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Eli Glatstein

Publications and source records attributed to Eli Glatstein.

At least 19 recordsLinked to original sources
PubMed2006

Photofrin uptake in the tumor and normal tissues of patients receiving intraperitoneal photodynamic therapy.

PURPOSE: A phase II trial of Photofrin-mediated i.p. photodynamic therapy shown in a previous report limited efficacy and significant acute, but not chronic, toxicity. A secondary aim of this trial and the subject of this report is to determine Photofrin uptake in tumor and normal tissues. EXPERIMENTAL DESIGN: Patients received Photofrin, 2.5 mg/kg, i.v., 48 hours before debulking surgery. Photofrin uptake was measured by spectroflurometric analysis of drug extracted from tumor and normal tissues removed at surgery. Differences in drug uptake among these tissues were statistically considered using mixed-effects models. RESULTS: Photofrin concentration was measured in 301 samples collected from 58 of 100 patients enrolled on the trial. In normal tissues, drug uptake significantly (P<0.0001) differed as a function of seven different tissue types. In the toxicity-limiting tissue of intestine, the model-based mean (SE) Photofrin level was 2.70 ng/mg (0.32 ng/mg) and 3.42 ng/mg (0.24 ng/mg) in full-thickness large and small intestine, respectively. In tumors, drug uptake significantly (P=0.0015) differed as a function of patient cohort: model-based mean Photofrin level was 3.32 to 5.31 ng/mg among patients with ovarian, gastric, or small bowel cancer; 2.09 to 2.45 ng/mg among patients with sarcoma and appendiceal or colon cancer; and 0.93 ng/mg in patients with pseudomyxoma. Ovarian, gastric, and small bowel cancers showed significantly higher Photofrin uptake than full-thickness large and/or small intestine. However, the ratio of mean drug level in tumor versus intestine was modest (<or=2.31). CONCLUSIONS: Some selectivity is found in Photofrin uptake between tumor and normal tissues of the peritoneal cavity, but absolute differences in drug uptake relative to toxicity-limiting normal tissues (intestine) are small. This narrow differential in drug selectivity likely contributes to a narrow window in therapeutic application, which has been previously reported.

Biopsy↗
PubMed2006

A phase II trial of intraperitoneal photodynamic therapy for patients with peritoneal carcinomatosis and sarcomatosis.

PURPOSE: A previous phase I trial of i.p. photodynamic therapy established the maximally tolerated dose of Photofrin (Axcan Pharma, Birmingham, AL)-mediated photodynamic therapy and showed encouraging efficacy. The primary objectives of this phase II study were to determine the efficacy and toxicities of i.p. photodynamic therapy in patients with peritoneal carcinomatosis and sarcomatosis. EXPERIMENTAL DESIGN: Patients received Photofrin 2.5 mg/kg i.v. 48 hours before debulking surgery. Intraoperative laser light was delivered to the peritoneal surfaces of the abdomen and pelvis. The outcomes of interest were (a) complete response, (b) failure-free survival time, and (c) overall survival time. Photosensitizer levels in tumor and normal tissues were measured. RESULTS: One hundred patients were enrolled into one of three strata (33 ovarian, 37 gastrointestinal, and 30 sarcoma). Twenty-nine patients did not receive light treatment. All 100 patients had progressed by the time of statistical analysis. The median failure-free survival and overall survival by strata were ovarian, 2.1 and 20.1 months; gastrointestinal cancers, 1.8 and 11.1 months; sarcoma, 3.7 and 21.9 months. Substantial fluid shifts were observed postoperatively, and the major toxicities were related to volume overload. Two patients died in the immediate postoperative period from bleeding, sepsis, adult respiratory distress syndrome, and cardiac ischemia. CONCLUSIONS: Intraperitoneal Photofrin-mediated photodynamic therapy is feasible but does not lead to significant objective complete responses or long-term tumor control. Heterogeneity in photosensitizer uptake and tumor oxygenation, lack of tumor specificity for photosensitizer uptake, and the heterogeneity in tissue optical properties may account for the lack of efficacy observed.

Adult↗
PubMed2006

Updated results of a phase I trial of motexafin lutetium-mediated interstitial photodynamic therapy in patients with locally recurrent prostate cancer.

Locally recurrent prostate cancer after treatment with radiation therapy is a clinical problem with few acceptable treatments. One potential treatment, photodynamic therapy (PDT), is a modality that uses laser light, drug photosensitizer, and oxygen to kill tumor cells through direct cellular cytotoxicity and/or through destruction of tumor vasculature. A Phase I trial of interstitial PDT with the photosensitizer Motexafin lutetium was initiated in men with locally recurrent prostate cancer. In this ongoing trial, the primary objective is to determine the maximally tolerated dose of Motexafin lutetium-mediated PDT. Other objectives include evaluation of Motexafin lutetium uptake from prostate tissue using a spectrofluorometric assay and evaluation of optical properties in the human prostate. Fifteen men with biopsy-proven locally recurrent prostate cancer and no evidence of distant metastatic disease have been enrolled and 14 have been treated. Treatment plans were developed using transrectal ultrasound images. The PDT dose was escalated by increasing the Motexafin lutetium dose, increasing the 732 ran light dose, and decreasing the drug-light interval. Motexafin lutetium doses ranged from 0.5 to 2 mg/kg administered IV 24, 6, or 3 hr prior to 732 ran light delivery. The light dose, measured in real time with in situ spherical detectors was 25-100 J/cm2. Light was delivered via optical fibers inserted through a transperineal brachytherapy template in the operating room. Optical property measurements were made before and after light therapy. Prostate biopsies were obtained before and after light delivery for spectrofluorometric measurements of photosensitizer uptake. Fourteen patients have completed protocol treatment on eight dose levels without dose-limiting toxicity. Grade I genitourinary symptoms that are PDT related have been observed. One patient had Grade II urinary urgency that was urinary catheter related. No rectal or other gastrointestinal PDT-related tox-icities have been observed to date. Measurements of Motexafin lutetium demonstrated the presence of photosensitizer in prostate tissue from all patients. Optical property measurements demonstrated substantial heterogeneity in the optical properties of the human prostate gland which supports the use of individualized treatment planning for prostate PDT.

Adenocarcinoma↗
PubMed2005

Noninvasive monitoring of murine tumor blood flow during and after photodynamic therapy provides early assessment of therapeutic efficacy.

PURPOSE: To monitor tumor blood flow noninvasively during photodynamic therapy (PDT) and to correlate flow responses with therapeutic efficacy. EXPERIMENTAL DESIGN: Diffuse correlation spectroscopy (DCS) was used to measure blood flow continuously in radiation-induced fibrosarcoma murine tumors during Photofrin (5 mg/kg)/PDT (75 mW/cm2, 135 J/cm2). Relative blood flow (rBF; i.e., normalized to preillumination values) was compared with tumor perfusion as determined by power Doppler ultrasound and was correlated with treatment durability, defined as the time of tumor growth to a volume of 400 mm3. Broadband diffuse reflectance spectroscopy concurrently quantified tumor hemoglobin oxygen saturation (SO2). RESULTS: DCS and power Doppler ultrasound measured similar flow decreases in animals treated with identical protocols. DCS measurement of rBF during PDT revealed a series of PDT-induced peaks and declines dominated by an initial steep increase (average +/- SE: 168.1 +/- 39.5%) and subsequent decrease (59.2 +/- 29.1%). The duration (interval time; range, 2.2-15.6 minutes) and slope (flow reduction rate; range, 4.4 -45.8% minute(-1)) of the decrease correlated significantly (P = 0.0001 and 0.0002, r2= 0.79 and 0.67, respectively) with treatment durability. A positive, significant (P = 0.016, r2= 0.50) association between interval time and time-to-400 mm3 was also detected in animals with depressed pre-PDT blood flow due to hydralazine administration. At 3 hours after PDT, rBF and SO2 were predictive (P < or = 0.015) of treatment durability. CONCLUSION: These data suggest a role for DCS in real-time monitoring of PDT vascular response as an indicator of treatment efficacy.

Animals↗
PubMed2005

Gemcitabine-induced pericardial effusion and tamponade after unblocked cardiac irradiation.

Gemcitabine therapy has been associated with radiation recall reactions when used in the treatment of carcinoma. We report four cases of hemodynamically significant pericardial effusion in patients with refractory lymphoma who were receiving gemcitabine, all of whom had a history of mediastinal radiation without subcarinal blocking. All four patients had pericardial abnormalities on echocardiography prior to receiving gemcitabine. Two patients required emergent surgical procedures. Of twenty other patients in our practice who received gemcitabine for refractory lymphoma without developing pericardial effusion, none had received prior direct radiation to the heart. The overall response rate of these 24 refractory lymphomas to gemcitabine-containing regimens was 46%. Although gemcitabine-based regimens have clear efficacy in refractory lymphoma, prior mediastinal radiation without subcarinal blocking may be a relative contraindication, especially in the presence of pericardial abnormalities on echocardiography. Physicians should be aware of the potential for developing a gemcitabine-induced radiation recall reaction resulting in hemodynamically significant pericardial effusion.

Adult↗
PubMed2004

Treatment-induced changes in tumor oxygenation predict photodynamic therapy outcome.

Photodynamic therapy (PDT) requires oxygen to cause tumor damage, yet therapy itself can deplete or enhance tumor oxygenation. In the present work we measured the PDT-induced change in tumor oxygenation and explored its utility for predicting long-term response to treatment. The tissue hemoglobin oxygen saturation (SO(2)) of murine tumors was noninvasively measured by broadband diffuse reflectance spectroscopy. In initial validation studies, the oxyhemoglobin dissociation curve for mouse blood was accurately recreated based on measurements during deoxygenation of a tissue phantom of mouse erythrocytes. In vivo studies exhibited excellent correlation between carbogen-induced changes in SO(2) and pO(2) of radiation-induced fibrosarcoma tumors measured by reflectance spectroscopy and the Eppendorf pO(2) histograph, respectively. In PDT studies radiation-induced fibrosarcoma tumor SO(2) was measured immediately before and after Photofrin-PDT (135 J/cm(2), 38 mW/cm(2)). Animals were subsequently followed for tumor growth to a volume of 400 mm(3) (time-to-400 mm(3)) or the presence of tumor cure (no tumor growth at 90 days after treatment). In animals that recurred, the PDT-induced change in tumor SO(2), i.e., relative-SO(2) (SO(2) after PDT/SO(2) before PDT) was positively correlated with treatment durability (time-to-400 mm(3)). The predictive value of relative-SO(2) was confirmed in a second group of animals with enhanced pre-PDT oxygenation due to carbogen breathing. Furthermore, when all of the animals were considered (those that recurred and those that were cured) a highly significant association was found between increasing relative-SO(2) and increasing probability of survival, i.e., absence of recurrence. As independent variables, the SO(2) after PDT, the pre-PDT tumor volume, and light penetration depth all failed to predict response. As an independent variable, the SO(2) before PDT demonstrated a weak negative association with treatment durability; this association was driven by a correlation between decreasing pre-PDT SO(2) and increasing relative-SO(2). These data suggest that monitoring of PDT-induced changes in tumor oxygenation may be a valuable prognostic indicator.

Animals↗
PubMed2004

A phase I study of topical Tempol for the prevention of alopecia induced by whole brain radiotherapy.

PURPOSE: Complete alopecia is a universal complication of whole brain radiation therapy which contributes to patient anxiety over treatment. Tempol, a nitroxide radioprotector, has been shown to protect against radiation-induced alopecia in an animal model. This phase Ib study was designed to evaluate the safety and side effect profile of topical Tempol in patients with brain metastases being treated with whole brain radiotherapy. EXPERIMENTAL DESIGN: Twelve patients with metastatic cancer to the brain were enrolled in the study between October 2000 and February 2003. Tempol (70 mg/ml concentration solution) was applied topically to the scalp 15 minutes before and washed off immediately after the completion of each of 10 fractions of whole brain radiation. Pharmacokinetic studies to evaluate the systemic absorption of Tempol were performed. Patients were assessed for toxicity before, during, and after Tempol administration. A secondary end point of the study, hair retention, was also scored. RESULTS: Eleven patients were treated with topical Tempol. Adverse events that were considered possibly, probably, or definitely related to Tempol, included asymptomatic grade 2 (two patients) and grade 1 (one patient) hypoglycemia, grade 1 forehead skin redness (one patient), grade 1 dry scalp (one patient), and grade 1 tingling sensation on the scalp (one patient). Tempol was not detected in blood samples from more than 50% of the patients. Mean maximum Tempol levels for individual patients at any time point varied from 0.4 to 3.1 micromol/L. Hair retention was localized to the base of the scalp where the Tempol solution pooled after application in the first four patients on the study. Subsequently, full scalp hair retention was seen in three of final five evaluable patients after gauze had been wrapped around the head to hold the solution against the scalp. CONCLUSIONS: This study demonstrates that topical application of Tempol to the scalp before whole brain radiation is safe and well tolerated. Evidence of protection against radiation-induced alopecia was observed. A phase II study that uses a gel formulation to increase the exposure of scalp to Tempol has been initiated.

Administration, Topical↗
PubMed2004

Hypoxia and Photofrin uptake in the intraperitoneal carcinomatosis and sarcomatosis of photodynamic therapy patients.

PURPOSE: Response to photodynamic therapy depends on adequate tumor oxygenation as well as sufficient accumulation of photosensitizer in the tumor. The goal of this study was to investigate the presence of hypoxia and retention of the photosensitizer Photofrin in the tumors of patients with intra-abdominal carcinomatosis or sarcomatosis. EXPERIMENTAL DESIGN: Tumor nodules from 10 patients were studied. In nine of these patients, hypoxia was identified in histological sections of biopsied tumor after administration of the hypoxia marker 2-(2-nitroimidazol-1[H]-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide (EF5). In separate tumor nodules from 10 patients, Photofrin uptake was measured by fluorescence after tissue solubilization. RESULTS: Hypoxia existed in the tumors of five patients, with three of these patients demonstrating at least one severely hypoxic nodule. Physiological levels of oxygen were present in the tumors of four patients. An association between tumor size and hypoxia was not evident because some tumor nodules as small as approximately 2 mm in diameter were severely hypoxic. However, even these tumor nodules contained vascular networks. Three patients with severely hypoxic tumor nodules exhibited moderate levels of Photofrin uptake of 3.9 +/- 0.4 to 3.9 +/- 0.5 ng/mg (mean +/- SE). The four patients with tumors of physiological oxygenation did not consistently exhibit high tumor concentrations of Photofrin: mean +/- SE drug uptake among these patients ranged from 0.6 +/- 0.8 to 5.8 +/- 0.5 ng/mg. CONCLUSIONS: Carcinomatosis or sarcomatosis of the i.p. cavity may exhibit severe tumor hypoxia. Photofrin accumulation in tumors varied by a factor of approximately 10x among all patients, and, on average, those with severe hypoxia in at least one nodule did not demonstrate poor Photofrin uptake in separate tumor samples. These data emphasize the need for reconsideration of the generally accepted paradigm of small tumor size, good oxygenation, and good drug delivery because this may vary on an individual tumor basis.

Appendiceal Neoplasms↗
PubMed2004

Phase II trial of pleural photodynamic therapy and surgery for patients with non-small-cell lung cancer with pleural spread.

PURPOSE: Non-small-cell lung cancer (NSCLC) with pleural spread is incurable, with median survival rates ranging from 6 to 9 months. Surgery alone fails to locally control this disease or extend survival beyond the accepted treatment, palliative chemotherapy. METHODS: We conducted a phase II trial to evaluate the effects on local control and survival of combining surgery with intraoperative photodynamic therapy (PDT), a light-based cancer treatment, in patients with NSCLC with pleural spread. Patients received porfimer sodium (2 mg/kg), 24 hours before surgery, at which time all gross tumor was resected and followed by illumination of the hemithorax with 630 nm light to a measured dose of 30 J/cm(2). Photosensitizer levels in tumor and surrounding normal tissue were measured. RESULTS: Twenty-two patients with NSCLC were enrolled; 17 underwent complete debulking and PDT, three underwent partial debulking/PDT, and two patients were unresectable. Local control of pleural disease at 6 months was achieved in 11 of 15 (73.3%; 95% CI, 44.9% to 92.2%) assessable patients. Median overall survival for all 22 patients was 21.7 months (95% CI, 17.7 to 25.8 months). Measured levels of porfimer sodium in tumor were greater than those measured in normal tissues, with ratios ranging from 1.19 to 22.42. CONCLUSION: Our results indicate surgery and PDT can be performed safely with very good local control. The median survival of 21.7 months, calculated from the time of surgery and PDT is encouraging. Further evaluation of this therapy is warranted.

Adult↗
PubMed2004

Use of iodine 131I-tositumomab radioimmunotherapy in a patient with Waldenstrom's macroglobulinemia.

Waldenstrom's macroglobulinemia is an indolent B-cell malignancy that is characterized by high levels of IgM paraprotein production and is incurable with standard chemotherapy. Iodine 131I-Tositumomab (iodine-131-labeled murine anti-CD20 monoclonal antibody; Bexxar) is a novel radioimmunotherapeutic agent that has a high response rate in relapsed or chemotherapy refractory, CD20-positive, low grade or transformed B-cell non-Hodgkin's lymphomas. There are no data on the use of radioimmunotherapy in Waldenstrom's macroglobulinemia. We report a patient with Waldenstrom's macroglobulinemia with transformation to a large B-cell lymphoma, who was treated successfully with iodine 131I-tositumomab. The patient had a complete response to the treatment, including disappearance of any detectable IgM paraprotein. This case report demonstrates the potential for radioimmunotherapy in CD20 positive B-cell malignancies.

Aged↗
PubMed2004

Patterns of recurrence in patients treated with photodynamic therapy for intraperitoneal carcinomatosis and sarcomatosis.

The purpose of this study was to evaluate the patterns of recurrence in patients treated with Photofrin-mediated intraperitoneal photodynamic therapy (IP PDT). Sixty-six patients with gastrointestinal cancers, ovarian cancers, and sarcomas have been enrolled to date and 51 patients underwent IP PDT. Photofrin, 2.5 mg/kg, was administered intravenously 48 h prior to surgical debulking and intraoperative light treatment. Forty-five, and 49 patients were evaluable for response rates, and patterns of recurrence, respectively. Response to treatment was evaluated by CT or MRI scans of the abdomen and pelvis every 3 months. Patterns of recurrence were determined by evaluating the abdomen as a combination of different treatment regions. Of the 51 patients enrolled and treated with IP PDT two are alive without evidence of recurrence. Eleven of 45 patients showed no evidence of recurrence 3 months after treatment. No evidence of recurrence was noted in 7/17 sarcoma patients, 2 of 13 ovarian cancer patients, and 2 of 15 gastrointestinal cancer patients. The most common site of recurrence as determined by radiographs was the pelvis, which was noted in 19 of 49 (39%) patients. The presence of gross residual disease before light treatment (as determined by the attending surgeon) did not affect the site of recurrence. When studying those patients who had only locoregional recurrence, 9 of 33 evaluated radiographically and 10 of 24 evaluated operatively recurred only in peritoneal areas not previously involved with gross disease. The pelvis was the site with the highest rate of recurrence after IP PDT. A significant minority of patients recurred only in sites not previously involved with gross disease. Patients with gross residual disease before light therapy had similar recurrence rates to those without gross residual disease. Since sites involved with gross residual tumor often received boost doses of light, this could suggest a dose-response relationship for IP PDT.

Adult↗