Phase II study of the PI3K inhibitor BKM120 in patients with advanced or recurrent endometrial carcinoma: a stratified type I-type II study from the GINECO group.

Backround:Patients with metastatic endometrial carcinoma have a poor prognosis and PIK3CA mutations and amplifications are common in these cancers. This study evaluated the efficacy and safety of the pure PI3K inhibitor BKM120 in advanced or recurrent endometrial carcinoma. METHODS: This phase II, multicentre, single-arm, double strata (histological low grade (LG) or high grade (HG)) open-label study enrolled patients with histologically confirmed advanced or recurrent endometrial carcinoma who had received not more than one prior chemotherapy regimen. Patients received initially BKM120 100 mg tablets once daily. Primary end points were proportion of patients free of progression at 2 months (HG strata) or at 3 months (LG strata), objective response rate (ORR), and safety. RESULTS: A total of 40 patients were enrolled, of whom 16 patients had received BKM120 at 100 mg. Because of high toxicities (cutaneous rash (54%), depressive events (47%), and anxiety (40%), the IDMC has proposed to stop recruitment at 100 mg and to continue the clinical trial with a lower dose of 60 mg per day. In addition, 24 patients (median age 67 years old) were newly enrolled (14 in the LG strata and 10 in the HG strata). Rate of nonprogression at 2 months in the HG strata was 70% and at 3 months was 60% in the LG strata. Median progression-free survival (PFS) for all patients is 4.5 months (CI 95% 2.8-6.1), and the median PFS for LG strata is 8.3 months compared with 3.8 months for the HG strata. No response was reported. At 60 mg per day, the most commonly reported treatment-related adverse events (AEs) were hyperglycaemia (58%), cognitive (31%), digestive (28%), hepatic liver functions (26%), and rash (23%). The most commonly reported treatment-related grade ⩾3 AEs were HTA (17%), hyperglycaemia (17%), and increased alanine aminotransferase (24%). Five patients (21%) stopped BKM120 for toxicity. CONCLUSIONS: The BKM120 was associated with an unfavourable safety profile and minimal antitumour activity in monotherapy in advanced or recurrent endometrial carcinoma. The clinical trial was stopped before end of recruitment for toxicity.

[Guillain-Barré syndrome and non-Hodgkin's lymphoma. Report of one case and review of literature]. / Syndrome de Guillain-Barré et lymphome non-hodgkinien. A propos d'une observation et revue de la littérature.

Patients with lymphoma frequently develop neurologic abnormalities mainly due to nervous system infiltration but also direct drug toxicity. Moreover Guillain-Barré syndrome (GBS) remains a possible neuropathy, rarely described in non-Hodgkin's lymphoma. We describe a case of GBS in a patient with non-Hodgkin's high grade lymphoma. A 74-year old man with a newly diagnosed stage I high-grade lymphoma (precursor B-cell Burkitt like type according to the R.E.A.L. Classification) develop flaccid quadriparesis, 7 days after the end of the third course of CHOP treatment. The clinical course and neurological examination were consistent with GBS. The patient was in tumoral complete response. Despite appropriate treatment and a transfer in a reanimation unit, the patient died 3 days after the beginning of neurologic symptoms. The low number of cases described in the international literature doesn't permit to understand the association of this neurologic disease with non-Hodgkin's lymphoma. Collecting more data could lead interesting information to know the place of malignant hematological disease in the natural history of GBS.

A weekly schedule of docetaxel for metastatic hormone-refractory prostate cancer.

RATIONALE: Docetaxel has proven its efficacy in the management of hormone-refractory prostate cancer (HRPC). Schedules of docetaxel administration differ. This prospective phase II study was designed to reevaluate the activity and toxicity of docetaxel administered weekly at an optimal dose to a large cohort of HRPC patients. PATIENTS AND METHODS: Sixty-four patients were treated with docetaxel 40 mg/m(2) i.v., administered weekly for 6 consecutive weeks followed by a 2-week recovery period. Three treatment cycles were planned in the absence of progression or toxicity. The principal end point was the biochemical response based on the prostate-specific antigen (PSA) level (a decline of more than 50% for at least 4 weeks). Secondary end points were objective response to measurable disease, survival and toxicity. RESULTS: Toxicity was assessed in 64 patients. Toxicity was acceptable, with no toxicity-related deaths. Twenty-one percent of the patients developed grade 3-4 hematological toxicity. Sixty-four patients were evaluable for the PSA response. Forty-one patients (64%) achieved a decrease in PSA of >50%, 13 of whom had a PSA <4 ng/ml. Two out of 12 patients with measurable disease exhibited an objective response. With respect to PSA, the median progression-free survival was 29 weeks (95% confidence interval: 18-46 weeks). The global 1-year survival rate was 58%. CONCLUSION: Weekly docetaxel at a dosage of 40 mg/m(2) is a well-tolerated treatment, which has very promising activity on the reduction of PSA in metastatic HRPC. A large phase III study is underway.

[Image processing and radiotherapy].

Medical images are of great importance in radiotherapy, which became a privileged application field for image processing techniques. Moreover, because of the progression of the computers' performances, these techniques are also in full expansion. Today, the recent developments of the radiotherapy (3DCR, IMRT) offer a huge place to them. Effectively, they can potentially answer to the precision requirements of the modern radiotherapy, and may then contribute to improve the delivered treatments. The purpose of this article is to present the different image processing techniques that are currently used in radiotherapy (including image matching and segmentation) as they are described in the literature.

[Treatment of brain metastasis from ovarian cancer]. / Traitement des métastases cérébrales du cancer de l'ovaire.

Systemic metastases from ovarian carcinoma are frequent, but they seldom affect the central nervous system. We present here the case of a patient treated for an ovarian cancer by surgery and chemotherapy. Three months after the end of chemotherapy, the patient developed cerebral metastases from ovarian carcinoma (CMOC) treated by iterative surgery and and whole brain irradiation. As the frequency of solitary cerebral metastasis of ovarian cancer is higher than with other cancers, it is likely that they behave slightly differently. Literature analysis reveals an increase in the incidence of CMOC since the middle of the nineties. CMOC can occur during or after adjuvant chemotherapy and the best management strategies to better define determinants of survival for patients are not well known. It appears that a better outcome of CMOC may be obtained by an aggressive treatment, if possible, including surgery, radiotherapy, and chemotherapy. Taking into account the increase in the incidence of the CMOC and their early occurrence, some authors have proposed a prophylactic brain radiotherapy in patients who receive adjuvant chemotherapy.

Clinical prognostic factors for patients with recurrent head and neck cancer: implications for randomized trials.

The purpose of our study was to determine the clinical prognostic factors for the duration of the overall survival from recurrence (OSR) in patients with recurrent head and neck squamous-cell carcinoma. We performed a retrospective analysis on 496 patients treated between 1982 and 1993 at the Antoine Lacassagne Center. The significant favorable prognostic factors for the OSR were: initial T(1-2) (p = 0.008), no initial nodal involvement (p = 0.002), no initial chemotherapy exposure (p = 0.002), induction chemotherapy response (p = 0.001), duration of disease-free interval (DFI; p = 0.0001), performance status (PS) 0-1 (p = 0.004) and local-regional recurrence (p = 0.001). In the multivariate analysis, the apparent nonsignificance of all factors apart from the DFI suggested that relevant prognostic factors could be embedded in the DFI. Multivariate analysis was performed after excluding the DFI. The results indicated that local-regional recurrence, PS 0-1 and no initial chemotherapy exposure remained significant favorable prognostic factors for the OSR. The advantages of taking into account such prognostic factors are to eliminate the patient selection bias and to ensure a fairer comparative evaluation of new or already existing agents in recurrent head and neck cancer.

Comparison between nasogastric tube feeding and percutaneous fluoroscopic gastrostomy in advanced head and neck cancer patients.

Wasting is a major complication of advanced head and neck cancer and the aim of this study was to compare nasogastric tube feeding (NG) and percutaneous fluoroscopic gastrostomy (PFG) in these patients. The goal of these two methods of nutritional support was to improve or maintain the initial nutritional status during treatment. A total of 90 patients, all stage IV oropharynx or hypopharynx tumor, were reviewed from a prospective databank. All these patients were treated by concomitant chemotherapy and twice-daily continuous radiotherapy with no acceleration. Fifty patients were managed by PFG, and the rest by NG. Mechanical failure, duration of feeding, complications, nutritional evaluation and quality of life were analysed. Mechanical failure occurred in 32 of the 40 NG patients and in seven of the gastrostomy group. In the PFG group, 80% of patients conserved their nutritional support after the end of the radiotherapy, none patient in the NG group. In the PFG group, two presented a wound infection and six had aspiration pneumonia while in the NG group, 21 had aspiration pneumonia probably due to the NG tube (gastroesophageal reflux). The feeding methods were found to be equally effective at maintaining body weight and body mass index at time 1 (3 weeks) and at time 2 (6 weeks). Advantages were associated with PFG cosmesis, mobility and quality of life. PFG is a safe and effective method of providing enteral nutrition during treatment to patients with advanced head and neck cancer and offers important advantages over NG.

Primary lung sarcomas: long survivors obtained with iterative complete surgery.

Primary lung sarcomas are uncommon histologic types of primary lung cancer and presents a wide spectrum of clinical behaviour. Nine patients treated at Antoine Lacassagne Cancer Center between 1982 and 1995 were studied. The median age was 63 years (range, 35-73 years) and the most common histologic types were malignant fibrous histiocytoma (four) and leiomyosarcoma (three). All of them underwent surgery, six patients had a complete surgery and three patients incomplete resections. The median overall survival for all patients was 36 months. In the subgroup of patients with initial complete resection, the median survival was significantly longer (47 months) than in the subgroup of patients with incomplete resection (6 months) (P<0.05, log-rank test). Moreover, two patients had a second complete resection for ipsilateral lung relapse and were long survivors (overall survival of 58 and 83 months, respectively). The ability to achieve a complete second surgery stress the possible benefit of an early detection of local recurrence. Because no specific symptom was linked with the local relapse, a systematic CT scan every 2 or 3 months could be required.

[Testicular seminoma and multifocal aseptic osteonecrosis following chemotherapy]. / Séminome du testicule et ostéonécrose aseptique multifocale au décours d'une chimiothérapie.

INTRODUCTION: Multifocal osteonecrosis has a wide variety of etiologies, but in the cancer patient several risk factors could have a synergic effect (chemotherapy, radiotherapy, corticosteroid, metabolism disorder). EXEGESIS: A patient with testicular seminoma receiving cisplatin-based chemotherapy and short-term corticosteroid developed multifocal osteonecrosis. Early diagnosis of osteonecrosis is important to prevent orthopedic complications. CONCLUSION: Cisplatin could represent one of the possible etiologies of multifocal osteonecrosis. Magnetic resonance imaging has a high sensitivity and specificity in the diagnosis of osteonecrosis and should be used when this condition is suspected.

An analysis of potential factors allowing an individual prediction of cisplatin-induced anaemia.

Severe cisplatin (CP)-induced anaemia significantly impairs the patient's quality of life. Prevention based on erythropoietin (EPO) administration would be cost-effective providing that individual predictive factors of anaemia are identified. The aim of the present study was to identify parameters able to predict the occurrence of CP-related anaemia. This prospective study was conducted on 40 head and neck cancer patients receiving a CP (100 mg/m(2), intravenous (i. v.) on day 1) - 5-fluorouracil (5-FU, 1 g/m(2)/dx5 days by continuous infusion) induction chemotherapy. Three cycles were given at 3-weekly intervals. Platinum pharmacokinetics (total and ultrafilterable plasma platinum concentration measured 16 h after CP administration) and 5-FU pharmacokinetics (full-cycle plasma area under the curve, (AUC(0-105h)30 g/l) occurred in 15 patients (38%) and 3 of them also received a blood transfusion. Patient age, 5-FU AUC(0-105h) and total platinum concentration were unrelated to Hb loss. In contrast, ultrafilterable (UF) platinum concentration was significantly correlated to Hb loss: the higher the UF platinum concentration, the greater the Hb loss (P=0.015). A discriminant analysis allowed a cut-off value for UF platinum to be proposed to identify patients developing significant loss of Hb: 91% of patients exhibiting a UF platinum concentration above 50 ng/ml developed significant loss of Hb in contrast to 18% in the group of patients with a UF platinum concentration below 50 ng/ml (odds ratio (95% confidence interval, CI) of 46 (4.7-446)). In conclusion, the present platinum pharmacokinetic survey may be proposed as a valuable approach to identify patients at risk for developing severe anaemia.

Thymocytes in Thy-1-/- mice show augmented TCR signaling and impaired differentiation.

Thy-1, a single variable-like immunoglobulin superfamily domain anchored in the plasma membrane by a glycosyl phosphaditylinositol tail [1], is a major surface glycoprotein in adult mammalian neurons and rodent thymocytes [2]; the function of Thy-1 has remained enigmatic since its discovery [3]. Studies in vitro have implicated Thy-1 in homotypic and heterotypic cell-cell interactions [2,4]. Ligation of Thy-1 initiates transmembrane signaling pathways that lead to diverse physiological outcomes in different cells [2,5-7]. In rodents, Thy-1 is highly expressed on the surface of CD4+CD8+ double-positive immature thymocytes and downregulated in mature T cells. Here, we report that thymocytes from Thy-1-/- mice [8] had altered cell-cell contacts, and hyperresponsiveness to T-cell receptor (TCR) triggering as demonstrated by the heightened activation of p56lck, phosphorylation of TCR subunits, Ca2+ fluxes and cell proliferation. Thy-1-/- thymocytes exhibited impaired maturation from the double positive to single positive stage of thymocyte development, possibly due to inappropriate negative selection, and were prone to T lymphomas in aged mice. These observations indicate that Thy-1 negatively regulates TCR-mediated signaling and controls activation thresholds during thymocyte differentiation.

Leukosialin (CD43) behavior during adhesion of human monocytic THP-1 cells to red blood cells.

To understand the modulation and the behavior of glycocalyx elements during adhesion, we explored one of its components, the CD43 molecule, on human monocytic THP-1 cells exposed to cytokine stimulation and its redistribution during heterotypic adhesion to opsonized erythrocytes. First we demonstrated by immunofluorescence and immunoprecipitation that CD43 is dys-sialylated in monocytic THP-1 cells stimulated by interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) and stimulation increased correlated to heterotypic adhesion. CD43 anti-adhesive effect seemed to be related to sialic acid moeties because an increase in adhesion was also induced by sialidase treatment and by monoclonal antibodies recognizing sialic acid-dependent epitopes on CD43. Second, a redistribution of CD43 molecules was observed after adhesion, resulting in the exclusion of CD43 molecules from contact areas as demonstrated by immunofluorescence and by ultrastructural immunogold localization. We therefore demonstrated in monocytic THP-1 cells that some glycocalyx molecules can be modulated by cytokines and redistributed during adhesion. These results support the concept that CD43 can regulate cell interactions.

Relationship between phagosome acidification, phagosome-lysosome fusion, and mechanism of particle ingestion.

The fate of pathogens ingested by macrophages is dependent on phagosome acidification and fusion with different intracellular vesicles. Whereas the mode of particle recognition by the phagocyte seems the main determinant of phagosome-lysosome fusion, the influence of membrane reorganization, fusion events, and cell activation in phagosome acidification is not well known. We looked for a relationship between the nature of receptors involved in phagocytosis, phagosome acidification, and phagosome-lysosome fusion. Murine macrophage-like P388D1 cells were made to ingest sheep erythrocytes coated with immunoglobulin G (EIgG) or IgM and complement (EIgMC) or treated with glutaraldehyde and periodate (EGP). The following results were obtained: (1) As expected, the adhesion of the three particle types was differentially inhibited by monoclonal antibodies specific for Fc gamma RII and CD11b/CD18. (2) The phagosomes containing all three particle types displayed similar acidification kinetics with a pH decrease to 6 within the first 10 min after ingestion. (3) Only phagosomes containing EIgG or EIgMC were fused with peroxidase-loaded secondary lysosomes. (4) Coating EGP with IgG only partially restored fusion, even when the surface density of IgG was markedly higher than found on EIgG. It is concluded that phagosome acidification and fusion are regulated by different mechanisms. Also, the lack of fusion observed with EGP is not entirely accounted for by the absence of stimulation of suitable receptors on the phagocyte membrane, because it cannot be restored by providing such a stimulus.