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Faheez Mohamed

Publications and source records attributed to Faheez Mohamed.

At least 19 recordsLinked to original sources

Optimizing the factors which modify thermal enhancement of melphalan in a spontaneous murine tumor.

BACKGROUND: Hyperthermia enhances the cytotoxicity of some chemotherapeutic agents. Both clinical and laboratory studies suggest melphalan may be an important drug when hyperthermia is added to chemotherapy treatments. Factors that may modify the thermal enhancement of melphalan were studied to optimize its clinical use with hyperthermia. METHODS: The tumor studied was an early-generation isotransplant of a spontaneous C3Hf/Sed mouse fibrosarcoma, Fsa-II. All studies were performed under supervision of the Animal Care and Use Committee. Hyperthermia was administered by immersing the tumor-bearing foot into a constant temperature water bath. Four factors were studied: duration of hyperthermia, sequencing of hyperthermia and melphalan, intensity of hyperthermia, and tumor size. To study duration of hyperthermia tumors were treated at 41.5 degrees C for 30 or 90 min immediately after intraperitoneal administration of melphalan. For sequencing of hyperthermia and melphalan, animals received hyperthermia treatment of tumors for 30 min at 41.5 degrees C immediately after drug administration, both immediately and 3 h after administration of drug or only at 3 h after administration of drug. Intensity of hyperthermia was studied using heat treatment of tumors for 30 min at 41.5 or 43.5 degrees C immediately following drug administration. Effect of tumor size was studied by delaying experiments until three times the tumor volume (113 mm3) was observed. Treatment of tumors was for 30 min at 41.5 degrees C immediately following drug administration. Tumor response was studied by the mean tumor growth time. RESULTS: Hyperthermia in the absence of melphalan had a small but significant effect on tumor growth time at 43.5 degrees C but not at 41.5 degrees C. Hyperthermia at 41.5 degrees C immediately after melphalan administration doubled mean tumor growth time at 30 min and caused a threefold increase at 90 min (P=0.0002) when compared to tumors treated with melphalan alone at room temperature. Application of hyperthermia for one-half hour immediately following drug administration was the most effective in delaying tumor growth. No significant difference in mean tumor growth time was observed with an increase in temperature from 41.5 to 43.5 degrees C. For large tumors heat alone and melphalan alone caused a moderate increase in tumor growth delay. These effects in large tumors were greatly increased by a combination of chemotherapy and hyperthermia. CONCLUSIONS: From our data it would appear that the administration of intraperitoneal melphalan immediately prior to 90 min of heat at 41.5 degrees C may optimize anti-neoplastic activity. These data may be useful in formulating clinical protocols in which melphalan and heat are combined.

Animals↗

Docetaxel and hyperthermia: factors that modify thermal enhancement.

BACKGROUND: Hyperthermia enhances the cytotoxicity of some chemotherapeutic agents and recent studies suggest that docetaxel may show improved response at elevated temperatures. Factors that may modify the thermal enhancement of docetaxel were studied to optimize its clinical use with hyperthermia. METHODS: The tumor studied was an early-generation isotransplant of a spontaneous C3Hf/Sed mouse fibrosarcoma, Fsa-II. All studies were approved by the Animal Care and Use Committee. Docetaxel was given as a single intraperitoneal injection. Hyperthermia was achieved by immersing the tumor-bearing foot into a constant temperature water bath. Four factors were studied: duration of hyperthermia, sequencing of hyperthermia with docetaxel, intensity of hyperthermia, and tumor size. To study duration of hyperthermia tumors were treated at 41.5 degrees C for 30 or 90 min immediately after intraperitoneal administration of docetaxel. For sequencing of hyperthermia and docetaxel, animals received hyperthermia treatment of tumors for 30 min at 41.5 degrees C immediately after drug administration, hyperthermia both immediately and 3 hr after docetaxel administration and hyperthermia given only at 3 hr after administration of docetaxel. Intensity of hyperthermia was studied using heat treatment of tumors for 30 min at 41.5 or 43.5 degrees C immediately following docetaxel administration. Effect of tumor size was studied by delaying experiments until three times the tumor volume (113 mm(3)) was observed. Treatment of tumors lasted for 30 min at 41.5 degrees C immediately following drug administration. Tumor response was studied using the mean tumor growth time. RESULTS: Hyperthermia in the absence of docetaxel had a small but significant effect on tumor growth time at 43.5 degrees C but not at 41.5 degrees C. Hyperthermia at 41.5 degrees C for 90 min immediately after docetaxel administration significantly increased mean tumor growth time (P = 0.0435) when compared to tumors treated with docetaxel at room temperature. Treatment for 30 min had no effect. Application of hyperthermia immediately and immediately plus 3 hr following docetaxel was effective in delaying tumor growth. Treatment at 3 hr only had no effect. No significant difference in mean tumor growth time was observed with docetaxel and one half hour of hyperthermia at 41.5 or 43.5 degrees C. For larger tumors, hyperthermia alone caused a significant delay in tumor growth time. Docetaxel at 41.5 degrees C for 30 min did not significantly increase mean tumor growth time compared to large tumors treated with docetaxel at room temperature. CONCLUSIONS: Docetaxel shows a moderate increase in anti-tumor activity with hyperthermia. At 41.5 degrees C the thermal enhancement of docetaxel is time dependent if hyperthermia is applied immediately following drug administration. With large tumors docetaxel alone or docetaxel plus hyperthemia showed the greatest delays in tumor growth time in the experiments.

Animals↗

Clinically aggressive pseudomyxoma peritonei: a variant of a histologically indolent process.

BACKGROUND: Three distinct morphologic types of pseudomyxoma peritonei syndrome have been defined: disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinoma (PMCA), and a hybrid morphologic type. Prognosis is best in patients with DPAM; unfortunately, some patients with DPAM succumb to a rapidly progressive disease process. METHODS: We identified a subset of 11 patients with a histopathology of DPAM but a clinical course showing an invasive disease process. As a comparison group, from a database of 501 patients with pseudomyxoma peritonei, we selected 22 age- and sex-matched controls with a DPAM histology who are alive with no evidence of disease. Clinical factors were identified for comparison of case and control groups. Expression of mucin antigens, mucin (MUC)1 and MUC2, were evaluated using immunohistochemistry. RESULTS: The study group consisted of 11 patients (five men and six women), with a median survival of 52.2 months (SD 7.46) and a 31% 5-year survival. All 22 matched control cases (10 men and 12 women) are alive and disease-free. Clinical data on the study and control groups including co-morbidity were similar. No significant difference in the expression of MUC1 (P = 0.74, Fisher's exact test) or MUC2 (P = 0.34, Fisher's exact test) was demonstrated between groups. CONCLUSIONS: Further investigation of pseudomyxoma peritonei at a molecular and genetic level may help to formulate a more comprehensive classification.

Adult↗

Peritoneal carcinomatosis from digestive tract cancer: new management by cytoreductive surgery and intraperitoneal chemohyperthermia.

Peritoneal carcinomatosis is a common manifestation of digestive-tract cancer and has been regarded a terminal disease with a short median survival. Over the past decade, a new locoregional therapeutic approach combining cytoreductive surgery with intraperitoneal chemohyperthermia (IPCH) has evolved. Because of its limited benefits, high morbidity and mortality, and high cost, this comprehensive management plan requires accurate patient selection. Quantitative prognostic indicators are needed to assess a patient's eligibility for combined treatment, including tumour histopathology, classification of carcinomatosis extent, assessment of completeness of cytoreduction, and determination of the extent of previous surgery. Patients with pseudomyxoma peritonei and those with peritoneal dissemination of digestive-tract cancer have shown promising survival. Complete cytoreduction with no visible disease persisting is a requirement for long-term benefit. In Japan and Korea, use of IPCH as prophylactic treatment in potentially curative gastric-cancer resection has shown improved survival and lower peritoneal recurrence rates. IPCH combined with cytoreductive surgery seems to be an effective therapeutic approach in carefully selected patients, and offers a chance for cure or palliation in this condition with few alternative treatment options.

Antineoplastic Combined Chemotherapy Protocols↗

Incomplete cytoreduction in 174 patients with peritoneal carcinomatosis from appendiceal malignancy.

OBJECTIVE: The aim of this study was to analyze the survival of patients with peritoneal dissemination of appendiceal malignancy having incomplete cytoreductive surgery. SUMMARY BACKGROUND DATA: Cytoreductive surgery plus perioperative intraperitoneal chemotherapy has emerged as a new and potentially curative treatment option for patients with peritoneal dissemination of appendiceal mucinous tumors. The goal of surgery is to remove all visible disease. Nevertheless, in some patients, complete cytoreduction is not possible. METHODS: Over a 30-year period, 645 patients with epithelial peritoneal surface malignancy of appendiceal origin were treated with cytoreductive surgery and intraperitoneal chemotherapy by a single surgeon. One hundred seventy-four (27.1%) of these patients had an incomplete cytoreduction. A critical statistical analysis of the impact of selected clinical features on survival was performed from a prospective database. RESULTS: Mortality and morbidity rates were 0% and 33.3%, respectively. Median survival of these 174 patients was 20.5 months and their 1-year, 3-year, and 5-year survival rates were 71%, 34%, and 15%, respectively. By multivariate analysis, the presence of signet ring cells and lymph node involvement were independent prognostic indicators of poor survival (P = 0.047 and P < 0.001, respectively). Patients who underwent more than 1 cytoreduction or repeat intraperitoneal chemohyperthermia showed significant improvement in survival (P = 0.018 and P < 0.001, respectively) CONCLUSION: Incomplete cytoreduction plus perioperative intraperitoneal chemotherapy of peritoneal dissemination from appendiceal malignancy results in limited long-term survival. Patients with signet ring histology or lymph node involvement have an especially poor outcome. Repeat cytoreduction and intraperitoneal chemohyperthermia may improve outcome.

Antineoplastic Combined Chemotherapy Protocols↗

Pharmacokinetics and tissue distribution of intraperitoneal paclitaxel with different carrier solutions.

BACKGROUND: For cancers that have disseminated to peritoneal surfaces, intraperitoneal chemotherapy administration results in high drug concentration locally with low systemic toxicity. Using a rat model we compared the pharmacokinetics and tissue absorption of paclitaxel infused intraperitoneally in two isotonic carrier solutions: 1.5% dextrose peritoneal dialysis solution (peritoneal dialysis solution) and hetastarch (6% hydroxyethyl starch), a high molecular weight solution. METHODS: A total of 60 Sprague Dawley rats were randomized into groups according to the carrier solution administered. Rats were given a single dose of intraperitoneal paclitaxel (40 mg/m2) in 0.1 ml/g body weight of each carrier solution. Each group was further randomized according to the intraperitoneal dwell period (3, 6, 12, 18 and 24 h). At the end of the procedure the rats were killed, the peritoneal fluid was withdrawn completely and the volume recorded. Blood and tissues were sampled using a standardized protocol. Drug concentrations in peritoneal fluid, plasma, and tissues were determined by high-performance liquid chromatography. RESULTS: Fluid clearance from the peritoneal cavity was lower in the presence of hetastarch than in the presence of peritoneal dialysis solution. The mean volumes remaining in the peritoneal cavity were significantly higher with hetastarch at 18 h (P=0.0079). No excess peritoneal fluid remained with peritoneal dialysis solution at 24 h. Mean plasma paclitaxel concentrations were significantly lower with hetastarch at 3 h (P=0.0079), 12 h (P=0.0079), and 18 h (P=0.0317). The mean total quantity of drug remaining in the peritoneal cavity was significantly greater with hetastarch at 12 h (P=0.0079) and 18 h (P=0.0317). There was a 105% increase in the area under the curve ratio of peritoneal fluid to plasma paclitaxel concentrations with hetastarch (391) vs peritoneal dialysis solution (191). Paclitaxel concentrations were significantly greater with peritoneal dialysis solution at 6 h in colon, abdominal wall, and myocardium. CONCLUSIONS: The use of intraperitoneal paclitaxel with hetastarch carrier solution provides a pharmacologic advantage for a local-regional killing of residual tumor cells with decreased systemic toxicity. Clinical investigations into the use of 6% hetastarch with high molecular weight chemotherapeutic agents are warranted.

Animals↗

Extent of parietal peritonectomy does not change intraperitoneal chemotherapy pharmacokinetics.

PURPOSE: To measure the clearance intraperitoneal mitomycin C and doxorubicin in patients having peritonectomy and analyze the impact of the extent of peritoneal resection on pharmacokinetics. METHODS: A group of 15 patients with peritoneal carcinomatosis were submitted to cytoreductive surgery and heated intraperitoneal chemotherapy. Ten patients received mitomycin C and five, doxorubicin. Six patients underwent total parietal peritonectomy and nine had less-extensive peritonectomy. Pharmacokinetics were determined by sampling peritoneal fluid and blood. Drug concentrations over time, area under the curve ratios and the amount of drug recovered from the peritoneal cavity were calculated and compared between the groups. RESULTS: The concentrations of mitomycin C over time in the peritoneal fluid and plasma were similar in five patients with total parietal peritonectomy as compared to five patients with less-extensive peritonectomy ( P=0.5350 and 0.6991; Mann-Whitney test). Mitomycin C area under the curve ratio in total peritonectomy patients was 20.5 and 25.7 in patients with less-extensive peritonectomy. The difference in total amount of drug recovered from the peritoneal cavity was not significant (30.6+/-6.188% versus 22.6+/-3.84%, P=0.095). In the studies with doxorubicin, one patient underwent total parietal peritonectomy with similar pharmacokinetics to four patients submitted to partial peritonectomy. CONCLUSIONS: The extent of parietal peritoneal resection did not affect the pharmacokinetics of intraoperative intraperitoneal chemotherapy. The pharmacological barrier between the abdominopelvic cavity and plasma is not directly related to an intact peritoneum.

Adenocarcinoma, Mucinous↗

Third look surgery and beyond for appendiceal malignancy with peritoneal dissemination.

BACKGROUND AND OBJECTIVES: Second look surgery has been previously studied in patients with recurrent peritoneal dissemination from appendiceal malignancy. However, selection criteria for third, fourth, and subsequent reoperations are not available. METHODS: Five hundred and one patients with epithelial peritoneal surface malignancy of appendiceal origin underwent treatment with cytoreductive surgery and intraperitoneal chemotherapy during an 18-year period. Forty-five of these patients (8.9%) underwent three or more operative interventions. A critical statistical analysis of the impact of selected clinical features on survival was performed from a prospective database. RESULTS: Overall 5-year survival of these 45 patients was 70%. Five- and ten-year survival rates for patients with three interventions were 60 and 48%, for four interventions were 78 and 36%, and for five or more interventions were 100 and 80%. Sites of recurrent disease, histopathologic type of tumor, and lymph node status had no impact on survival. A complete second and third cytoreduction was associated with an improved 5-year survival rate. CONCLUSIONS: Prolonged survival in patients with three or more reoperations was significantly associated with a complete cytoreduction. However, after four or more interventions, the effects of tumor biology may predominate. Although 5-year survival is likely with multiple reoperations, prolonged follow-up shows that cancer cure is a rare event.

Adenocarcinoma, Mucinous↗

Pharmacokinetics and tissue distribution of intraperitoneal docetaxel with different carrier solutions.

BACKGROUND: Intraperitoneal chemotherapy administration results in high drug concentration locally with low systemic toxicity. Using a rat model we compared the pharmacokinetics and tissue absorption of docetaxel infused intraperitoneally in two isotonic carrier solutions; 1.5% dextrose peritoneal dialysis solution (peritoneal dialysis solution) and hetastarch (6% hydroxyethyl starch), a high molecular weight solution. MATERIALS AND METHODS: Sixty Sprague-Dawley rats were randomized into groups according to the carrier solution administered. Rats were given a single dose of intraperitoneal docetaxel (80 mg/m(2)) in 0.1 ml/g body weight of each carrier solution. Each group was further randomized according to the intraperitoneal dwell period (3, 6, 12, 18, and 24 h). At the end of the procedure the rats were killed, the peritoneal fluid was withdrawn completely and the volume recorded. Blood and tissues were sampled using a standardized protocol. Drug concentrations in peritoneal fluid, plasma, and tissues were determined by high-performance liquid chromatography. RESULTS: Hetastarch clearance from the peritoneal cavity was reduced when compared to peritoneal dialysis solution. The mean volumes remaining in the peritoneal cavity were significantly higher with hetastarch at 6 h (P = 0.022) and 12 h (P = 0.0012). Plasma docetaxel concentrations were similar for both carrier solutions. The mean total amount of docetaxel remaining in the peritoneal cavity was significantly greater with hetastarch at 3 h (P = 0.0022), 6 h (P = 0.0043), and 12 h (P = 0.0023). There was a 39% increase in the area under the curve ratio of peritoneal fluid to plasma docetaxel concentrations with hetastarch (227) versus peritoneal dialysis solution (163). Docetaxel concentrations were significantly greater with hetastarch in colonic tissue at 18 and 24 h, and in gastric tissue at 6, 12, and 18 h. CONCLUSION: The use of intraperitoneal docetaxel with a hetastarch carrier solution provides a pharmacologic advantage for a local-regional killing of residual intraperitoneal tumor cells without increasing systemic toxicity.

Animals↗

Intraperitoneal taxanes.

The taxanes appear to be promising agents for intraperitoneal use. Paclitaxel is currently undergoing Phase III investigation for the treatment of ovarian cancer. Docetaxel requires further Phase II study, but its impressive activity with systemic administration may be optimized with intraperitoneal administration for the treatment of peritoneal surface malignancy.

Antineoplastic Agents, Phytogenic↗

Carrier solutions for intraperitoneal chemotherapy.

Two pharmacokinetic problems appear to limit the effectiveness of intraperitoneal therapy: poor tumor penetration and nonuniform intraperitoneal distribution by the drug-containing solution. A better understanding of the pharmacodynamics of carrier solutions for intraperitoneal chemotherapy may impact on both these problems. Not only is the choice of drug important, but also the matching of the chosen drug to an appropriate carrier solution. It would appear that high molecular weight solutions offer a number of advantages over low molecular weight glucose and saline solutions for chemotherapeutic agents that have a high molecular weight with a slow peritoneal clearance. The use of carrier solutions of varying tonicity requires further investigation.

Antineoplastic Agents↗

A review of peritoneal mesothelioma at the Washington Cancer Institute.

This article reviews a single institution's experience with 68 patients (21 females, 47 males) prospectively treated over the last 2 decades with an aggressive local-regional approach, combining maximal cytoreductive surgery with heated intraoperative intraperitoneal chemotherapy and early postoperative intraperitoneal chemotherapy. This multimodality treatment has resulted in a median survival of 67 months. Female patients had a significantly better prognosis than males. The other significant predictive factors of survival were: age, diagnosis by incidental findings, tumor extent, pathology, and completeness of cytoreduction.

Adult↗

Thermal enhancement of new chemotherapeutic agents at moderate hyperthermia.

BACKGROUND: Hyperthermia enhances the cytotoxicity of some chemotherapeutic agents. We have studied the effect of moderate hyperthermia (41.5 degrees C) on the cytotoxicity of five new chemotherapeutic agents (docetaxel, paclitaxel, irinotecan, oxaliplatin, and gemcitabine) and melphalan against a spontaneous murine fibrosarcoma. METHODS: The tumor was an early-generation isotransplant of a spontaneous C3Hf/Sed mouse fibrosarcoma, FSa-II. Hyperthermia was administered by immersing the tumor-bearing foot into a constant temperature water bath set at 41.5 degrees C for 30 minutes when the tumor reached 34 mm(3). Chemotherapy was administered intraperitoneally immediately before hyperthermia. Tumor response was studied by the mean tumor growth time and the mean tumor growth delay time. RESULTS: Hyperthermia significantly increased the tumor growth times of the animals treated with docetaxel, irinotecan, and gemcitabine at low dose and these drugs plus oxaliplatin at high dose. Docetaxel at high dose showed the greatest control of tumor growth by hyperthermia, with a 26% reduction. Concerning the taxanes, paclitaxel cytotoxicity was not enhanced by hyperthermia, but docetaxel was enhanced by hyperthermia at both doses of drug. CONCLUSIONS: Moderate hyperthermia increases the cytotoxicity of docetaxel, irinotecan, and gemcitabine on mouse fibrosarcoma. Paclitaxel did not show heat enhancement. Oxaliplatin and docetaxel showed greater heat enhancement when the drug dose was high.

Animals↗

Docetaxel: pharmacokinetics and tissue levels after intraperitoneal and intravenous administration in a rat model.

PURPOSE: Docetaxel (Taxotere) has been shown to possess a broad spectrum of antitumor activity against various malignancies such as breast and lung cancers, but also against intraabdominal malignancies such as mesothelioma and ovarian cancer. For cancers occurring within the abdominal cavity, the advantage of intraperitoneal chemotherapy is the prolonged high drug concentration that can be achieved locally with low systemic toxicity. Using a rat model, this study was designed to compare the pharmacokinetics and tissue distribution of intraperitoneal versus intravenous docetaxel. METHODS: The study animals were comprised of 15 Sprague Dawley rats. They were randomized into three groups according to dose and route of administration (15 mg/kg intravenously, 15 mg/kg intraperitoneally, or 150 mg/kg intraperitoneally) and then given a single dose of docetaxel. Blood and peritoneal fluid were sampled using a standardized protocol for 90 min. At the end of the procedure the rats were killed and docetaxel concentrations in peritoneal fluid, plasma and selected tissue samples were determined by high-performance liquid chromatography (HPLC). RESULTS: When docetaxel was delivered at 15 mg/kg the area under the curve (AUC) of the peritoneal fluid was significantly higher with intraperitoneal administration (110.6 microg/ml.min) as compared to intravenous administration (0.043 microg/ml.min; P=0.0079). This represents more than a 2500-fold increase in exposure for tissues at peritoneal surfaces after intraperitoneal administration. Conversely, at the same dose the AUC of the plasma was significantly lower with intraperitoneal administration (0.11 microg/ml.min) as compared to intravenous administration (4.25 microg/ml.min; P=0.0079). The AUC ratio (AUC peritoneal fluid/AUC plasma) was 976 for intraperitoneal administration as opposed to 0.01 for intravenous delivery. The AUC ratio for intraperitoneal docetaxel at 150 mg/kg was 3004. There were significantly different concentrations in the heart and the abdominal wall ( P=0.0079) and in the stomach and colon ( P=0.0159) when intraperitoneal versus intravenous docetaxel were compared. CONCLUSIONS: The exposure of the peritoneal surface to docetaxel is significantly increased and the systemic exposure decreased with intraperitoneal docetaxel administration. Also, high concentrations of drug were observed in the abdominal wall and in the colon after intraperitoneal delivery. This experiment suggests the need for clinical studies to evaluate intraperitoneal administration of docetaxel in humans.

Absorption↗

Peritoneal mesothelioma.

Peritoneal mesothelioma is usually a rapidly fatal primary peritoneal surface malignancy with a median survival time of less than 1 year, mainly because of lack of effective treatment. The incidence is approximately one per 1,000,000; approximately one fifth to one third of all mesotheliomas are peritoneal. Because of its unusual nature, the disease has not been clearly defined in terms of its natural history, diagnosis, or management. Treatment options with intravenous chemotherapy are far from satisfactory. However, because malignant peritoneal mesothelioma usually remains confined to the peritoneal cavity for most of its natural history, regional chemotherapy is an attractive option. From a theoretic perspective, the treatments are most likely to succeed in selected patients with small-volume residual disease after cytoreductive surgery. Advantages of intraperitoneal chemotherapy include greatly enhanced drug concentrations in the peritoneal cavity and decreased systemic toxicity. In designing an intraperitoneal treatment strategy for the management of peritoneal mesothelioma, the limited number of active cytotoxic drugs and the timing of drug delivery pose problems. Prognosis as determined by clinical presentation, the completeness of cytoreduction, and gender (female patients survive longer than male patients) appears to be improved by the use of intraperitoneal chemotherapy. Over the past decade, the management of these patients has evolved similarly to ovarian cancer treatment and now involves cytoreductive surgery, heated intraoperative intraperitoneal chemotherapy with cisplatin and doxorubicin, and early postoperative intraperitoneal paclitaxel. These perioperative treatments are followed by adjuvant intraperitoneal paclitaxel and second-look cytoreduction. Prolonged disease-free survival and reduced adverse symptoms with the current management strategy are documented by a high complete response rate as assessed by a negative second look. This multimodality treatment approach with debulking surgery and intraperitoneal chemotherapy has resulted in a median survival of 50 to 60 months. Peritoneal mesothelioma is an orphan disease that is treatable, with expectations for "potential" cure in a small number of patients diagnosed and treated early with definitive local/regional treatments. A prolonged high quality of life is possible in the majority of patients.

Combined Modality Therapy↗