Evaluation of the relevance of the growth modulation index (GMI) from the FFCD 0307 randomized phase III trial comparing the sequence of two chemotherapeutic regimens.

BACKGROUND: Precision medicine trials disrupted the paradigm of randomized controlled trials in large populations. Patient selection may be based on molecular alterations rather than on primary tumor location. In small patient populations, the growth modulation index (GMI) has been developed to evaluate treatment efficacy by using each patient as its own control. The FFCD 0307 randomized phase III trial compared two sequences of chemotherapy in advanced gastric cancer, which represents a unique opportunity to evaluate the relevance of the GMI. PATIENTS AND METHODS: In the FFCD 0307 trial, patients with advanced gastric cancer were randomized between two chemotherapy sequences [ECX followed by FOLFIRI at disease progression (arm A) versus FOLFIRI followed by ECX (arm B)]. GMI was defined as the ratio of the progression-free survival on second treatment (PFS2) to the time to progression on first treatment (TTP1). Sequence benefit was defined as a GMI exceeding 1.3 (GMI-high). GMI was correlated with overall survival (OS). OS1 and OS2 were measured from first randomization and second-line failure to death. RESULTS: Four hundred and sixteen patients were randomized (209 in arm A, 207 in arm B). One hundred and seventy-five patients (42%) received the two sequences and were assessable for GMI (97 in arm A, 79 in arm B). The median GMI was higher in arm A than in arm B (0.62 versus 0.47, P = 0.04). Patients with a high GMI had a longer OS1 (median 14.9 versus 11.5 months, NS). Median OS2 was doubled in the GMI-high group (3.4 versus 1.6 months, NS). CONCLUSION: GMI analyses suggest that ECX followed by FOLFIRI might represent a better therapeutic strategy than FOLFIRI followed by ECX. High GMI was associated with prolonged survival.

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.

Phase II study of UFT with leucovorin and irinotecan (TEGAFIRI): first-line therapy for metastatic colorectal cancer.

This phase II trial was performed to evaluate the efficacy and tolerability of oral tegafur-uracil (UFT) with leucovorin (LV) combined with intravenous (i.v.) irinotecan every 3 weeks (TEGAFIRI) as first-line treatment for patients with metastatic colorectal cancer (mCRC). Patients received oral UFT 250 mg m(-2) day(-1) and LV 90 mg day(-1) in three divided daily doses for 14 days followed by a 1-week rest and i.v. irinotecan 250 mg m(-2) as a 90-min infusion every 3 weeks. Tumour responses, assessed every two cycles using RECIST criteria, were reviewed by an independent review committee. In 52 evaluable patients, the best overall response rate was 33% (95% confidence intervals (CI) 20-47%; 1 complete and 16 partial responses). The median time to progression was 5.4 months (95% CI 3.02-7.52 months) and median overall survival was 14.9 months (11.73-17.97 months). A total of 307 cycles were administered, with a median number of five cycles per patient (range: 1-10). The most common grade 3/4 toxicities were neutropenia (25% of patients), diarrhoea (22%), vomiting (11%) and anaemia (11%). The TEGAFIRI regimen is a feasible, well-tolerated and convenient treatment option for patients with non-resectable mCRC.

'A phase II study of oral uracil/ftorafur (UFT) plus leucovorin combined with oxaliplatin (TEGAFOX) as first-line treatment in patients with metastatic colorectal cancer'.

This phase II trial was performed to evaluate the efficacy and tolerability of a new combination of Uracil/Ftorafur (UFT)/leucovorin (LV) and oxaliplatin in patients (pts) with metastatic colorectal cancer (MCRC) who had not received prior chemotherapy for metastatic disease. Between February 2002 and October 2002, 64 patients received UFT 300 mg m(-2) day(-1) and LV 90 mg day(-1) from day 1 to day 14 combined with oxaliplatin 130 mg m(-2) on day 1, every 3 weeks. All patients were evaluable for safety analysis and 58 of 64 patients were eligible for efficacy. Responses were reviewed by an independent review committee. Of the 58 per-protocol defined assessable patients, 1 complete response and 20 partial responses were observed yielding a response rate of 34% (95% CI: 22-47). The median response duration was 8.74 months (range 1.6-14). The median time to progression and the median survival were 5.88 months (95% CI: 4.34-8.21) and 18.2 months (95% CI: 10-20.7), respectively. Diarrhoea and peripheral neuropathy were the most frequent and predictable toxicities. These events were reversible, noncumulative and manageable. Grade 3 diarrhoea occurred in only 11% of the patients. No grade 4 gastrointestinal toxicity was reported in the study. The incidence of grade 3/4 (National Cancer Institute Common Toxicity Criteria 2: NCI-CTC 2) peripheral neuropathy was 15%. Haematological toxicity was of mild to moderate intensity with 10% of the patients with Grade 3/4 neutropenia without any episode of complication. The TEGAFOX regimen, a new combination using UFT/LV and oxaliplatin every 3 weeks is feasible on an outpatient basis. The combination is safe and active and may offer a promising alternative to the intravenous route. Nevertheless this efficacy results should be confirmed by randomized phase III trials.

A phase II trial of raltitrexed (Tomudex) in advanced pancreatic and biliary carcinoma.

PURPOSE: To evaluate the impact of raltitrexed (Tomudex) on the quality of life in a multicenter, phase II study in advanced pancreatic and biliary carcinomas. PATIENTS AND METHODS: Forty-six patients with advanced, histologically proven pancreatic (n = 37, 80.4%) or biliary (n = 9, 19.6%) carcinoma received 3 mg/m2 raltitrexed intravenously once every 3 weeks. For the quality of life assessments, EORTC QLQ-C30 was used, and the evaluation of the clinical benefit was performed according to the 4 criteria of the clinical benefit response. All patients were assessed for safety, and 41 patients were evaluable for objective response. RESULTS: Patients (63% male/37% female) had a mean age of 61.2 years, 71.7% had a PS of 0-1, 78.3% had metastatic disease, and 63% had at least 2 tumoral sites. A total of 176 cycles were administered with a mean of 4 cycles per patient (range 1-12). Three out of 43 patients evaluable for EORTC QLQ-C30 (7.0%; CI(95%) 1.4-19.0%) had a quality of life improvement. Thirty-two patients fulfilled the 4 criteria required to evaluate the clinical benefit response; 5 were responders (15.6%; CI(95%) 5.3-32.8%); 1 patient was a good responder based on both the EORTC questionnaire and the clinical benefit response. Forty-one patients were assessable for response, 3 responded to treatment (response rate: 6.5 %; CI(95%) 1.3-17.9%). Median survival was 4.6 months (CI(95%) 2.9-8.2 months), the 1-year survival rate was 21.8%. The most common grade 3-4 toxicities were neutropenia (8%), leukopenia (8%), thrombopenia (6%), anemia (6%), liver enzyme elevations (11%), asthenia (9%), vomiting (9%), abdominal pain (7%), and phlebitis (6%). One treatment-related death occurred (neutropenic sepsis). CONCLUSION: Raltitrexed appeared to be generally well tolerated and showed a clinical benefit response and/or quality of life improvement in a limited number of patients.

Epidemiological changes in hepatitis C virus genotypes in France: evidence in intravenous drug users.

Hepatitis C virus (HCV) genotypes are distributed differently depending on geography and route of infection. We characterized the distribution of genotypes in a large cohort of patients with chronic hepatitis C in the South-east of France and evaluated the relative prevalence according to time of acquisition. One thousand, one hundred-and-eighty-three patients who were anti-HCV-positive were studied. HCV genotype distribution has changed significantly from the 1960s to 2000. The prevalence of genotype 1b decreased from 47% before 1978 to 18.8% in the 1990s while the prevalence of genotype 1a and 3a increased during the same period from 18% and 15.3% to 28.8% and 26.3%, respectively. The logistic regression model showed that genotype 1a was significantly more common in patients infected through intravenous drug injection odds ratio ((OR): 2.08, P < 0.01) and after 1990 (OR: 1.98, P < 0.05). Genotype 1b was significantly less frequent in patients infected through intravenous drug injection (OR: 0.17, P < 0.001) and has decreased since 1978 (OR: 0.27, P < 0.001). Genotype 3a was independently associated with intravenous drug injection (OR: 6.1, P < 0.001) and tattooing (OR: 8.01, P < 0.001) and was more frequent in the 1979-90 period (OR: 2.05 and 1.74, P < 0.001 and P < 0.05). Our results show a modification of HCV genotypes distribution over the last four decades due to an increase of intravenous drug use (IVDU) contamination and an evolution of HCV genotypes distribution only in IVDU population characterized by a decrease of genotype 1b, an increase of genotype 3a from 1970 to 1990 and a higher increase of genotype 1a which is currently the predominant genotype in our population.

Autoantibodies directed against ribosomal proteins in systemic lupus erythematosus and rheumatoid arthritis: a comparative study.

To assess the specificity of autoantibodies (aAbs) directed against the ribosomal P-proteins (RPPaAbs) in patients with systemic lupus erythematosus (SLE) and to investigate aAbs directed to other ribosomal proteins, 100 SLE, 100 rheumatoid arthritis (RA), 25 thyroiditis and 20 blood-donors were analyzed in a comparative study using an immunoblotting technique. Forty-eight percent of SLB sera contained aAbs directed against the ribosomal proteins of the 60 S subunit compared to 9% for RA, 5% for blood donors and 0% for thyroiditis. RPPaAbs were only found in SLE (25%) and aAbs directed to a 31 kDa and/or a 28 kDa protein of the 60 S subunit were found with a statistically higher frequency for SLE compared to RA (p < 0.0001). aAbs directed to proteins of the 40 S subunit were present in 63% of the SLE sera compared to 42% for RA, 4% for thyroiditis and 5% for blood donors. The number of positive sera was not statistically different between SLE and RA but a much more intense reactivity was observed for SLE sera. These data shows that the aAbs against the ribosomal proteins, especially the P-proteins along with the 28 and 31 kDa proteins of the 60 S subunit proteins, can be considered as useful biological markers for t he diagnosis of SLE inclinical practice.

Investigation of the in vitro metabolism profile of a phosphodiesterase-IV inhibitor, CDP-840: leading to structural optimization.

CDP-840 is a selective and potent phosphodiesterase type IV inhibitor, whose in vitro metabolism profile was first investigated using liver microsomes from different species. At least 10 phase I oxidative metabolites (M1-M10) were detected in the microsomal incubations and characterized by capillary high-performance liquid chromatography continuous-flow liquid secondary ion mass spectrometry (CF-LSIMS). Significant differences in the microsomal metabolism of CDP-840 were found between rat and other species. The major route of metabolism in rat involved para-hydroxylation on the R4 phenyl. This pathway was not observed in human and several other species. The in vitro metabolism profile of CDP-840 was further examined using freshly isolated hepatocytes from rat, rabbit, and human. The hepatocyte incubations indicated more extensive metabolism relative to that in microsomes. In addition to the phase I oxidative metabolites observed in microsomal incubations, several phase II conjugates were identified and characterized by CF-LSIMS. Interspecies differences in phase II metabolism were also found in these hepatocyte incubations. The major metabolite in human hepatocytes was identified as the pyridinium glucuronide, which was not detected in rat hepatocytes. Simple structural modification on R4, such as p-Cl substitution, greatly reduced the species differences in microsomal metabolism. Furthermore, modifications on R3, such as the N-oxide, eliminated the N-glucuronide formation in human. These results not only helped in determining the suitability of animal species used in the preclinical safety studies but also provided valuable directions for the synthetic efforts in finding backup compounds that are more metabolically stable.

[Use of echocardiography in the diagnosis of carcinoid tumors. Report of 4 cases]. / Apport de l'échocardiographie dans le diagnostic des tumeurs carcinoïdes. A propos de 4 observations.

Carcinoid tumours are the most common neuro-endocrine tumours but cardiac involvement is rarely symptomatic although often observed at post-mortem and rarely revelatory of the disease. The authors report 4 cases in which echocardiographic detection of characteristic right ventricular involvement led to the confirmation of the diagnosis of carcinoid tumour leading to the secondary diagnosis of the primary carcinoid tumour. The clinical, physiopathological echocardiographic and therapeutic characteristics of this condition are discussed.

Covert transmission of hepatitis C virus during bloody fisticuffs.

Hepatitis C virus (HCV) is transmitted primarily through direct percutaneous exposure to infected blood. Sporadic HCV cases exist and may represent more than 10% of HCV transmission. We report the first case of documented transmission of HCV during a fight from a person who unknowingly had chronic HCV infection to a person who subsequently contracted acute hepatitis C. Patient-to-patient transmission was ascertained by sequence analysis of part of the NS5B genome and phylogenetic analysis. This case report suggests that sporadic HCV infection may be a result of blood exposure. This example of transmission could have a major impact in sports such as boxing or rugby. We suggest that in any fight, single use or nondisposable material should be used to dry blood to avoid such contamination.

Autoantibodies directed against the ribosomal P proteins are not only directed against a common epitope of the P0, P1 and P2 proteins.

The autoantibodies (aAbs) directed against the ribosomal P proteins (RPP aAbs) are known to react mainly against epitopes localized within the common C-terminal sequence of the three acidic ribosomal P proteins, P0, P1 and P2. In order to investigate the opportunity to select short recombinant peptides of this common C-terminal sequence to detect the RPP-aAbs, the location of the epitopes recognized by ribosomal proteins (RP) aAb(+)sera of systemic lupus erythematosus patients (SLE) was investigated. Immunoblotting and ELISA techniques using extracted or recombinant, entire or cleaved RPP showed that 55% of the RP aAbs were directed against the three ribosomal P0, P1, and P2 proteins. The epitopes recognized by the RPP aAbs are located not only within the C-terminal sequence common to the three proteins but also within the N-terminal sequence of the P2 or P1 protein. The other RP aAbs sera (45%) did not react with all three proteins but with some of them, and showed the following pattern: P0(+)P1(+); P1(+); P2(+); P0(+)and P1(+). They recognized epitopes located in the region of the C-terminal sequence of the protein but not common to the three proteins. In addition two out of the six monoclonal Abs produced by immunization of mice using the P1 protein did not react with the peptide N-65 or N-71 of the P2 protein or with the C-terminal sequence of the three proteins. In conclusion, this study showed that the RPP aAb in SLE patients are not only directed against epitopes within the C-terminal sequence shared by the three acidic ribosomal P proteins. In view of these data it seems necessary to be cautious in using only a C-terminal peptide of ribosomal P proteins in tests performed to detect RPP aAb in human sera.

Rofecoxib [Vioxx, MK-0966; 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone]: a potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and biochemical profiles.

The discoveries that cyclooxygenase (COX)-2 is an inducible form of COX involved in inflammation and that COX-1 is the major isoform responsible for the production of prostaglandins (PGs) in the gastrointestinal tract have provided a rationale for the development of specific COX-2 inhibitors as a new class of anti-inflammatory agents with improved gastrointestinal tolerability. In the present study, the preclinical pharmacological and biochemical profiles of rofecoxib [Vioxx, also known as MK-0966, 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone], an orally active COX-2 inhibitor, are described. Rofecoxib is a potent inhibitor of the COX-2-dependent production of PGE(2) in human osteosarcoma cells (IC(50) = 26 +/- 10 nM) and Chinese hamster ovary cells expressing human COX-2 (IC(50) = 18 +/- 7 nM) with a 1000-fold selectivity for the inhibition of COX-2 compared with the inhibition of COX-1 activity (IC(50) > 50 microM in U937 cells and IC(50) > 15 microM in Chinese hamster ovary cells expressing human COX-1). Rofecoxib is a time-dependent inhibitor of purified human recombinant COX-2 (IC(50) = 0.34 microM) but caused inhibition of purified human COX-1 in a non-time-dependent manner that could only be observed at a very low substrate concentration (IC(50) = 26 microM at 0.1 microM arachidonic acid concentration). In an in vitro human whole blood assay, rofecoxib selectively inhibited lipopolysaccharide-induced, COX-2-derived PGE(2) synthesis with an IC(50) value of 0.53 +/- 0.02 microM compared with an IC(50) value of 18.8 +/- 0.9 microM for the inhibition of COX-1-derived thromboxane B(2) synthesis after blood coagulation. Using the ratio of the COX-1 IC(50) values over the COX-2 IC(50) values in the human whole blood assay, selectivity ratios for the inhibition of COX-2 of 36, 6.6, 2, 3, and 0.4 were obtained for rofecoxib, celecoxib, meloxicam, diclofenac, and indomethacin, respectively. In several in vivo rodent models, rofecoxib is a potent inhibitor of carrageenan-induced paw edema (ID(50) = 1.5 mg/kg), carrageenan-induced paw hyperalgesia (ID(50) = 1.0 mg/kg), lipopolysaccharide-induced pyresis (ID(50) = 0.24 mg/kg), and adjuvant-induced arthritis (ID(50) = 0.74 mg/kg/day). Rofecoxib also has a protective effect on adjuvant-induced destruction of cartilage and bone structures in rats. In a (51)Cr excretion assay for detection of gastrointestinal integrity in either rats or squirrel monkeys, rofecoxib has no effect at doses up to 200 mg/kg/day for 5 days. Rofecoxib is a novel COX-2 inhibitor with a biochemical and pharmacological profile clearly distinct from that of current nonsteroidal anti-inflammatory drugs and represents a new therapeutic class of anti-inflammatory agents for the treatment of the symptoms of osteoarthritis and rheumatoid arthritis with improved gastrointestinal tolerability.

The discovery of rofecoxib, [MK 966, Vioxx, 4-(4'-methylsulfonylphenyl)-3-phenyl-2(5H)-furanone], an orally active cyclooxygenase-2-inhibitor.

The development of a COX-2 inhibitor rofecoxib (MK 966, Vioxx) is described. It is essentially equipotent to indomethacin both in vitro and in vivo but without the ulcerogenic side effect due to COX-1 inhibition.

Substituted furans as inhibitors of the PDE4 enzyme.

The synthesis and in vitro activity of a series of substituted furans as a novel structural class of PDE4 inhibitors is described. Comparison of emetic threshold with known PDE4 inhibitors is presented.

5-Fluorouracil, high-dose folinic acid and mitomycin C combination chemotherapy in previously treated patients with advanced colorectal carcinoma.

The aim of this study was to evaluate the efficacy and tolerance of second-line continuous 5-fluorouracil (5FU) chemotherapy combined with folinic acid and mitomycin C in patients with advanced colorectal cancer who progressed on first-line chemotherapy. From June 1992 to April 1994, 24 consecutive patients, median age 59.7 years (range 41-73), performance status (PS) 0 to 2, were treated as second-line chemotherapy with mitomycin C, 7 mg/m2 every 4 weeks, folinic acid 200 mg/m2/day as a 2 h infusion followed by 400 mg/m2 of 5FU bolus and 600 mg/m2 continuous 5FU infusion for 22 h on days 1 and 2 and every 14 days; 19 patients did not respond to folinic acid and 5FU bolus regimen (in 2 patients, this was associated with pirarubicin in a continuous hepatic artery infusion) and 3 did not respond to irinotecan; 2 patients had disease progression during adjuvant chemotherapy with folinic acid and 5FU bolus. Tumor response was assessed every 12 weeks. One patient died before evaluation and 1 was lost to follow-up after 3 cycles; 7/24 patients had an objective response (29.2%, 95% confidence interval (CI): 11.0-47.4) including 2 complete responses; 7 additional patients had stable disease or minor response. Mean duration of response was 7.5 months. Median survival was 10 months and survival at 1 year was 39.4% (95% CI: 4-59.4). One patient who had a disease progression under irinotecan presented an objective response. No iatrogenic deaths occurred, nor was any grade 3 or 4 myelotoxicity seen. No hand-foot syndrome nor any cardiotoxicity arose but 2 grade II alopecia were seen. Digestive toxicities were the most frequent but with only 4 grade III toxicities (1 vomiting, 1 mucositis and 2 diarrhea) and no grade IV. With nearly 30% objective response and acceptable toxicity this treatment seems to offer a good alternative in the treatment of advanced colorectal cancers after the failure of first-line chemotherapy.

[Recurrence after surgical treatment of epidermoid cancers of the esophagus. Therapeutic approach in 19 patients]. / Récidives après traitement chirurgical des cancers épidermoïdes de l'oesophage. Approche thérapeutique chez 19 malades.

OBJECTIVES: The aim of this study was to report the management of 19 patients with recurrence of esophageal squamous cell carcinoma after surgical treatment. PATIENTS-METHODS: Nineteen patients with loco-regional recurrent invasion (n = 13) or metastasis (n = 6) of esophageal squamous cell carcinoma were included. Four of the 13 patients with loco-regional recurrent invasion had tracheal involvement. The treatment of the recurrence was a combined radiochemotherapy (n = 12) for loco-regional recurrent invasion in 11 cases and for metastasis in 1 case, associated with a tracheal prosthesis in 1 patient. The other treatments were chemotherapy alone (n = 5), esophageal prosthesis (n = 1) and surgical treatment (n = 1). RESULTS: There were 7 objective responses among the 12 patients treated with combined radiochemotherapy and none in the group treated with chemotherapy alone. Grade 3-4 toxicity was noticed in 2 cases (severe mucositis). Survival rate of the 19 patients was 52.6% at 1 year and 13.1% at 2 years; it was linked with general health (P = 0.09) and with tracheal involvement (P = 0.04). Survival rate of the 12 patients treated by combined radiochemotherapy was higher: 66% at 1 year and 22.2% at 2 years (median survival time = 16 months). CONCLUSION: Active medical treatment of recurrence of esophageal squamous cell carcinoma by combined radiochemotherapy can provide a median survival time of 16 months, with a moderate toxicity.