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.

5-lipoxygenase-activating protein is an arachidonate binding protein.

5-Lipoxygenase-activating protein (FLAP) is an 18-kDa integral membrane protein which is essential for cellular leukotriene (LT) synthesis, and is the target of LT biosynthesis inhibitors. However, the mechanism by which FLAP activates 5-LO has not been determined. We have expressed high levels of human FLAP in Spodoptera frugiperda (Sf9) insect cells infected with recombinant baculovirus, and used this system to demonstrate that FLAP specifically binds [125I]L-739,059, a novel photoaffinity analog of arachidonic acid. This binding is inhibited by both arachidonic acid and MK-886, an LT biosynthesis inhibitor which specifically interacts with FLAP. These studies suggest that FLAP may activate 5-LO by specifically binding arachidonic acid and transferring this substrate to the enzyme.

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.

Structural requirements for the binding of fatty acids to 5-lipoxygenase-activating protein.

5-Lipoxygenase-activating protein is required for cellular leukotriene synthesis and is the target of the leukotriene biosynthesis inhibitors MK-886 (3-[1-(p-chlorophenyl)-5-isopropyl-3-tert-butylthio-1H- indol-2-yl]-2,2-dimethylpropanoic acid) and MK-591 (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)-indol-2-yl] - 2,2-dimethylpropanoic acid). Recent studies demonstrate that 5-lipoxygenase-activating protein binds arachidonic acid and stimulates the utilization of this substrate by 5-lipoxygenase. The present study utilizes a radioligand binding assay to assess the affinity of 5-lipoxygenase-activating protein for arachidonic acid and the specificity of the fatty acid binding site on 5-lipoxygenase-activating protein. Our findings demonstrate that the presence of a free carboxyl group on fatty acids or leukotriene biosynthesis inhibitors which interact with 5-lipoxygenase-activating protein is not required for specific binding to the protein. However, the degree of saturation significantly affects the affinity of fatty acids for 5-lipoxygenase-activating protein.

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.

[5-fluorouracil, high dose folinic acid and mitomycin C in the treatment of advanced digestive cancers]. / Association 5-fluorouracile, acide folinique à haute dose et mitomycine C dans le traitement des cancers digestifs avancés.

Thirty five patients presenting with advanced unresectable digestive tract cancers were treated with high-dose folinic acid (200 mg/m2/d, i.v. bolus) followed by 5-fluorouracil (400 mg/m2 i.v. bolus) on day 2 of uneven courses (day 2, day 58, day 114...). There were 20 colorectal cancers, nine gastric cancers, two oesophageal cancers, two cholangiocarcinomas, one islet cell pancreatic carcinoma and one adenocarcinoma of unknown origin. An objective response was noted in 11/27 evaluable patients (40.7 +/- 19%): four complete and seven partial responses including three of the seven patients who previously failed to respond to 5FU-containing regimen, and eight of the 20 patients who received no prior chemotherapy. Objective responses were encountered in three of the five gastric cancers, five of the 17 colorectal cancers, one oesophageal cancer, one islet cell pancreatic carcinoma and one cholangiocarcinoma. The median duration of response was 6 months and overall median survival was 12 months (range: 1-48). There was one toxic death (non reversible medullar aplasia after the 1st course). This study confirms that this combination is an active regimen both for patients previously resistant to 5FU or untreated patients. It warrants further evaluation (perhaps with continuous 5FU infusions).

[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.

[Multivariate analysis of the prognostic and predictive factors of response to concomitant radiochemotherapy in epidermoid cancers of the esophagus. Value of immunodetection of protein p53]. / Analyse multifactorielle des facteurs pronostiques et prédictifs de réponse à la radiochimiothérapie concomitante dans les cancers épidermoïdes de l'oesophage. Intérêt de l'immunodétection de la protéine p53.

OBJECTIVE: The purpose of this study was to determine the prognostic value of the expression of protein p53, EGF receptors (EGR-R), cell proliferation antigen (Ki67) and DNA analysis by flow cytometry on per-endoscopic biopsies as well as the ability of these factors to predict response to concomitant chemoradiation in patients with squamous cell oesophageal carcinoma. METHODS: Sixty-two patients with squamous cell oesophageal carcinoma were prospectively included in this study. For 58 patients (51 men, 7 women; mean age: 59.1 +/- 9.3 years), clinical response to chemoradiation was correlated with the findings of flow cytometry (ploidy, % of cells in S-phase) and immunohistochemistry (p53, EGF-R, Ki67). There were 4 patients in stage I, 14 in stage II, 27 in stage III, and 13 in stage IV. Chemoradiation (2 cycles associating continuous 5FU 800 mg/m2/24 h from D1 to 5 and from D22 to 26, Cisplatyl 70 mg/m2 on D1 and D22; 15 Gy/5d from D1 to 5 and from D22 to 26), was performed prior to surgery in 19 patients (group I) and as the only treatment in 39 patients (group II), with a third cycle from D43. Clinical response was defined as complete or incomplete, ascertained by endoscopy and biopsy, 2 to 3 weeks after the end of chemoradiation. RESULTS: Mean survival in all 58 patients was 13.0 months. Survival was significantly longer in responders than in non responders (14.7 vs 9.6 months; P = 0.03). Among M0 patients, survival was not different in case of exclusive chemoradiation therapy or chemoradiation therapy followed by surgical excision (17.6 vs 13.0 months; NS). Monofactorial analysis showed that, in addition to response, the variables related to survival were stage, non-metastatic status, and absence of p53 surexpression. After multifactorial analysis according to the Cox model, the remaining variables were non-metastatic status, and absence of p53 surexpression. A complete response with negative biopsies was observed in 39 out of 58 patients, i.e. 67.3 +/- 12.1 % (group I: 12 out of 19; group II: 27 out of 39; NS). According to monofactorial analysis, 3 factors were predictive of complete response, i.e. non surexpression of p53 (P < 0.05) and tumour diameter (P = 0.04). After step-by-step logistic regression, non surexpression of p53 and tumour diameter continued to be predictive. The relative risk of a non-complete response was 5.46 if p53 was detected and 1.84 for each cm of added tumour diameter. These two factors were independent. CONCLUSIONS: In this study the predictors of complete response were absence of p53 surexpression and tumour diameter ascertained by CT-scan. Flow cytometry and Ki67 antigen had no prognostic value and were not predictors of response.

[Guided puncture-cytology under electronic sectorial ultrasound endoscopy. Results in 26 patients]. / Ponction-cytologie guidée sous échoendoscopie sectorielle électronique. Résultats chez 26 malades.

The diagnosis of submucosal tumors, extrinsic lesions of gastrointestinal tract and mediastinal or celiac masses can be made by endoscopic ultrasonography (EUS) but histological confirmation (benign or malignant lesion) is still required. The aim of this study was to determine the efficacy of a new method, enabling EUS (curved array transducer)--guided fine needle aspiration of deep lesions. From October 1991 to August 1992, EUS-guided fine needle aspiration was performed in 26 patients in whom a mediastinal mass (6 cases), mediastinal lymph nodes (4 cases), submucosal tumor (5 cases), extrinsic masses (4 cases) and large fold gastric disease with negative endoscopic biopsy (7 cases) was detected by EUS. Diagnostic results were obtained in 19 of 26 patients (73.1%). A malignant tumor was detected in 21 of 26 patients. The EUS-guided fine needle aspiration was positive in 16 cases. The sensitivity for diagnosis of malignancy was 76.2% while specificity was 100%. The development of this new technique in the future needs further study.

[Uterine metastasis revealing gastric adenocarcinoma]. / Métastase utérine révélatrice d'un adénocarcinome gastrique.

We report a case of metastasis to the uterine corpus revealing a primary gastric adenocarcinoma. A 26-year-old woman suffered from weight loss, vaginal bleeding, abdominal pain. An endometrial curettage showed apparently metastatic adenocarcinoma. The primary site of the tumour was gastric. The upper gastrointestinal endoscopy revealed an ulcus and aspect of linitis plastica in the fundus. Biopsies showed diffuse type adenocarcinoma. Because of extensive disease, laparotomy was not performed and exclusive palliative chemotherapy was started. The patient died 10 months after the diagnosis. Metastasis from primary gastric cancer to the female genital tract are rare and are usually observed in young premenopausal women with diffuse type gastric adenocarcinoma. This case report underlines the interest, for those patients of careful gynaecologic examination at the initial staging and after treatment.

[Linear electronic intrarectal ultrasonography and cancer of the rectum. Results in 45 patients]. / Echographie endo-rectale électronique linéaire et cancer du rectum. Résultats chez 45 patients.

The aim of this study was to evaluate the preoperative staging of rectal carcinoma by intrarectal ultrasonography using linear probe or curved array transducer. Between October 1991 and July 1993, preoperative staging with endoscopic ultrasound was performed in 45 patients with rectal carcinoma. Twenty-four received preoperative radiation therapy. For carcinoma of the middle and the lower part of rectum, the distance between the inferior pole of the tumour and the levator ani muscle was systematically measured. The ultrasound results were compared with histological and surgical findings. The staging was accurately predicted in 82.2% of cases. The depth of cancer invasion was correct in 93.3% (95.2% when preoperative radiation therapy was not applied and 79.1% after radiation therapy). Presence or absence of lymph nodes metastasis was correctly determined in 84.4% (90.5% when preoperative radiation therapy was not applied and 79.1% after radiation therapy). The distance between the inferior pole of the tumour and the levator ani muscle was correctly determined in 29/31 carcinoma of the middle and the lower part of rectum. While the linear and sectorial technique is more difficult when the tumour was circular, the staging of the lower part of rectum carcinoma and anal canal was easier.

[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.

[Induction treatment of locally advanced operable cancers of the esophagus. Prognostic significance of the histologic response]. / Traitement d'induction des cancers de l'oesophage opérables localement avancés. Signification pronostique de la réponse histologique.

OBJECTIVE: The purpose of this study was to determine the prognostic significance of the histopathological response to preoperative radio-chemotherapy in patients with locally advanced oesophageal cancer. METHODS: Among the 57 patients included in this open prospective study, the disease-free survival of 48 patients (8 females 40 males; mean age: 56.6 years +/- 8.4) who underwent an oesophagectomy after induction therapy for oesophageal squamous cell (n = 38) or adenocarcinoma (n = 10) was correlated with the histopathological findings. Chemoradiation included 2 cycles associating continuous 5 FU from D1 to 5 and from D22 to 26, cisplatyl on D1 and D22, 15 Gy/5d from D1 to 5 and from D22 to 26. Histopathological response was assessed on the operative specimens by routine examination of serial thin sections each 5 mm along the full oesophageal length, the resection margins and the lymph node dissection. RESULTS: A wide interindividual variability was seen regarding tissue changes related to induction therapy, with a grading in tumor regression and the possibility of dissociated effects on the various treatment targets: tumor, adenopathy and vessel invasion. The 5-year probability of disease-free survival was 22% for the 48 resected patients. The presence of a complete histopathological response (n = 12) did not preclude metastatic spread in half the cases. Furthermore, it did not result in improved survival when compared to that of non-responder patients. Survival of patients who had a complete or major oesophageal response (n = 29, 35% at 5 years) was significantly lower than that of patients who were operated on during the same period for a superficial oesophageal cancer at presentation (n = 29, 57% at 5 years; P = 0.03). After multivariate analysis according to the Cox model, downstaging of the primary tumor was not identified as an independent predictor of disease-free survival. CONCLUSIONS: Pathologic assessment of tumor regression on the operative specimen provides little prognostic information.