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.

[Normal tissue tolerance to external beam radiation therapy: small bowel]. / Dose de tolérance à l'irradiation des tissus sains: intestin grêle.

The small bowel is a hollow organ involved in the transit and absorption of food. In relation to its anatomical location, a significant amount of this organ is exposed in whole or in part to ionizing radiation in external radiotherapy during abdominal or pelvic irradiation either for primary cancers or metastasis. The acute functional changes during external beam radiation are mainly leading to diarrhea, abdominal pain and bloating. The main late side effects of irradiation of the small intestine are chronic diarrhea, malabsorption with steatorrhea, abdominal spasms, intestinal obstruction, bleeding and fistulas. The architecture of the small intestine may be considered as parallel with a significant correlation between the irradiated volume of small bowel and the likelihood of acute toxicity, whatever the dose. The literature analysis recommends to consider the volume of small bowel receiving 15 Gy (threshold of 100 to 200 cm(3)) but also 30 and 50 Gy (thresholds of 35 to 300 cm(3), depending on the level of dose considered). Modern techniques of conformal radiotherapy with modulated intensity will probably have beneficial impact on small bowel toxicity.

Non-invasive in vivo determination of UVA efficacy of sunscreens using diffuse reflectance spectroscopy.

BACKGROUND: Evaluation of sunscreen efficacy is most relevant when measured on the surface it is meant to protect, namely on human skin in vivo. Application of any material to the surface of the skin alters its optical properties. Diffuse reflectance spectroscopy (DRS) is a non-invasive technique to measure changes in the optical properties of the skin decoupled from its biological responses following sunscreen application. METHODS: This study compared measurements of UVA efficacy of oxybenzone and avobenzone at different concentrations (0-5%) using DRS, human phototest and an in vitro technique. Twenty subjects were enrolled for each product measured by DRS and 10 different subjects were enrolled for each product measured by human phototest. Six areas 5 cm x 10 cm were outlined on each subject's back. DRS measurements were performed on four subsites within each area before and 20 min after sunscreen application. UVA efficacy for each concentration of product was calculated from the measured transmission spectrum of a given product convoluted with the spectrum of a Xenon light source adequately filtered to obtain the UVA spectrum from 320 to 400 nm and the erythema action spectrum. Phototesting was performed using the same light source and persistent pigment darkening as the biological endpoint. Measurements were made with sunscreen coverage of 2 mg/cm2. In vitro measurements were performed using an Optometrics instrument. RESULTS: All three techniques showed a linear response between calculated UVA efficacy and product concentration. CONCLUSIONS: This study showed that DRS is a rapid and reproducible method to calculate UVA efficacy of sunscreen materials and that its results correlate closely with those obtained by human phototesting.

A new validation of the Scholander pressure chamber technique based on stem diameter variations.

The Scholander pressure chamber is one of the most widely used techniques for measuring plant water status. However, the technique has been the subject of recent controversies, and its validity awaits new experimental evidence. This paper presents a new test based on the analysis of the dependence on water potential difference (DeltaPsi) of stem diameter variation (DeltaD) in walnut (Juglans regia L.). The correlation between DeltaPsi and DeltaD was established (1) on transpiring potted trees, (2) on dehydrating cut branches, (3) by perfusing the xylem of branch segments with mannitol and sucrose solutions, and (4) by pressurizing segments in a pressure sleeve. The DeltaPsi was respectively assessed with a pressure chamber (1, 2), a freezing point osmometer (3) and an air pressure transducer (4). A single relationship was established between DeltaPsi (ranging from 0 to -2 MPa) and DeltaD for all the experiments. This shows that the measured changes of water potential were correlated to similar modifications of water content in the stems, irrespective of the technique used to induce these changes, and therefore validates the pressure chamber technique and confirms the occurrence of large negative pressures in the xylem of walnut branches.

[Effectiveness and safety of lansoprazole in the treatment of Zollinger-Ellison syndrome. First six months of treatment]. / Efficacité et tolérance du lansoprazole dans le traitement du syndrome de Zollinger-Ellison. Etude sur les six premiers mois de traitement.

OBJECTIVES: The aim of this prospective study was to confirm the efficacy and safety of lansoprazole in patients with Zollinger-Ellison syndrome (ZES). METHODS: Fourteen patients (5 W, 9 M) with ZES, age (mean +/- SD) 55.5 +/- 12.8 years, were included in the study. STUDY DESIGN: initially and at 1, 3 and 6 months thereafter the following items were assessed: clinical signs, fasting serum gastrin (FSG), basal acid output (BAO) before next dose of lansoprazole. BAO < 10 mmol H+/h was considered as efficient. Initially and at 6 months, laboratory tests (hematology, liver, renal and hormonal), endoscopy and histological enterochromaffin-like cell and gastrin cell density assessments were performed. Lansoprazole initial dose was adjusted according to clinical symptoms and secretory studies. RESULTS: At 6 months, lansoprazole doses of 60, 90, 120 and 180 mg/d maintained BAO < 10 mmol H+/h in 9, 2, 1 and 1 patient, respectively. No significant changes in FSG, endocrine cells densities and biological parameters were noted during treatment. Neither adverse events nor carcinoid tumors were observed. We conclude that lansoprazole is efficient and well tolerated in patients with ZES.

Dual therapy using a double dose of lansoprazole with amoxicillin versus triple therapy using a double dose of lansoprazole, amoxicillin, and clarithromycin to eradicate Helicobacter pylori infection: results of a prospective randomized open study.

OBJECTIVES: The eradication of Helicobacter pylori is recommended in duodenal ulcer disease. The aim of this randomized open trial was to evaluate and compare H. pylori eradication and safety after a dual therapy consisting of lansoprazole (30 mg b.i.d.) and amoxicillin (1 g b.i.d.) versus a triple therapy consisting of lansoprazole (30 mg b.i.d.), amoxicillin (1 g b.i.d.), and clarithromycin (500 mg b.i.d.) administered from day 1 to day 14. METHODS: All patients with an ulcer received lansoprazole (30 mg) from day 15 to day 28. H. pylori status was determined from antral biopsies using histology, culture, and polymerase chain reaction (PCR) upon inclusion and 1-3 months after the end of the treatment. RESULTS: Of the 50 patients included in the study, five did not adhere to the protocol. H. pylori eradication was obtained in 37.5% of the patients receiving lansoprazole-amoxicillin (n = 9/24) and in 95.2% of the patients receiving lansoprazole-amoxicillin-clarithromycin (n = 20/21, p < 0.0002). Minor side effects appeared in 8.3% of the cases during dual therapy (n = 2/24) and in 52% during triple therapy (n = 13/22, p < 0.001). These side effects consisted mainly of diarrhea and a metallic taste. CONCLUSION: Concomitant administration of double doses of lansoprazole with amoxicillin and clarithromycin is very efficacious against H. pylori infection compared with dual therapy.

Twenty-four-hour monitoring of intragastric acidity: comparison between lansoprazole 30mg and pantoprazole 40mg.

OBJECTIVE: To date, there is no published study, comparing the effects of lansoprazole and pantoprazole on gastric acid secretion inhibition. The aim of this study, was to compare the effects of these two drugs on 24-h intragastric pH-metry. DESIGN: Twelve healthy volunteers were included in an open, randomized, crossover study. Each subject received lansoprazole 30mg during 7 days followed, after a 14-day wash-out period, by pantoprazole 40 mg for 7 days or vice versa. Intragastric 24-h pH monitoring was performed before the treatment, and then after the first and seventh intake in each treatment period. RESULTS: The decrease in gastric acidity on daytime, night-time and total 24-h periods during both treatments was significantly different from the base value. Significant differences in acid inhibition were found between lansoprazole 30mg and pantoprazole 40 mg during daytime and 24 h after the first intake. After repeated dose regimens, a significant difference was detected between treatment periods but only for pH above 4. After the first dose, the median pH value with lansoprazole was also significantly greater than for pantoprazole. Pantoprazole activity increased significantly from first to seventh intake, in contrast to lansoprazole. CONCLUSION: Lansoprazole 30 mg was significantly more potent than pantoprazole 40 mg on 24-h pH profiles on the first and seventh days. The antisecretory effect of lansoprazole was maximum after the first intake whereas pantoprazole activity increased significantly between the first and last intake.

[Dose-response effect of lansoprazole in patients with Zollinger-Ellison syndrome]. / Effet dose-réponse du lansoprazole chez des malades atteints d'un syndrome de Zollinger-Ellison.

Lansoprazole, a new substituted benzimidazole, is an effective acid proton pump inhibitor acting by inhibiting selectively H+/K+ ATPase of the gastric parietal cell. This study was performed to assess the effect of successive 30, 60, 90 and 120 mg dosages of lansoprazole in 4 patients suffering from Zollinger-Ellison syndrome. The basal gastric acid output was markedly inhibited in comparison with baseline values (mean maximal reduction: 87%; extremes: 75-99%) and was dose-related. Lansoprazole inhibited pepsin output globally with a dose range effect between 30 and 90 mg/day. The treatment induced a rapid relief of clinical symptoms. No biological abnormality was noted. These data proved that lansoprazole is efficient for treating gastric acid hypersecretion in patients suffering from ZES.

[Comparative efficacy of lansoprazole and omeprazole on the intragastric pH measured over a period of 24 hours and on the basal]. / Efficacité comparée du lansoprazole et de l'oméprazole sur le pH intragastrique mesuré sur 24 heures et sur le débit acide basal chez 9 malades atteints de syndrome de Zollinger-Ellison.

OBJECTIVES: This paper aimed at evaluating the comparative efficacy of lansoprazole and omeprazole in reducing gastric acid secretion in patients suffering from Zollinger-Ellison syndrome. METHODS: Nine patients with non-resected gastrinoma(s) an previously well controlled by omeprazole (mean dosage 75 +/- 12.4 (SEM) mg/day; extremes: 20-160 mg/day) underwent 24-hour intragastric pH-metry, baseline acid output before next dosing and serum gastrin dosages, receiving their usual therapy and thereafter lansoprazole at a weight equivalent posology (mean dosage 81.6 +/- 12.5 (SEM) mg/day; extremes: 30-165 mg/day). RESULTS: Lansoprazole maintained intragastric pH and basal acid output at therapeutic levels, but a discrete reacidification, that deserves confirmation on a larger group of patients, was observed between the meals. CONCLUSIONS: The possible long-term benefit of this phenomenon, especially on gastrinemia and the fundic ECL-cells density and gastric bacterial content, remains to be evaluated.

Treatment of patients with Zollinger-Ellison syndrome.

In the treatment of Zollinger-Ellison syndrome patients with severe disease and acid hypersecretion, proton pump inhibitors are the drugs of choice. Data have now been accumulated on lansoprazole treatment of 41 patients (21 treated at the National Institutes of Health [NIH], Bethesda, Maryland, USA, and 20 treated at the Bichat-Claude Bernard Hospital, Paris, France). Short-term studies of the inhibitory action of lansoprazole on acid secretion have been carried out in both institutions. Our group first performed a dose-response analysis of the efficacy of lansoprazole in reducing basal acid output (BAO) in four patients with severe Zollinger-Ellison syndrome (mean BAO 52 +/- 9 [SD] mmol H+/h) who had previously been treated with a mean omeprazole dosage of 75 mg/day. The maximum acid inhibitory effect was obtained with lansoprazole 60-90 mg/day. The 40-hour duration of action of lansoprazole appears equivalent to that of omeprazole. In a second study at the Bichat-Claude Bernard Hospital, nine Zollinger-Ellison syndrome patients underwent 24-hour intragastric pH monitoring while receiving lansoprazole (mean dosage 80 mg/day, range 30-165 mg/day) or omeprazole (mean dosage 75 mg/day, range 20-180 mg/day). The acid inhibitory activity of the two drugs was comparable. Those patients are currently receiving long-term maintenance treatment with lansoprazole, and satisfactory clinical and biological secretory control has been achieved. The long-term safety and efficacy of lansoprazole administration were studied in the 21 patients followed at the NIH. In those patients the initial maintenance dose was determined using acid inhibition studies; in all patients lansoprazole controlled gastric acid hypersecretion and peptic symptoms in both the short and long term. The mean initial maintenance dose was 60 mg QID, except for two patients who required 60 mg BID. During long-term treatment (mean duration 31 months, range 1-43 months), six patients required a dosage increase within the first year, while the lansoprazole dose could be reduced in six others. The safety profile of lansoprazole has been excellent. Comparable results have been noted in nine Zollinger-Ellison syndrome patients during an ongoing evaluation in our institution. These studies indicate that lansoprazole is an efficacious, well-tolerated antisecretory agent in patients with Zollinger-Ellison syndrome.