Surgical resection of residual disease in initially inoperable imatinib-resistant/intolerant gastrointestinal stromal tumor treated with sunitinib.

AIM: Sunitinib malate therapy in inoperable and/or metastatic gastrointestinal stromal tumor (GIST) resistant to imatinib mesylate may facilitate surgical removal of residual disease. We explored this possibility in the course of treating patients as part of a treatment-use trial, the objective of which was to provide access to sunitinib treatment. METHODS: Four patients with inoperable and/or metastatic GIST resistant to imatinib who had responded to sunitinib therapy administered at a starting dose of 50 mg daily in 6-week cycles of 4 weeks on treatment followed by 2 weeks off underwent surgical removal of residual disease. Disease progression on or clinical response to treatment was defined based on Response Evaluation Criteria in Solid Tumors. RESULTS: In three of four cases it was possible to perform macroscopically complete resection of residual disease, resulting in surgical complete clinical responses, two with durations of 13 months. The fourth patient achieved a dramatic partial response to sunitinib that required emergency surgical resection of the necrotic tumor mass, with the partial response having been maintained for 15 months. In all cases, viable GIST cells were detected histologically in the resection specimens, and sunitinib treatment was resumed post-surgery. None of the patients experienced any postoperative complications during 13-16 months of follow-up. CONCLUSIONS: Combining sunitinib treatment with surgical removal of residual disease may allow selected imatinib-resistant GIST patients who have shown a favorable response to sunitinib to achieve complete and sustained remission or durable control of previously progressive disease beyond that expected for sunitinib treatment alone.

Endosonography versus helical computed tomography for locoregional staging of gastric cancer.

BACKGROUND AND STUDY AIMS: Endosonography (EUS) has been shown to be more accurate than incremental computed tomography (CT) in the local (T) and regional (N) staging of gastric carcinoma; however, EUS has never been compared with helical CT (HCT). The fifth edition of the TNM classification changed the guidelines for N-staging of gastric carcinoma. The accuracy of imaging methods in this new system remains unknown. PATIENTS AND METHODS: Staging accuracy of EUS and HCT were compared prospectively with pathological or intraoperative findings in 88 gastric carcinoma patients. Staging was done according to the fourth and fifth editions of the TNM classification. EUS was done with a radial echo endoscope, and HCT with a scanner with two rows of detectors (two-phase contrast-enhanced scanning of a water-filled stomach). RESULTS: The T-staging accuracy of EUS (63 %, CI 52 - 73 %) was superior to the accuracy of HCT (44 %, CI 34 - 55 %; P = 0.021). N-staging accuracy of both methods was similar when the fourth edition of the TNM classification was used (EUS 47 %, CI 34 - 60 %; HCT 52 %, CI 38 - 65 %). However, HCT was more accurate than EUS when the fifth edition of the classification was applied (EUS 30 %, CI 18 - 43 %, HCT 47 %, CI 34 - 60 %; P = 0.044). The accuracy of detection of lymph node metastases was similar for both methods (EUS 67 %, CI 54 - 78 %; HCT 77 %, CI 64 - 86 %). CONCLUSIONS: EUS is more accurate than HCT in the T-staging of gastric carcinoma. Both methods are comparable for N-staging, when this is done according to the older, fourth edition of the TNM classification. If the fifth edition is used, EUS is less accurate than HCT.

Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer.

PURPOSE: To determine whether addition of the farnesyltransferase inhibitor tipifarnib (Zarnestra, R115777; Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium) to standard gemcitabine therapy improves overall survival in advanced pancreatic cancer. PATIENTS AND METHODS: This randomized, double-blind, placebo-controlled study compared gemcitabine + tipifarnib versus gemcitabine + placebo in patients with advanced pancreatic adenocarcinoma previously untreated with systemic therapy. Tipifarnib was given at 200 mg bid orally continuously; gemcitabine was given at 1,000 mg/m(2) intravenously weekly x 7 for 8 weeks, then weekly x 3 every 4 weeks. The primary end point was overall survival; secondary end points included 6-month and 1-year survival rates, progression-free survival, response rate, safety, and quality of life. RESULTS: Six hundred eighty-eight patients were enrolled. Baseline characteristics were well balanced between the two treatment arms. No statistically significant differences in survival parameters were observed. The median overall survival for the experimental arm was 193 v 182 days for the control arm (P =.75); 6-month and 1-year survival rates were 53% and 27% v 49% and 24% for the control arm, respectively; median progression-free survival was 112 v 109 days for the control arm. Ten drug-related deaths were reported for the experimental arm and seven for the control arm. Neutropenia and thrombocytopenia grade > or = 3 were observed in 40% and 15% in the experimental arm versus 30% and 12% in the control arm. Incidences of nonhematologic adverse events were similar in two groups. CONCLUSION: The combination of gemcitabine and tipifarnib has an acceptable toxicity profile but does not prolong overall survival in advanced pancreatic cancer compared with single-agent gemcitabine.

p53 Protein accumulation as a prognostic marker of preoperative radiotherapy and/or chemotherapy in advanced squamous cell esophageal carcinoma--preliminary report.

The correlation between immunohistochemical detection (IH) of p53 protein and tumor response to preoperative chemotherapy and/or radiotherapy in advanced esophageal squamous cell carcinoma was evaluated. Fifty-six patients with advanced esophageal squamous cell carcinoma were included in the study. All patients were staged and diagnosed microscopically before treatment. Patients were divided into three groups: 17 patients treated with chemotherapy and radiotherapy preoperatively (group I) (cisplatin and 5-fluorouracil, cobalt-60 therapy; total dose 3000 Gy); 19 patients treated with chemotherapy only (group II); and 20 patients who did not receive preoperative therapy (group III). The response of the tumor tissue to preoperative treatment was evaluated macroscopically and microscopically in operated specimens according to the classification: CR, complete response; PR1, major partial response with regression of at least 50% of initial tumor mass; PR2, minor partial response with regression of less than 50% of initial tumor mass. In all 56 patients immunohistochemistry was used to detect anti-p53 antibody (Dako, DO-7) in normal mucosa and cancer tissue. The response of the tumor was similar in both group I and group II. p53 protein was not expressed in the normal esophageal mucosa. A high level of p53 in operated specimens was associated with unfavorable tumor response to preoperative treatment. Therefore, immunohistochemical detection of p53 protein can be considered to predict the outcome of preoperative therapy.

Preoperative concurrent chemotherapy and radiotherapy for local-regional and advanced squamous cell carcinoma of the thoracic oesophagus: preliminary results of a pilot study.

Preliminary experience based on the results of a pilot study on preoperative concurrent continuous i.v. infusion chemotherapy and radiotherapy for squamous cell carcinoma of the oesophagus in eight consecutive patients is presented. Chemotherapy consisted of 5-fluorouracil and cisplatin. Radiotherapy (Co-60) was delivered to a total dose of 3000 cGy. Clinical tolerance was good in four of eight patients, but poor in the remaining four, including three septic deaths. Oesophagectomy was performed in five patients with no postoperative deaths. Postoperative complications (Horner syndrome, hydrothorax, abdominal wound dehiscence) were observed in three cases. The response was categorized as complete (CR), partial (PR) or stable disease (SD), based on a comparison of the initial and immediate preoperative imaging studies and on the presence of tumour degeneration and/or necrosis in pathological examination of operative specimens. CR was observed in 1/8 patients, PR in 4/8 and SD in 3/8. Concurrent preoperative chemo- and radiotherapy may be effective as a neo-adjuvant or remission-inducing modality in the combined treatment of oesophageal carcinoma, however, it may also lead to fatal complications.

Montpellier Cancer Institute strategy and experience in surgical treatment of multi-bilateral hepatic metastases from digestive tract cancers.

Montpellier Cancer Institute strategy and experience in surgical treatment of multi-bilateral hepatic metastases from digestive tract cancers is presented based on retrospective case by case analysis of survival time of 38 patients. The mean age was 46.2 years and the primaries were colorectal (22 patients) and endocrine (16 patients). Liver surgery was synchronous to the resection of primary lesions in 8 patients and metachronous in 22 patients. Two-step liver surgery was performed in 8 patients. Overall thirty-days postoperative mortality was 7.8% and morbidity 15.7% (wound sepsis, subphrenic abscess, transitory jaundice, biliary fistula). The analysis of survival time evidenced that with reasonable risk-benefit ratio the aggressive surgical approach can be justified especially in patients with endocrine primaries.

Home enteral nutrition system: one patient, one daily ration of an "all-in-one" sterile and modular formula in a single container.

A home enteral nutrition (HEN) system was introduced to deliver a day's ration of an "all-in-one" sterile and modular formula from a large container. The nutrient formula consisted of carbohydrate, protein, and lipid modules sterilized separately, in an autoclave at 120 degrees C, then mixed and supplemented with minerals and trace elements. Vitamins were given the patients through a feeding tube before connecting the nutrient container. The system was used to feed 12 malnourished patients (10 men and two women) with cancer (carcinoma of esophagus or tongue) or without cancer (esophageal perforation). All patients had normal gastrointestinal function but could not take in more than 500 kcal/day orally, because of their primary disease or the treatment for it (surgery in four patients; and radiotherapy, associated in some cases with chemotherapy, in eight). HEN duration ranged from 30 to 435 days at a daily cost of approximately US $15 to $20. Statistical analysis (Student's t-test for paired data) showed significant body weight gain (p less than 0.05) and significant increases in serum levels of albumin, transthyretin (p less than 0.05, respectively), and transferrin (p less than 0.01). Increases of serum total protein level were not statistically significant (p less than 0.09). The nutrient formula was well tolerated and there were no HEN-related rehospitalizations. Seventy-five % (nine of the patients) considered that HEN had improved their quality of life. The daily savings per patient, compared to the cost of treatment in a hospital, was about $260/day.(ABSTRACT TRUNCATED AT 250 WORDS)

The thumb and index finger as principal surgical instruments to secure the inferior vena cava between the liver and the diaphragm in routine operations of the liver.

Presented herein is a simple and safe technique to secure the IVC in its segments above the liver and below the diaphragm through a simple incision in the abdomen. After complete division of the hepatic ligaments, the index finger is passed through the upper recessus of the lesser sac, behind the vein, and just above the caudate lobe, meeting the right thumb on the right side of the vein. A tissue string is then passed, and the IVC is secured. The experience of the authors with more than 100 consecutive hepatectomies has shown this technique to be a reliable approach to secure the IVC during routine hepatic operations.

Immunohistochemical detection of carcinoembryonic antigen (CEA) in non-cancerous and cancerous gastric mucosa.

Carcinoembryonic antigen (CEA) was stained by the PAP immunoperoxidase method in cancerous and non-cancerous gastric mucosa of 40 patients (25 non-cancerous dyspeptic patients and 15 patients with gastric carcinoma). The pattern of CEA localization was apical or membranous-cytoplasmic and immuno-reactivity was mild (+), moderate (++) or intensive ( ). No CEA immunoreactivity was detected in normal gastric mucosa whereas it was marked in gastric mucosa of non-cancerous dyspeptic patients with chronic atrophic gastritis and dysplasia (intense). In patients with superficial gastritis and epithelial hyperplasia it was mild or absent. The CEA localization pattern was also apical in non-cancerous dyspeptic patients with microscopic changes, e.g. superficial or chronic atrophic gastritis, epithelial hyperplasia and dysplasia, and in non-cancerous mucosa and cancerous tissue of patients with well (G1) and moderately (G2) differentiated adenocarcinoma.

Estimation of hepatic volume by SPECT during liver regeneration: an experimental study in an animal model.

To calculate hepatic volume in the dog by single photon emission computerized tomography (SPECT), we determined the limits of the organ by choosing an isocontour on each section. This choice entailed prior calculation of an overestimated pseudovolume. The accuracy of the measurement in the animal then approached that of measurements in vitro. We used the method to monitor hepatic regeneration in the dog after 65% hepatectomy and detected oedema and postoperative trauma, and over a longer timespan, stagnation of regeneration and a secondary drop in hepatic volume.

Inhibition of cytochrome P-450p (P450IIIA1) gene expression during liver regeneration from two-thirds hepatectomy in the rat.

Regenerating liver from partial hepatectomy (HPX) is known to exhibit a strong and transient deficiency in both spectrally detectable microsomal cytochrome P-450 (P-450) and related monooxygenase activities. Male Wistar rats (250-300 g) were HPX or sham operated and liver was excised at different times after operation. The time course of accumulation of five different forms of P-450 (including P-450b/e, P-450c, P-450d, P-450p and P-450UT-A) was determined in the regenerating liver, by Western blots developed with specific antibodies. With the exception of P-450c, whose level was not affected, the accumulation of other forms strongly decreased during the first 24 hr after HPX. For P-450b/e and P-450d, 80% of initial level was restored at 96 hr, whereas for P-450p and P-450UT-A, two major forms in control rat liver, the accumulation was only 20-25% of the initial, 1 week after HPX. No significant decrease was observed in sham operated animals. Plasmid pDex 12 containing a cDNA insert coding for P-450p was used to further investigate the effects of HPX on P-450p mRNA level and gene transcription. Northern blot analysis of RNA from regenerating liver (cDNA insert of pDex 12 being used as a probe) demonstrated that P-450p mRNA level decreased strongly to a minimum 12 hr after operation. This was correlated with a strong and transient decrease in P-450p gene transcription determined from nuclear run on experiments, the time course of which, however, did not account for the early decrease in mRNA level. We conclude that P-450p deficiency in the regenerating liver results from a combination of transient inhibition of gene transcription and early increase of mRNA degradation. Time course and amplitude of the decrease in P-450 UT-A accumulation suggest an inhibition of gene transcription as observed with P-450p.

Serum levels of carcinoembryonic antigen, gastrointestinal cancer-associated antigen and alphafetoprotein in staging and management of patients with advanced carcinoma of the stomach.

Serum levels of carcinoembryonic antigen (CEA), gastrointestinal cancer-associated antigen (GICA or CA 19-9), and alphafetoprotein (AFP) were concurrently determined in patients with carcinoma of the stomach: in 84 preoperatively, and in 67 serially postoperatively. Before surgery, serum CEA gave information about the tumor load analogous to serum GICA in 69% of the patients: true-positive in 25% and false-negative in 43%; less information in 18% and more in 14%. The sensitivity of the test tended to be better in the more advanced stages, and was higher for CEA with GICA than for CEA alone or GICA alone. During follow-up, serum CEA gave information about the presence or absence of active disease analogous to serum GICA in 78% of the patients: true-positive in 30%, true-negative in 36% and false-negative in 12%; less information in 9% and more in 13%. Neither test gave any false-positive indications. Sensitivity of the test rose from 67% for CEA alone and 60% for GICA alone to 81% for CEA with GICA. Serum AFP was elevated only preoperatively in 2% of patients. We conclude that joint application of CEA and GICA tests gave only slightly better preoperative sensitivity than CEA alone or GICA alone but proved fairly sensitive for postoperative follow-up of the patients. AFP was of little value for either purpose.

Experimental model of extended repeated partial hepatectomy in the dog.

The model of extended repeated partial hepatectomy without vascular shunt in dogs is presented. It consisted of 65% initial hepatectomy and after liver regeneration (6-10 weeks) repeated hepatectomy. Finally, only the papillary process of the caudate lobe (PPC), which constitutes 5% of the initial hepatic mass, was left intact. The most important finding was an ability of PPC to reconstitute the liver mass which enabled survival without the vascular shunt. After repeated hepatectomy the need for artificial hepatic assistance (parenteral nutritional support with frozen plasma) was imperative to offset the effects of acute hepatic failure and to support PPC regeneration.

Single photon emission computerized tomography (SPECT) for monitoring regeneration of the human liver after partial hepatectomy for secondary tumours.

In 18 patients, the liver volume during regeneration after partial hepatectomy for secondary tumours was estimated by single photon emission computerized tomography (SPECT). Hepatic weight index (HWI) was subsequently calculated to follow evolution of the regeneration as a function of postoperative complications over a 30-day period. In patients with postoperative complications the HWI curves initially rose progressively and either reached a plateau or declined thereafter. The same pattern of HWI evolution was observed in patients with tumour recurrence, which was diagnosed later. On the other hand, in patients without postoperative complications the HWI curves rose continuously. These findings showed that a regenerative response was not the same in patients with or without postoperative complications; whereas in patients with tumour recurrence it could additionally provide prognostic information.

Parks' coloanal sleeve anastomosis for treatment of postirradiation rectovaginal fistula.

Postirradiation rectovaginal fistula is a complex problem in colorectal surgery. The modified Parks procedure curettage of rectal mucosa heavily damaged by radiation is introduced. Fifteen cases of coloanal sleeve anastomosis for the repair of rectovaginal postirradiation fistula are described. All patients previously were irradiated heavily because of carcinoma of the uterine cervix. Three patients had simultaneous repair of vesicovaginal fistula. One postoperative death was observed. Of the surviving patients, functional results have been good in 11. In the seven patients with difficult stripping of the rectal mucosa, surgical curettage was performed. The latter procedure is suggested as the method of choice in relevant cases.

Aggressive regional surgery for advanced ovarian carcinoma.

Between January 1975 and December 1983 in the Cancer Institute, Montpellier, France, regional surgery (RS) was performed on 18 Stage III and 3 Stage IV patients (International Federation of Gynecology and Obstetrics [FIGO]) with histologically proven cystadenocarcinoma of the ovary. All patients were placed into one of three nonrandomized groups: Group A (9 patients), RS at first-look surgery; Group B (7 patients), RS at second-look surgery; and Group C (5 patients), RS at third-look surgery. Group A was given adjuvant chemotherapy, whereas Group B and C patients underwent nonregional surgery at first- or second-look operation, and received chemotherapy supplemented in some Group C cases by radiotherapy before RS. The adjuvant chemotherapy consisted of: cyclophosphamide plus Alkeran (mephalan) plus 5-fluorouracil (the first 7 patients) and Adriamycin (doxorubicin) plus cisplatin plus hexamethylmelamine (14 additional patients). RS consisted of basic procedures--abdominal hysterectomy; bilateral salpingo-oophorectomy; omentectomy--and specific procedures--abdominal and pelvic peritonectomy; either total or partial colectomy; jejunoilectomy, leaving at least 150 cm of the jejunum; and retroperitoneal lymph node dissection aimed at maximal cytoreduction of tumor mass. There was no operative mortality. The overall postoperative morbidity was 33.3% (seven patients) due to wound sepsis. The survival from the beginning of treatment (absolute survival [AS]) and survival after RS (RSS) were compared. In Group A (AS = RSS) the probability of survival at 112 months (6/9 patients are still alive) was 0.52. In Groups B and C the median survival times (AS and RSS) were 37 and 17 months and 18 and 1 month, respectively. The difference in AS among the three groups of patients was not statistically significant (log-rank test), whereas the RSS was statistically significant between Group A versus Groups B, C, and Groups B and C combined (P less than 0.05).