Anti-genotoxic activity of the mushroom Lactarius vellereus extract in bacteria and in mammalian cells in vitro.

In a previous study we screened a range of mushroom species growing in Slovenia for their anti-genotoxic potential and found Lactarius vellereus to be the most effective. In this study genotoxic and anti-genotoxic activities of methanol extracts of Lactarius vellereus (Fr.: Fr.) Fr. were evaluated in the bacterial reverse mutation test with Salmonella typhimurium TA98 and, in the mammalian cell test with human hepatoma (HepG2) cells, using the comet assay to measure DNA damage. The extract induced no mutations in S. typhimurium TA98 and no DNA damage in HepG2 cells. Against the indirect acting mutagen 2-amino-3-methylimidazo(4,5-f)quinoline (IQ) the extract showed significant, dose dependent antimutagenic activity, while it did not counteract the direct acting mutagen 4-nitroquinoline oxide (4-NQO). The extract also exerted a protective effect against IQ induced genotoxicity in mammalian cells of human origin. Treatment of HepG2 cells with the L. vellereus extract (125-500 microg/ml) together with IQ, reduced the genotoxic effect of the latter in a dose dependent manner. Our findings show that a methanol extract of L. vellereus is highly protective against IQ induced DNA damage in human derived cells and L. vellereus can be considered as a natural source of antimutagens with potential pharmacological applications in cancer prevention.

Circumferential pharyngolaryngectomy with total esophagectomy for locally advanced carcinomas.

BACKGROUND: Forty-nine cases of circumferential pharyngolaryngectomy with total esophagectomy (PLTE) done between 1982 and 1996 were studied retrospectively. These procedures were performed for advanced squamous cell tumors of the superior esophageal sphincter (n = 23), for hypopharyngeal tumors with synchronous esophageal carcinoma (n = 15), and for hypopharyngeal tumors extensively invading the cervical esophagus (n = 11). METHODS: Ninety-six percent of the patients had T3-4 lesions, and it was impossible to use a free jejunal graft reconstruction. Patients underwent primary surgery in 70% of the cases, and salvage surgery (after failure of chemoradiotherapy) in 30%. In most patients, esophagectomy was performed without thoracotomy (n = 45). Resection was curative (R0) in 70% of the cases, in spite of lymph node invasion in 94%. Reconstruction of the digestive tract was achieved with the stomach in 33 patients (67%) or with the colon in 16 patients (33%). RESULTS: Before 1989, postoperative mortality was high, was correlated with the high frequency of palliative surgery, and resulted in unsatisfactory survival results (overall 5-year survival rate of 7%). After 1989, as a result of better selection of patients and appropriate training of our team, postoperative mortality decreased from 33% to 10%, R1-2 resections decreased from 39% to 26%, and a 3-year overall survival rate of 28% was obtained for the last 25 patients, all of whom were able to eat without difficulty. These results are superior to the survival rates and functional results obtained with radiochemotherapy alone for such advanced tumors, even though the voice is preserved with radiochemotherapy alone. CONCLUSIONS: PLTE for advanced pharyngeal or cervical esophageal tumors is the best treatment currently available, but it is indicated only in very selected cases: when it is technically impossible to perform reconstruction with a free jejunal graft after circumferential pharyngolaryngectomy; as primary surgery, rather than as salvage surgery following chemoradiotherapy; after careful preoperative morphologic and endoscopic assessment of the extent of the tumor; and in patients able to tolerate a thoracotomy for an esophagectomy with lymphadenectomy. Selection according to these guidelines should improve results.

[Importance of a multidisciplinary approach to metastatic cancer of the rectum]. / Intérêt d'une approache multidisciplinaire des cancers du rectum initialement métastatiques.

Management of rectal cancers with synchronous metastasis is difficult. We evaluated in 23 patients a combination of pelvic radiotherapy at the dose of 45 Gy in 5 weeks and 25 fractions with chemotherapy by 5-fluorouracil (350 mg/m2/day) and folinic acid (20 mg/m2/day) for 5 days at the time of the first and the fifth week of the irradiation. Surgery was indicated firstly in cases of stricture or secondarily for resection of the primary location and, when possible, of the metastasis. General state of health of the patients improved in 35%, symptomatology in 86% and comfort in 72% of the cases. Response rates for the primary tumor were 41% of partial response and 50% of stable disease. For the metastatic lesions, they were 9% and 59% respectively. Sixty-one per cent of patients were secondarily operated with resection of the primary tumor in 12 cases and of hepatic metastases in 2 cases. The median survival and the median survival without progression were respectively 13 and 9 months. Radiochemotherapy combination as the first treatment was beneficial in 4/5 of the patients presenting a rectal cancer with synchronous metastasis and allowed us to select those that would secondarily benefit from a surgical resection.

[Esophagectomy for epidermoid cancer discovered during evaluation of ENT cancer]. / Oesophagectomie pour cancer épidermoïde découvert lors du bilan d'un cancer ORL.

UNLABELLED: The treatment of synchronous esophageal and head and neck carcinomas is difficult. MATERIAL AND METHOD: Retrospective study of 33 patients treated with esophagectomy for an intrathoracic squamous cells carcinoma discovered during pan-endoscopy for a synchronous head and neck cancer. RESULTS: In 7 cases (21%) it was advanced (pT3-4) esophageal cancers. The hospital mortality was 9%. Five year survival was 18% without stabilization of the survival curve, 60% of patients died of recurrence of tumor. CONCLUSION: Esophagectomy is suitable for usT1-2 tumors if surgery is also indicated for the head and neck tumor. Radiochemotherapy is indicated for advanced usT3-4 esophageal tumors or when the treatment of the head and neck tumor is not surgery.

Accelerated fractionation in esophageal cancers: a multivariate analysis on 88 patients.

PURPOSE: Accelerated fractionation was used to shorten overall treatment time to increase locoregional control and cause-specific survival. METHODS AND MATERIALS: Eighty-eight patients with cancer of the esophagus ineligible for surgery were entered in the study between 1986 and 1993. Neoadjuvant chemotherapy was given to 64% of patients. Accelerated radiotherapy using the concomitant boost technique delivered a median dose of 65 Gy in a median overall treatment time of 32 days. RESULTS: The 3-year actuarial local control rate in patients with T1, T2, and T3 tumors was 71%, 42%, and 33%, respectively. The 3-year cause-specific survival rates were 40%, 22%, and 6%, respectively. Sixteen percent of patients experienced Grade 3 esophagitis. Late toxicity included esophageal stenosis and pulmonary fibrosis in 8% and 9% of the patients, respectively. Multivariate analysis demonstrated that T stage and overall treatment time were prognostic factors for cause-specific survival. T stage and neoadjuvant chemotherapy were independent prognostic factors for locoregional control. CONCLUSION: These findings suggest that accelerated fractionation given in an overall treatment time of <35 days might be beneficial for early-stage cancer of the esophagus. Neoadjuvant chemotherapy is not recommended, as it was a significant adverse prognostic factor in the multivariate analysis for local control. Accelerated fractionation can be carried out with moderate acute and late toxicity.

[Value of endorectal ultrasonography in the treatment of rectal tumors]. / Intérêt de l'échographie endorectale pour le traitement des tumeurs rectales.

OBJECTIVES: To determine the diagnostic accuracy of endosonography and to appreciate its influence on the therapeutic strategy. METHODS: Sixty-two patients referred to the gastroenterology unit between April 1990 and February 1995 for a rectal tumor. Thirty-two patients did not receive any preoperative treatment (group A) and 30 were treated by radiotherapy or chemoradiotherapy before surgery (group B). Transrectal ultrasonography was performed with a Bruel and Kjaer device. RESULTS: Diagnostic accuracy for parietal infiltration was 84% for the entire series, 94% for group A and 73% for group B. Diagnostic accuracy of lymph node invasion was 71% for the entire series, 81% and 60% for groups A and B, respectively. It is highly probable that a histopathologic down-staging due to preoperative treatment explained the results in the group B. Using a pragmatic approach which combined the results for parietal infiltration and for lymph node invasion, transrectal ultrasonography would have correctly selected 20 among the 25 patients who could have been treated by local excision. The use of this same pragmatic approach in patients with high risk of local recurrence enabled correct selection of 26 among the 32 exposed patients. CONCLUSION: We conclude that transrectal ultrasonography: 1. is a reliable technique for the pretherapeutic staging of rectal cancer, especially for the assessment of parietal infiltration. Progress is needed for the diagnosis of lymph node invasion; 2. selects well the patients who can be treated by local excision; 3. is a reliable technique for the selection of patients who need preoperative treatment.

[Treatment of hepatocellular carcinoma in the presence of liver cirrhosis]. / Traitement du carcinome hépatocellulaire sur cirrhose.

Hepatocellular carcinoma accounts for 90% of the primary malignant liver tumours. Most cases occur in cirrhotic livers. Management decisions should not be based on the stage of the tumour extension but rather on the functional situation of the liver. The first therapeutic option which should be considered is surgical resection if the case presents with a single tumour (or less than 4 tumours for some teams) without detectable metastasis nor intraportal thrombosis and if the liver remaining after surgery will be sufficient for normal hepatic functions. The disadvantage of resection is the high risk of recurrence in the long term. Liver transplantation cannot be proposed if the hepatocellular carcinoma has produced clinical signs but it can be a possibility in case of a resectable tumour in the framework of a prospective protocol comparing transplantation and resection. Intra-arterial injection of 131-iodine linked lipiodol is the only effective treatment in case of portal thrombosis. Chemoembolization of nonresectable hepatocellular carcinoma has led to spectacular tumour response but its effect on survival has not been demonstrated by randomized studies. For tumours less than 3 cm in diameter, even multifocal alcoholization has proved encouraging results. Although a randomized study of questionable quality suggested tamoxifen could be effective, there is no current indication for this drug. External radiotherapy may be a possibility in the future, especially with proton irradiation. Thus the current management of hepatocellular carcinoma is in a difficult, even paradoxical, situation since there is a wide therapeutic choice (resection, alcoholization, transplantation) for the rare cases with small tumours but almost no possibilities for the more severe cases most frequently encountered.

Prognostic value of neural invasion in rectal carcinoma: a multivariate analysis on 339 patients with curative resection.

To determine whether neural invasion or other clinico-pathological factors are prognostic, we performed a retrospective study on 339 rectal carcinomas. The overall 5-year survival was 62%. In the multivariate analysis, age over 60 years, a distance from the anal verge of less than 6 cm, the number of positive lymph nodes, neural invasion and tumour penetration were found to be prognostic. A scoring system identified five prognostic groups of patients. Neural invasion is an independent prognostic factor in our scoring system and it is suggested that this parameter should be taken into consideration for postsurgical treatment.

[Single and multifactorial prognostic study of 400 operated rectal adenocarcinomas]. / Etude pronostique uni et multi-factorielle de 400 adénocarcinomes rectaux réséqués.

From 1976 to 1988, 496 patients with rectal adenocarcinoma have been treated at Gustave-Roussy Institute. There were 258 men (52%) and 238 women (48) with a median age of 61 years. Sixty pts (12%) had local treatment (contact-therapy or electro-resection). Thirty six pts (8.25%) had a simple exploration with colostomy. Four hundred pts had a resection: 202 abdomino-perineal resection, 7 perineal resection, 167 anterior resection, and 24 Hartmann's technique. Post-operative mortality was 1% (4 pts). Among these 400 pts, 208 had no complementary treatment, 134 had pre +/- post-operative radiotherapy and 58 had post-operative radiotherapy. Sixty one pts had palliative resection. The actuarial survival of the 400 pts at 3, 5 and 10 years are respectively 65%, 51% and 37.5%. The number of lost to follow-up patients was 11 (2.5%) at 5 years and 24 (5.5%) at 10 years. A retrospective uni and multifactorial analysis of the clinical, biological and histopathological data of the 400 pts was done, 18 factors were studied. Our judgement criterion was 5 year survival. The uni-factorial analysis showed 7 variables which had great influence on survival: age > 60 (p = 0.001), signs of severe illness (p < 0.0001), curative or palliative criterion of the surgery (p = 0.0001), depth of invasion (p = 0.0001), lymph node invasion (p = 0.0001), neural invasion (p = 0.0001) and positive emboli (p = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

[A multivariate prospective study of prognostic factors in 200 operated epidermoid cancers of the esophagus. Definition of patients for whom surgical resection was of benefit]. / Etude multifactorielle prospective des facteurs pronostiques de 200 cancers épidermoïdes de l'oesophage opérés. Définition des malades tirant bénéfice de l'exérèse chirurgicale.

From 1982 to 1991, 200 patients with squamous-cell esophageal cancers underwent operation. Sixteen prognostic parameters were prospectively collected and analyzed. The main aim of this study was to define the best preoperative criteria for selection for curative surgery and which patients would benefit most from radical resection. Squamous-cell head and neck carcinoma was associated in 43.5% of cases. Of these, 24% preceded the esophageal carcinoma while 19.5% were synchronous. Resection was curative (i.e. grossly complete) in 144 cases, palliative (leaving gross tumor behind) in 25 cases, and judged impossible in 31 cases. Twenty-one patients died during their hospitalization. Five-year survival, according to the Kaplan-Meier method, was 18 +/- 3.6% for all patients, and 27 +/- 4.8% for patients undergoing curative resection (including postoperative mortality). Palliative resections or invasion of adjacent organs, but not resection with positive lymph nodes, was thought to be synonymous with incurability. Multivariate analysis showed that the two principal statistically significant characteristics were the stage as determined by roentgenological and endoscopic evaluation (P = 0.003) (clearly assessable during initial work-up) and type of resection (complete or not) (P = 0.04). Tumor diameter, as determined on CT-scan (< or > than 30 mm), was at the limit of statistical significance (P = 0.09). A second multivariate analysis of prognostic factors was conducted in 128 patients undergoing resection with curative intent and who survived the initial postoperative period. Roentgenologic/endoscopic staging alone emerged as being statistically significant (P = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Esophageal squamous cell carcinoma: the specific limited place of surgery defined by a prospective multivariate study of prognostic factors after surgical approach.

From 1982 to 1990, 181 patients underwent surgery for esophageal squamous cell carcinoma, for which 14 prognostic parameters were prospectively recorded in order to perform a multivariate study. A squamous cell head and neck cancer was associated with the esophageal tumor in 40% of the cases (synchronous 18% and metachronous 22%). Resection was curative (i.e. macroscopically complete) in 128 cases, palliative (i.e. with residual tumor) in 24 cases and not possible in 29 cases. There were 21 deaths in hospital (hospital mortality was 11.7%). One hundred and twenty-two patients received preoperative chemotherapy and 77 received postoperative radiotherapy according to different phase II prospective studies. The 5-year survival rate according to the Kaplan-Meier method was 15.8% (+/- 3.4) for all patients and 23.5% (+/- 4.8) for the patients who had a curative resection. A palliative resection or the invasion of a neighbouring organ was synonymous with incurability, but positive lymph nodes were not considered proof of incurability. The multifactorial study concerning all the patients highlighted two main prognostic parameters: the histological staging according to the Japanese classification (P = 0.0006) and the type of resection (curative or not) (P = 0.006). An objective response to preoperative chemotherapy was the third and last parameter revealed by Cox's model. The multivariate study, which was limited to the 112 patients who were alive after a curative resection, showed that only the stage was an important prognostic factor (P = 0.003), with stages 2 and 3 carrying a worse prognosis. We propose a therapeutic scheme, based on these prognostic data and on the usual pre-therapeutic workup with three additional exams: CT scan measurement of tumor diameter, ultrasound examination +/- fine needle aspiration cytology of supra-clavicular lymph nodes and echo-endoscopy. The aim of this scheme is to limit surgery to the subgroup of patients for whom this modality is really beneficial.

[Epidermoid cancers of the operated esophagus. High incidence of associated neoplasia]. / Cancers épidermoïdes de l'oesophage opéré. Incidence élevée des néoplasies associées.

In a retrospective study we counted the number of neoplasias associated with oesophageal epidermoid cancer, as we thought that their frequency and influence on treatment had been underestimated. Between 1982 and 1990, 181 patients underwent surgery of oesophageal epidermoid cancer. The global actuarial 5-year survival rate was 20.7 percent (28.8 percent after complete excision of the tumour). The mean follow-up period was 4.2 +/- 2.6 years. These 181 patients had a total of 324 cancers, 97 percent of which were cancers of the upper respiratory and digestive tracts. The frequency of associated cancers was 56 percent (102 out of 181), and 50 percent of the patients presented with at least one associated head and neck cancer. Twenty-two percent of the patients had been treated for another cancer before the oesophageal epidermoid cancer, and in 19 percent of the cases this was a head and neck cancer. Thirty-five percent had a malignancy that was contemporary with the oesophageal cancer (this malignancy affected the head and neck in 18 percent of the cases and consisted of multiple lesions in 25 percent). During the short period under study, in only 10 percent of the patients did a cancer develop after the oesophageal one, and 6 percent of these affected the head and neck. This high incidence of associated neoplasia was due to tobacco and alcohol abuse. The presence of multiple cancers should alter as least as possible the treatment required by each associated cancer in order to optimize the chances of complete cure. Close surveillance of the high-risk population may result in the early discovery of a 2nd cancer at a curable stage. For the time being, the prevention of such associated cancers relies more on daily administration of retinoids than on alcohol and tobacco abstinence which is difficult to obtain.

Neoadjuvant chemotherapy in multiple synchronous head and neck and esophagus squamous cell carcinomas.

A consecutive series of 22 patients with multiple synchronous squamous cell carcinomas of the upper aerodigestive tract was retrospectively reviewed. These patients were treated initially with cis-platinum combination chemotherapy before definitive locoregional therapy (surgery and/or radiation therapy). Sixteen of 21 patients had simultaneous head and neck and esophageal primaries, 3 patients had multiple synchronous head and neck primaries, 2 patients had head and neck (HN) and a bronchial epidermoid cancer, and 1 patient had simultaneous esophageal and bronchial carcinomas of epidermoid lineage. Sixteen (77%) of the 21 patients responded to chemotherapy in all the tumor sites evaluated, and a clinically complete response was obtained in 6 (29%). After definitive locoregional treatment, the complete local control rate was 68%, with 34 complete responses for 50 primary tumor sites in 21 patients. Twelve patients were free of disease after locoregional treatment. Six patients are still alive 27 to 57 months after complementary definitive locoregional treatment and a minimum follow-up of 27 months. Median survival for the overall group is 17 months. The response to chemotherapy is remarkable, which may be due to the small tumoral volume present in many of the cases (T1 to T2). Nevertheless, the present report stresses the importance of an aggressive combined therapeutic approach in this difficult clinical situation.

[Efficacy of a daily application of mesalazine (Pentasa) suppository with progressive release, in the treatment of ulcerative proctitis. A double-blind versus placebo randomized trial]. / Efficacité d'une application quotidienne d'un suppositoire de mésalazine (Pentasa) à libération progressive, dans le traitement des poussées de rectite ulcéro-hémorragique. Essai randomisé en double aveugle contre placebo.

Therapeutic efficacy of mesalazine controlled-release suppository 1 g once daily was compared with that of a placebo during 2 weeks in 50 patients (26 in the mesalazine group, 24 in the placebo group) with ulcerative proctitis, in a double-blind randomized trial. Endoscopic and clinical remission was seen in 69 and 65% of mesalazine-treated patients and in 33 and 25% of placebo-treated patients respectively (P < or = 0.01). No side effects were seen. It is concluded that a once-a-day administration of 1 g mesalazine controlled-release suppository is effective for topical treatment of patients with ulcerative proctitis.

Phase II trial of 7-day continuous 5-fluorouracil infusion in the treatment of advanced colorectal carcinoma.

Thirty-eight patients with advanced colorectal adenocarcinoma were entered on a phase II trial of 5-fluorouracil (5-FU) in continuous infusion, using a portable pump. Half of the patients had been pretreated (n = 19) and 16 of them had received intravenous bolus 5-FU alone or in combination. At the first cycle patients received continuous intravenous 5-FU at the dose of 650 mg/m2 per day for 7 consecutive days. Doses were escalated during the following cycles and adjusted according to the toxicities encountered in the previous cycle. Treatment was repeated every 3 weeks. A mean dose of 750 mg/m2/day (500-1,000) was administered for a mean number of 10 (1-25) cycles. We observed 1 complete response, 7 partial responses for a response rate of 21 +/- 13% (CI95%), 16 had stable disease (42%) and 14 a progression (37%). In 2 patients subsequently the residual tumors could be excised after chemotherapy. Median survival was 13.5 months. Toxicity was: grade 2 leukopenia in 1 patient (3%), mucositis grade 2-4 in 11 patients (29%), diarrhea grade 2-3 in 7 patients (18%), and hand and foot syndrome in 12 patients (31%). There was a correlation between the mean dose administered and the responses. However no clear correlation was found between toxicity and tumoral response for the first two cycles. These results confirm the limited efficacy of continuous intravenous 5-FU and its good tolerance in ambulatory patients.

[Synchronous cancers of the esophagus and of the ORL area: results of combined treatments with esophagectomy (28 cases)]. / Cancers synchrones de l'oesophage et de la sphère ORL: résultats des traitements combinés avec oesophagectomie (28 cas).

Twenty-eight patients with synchronous esophageal and head and neck epidermoid cancers have been treated by a combined protocol including esophagectomy. Seventy-nine percent received pre-operative chemotherapy, 50% had resection of the head and neck lesion at the same time as the esophagectomy and 79% received post-operative irradiation. Two patients died during the post-operative period (7%), and 1, 2 and 3-yr survival rate (Kaplan-Meier) was respectively 64, 32 and 27%. Contrary to our initial assumption, there was no significant decrease in survival compared to patients operated on for an isolated esophageal cancer. The patients were divided into 4 very simple prognostic groups based on the T and N stages of the clinical pre-therapeutic TNM classification: T1 or T2 for esophageal lesions and different T or N stages according to the prognosis for head and neck lesions. A study of each group tended to show that esophagectomy was beneficial except in cases of synchronous T2 esophageal cancer and locally advanced head and neck cancer (there was 2-yr survival in this group). The 28 patients studied represent a particular population which presented 91 cancerous localisations during the duration of the study (mean: 3.25 localisations per patient).

Metastatic carcinoid and islet cell tumours of the pancreas: a phase II trial of the efficacy of combination chemotherapy with 5-fluorouracil, doxorubicin and cisplatin.

A phase II trial of chemotherapy in carcinoid and islet cell pancreatic tumours has been conducted with the FAP protocol: 5-fluorouracil 400 mg/m2 per day (5-FU) for 3 days, 50 mg/m2 doxorubicin on day 2, and 90 mg/m2 cisplatin on day 2, repeated every 4 weeks. 24 patients, 20 non-pretreated and 4 pretreated, were included. For non-pretreated patients we observed 1 complete response and 2 partial responses. The response rate was 15% (95% confidence interval 0-31%). No response was observed in the pretreated patients. The toxicity was mainly digestive and haematological with 7 patients experiencing vomiting grade 3 and 3 patients with leucopenia grade 3. We conclude that the FAP protocol is of poor efficiency in endocrine tumours.