Biomedical subjects

Ronald D Alvarez

Publications and source records attributed to Ronald D Alvarez.

64 records · Page 4Linked to original sources

PubMed2002

Conservative management of stage I endometrial carcinoma after surgical staging.

OBJECTIVE: The aim of this study was to determine the outcomes of Stage I endometrial carcinoma patients who are managed without adjuvant radiation after comprehensive surgical staging. METHODS: A computerized hospital database identified women diagnosed with adenocarcinoma of the endometrium from 1993 to 1998. A chart review identified 864 women as having primary surgery for adenocarcinoma of the endometrium. A total of 670 of 864 patients (78%) underwent comprehensive surgical staging with total hysterectomy, bilateral salpingo-oophorectomy, pelvic/para-aortic lymphadenectomy, and peritoneal cytology. After 57 patients with high-risk histologic subtypes were excluded, 613 patients remained for analysis. RESULTS: A total of 321 of 325 Stage IB patients (99%) did not receive adjuvant radiation. Fifteen of 321 patients (5%) recurred; 9 recurred in the pelvis or vagina. All 9 local recurrences were salvaged with whole pelvic radiation (XRT) and brachytherapy (BT). Seventy-seven patients were diagnosed with Stage IC disease; 53 (69%) received no adjuvant therapy. Four patients (8%) recurred, of which 2 recurred in the vagina. Three of 4 patients (75%) were salvaged, 2 with XRT/BT and 1 with surgery and chemotherapy. For all Stage I patients, the 5-year disease-free survival was 93% and the 5-year overall survival was 98%. CONCLUSIONS: Surgically staged patients with endometrial carcinoma confined to the uterine corpus have a small risk of recurrence and the majority of these recurrences can be salvaged with radiation therapy. Conservative management of Stage I endometrial carcinoma patients is an effective treatment strategy.

Adenocarcinoma↗

PubMed2002

Prediction of the need for red cell transfusion in newly diagnosed ovarian cancer patients undergoing platinum-based treatment.

OBJECTIVE: The objective of this study was to develop a predictive algorithm for the likelihood of red blood cell transfusion in women with ovarian cancer undergoing platinum-based chemotherapy. METHODS: Patients in this analysis came from two phase III studies conducted by the Southwest Oncology Group and Gynecologic Oncology Group of platinum-based chemotherapy in advanced ovarian cancer patients, SWOG 8412 and SWOG 8501/GOG 104. The probability of packed red blood cell (PRBC) transfusion was modeled as a function of stage of disease, age, weight, creatinine clearance, hemoglobin (Hb) prior to the start of therapy, the platinum agent administered (i.e., cisplatin vs carboplatin), and the route of drug administration (i.e., intravenous vs intraperitoneal). RESULTS: Overall, 16% of patients developed at least grade 3 anemia (Hb < 8 g/dL) during primary chemotherapy, with 2% experiencing grade 4 anemia (Hb < 6.5 g/dL). PRBC transfusions were administered to 32% of patients. Factors that were determined to be predictive of PRBC transfusions were age and baseline Hb. In patients with bulky stage III or stage IV disease, the odds of transfusion increased by 66% for each 10-year increase in age and by 65% for each 1 g/dL decrease in baseline hemoglobin. Thus a patient aged 65 with a baseline Hb of 10.5 g/dL has approximately a 40% chance of transfusion. CONCLUSIONS: Older ovarian cancer patients (>65 years) with low baseline Hb levels (<10.5) at initiation of platinum-based chemotherapy are likely to become more anemic during treatment and should be considered for prophylactic erythropoietin therapy as an alternative to transfusion.

Aged↗

PubMed2002

Gene transfer to ovarian cancer versus normal tissues with fiber-modified adenoviruses.

Adenovirus serotype 5 (Ad5) displays unparalleled gene transfer efficacy to cells with high coxsackie-adenovirus receptor (CAR) expression. Unfortunately, cells isolated from clinical human cancers, both ovarian and other types, express highly variable and often low levels of CAR. Fortunately, native Ad5 tropism can be modified to circumvent CAR deficiency and to enhance infectivity. Ad5/3luc1 incorporates the serotype 3 fiber knob and binds to a receptor distinct from CAR, while the fiber of Ad5lucRGD is modified with an RGD-4C motif, allowing CAR-independent binding to integrins. We studied the liver tropism and blood clearance of these viruses after intravenous (i.v.) injection, and biodistribution after intraperitoneal (i.p.) injection to tumor-bearing mice. To estimate efficacy, we assessed gene transfer to purified human primary ovarian cancer cells, and in a mouse model of ovarian cancer. Ad5/3luc1 achieved improved gene transfer over Ad5lucRGD, and both infectivity-enhanced viruses were superior to the isogenic control with an unmodified Ad5 capsid. In the presence of malignant ascites, gene transfer was improved with both Ad5/3luc1 and Ad5lucRGD. Thus, retargeting to the Ad3 receptor enhances gene transfer to clinically relevant ovarian cancer substrates, while the mouse toxicity and biodistribution profile of both fiber-modified Ad vectors is comparable to Ad5.

Adenoviridae↗

PubMed2002

Gene therapy.

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Adjuvants, Immunologic↗

PubMed2002

Adenoviruses in oncology: a viable option?

The feasibility of using adenoviruses for gene therapy has been under close scrutiny recently, as it has become clear that significant toxicity can result from the strong immune response created by intravenous administration of large doses of first generation adenovirus vectors. This suggests that other vectors could be more useful for treatment of metabolic and hereditary disease, where widespread transduction is often necessary for effective gene replacement, and the viability of target cells is important. However, promising recent results in human cancer trials have confirmed that adenoviruses can be very useful in oncology. For cancer treatment, the unparalleled transduction efficacy of adenovirus in dividing and dormant cells is a major benefit. As the goal in cancer gene therapy is to kill infected tumour cells, long-term transgene expression is not necessary. In addition, the immune response generated against infected cells could be useful for eradicating uninfected tumour. Importantly, more than 670 cancer patients have been treated with adenovirus intratumorally, intra-arterially, intraperitoneally and intravenously with very manageable adverse effects and no unexpected severe or lethal toxicity. Currently, the most promising approaches are based on replication-competent agents that allow efficient tumour penetration because of their capacity for tissue-specific replication. In addition to transcriptional control, it is becoming clear that targeting is necessary for efficient tumour transduction and less infection of normal tissues. Exciting results are anticipated when the first selectively replicating targeted adenoviruses go to clinical trials. In conclusion, intense gene therapy and virological research have suggested that while other vectors could be more useful for treatment of hereditary disease, adenoviruses are highly promising and safe agents for oncology, as suggested in a number of early phase clinical trials.

Adenoviridae↗

PubMed2002

Targeting adenovirus to the serotype 3 receptor increases gene transfer efficiency to ovarian cancer cells.

Gene delivery efficiency in clinical cancer gene therapy trials with recombinant adenoviruses (Ads) based on serotype 5 (Ad5) has been limited partly because of variable expression of the primary Ad5 receptor, the coxsackie and adenovirus receptor (CAR), on human primary cancer cells. As a means of circumventing CAR deficiency, Ad vectors have been retargeted by creating chimeric fibers possessing knob domains of alternate Ad serotypes. In this study, we have constructed an Ad5-based vector, Ad5/3luc1, with a chimeric fiber protein featuring a knob domain derived from Ad3. This virus is retargeted to the Ad3 receptor and, therefore, has different tissue tropism. A novel knob binding assay was used to measure expression of CAR and the Ad3 receptor. Further, to evaluate the correlation of receptor expression and infectivity by Ad, a panel of ovarian cancer cell lines and purified primary cancer cells were infected with Ad5luc1 and Ad5/3luc1 at 50, 200, and 1000 viral particles/cell. Our results confirm that Ad5/3luc1 is retargeted to the Ad3 receptor. Furthermore, the Ad3 receptor is present at higher levels than CAR on ovarian adenocarcinoma cells. Also, the amount of binding to primary receptor appears to be the major factor determining the efficiency of transgene expression. The Ad5/3 chimera displays enhanced infectivity for ovarian cancer cell lines and purified primary tumor cells, which could translate into increased efficacy in clinical trials.

Adenocarcinoma↗

PubMed2002

A Phase I study of combined modality (90)Yttrium-CC49 intraperitoneal radioimmunotherapy for ovarian cancer.

PURPOSE: The purpose of this study was to determine the feasibility and maximum tolerated dose of (90)Yttrium-CC49 ((90)Y-CC49) as the radioimmunotherapy (RIT) component of an i.p. combined modality treatment for recurrent ovarian cancer. EXPERIMENTAL DESIGN: A Phase I trial of (90)Y-CC49 RIT was conducted in ovarian cancer patients who had persistent or recurrent intra-abdominal disease, had failed one or two prior chemotherapy regimens, and demonstrated TAG-72 expression. Patients were treated with a previously established combined modality treatment protocol of s.c. IFN alpha2b, i.p. paclitaxel, and increasing dosages of i.p. (90)Y-CC49. Patients were monitored for toxicity, generation of human antimouse antibody response, and clinical efficacy. RESULTS: Twenty eligible patients were treated per study specifications. All patients had been treated with debulking and paclitaxel/carboplatin-based chemotherapy at initial diagnosis. The patients included 11 patients with persistent disease at the time of second look laparotomy and 9 patients with delayed recurrence. Patients were treated with i.p. (90)Y-CC49 given in combination with s.c. IFN alpha2b (dose of 3 x 10(6) units for a total of four doses) and i.p. paclitaxel (dose of 100 mg/m(2)). RIT treatment was associated with primarily hematological toxicity. The maximum tolerated dose of i.p. (90)Y-CC49 was established at 24.2 mCi/m(2) in this combined regimen. Of nine patients with measurable disease, two had partial responses lasting 2 and 4 months. Of 11 patients with nonmeasurable disease, median time to progression was 6 months in 7 patients who recurred; 4 of these patients remain no evidence of disease at 9+, 18+, 19+, and 23+ months. CONCLUSIONS: (90)Yttrium-CC49-based RIT in combination with IFN alpha2b and i.p. paclitaxel is feasible and well tolerated at a dose of < or =24.2 mCi/m(2).

Adenocarcinoma↗

PubMed2002

Advances in the treatment of gynecologic malignancies. Part 1: Cancers of the cervix and vulva.

Two recent multicenter randomized trials have greatly advanced our understanding of the role of postoperative radiation therapy in operable cervical cancer. In locally advanced cervical cancer, such studies have shown a significant improvement in survival with the use of concurrent cisplatin-based chemoradiotherapy and have redefined standard therapy for women with this presentation. In vulvar cancer, adjuvant chemoradiotherapy is emerging as an effective therapeutic approach, permitting less morbid surgery. Although the results of treatment with concurrent chemoradiotherapy are encouraging in both cervical and vulvar cancer, efforts to minimize the associated toxicity are needed.

Antineoplastic Agents↗

PubMed2002

Conditionally replicative adenoviruses for ovarian cancer therapy.

The purpose of this review article is to present a logical rationale for the investigation of conditionally replicative adenoviral vectors for the treatment of ovarian carcinoma. A medline database search was performed to identify relevant articles in the English language for the years 1966 to present. The key words used included replicative adenovirus, conditionally replicative adenovirus, transcriptional targeting, replication selective adenovirus, and "ONYX." A total of 89 references were identified and reviewed. Each reference was reviewed for relevance to clinical translation of conditionally replicative adenoviral vector therapy for ovarian cancer. Data from current clinical trials would suggest that potential obstacles for effective replicative viral therapy of ovarian carcinoma include efficient tumor cell infection, restrictions of the cell surface coxsackie and adenovirus receptor, rapid clearance of vector in the ascites environment, tumor cells specificity, and limitations of current findings of clinical trials. The articles were, therefore, evaluated and included if they addressed these shortcomings. Current data would suggest that advanced generation conditionally replicative adenoviral vectors will soon be available for clinical trials in ovarian cancer. Ovarian cancer, because of expression of targetable receptors, transducible cells, and containment within the i.p. cavity, represents a solid tumor suited uniquely for investigation with advanced generation conditionally replicative adenoviral vectors.

Adenoviridae↗

PubMed2002

Advances in the treatment of gynecologic malignancies. Part 2: Cancers of the uterine corpus and ovary.

Over the past few decades, we have gained a better understanding of the risk factors associated with the recurrence of endometrial cancer. Adjuvant postoperative radiotherapy in an intermediate-risk group of endometrial cancer patients resulted in improvement in local control, but survival was not improved significantly. Postoperative management of uterine sarcomas remains investigational. The management of ovarian cancer has notably advanced during the 1990s. Platinum- and paclitaxel-based combination chemotherapy set a new standard of care for patients with advanced ovarian cancer. During the late 1990s, a trend emerged favoring the use of carboplatin over cisplatin for first-line management of advanced ovarian cancer because of its more favorable safety profile. Adjuvant therapy for early-stage high-risk ovarian cancer continues to be actively investigated.

Antineoplastic Combined Chemotherapy Protocols↗