EIF4A inhibition targets bioenergetic homeostasis in AML MOLM-14 cells in vitro and in vivo and synergizes with cytarabine and venetoclax.

BACKGROUND: Acute myeloid leukemia (AML) is an aggressive hematological cancer resulting from uncontrolled proliferation of differentiation-blocked myeloid cells. Seventy percent of AML patients are currently not cured with available treatments, highlighting the need of novel therapeutic strategies. A promising target in AML is the mammalian target of rapamycin complex 1 (mTORC1). Clinical inhibition of mTORC1 is limited by its reactivation through compensatory and regulatory feedback loops. Here, we explored a strategy to curtail these drawbacks through inhibition of an important effector of the mTORC1signaling pathway, the eukaryotic initiation factor 4A (eIF4A). METHODS: We tested the anti-leukemic effect of a potent and specific eIF4A inhibitor (eIF4Ai), CR-1-31-B, in combination with cytosine arabinoside (araC) or the BCL2 inhibitor venetoclax. We utilized the MOLM-14 human AML cell line to model chemoresistant disease both in vitro and in vivo. In eIF4Ai-treated cells, we assessed for changes in survival, apoptotic priming, de novo protein synthesis, targeted intracellular metabolite content, bioenergetic profile, mitochondrial reactive oxygen species (mtROS) and mitochondrial membrane potential (MMP). RESULTS: eIF4Ai exhibits anti-leukemia activity in vivo while sparing non-malignant myeloid cells. In vitro, eIF4Ai synergizes with two therapeutic agents in AML, araC and venetoclax. EIF4Ai reduces mitochondrial membrane potential (MMP) and the rate of ATP synthesis from mitochondrial respiration and glycolysis. Furthermore, eIF4i enhanced apoptotic priming while reducing the expression levels of the antiapoptotic factors BCL2, BCL-XL and MCL1. Concomitantly, eIF4Ai decreases intracellular levels of specific metabolic intermediates of the tricarboxylic acid cycle (TCA cycle) and glucose metabolism, while enhancing mtROS. In vitro redox stress contributes to eIF4Ai cytotoxicity, as treatment with a ROS scavenger partially rescued the viability of eIF4A inhibition. CONCLUSIONS: We discovered that chemoresistant MOLM-14 cells rely on eIF4A-dependent cap translation for survival in vitro and in vivo. EIF4A drives an intrinsic metabolic program sustaining bioenergetic and redox homeostasis and regulates the expression of anti-apoptotic proteins. Overall, our work suggests that eIF4A-dependent cap translation contributes to adaptive processes involved in resistance to relevant therapeutic agents in AML.

Predicting the influence of multiple components on microbial inhibition using a logistic response model--a novel approach.

BACKGROUND: There are several synergistic methods available. However, there is a vast discrepancy in the interpretation of the synergistic results. Also, these synergistic methods do not assess the influence the tested components (drugs, plant and natural extracts), have upon one another, when more than two components are combined. METHODS: A modified checkerboard method was used to evaluate the synergistic potential of Heteropyxis natalensis, Melaleuca alternifolia, Mentha piperita and the green tea extract known as TEAVIGO™. The synergistic combination was tested against the oral pathogens, Streptococcus mutans, Prevotella intermedia and Candida albicans. Inhibition data obtained from the checkerboard method, in the form of binary code, was used to compute a logistic response model with statistically significant results (p < 0.05). This information was used to construct a novel predictive inhibition model. RESULTS: Based on the predictive inhibition model for each microorganism, the oral pathogens tested were successfully inhibited (at 100% probability) with their respective synergistic combinations. The predictive inhibition model also provided information on the influence that different components have upon one another, and on the overall probability of inhibition. CONCLUSIONS: Using the logistic response model negates the need to 'calculate' synergism as the results are statistically significant. In successfully determining the influence multiple components have upon one another and their effect on microbial inhibition, a novel predictive model was established. This ability to screen multiple components may have far reaching effects in ethnopharmacology, agriculture and pharmaceuticals.

Sorafenib and irinotecan (NEXIRI) as second- or later-line treatment for patients with metastatic colorectal cancer and KRAS-mutated tumours: a multicentre Phase I/II trial.

BACKGROUND: This trial evaluated the feasibility and efficacy of combined sorafenib and irinotecan (NEXIRI) as second- or later-line treatment of patients with KRAS-mutated metastatic colorectal cancer (mCRC), who had progressed after irinotecan-based chemotherapy. METHODS: In Phase I, in a 3+3 dose escalation schedule, patients received irinotecan (125, 150 or 180 mg m(-2) every 2 weeks), in combination with 400 mg sorafenib b.d. The primary end point was the maximum-tolerated dose of irinotecan. In Phase II, the primary end point was disease control rate (DCR). Secondary end points were progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS: Phase I included 10 patients (median age 63 (49-73)); no dose-limiting toxicity was seen. In Phase II, 54 patients (median age 60 (43-80) years) received irinotecan 180 mg m(-)(2) every 2 weeks with sorafenib 400 mg b.d. Nine patients (17%) remained on full-dose sorafenib. The DCR was 64.9% (95% CI, 51-77). Median PFS and OS were 3.7 (95% CI, 3.2-4.7) and 8.0 (95% CI, 4.8-9.7) months, respectively. Toxicities included Grade 3 diarrhoea (37%), neutropenia (18%), hand-foot syndrome (13%) and Grade 4 neutropenia (17%). CONCLUSION: The NEXIRI regimen showed promising activity as second- or later-line treatment in this heavily pretreated mCRC population (ClinicalTrials.gov NCT00989469).

Is restaging with chest and abdominal CT scan after neoadjuvant chemoradiotherapy for locally advanced rectal cancer necessary?

BACKGROUND: There is no evidence regarding restaging of patients with locally advanced rectal cancer after a long course of neoadjuvant radiotherapy with or without chemotherapy. This study evaluated the value of restaging with chest and abdominal computed tomographic (CT) scan after radiotherapy. METHODS: Between January 2000 and December 2010, all newly diagnosed patients in our tertiary referral hospital, who underwent a long course of radiotherapy for locally advanced rectal cancer, were analyzed. Patients were only included if they had chest and abdominal imaging before and after radiotherapy treatment. RESULTS: A total of 153 patients who met the inclusion criteria and were treated with curative intent were included. A change in treatment strategy due to new findings on the CT scan after radiotherapy was observed in 18 (12%) of 153 patients. Twelve patients (8%) were spared rectal surgery due to progressive metastatic disease. CONCLUSIONS: Restaging with a chest and abdominal CT scan after radiotherapy for locally advanced rectal cancer is advisable because additional findings may alter the treatment strategy.

BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer.

BACKGROUND: Sorafenib is an oral anticancer agent targeting Ras-dependent signaling and angiogenic pathways. A phase I trial demonstrated that the combination of gemcitabine and sorafenib was well tolerated and had activity in advanced pancreatic cancer (APC) patients. The BAYPAN study was a multicentric, placebo-controlled, double-blind, randomized phase III trial comparing gemcitabine/sorafenib and gemcitabine/placebo in the treatment of APC. PATIENTS AND METHODS: The patient eligibility criteria were locally advanced or metastatic pancreatic adenocarcinoma, no prior therapy for advanced disease and a performance status of zero to two. The primary end point was progression-free survival (PFS). The patients received gemcitabine 1000 mg/m(2) i.v., weekly seven times followed by 1 rest week, then weekly three times every 4 weeks plus sorafenib 200 mg or placebo, two tablets p.o., twice daily continuously. RESULTS: Between December 2006 and September 2009, 104 patients were enrolled on the study (52 pts in each arm) and 102 patients were treated. The median and the 6-month PFS were 5.7 months and 48% for gemcitabine/placebo and 3.8 months and 33% for gemcitabine/sorafenib (P = 0.902, stratified log-rank test), respectively. The median overall survivals were 9.2 and 8 months, respectively (P = 0.231, log-rank test). The overall response rates were similar (19 and 23%, respectively). CONCLUSION: The addition of sorafenib to gemcitabine does not improve PFS in APC patients.

Chronopharmacokinetics of oral tegafur and uracil in colorectal cancer patients.

Uracil-Ftorafur (UFT) combines the 5-fluorouracil (FU) prodrug tegafur with uracil (at a 1:4 molar ratio), which is a competitive inhibitor of dihydropyrimidine dehydrogenase (DPD), the limiting enzyme of FU catabolism. As a result, sustained FU concentrations are obtained in both plasma and tumor. UFT is an effective alternative to intravenous FU-Leucovorin (LV) in metastatic and adjuvant colorectal cancer treatment. A circadian rhythm for DPD activity has been shown in both human and animal studies, with consequences on FU plasma concentrations in patients receiving FU as a continuous infusion. The chronopharmacokinetics of FU has stimulated clinical trials of chronomodulated delivery schedules for floxuridine and FU infusions, suggesting that such schedules may improve the fluoropyrimidine therapeutic index. Molecular mechanisms responsible for the circadian dependence of FU pharmacodynamics include circadian rhythms in thymidylate synthase activity and DNA synthesis, as recently reported. Chronopharmacology of FU prodrugs is poorly documented. Recently, a feasibility study of chronomodulated administration of the FU oral prodrug capecitabine was reported. To our knowledge, the only study reporting on the time dependency of UFT pharmacokinetics is a phase I study by Muggia et al.

Phase II study of oxaliplatin, fluorouracil, and folinic acid in locally advanced or metastatic gastric cancer patients.

PURPOSE: To evaluate the efficacy and safety of an oxaliplatin, fluorouracil (5-FU), and folinic acid (FA) combination in patients with metastatic or advanced gastric cancer (M/AGC). PATIENTS AND METHODS: Of the 54 eligible patients with measurable or assessable M/AGC, 53 received oxaliplatin 100 mg/m(2) and FA 400 mg/m(2) (2-hour intravenous infusion) followed by 5-FU bolus 400 mg/m(2) (10-minute infusion) and then 5-FU 3,000 mg/m(2) (46-hour continuous infusion) every 14 days. RESULTS: Patients (69% male, 31% female) had a median age of 61 years (range, 31 to 75 years), 89% had a performance status of 0 or 1, 70% had newly diagnosed disease, and 87% had metastatic disease. All had histologically confirmed adenocarcinoma. With a median of three involved organs, disease sites included the lymph nodes (67%), stomach (65%), and liver (61%). A median of 10 cycles per patient and 468 complete cycles were administered. Best responses in the 49 assessable patients were two complete responses and 20 partial responses, giving an overall best response rate of 44.9%. Eight patients underwent complementary treatment with curative intent (six with surgery and two with chemoradiotherapy). Median follow-up, time to progression, and overall survival were 18.6 months, 6.2 months, and 8.6 months, respectively. Grade 3/4 neutropenia, leukopenia, thrombocytopenia, and anemia occurred in 38%, 19%, 4%, and 11% of patients, respectively, and febrile neutropenia occurred in six patients (one episode each). Grade 3 peripheral neuropathy occurred in 21% of patients (oxaliplatin-specific scale). Seven patients withdrew because of treatment-related toxicity. CONCLUSION: This oxaliplatin/5-FU/FA regimen shows good efficacy and an acceptable safety profile in M/AGC patients, and may prove to be a suitable alternative regimen in this indication.

High-dose radiation therapy and neoadjuvant plus concomitant chemotherapy with 5-fluorouracil and cisplatin in patients with locally advanced squamous-cell anal canal cancer: final results of a phase II study.

PURPOSE: To analyse toxicity and response to a new scheme of neoadjuvant chemotherapy (CT) and concomitant radiochemotherapy (RT-CT) for locally advanced anal canal squamous-cell carcinoma (ACC). PATIENTS AND METHODS: Eighty patients with an ACC > 40 mm and/or with lymph node involvement were included (1 T1, 52 T2, 14 T3, 13 T4, 18 N0, 30 N1, 32 N2-N3). Two cycles of 5-fluorouracil (5-FU) and CDDP were delivered as neoadjuvant CT and two during RT-CT. Pelvic (+/- inguinal) RT delivered 45 Gy in 25 fractions of 1.8 Gy. Involved fields were boosted after a one to two month gap (15-20 Gy). The median follow-up was 29 months. RESULTS: One patient died of a pulmonary embolism on day 4. All patients received the entire treatment, with reduced 5-FU doses in 27% of the cases because of acute toxicity. Sixty-four grade 3 and five grade 4 toxicities were observed. No toxic death occurred. Complete response (CR) and partial response (PR) rates were, respectively, 10% and 51% after neoadjuvant CT, 67% and 28% after RT-CT and 93% and 5% after treatment completion (including 4 abdomino-perineal resections). The three-year actuarial overall, tumour-specific, colostomy-free, relapse-free, disease-free and event-free survivals were 86%, 88%, 73%, 70%, 67% and 63%, respectively. CONCLUSIONS: Tolerance was good. After neoadjuvant CT, most of the patients were objective responders. After treatment completion, all but five achieved CR. The long-term results confirm the durability of local control and low toxicity on the sphincter. An ongoing phase III intergroup trial analyses the impact of neoadjuvant CT, and the benefit of a high-dose boost irradiation, on local control and colostomy-free survival.

Multicenter phase II study of bimonthly high-dose leucovorin, fluorouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen.

PURPOSE: To evaluate the objective tumor response rates and toxicities of leucovorin (LV) plus fluorouracil (5-FU) cancer regimen combined with oxaliplatin (85 mg/m(2)) every 2 weeks on metastatic colorectal cancer patients with documented proof of progression while on bimonthly LV and 5-FU alone. PATIENTS AND METHODS: One hundred patients were enrolled onto this study and 97 received the study drugs between October 1995 and December 1996. Eighty-nine patients were eligible for per-protocol efficacy analysis with documented proof of progression on one of the following two treatments: LV 500 mg/m(2) and continuous 5-FU infusion 1.5 to 2 g/m(2)/22 hours, days 1 through 2 every 2 weeks (FOLFUHD); or LV 200 mg/m(2), bolus 5-FU 400 mg/m(2), and continuous 5-FU infusion 600 mg/m(2)/22 hours, days 1 through 2 every 2 weeks (LV5FU2). In our study, 40 patients received FOLFUHD + 85 mg/m(2) of oxaliplatin day 1 (FOLFOX3) and 57 patients received LV5FU2 + 85 mg/m(2) of oxaliplatin day 1 (FOLFOX4). RESULTS: Of the 97 patients treated, 20 partial responses were observed (FOLFOX3/4: response rate, 20.6%; 95% confidence interval, 13% to 31.1%; FOLFOX3: response rate,18.4%; FOLFOX4: response rate, 23.5%). For patients treated with FOLFOX3/4, the median response duration for was 7.5 months, and the major toxicities were peripheral neuropathy and neutropenia. The incidence of grade 3 (National Cancer Institute common toxicity criteria) peripheral neuropathy was 20.6%; whereas the overall incidence of grade 3 to 4 neutropenia was 27.8%, 15%, and 36.9% for FOLFOX3/4, FOLFOX3, and FOLFOX4, respectively (P =.02). From the start of treatment, median progression-free survival was 4. 7, 4.6, and 5.1 months for FOLFOX3/4, FOLFOX3, FOLFOX4, respectively, and median overall survival was 10.8, 10.6, and 11.1 months, respectively. CONCLUSION: This phase II study of oxaliplatin at 85 mg/m(2) in combination with bimonthly LV plus 5-FU in patients with colorectal cancer resistant to LV plus 5-FU alone confirms the enhanced antitumor activity of oxaliplatin in combination with 5-FU.

Open, randomized, multicenter trial of raltitrexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer. Tomudex Colorectal Cancer Study Group.

PURPOSE: To compare raltitrexed (Tomudex; Zeneca Pharmaceuticals Ltd, Macclesfield, United Kingdom) a direct, specific thymidylate synthase (TS) inhibitor with fluorouracil (5-FU) plus high-dose leucovorin (LV) as first-line treatment for advanced colorectal cancer (ACC). PATIENTS AND METHODS: A total of 495 patients were randomized to raltitrexed (3 mg/m2) once every 3 weeks or 5-FU (400 mg/m2) plus LV (200 mg/m2) daily for 5 days every 4 weeks. RESULTS: The randomized groups were well balanced demographically. With a minimum 17-month follow-up, median survival was comparable between groups (10.9 months raltitrexed v 12.3 months 5-FU/LV; hazards ratio, 1.15; 95% confidence interval [CI], 0.93 to 1.42; P=.197), although time to progression was statistically significantly shorter in the raltitrexed group. Overall objective responses were comparable (19% raltitrexed v 18% 5-FU/LV), with more than 50% of patients in each group having stable disease. Significantly less World Health Organization (WHO) grade 3 and 4 stomatitis (2% v 16%, P < .001) and a reduced incidence of leukopenia (6% v 13%) and diarrhea (10% v 19%) occurred in the raltitrexed group (particularly at cycle 1 ). This resulted in fewer dose reductions at cycle 2 (4% raltitrexed v 28% 5-FU/LV) and early quality-of-life (QoL) benefits for raltitrexed patients. Reversible, clinically insignificant increases in transaminases were reported in 13% of raltitrexed patients. Palliative benefits of weight gain, improved performance status, and reduced disease-related symptoms were evident in both groups. CONCLUSION: Raltitrexed is confirmed as an effective option in the first-line palliative management of ACC, with comparable efficacy to and tolerability advantages (in terms of reduced incidence of stomatitis, diarrhea, and leukopenia) over 5-FU/LV. Raltitrexed has the added convenience of an every 3 weeks dosing schedule.

Preliminary results of a phase II study of high-dose radiation therapy and neoadjuvant plus concomitant 5-fluorouracil with CDDP chemotherapy for patients with anal canal cancer: a French cooperative study.

BACKGROUND: Chemotherapy (5-fluorouracil-mitomycin C) concomitant with radiotherapy (RT) increases local control and colostomy-free survival in advanced anal canal carcinomas (ACC). The purpose of this prospective trial was to analyse the toxicity of and response to an induction chemotherapy combining 5-fluorouracil (5-FU) and CDDP administered concomitantly with irradiation. PATIENTS AND METHODS: Thirty patients (24 F/6 M, mean age 60, range 38-74) with an advanced ACC > 40 mm and/or with node involvement were prospectively treated (1 T1, 16 T2, 8 T3, 5 T4, 10 N1, 1 N2, 8 N3) from November 1994 to January 1996. Two induction and two concomitant cycles of 5-FU (800 mg/ m2 D1-4 infusion) and CDDP (80 mg/i.v./m2 at D1) were delivered. RT consisted of 45 Gy (1.8 Gy/fr, 5 fr/w) on pelvis +/- inguinal nodes or 30 Gy (3 Gy/fr, 4 fr/w) by direct perineal field. A boost (15-20 Gy) was delivered six weeks later. TOXICITY: one patient died of a pulmonary embolism on D4. The remaining 29 received the entire treatment, with reduced 5-FU doses in 11 patients because of acute toxicity. The RT boost was delayed for one patient (aplasia). In 109 cycles, 3 grade 4 and 17 grade 3 toxicities were observed; there were no toxic deaths. Tumor response: the complete response (CR) and partial response (PR) rates were, respectively, 11% and 61% after induction chemotherapy, 59% and 31% after concomitant radiochemotherapy and 96% and 0% two months after completion of the treatment. No tumor progression was observed. CONCLUSION: the treatment was well tolerated and there was good compliance. After induction chemotherapy, most of the patients were in PR, with some even in CR. After completion of the treatment all but one were in CR. The tumor response and the long term results of 50 patients will be analysed before initiation of a randomised trial is considered.

Decreased folylpolyglutamate synthetase activity in tumors resistant to fluorouracil-folinic acid treatment: clinical data.

Thymidylate synthase (TS) is the main target for fluorouracil (FU). Optimal cellular concentrations of reduced folates in polyglutamated forms [via folylpolyglutamate synthetase (FPGS)] are necessary for achieving maximal TS inhibition. The aim of this multicentric prospective study was to analyze the link between clinical response to FU therapy for liver metastases of colorectal carcinoma and tumoral TS and FPGS activities. Forty-four advanced colorectal cancer patients (15 women and 29 men; median age 63, range, 27-78 years) receiving a standard FU-folinic acid protocol were included. A single hepatic tumoral biopsy was obtained systematically at the time of diagnosis. For 24 patients, a biopsy in the primary colon tumor was available. TS and FPGS activities were measured by radioenzymatic assays. Clinical response on hepatic metastases was 1 complete response, 12 partial responses, 14 stabilizations, and 17 progressions. In hepatic biopsies, TS activity (median, 185; range, <10-3111 fmol/min/mg protein) and FPGS activity (median, 1270; range, <400-3730 fmol/min/mg protein) exhibited a wide variability. TS activity in primary tumors (median, 461; range, 35-2565 fmol/min/mg protein) was significantly higher than in hepatic metastases. No difference was observed between primaries and metastases for FPGS. FPGS activity expressed in liver metastases was significantly correlated to that expressed in primaries. The distribution of TS activity in liver metastases was not significantly different between responsive and nonresponsive patients. However, FPGS activity measured in liver metastases was significantly higher in responsive patients (median, 1550 fmol/min/mg protein) than in nonresponsive patients (median, 1100 fmol/min/mg protein). A discriminant analysis revealed that 24 of the 25 patients exhibiting a liver FPGS activity 320 fmol/min/mg protein were nonresponding patients. These data establish for the first time the potential importance of tumoral FPGS activity for assessing FU-folinic acid responsiveness in the clinical setting.

Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study.

PURPOSE: This multicenter study compared the therapeutic ratio of a monthly schedule of low-dose leucovorin (LV) and fluorouracil (5-FU) bolus with a bimonthly schedule of high-dose LV and 5-FU bolus plus continuous infusion in patients with advanced colorectal cancer. PATIENTS AND METHODS: Of the 448 patients randomly assigned to treatment, 433 were assessable. Treatment A was a monthly regimen of intravenous (IV) LV 20 mg/m2 plus bolus 5-FU 425 mg/m2 for 5 days every 4 weeks. Treatment B was a bimonthly regimen of IV LV 200 mg/m2 as a 2-hour infusion followed by bolus 5-FU 400 mg/m2 and 22-hour infusion 5-FU 600 mg/m2 for 2 consecutive days every 2 weeks. Therapy was continued until disease progression. Second-line chemotherapy, which included 5-FU continuous infusion, was allowed in both arms. RESULTS: The response rates in 348 patients with measurable lesions were 14.4% (monthly regimen) and 32.6% (bimonthly regimen) (P = .0004). The median progression-free survival times were 22 weeks (monthly regimen) and 27.6 weeks (bimonthly regimen) (P = .0012). The median survival times were 56.8 weeks (monthly regimen) and 62 weeks (bimonthly regimen) (P = .067). Grade 3-4 toxicities occurred in 23.9% of patients in the monthly arm compared with 11.1% of those in the bimonthly arm (P = .0004). Patients in arm A more frequently experienced severe granulocytopenia (7.3% v 1.9%), diarrhea (7.3% v 2.9%), and mucositis (7.3% v 1.9%) than patients in arm B. CONCLUSION: The bimonthly regimen was more effective and less toxic than the monthly regimen and definitely increased the therapeutic ratio. However, there was no evidence of increased survival.

[Fortuitous discoveries of digestive tract tumors during the evaluation of hepatic tumors by lipiodol intra-arterial injection. Diagnostic application in a case of pancreatic tumor]. / Découvertes fortuites de tumeurs du tube digestif lors de bilan de tumeurs hépatiques par injection intra-artérielle lipiodolée. Application diagnostique dans un cas de tumeur pancréatique.

The authors report three cases of extrahepatic lipiodol enhancement: two fortuitous discoveries of gastric and duodenal leiomyomas during the management of malignant hepatic lesion and a pancreatic surgical detection of an insulinoma which had not been detected with conventional techniques. The principles of the technique are described. The basis of its application to the pancreatic region is purposed and the future developments of pancreatic studies are discussed.

Ischemic pathology of the colon.

Ischemic colitis is a disease with a polymorphic clinical picture, which may be of a formidable gravity in gangrenous forms. Its etiologies are varied and more and more due to a low arterial output. The examinations permitting to establish the diagnosis are barium enema and mostly colonoscopy which should be performed early and repeated often. The treatment vary according to the severity of the disease; prognosis is always reserved.