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Biomedical subjects

D Finkelstein

Publications and source records attributed to D Finkelstein.

At least 19 recordsLinked to original sources
PubMed2001

A prospective study of discontinuing primary and secondary Pneumocystis carinii pneumonia prophylaxis after CD4 cell count increase to > 200 x 106 /l.

OBJECTIVE: To assess the incidence of Pneumocystis carinii pneumonia (PCP) after discontinuation of either primary or secondary prophylaxis. DESIGN: This was a prospective, non-randomized, non-blinded study. SETTING: Twenty-five University-based AIDS Clinical Trials Group units. PARTICIPANTS: Participants either had a CD4 cell count < or = 100 x 106/l at any time in the past and no history of confirmed PCP (group I; n = 144), or had a confirmed episode of PCP > or = 6 months prior to study entry (group II; n = 129). All subjects had sustained CD4 cell counts > 200 x 106/l in response to antiretroviral therapy. INTERVENTIONS: Subjects discontinued PCP prophylaxis within 3 months or at the time of study entry. Evaluations for symptoms of PCP and CD4 cell counts were performed every 8 weeks. Prophylaxis was resumed if two consecutive CD4 cell counts were < 200 x 106/l. MAIN OUTCOME MEASURE(S): The main outcome was development of PCP. RESULTS: No cases of PCP occurred in 144 subjects (median follow-up, 82 weeks) in group I or in the 129 subjects (median follow-up, 63 weeks) in group II (95% upper confidence limits on the rates of 1.3 per 100 person-years and 1.96 per 100 person-years for groups I and II, respectively). Eight subjects (five in group I and three in group II) resumed PCP prophylaxis after two consecutive CD4 cell counts < 200 x 106/l. CONCLUSIONS: The risk of developing initial or recurrent PCP after discontinuing prophylaxis is low in HIV-infected individuals who have sustained CD4 cell count increases in response to antiretroviral therapy. Neither lifelong primary nor secondary PCP prophylaxis is necessary.

AIDS-Related Opportunistic Infections↗
PubMed2001

Fine-needle aspiration cytology of the breast: Invasive vs. in situ carcinoma.

The surgical management of invasive breast carcinoma differs from that of in situ disease. Invasive carcinoma necessitates axillary lymph node dissection, a procedure that has associated morbidity. We studied 80 cases (66 invasive, 14 in situ) of breast carcinoma that had a histological diagnosis and a preoperative fine-needle aspirate. All slides were reviewed, with 17 cytologic features assessed. We found that six of these features showed a statistically significant difference between the invasive and in situ cases. These were infiltration of fat or stroma by malignant cells (72% of invasive cases demonstrated this feature, but it was not present in any of the in situ cases, P = 0.0002), the presence of myoepithelial cells overlying clusters of tumor cells (seen in 86% of in situ tumors and 7% of invasive cases, P < 0.00001), calcification (present in 71% of in situ and 15% of the invasive group, P = 0.001), foamy macrophages (noted in 64% of in situ tumors and 16% of invasive carcinomas, P = 0.0007), intracytoplasmic vacuoles (seen in 50% of invasive cases and 21% of in situ lesions, P = 0.08), and tubules (present in 30% of invasive and 7% of in situ tumors, P = 0.10). We demonstrate that invasion can be suggested in fine-needle aspirates of carcinomas, provided that true infiltration of fibrofatty connective tissue by neoplastic cells is present. In situ disease has characteristic features, but the presence of invasion cannot be excluded, even in the presence of stromal or adipose tissue fragments without tumor infiltration.

Biopsy, Needle↗
PubMed2001

A reliable method of demonstrating HER-2/neu, estrogen receptors, and progesterone receptors on routinely processed cytologic material.

Estrogen (ER) and progesterone receptors (PR) and HER-2/neu (c-erbB-2) protein overexpression are important prognostic factors for breast carcinoma. This study describes a simple, rapid method that demonstrates the applicability of these tests to cytology smears. Smears were made from scrape samples of fresh breast tumors and were fixed in 95% alcohol for immunohistochemical staining for ER and PR and HER-2/neu protein overexpression. Scraped material was suspended in phosphate-buffered saline, and cytospin slides were prepared from the suspension and air dried for fluorescence in situ hybridization (FISH). The results for ER performed on cytology compared with the gold standard (immunohistochemistry on histology) showed 94% accuracy (95% confidence bounds (0.8432 0.9823)); PR results showed 71% accuracy (95% confidence bounds (0.5805 0.8180)) and HER-2/neu results showed 77% accuracy (95% confidence bounds (0.6500 0.8709)). Using HER-2/neu gene overamplification detected by FISH as the gold standard, immunohistochemistry for HER-2/neu protein overexpression showed sensitivity, specificity, and a positive predictive value of 88.8%, 77.7%, and 80% for histology, respectively, and 69%, 87%, and 90% for cytology, respectively. This study showed that fixation and storage of smears in 95% alcohol were effective for receptor studies, whereas air-dried cytospin smears were well suited to FISH.

Breast Neoplasms↗
PubMed2000

Benign meningioma: partially resected, biopsied, and recurrent intracranial tumors treated with combined proton and photon radiotherapy.

PURPOSE/OBJECTIVE: To evaluate the recurrence-free survival and complications of combined proton and photon radiotherapy of patients with incompletely resected or recurrent histologically-confirmed benign meningioma. METHODS AND MATERIALS: Between May 1981 and November 1996, 46 patients with partially resected, biopsied, or recurrent meningiomas (median age of 50 years; range 11-74 years) were treated with combined photon and 160-MeV proton beam therapy at the Massachusetts General Hospital (MGH) and the Harvard Cyclotron Laboratory, using computed tomography-based conformal 3D treatment planning. Nine patients were treated after incomplete tumor resection, 8 patients after tumor biopsy only, and 29 patients after tumor recurrence following gross total (10/29 patients) or progression after subtotal (19/29 patients) resection. All patients were classified as benign meningioma on review slides at MGH. The median dose to the macroscopic gross tumor volume was 59.0 CGE (range 53.1-74.1 CGE, CGE = proton Gy x 1.1 RBE). The median follow-up was 53 months (range 12-207). RESULTS: Overall survival at 5 and 10 years was 93 and 77%, respectively, and the recurrence-free rate at 5 and 10 years was 100% and 88%, respectively. Survival without severe toxicity was 80% at 5 and 10 years. Three patients presented with local tumor recurrence at 61, 95, and 125 months. One patient developed distant intradural metastasis at 21 and 88 months. No patient died from recurrent meningioma; however, 4 patients died of other causes. A fifth patient died from a brainstem necrosis after 22 months. Eight patients developed severe long-term toxicity from radiotherapy, including ophthalmologic (4 patients), neurologic (4 patients), and otologic (2 patients) complications. All patients with ophthalmologic toxicity received doses higher than those allowed for the optic nerve structures in the current protocol. CONCLUSION: Combined proton and photon radiotherapy is an effective treatment for patients with recurrent or incompletely resected benign intracranial menigiomas. Observed toxicity appears to be dose-related; with currently employed dose constraints, toxicity should not exceed that seen in patients treated with conformal fractionated supervoltage photon radiotherapy.

Adolescent↗
PubMed2000

Genetic susceptibility to breast cancer: HLA DQB*03032 and HLA DRB1*11 may represent protective alleles.

Tumors are believed to emerge only when immune surveillance fails. We wished to ascertain whether the failure to inherit putative protective alleles of HLA class II genes is linked to the development of breast cancer. We molecularly typed HLA DPB1, DQB1, DRB1, and DRB3 alleles in 176 Caucasian women diagnosed with early-onset breast cancer and in 215 ethnically matched controls. HLA DQB*03032 was identified in 7% of controls but in no patients with early-onset breast cancer (P = 0.0001). HLA DRB1*11 alleles were also significantly overrepresented (P < 0.0001) in controls (16. 3%) as compared with patients with early-onset breast cancer (3.5%). HLA DQB*03032 and HLA DRB1*11 alleles may have a protective role in human breast cancer.

Adult↗
PubMed2000

Reduced toxicity with gradual initiation of trimethoprim-sulfamethoxazole as primary prophylaxis for Pneumocystis carinii pneumonia: AIDS Clinical Trials Group 268.

Trimethoprim-sulfamethoxazole (TMP/SMX) is recognized as the superior agent for Pneumocystis carinii pneumonia (PCP) prophylaxis but a high incidence of adverse drug reactions, which may be due to toxic drug metabolites, limits its use. AIDS Clinical Trials Group protocol 268 was a randomized, double-blind, controlled two-arm trial designed to determine whether gradual initiation of TMP/SMX suspension reduced the incidence of treatment-limiting adverse drug reactions compared with routine initiation of double-strength (DS; 160 mg/800 mg) tablets. In all, 372 HIV-1-infected study subjects with a CD4+ cell count <250 x 10 cells/mm3 who had not previously received TMP/SMX for PCP prophylaxis were randomized to receive either daily TMP/SMX DS tablets or a gradually increasing dose of TMP/SMX suspension. The suspension dose was increased to reach the equivalent of a DS tablet by study day 13. During the first 2 weeks, study subjects also received a matching placebo tablet/suspension. After week 2, all study subjects received TMP/SMX tablets for the next 10 weeks. There were significantly fewer study subjects who discontinued prophylaxis during the first 12 weeks when TMP/SMX therapy was initiated gradually (17%) than when initiated in DS tablet formulation (33%) (p =.0002). Gradual initiation was also associated with significantly fewer adverse drug reactions. Gradual initiation of TMP/SMX for primary PCP prophylaxis reduces the incidence of its treatment-limiting adverse effects.

AIDS-Related Opportunistic Infections↗
PubMed2000

A phase I study of gemcitabine and docetaxel in patients with metastatic solid tumors.

BACKGROUND: A Phase I study was initiated to determine the maximum tolerated dose of weekly gemcitabine combined with monthly, fixed-dose docetaxel. METHODS: Patients with metastatic solid tumors were treated with docetaxel, 60 mg/m(2), on Day 1 every 28 days. Gemcitabine was administered on Days 1, 8, and 15 and underwent dose adjustment in cohorts of 3-6 patients. At the maximum tolerated dose, 11 additional patients were enrolled. RESULTS: Twenty-six patients received 85 cycles of therapy. At the first dose level, the planned gemcitabine dose on Days 1, 8, and 15 was 800 mg/m(2). Two of the 6 patients treated at this dose level experienced dose-limiting toxicities (DLTs) requiring the reduction of gemcitabine to 600 mg/m(2) per dose and the administration of ciprofloxacin, 500 mg orally twice daily, on Days 8-18. At the second dose level the first 3 patients experienced no DLTs and the dose of gemcitabine was increased to 700 mg/m(2). Two of the 6 patients treated at the 700 mg/m(2) dose level experienced DLTs. Eleven additional patients were enrolled at the recommended Phase II dose of gemcitabine (600 mg/m(2)). At this dose level, Grade 3/4 (according the National Cancer Institute's common toxicity criteria) neutropenia and thrombocytopenia occurred in 12.5% and 2.1% of cycles, respectively. Grade 3 and 4 nonhematologic toxicities were uncommon. Three of seven evaluable patients with pancreatic carcinoma had evidence of significant antineoplastic activity (three partial responses). In addition, two complete responses (one patient with gastric carcinoma and one patient with ovarian carcinoma) and one partial response (patient with hepatocellular carcinoma) were noted in patients with other solid tumors. CONCLUSIONS: The regimen comprised of docetaxel, 60 mg/m(2), on Day 1 and gemcitabine, 600 mg/m(2), on Days 1, 8, and 15 with ciprofloxacin on Days 8-18 every 28 days is safe, well tolerated, and active.

Antimetabolites, Antineoplastic↗
PubMed2000

Adult-onset foveomacular pigment epithelial dystrophy: clinicopathologic correlation of three cases.

PURPOSE: The authors describe the clinicopathologic features of three patients with adult onset foveomacular pigment epithelial dystrophy (AOFPED). METHODS: The eyes of three patients were studied ophthalmoscopically and by fluorescein angiography, and obtained postmortem and studied by light and electron microscopy. RESULTS: Histopathologic study of the three patient's eyes disclosed central loss of the retinal pigment epithelium and photoreceptor cell layer with a moderate number of pigment-containing macrophages present in the subretinal space and outer retina. To either side, the retinal pigment epithelium was distended with much lipofuscin. Basal laminar and basal linear deposits were present throughout the central area. No discontinuities of Bruch membrane were present. CONCLUSION: The findings in the eyes of three patients with AOFPED included marked aging changes that are similar to those seen in age-related macular degeneration. Pigmented cells with lipofuscin in the subretinal space account for the vitelliform appearance.

Age of Onset↗
PubMed2000

Thymidine kinase activation of ganciclovir in recurrent malignant gliomas: a gene-marking and neuropathological study.

OBJECT: The gene therapy paradigm of intratumoral activation of ganciclovir (GCV) following transduction of tumor cells by retroviral vectors bearing the thymidine kinase (tk) gene has produced dramatic remissions of malignant gliomas in animal models. In human trials, although the technique has been deemed safe, little antitumor effect has been demonstrated. To evaluate the basis of this inefficacy in human gliomas, the authors conducted a gene-marking trial involving neuropathological and biochemical studies of treated tumor specimens. METHODS: Five patients with malignant recurrent gliomas underwent stereotactic biopsy sampling and intratumoral implantation procedures with three aliquots of 10(6) vector-producing cells (VPCs) in columns. After 5 days, the tumor was resected and the tumor bed reimplanted with VPCs, and a course of GCV was given. Patients received clinical and radiological follow up for 6 months. Tumor specimens were analyzed neuropathologically and for tk gene expression by anti-TK immunohistochemistry and TK enzymatic activity. Four patients tolerated the treatment well but experienced tumor progression. The other developed an abscess after the second operation and died. Increased TK enzymatic activity was demonstrated in the one tumor specimen analyzed. Immunohistochemical evidence of tk gene expression was limited to VPCs. Transduction of tumor cells was not seen. Viable tumor cells were seen near VPCs containing TK. The lymphocytic immune response was mild. CONCLUSIONS: Except for the risk of infection inherent in reoperation, this tk-GCV paradigm was both feasible and safe. Pathological studies indicated that limited dissemination of VPCs and vector from the infusion site and failure to transduce tumor cells with the tk gene are major barriers to efficacy.

Adult↗
PubMed1999

Analysis of the relationship between tumor dose inhomogeneity and local control in patients with skull base chordoma.

PURPOSE: When irradiating a tumor that abuts or displaces any normal structures, the dose constraints to those structures (if lower than the prescribed dose) may cause dose inhomogeneity in the tumor volume at the tumor-critical structure interface. The low-dose region in the tumor volume may be one of the reasons for local failure. The aim of this study is to quantitate the effect of tumor dose inhomogeneity on local control and recurrence-free survival in patients with skull base chordoma. METHODS AND MATERIALS: 132 patients with skull base chordoma were treated with combined photon and proton irradiation between 1978 and 1993. This study reviews 115 patients whose dose-volume data and follow-up data are available. The prescribed doses ranged from 66.6 Cobalt-Gray-Equivalent (CGE) to 79.2 CGE (median of 68.9 CGE). The dose to the optic structures (optic nerves and chiasm), the brain stem surface, and the brain stem center was limited to 60, 64, and 53 CGE, respectively. We used the dose-volume histogram data derived with the three-dimensional treatment planning system to evaluate several dose-volume parameters including the Equivalent Uniform Dose (EUD). We also analyzed several other patient and treatment factors in relation to local control and recurrence-free survival. RESULTS: Local failure developed in 42 of 115 patients, with the actuarial local control rates at 5 and 10 years being 59% and 44%. Gender was a significant predictor for local control with the prognosis in males being significantly better than that in females (P = 0.004, hazard ratio = 2.3). In a Cox univariate analysis, with stratification by gender, the significant predictors for local control (at the probability level of 0.05) were EUD, the target volume, the minimum dose, and the D5cc dose. The prescribed dose, histology, age, the maximum dose, the mean dose, the median dose, the D90% dose, and the overall treatment time were not significant factors. In a Cox multivariate analysis, the models including gender and EUD, or gender and the target volume, or gender and the minimum target dose were significant. The more biologically meaningful of these models is that of gender and EUD. CONCLUSION: This study suggests that the probability of recurrence of skull base chordomas depends on gender, target volume, and the level of target dose inhomogeneity. EUD was shown to be a useful parameter to evaluate dose distribution for the target volume.

Adult↗
PubMed1999

Oncolytic virus therapy of multiple tumors in the brain requires suppression of innate and elicited antiviral responses.

The occurrence of multiple tumors in an organ heralds a rapidly fatal course. Although intravascular administration may deliver oncolytic viruses/vectors to each of these tumors, its efficiency is impeded by an antiviral activity present in complement-depleted plasma of rodents and humans. Here, this activity was shown to interact with complement in a calcium-dependent fashion, and antibody neutralization studies indicated preimmune IgM has a contributing role. Short-term exposure to cyclophosphamide (CPA) partially suppressed this activity in rodents and humans. At longer time points, cyclophosphamide also abrogated neutralizing antibody responses. Cyclophosphamide treatment of rats with large single or multiple intracerebral tumors substantially increased viral survival and propagation, leading to neoplastic regression.

Animals↗
PubMed1999

A prospective randomized trial comparing the toxicity and safety of atovaquone with trimethoprim/sulfamethoxazole as Pneumocystis carinii pneumonia prophylaxis following autologous peripheral blood stem cell transplantation.

Pneumonia due to Pneumocystis carinii is an infrequent complication following autologous stem cell transplantation (ASCT) which is associated with a high mortality. Although administration of trimethoprim/sulfa- methoxazole (TMP/SMX) is an effective prophylactic strategy for Pneumocystis carinii pneumonia (PCP), treatment-associated toxicity frequently results in discontinuation of therapy. We have conducted a prospective randomized trial comparing atovaquone, a new anti-Pneumocystis agent, with TMP/SMX for PCP prophylaxis following autologous peripheral blood stem cell (PBSC) transplantation. Thirty-nine patients were studied. Twenty patients received atovaquone suspension and 19 patients received TMP/SMX. The median ages were 44 (range 20-68) and 47 (range 32-63) years, respectively. A similar number of patients with solid tumors (14 vs 15) and hematologic malignancies (five vs five) were treated in each group. Either TMP/SMX (160/800 mg) or atovaquone (1500 mg) was administered daily from transplant day -5 until day -1, discontinued from day 0 to engraftment, then resumed 3 days per week until day +100 post-transplant. The median time to engraftment (ANC >0.5 x 109/l) was similar in both groups. Eighty percent of the patients randomized to atovaquone prophylaxis completed the study. Four atovaquone-treated patients were removed from study; two patients (10%) did not receive a transplant and two patients (10%) were removed due to a protocol violation. None of the 16 patients treated with atovaquone experienced treatment-associated adverse effects. Of the 19 patients randomized to receive TMP/SMX, 55% completed the study. Nine TMP/SMX-treated patients were removed from the study; one patient (5%) did not receive a transplant and eight patients (40%) were removed due to drug intolerance (P < 0.003). The rate of intolerance to TMP/SMX led to the early discontinuation of this randomized trial. Intolerance of TMP/SMX included elevated transaminase levels (n = 1), nausea or vomiting (n = 3), thrombocytopenia (n = 2) and neutropenia (n = 2). All episodes of TMP/SMP intolerance occurred following transplantation after a median duration of 17.5 (range 2-48) days and a median of 7 (range 1-20) doses. Resolution of adverse side-effects occurred in all eight patients within a median of 7 (range 2-20) days following discontinuation of therapy. Neither PCP nor bacterial infections were identified in any of the patients treated. This prospective randomized study demonstrated that atovaquone is well-tolerated for anti-Pneumocystis prophylaxis in autologous PBSC transplant patients intolerant of TMP/SMX.

Adult↗
PubMed1998

Laser-induced chorioretinal venous anastomosis for nonischemic central or branch retinal vein occlusion.

OBJECTIVE: To establish a communication between an obstructed retinal vein and the choroid by means of laser in eyes with nonischemic central or branch vein occlusion. METHODS: Retrospective review identified eyes with nonischemic central or branch vein occlusion, and with decreasing or persistently decreased visual acuity of 20/100 or worse for 4 months or more before treatment, that received 1 or more sessions of laser photocoagulation to create a chorioretinal anastomosis. RESULTS: Of 24 eyes with central vein occlusion, an anastomosis formed in 9 (38%) within 2 months after treatment, with visual improvement of 6 or more lines in 2 (8%) of 24 eyes, 1 to 3 lines in 5 (21%), and no improvement in 2 (8%). Of 6 eyes with branch vein occlusion, an anastomosis formed in 3 (50%) within 2 months after treatment, with visual improvement of 1 to 3 lines in 2 (33%) of 6 and no improvement in 1 (16%). No permanent, vision-limiting complications occurred during a mean follow-up of 13 months after the first treatment session or 8 months after the last session. CONCLUSIONS: Laser photocoagulation of a retinal vein and Bruch's membrane may create a chorioretinal anastomosis in some eyes with a nonischemic vein occlusion. Progression to an ischemic status may possibly be prevented with successful anastomosis formation. Marked visual improvement may occur. Treatment techniques to create reliably an anastomosis with subsequent visual improvement, while minimizing potential complications, continue to evolve.

Aged↗
PubMed1998

Pre-existing herpes simplex virus 1 (HSV-1) immunity decreases, but does not abolish, gene transfer to experimental brain tumors by a HSV-1 vector.

The influence of pre-existing anti-herpes simplex type 1 (HSV-1) immunity on HSV-1 vector-mediated gene transfer to glioma cells was analyzed in this gene marking study using intracranial D74 gliomas in syngeneic Fischer rats. The HSV-1 mutant virus used, hrR3, is defective in ribonucleotide reductase and bears the marker genes E. coli lacZ and HSV-1 thymidine kinase (HSVtk). Initial marker gene expression in tumors 12 h after direct virus injection was reduced in immunized animals to about 15% of that in nonimmunized animals. Marker gene expression in both sets stayed at initial levels for 2 days after intratumoral injection and declined markedly on day 5. Inflammatory infiltrates in the tumor were more prominent in HSV-1-immunized, as compared with nonimmunized animals, at 12 and 24 h, but appeared similar at 2-5 days after injection. By day 10, the immune reaction had subsided in immunized animals and macrophages remained only in nonimmunized animals. In conclusion, gene transfer to brain tumors using a HSV-1 vector was greatly reduced, but not completely abolished, under pre-immunization conditions. Pre-existing antibodies to HSV-1 may also serve a positive role in providing an increased margin of safety in intracranial application of HSV-1 vectors by limiting spread of the virus within the brain and to other tissues.

Animals↗
PubMed1998

Current concepts in the management of central retinal vein occlusion.

The results of the Central Vein Occlusion Study guide the management of complications of macular edema and neovascularization. Panretinal photocoagulation was shown to be beneficial for eyes with at least 2 hours of iris neovascularization or any angle neovascularization. Grid-pattern laser photocoagulation for perfused macular edema did not show a significant beneficial effect. Recently, several reports have suggested restoring venous outflow by 1) creating a chorioretinal anastomosis, 2) administering recombinant tissue plasminogen activator, 3) cannulating the retinal vein transvitreally, or 4) transecting the posterior scleral ring.

Humans↗