Regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced/metastatic biliary tumors: REACHIN, a randomized, double-blind, phase II trial.

BACKGROUND: There is a high unmet clinical need for treatments of advanced/metastatic biliary tract cancers after progression on first-line chemotherapy. Regorafenib has demonstrated efficacy in some gastrointestinal tumors that progress on standard therapies. PATIENTS AND METHODS: REACHIN was a multicenter, double-blind, placebo-controlled, randomized phase II study designed to evaluate the safety and efficacy of regorafenib in patients with nonresectable/metastatic biliary tract cancer that progressed after gemcitabine/platinum chemotherapy. Patients were randomly assigned 1 : 1 to best supportive care plus either regorafenib 160 mg once daily 3 weeks on/1 week off or placebo until progression or unacceptable toxicity. No crossover was allowed. The primary objective was progression-free survival (PFS). Secondary objectives were response rate, overall survival, and translational analysis. RESULTS: Sixty-six patients with intrahepatic (n = 42), perihilar (n = 6), or extrahepatic (n = 9) cholangiocarcinoma, or gallbladder carcinoma (n = 9) were randomized, 33 to each treatment group (33 per group). At a median follow-up of 24 months, all patients had progressed and six patients were alive. Median treatment duration was 11.0 weeks [95% confidence interval (CI): 6.0-15.9] in the regorafenib group and 6.3 weeks (95% CI: 3.9-7.0) in the placebo group (P = 0.002). Fourteen of 33 patients (42%) in the regorafenib group had a dose reduction. Stable disease rates were 74% (95% CI: 59-90) in the regorafenib group and 34% with placebo (95% CI: 18-51; P = 0.002). Median PFS in the regorafenib group was 3.0 months (95% CI: 2.3-4.9) and 1.5 months (95% CI: 1.2-2.0) in the placebo group (hazard ratio 0.49; 95% CI: 0.29-0.81; P = 0.004) and median overall survival was 5.3 months (95% CI: 2.7-10.5) and 5.1 months (95% CI: 3.0-6.4), respectively (P = 0.28). There were no unexpected/new safety signals. CONCLUSION: Regorafenib significantly improved PFS and tumor control in patients with previously treated metastatic/unresectable biliary tract cancer in the second- or third-line setting. CLINICAL TRIAL REGISTRATION: The trial is registered in the European Clinical Trials Register database (EudraCT 2012-005626-30) and at ClinicalTrials.gov (NCT02162914).

DLL4 expression is a prognostic marker and may predict gemcitabine benefit in resected pancreatic cancer.

BACKGROUND: There is an increasing interest for Notch signalling pathway and particularly Delta-like ligand 4 (DLL4) as potential therapeutic target to improve outcome for patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Using immunohistochemistry (IHC) and tissue microarray (TMA), we assessed the expression patterns of DLL4, Notch1 and Notch3 in 151 patients from two independent cohorts of resected PDAC. We investigated the prognostic and the predictive significance of these proteins. RESULTS: High IHC DLL4 expression in cancer cells was associated with worse overall survival (OS) and disease-free survival (DFS) than low DLL4 expression (median OS: 12.9 vs 30.4 months, P=0.004 and median DFS: 8.8 vs 17.4 months, P=0.02). High DLL4 expression remained a significant negative prognostic factor in multivariate analysis (HR for OS: 2.1, P=0.02 and HR for DFS: 2.0, P=0.02). Low DLL4 abundance was associated with a longer OS-only for patients who received an adjuvant gemcitabine-based chemotherapy (P<0.001) but not for patients who did not receive gemcitabine (P=0.72). Furthermore, the interaction test for adjuvant gemcitabine therapy was statistically significant (P<0.001). The validating cohort recapitulated the findings of the training cohort. CONCLUSIONS: Low DLL4 abundance in tumour cells may predict the benefit from adjuvant gemcitabine therapy after PDAC resection.

[Evolution in the therapeutic strategy of localized resectable pancreatic ductal adenocarcinoma]. / Evolution dans la prise en charge de l'adénocarcinome du pancréas localisé estimé résécable.

Pancreatic ductal adenocarcinoma is characterized by a high rate of early metastatic relapse. Surgical resection is still recognized as the cornerstone upfront therapy. However, reported 5 years survival rates are inferior to 20-25% even when surgery is followed by chemotherapy. Margins involvement on the surgical specimen (50 to 85%) and lymph node involvement (around 70%) both strongly impact survival. Median survivals are close to those of locally advanced diseases treated by chemotherapy or chemoradiotherapy, 15 to 16 months. This review focuses on adverse prognostic factors, post-operative outcomes and their impact on multimodality therapy completion rates and survivals in patients undergoing upfront surgery. Current data and emerging results from neoadjuvant series could lead to a change in the therapeutic strategy.

Osmotic stress affects the stability of freeze-dried Lactobacillus buchneri R1102 as a result of intracellular betaine accumulation and membrane characteristics.

AIMS: To help cells to better resist the stressful conditions associated with the freeze-drying process during starter production, we investigated the effect of various osmotic conditions on growth, survival and acidification activity of Lactobacillus buchneri R1102, after freeze-drying and during storage for 3 months at 25°C. METHODS AND RESULTS: High survival rates during freeze-drying, but not during storage, were obtained when 0·1 mol l(-1) KCl was added at the beginning of fermentation, without any change in membrane properties and betaine accumulation. This condition made it possible to maintain a high acidification rate throughout the process. In contrast, the addition of 0·6 mol l(-1) KCl concentrations at the beginning of fermentation led to a high survival rate during storage that was related to high intracellular betaine levels, low membrane fluidity and high cycC19:0 concentrations. However, these modifications induced the degradation of acidification activity during storage. When a moderate stress was applied by combining 0·1 mol l(-1) KCl at the beginning and 0·6 mol l(-1) KCl at the end of fermentation, betaine accumulated in the cells without any membrane alteration, allowing them to maintain high acidification activity and survival rate during storage. CONCLUSION: Specific osmotic conditions during fermentation induced intracellular betaine accumulation and modifications of membrane character-istics, thus affecting stress resistance of Lact. buchneri R1102. A slight osmotic stress made it possible to maintain a high acidification activity, whereas a high osmotic stress at the end of fermentation led to the preservation of cell survival during freeze-dried storage. SIGNIFICANCE AND IMPACT OF THE STUDY: This study revealed that the survival and preservation of acidification activity of freeze-dried Lact. buchneri R1102 during starter production can be improved by using appropriate osmotic conditions.

Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study.

BACKGROUND: Induction chemotherapy has been suggested to impact on preoperative chemoradiation efficacy in locally advanced rectal cancer (LARC). To evaluate in LARC patients, the feasibility and efficacy of a short intense course of induction oxaliplatin before preoperative chemoradiotherapy (CRT). PATIENTS AND METHODS: Patients with T2-T4/N+ rectal adenocarcinoma were randomly assigned to arm A-preoperative CRT with 5-fluorouracil (5-FU) continuous infusion followed by surgery-or arm B-induction oxaliplatin, folinic acid and 5-FU followed by CRT and surgery. The primary end point was the rate of ypT0-1N0 stage achievement. RESULTS: Fifty seven patients were randomly assigned (arm A/B: 29/28) and evaluated for planned interim analysis. On an intention-to-treat basis, the ypT0-1N0 rate for arms A and B were 34.5% (95% CI: 17.2% to 51.8%) and 32.1% (95% CI: 14.8% to 49.4%), respectively, and the study therefore was closed prematurely for futility. There were no statistically significant differences in other end points including pathological complete response, tumor regression and sphincter preservation. Completion of the preoperative CRT sequence was similar in both groups. Grade 3/4 toxicity was significantly higher in arm B. CONCLUSIONS: Short intense induction oxaliplatin is feasible in LARC patients without compromising the preoperative CRT completion, although the current analysis does not indicate increased locoregional impact on standard therapy.

Contribution of CXCR4 and SMAD4 in predicting disease progression pattern and benefit from adjuvant chemotherapy in resected pancreatic adenocarcinoma.

BACKGROUND: Prognosis of patients with pancreatic adenocarcinoma is poor. Many prognostic biomarkers have been tested, but most studies included heterogeneous patients. We aimed to investigate the prognostic and/or predictive values of four relevant biomarkers in a multicentric cohort of patients. PATIENTS AND METHODS: A total of 471 patients who had resected pancreatic adenocarcinoma were included. Using tissue microarray, we assessed the relationship of biomarker expressions with the overall survival: Smad4, type II TGF-ß receptor, CXCR4, and LKB1. RESULTS: High CXCR4 expression was found to be the only independent negative prognostic biomarker [hazard ratio (HR) = 1.74; P < 0.0001]. In addition, it was significantly associated with a distant relapse pattern (HR = 2.19; P < 0.0001) and was the strongest prognostic factor compared with clinicopathological factors. In patients who did not received adjuvant treatment, there was a trend toward decrease in the overall survival for negative Smad4 expression. Loss of Smad4 expression was not correlated with recurrence pattern but was shown to be predictive for adjuvant chemotherapy (CT) benefit (HR = 0.59; P = 0.002). CONCLUSIONS: CXCR4 is a strong independent prognostic biomarker associated with distant metastatic recurrence and appears as an attractive target to be evaluated in pancreatic adenocarcinoma. Negative SMAD4 expression should be considered as a potential predictor of adjuvant CT benefit.

New strategies and designs in pancreatic cancer research: consensus guidelines report from a European expert panel.

Although the treatment of pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge, it is entering a new era with the development of new strategies and trial designs. Because there is an increasing number of novel therapeutic agents and potential combinations available to test in patients with PDAC, the identification of robust prognostic and predictive markers and of new targets and relevant pathways is a top priority as well as the design of adequate trials incorporating molecular-driven hypothesis. We presently report a consensus strategy for research in pancreatic cancer that was developed by a multidisciplinary panel of experts from different European institutions and collaborative groups involved in pancreatic cancer. The expert panel embraces the concept of exploratory early proof of concept studies, based on the prediction of response to novel agents and combinations, and randomised phase II studies permitting the selection of the best therapeutic approach to go forward into phase III, where the recommended primary end point remains overall survival. Trials should contain as many translational components as possible, relying on standardised tissue and blood processing and robust biobanking, and including dynamic imaging. Attention should not only be paid to the pancreatic cancer cells but also to microenvironmental factors and stem/stellate cells.

High expression of CXCR4 may predict poor survival in resected pancreatic adenocarcinoma.

Chemokines and their receptors are involved in tumourigenicity and clinicopathological significance of chemokines receptor expression in pancreatic adenocarcinoma (PA) is not fully understood. This study was conducted to determine patients' outcome according to the expressions of CXCR4, CXCR7 and HIF-1alpha after resection of PA. Immunohistochemistry for CXCR4, CXCR7 and HIF-1alpha expressions as well as cell proliferative index (Ki-67) was conducted in 71 resected (R0) PA and their 48 related lymph nodes (LN) using tissue microarray. CXCR4 and CXCR7 expressions were positively correlated to HIF-1alpha suggesting a potential role of HIF-1alpha in CXCR4 and CXCR7 transcription activation. Patients with CXCR4(high) tumour expression had shorter OS than those with low expression (median survival: 9.7 vs 43.2 months, P=0.0006), a higher risk of LN metastases and liver recurrence. In multivariate analysis, high CXCR4 expression, LN metastases and poorly differentiated tumour are independent negative prognosis factors. In a combining analysis, patients with a CXCR7(high)/CXCR4(high) [corrected] tumour had a significantly shorter DFS and OS than patients with a CXCR4(low)/CXCR7(low) [corrected] tumour. CXCR4 in resected PA may represent a valuable prognostic factor as well as an attractive target for therapeutic purpose.

The Relationship between a New Biomarker of Vagal Neuroimmunomodulation and Survival in Two Fatal Cancers.

BACKGROUND: The vagus nerve may slow tumor progression because it inhibits inflammation. This study examined the relationship between a new vagal neuroimmunomodulation (NIM) index and survival in fatal cancers. METHOD: We retroactively derived markers of vagal nerve activity indexed by heart rate variability (HRV), specifically the root mean square of successive differences (RMSSD), from patients' electrocardiograms near diagnosis. The NIM index was the ratio of RMSSD to C-reactive protein levels (RMSSD/CRP). Sample 1 included 202 Belgian patients with advanced pancreatic cancer (PC), while sample 2 included 71 Belgian patients with non-small cell lung cancer (NSCLC). In both samples, we examined the overall survival, while in sample 2, we additionally examined the survival time in deceased patients. RESULTS: In PC patients, in a multivariate Cox regression controlling for confounders, the NIM index had a protective relative risk (RR) of 0.68 and 95% confidence interval (95% CI) of 0.51-0.92. In NSCLC patients, the NIM index also had a protective RR of 0.53 and 95% CI of 0.32-0.88. Finally, in NSCLC, patients with a higher NIM index survived more days (475.2) than those with lower NIM (285.1) (p < 0.05). CONCLUSIONS: The NIM index, reflecting vagal modulation of inflammation, may be a new independent prognostic biomarker in fatal cancers.

Prognostic factors and prognostic index for chemonaïve and gemcitabine-refractory patients with advanced pancreatic cancer.

BACKGROUND: Gemcitabine monotherapy is the cornerstone of the treatment of patients suffering from advanced pancreatic cancer (PC). For a few years, new chemotherapeutic agents and combinations have been under validation. The use of such treatment makes it necessary to determine factors that could predict survival time. PATIENTS AND METHODS: To identify factors that predict survival time in chemonaïve patients with advanced PC and after gemcitabine failure, a retrospective analysis was performed on patients with advanced PC coming from phase II and III studies and treated with gemcitabine-based first-line chemotherapy. RESULTS: Ninety-nine patients (median age 66 years, range 27-87) suffering from pathologically proven unresectable or metastatic adenocarcinoma of the pancreas were reviewed. Median overall survival time for the whole population was 251 days and progression-free survival in first- and second-line treatment was 108 and 67 days, respectively. The Cox regression analysis identified aspartate transaminase >53 IU/l, weight loss > or =10% and Karnofsky performance status <90 as significant independent negative prognostic factors in first-line and CA 19-9 >400 IU/ml and albumin < or =3.5 mg/dl in second-line chemotherapy. A prognostic index was calculated from the regression coefficients for each independent prognostic factor and used to classify the patients in 3 different groups with good, intermediate and poor prognosis. The prognosis index in chemonaïve and gemcitabine-refractory patients was (Karnofsky performance status x 0.52) + (weight loss x 1.10) + (aspartate transaminase x 0.82) and (albumin x 1.40) + (CA 19-9 x 0.74), respectively. CONCLUSIONS: Predictive factors could be identified in first- and second-line treatments, although they require prospective validation before they could be used in the design and analysis of future clinical trials.

[Spontaneous intrahepatic haemorrhage due to peliosis hepatis]. / Hémorragie intrahépatique spontanée révélant une péliose hépatique.

Liver vascular lesions may occur in women on oral contraceptives. We report here spontaneous liver haemorrhage caused by peliosis hepatis, occuring in a 47-year old patient. She used oral contraceptives for many years. A computerized tomography and a magnetic resonance of the abdomen revealed a subcapsular liver hematoma without hemoperitoneum. Treatment consisted of supportive care with favourable clinical outcome. This observation point out a severe complication of peliosis hepatis. The authors review the etiology, diagnosis, complications, treatment and potential role of estrogen/progesterone supplementation as an etiological factor, in peliosis hepatis.

Acid sensitivity of neomycin-resistant mutants of Oenococcus oeni: a relationship between reduction of ATPase activity and lack of malolactic activity.

Mutants of Oenococcus oeni were isolated as spontaneous neomycin-resistant mutants. Three of these mutants harbored a significantly reduced ATPase activity that represented 50% of that of the wild-type strain. Their growth rates were also impaired at pH 5.3 (46-86% of the wild-type level). However, the profiles of sugar consumption appeared identical to those of the parental strain. At pH 3.2, all the mutant strains failed to grow and a drastic decrease in viability was observed after an acid shock. Surprisingly, all the isolated mutants were devoid of malolactic activity. These results suggest that the ATPase and malolactic activities of O. oeni are linked to each other and play a crucial role in the mechanism of resistance to an acid stress.

Free radical evolution in rat liver following the ingestion of DAB.

The effect of the ingestion of the carcinogenic substance DAB on the density and distribution of organic free radicals in rat liver is studied by the electron spin resonance method. There is a remarkable parallelism between what is known about the evolution of the activity of mitochondria and the concentration variations of free radicals.

Membrane fluidity of stressed cells of Oenococcus oeni.

The determination of membrane fluidity in whole cells of Oenococcus oeni was achieved by membrane probe 1,6-diphenyl-1,3,5-hexatriene fluorescence anisotropy measurements. The results demonstrated instantaneous fluidity variations with cells directly stressed during the measure. Heat (42 degrees C) or acid (pH 3.2) shocks decreased the anisotropy values (fluidising effects), whereas an ethanol shock (10% ethanol, v/v) increased the membrane rigidity. The velocities of fluidity variation with non-adapted or adapted cells (incubation in inhibitory growth conditions) were compared. The adaptation of the cells to acid conditions had no effect on the membrane fluidity variation after an acid shock. In contrast, the rates of membrane fluidity variation of adapted cells were 5- and 3-fold lower after a heat shock and an ethanol shock, respectively. These results suggest the positive effect of an adaptation on the membrane response and can help to explain the mechanisms of stress tolerance in Oenococcus oeni.

Involvement of osmotic cell shrinkage on the proton extrusion rate in Saccharomyces cerevisiae.

Saccharomyces cerevisiae has been subjected to hyperosmotic shocks by using permeating (sorbitol, xylitol, glycerol, NaCl) and nonpermeating (PEG 600) solutes. The proton extrusion rate decreased as the osmotic pressure increased, whichever solute was used. However, the total inhibition of the cellular H+ extrusion depended on the solute used. A total inhibition was observed at about 20 MPa with glycerol, xylitol and sorbitol. With PEG 600, a total inhibition of extracellular acidification was obtained at 8.5 MPa. NaCl, with an extracellular pressure of 37.8 MPa (near saturation), did not completely inhibit the extracellular acidification. These results showed that the total inhibition of proton extrusion, involving probably the membrane H+-ATPase. was not correlated to the hydric state of the external medium but was strictly linked to the degree of permeation of solutes across the plasma membrane. The extracellular acidification was totally inhibited by a critical final cell volume reached after the osmotic shrinkage, whichever solute was used. This critical final cell volume represented 50% of the initial cell volume. This result suggests that the final cell volume reached after an osmotic stress represents a key thermodynamic parameter for cell osmoregulation in which H+-ATPase would be implicated.

Regulation of stress response in Oenococcus oeni as a function of environmental changes and growth phase.

Oenococcus oeni is a lactic acid bacterium which is able to grow in wine and perform malolactic fermentation. To survive and grow in such a harsh environment as wine, O. oeni uses several mechanisms of resistance including stress protein synthesis. The molecular characterisation of three stress genes hsp18, clpX, trxA encoding for a small heat shock protein, an ATPase regulation component of ClpP protease and a thioredoxin, respectively, allow us to suggest the existence in O. oeni of multiple regulation mechanisms as is the case in Bacillus subtilis. One common feature of these genes is that they are expressed under the control of housekeeping promoters. The expression of these genes as a function of growth is significantly different. Surprisingly, the clpX gene, which is induced by heat shock, was highly expressed in the early phase of growth. In addition to stress protein synthesis, adaptation to the acid pH of wine requires efficient cellular systems to extrude protons. Using inhibitors specific for different types of ATPases, we demonstrated the existence of H+-ATPase and P-type ATPase.

New treatment for seborrheic alopecia: the ligature of the arteries of the scalp.

Bilateral ligature of the superficial temporal arteries and of the posterior auricular arteries is proposed as a treatment for seborrheic alopecia. The arterial circulatory dynamics are, thus, replaced by capillary circulatory dynamics. Hypoxia is produced which inhibits enzymatic systems and lessens nocuous action of androgen and lipid factors on the pilosebaceous effectors. The histologic study shows that the production of sebum is greatly reduced and the condition of the hair follicle is strikingly improved.

Molecular changes in pancreatic cancer: implications for molecular targeting therapy.

Pancreatic ductal adenocarcinoma has a high mortality rate, which is generally related to the initial diagnosis coming at late stage disease combined with a lack of effective treatment options. Gemcitabine has been the most commonly used drug over the past decade and is still the cornerstone of therapy in adjuvant and metastatic settings. Intrinsic or acquired resistance of tumours to gemcitabine is, however, a major clinical problem. New therapeutic strategies are urgently needed whereas we also need to identify new prognostic and predictive biomarkers. This article focuses on gemcitabine resistance, on the role of chemokines and chemokine receptors in pancreatic carcinoma initiation and progression, and on stellate cells as partners in crime with neoplastic epithelial cells.