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Biomedical subjects

D Kelsen

Publications and source records attributed to D Kelsen.

At least 37 records · Page 2Linked to original sources
PubMed1994

Defining the invasive phenotype of proximal gastric cancer cells.

BACKGROUND: Adenocarcinoma of the proximal stomach is now the most rapidly rising cancer among men in the United States. The development of metastases is the major cause of morbidity and mortality for this aggressive disease. The mechanisms by which tumor cells invade the basement membrane are unknown for this disease. We have identified and established 5 invasive and noninvasive adenocarcinoma cell lines arising from the proximal stomach, which can be used to examine the mechanisms involved in tumor cell invasion. METHODS: The expression of factors associated with tumor cell attachment, proteolysis, and inhibition of proteolysis was determined by reverse transcription of mRNA to cDNA and subsequent amplification by the polymerase chain reaction. In addition, cells were examined for morphologic changes by scanning electron microscopy. RESULTS: Invasive proximal gastric cancer cells express the 72-kD form of collagenase type IV, whereas the noninvasive cells do not. Other factors examined (including the laminin receptor, cathepsin B, cathepsin L, urokinase-type plasminogen activator, and tissue inhibitor metalloproteinases) are expressed by both invasive and noninvasive gastric cancer cells, whereas collagenase type IV 92-kD form is not expressed by any of the cells examined. In addition, scanning electron microscopy revealed that all the invasive cell lines exhibit long cytoplasmic extensions. The noninvasive cells express short cytoplasmic projections and are rounder than the invasive proximal gastric cancer cell lines. CONCLUSIONS: There are distinct phenotypic differences between invasive and noninvasive proximal gastric cancer cell lines both at the level of expression of mRNA for collagenase Type IV 72-kD and at the level of scanning electron microscopy with the expression of cytoplasmic projections. Clinical outcome may be associated with these phenotypic differences.

Adenocarcinoma↗
PubMed1994

Phase II trial of gemcitabine in patients with advanced gastric cancer.

BACKGROUND: Approximately 22,000 new cases of gastric cancer are diagnosed each year in the United States, most of which are advanced disease and thus are not curable by surgery. Chemotherapy has had little impact on patient survival. Consequently, the evaluation of new agents is needed. Gemcitabine, a cytosine arabinoside analogue, was evaluated in a Phase II trial to assess its efficacy in previously untreated patients with advanced gastric cancer. METHODS: Patients were treated with weekly gemcitabine, 800 mg/m2, for 3 consecutive weeks, followed by a 1-week rest period. Eighteen patients were enrolled. Fifteen patients were evaluable for response; 2 patients refused therapy before the completion of one cycle of treatment, and one patient was found to have nonmeasurable disease. RESULTS: No major objective responses were seen. Two minor responses occurred. One patient with a minor response was removed from the study at his request after ten cycles of treatment. The other patient remains on the study with stable disease at more than 17 months. Toxicities on this study were mild. Median leukocyte count and platelet nadirs were 5.0 (range, 2.2-51.0) and 234,000/microliters (range, 59,000-554,000/microliters), respectively. CONCLUSION: Gemcitabine at this dose and schedule has no significant antitumor activity in gastric cancer.

Adenocarcinoma↗
PubMed1994

A phase II trial of pleurectomy/decortication followed by intrapleural and systemic chemotherapy for malignant pleural mesothelioma.

PURPOSE: This study investigated the feasibility of a novel approach to the treatment of malignant pleural mesothelioma by combining surgical resection with immediate postoperative intrapleural chemotherapy and subsequent systemic chemotherapy. PATIENTS AND METHODS: Patients with biopsy-proven, resectable malignant pleural mesothelioma underwent pleurectomy/decortication immediately followed by intrapleural chemotherapy with cisplatin 100 mg/m2 and mitomycin 8 mg/m2. Systemic chemotherapy was started 3 to 5 weeks postoperatively and included cisplatin 50 mg/m2 on days 1, 8, 15, 22, 36, 43, 50, and 57, and mitomycin 8 mg/m2 on days 1 and 36. Patients were then monitored by serial chest and abdominal computed tomographic (CT) scans every 3 months until death or for a minimum of 18 months, whichever occurred first. RESULTS: Of 36 patients entered onto the study, 28 had pleurectomy/decortication and intrapleural chemotherapy. There was one postoperative death, and two episodes of grade 4 renal toxicity after intrapleural chemotherapy. The 23 patients who also had systemic chemotherapy received a median of 80% and 87% of the planned total cisplatin and mitomycin doses, respectively. No grade 3 or 4 toxicities were observed. The overall survival rate of the 27 patients who were originally candidates for systemic chemotherapy was 68% at 1 year and 40% at 2 years, with a median survival duration of 17 months. Locoregional disease was the most common form of relapse (16 of 20 patients). CONCLUSION: This short but aggressive combined modality regimen was generally well tolerated, but should not be used outside of a protocol setting because of the potential for serious toxicity. Overall survival was as good or better than with previously reported multimodality approaches, but other strategies are needed to improve local control.

Aged↗
PubMed1994

A phase II trial of paclitaxel (Taxol) in advanced esophageal cancer: preliminary report.

A cooperative, phase II single-arm trial was conducted at two large tertiary referral cancer centers to evaluate the antineoplastic activity and toxicities of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in the treatment of patients with advanced esophageal cancer. The drug was given at a dose of 250 mg/m2 as a 24-hour continuous infusion. Repeat courses were given at 21-day intervals. De-escalation was based primarily on myelosuppression. All patients received recombinant human granulocyte colony-stimulating factor to minimize the risk of neutropenic fever. The primary goal of the study was tumor response. In the trial, which is ongoing, 42 patients have been assessed to date. Adenocarcinoma was the predominant histology in 30 patients, while epidermoid cancer was seen in 13 patients. Paclitaxel was identified as an active agent. Thirty percent of patients with adenocarcinoma and 25% of the smaller group with epidermoid carcinoma have had partial remissions. Complete remissions have not been seen to date. The median duration of response was 9 weeks. The major toxicity was myelosuppression; 11 patients required admission for neutropenic fever on 13 different occasions. Paclitaxel is an active drug in the treatment of esophageal cancer. Currently, there does not appear to be a difference in response on the basis of histologic subtype. Further studies with paclitaxel in combination with other drugs (eg, cisplatin and 5-fluorouracil), on different treatment schedules, and as part of multimodality therapy are indicated.

Adenocarcinoma↗
PubMed1994

The use of chemotherapy in the treatment of advanced gastric and pancreas cancer.

Patients with advanced adenocarcinomas of the stomach and pancreas have an exceptionally poor prognosis. Curative surgery in these patients is either impossible (metastatic disease) or exceedingly difficult (locally advanced tumors). In gastric cancer, single-agent chemotherapy with drugs like 5-fluorouracil (5-FU), mitomycin, doxorubicin, and cisplatin has achieved overall response rates of 19% to 30%; slightly higher response rates have been reported in single-arm trials of 5-FU-containing combinations. However, random assignment trials, with rare exceptions, failed to demonstrate a survival advantage for combination therapy. Overall survival in this disease remains poor. In pancreatic cancer, only modest activity has been demonstrated with single agents (response rates of 25% and 24% at best, respectively, with 5-FU and mitomycin), and combination chemotherapy has not yielded better results. Modest improvements in the palliation of locally advanced pancreatic cancer have been achieved by combining 5-FU with radiation therapy. New, more effective treatment strategies are clearly indicated for both gastric and pancreatic cancer.

Adenocarcinoma↗
PubMed1993

A phase II trial of carboplatin in patients with advanced APUD tumors.

BACKGROUND: Chemotherapy remains inadequate for patients with carcinoid tumors, islet cell tumors, and medullary carcinomas of the thyroid. Carboplatin has shown activity in oat cell carcinoma of the lung, another tumor of neuroectodermal origin. METHODS: Forty-two patients with advanced APUD tumors (20 carcinoid tumors, 9 islet cell carcinomas, 5 medullary carcinomas of the thyroid, and 9 neuroendocrine tumors of unknown primary site) were treated with carboplatin in a Phase II study. RESULTS: Carboplatin was inactive in carcinoid and islet cell tumors, with 0 of 20 and 0 of 9 patients responding, respectively. Of the 41 total patients evaluable for response, only 2 (5%) achieved a partial response. Both of these responding patients had neuroendocrine tumors of unknown primary site. No complete responses were seen. Toxicities were those previously noted with carboplatin, with myelosuppression, particularly thrombocytopenia, being dose limiting. CONCLUSIONS: Carboplatin is inactive in carcinoid tumors and did not show evidence of activity in islet cell tumors. Further investigations are needed to identify active agents in the treatment of neuroendocrine malignancies.

Adenoma, Islet Cell↗
PubMed1993

Octreotide as an antineoplastic agent in the treatment of functional and nonfunctional neuroendocrine tumors.

BACKGROUND: Although patients with neuroendocrine tumors typically exhibit an indolent clinical course, the pace of disease accelerates and the prognosis deteriorates once objective progression of disease begins. Thirty-four patients with advanced neuroendocrine tumors were treated with octreotide as antineoplastic therapy. This treatment was begun only after documentation of clear objective progression of disease. METHODS: A Phase II trial was performed at a tertiary comprehensive cancer center. RESULTS: The median survival for this patient population from the start of octreotide therapy has not been reached, with a median follow-up of 29 months (range, 1-47 months). No major objective tumor regressions were seen. Seventeen patients (50%) experienced a computed tomography-documented stabilization of disease that was maintainable for a minimum of 2 months (median, 5 months; range, 0-27 months). Of the 34 patients, 20 patients received octreotide as their first antineoplastic therapy. The median survival for these 20 patients has not been reached, with a median follow-up also of 29 months (range, 12-41 months). CONCLUSIONS: Octreotide may influence the natural history of neuroendocrine tumors. The survival in patients treated with octreotide, as measured from the time of progression of disease, compares favorably with that of historical controls. Proof of a survival advantage for patients treated with octreotide would require a multicenter, randomized trial.

Adenoma, Islet Cell↗
PubMed1993

Protein kinase C: a novel target for inhibiting gastric cancer cell invasion.

BACKGROUND: Gastric adenocarcinoma is a common neoplasm worldwide. Patients with completely resected disease often have locoregional recurrence, and adjuvant chemotherapy has failed to reduce the common occurrence of metastases. Protein kinase C (PKC) is thought to be important in tumor cell invasion, but its relationship to gastric cancer cell invasion, and thus metastases, remains unexplored. We recently identified and established invasive and noninvasive human gastric adenocarcinoma cell lines, which can now be used to test agents for inhibition of tumor cell invasion by inhibition of PKC activity. PURPOSE: The objectives were (a) to test threo-dihydrosphingosine (SPC100221), a specific inhibitor of PKC at its regulatory site, and staurosporine, a potent but nonspecific inhibitor of PKC at its catalytic site, for their effects on gastric cancer cell invasion in vitro and (b) to determine whether the expression of PKC isoforms can distinguish invasive from noninvasive gastric cancer cells. METHODS: Gastric cancer cell invasion through Matrigel-coated Nuclepore filters in the Boyden chamber assay was analyzed in the presence of graded concentrations of SPC100221 and staurosporine. The invasive SK-GT-1 and SK-GT-5 cell lines and the noninvasive SK-GT-2 and SK-GT-4 cell lines were used. PKC isoform expression was determined by reverse transcription of messenger RNAs to complementary DNA and subsequent amplification by the polymerase chain reaction. RESULTS: The effects of staurosporine and SPC100221 on tumor cell invasion were tested at drug concentrations that did not inhibit cell proliferation, as evidenced by [3H]thymidine uptake. Staurosporine and SPC100221 at subtoxic doses inhibited human gastric cancer cell invasion by 50% at 5 x 10(-9) M and 2 x 10(-7) M, respectively. The expression of PKC beta was observed in the invasive but not the noninvasive gastric cancer cells. Both types of cells, however, expressed the PKC alpha and PKC gamma isoforms. CONCLUSIONS: Gastric cancer cell invasion can be inhibited by PKC inhibitors, and expression of PKC beta may be a marker of invasiveness in gastric cancer. IMPLICATIONS: PKC appears to represent a new target for inhibition of gastric cancer cell invasion, and SPC100221, in view of its PKC specificity, may provide a model for future drug development in this area. Moreover, PKC beta may have a fundamental role in the development of invasive potential in gastric cancer.

Alkaloids↗
PubMed1993

Neoadjuvant therapy for gastrointestinal cancers.

Neoadjuvant (primary) chemotherapy is an attractive concept for upper GI tract malignancies and to a lesser extent rectal cancer to increase local control, as well as to destroy micrometastasis. Endoscopic ultrasonography for esophageal, gastric, and rectal cancers is a new tool that may allow identification of appropriate high-risk patients for such investigational approaches. In esophageal cancer, radiation therapy alone has probably been supplanted by combined concurrent systemic chemotherapy and radiation. Phase III trials of chemotherapy prior to operation are currently underway. Phase II trials of neoadjuvant chemotherapy are underway in gastric cancer. In rectal cancer, while the use of postoperative adjuvant chemotherapy plus radiation is firmly established, more recent data suggest that there may be less toxicity with preoperative treatment, and in selected patients may result in increased potentially curative resection rates.

Chemotherapy, Adjuvant↗
PubMed1992

A phase II trial of biochemical modulation using N-phosphonacetyl-L-aspartate, high-dose methotrexate, high-dose 5-fluorouracil, and leucovorin in patients with adenocarcinoma of unknown primary site.

BACKGROUND: 5-Fluorouracil (5-FU) has modest activity as a single agent in a number of human adenocarcinomas. The technique of biochemical modulation has been used preclinically to increase the activity of 5-FU. METHODS: With doses based on a Phase I study, the authors performed a Phase II trial in patients with advanced metastatic adenocarcinoma of an unknown primary site using N-phosphonacetyl-l-aspartate (PALA), methotrexate (MTX), 5-FU, and leucovorin. In some patients, 5-phosphoriosyl-l-pyrophosphate (PRPP) and uridine triphosphate (UTP) metabolite pools were assayed before and after PALA and MTX to assess metabolite pool shifts. RESULTS: Twenty-one patients were treated in this Phase II trial. Toxicity was tolerable. Biopsy specimens of tumor tissue showed increases in PRPP and decreases in UTP levels in two of three and three of four patients, respectively. However, only one objective response was seen, which is not different from that expected with 5-FU alone. CONCLUSIONS: Expected PRPP and UTP metabolite pool shifts were seen when biochemical modulation was performed with these drugs according to this schedule. Because toxicity was mild, more intense dose schedules of 5-FU are planned for future studies.

Adenocarcinoma↗
PubMed1992

Efficacy of cisplatin-based intraperitoneal chemotherapy as treatment of malignant peritoneal mesothelioma.

In an effort to examine the potential clinical utility of intraperitoneal (i.p.) therapy in the management of patients with malignant peritoneal mesothelioma, 19 individuals with this disease were treated with a cisplatin-based i.p. treatment regimen. All but 1 patient also received i.p. mitomycin. The treatment was generally well tolerated, although a maximum of only four or five courses of cisplatin (100 mg/m2 every 28 days) and mitomycin (5-10 mg/treatment given 7 days after each i.p. cisplatin administration) could be administered, the treatment principally being stopped because of disease progression or catheter failure. Of 15 patients with malignant ascites, 7 (47%) experienced control of fluid reaccumulation ranging from 2 months to 73+ months (median 8 months). While the median survival for the 19 patients was only 9 months, 4 (21%) patients survived for more than 3 years from the initiation of therapy, and 2 patients are currently alive and clinically disease-free more than 5 years from the start of the i.p. treatment program. We conclude that a subset of patients with peritoneal mesothelioma, principally those with small-volume residual disease following surgical tumor debulking, can benefit from a cisplatin-based i.p. treatment strategy with control of ascites and prolonged disease-free survival.

Adult↗
PubMed1992

Interferon alfa-2a and fluorouracil in the treatment of patients with advanced esophageal cancer.

PURPOSE: The trial was undertaken to determine the response rate to and toxicities from the combination of interferon alfa-2a (IFN) and fluorouracil (FU) in patients with advanced esophageal cancer. MATERIALS AND METHODS: In this prospective phase II trial conducted at a large tertiary referral cancer center and university hospital, 40 patients with advanced locoregional, metastatic epidermoid, or adenocarcinoma of the esophagus were given FU 750 mg/m2 by 24-hour continuous intravenous infusion days 1 to 5, followed by weekly outpatient bolus FU 750 mg/m2 and IFN 9 x 10(6) U three times per week from day 1. Dose was attenuated for fatigue, neurotoxicity, gastrointestinal toxicity, and myelosuppression. RESULTS: Complete and partial responses were seen in 10 of 37 assessable patients with esophageal cancer (27%; 95% confidence interval, 0.13 to 0.41). Although substantial, toxicity was tolerable and primarily involved fatigue and mild myelosuppression. The median duration of response was 6.4 months (range, 2.8 to 14+ months). CONCLUSION: The combination of IFN and FU is an active regimen in the treatment of advanced esophageal cancer with a response rate similar to that reported for cisplatin-containing combinations in similar patient populations. Further studies based on this combination are indicated.

Adenocarcinoma↗
PubMed1992

FAMTX versus etoposide, doxorubicin, and cisplatin: a random assignment trial in gastric cancer.

PURPOSE: The chemotherapy regimens of high-dose methotrexate, high-dose fluorouracil (FU), Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and leucovorin (FAMTX) and etoposide, Adriamycin, and cisplatin (EAP) have both been reported in nonrandom assignment trials to have high overall response rates and substantial complete response rates in patients with gastric cancer, as well as major toxicities of myelosuppression. Here we report a prospective, stratified, random-assignment comparison of the two combinations in previously untreated patients with advanced gastric cancer. PATIENTS AND METHODS: Sixty patients were entered onto the trial, 30 receiving EAP and 30 FAMTX. All patients had measurable or assessable tumor masses. Patient entry was stopped at the point when significant toxicity differences were seen at interim analysis. RESULTS: Response rates were similar between the two arms (FAMTX, 33% [95% confidence interval (CI), 16% to 50%]; EAP, 20% [95% Cl, 6% to 34%]). Three FAMTX and no EAP patients had complete remissions. The median survival for the two arms were similar (EAP, 6.1 months; FAMTX, 7.3 months). At 1 year, 7% of EAP and 17% of FAMTX patients were alive. EAP caused significantly more myelosuppression (leukopenia, P = .002; anemia, P = .03; thrombocytopenia, P = .0001) than did FAMTX. EAP also resulted in significantly longer hospitalizations per study month (8 v 5 days). Four EAP patients died of lethal toxicity, whereas no FAMTX patients died of treatment-related causes (P = .04). CONCLUSIONS: FAMTX is at least as active as EAP and is significantly less toxic. Although both regimens remain investigational, the toxicities of FAMTX are more manageable. Further studies involving FAMTX in both the adjuvant and advanced disease setting are underway.

Adult↗
PubMed1992

Intrapleural cisplatin and mitomycin for malignant mesothelioma following pleurectomy: pharmacokinetic studies.

PURPOSE: Intrapleural cisplatin-based chemotherapy has been used in the treatment of patients with malignant pleural mesothelioma and malignant pleural effusions, but the pharmacokinetics of this form of chemotherapy have not been previously evaluated. We performed pharmacokinetic studies on 12 patients who received both intrapleural cisplatin and mitomycin immediately following pleurectomy/decortication for malignant pleural mesothelioma. PATIENTS AND METHODS: Simultaneous pleural fluid and plasma samples were collected at 15 and 30 minutes, and at 1, 2, 3, 4, and 24 hours after administration of the intrapleural chemotherapy (cisplatin 100 mg/m2 and mitomycin 8 mg/m2), and after cisplatin (total and free) and mitomycin levels were measured. The mean peak levels, the areas under the concentration-time curve (AUC) and the drug half-lives (t1/2s) in plasma and pleural fluid were compared using the paired t test. Differences were considered significant if P less than or equal to .05. RESULTS: Systemic absorption was rapid, with peak plasma levels being reached within 1 hour of administration of the intrapleural chemotherapy. Peak plasma levels measured after intrapleural chemotherapy approximated those reportedly attained during systemic administration of these drugs at similar doses. However, the mean peak cisplatin and mitomycin levels, and their mean AUCs, were significantly higher in the pleural fluid than in the plasma. There was a three- to fivefold advantage (on a logarithmic scale) for pleural to plasma AUCs for both cisplatin and mitomycin. The mean t1/2s for cisplatin and mitomycin were significantly longer in the plasma than in the pleural fluid. CONCLUSIONS: The pharmacokinetics of intrapleural cisplatin-based chemotherapy are analogous to those of intraperitoneal chemotherapy. Our findings show that intrapleural cisplatin-based chemotherapy has a distinct local pharmacologic advantage, but also produces significant and sustained drug plasma levels.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

A phase III comparison trial of streptozotocin, mitomycin, and 5-fluorouracil with cisplatin, cytosine arabinoside, and caffeine in patients with advanced pancreatic carcinoma.

Conventional chemotherapy for unresectable or metastatic adenocarcinoma of the pancreas has had little effect on palliation or survival. Almost all studies of systemic therapy have involved empiric use of a variety of Phase II or conventional agents alone or in combination. On the basis of recent studies using a human tumor pancreatic cancer (PC) xenograft in nude mice, a Phase I clinical trial of cisplatin, high-dose cytosine arabinoside (Ara-C), and caffeine (CAC) was performed in patients with advanced incurable PC. A tolerable dose and schedule of the three agents were developed. Seven of 18 patients with measurable disease in this Phase I trial had partial responses to CAC. A Phase III comparison of CAC versus standard treatment using streptozotocin, mitomycin, and 5-fluorouracil (SMF) was performed. Eighty-two patients with advanced PC were entered into this random assignment trial. The two treatment arms were well balanced for the usual prognostic factors. Although the acute (e.g., nausea and vomiting) toxicities of CAC were greater than those of SMF, both groups of patients tolerated treatment resonably well. Ninety percent of patients were evaluable for response. Two patients (5.5%) on the CAC treatment arm (95% confidence interval [CI], 0% to 15%) and four patients (10.2%) on the SMF treatment arm (95% CI, 1% to 22%) had objective responses (partial response in measurable disease or improvement in evaluable disease). No complete remissions were observed. The 95% confidence limits of response for CAC and SMF overlapped. The median duration of survival for all patients on the SMF treatment arm was 10 months, although it was 5 months on the CAC treatment arm (P = 0.008). In this Phase III comparison, CAC was not superior to conventional therapy with SMF in terms of response and was inferior for survival. Neither regimen is effective treatment for advanced PC.

Adenocarcinoma↗
PubMed1991

A phase II trial of carboplatin and vinblastine in the treatment of advanced squamous cell carcinoma of the esophagus.

Cisplatin-containing regimens are active in the treatment of esophageal cancer, with response rates of 25% to 35% in advanced disease. Carboplatin is less toxic than cisplatin; as a single agent, several responses were seen against esophageal tumors. To better define the role of carboplatin in esophageal cancer, the authors treated 19 chemotherapy-naive patients with advanced squamous cell carcinoma of the esophagus with carboplatin and vinblastine. Carboplatin (450 mg/m2 intravenously [IV] on days 1, 29, 57, and every 6 weeks thereafter) was given with vinblastine (5 mg/m2 IV on day 1 and then every 2 weeks). No major responses were seen. No significant renal toxicity and only mild gastrointestinal toxicity (emesis, diarrhea) were observed. Hematologic toxicity was more severe in patients with prior radiation therapy (RT), with three of six patients with prior RT exhibiting Grade 4 hematologic toxicity. Although generally less toxic than cisplatin-containing regimens, carboplatin and vinblastine is also less active in the treatment of squamous cell carcinoma of the esophagus. Hematologic toxicity with this regimen was severe in patients who had received prior RT.

Adult↗