The antitumor drug F14512 enhances cisplatin and ionizing radiation effects in head and neck squamous carcinoma cell lines.

BACKGROUND: Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer worldwide. The treatment of advanced stages HNSCC is based on surgical treatment combined with radiotherapy and chemotherapy or concomitant chemo-radiotherapy. However, the 5-year survival remains poor for advanced stages HNSCC and the development of new targeted therapies is eagerly awaited. F14512 combines an epipodophyllotoxin core-targeting topoisomerase II with a spermine moiety introduced as a cell delivery vector. This spermine moiety facilitates selective uptake by tumor cells via the Polyamine Transport System (PTS) and reinforces topoisomerase II poisoning. Here we report the evaluation of F14512 toward HNSCC. MATERIALS AND METHODS: Four cell lines representative of head and neck cancer localizations were used: Fadu (pharynx), SQ20B (larynx), CAL33 and CAL27 (base of the tongue). PTS activity and specificity were evaluated by confocal microscopy and flow cytometry using the fluorescent probe F17073 which contains the same spermine moiety as F14512. Cytotoxicity, alone or in association with standard chemotherapeutic agents (cisplatin, 5FU), and radio-sensitizing effects were investigated using MTS and clonogenic assays, respectively. F14512 efficiency and PTS activity were also measured under hypoxic conditions (1% O2). RESULTS: In all 4 tested HNSCC lines, an active PTS was evidenced providing a specific and rapid transfer of spermine-coupled compounds into cell nuclei. Interestingly, F14512 presents a 1.6-11-fold higher cytotoxic effect than the reference compound etoposide (lacking the spermine chain). It appears also more cytotoxic than 5FU and cisplatin in all cell lines. Competition experiments with spermine confirmed the essential role of the PTS in the cell uptake and cytotoxicity of F14512. Hypoxia had almost no impact on the drug cytotoxicity. The combination of F14512 with cisplatin, but not 5FU, was found to be synergistic and, for the first time, we demonstrated the significant radio-sensitizing potential of F14512. CONCLUSION: The spermine moiety of F14512 confers a targeted effect and a much better efficacy than etoposide in HNSCC lines. The synergistic effect observed in association with cisplatin and radiotherapy augurs well for the potential development of F14512 in HNSCC.

TrkA overexpression enhances growth and metastasis of breast cancer cells.

The Trk family of neurotrophin tyrosine kinase receptors is emerging as an important player in carcinogenic progression in non-neuronal tissues. Here, we show that breast tumors present high levels of TrkA and phospho-TrkA compared to normal breast tissues. To further evaluate the precise functions of TrkA overexpression in breast cancer development, we have performed a series of biological tests using breast cancer cells that stably overexpress TrkA. We show that (1) TrkA overexpression promoted cell growth, migration and invasion in vitro; (2) overexpression of TrkA per se conferred constitutive activation of its tyrosine kinase activity; (3) signal pathways including PI3K-Akt and ERK/p38 MAP kinases were activated by TrkA overexpression and were required for the maintenance of a more aggressive cellular phenotype; and (4) TrkA overexpression enhanced tumor growth, angiogenesis and metastasis of xenografted breast cancer cells in immunodeficient mice. Moreover, recovered metastatic cells from the lungs exhibited enhanced anoikis resistance that was abolished by the pharmacological inhibitor K252a, suggesting that TrkA-promoted breast tumor metastasis could be mediated at least in part by enhancing anoikis resistance. Together, these results provide the first direct evidence that TrkA overexpression enhances the tumorigenic properties of breast cancer cells and point to TrkA as a potential target in breast cancer therapy.

[Medical characteristics of patients in long-term care facilities and predictions on the weight of their management]. / Caractéristiques médicales des patients en unités de soins de longue durée et prédictions de la lourdeur de la prise en charge.

The objective of this study was to highlight the heterogeneous nature of the medical profiles of patients living in long term care units (LCU) and to present the morbidity factors associated with-the weight and burden of ensuring long term medical care and treatment. Typology analysis, performed on a group of 600 LCU patients, highlights two types of patients: one who is characterised by having few or no serious diseases, and the other (representing nearly one-third of the sample population) corresponding to patients with serious poly-pathologies and requiring a high level of medical attention and nursing care. Factors associated with a higher level of care are diseases such as those related to cardiac or respiratory deficiencies. This predictive model for the burden of care could be used to measure the suitability between the state of the patients and the their optimum structures for care.

Suspected role of ofloxacin in a case of arthalgia, myalgia, and multiple tendinopathy.

A 53-year-old woman on ofloxacin developed myalgia, arthralgia, and tendinopathy. Her symptoms resolved after ofloxacin discontinuation. Although tendinopathy is a well-documented complication of quinolone therapy, there have been few reports of muscle symptoms. Concomitant involvement of the tendons, muscles, and joints has been exceedingly rare. Inhaled glucocorticoid therapy and moderate hypothyroidism were probably precipitating factors in our patient.

[Bi- and tri-clonal gammopathies and the elderly]. / Gammapathies bi- et triclonales et sujet âgé.

Between 1985 and 1990, bi- or triclonal gammopathies were diagnosed in 6 patients (4 women and 2 men) aged 86-93 years. These gammopathies were diagnosed based on the existence of 2 or 3 monoclonal immunoglobulin peaks separated by immunoelectrophoresis of serum proteins (a technique using monospecific anti-gamma, -kappa and -lambda antisera, followed by immunofixation). The 2 biclonal gammopathies were associated with malignancies: on bronchial small cell carcinoma, the other colon cancer; both patients died soon after the discovery of their respective tumors. The 4 triclonal gammopathies had the following associations: 1 non-Hodgkin's large-cell lymphoma, 1 breast cancer with possible lymphoma and 2 severe inflammatory pathologies that we were unable to further identify; 3 patients in this group died. We present these data in light of the rarity of reported cases of bi- and triclonal gammopathies and the controversies surrounding their possible association with a malignant pathology.

[Secondary hyperparathyroidism and articular chondrocalcinosis in the aged]. / Hyperparathyroïdie secondaire et chondrocalcinose articulaire chez le sujet âgé.

The incidence of articular chondrocalcinosis (ACC) in elderly patients hospitalised in geriatric departments is approximately 30%. Routine studies including a 2 hour calcium/phosphorus balance, parathormone assay and radiological investigations enabled the selection of 73 patients with secondary hyperparathyroidism. ACC was present in 38 of these individuals (52%). They were slightly older (87 +/- 5) than cases of secondary hyperparathyroidism without radiological ACC (84 +/- 8). Among patients with secondary hyperparathyroidism with ACC, there were 90% women and 10% men, while the sex ratio in the department was 77% women and 23% men. Results of calcium/phosphorus balance and parathormone levels were similar, in the presence or absence of ACC.

Pharmacokinetics of nalbuphine in infants, young healthy volunteers, and elderly patients.

Nalbuphine is a new agonist and antagonist opioid analgesic agent that undergoes an important hepatic metabolism. In this study, we compared the pharmacokinetics of intravenous and oral nalbuphine in three groups of subjects: group I consisted of 14 children from 1 1/2 to 5 years of age (group IA) and from 5 through 8 1/2 years of age (group IB), group II consisted of 9 healthy male volunteers from 23 to 32 years of age, and group III consisted of 9 elderly patients from 65 to 90 years of age. All subjects and patients had normal hepatic and renal functions. The children received an intravenous injection of nalbuphine (0.2 mg/kg), and the subjects and patients in groups II and III received, at random, 10 mg intravenous injections and 30 mg oral doses of nalbuphine on two separate occasions. The distribution of nalbuphine was not modified with age. Elimination half-life (t1/2) was significantly shorter in group I (0.9 hour) than it was in group II (1.9 hours) and in group III (2.3 hours). Systemic clearance of nalbuphine decreased significantly with age. Absolute bioavailability of nalbuphine increased from F = 12% in group II to 46.3% in group III (p less than 0.01). These findings suggest that doses and rates of administration of nalbuphine should be adapted in younger patients and in elderly patients.

[Serotype 5 pneumococcus in epidemiology and vaccine]. / Place du sérotype 5 du pneumocoque dans l'épidémiologie et le vaccin.

The Streptococcus pneumoniae serotype 5 is commonly isolated in human pathology. In France, it is the fourth pneumococcal serotype for acute pneumonia (9.1%) and bacteremia (6.9%). It appears to be more frequently encountered in Africa: in Dakar, this serotype is the third pneumococcal agent and is one of the more often isolated in meningitis; moreover, its is the third serotype isolated in Nigeria. In the intention of its incorporation in the yet available 14-valent pneumococcal vaccine, we have compared serological response and tolerance among four groups of adults: 1) the first group (23 persons) was only immunized by serotype 5 pneumococcal polysaccharide (50 micrograms); 2) the second group (23 persons) by the 15-valent pneumococcal vaccine (14-valent + serotype 5); 3) the third and the fourth groups (21 and 97 persons) were immunized by the 14-valent pneumococcal vaccine. By comparing the multiplying factors of geometrical means of antibodies levels measured by RIA, it appears that the pneumococcal polysaccharide serotype 5 is immunogenic, dispensed alone (first group) or associated with 14-valent pneumococcal vaccine (second group). No reciprocal interference can be detected between this polysaccharide and the other 14 polysaccharides. The tolerance of the serotype 5 polysaccharide is as good as that of these 14 antigens.

[Comparison of treatment with griseofulvin, beta blockers and calcitonin in 55 cases of post-traumatic algoneurodystrophies]. / Comparaison du traitement par la griséofulvine, les bêtabloquants et la calcitonine dans 55 cas d'algoneurodystrophie post-traumatique.

A comparative study of three treatments of reflex sympathetic dystrophy (selected at random) was carried out on 55 cases : 20 patients were treated with calcitonin, 19 with beta-blocking agents, and 16 with griseofulvin. The delay in drug effect seems similar for the 3 drugs but griseofulvin is associated with a greater failure rate. The beta-blocking agents and calcitonin gave comparable results. beta-Blocking agents appear to obtain better results than other 2 treatments in patients with a psychological component to their disease.

[Polyradiculoneuritis associated with plasmocytoma. Recovery following radiotherapy (author's transl)]. / Polyradiculonévrite au cours d'un plasmocytome: guérison après radiothérapie.

A new case of extensive subacute polyradiculoneuritis associated with a costal plasmocytoma secreting IgG lambda is reported. Radiotherapy of the rib, resulted in remarkable neurological improvement and haematological cure, which have now persisted for more than 5 years, though treatment was discontinued 3 years ago. By its distinctive haematological features, this case illustrates the lack of clear-cut distinction between "solitary" plasmocytoma and multiple myeloma. It also emphasizes the need for systematic testing for plasma cell proliferation when confronted with a subacute or chronic neuropathy of obscure origin.

[The cardiovascular manifestations of Paget's disease]. / Les manifestations cardio-vasculaires de la maladie de Paget

After reviewing the old ideas (peripheral syndrome and cardiac insufficiency at high outputs) and more recent ideas (arterial and intracardiac vascular calcification), the authors report their experiences based on the study of the histories of 150 patients suffering from Paget's disease followed for several years. First they emphasize the frequent latency of cardiac manifestations looked for systematically by means of the electrocardiogram particularly during evolutive stages of the disease. Electrocardiographic disturbances were observed 91 times and included 43 cases of conduction disorders and 48 of repolarization disorders; their distribution was studied as a function of various inherent parameters, of the patient (age and sex) and of the disease (its evolutive character and its degree of diffusion). On the basis of the anti-arythmic power of calcitonin found during experiments and obtained excellent results three times. Finally the place of cardiovascular manifestations in the pathogenic hypotheses and nosology of Paget's disease is discussed.