Evaluation of a prediction model of cisplatin dose based on total platinum plasma concentration.

The aim of this study was to validate prospectively a model of cisplatin dose adjustment. 27 patients (63 courses) with lung cancer were treated by a 5 day continuous infusion of cisplatin and etoposide. The dose of cisplatin was adjusted in order to reach a target plasma concentration of total platinum (TP) of 2000 mu/l at the end of the infusion. The target concentration was reached with a mean bias of 2.7% and a precision of 7.8%. The results were compared with those of a population of 38 patients (97 courses) with lung cancer and treated with the same protocol of chemotherapy, but without dose adjustment. The average dose adjustment was an increase of cisplatin dose of 20.2%. This augmentation was most important during the first course, decreasing during the following courses. There was also an increase in the etoposide AUC, although its dose was not modified. Toxicity to polymorphonuclear cells was significantly increased and was linked to etoposide AUC.

Relation between responses to induction chemotherapy and subsequent radiotherapy in advanced or multicentric squamous cell carcinomas of the head and neck.

Between 1984 and 1986, 85 consecutive patients with Stage III-IV or multi-centric squamous cell carcinoma of the head and neck were given three courses of chemotherapy followed by curative external radiotherapy. Induction chemotherapy consisted of either DDP (100 mg/m2, d 1) + 5 FU (1 g/m2/d, d 1-5, continuous infusion) or DDP (100 mg/m2, d4) + Etoposide (60 mg/m2/d, d 1-5, intravenously). Radiotherapy was delivered 70 Gy over 7 weeks in gross tumor and palpable nodes and 50 Gy over 5 weeks in clinically negative nodal areas. Complete response (CR) rates of both the chemotherapies were 39% for the primary and 20% for the nodes whereas partial response (PR) rates were 22% and 40%, respectively. Six months after completion of radiotherapy, 70% of the primaries and 63% of the nodes achieved complete response. The analysis of responses to chemotherapy on one hand and to subsequent radiotherapy on the other shows that the response to chemotherapy can be regarded as predictive for subsequent radiotherapy (p less than 0.001) except in T1-T2 tumors. In these early stages radiotherapy can be efficacious despite a previous failure of chemotherapy (p less than 0.01).

Analysis of late complications after rapid hyperfractionated radiotherapy in advanced head and neck cancers.

Late effects were analyzed in a series of 39 patients with a 2-year minimal follow-up who were treated by rapid hyperfractionated radiotherapy. The total dose was 66-72 Gy delivered in two series of 33-36 Gy separated by a 2-4 week rest interval. The number of daily fractions ranged from 8 to 6 and the interval between each fraction was 2 hr. Late complications consisted of cervical fibrosis, mucosal necrosis, bone necrosis, trismus, and laryngeal edema. Seventy percent of patients experienced late complications, and in 54% of cases, these reactions were considered severe, causing death in 13% of patients. No relationship was found between field sizes, dosimetric data and type and frequency of late effects. It is therefore suggested that the interval between two daily sessions in any multifractionated protocol may be of critical importance.

Phosphatase isoenzymes as bone metastasis markers in prostatic carcinoma.

Bone alkaline phosphatase (b-ALP) and tartrate resistant acid phosphatase (tr-ACP) are markers of the activity of osteoblasts and osteoclasts, respectively. We have already shown that the serum activity of these isoenzymes was elevated in breast cancer patients with bone metastasis (BM); we show here that the serum activity of b-ALP and tr-ACP were also elevated in prostate cancer patients with BM. Specificity and sensitivity of b-ALP for BM were 0.90 and 0.75, respectively; and for tr-ACP, 0.60 and 0.60, respectively. The accuracy of b-ALP as a BM marker was higher than the accuracy of usual markers of prostatic carcinoma (tartrate labile ACP [tl-ACP], prostatic acid phosphatase [PAP] and prostate specific antigen [PSA]). The highest value predictive of a positive bone scan was obtained with b-ALP (0.88); this increased to 0.97 when b-ALP was coupled with PAP.

Carcinomatous meningitis and solid tumours.

This retrospective study concerning patients with a carcinomatous meningitis (CM) associated with solid tumour aimed at identifying risk markers of CM which could be used in the future in order to prevent from this neurological complication. From 1976 to 1996, the patients whose CSF sampling was positive cytologically, were registered recording baseline clinical data, tumour histology with grade, tumour dissemination, treatments and follow-up. Simultaneously to the recruitment of the patients the incidence of CM was derived at each 5-year period. The variables were analysed by uni- and multivariate statistics. Among the 41 cases, the first three sites of the primary were breast, lung, essentially small cell lung cancer, and urinary tumours. At their initial presentation, 22 patients revealed an M1 dissemination and 22 tumours were undifferentiated. Over the 20 years, the incidence of CM has significantly increased for urinary cancers, decreased for breast cancer while the administration of neoadjuvant chemotherapy was increasing, and remained unchanged for lung cancer. M1 and/or undifferentiated tumours shortened the time-to-CM whereas bone metastases, that were the most frequent site for secondary deposits, did not. Breast, lung and urinary cancers produced 80% of the CM in the series. Neoadjuvant chemotherapy possibly could save patients from the meningeal dissemination. M1 and undifferentiated tumours appeared to be independent risk factors, as well as osseous metastases. Other risk factors of CM should be identified in prospective trials.

Puzzles in the clinical pharmacokinetics of fluorouracil.

The pharmacokinetics of fluorouracil (5FU) were studied in two groups of patients, the administration of 105 i.v. as daily bolus (x5) or 5-day continuous infusions. The 5FU pharmacokinetics were extremely variable from day to day, i.e. from one bolus to the next or during the continuous infusion, especially in some patients. The variations were lower for the daily bolus, but still remained high. The pharmacokinetics of cisplatin, given simultaneously during continuous infusions did not show the same variability; therefore the variability could be specific for 5FU. The role of implantable subcutaneous ports as the most probable source of this extraordinary variability is discussed. We hypothesise that in some patients the implantable subcutaneous ports used for 5FU infusion, could cause transient and extremely high plasma concentrations, exacerbated by the very short half life of the drug and by saturation of its catabolism.

Effect of gallium at two phases of the CA 755 tumour growth.

GaCl3 efficiency was evaluated for mice mammary adenocarcinoma Ca-755 separately at two stages of tumour growth: the exponential and plateau phase. Two modalities of drug administration were evaluated: once only and twice a day for five days. Comparisons were made with the efficiency observed when saline liquid and cyclophosphamide were used. The comparisons between tumour shrinkages were carried out by non-parametric tests. GaCl3 was more often efficient for tumours at the exponential phase than for those at the plateau phase of growth. GaCl3 always appeared less efficient than cyclophosphamide. The treatment schedule did not result in any significant alteration of tumour regression.

Early death during initial chemotherapy of squamous cell carcinoma of the oro- or hypopharynx.

Neoadjuvant chemotherapy produces high response rates in squamous cell carcinoma of the head and neck without increasing the survival time. Furthermore authors have observed a death rate of about 5% (up to 10%) during chemotherapy. A series of patients with an oro- or hypo-pharynx cancer, were retrospectively divided into two groups on the basis of a short (< or = 2 months) or long (> or = 2 years) survival time. Clinical, tumoral and usual biological data from either group were compared. By univariate analysis, obesity index, hemoglobin, albumin concentrations and mononuclear cell counts were lower in patients with a short survival time compared with those in the other group. On the contrary, polymorphonuclear cell and platelet counts were higher. Infection appeared to be more frequent for patients with a poor prognosis without being entirely responsible for early death. By multivariate analysis, obesity index and platelet count were both independent variables associated with prognosis. These results call for further investigation of cardiac function, inflammatory, nutritional and immunological status of patients with squamous cell carcinoma of the head and neck who were given initial chemotherapy, particularly Cisplatin and Fluorouracil.

Contribution of quantitative cytology to the cytological diagnosis of thyroid neoplasms.

In a previous study we determined that the fine needle aspiration (FNA) biopsy of thyroid produces 16% of false-negative cases (FNC). In order to determine the value of quantitative cytology (QC) as a tool for predicting the FNC result, thirty-seven cases, 18 of which were operated (histologically benign: 13; malignant: 3; atypical adenoma; 2) were examined for quantitative morphologic characteristics. The smears were stained by the Feulgen method and nuclear parameters of morphometry, densitometry and texture were computed by a cell image processor. The system was first taught to recognize the benign and malignant cells from 3 histologically benign and malignant lesions. Thereafter, prospective cases were submitted to decisional analysis. For 10 histologically benign cases, the benign cell rate (bcr) ranged from 65% to 99.4 (95% confidence interval). Among the patients with a cytologically benign lesion (and an unknown histological diagnosis), 2 had a bcr less than 65% and so were not to be regarded as benign. The follow-up of these patients will show whether they represent FNC and whether QC can be of predictive value in assessing the FNC.

A phase III of cisplatinum versus cisplatinum-etoposide for previously untreated squamous cell carcinoma of the head and neck.

136 patients with previously untreated stage III or IV squamous cell carcinoma of the head and neck entered a prospective randomized trial to compare the efficacy and toxicity of DDP vs DDP-VP 16 213 (Etoposide). 69 patients (group A) were given three courses of DDP 100 mg/m2 administered on day 1, while 67 patients (group B) were given three courses of a combination of Etoposide 100 mg/m2 per os administered on days 1 to 5 and DDP 100 mg/m2 on day 4. Objective response rate appeared to be low in both groups: in group A (60 evaluated patients) CR = 1, PR = 9; CR + PR = 14.5%, and in group B (57 evaluated patients) CR = 3, PR = 8; CR + PR = 16.4% (p greater than 0.4). One drug-related death occurred in each group. There was no difference in toxicity between the two treatments with regard to leukopenia, thrombopenia, vomiting and nephrotoxicity. Thus this schedule of oral Etoposide does not seem to increase either the efficacy or the toxicity of DDP.

Prognostic significance of routine clinical and laboratory data in advanced head and neck cancers.

Predictive factors for toxicity and response to chemotherapy in patients with advanced head and neck cancer are seldom reported. Therefore, from a short series of patients with a histologically proven cancer, who were treated by a neo-adjuvant protocol with cisplatin and fluorouracil, routine clinical and laboratory data were investigated. ALT (alanine aminotransferase) and Hb (hemoglobin) appeared to be predictive for efficacy. By multivariate analysis (principal component analysis), these laboratory data were involved in two independent axes: one which was considered as "inflammatory" and the other as "hepatic". Initial obesity indices were associated with the former. The predictive variables for toxicity (i.e. age, serum creatinine level, weight loss and plasma cisplatin) were probably biased in this series. Nevertheless cisplatin concentration regularly increased in each cycle. Hence it was dependent on the rank of the course. According to this preliminary study, it would be of interest to conduct future investigations on acquired protein-energy malnutrition, as well as on selected soluble mediators of cellular and humoral immune response.

Nucleus image analysis as a possible prognostic tool in grading breast cancer.

The WHO grading system for breast cancer is based on the subjective, poorly reproducible evaluation of two cytological criteria (Mitotic Activity: MA and Nuclear Pleiomorphism: NP) and one histological criterion (Tubular Differentiation: TD). In order to improve the reproducibility of the assessment of tumour differentiation, we have looked for nuclear cytophotometric parameters (densitometry, geometry and texture) that could be measured objectively on smears stained by the Feulgen method. Tumour cell populations from 36 breast cancers were investigated by nuclear image analysis according to NP scores, MA scores, TD scores (ie for each variable, three categories), WHO total scores (3 to 9 or 7 categories) and WHO grades (grade I: 13 patients, whereas 13 and 10 for grade II and III respectively). Discrimination between each score or grade could be displayed by the average profiles of the nuclear cytophotometric parameters provided by multivariate analysis. Discrimination between TD scores was based on two parameters of nuclear texture. All these data suggest that WHO grading could be obtained in an objective manner by nuclear image analysis.

Evaluation of morphological criteria in the cytological diagnosis of thyroid cold nodules. A preliminary study.

Although cytological diagnosis plays a significant role in the management of thyroid cold nodules, the rather high rates of false negative cases diminishes its usefulness. The purpose of this preliminary study is to evaluate the utility of numerous morphological criteria used by the cytologist to exclude benign tumours. Thirty-one cytological criteria were routinely scored as binary (yes/no) or as categories: 6 referred to the general arrangement and frequency of thyroid cells, 9 to the associated cellular and cell product elements, and 16 to the morphological features of the cells. We examined the manner in which these criteria, alone or combined, contributed to the diagnosis. The data base consisted of 171 intraoperative imprint cytological samples (143 histologically benign, 1 atypical adenoma and 27 cancers), as well as 257 thyroid cold nodule aspirates from another set of patients (198 histologically benign, 7 atypical adenomas and 52 cancers). For the imprint cytology, the diagnostic power of each criterion was individually assessed by the likelihood ratio (LR) which eliminated 11 as being undiscriminatory. The remaining independent criteria were subjected to logistic regression analysis to determine the most discriminant. Three were selected: Cellular clustering organisation, nuclear hypertrophy and colloid quantity with the latter being somewhat less powerful. Furthermore, it appears that the diagnostic power of the criteria was significantly lower when there was at least one nucleolus (number of nucleoli greater than 0). The smears gave essentially the same results as the imprints.(ABSTRACT TRUNCATED AT 250 WORDS)

[Carcinomatous meningitis: rare complication of bladder cancer]. / La méningite carcinomateuse: une complication rare du cancer de la vessie.

The sites of metastases of transitional cell carcinoma of the bladder are nodes, liver, lung and bone, but the meningeal infiltration is rare. Therefore, one case of meningeal carcinomatosis is reported. After cystectomy for an undifferentiated carcinoma of the bladder, the patient received adjuvant chemotherapy. Three months after treatment completion, symptoms of cerebellar ataxia occurred and gradually confusion appeared. The initial cerebra spinal fluid showed clumps of malignant cells. The patient died 15 days after the neurological symptoms occurred. The clinical diagnosis of meningeal carcinomatosis is based on neurological manifestations at more than one level of the neuraxis. Symptoms may present simply as headache or confusion. Meningeal carcinomatosis from urothelial cancer seems to show some specific features: poorly differentiated tumour and high frequency of cerebellar symptoms. Intrathecal treatment essentially has a pain-effect. Mean survival time is as short as 20 weeks. The increasing incidence of this neurological complication in urothelial cancer does not only result from an increase in patient longevity but also from possible side-effects of chemotherapy, so as localized changes in blood-brain barrier permeability induced by antineoplastic drugs. Therefore, we may wonder whether meningeal carcinomatosis might not be regarded as an iatrogenic effect.

[Benefit of pharmaceutical anti-oedematous treatment in acute adult epiglottitis]. / Intérêt du traitement médicamenteux anti-oedémateux au cours de l'épiglottite aiguë de l'adulte.

Acute adult epiglottitis is a potentially life threatening infectious and respiratory emergency as it may result in airway obstruction. Endotracheal intubation, if needed, is a highly risky option in this situation and responsible for important morbidity and mortality rate. The option of a pharmaceutical anti-oedematous treatment, in order to avoid the risks involved in the endotracheal route has rarely been described. We here report the case of a 50-year-old man with a serious acute infectious epiglottitis who was treated at home by a Mobile Intensive Care Unit where a treatment of nebulized epinephrine and intravenous steroids was undoubtedly a successful option to the endotracheal route. So that, for adult patients and in the absence of any risk of an imminent respiratory arrest, this anti-oedematous treatment should be considered in order to avoid endotracheal route, an option which should be undertaken in case of complications. Nevertheless, this isolated case study concerning an adult is not transposable to children for which airway obstruction tolerance is lower.

[Primary lymphoma on a pouch following collapse therapy]. / Lymphome primitif sur poche séquellaire de collapsothérapie.

The development, often after a long delay, of cancer in post-pneumothorax pouches is well known. A case of lymphoma developed on such a pouch is reported. Although cases of lymphoma developed on pulmonary scars have been published, we were unable to find in the literature cases of lymphoma developed on a sequela of old therapeutic pneumothorax.