K 12 substitutions more prone to develop bone metastases. (5) Although a genotypic K-ras classification of NSCLC may not yet be formulated, our accumulated data (unpublished) suggest a trend toward it. (6) Patients with mutated K-ras tumors in the surgery group had no different survival than those with normal K-ras. However our pooled data as well as other authors' results assert that mutated K-ras constitute an additional prognostic datum that deserves to be included together with TNM classification. In the design of new preoperative (neoadjuvant) chemotherapy trials, stratification of tumors by K-ras status deserves to be further investigated in order to correlate with response, relapse and survival. Mutated K-ras genotype merits further research. Finally, the paradigm of uneven histological distribution and mutated K-ras spectra among researchers should serve as a stimulus to search for further contributions in this field.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

K-ras genotypes and prognosis in non-small-cell lung cancer.

BACKGROUND: Despite major advances in the treatment of many kinds of cancer over the past 25 years, the overall 5-year survival of non-small-cell lung cancer patients has scarcely improved. Even in stage I which has the best outcome long-term survival still falls below 70%. Since intriguing data suggest that the identification of genetic markers might allow prognosis to be assessed case by case. We were prompted to evaluate K-ras gene mutations as a putative prognostic marker in this neoplasm. MATERIALS AND METHODS: We used the polymerase chain reaction (PCR) followed by allele specific oligonucleotide (ASO) hybridization or single-strand conformation polymorphism (SSCP) assays, to detect K-ras mutations in DNA from formalin-fixed, paraffin-embedded tumor samples. K-ras mutations were examined in 192 stage I to IV non-small-cell lung cancer patients. RESULTS: K-ras mutations were detected in 51 of 192 of the cases studied (27%). All K-ras mutations detected by PCR/ASO hybridization were also identified by SSCP. In stage I disease, the median survival was 46 months in those patients whose tumors had no K-ras mutations and 21 months in those with aspartic acid and serine mutations at K-ras codon 12; in patients with stage IIIA disease, median survival time was 16 months in the K-ras negative group and 7 months in the aspartic acid and serine mutation group. No significant differences were observed for the remaining amino acid substitutions of K-ras, nor were they observed at all in more advanced disease. CONCLUSIONS: K-ras gene status has strong prognostic value in patients with stage IIIA non-small-cell lung cancer. The survival curve for patients with stage I and K-ras codon 12 aspartic or serine mutations is close to that of patients with stage IIIA without K-ras mutations. However, a non-small-cell lung cancer K-ras genotypic classification should be validated in larger studies.

Aged↗
PubMed1995

Acute intrinsic renal failure and blood coagulation disorders after a snakebite in a dog.

Acute intrinsic renal failure was diagnosed in a two-year-old, male, German shepherd dog following a Vipera aspis bite. Clinical signs included depression, hypersalivation, vomiting, tachypnoea, abdominal pain, splenomegaly, oliguria with haematuria and haemolysed serum. Leucocytosis with a shift to the left, thrombocytopenia, prolonged coagulation times (activated partial thromboplastin time, prothrombin time and thrombin time), hypofibrinogenaemia, azotaemia and hyposthenuria were the most prominent laboratory abnormalities. Histopathological evaluation of the kidneys showed a discrete glomerular hypercellularity, mesangial lysis and renal tubules filled with many hyaline casts and some necrotic cells.

Acute Kidney Injury↗
PubMed1994

Visceral leishmaniasis and disseminated intravascular coagulation in a dog.

A dog being treated with meglumine antimonate for leishmaniasis was examined because of anorexia, vomiting, diarrhea, weakness, and signs of abdominal discomfort. The history, physical examination findings, clinicopathologic abnormalities, and results of coagulation testing were compatible with a diagnosis of renal failure and disseminated intravascular coagulation. The signs of abdominal pain were most likely a result of microcirculatory obstruction. The cause of disseminated intravascular coagulation in this dog was not determined; however, visceral leishmaniasis could have been associated.

Animals↗
PubMed1994

K-ras gene point mutation: a stable tumor marker in non-small cell lung carcinoma.

K-ras gene point mutation is a highly frequent event in human malignancy. About one third of non-small cell lung cancer (NSCLC) patients harbor K-ras gene point mutational activations. This study investigates the prevalence of K-ras mutation in autopsy tumors with NSCLC, and the correlation of K-ras gene point mutations between primary tumors and metastases in NSCLC. Formalin-fixed, paraffin-embedded tissue sections of 15 primary lung tumors and their metastases, (obtained from autopsy), were examined for the presence of point mutations in K-ras gene codon 12, 13 and 61 by oligodeoxynucleotide hybridization analysis of DNA fragments, amplified by polymerase chain reaction (PCR). K-ras gene point mutations were detected in five cases of lung carcinoma, of which four were adenocarcinomas and one was squamous cell carcinoma. In each of these cases, identical K-ras gene mutations were found in the DNA of both the primary tumor and its corresponding distant metastases. Activating K-ras base-substitutions correlate well between the primary tumor and its corresponding metastases in NSCLC. In the negative cases where no K-ras mutation was found in the primary tumors, no newly acquired K-ras mutation appeared in the metastases. Our study indicates that K-ras point mutation serves as a stable tumor marker in NSCLC.

Adenocarcinoma↗
PubMed1994

A randomized trial of mitomycin/ifosfamide/cisplatin preoperative chemotherapy plus surgery versus surgery alone in stage IIIA non-small cell lung cancer.

The efficacy of surgery or radiotherapy as conventional treatment for stage IIIA non-small cell lung cancer (NSCLC) is limited. Recent studies have pointed out that preoperative chemotherapy may improve survival. To reconcile the two approaches, we undertook a multidisciplinary randomized trial to examine the possible synergism between preoperative chemotherapy and surgery in improved survival. Stage IIIA NSCLC patients were randomly assigned to receive either three preoperative courses of mitomycin/ifosfamide/cisplatin chemotherapy and surgery or surgery alone. The median survival was significantly greater in the chemotherapy plus surgery group than in the surgery group (26 months v 8 months; P < .001). However, the prognostic value of the mutated K-ras gene data presented awaits the analysis of larger sample populations. Similarly, the role of high-dose cisplatin in inducing higher pathologic complete remissions has to be corroborated in future randomized trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Antibodies to Rickettsia conorii in dogs: seasonal differences.

Eight dogs, having showed positivity to Rickettsia conorii in serum samples obtained during the spring and summer, were studied again by means of a second determination during the next winter, 4-10 months later. Serum titer became negative in six dogs, persisted high in one, and fell from 1:640 to 1:40 in another dog. This seasonal difference suggests a short persistence of antibodies in dogs after contact with R. conorii in the Mediterranean area.

Animals↗
PubMed1992

Comparison of three protracted antiemetic regimens for the control of delayed emesis in cisplatin-treated patients.

Antiemetic activity of three protracted regimens for the control of cisplatin-evoked delayed emesis was explored. 63 patients were randomly assigned to receive one of three protracted antiemetic schedules over 4 days. Group C patients received dexamethasone 8 mg twice daily on days 2 and 3, then 4 mg twice daily on days 4 and 5; in group B, alizapride 2.5 mg/kg four times daily on days 2-5 plus dexamethasone as in group C was administered; and in group A, metoclopramide 0.5 mg/kg four times daily on days 2-5 plus dexamethasone was given at the same dose-schedule as in groups C and B. Complete protection from delayed vomiting was achieved in 44% of group C, 30% of B and 70% of group A (P = 0.02). Mild side-effects were noted in all three groups. A higher complete protection for delayed emesis was obtained in metoclopramide-dexamethasone-treated patients. Neither of the regimens used in the protection of delayed emesis controlled late nausea.

Adult↗