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Biomedical subjects

D Raben

Publications and source records attributed to D Raben.

At least 19 recordsLinked to original sources
PubMed2005

Treatment of locally advanced non-small cell lung cancer in the elderly.

PURPOSE OF REVIEW: Non-small cell lung cancer (NSCLC) may be considered typical of advanced age. Most cases of NSCLC are diagnosed in the advanced or locally advanced stage. It has been shown that combined chemo-radiotherapy is more efficient than either chemotherapy alone or radiation alone, for the therapeutic management of localized unresectable NSCLC. However, chemo-radiotherapy, even if given with sequential approach, in clinical practice can be contraindicated in elderly patients. In fact, this patient population often present at diagnosis with cardiovascular and/or pulmonary comorbidities that increase the risk of severe side effects from chemo-radiotherapy. The present review aims at focusing the currently available evidences on the treatment of elderly patients affected by locally advanced NSCLC and at giving future perspectives on this topic. RECENT FINDINGS: Very few specific prospective data are available on the treatment of locally advanced NSCLC in the elderly. Some phase II studies suggest that low-dose chemotherapy given concurrently with radiotherapy could be safely administered to this patient population. Retrospective analyses on full-dose sequential and concurrent chemo-radiation are to be considered globally ambiguous and at risk of selection bias. SUMMARY: Only specifically designed prospective studies will elucidate the real role and feasibility of combined chemo-radiotherapy in the treatment of locally advanced NSCLC in the elderly. Future perspectives on this topic include the evaluation of alternative schedules of chemo-radiotherapy, innovative radiation techniques more suitable to elderly patients, and the introduction of new, well-tolerated, molecularly targeted agents combined with standard treatments.

Aged↗
PubMed2001

Management of primary cutaneous melanoma of the head and neck: The University of Colorado experience and a review of the literature.

BACKGROUND: While elective lymph node dissection (ELND), adjuvant radiation therapy and sentinel lymph node biopsy have all been advocated in the routine management of primary cutaneous melanoma arising in the head and neck, the optimal management has not been defined. METHODS: We have reviewed our experience of 273 patients with primary melanoma of the head and neck entered into a prospective database at the University of Colorado Health Sciences Center (UCHSC) from 1978 through 1998 and contrasted this with other reports in the literature. RESULTS: A total of 168 patients were identified that received their initial management at UCHSC and had no clinical evidence of distant disease. Only nine patients (5%) underwent ELND, and no patients received adjuvant radiation therapy. The local recurrence rate and 5-year melanoma specific survival, according to Breslow thickness, were similar to centers where adjuvant radiation therapy or ELND are routinely performed. Our preliminary experience and a review of the literature suggests that the technique of sentinel lymph node biopsy is an accurate and low risk procedure that provides valuable prognostic information useful in the further management of these patients. CONCLUSIONS: There is no clear indication that either ELND or adjuvant radiation therapy impacts on the outcome of patients with primary melanoma of the head and neck. Sentinel lymph node biopsy, in appropriate cases, is becoming the standard of care.

Adolescent↗
PubMed2000

A prospective evaluation of the timing of postoperative radiotherapy for preventing heterotopic ossification following traumatic acetabular fractures.

PURPOSE: Preoperative and immediate postoperative irradiation of traumatic acetabular fractures (TAF), although known to reduce heterotopic ossification (HO), can cause significant organizational and logistic difficulties. We sought to determine an acceptable time interval between surgery and radiation without compromising control, as well as to update our large experience and to further validate our treatment philosophy. METHODS AND MATERIALS: Beginning in June 1995, we began a prospective study, irradiating 152 patients on postoperative days 1, 2, or 3. There were also 17 patients delayed further secondary to medical difficulties. RESULTS: All patients treated since June 1995 received 700 cGy/1 fx. Fifty-eight patients received radiation within 24 hours of surgery, 41 within 2 days, 53 within 3 days, 13 within 4 days, and 4 were delayed further. Delaying irradiation for up to 4 days postoperatively caused no statistical increase in HO (p = 0.625). Of 263 patients in our retrospective cohort, HO occurred in 5.3% of patients who received irradiation versus 60% of patients who did not. CONCLUSION: In our prospective study, we noted no perceptible increase in HO with up to a 3-day interval between surgery and radiotherapy. This allows a more structured treatment schedule and allows the patient more time to heal and recover. Updated results from our overall series continue to demonstrate that adjuvant radiation decreases the incidence and severity of HO after TAF.

Acetabulum↗
PubMed2000

A phase I study of combined UFT plus leucovorin and radiotherapy for pancreatic cancer.

PURPOSE: This Phase I study combines tegafur and uracil (UFT) with leucovorin and conventional radiation for the treatment of pancreatic cancer. The design seeks to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of this regimen as well as to define a future Phase II dose level. METHODS: Patients with locally advanced and unresectable pancreatic cancer were treated with 45 Gy of radiation therapy. The initial UFT dose was 150 mg/m(2)/day given with leucovorin 90 mg/day, both divided into 3 daily doses for 35 days concurrent with radiation. UFT doses were escalated at increments of 50 mg/m(2)/day. Dose-limiting toxicity (DLT) was defined as Grade 3 or greater nausea, vomiting or diarrhea despite medical intervention; or Grade 3 or greater neutropenia/thrombocytopenia; or Grade 3 or greater hepatic toxicity; or inability of the patient to take 75% or more of the planned UFT/leucovorin; or radiotherapy interruption of greater than 1 week. The MTD for UFT/leucovorin was exceeded by one dose level when a certain dose caused DLT in 2 or more patients of 6. RESULTS: Five evaluable patients had Stage I resectable disease but had pathologic adenopathy. Seven had Stage II unresectable disease. Compliance with therapy was excellent. At a daily dose of 300 mg/m(2) of UFT, we noticed minimal diarrhea and hematologic toxicity with mild-moderate nausea, anorexia, and fatigue. Three patients had Grade 4 toxicity: 1 had neutropenia on Day 38, 1 had diarrhea on Day 55, and 1 had vomiting on Day 15. CONCLUSION: Oral UFT/leucovorin and radiation therapy offers patients a viable treatment option for pancreatic cancer. The major known toxicity of diarrhea was tolerable. The MTD was not reached in this study. Our current plan is to expand this into a Phase I/II trial beginning at a UFT dose of 300 mg/m(2) and correlate this with clinical pharmacologic parameters. The potential benefit of long bioavailability and oral delivery of UFT compares favorably with continuous infusion regimens without the added morbidity of a catheter and pump.

Adenocarcinoma↗
PubMed1999

UFT/oral calcium folinate plus radiation in pancreatic cancer.

A phase I, single-center, open-label, dose-escalation study (University of Alabama [UAB] 9614) has been undertaken to evaluate the feasibility and safety of uracil and tegafur (in a molar ratio of 4:1 [UFT]) plus oral calcium folinate (Orzel) plus radiotherapy in patients with pancreatic cancer. A total of 11 patients with a median age of 59 years have been treated for 35 days with 150 mg/m2/day of UFT and 90 mg/day of oral calcium folinate, divided into three daily doses. Radiotherapy began on day 1, to a total dose of 45 Gy at 1.8 Gy per day (for approximately 5 weeks). Dose escalation of UFT will be performed until the maximum tolerated dose is defined. Overall, therapy has been well tolerated and the maximum tolerated dose has not yet been reached.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Differential susceptibility of primary and established human glioma cells to adenovirus infection: targeting via the epidermal growth factor receptor achieves fiber receptor-independent gene transfer.

Adenovirus (Ad) vectors are promising for gene therapy of glioma due to their ability to achieve efficient gene transfer upon intratumoral administration. Yet in this context, Ad mediates widespread gene transfer to both tumor and surrounding parenchyma. Ad entry is dependent upon the expression of fiber receptors, such as coxsackie/adenovirus receptor, and alpha(v) integrins on the target cells for binding and internalization, respectively. We hypothesized that the susceptibility of human gliomas to Ad would likely be heterogeneous due to variable expression of these receptors. It was found that established human glioma cell lines exhibited differential susceptibility to Ad-mediated gene transfer, which correlated directly with the level of radiolabeled Ad binding and with the expression of coxsackie/adenovirus receptor but not with the expression of alpha(v) integrins. To circumvent the lack of fiber receptors and to target Ad gene transfer specifically to tumor cells, we used a bispecific antibody conjugate to ablate Ad binding to fiber receptors and retarget binding to the epidermal growth factor receptor (EGFR), a tumor-associated marker negligibly expressed in normal, mitotically quiescent neural tissues. The results demonstrate that EGFR-targeted Ad gene transfer was EGFR specific and independent of fiber-fiber receptor interactions. Furthermore, EGFR targeting significantly enhanced Ad gene delivery to 7 of 12 established glioma cell lines and to 6 of 8 cultured primary gliomas. Interestingly, EGFR-targeted Ad gene transfer did not correlate with EGFR expression across cell lines, suggesting the importance of other factors. This study establishes that fiber receptor expression limits the utility of Ad vectors for gene transfer to glioma cells and suggests that targeting Ad via EGFR may prove valuable for tumor-specific gene transfer to high-grade gliomas. These findings have key relevance in the context of Ad vector-based approaches for glioma gene therapy.

Adenoviruses, Human↗
PubMed1997

Pancreatic carcinoma cell killing via adenoviral mediated delivery of the herpes simplex virus thymidine kinase gene.

OBJECTIVE: Use of adenoviral mediated delivery of the herpes simplex virus thymidine kinase (HSV-TK) gene as a gene therapy strategy for carcinoma of the pancreas. SUMMARY BACKGROUND DATA: Expression of HSV-TK selectively sensitizes cells to the nucleoside analog ganciclovir (GCV). This strategy has been used to treat other compartmentalized tumor models. Therefore, the containment of pancreatic carcinoma makes it amenable to this gene therapy approach. METHODS: A recombinant adenoviral vector encoding the HSV-TK gene was used to induce GCV sensitivity and test the potential bystander effect in established pancreatic carcinoma cell lines and patient-derived tumor material. Additionally, Balb/C nude mice were injected intraperitoneally with human pancreatic carcinoma cells and treated with GCV (50 mg/kg per day) for 14 days. RESULTS: Expression of the HSV-TK gene elicited a significant bystander effect in the presence of GCV. Pancreatic tumor cells injected intraperitoneally into nude mice resulted in significant tumor formation. Treatment of animals with AdCMVHSV/HSV-TK and GCV induced a dramatic decrease in overall tumor burden for up to 8 weeks post-GCV treatment. CONCLUSIONS: Pancreatic carcinoma cells are highly susceptible to transduction with recombinant adenoviral vector and elicit a potent bystander effect on neighboring tumor cells. Additionally, in vivo treatment of tumor-bearing animals results in dramatic reduction of overall tumor burden, thus providing the rationale for molecular chemotherapy of pancreatic carcinoma.

Adenoviridae↗
PubMed1997

Adenoviral-mediated delivery of gastrin-releasing peptide receptor results in specific tumor localization of a bombesin analogue in vivo.

Radioimmunotherapy is hindered by a variety of factors linked to the utilization of monoclonal antibodies. These limitations include restricted tumor penetration as well as low levels of intratumoral antigen expression. To address the latter problem, we used a gene therapy approach to induce tumor cells to express enhanced levels of receptor with high binding affinity for a radiolabeled peptide. In this regard, a radiolabeled bombesin analogue was used in conjunction with a recombinant adenoviral vector encoding the murine gastrin-releasing peptide receptor (mGRPr). A panel of human carcinoma cell lines was infected in vitro with the recombinant adenoviral vector encoding the mGRPr vector to examine the induced binding of a 125I-labeled bombesin peptide. All cell lines examined displayed high levels of induced peptide binding, with approximately 60-80% of the radioactivity bound to the cells, in a live-cell binding assay. The human ovarian carcinoma cell line SKOV3.ip1 was chosen for in vivo analysis of radiolabeled bombesin analogue tumor localization in biodistribution and pharmacokinetic studies in athymic nude mice. Genetic induction of mGRPr in vivo resulted in selective tumor uptake of the radiolabeled peptide and high tumor:blood ratios. The biodistribution results compared favorably to those obtained with 131I-labeled e21 anti-erbB-2 monoclonal antibody in animals bearing i.p. SKOV3.ip1 tumors that endogenously express erbB-2. Thus, a novel method to combine gene transfer and radioimmunotherapy may result in augmented tumor cell targeting of radiopharmaceuticals.

Adenoviridae↗
PubMed1996

Enhancement of radiolabeled antibody binding and tumor localization through adenoviral transduction of the human carcinoembryonic antigen gene.

Conventional radiolabeled antibody targeting utilized in radioimmunotherapy has resulted in limited success clinically due in part to inadequate tumor localization resulting from low expression of human tumor-associated antigens on target cells. We hypothesized that one could improve upon these limitations by genetically inducing tumor cells to express high levels of a new membrane-associated receptor with high affinity for a radioligand. As a preliminary strategy, we induced a human glioma cell line (D54 MG) to express human carcinoembryonic antigen (CEA) in vitro. To accomplish this, we constructed a recombinant adenoviral vector encoding the CEA cDNA inserted downstream of a cytomegalovirus (CMV) promoter (AdCMVCEA). D54 MG cells were transfected with AdCMVCEA or an adenoviral vector encoding lacZ reporter gene as a control (AdCMVlacZ). LS174T human colon cancer cells, known to express CEA constitutively, served as positive controls. Immunofluorescence and immunohistochemistry assays employing unlabeled anti-CEA COL-1 monoclonal antibody demonstrated expression of CEA antigen on the cell surface of transduced D54 MG cells in culture. In addition, assays utilizing 125I-labeled COL-1 indicated high binding to transduced D54 MG cells expressing CEA (4.7 +/- 0.5 x 10(5) COL-1 molecules bound per cell) as compared with minimal binding to nontransduced D54 MG cells. LS174T cells demonstrated only 2.7 +/- 0.5 x 10(6) COL-1 molecules bound per cell. Thus, AdCMVCEA was able to induce levels of cell surface CEA in target cells at a higher level than CEA-overexpressing tumor cells (P < 0.01). The efficacy of transduction of recombinant AdCMVCEA by direct intratumoral injection into D54 MG xenografts was investigated by immunohistochemical analysis, immunofluorescence and by measuring 131I-labeled COL-1 uptake through external scintigraphic imaging and biodistribution studies. Expression of CEA in the tumor xenografts by, and radiolabeled antibody tumor targeting to, AdCMVCEA transduced D54 MG xenografts was comparable to that seen with LS174T xenografts. Results of these studies indicate the potential of adenovirus-mediated delivery of targets to improve radiopharmaceutical tumor localization.

Adenoviruses, Human↗
PubMed1996

Approaches to enhance cancer radiotherapy employing gene transfer methods.

This review presents an overview and discussion of the potential synergistic strategies of radiation therapy and gene transfer for treating neoplastic disease. Topics discussed include radiation-inducible promoters coupled to genes which produce proteins that are cytotoxic or enhance radiosensitivity, employment of molecular chemotherapy approaches in conjunction with radiation therapy, and genetic induction of radiosensitization through modification of DNA repair, signal transduction, and cell cycle control genes. Additional topics discussed relate to gene transfer augmentation of radioimmunotherapy of cancer. Specifically, gene transfer methods to genetically induce tumor cells to express enhanced levels of cell surface antigens and receptors to increase radiolabeled antibody and peptide targeting and thus increase their therapeutic effect, selection of radionuclides for therapeutic ligand labeling, and computer simulation of genetic tumor-specific delivery of radiolabeled ligands are proposed.

Animals↗
PubMed1993

Concurrent expression of erythroid and renal aquaporin CHIP and appearance of water channel activity in perinatal rats.

Major phenotypic changes occur in red cell membranes during the perinatal period, but the underlying molecular explanations remain poorly defined. Aquaporin CHIP, the major erythroid and renal water channel, was studied in perinatal rats using affinity-purified anti-CHIP IgG for immunoblotting, flow cytometry, and immunofluorescence microscopy. CHIP was not detected in prenatal red cells but was first identified in circulating red cells on the third postnatal day. Most circulating red cells were positive for CHIP by the seventh postnatal day, and this proportion rose to nearly 100% by the 14th day. The ontogeny of red cell CHIP correlated directly with acquisition of osmotic water permeability and inversely with Arrhenius activation energy. Only minor alterations in the composition of red cell membrane lipids occurred at this time. Immunohistochemical analysis of perinatal kidneys demonstrated a major induction of CHIP in renal proximal tubules and descending thin limbs at birth, coincident with the development of renal concentration mechanisms. Therefore, water channels are unnecessary for oxygen delivery or survival in the prenatal circulation, however CHIP may confer red cells with the ability to rehydrate rapidly after traversing the renal medulla, which becomes hypertonic after birth.

Aging↗
PubMed1990

Human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus type 2 (HSV-2) can coinfect and simultaneously replicate in the same human CD4+ cell: effect of coinfection on infectious HSV-2 and HIV-1 replication.

Experiments were designed to determine whether HIV-1 and herpes simplex virus type 2 (HSV-2) coinfection leads to simultaneous replication of both viruses in the same human CD4+ cell (MT-4 cell line) and the possible effects of coinfection on infectious virus production. Results from transmission electron microscopy analysis revealed replication of typical HSV-2 nucleocapsids in the nucleus and budding of HIV-1 particles through the plasma membrane and through intracytoplasmic vacuoles containing enveloped HSV-2 particles in the same coinfected cell. Coinfection of HIV-1 persistently infected H9IIIB or promonocytic U1 cells with HSV-2 did not alter total production of infectious HSV-2 or the percentage of HSV-2 infectious centers compared with control H9 and U937 cells infected with HSV-2 alone. However, in coinfected promonocytic U1 cells HSV-2 induced infectious HIV-1 production measured by syncytial plaque assay. In summary, both HIV-1 and HSV-2 can coinfect and simultaneously replicate in the same human CD4+ cell. Interactions between HIV-1 and HSV-2 appear to be unidirectional, resulting in accelerated replication of HIV-1 as reported by Albrecht et al. (J Virol 1989;63:1861-1868), but not HSV-2 as shown by us.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Herpes simplex virus type 2 infection of unstimulated human T-lymphocytes.

Unstimulated human leukemia T-cell lines (MOLT-4, MT-4) were tested for their susceptibility to herpes simplex virus type 2 (HSV-2) infection. Permissive infection of MT-4 cells was demonstrated by growth curve and infectious center assays. In growth curve experiments new progeny virus replication was detected by 24 hrs and maximum titers of HSV-2 replication were measured by 72 hrs after infection of MT-4 cells, whereas, MOLT-4 cells did not produce detectable infectious HSV-2 in growth curve experiments. It may be that a T-cell subset is involved with infectious HSV-2 production, since 5.7% of MT-4 cells were scored as infectious centers after HSV-2 infection compared to only 0.06% of MOLT-4 cells. Furthermore, HSV-2 infected MT-4 (45% of cells) and MOLT-4 cells (30% of cells) expressed viral induced antigen(s) detected by immunofluorescence assays. These data provide the first evidence of infectious HSV-2 replication in T-cells not prestimulated in vitro with mitogens, pharmacologic agents or growth factors. The establishment of T-cell systems that permit rapid and efficient replication of HSV-2 could greatly facilitate studies on interactions between human herpesviruses and AIDS retroviruses since recent published evidence indicates possible synergistic interactions between these virus groups.

Antigens, Viral↗